Due to the multifaceted pharmacological activities of chalcones, these scaffolds have been considered one of the most privileged frameworks in the drug discovery process. Structurally, chalcones are α, β-unsaturated carbonyl functionalities with two aryl or heteroaryl units. Amongst the numerous pharmacological activities explored for chalcone derivatives, the development of novel chalcone analogs for the treatment of Alzheimer’s disease (AD) is among the research topics of most interest. Chalcones possess numerous advantages, such as smaller molecular size, opportunities for further structural modification thereby altering the physicochemical properties, cost-effectiveness, and convenient synthetic methodology. The present review highlights the recent evidence of chalcones as a privileged structure in AD drug development processes. Different classes of chalcone-derived analogs are summarized for the easy understanding of the previously reported analogs as well as the importance of certain functionalities in exhibiting cholinesterase inhibition. In this way, this review will shed light on the medicinal chemistry fraternity for the design and development of novel promising chalcone candidates for the treatment of AD. A family of cholinesterase (ChE) catalyzes the hydrolysis of the neurotransmitter acetylcholine (ACh) into acetic acid and choline. Acetylcholinesterase (AChE) is strategically located at all cholinergic sites and serves to inactivate ACh simultaneously, while butyrylcholinesterase (BChE), also known as pseudocholine esterase, present in plasma, serves to metabolize ingested esters. The main difference between AChE and BChE is that AChE inhibition is more sensitive to physostigmine, while BChE inhibition is more sensitive to organophosphates. The main role of AChE is the termination of ACh action, while the function of BChE is the hydrolysis of ingested esters ,2.The cholinergic enzyme AChE is predominantly present at postsynaptic neuromuscular junctions, particularly in muscles and nerves. The main function of AChE is to inhibit ACh dispersal and activation of adjacent receptors by terminating neuronal transmission and signaling between synapses. AChE is mainly distributed in nervous tissues such as the cerebellum, autonomic nervous systems, peripheral nervous systems, and brainstem. Red blood cell membranes and skeletal muscles also contain AChE .AChE catalyzes the breakdown, hydrolysis, and inactivation of ACh, thereby controlling its amount in the synapse. AChE is a serine hydrolase; through acid-based reactions, a tetrahedral intermediate is formed. The formation of a new acylated serine is facilitated via histidine, which helps in the proton transfer between the oxygen molecules within the serine, and ACh, which leads to the removal of the choline group. The protonated histidine is stabilized by the aspartate, and the deacylation of acylated serine takes place. This results in the regeneration of free AChE .AChE has been extensively studied in the tissues involved in Alzheimer’s disease (AD) since the finding of the cholinergic deficiency. AD is one of the most common neurodegenerative disorders, characterized by the diminishing of memory, orientation to physical surroundings, and language. Neurons present in the hippocampus and cortex are degenerated irreversibly as well as progressively. The reduction in the synthesis of ACh is one of the main factors, as per the cholinergic hypothesis. The inhibition of the biological activity of AChE results in the increase of cholinergic levels in the brain. The degradation of ACh is prevented by the AChE inhibitors; thus, ACh concentration is increased, and this can improve the function of neural cells. The concentration of the ACh level elevates at the synaptic junction as a result of AChE inhibition, and also permits the potentiation of the signal. This action eventually decreases the amount of choline absorbed and increases the number of M2 muscarinic receptors.Several other critical factors are involved in the pathogenesis of AD , includiAccording to the crystal structure of AChE, the catalytic triad of serine, histidine, and glutamate is positioned at the bottom of a narrow 20 A˚ deep gorge that penetrates halfway through the enzyme and widens near its base. Aromatic residues line the ligand-binding cavity, accounting for approximately 40% of the cavity surface. Due to its affinity for binding cationic ligands, the peripheral anionic site (PAS) at the gorge’s entrance was originally thought to include multiple negatively charged amino acids. The crystal structure shows that there are not enough acidic amino acids close to the ligand-binding cavity. ACh is assumed to bind to the PAS first, then diffuse down to the catalytic site quickly ,8.Numerous crystal structures have been used for molecular modelling studies, as follows: crystal structure of mouse AChE inhibited by non-aged methamidophos (2JGE) , recombiAcetylcholinesterase inhibitors (AChEIs) are the most commonly prescribed treatment strategy for AD. AChEIs have been found to reduce the progression of the disease as well as improve attention span. These compounds have unique patterns of structural diversity, possessing distinctive specificities for different types of ChE. After the introduction of AChEIs, cholinergic drugs like donepezil, galantamine, and rivastigmine were considered as first-line pharmacotherapy for mild to moderate AD . As ChEsMemory, thinking, language, judgment, and other mental processes are treated with reversible AChEI drugs. The level of ACh is upheld by these drugs, which boosts the cholinergic neurotransmission pathway. Donepezil, rivastigmine, and galantamine as reversible AChEIs, and memantine as the NMDA receptor antagonist, are the FDA- and the European Medicines Agency (EMA)-approved drugs to treat the cognitive manifestations of AD. Donepezil binds to the PAS and delays the deposition of amyloid plaque. Rivastigmine inhibits both AChE and BChE by binding at the ecstatic part of the active site. The selective AChEI galantamine interacts with the anionic subsite, as well as with the aromatic gorge, and also at the nicotinic cholinergic receptor. Thus, this molecule acts as an allosteric ligand and induces the modulation ,17,18,19Chalcone  is a simThe A ring refers to the phenyl ring linked to the carbonyl group, whereas the B ring refers to the other benzene ring . The preChalcones are the building blocks of numerous physiologically fascinating chemicals derived from natural sources, and they have piqued researchers’ curiosity for decades. Various biological activities of chalcones, such as anticancer, anti-inflammatory, antituberculosis, antimalarial, antioxidant, antimicrobial activity, antidiabetic, and antiviral activities, and cancer prevention and neuroprotective effects have been reported . This me−6 cm/s is considered a high permeation, while less than 2 × 10−6 cm/s is considered a low permeation. For those analogs with Pe in the range of 2 to 4 × 10−6 cm/s, the permeation ability is uncertain in nature.The structural modification of chalcones has been explored by numerous reports, wherein substituent-dependent pharmacological activities have resulted. For a promising drug candidate for AD, penetration ability through the blood–brain barrier (BBB) is essential. The structural modifications to the chalcone are also made by the consideration of BBB permeability. Some of these reports utilized the logP value, while in vitro parallel artificial membrane permeation assay of the blood–brain barrier (PAMPA-BBB) was also reported for expressing the BBB permeation. A logP value of less than 2 ± 0.7 is considered to have greater potential to cross the BBB. In the case of the PAMPA assay, a permeability (Pe) greater than 4 × 10Initial discussions in the present reports mainly focus on the incorporation of various substituents to the chalcone aromatic rings.i values from 0.61 to 86.11 μM. Further, these analogs exerted a competitive mode of enzyme inhibition. The attachment of electron-donating groups (EDG) resulted in an enhanced AChE inhibitory activity, while electron-withdrawing groups (EWG) resulted in a decremented activity . Th. Th38]. 3 functionalities, the AChE inhibition was varied, wherein di-substituted analogs exerted higher activities than mono substitution. Amongst the numerous substitutions on B rings, ortho substitution was found to be the most promising position for BChE inhibition. The meta and para substitutions on the B ring resulted in decreased activities. Further, the introduction of methoxy in the meta and para positions also exerted beneficial effects on the BChE inhibitory potential . De. De39]. 50 = 5.73 μM). It is also interesting to note that the anti-cholinesterase activity is proportional to the decreasing propensity of the 2-(4-substituted phenyl) ring, wherein the delocalization of π-electron into the α,β-unsaturated framework significantly varied. Further, the most active chalcone derivatives against the BChE tend to be moderately inhibiting against AChE . Ex. Ex40]. 50 values: 2-pyridyl ketone-containing analogs exerted activities of 9.55 μM to > 200 μM, followed by 2-acyl phenol-containing analogs (1.61 μM to > 200 μM). The most potent activities were exhibited by 2-acyl aniline moieties (IC50 = 0.503 μM to 4.0 μM). In the SAR perspective, for the pyridyl ring, methyl substitution did not exert any improvement in the inhibitory activity. Meanwhile, the attachment of -Br at the 2nd and 3rd position of pyridyl ring resulted in enhanced inhibitory activity. The replacement of 2-pyridyl ketone with 2-acyl phenol resulted in a slight enhancement of AChE inhibition. However, further substitution did not impart any inhibitory effects. Further substitution of 2-acyl aniline moieties resulted in potent activities. These analogs exerted lesser potential towards BChE inhibition. It is noteworthy that the presence of metal ions resulted in decreased activities by these analogs against ChEs . Al. Al41]. 50 value of 4.15 μM, which was a 2-fold increase in activity when compared to the standard rivastigmine (IC50 = 9.12 μM). Substitution with a hydrophobic group such as morpholine showed a drastic decrease in activity. The logP value of the active analogs was less than 2 ± 0.7 (1.58 to 1.77), suggesting the lipophilicity to pass the BBB. The docking studies of compound 1 with AChE (PDB ID:1EVE) supported the biological results, as it showed important interactions including π-π interactions of chalcone with Trp 29 and Tyr 334 of the PAS and cation-π interactions of piperidine nitrogen with Trp 84 and Phe 330.Flavokawain B, a natural chalcone derivative isolated from the roots of kava, showed promising pharmacological activities, but its studies were limited due to their low yields. Inspired by the promising role of Flavokawain B, Liu et al., reported the synthesis and AChE inhibitory activities of a series of Flavokawain Mannich bases  42]. Th. Th42]. Based on the potential role of amino functionalities in ChE inhibition, numerous groups have attempted the exploration of these substituents as a promising inhibitor. Numerous approaches have been made, such as the incorporation of other substituents along with amino substituents, the modification of open amino to rigid amine derivatives, and interchanging amine to sulphonamide. These kinds of structural modifications resulted in varied pharmacological potential.50 = 0.07 µM), whereas compound 3 (IC50 = 6.39 µM) with alkylamine substitution showed potent BChE inhibition. Donepezil was used as a positive control that exerted activity of 0.12 and 20.7 µM, respectively, towards AChE and BChE inhibition. PAMPA-BBB assay of compound 2 indicated its high potential to cross the BBB  . Th. Th43]. 50 = 1143.312 nM), but none of the compounds showed good activity against BChE. The phenyl ring substituted with EDG demonstrated a higher potency (compounds 4 and 5). The replacement of the phenyl B ring with heterocyclic rings like furan and thiophene decreased the ChEs inhibitory activities to a larger extent . Al. Al44]. 50 = 0.08 µM) compared to tacrine, which was used as a positive control (IC50 = 0.06 µM). However, these analogs exerted poor BChE inhibition. Molecular docking studies (PDB ID = 1EVE) were also in agreement with the in vitro results. The synthesized amino chalcones demonstrated poor aqueous solubility. Substitution of the amino functionalities with a methyl ester (by treating with methyl glycinate) resulted in the enhancement of AChE inhibitory potential (0.08–8.34 µM). The molecular descriptor-based results revealed that the majority of these compounds exerted moderate BBB permeability (Log BB–0 to 0.5) . Co. Co45]. 50; AChE = 6.1 μM, BChE = 18.09 μM). Tacrine was used as a positive control . The presence of dimethylamino, chloro, and bromo substituents at the para position on the chalcone B ring conferred moderate AChE inhibition. Further, these analogs exhibited weaker BChE inhibition (>40 μM). PAMPA-BBB assay suggested their higher membrane permeability to brain (Pe-14.44 to 16.34 × 10−6 cm/s) . Am. Am46]. 50 = 8.77 μM), followed by compound 9 and compound 10 , and tacrine was used as a standard compound (IC50 = 0.27 μM). Further molecular docking analysis (PDB ID: 4EY7) demonstrated a positive correlation between the docking score with the inhibitory activity. The ADME prediction of these analogs suggested higher BBB permeation properties . Co. Co47]. i values were in the ranges of 70.470–229.42 nM) and tacrine was used as a positive control (Ki = 446.56 nM) . Th. Th49]. From the previous parts, it is evident that the incorporation of hydroxyl functionalities resulted in an enhanced ChE inhibitory activity of chalcones. Derived from these observations, numerous efforts have occurred for examining the effects of modification  in ChEs inhibitory potential. Amongst these structural modifications, ether-based chalcones showed a better inhibitory profile against ChE.50 = 0.85 µM) and highest selectivity (ratio: 35:79), and rivastigmine was used as a positive control (IC50 = 10.54 µM). The alteration in the amino alkyl side chain and chalcone scaffold resulted in a drastic difference in the activity as well as the selectivity. For the simple alkyl chains (dimethylamine and diethylamine), the five carbon spacer resulted in the potential activity. However, for the cyclic chains (pyrrolidine and piperidine), the four carbon spacer revealed the maximum AChE inhibition. The three carbon spacer showed the poorest inhibition towards the screened enzymes. The kinetic enzyme inhibition of compound 11 revealed a mixed type of inhibition. Molecular docking was also in accordance with the obtained in vitro activities (AChE PDB ID = 1EVE). Further, the synthesized compounds demonstrated a logP value of 1.54 to 1.98, suggesting its higher brain permeation properties . Th. Th50]. 50 = 0.21 ± 0.03 μM), and the highest selectivity for AChE over BChE (IC50 (BChE)/IC50 (AChE) = 65.0). Amongst the screened analogs, the 3-fluoro-substituted analogs exerted weaker activity than the 2- and 4-fluoro-substituted analogs. In the simple alkyl chain analogs, the 2-fluoro-substituted analogs exerted higher AChE inhibition than the 4-fluoro substitutions, while for cyclic amine functionalities (piperidine- and pyrrolidine-containing amino acids), the 4-fluoro-substituted chalcones exerted higher activity than the 2-fluoro-substituted derivatives. Moreover, 4-fluoro substitution revealed a higher selectivity towards AChE inhibition than BChE inhibition. The enzyme kinetic analysis revealed a mixed type of inhibition by these analogs. Moreover, these compounds showed a logP of 1.65 to 1.80, suggesting the potential BBB permeation . Th. Th51]. A series of chalcone derivatives was reported by Liu et al., (2014) with different amino side chains on the para position  52]. Th. Th52]. 50 = 1535 nM), and physostigmine (AChE IC50 = 14.1 nM). Compound 17 showed the highest potency with an IC50 value of 0.81 nM for AChE inhibition. Compound 18 showed significant activities towards both enzymes .Carbamates have always been a molecule of interest due to their chemical stability and increased permeability across the cell membrane. A series of chalcone carbamates was designed by varying the linker length  53]. Th. Th53]. A series of chalcone–benzyl piperidine derivatives was synthesized using an alkyl amine linker and the effect of various substituents on the ChE inhibitory activity was evaluated  54]. Th. Th54]. Naturally inspired chalcone-based derivatives were designed and synthesized by Rampa et al., who evaluated the inhibitory activities against ChEs  55]. A . A 55]. O-alkylamine functionalities were incorporated into the chalcones . An optimal chain length of four methylene units resulted in potent BChE inhibition, whereas shifting the O-alkylamine to the A ring significantly decreased the BChE inhibition, but increased the AChE-inhibitory activity. The presence of EDG such as -OCH3 and N(CH3)2 was important for AChE/BChE inhibition, whereas EWG decreased the ChE-inhibitory activity. The permeability, Pe, of the synthesized compounds lies in the range of 10.02 to 16.79 × 10−6 cm/s, suggesting its potential BBB permeation . Co. CoO-alkO-alkylamine derivatives were reported by Bai et al., . The potential of the most active analogs was further investigated in human AChE (hAChE) and hBChE by using donepezil as a standard drug. Compound 24 displayed good hAChE- and hBChE-inhibitory activities, with IC50 values of 0.78 µM and 0.91 µM, respectively, and compound 25 showed good hAChE-inhibitory activity with an IC50 value of 3.2 µM, implying that AChE-inhibitory activity by human AChE was better than that by Electrophorus electricus AChE (eeAChE). Molecular docking studies with AChE (PDB code: 1EVE) and BChE (PDB code: 4TPK) highlighted that these compounds occupied the entire catalytic active sites. Most active analogs demonstrated a Pe value of 9.68 × 10−6 cm/s, suggesting its potential BBB permeation . Sy. SyO-alk50 = 0.17 μM) compared to rivastigmine (IC50 = 10.54 μM). Further, this analog demonstrated a mixed type of inhibition with AChE. These analogs exerted weaker activity against BChE (IC50 in the ranges of 27.62 to > 500 μM). Cyclization of α,β-unsaturated ketones resulted in the formation of pyrazoline derivatives, that exerted weaker inhibitory activity towards ChEs. These results suggested the importance of α,β-unsaturated ketones in the ChEs inhibition. Molecular docking studies (PDB ID: 1EVE) were also in accordance with their in vitro inhibitory activities. The logP values of the synthesized analogs ranged from 1.61 to 1.83, indicating the lipophilicity of these analogs for crossing the BBB . In. In58]. The multitargeted approach has become a prominent scientific approach to treat various neurodegenerative diseases . Chalcon50 = 0.027 µM) . Mo. Mo60]. Electrophorus electricus (EeAChE for AChE inhibition) and Equus ferus (EfBChE for BChE activity) , while compound 29 exerted the maximum EfBChE inhibition, with an IC50 value of 0.020 µM . Nu. NuElect50 = 0.36 μM), while the 4th and 5th substitutions of the carbamate group decreased the activity. The disubstitution of the carbamate group at the 3rd and 5th positions of the A ring abolished the BChE inhibitory activity. Alkyl substitution on carbamoyl nitrogen also affected the inhibitory profile and dimethyl substitution showed potent BChE and AChE inhibition. Except a few analogs, these molecules revealed poor BBB-crossing properties . Mo. Mo62]. −6 cm/s . Th. ThN-subN, N-disubstituted carbamate pharmacophore of rivastigmine was combined with an amino chalcone. The introduction of different amino groups on carbamoyl moiety with dimethyl amino group on the 4-position of chalcone scaffold (ring B) showed varying results. Cyclic amines showed better inhibition of AChE than noncyclic amines. Among the cyclic amines, the pyrrolidine ring showed potent inhibition . Changing the dimethylamino group on the 4-position with the morpholine ring greatly reduced the activity by several folds. The dual substitution of the carbamate group on 2′ and 4′ positions also reduced the activity. An increment in the overall size, as well as the hydrophilicity, might be the probable reason for the reduction in ChEs inhibitory potential. Further, compound 33 exhibited a Pe value of 7.03 × 10−6 cm/s, suggesting its higher BBB permeation properties . N,. N,65]. 50 ranges from 0.52 to 26.7 µM against eeAChE and eqBChE from equine serum). Parent flavonoids did not exert any kind of ChE inhibition. In the PAMPA-BBB assay, the most active analog showed a greater permeability (Pe: 15.72 × 10−6 cm/s) . Ap. Ap66]. 50 = 0.71–8.40 µM) than the control drug rivastigmine (IC50 = 10.54 µM). The most promising compounds, 34 (IC50: 0.71 ± 0.09 µM) and 35 (IC50: 1.11 ± 0.17 µM), possessed 15-fold and 9-fold more inhibitory activity, respectively, against AChE than that of rivastigmine. Moreover, compound 34 showed the highest selectivity for AChE over BChE (ratio: 18:3). The replacement of benzamide group by ethyl ester/acid functionalities resulted in a decrease in the AChE inhibition properties. An enzyme kinetic and molecular docking study (PDB ID: 1EVE) revealed that compound 34 presented a mixed-type inhibition against AChE. Further, the synthesized compounds showed a good lipophilicity  . Th. Th67]. Apart from the incorporation of various pharmacophoric features into a single chemical entity, numerous structural modification efforts have been performed for the discovery of potent ChE inhibitors. This includes the alteration of α, β unsaturated carbonyl functional group into rigid analogs, generation of two/three chalcone-coupled moieties via various linkers, structural expansion/reduction of A and/or B rings, open chalcones to rigid chalcones, and attachment of denser aromatic functionalities to chalcone via various functionalities. These kinds of structural modifications result in varied inhibitory activities.Stellenboom examined the AChE inhibitory effects of chalcone and its epoxidated derivative   68]. Ep. Ep68]. 50 = 48 μM). It is evident from the logP value (2.41 to 9.44) that the majority of the synthesized analogs can cross the BBB . Ch. Ch69]. 2CH2CH2O-). The studies indicated that the bis-chalcone analogs (compounds 37 and 38) exhibited more significant inhibition than the simple 4-hydroxy chalcone series. These studies further suggested the importance of bis-analogs for AChE inhibition . Th. Th70]. i = 3.1), and compound 40 with 2-bromo substitution on the B ring was the most potent BChE inhibitor (Ki= 4.9) . Th. Th71]. O-alkylation followed by a base catalyzed reaction with substituted aldehydes resulted in the title analogs. The screened analogs exerted Ki values ranging from 1.09 ± 0.20 to 6.84 ± 1.24 nM for AChE, and 85.24 ± 1.71 to 8.35 ± 0.54 nM for BChE. Tacrine was used as a positive control, possessing a Ki value of 5.99 ± 1.79 and 2.43 ± 0.92 nM towards AChE and BChE, respectively. Difluorine substitution in the chalcone framework resulted in enhanced activities . The variation in the inhibitory activities w.r.to substituent positions needs to be explored further for the deduction of SAR . Th. Th72]. O-carbamate derivatives and evaluated their ChE inhibitory potential . Rivastigmine was used as a positive control (BChE inhibition: IC50 = 1.3 µM). These reports suggested that the incorporation of carbamate does not produce any significant effects on the AChE inhibition. In addition, the carbamate substitution significantly affected the eqBChE inhibitory activity. Aliphatic series N,N-disubstituted carbamoyl contributed to the eqBChE inhibitory activity, while the aromatic N,N-disubstituted carbamoyl resulted in a negative effect on eqBChE inhibitory potency. Furthermore, the carbamate moieties at both 2′ and 3′ positions of the chalcone also had significant effects on the eqBChE inhibitory activity. Generally, the disubstituted carbamate derivatives exhibited better eqBChE-inhibitory activity than the monosubstituted carbamate derivatives. Moreover, for the disubstituted carbamate derivatives, the potencies to inhibit eqBChE were in the order N-ethyl-N-methylamine > N-methoxymethylamine > morpholine > N,N diethylamine > N,N-dimethylamine > N,N-diphenylamine. The results revealed that carbamate moieties containing aliphatic amine groups and cyclic amine contributed to the eqBChE-inhibitory activity, but the arylamine produced an adverse effect on eqBChE-inhibitory activity. As for the eeAChE inhibition, the carbamate moieties did not show a significant effect on AChE-inhibitory activity. Therefore, the target compounds were promising selective eqBChE inhibitors, and compounds 41 and 42 were selected for further study. In the in vitro PAMPA BBB assay, compounds 41 and 42 showed a Pe value of 15.67 and 23.17 × 10−6 cm/s, indicating their potential for BBB permeation . Th. ThO-car50 of 1.76 µM. In the case of BChE inhibition, the chalcone analogs exerted more activity than the coumarin-type analogs. However, all of the synthesized analogs exerted less activity compared to galantamine at 10 µM. Molecular docking studies highlighted that the coumarin compound 44 was properly oriented in the active site (PDB ID: 1E66). Compound 44 was stabilized by numerous hydrophobic interactions, π-π stacking, and H-bonding. Overall, the study suggested that the cyclic derivatives of α,β-unsaturated carbonyl scaffolds are more potent than the open chain in exerting ChE inhibition. In addition, the chalcones showed strong activity in BChE and fibrillogenesis inhibition only. In contrast, the coumarins performed more consistently, with significant inhibition in all assays, except against BChE, where they were moderate to weak inhibitors. At this point, the coumarin derivatives were limited to one head group and different tail groups possessing aryl-substituted piperidine, piperazine, and morpholine units. Compounds with the two nitrogen-containing piperazine rings performed the best overall. It appeared that the presence of basic nitrogens in the middle ring was advantageous; however, too many nitrogens  resulted in a slight decrease in activity in all assays . Th. Th74]. 50 = 0.15 ± 0.01 μM) with a good selectivity for AChE over BChE (ratio 27:4). In kinetic studies, these analogs exhibited a mixed-type inhibition against AChE. Molecular modeling studies (PDB ID: 1EVE/1P0I) also supported these facts, wherein these analogs interacted with the peripheral active sites (PAS) as well as the catalytic active sites (CAS) . Th. Th75]. N-Arylation of piperidine with 4-flurobenzaldehyde resulted in the formation of 4-(Piperidine-l-yl) benzaldehyde, which was further condensed with different substituted acetyl thiophene, resulting in the formation of piperidyl–thienyl chalcones. In another set, 2-pyrazoline-quinoline-containing chalcones were prepared by the treatment of 2-chloro-3-formyl quinolines with substituted acetyl thiophenes, followed by the treatment of hydrazine hydrate. The synthesized analogs demonstrated good inhibitory potential against AChE, while poor activity was obtained against BChE. Neostigmine was used as a standard inhibitor (IC50 = 22.2 µM). Analogs possessing 3-chlorothiophen-2-yl and 3-bromothiophen-2-yl (Compounds 46 and 47) moiety at the piperidine chalcones exhibited the highest AChE inhibition properties . In the enzyme inhibition kinetic experiments, piperidyl–thienyl chalcones showed a competitive mode of inhibition, while 2-pyrazoline-quinoline demonstrated a mixed type of enzyme inhibition. A molecular docking study (PDB ID: 1EVE) revealed that potent compounds and co-crystallized ligand had the same binding orientation within the active site of the target enzyme . Su. Su77]. 50 = 0.56 μM). The potential activity was assumed mainly due to the higher electronegativity of the attached 1,4 dioxane ring to ring A. Further, the dioxane-substituted compound with 6-methoxy substitution on the quinoline ring showed a decrease in activity, whereas the same compound with 6-methyl substitution showed significant AChE inhibition, highlighting the importance of the methyl group. Compound 51 exhibited significant AChE inhibition, which might be due to the high influence of the dimethyl furan ring as it is present in the A ring (IC50 = 0.32 μM). Based on the total polar surface area (TPSA) descriptor, it is suggested that these analogs (TPSA < 40) possessed greater BBB permeation [The effects of denser hydrocarbons such as quinoline associated with chalcones were also screened for their anticholinesterase activity  78]. Nu. Nu78]. i = 5.88 μM). However, 4-chlorobenzyl 1,2,3-triazole substituted chalcones exerted the potent BChE inhibition (compound 52)  . Up. Up79]. 1,3-Benzodioxole chalcones were evaluated for their multi-targeting potential  80]. Th. Th80]. 50 = 67.33–150.98 nM) than tacrine (IC50 = 436.00 nM). Further, the Ki values were in the range of 20.41 ± 6.04 to 125.94 ± 23.88 nM. The most active compounds, 56 and 57, showed Ki values of 20.41 ± 6.04 and 24.03 ± 11.01 nM, respectively. Except for -Cl- and -F-substituted analogs, meta-substituted Schiff bases analogs exerted more potential activity than the para substitutions. On the contrary, para-position substitutions of Schiff bases with -Cl and -F substitutions resulted in the potential AChE inhibition potential . Overall, these reports suggested the effects of substituents effects in AChE inhibition . In. In81]. 50 = 0.20 µM) . Th. Th82]. AD is a progressive neurodegenerative disorder and affects the entire globe. Though numerous medications are available for the management of these conditions, these medications lack certain kinds of efficacy parameters. Amongst the numerous scaffolds explored for the development of novel agents for AD, chalcone is one of the privileged scaffolds, possessing diverse biological functions. Numerous reports available on the ChEI potential of chalcone-derived agents are provided in the present article. The development of chalcone-based inhibitors mainly relies on the hybridization approach, wherein numerous chemical functionalities are incorporated into the single chemical entity. Various kinds of structural modification approaches have been explored for the identification of chalcone-inspired analogs. It includes the evaluation of various open or closed forms of numerous amine, the replacement of simple hydroxyl functionalities to ether derivatives, the replacement of simple aromatic functionalities to the denser/lighter heterocyclic rings, and the bis- or tris-type of chalcone derivatives. Apart from that, combinations of the USFDA-approved chalcones are also reported. The majority of these results are also supported by molecular modelling approaches as well.O and -N, exerted an overall enhancement in AChE inhibitory properties. The ring constriction of chalcone  results in decreased potential towards ChEs. The modification of simple -NH2 to a cyclic form was also reported by numerous researchers. It is interesting to note that, except for cyclic imides, all of the reported cyclic amide derivatives exerted maximum ChE inhibitory potential when a EWG is present at ring B. Interchanging -NH2 to sulphonamide derivatives revealed an increase in BChE inhibitory properties.The substitution of various functional groups resulted in altered ChE inhibitory properties. For instance, EDG was reported to have enhanced AChE inhibition, while the opposite effect was observed with EWG. The presence of multiple functionalities, derived from -The conversion of -OH functionalities to ester and ether has also been explored by various researchers, wherein ethers with amino terminal functionalities exerted maximum ChE inhibition. Depending on the alkyl chain length, the ChE inhibitory properties also varied. For instance, a four-carbon spacer exerted potential activity in cyclic amine functionalities, while a five-carbon spacer was beneficial for simple alkyl amines. Further, the effect of EWG on the B ring under these conditions was also evaluated. Meta-substituted analogs exerted weaker activity than the ortho and para substitutions. Furthermore, the ortho position was beneficial for ether derivatives with a simple alkyl amine derivative, while the para-position substitution was beneficial for ethers with a cyclic amine-type terminal group. The attachment of an alkyl chain through an ether linkage via both of the aromatic rings was also explored. A six-carbon spacer was found to be the most beneficial spacer for these kinds of analogs. Structural modifications of amino terminals with other functional groups, such as the addition of carbamates, benzyl piperidine, and tetrahydroisoquinoline derivatives, have also been reported. In the case of carbamates attached to the chalcone scaffold via ether linkage, three- to seven-carbon spacers demonstrated the optimum desired activity. In the case of the benzyl piperidine modification, substitution with EDG groups resulted in enhanced ChE inhibitory potential, while in the case of tetrahydroisoquinoline, attachment at the B ring resulted in BChE inhibition and attachment at the A ring resulted in enhanced AChE inhibitory potential. Similar to the previous cases, EDG groups revealed an enhancement in the activity, while EWG resulted in decreased ChE inhibitory potential.N-Benzyl pyridinium motif (inspired from donepezil) with benzofuran-containing chalcones, donepezil–chalcone hybrid analogs, carbamates from rivastigmine to chalcone, and flurbiprofen–chalcone analogs are the few representative examples for novel agents conceived from the USFDA-approved drugs modifications.In another approach, clinically used drugs appending chalcone derivatives were also explored for the identification of potential ChE inhibitors. The The structural modification of the chalcone scaffold has also been explored for the development of ChE inhibitors, which resulted in a varied effect. For instance, unsaturated ketone into saturated derivatives or pyrazoline and chalcone to chalcone epoxide resulted in the reduction of ChE inhibitory properties. Further, the conversion of rotatable chalcone to rigid chalcone resulted in an enhancement of the ChEs inhibitory profile. It is also interesting to note that the bis- and tris-type of chalcone derivatives exerted enhanced ChE inhibition. The SAR points in this review are summarized in Overall, the information compiled in this review will provide a detailed SAR of various functional groups, which are associated with the chalcone scaffolds. The authors expect that this detailed information will encourage the medicinal chemist fraternity to explore chalcones as potential therapeutic agents for AD.


Ice swimming following the rules of IISA  is a recent sports discipline starting in 2009. Since then, hundreds of athletes have completed an Ice Mile or an Ice Km in water colder than 5 °C. This study aimed to expand our knowledge about swimmers completing an Ice Mile or an Ice Km regarding the influence of anthropometric characteristics  on performance. We analyzed data from 957 swimmers in the Ice Km (590 men and 367 women) and 585 swimmers in the Ice Mile (334 men and 251 women). No differences were found for anthropometric characteristics between swimmers completing an Ice Mile and an Ice Km although water temperatures and wind chill were lower in the Ice Km than in the Ice Mile. Men were faster than women in both the Ice Mile and Ice Km. Swimming speed decreased significantly with increasing age, body mass, and BMI in both women and men in both the Ice Mile and Ice Km. Body height was positively correlated to swimming speed in women in the Ice Km. Air temperature was significantly and negatively related to swimming speed in the Ice Km but not in the Ice Mile. Water temperature was not associated with swimming speed in men in both the Ice Mile and Ice Km but significantly and negatively in women in Ice Km. In summary, swimmers intending to complete an Ice Mile or an Ice Km do not need to have a high body mass and/or a high BMI to swim these distances fast. Cold water swimming, including ice swimming and winter swimming, has been a popular recreational past time for nearly 500 years ,2. HistoThe International Ice Swimming Association (IISA) was created in 2009 to formalize ice swimming events, including developing specific rules and guidelines to have an event or an individual swim recognized . In 2008The competitive aspect may also introduce other elements of anxiety and increased breathing, which may increase the health risk if not adequately trained and acclimatized ,10. In cFew studies demonstrated performance and participation trends in various open-water long-distance swimming events ,23,24,25However, it is also noteworthy that men were faster than women in the Ice Mile and Ice Km events . For lonTherefore, the present study aimed to expand our knowledge about swimmers completing an Ice Mile or an Ice Km regarding the influence of anthropometric characteristics on performance. Based on current findings, we hypothesized that more female and male swimmers with a higher BMI would have successfully finished an Ice Mile than an Ice Km. With increasing length of the swim and increasing duration of staying in ice-cold water, the aspect of a higher BMI would become more critical.This study was approved by the Institutional Review Board of Kanton St. Gallen, Switzerland, with a waiver of the requirement for informed consent of the participants, as the study involved the analysis of publicly available data (1 June 2010).2; overweight ≥25 to <30 kg/m2; obese ≥30 kg/m2 [The data used in this research was obtained from the website of IISA . Not all30 kg/m2 . All swi30 kg/m2  to provi30 kg/m2 .Tapparepη2). Pairwise comparisons were conducted using the least significant difference (LSD) post-hoc technique. Correlation analyses were conducted using Pearson’s correlation coefficient. All statistical analyses were carried out using Statistical Software for the Social Sciences .We applied Kolmogorov–Smirnov and Levene’s to test for normality and homogeneity, respectively. All variables presented a parametric or homogenous distribution. A general linear model with two factors (two-way ANOVA) was used for environmental conditions, age, and BMI, with sex and distance as independent factors. The primary outcome variable is individual performance; thus’ individual average speed was the dependent variable for all ANOVA models. Individual average race speed (m/s) was calculated individually considering the race time and distance. A general linear model adjusted by age (ANCOVA) was applied considering sex and distance as fixed and random factors, respectively. Effect size was estimated using partial eta square , with lower temperatures in Ice Km. No significant effects for sex or distance were identified (p > 0.05) for body mass, body height, BMI, and age .  and age .p = 0.027; pη2 = 0.997) and distance effect . Post-hoc analysis showed that men were faster than women in both distances, and athletes swimming an Ice Km were faster than athletes swimming an Ice Mile  and BMI . Similarly, for the Ice Km, we found a significant effect for sex  and BMI . Post-hoc analyses showed that men were faster in all BMI categories but the normal weight in Ice Km. Furthermore, subjects in the obese BMI category were slower regardless of their sex . Significant and negative correlations were found between performance and body mass  and BMI . Men’s performance in Ice Km showed a weak correlation with air temperature , but it was not correlated with water temperature, wind chill, and body height (p > 0.05)  .p < 0.001; Ice Mile: r = −0.402; p < 0.001). Significant and negative correlations were found between performance and body mass  and BMI . Women’s performance in Ice Km showed a small correlation with body height , water temperature , and air temperature . No other correlations with women’s performance were found  and wind chill  .Water temperature correlated significantly and positively with both air temperature  on swimming performance in both the Ice Mile and Ice Km. We hypothesized that more female and male swimmers with a higher BMI would successfully finish an Ice Mile than an Ice Km. The most important findings were (i) swimming speed decreased with increasing age, body mass, and BMI in both women and men in both Ice Mile and Ice Km; (ii) body height was positively correlated to swimming speed in women in Ice Km; and (iii) there were no differences for anthropometric characteristics between swimmers completing an Ice Mile and an Ice Km although water temperatures and wind chill were lower in Ice Km compared to Ice Mile. Further important findings were that men were faster than women in both Ice Mile and Ice Km, air temperature was significantly and negatively related to swimming speed in Ice Km but not in Ice Mile, and water temperature was not associated with swimming speed in men in both Ice Mile and Ice Km but in women in Ice Km.2 could swim for 6 h in the water of 9.9 °C without suffering from hypothermia [An important finding was that swimming speed has a small but significant negative correlation to body mass and BMI in both women and men in both Ice Mile and Ice Km. As a result, swimmers with a higher BMI were not faster than swimmers with a lower BMI. These results do not confirm our hypothesis. Several case studies showed that swimming an Ice Mile ,10,11,12othermia . An earlothermia .2) was lower than controls  but not different to the BMI of North American masters pool swimmers or international masters pool swimmers [However, a study investigating 103 recreational open-water swimmers swimming during winter months regularly and without wetsuits in the San Francisco Bay at water temperatures from 9.6 °C to 12.6 °C showed that the average BMI of those cold-water swimmers  and wind chill (Ice Mile and Ice Km).This study has some limitations. Body height and body mass were self-reported and not objectively measured before a swim. A disagreement between self-reported and measured anthropometric data has been reported for athletes ,40, leadSwimmers intending to complete an Ice Mile or an Ice Km do not need to have high body mass and/or a high BMI  to swim these distances fast. The general idea that there is an optimal body composition associated with success in ice swimming do seem to confirm our current results. Training and experience in these swimmers might be of higher importance. Future studies might investigate pre-event preparation  in ice swimmers. Also, physiological aspects, such as maximum oxygen uptake and swimming economy, might be of interest.


Here we show that El Niño is projected to (1) grow at a faster rate, (2) persist longer over the eastern and far eastern Pacific, and (3) have stronger and distinct remote impacts via teleconnections. These changes are attributable to significant changes in the tropical Pacific mean state, dominant ENSO feedback processes, and an increase in stochastic westerly wind burst forcing in the western equatorial Pacific, and may lead to more significant and persistent global impacts of El Niño in the future.Future changes in the seasonal evolution of the El Niño—Southern Oscillation (ENSO) during its onset and decay phases have received little attention by the research community. This work investigates the projected changes in the spatio-temporal evolution of El Niño events in the 21 The El Niño - Southern Oscillation can have global impacts, therefore assessing its future occurrence is needed. Here, the authors project that El Niño will grow at a faster rate, persist longer over the eastern and far eastern Pacific, and have stronger and distinct remote impacts in the 21st Century Previous studies based on the climate models participating in the Coupled Model Intercomparison Project Phase 5 (CMIP5) have suggested an increase in the frequency of extreme El Niño events in the 21st Century (21 C) in response to increasing greenhouse gases8, as well as an increase in ENSO amplitude9, and associated rainfall variability12, and further validated based on CMIP613. Several studies have attributed these shifts in El Niño frequency and amplitude to the projected changes in the tropical Pacific mean state. Specifically, the majority of CMIP6 models show a projected mean state that mimics an El Niño-like condition  is the dominant mode of interannual ocean-atmospheric variability in the tropical Pacific. Through its atmospheric teleconnections, ENSO is also the major source of seasonal predictability of global climate and extreme events23 and boosting the amplitude of El Niño in the eastern equatorial Pacific9. This El Niño-like pattern of equatorial Pacific SST warming would reduce the near-equatorial zonal and meridional sea surface temperature (SST) gradients, facilitating shifts of west Pacific convection toward the eastern equatorial Pacific, and potentially increasing the likelihood of extreme El Niño events24. In addition, a recent study found that a future La Niña-like pattern of SST change would increase the zonal temperature gradient and zonal advective feedback in the central equatorial Pacific, potentially increasing the frequency and amplitude of strong El Niño events7. That is, either El Niño-like or La Niña-like mean state changes could increase the likelihood of extreme El Niño events. While most of these projected changes in the tropical Pacific climatology and variability have yet to emerge clearly in instrumental observations26, paleo proxy evidence does suggest that ENSO has significantly strengthened in recent decades relative to prior centuries28.A future increase in equatorial Pacific upper-ocean thermal stratification and the associated surface warming of the eastern equatorial Pacific could increase the sensitivity of SSTs to fluctuations in local winds, upwelling, and thermocline depth, thereby enhancing the atmosphere-ocean coupling and the Bjerknes feedback loops30. Less attention has been paid to potential changes in the seasonal evolution of ENSO during the onset and decay phases with a few exceptions31. The onset and decay phases of ENSO, which typically occur in boreal spring and summer, have direct impacts on global climate variability and extreme events, including the Southeast Asian monsoon32, tropical cyclones34, and tornado outbreaks in the United States35. Therefore, there is an urgent need to better understand not only the spatial changes but also the temporal changes in ENSO characteristics arising from increasing greenhouse gases (GHGs), and the impacts of those ENSO changes on climate variability. This study examines a large suite of climate simulations—including the Community Earth System Model Large Ensemble (CESM-LENS), and available simulations from the Climate Model Intercomparison Project phase 6 (CMIP6), both driven by historical and projected future radiative forcing—in order to better understand potential future changes in El Niño’s onset, decay, and remote impacts. Details on the models and their representation of ENSO are provided in the Methods section and Previous studies have focused mainly on future changes of ENSO during the peak phase in boreal winter, or on changes in the diverse spatial patterns of ENSO SST anomalies36 , and 419 events for the late 21st century  in the 30 ensemble members from CESM-LENS. This indicates a 20% increase in the occurrence of El Niño. Similarly, we found 199 El Niño events in the 16 CMIP6 models for the 20 C period, and 234 events for the 21 C period. This indicates an increase of 17% in El Niño likelihood. Coincidentally, this increase in the occurrence of El Niño in CESM-LENS and CMIP6 models  is similar to the reported increase in occurrence of extreme El Niño events based on the results derived from CMIP5 models5. This increase is significant when compared to the expected natural variability  dissipate more rapidly during boreal winter and spring. These projected changes mark a contrast in El Niño SSTA evolution and a projected enhancement and eastward shift in convection over the tropical Pacific . While the start date of the events, appears to be model dependent, there is a consistent shift in the peak month from January to December based on Niño3.4 and Niño4. This, along with the projected higher amplitude of future events explains the faster growth rate of 21 C El Niño events compared to 20 C events. There is a projected decrease in the decay rate over the Niño3 region, with later end day of the events. In contrast, the decay rate over the Niño4 region is projected to increase, with earlier termination of the events. The projected persistence of the future El Niño events into the boreal spring over the eastern Pacific could have marked repercussions on remote teleconnections, as it has been shown that SSTA over the eastern Pacific would enhance air-sea coupling, an eastward shift in atmospheric convection, and a potential larger remote influence41. While the projected increase in the number of El Niño events reported here occur in all types of El Niño, those events that persist into the boreal spring are projected to increase by 47%, dominating the reported increase of El Niño occurrence . Figure 9 and also for their role in modulating the mean state changes13, as they govern characteristics of extreme ENSO events42. Therefore, the residual term in the heat budget is further decomposed into three nonlinear temperature advection terms .To further investigate what dynamical processes are responsible for the projected changes in feedbacks and thus El Niño growth and decay, we repeat the computations of the feedback terms in Eq. 13. It is well known that zonal SSTA propagation during the termination of El Niño is determined by the competing influences between the thermocline feedback, zonal advective and Ekman feedbacks43. Specifically, the thermocline feedback tends to drag SSTAs eastward, while the zonal advective and Ekman feedbacks tend to drag SSTAs westward, as evident in Figs. Analysis of future projections of ENSO SSTAs in the CMIP6 models has shown an increase in eastward SSTA propagation during the decay phase of El Niño44, the anomalous meridional winds may also drive convergent surface currents that induce anomalous equatorial downwelling in the equatorial Pacific45.The stronger El Niño events during 21 C are associated with stronger westerly wind anomalies and anomalous eastward currents  cause El Niño SSTAs to persist longer in the eastern Pacific in the late 21 C, in contrast to a westward propagation of SSTAs typically observed during the late 20 C Fig. .The projected increase in equatorial Pacific time-mean SST is the strongest over the cold-tongue region in boreal fall and winter Fig. , the seaThese future changes in the time-mean precipitation and thermocline in the central Pacific (160°E–120°W) during boreal summer provide a more favorable background environment to support faster and stronger development of El Niño, by enhancing the thermocline feedback. In the far eastern equatorial Pacific (100°W–80°W) in boreal spring and early summer of year +1 (decay year), the future climatology shows a deeper thermocline and more precipitation Fig. . These c8. A recent study showed that the interaction between the ITCZ and El Niño in boreal spring is a key element in determining the decay of El Niño47. In this season, the eastern Pacific SST reaches its annual maximum (minimum) in the Southern (Northern) Hemisphere; thus, the ITCZ is climatologically further south in boreal spring τx) from the 20 C and 21 C simulations of the CESM-LENS  and a state-dependent  components62. Such nonlinearity, in turn, modifies ENSO phase asymmetries of event amplitude, duration, and transition64, which are strongly linked to the El Niño spatiotemporal evolution discussed here. While most CMIP5 models do not show a discernible increase in state-dependent component of WWBs under anthropogenic forcing60, the CESM model is one of the few that show an increase in WWBs occurrence as noted in this paper60. The CESM is also the only CMIP5 model that readily simulated the correct state-dependent component of WWBs60.Previous studies have shown that the ITCZ position strongly influences the nonlinearity of the equatorial zonal wind response to SSTAs, which derives largely from WWBs state dependence65, influencing weather and climate over North America66. However, ENSO teleconnection is strongly modulated by internal atmospheric variability67, as well as the spatial details of the ENSO SSTAs in the tropical Pacific68.El Niño-related anomalous precipitation and upper-level divergence modulate the extratropical circulation via atmospheric westward Rossby wave propagation69. Changes in ENSO teleconnections under ACC are strongly linked to both the changes in oceanic and atmospheric mean state and in ENSO amplitude and spatial pattern70. The SST-rainfall relationship over the eastern Pacific is expected to strengthen under ACC driven by the exponential relationship between temperature and vapor pressure through the Clausius-Clapeyron relationship71. Therefore, even if the ENSO amplitude remains similar to that of the 20 C, the response of tropical and extratropical atmosphere to ENSO will be intensified72. While future projections suggest a systematic strengthening in ENSO remote teleconnections73, there is still large regional intermodel differences due to internal variability and model errors3.Previous studies have shown using several CMIP5 models a future projected increase in ENSO-driven precipitation of around 20% in regions that are largely impacted by ENSO signalsBesides the reported large uncertainties in future changes in ENSO teleconnections, the spatiotemporal changes in El Niño SSTA reported in this work can modulate the seasonally-dependent remote teleconnections. We investigate how remote effects of El Niño events will change in the future – owing to changes in both the spatial and temporal patterns with faster growth, larger amplitude, and extended persistence over the boreal spring. As such, remote teleconnections are quantified separately for the developing phase  and for the decay phase .74 , El Niño’s remote effects mimic those of the peak phase, with enhanced future teleconnections.The El Niño-driven atmospheric circulation changes, as measured by the composite of 500 hPa geopotential height, is dominated by the Pacific South American pattern during the developing phase77. This northeastward shift in the teleconnection is driven by the projected eastward shift of the PNA teleconnection pattern under global warming78, resulting from a systematic eastward migration of the tropical Pacific convection centers associated with both El Niño and La Niña in the future79. The enhanced cooling is a result of increased clouds and precipitation over the southern U.S, with changes in the teleconnections being generally consistent among climate models73. The projected enhancement of the 20 C teleconnection into the 21 C is consistent between CESM-LENS and CMIP6, which showed that sufficiently warm and persistent SSTA in the far eastern equatorial Pacific is required to excite teleconnection patterns that influence rainfall over the western U.S41.The projections show a northeastward shift and intensification in temperature and precipitation anomalies over North America , ENSO’s impacts over South America are also projected to increase in the 21 C, with a projected increase (reduction) in rainfall over Southeastern South America (Amazon basin)81. Over South America, El Niño’s remote effects are also projected to increase, with enhanced warming over the northern two thirds of the continent and drier Amazon basin during both the developing , producing a north-south dipole pattern in surface air temperature and rainfall with cooler and wetter (warmer and drier) conditions in the Southern (Northern) portion of the continent73, especially over the north and eastern portions of Australia83. However, the ENSO response over Australia varies significantly with the location of maximum ENSO SSTA. For instance, central Pacific events tend to produce more widespread precipitation and temperature signals in Australia than eastern Pacific events29. There is a projected significant increase in El Niño-induced surface warming across the entire continent during SON  grow at a faster rate, (2) persist longer over the eastern and far eastern Pacific, and (3) to produce larger and distinct remote impacts in surface temperatures and precipitation. These changes in El Niño are attributable to projected changes in the tropical Pacific climatology , and associated changes in the dominant ENSO feedbacks . We also identified a significant projected increase in the stochastic forcing of El Niño from WWBs, and an earlier onset of the WWBs forcing in boreal spring. These changes in WWBs forcing are consistent with the projections of a faster onset for El Niño , which may affect model projections of future ENSO behavior95. In addition, the observed historical trend in Pacific mean state changes so far remains well within the unforced variability range95. Continued advances in these models will be crucial to achieve more reliable projections of future ENSO variability and its impacts on society.Besides model biases, another limiting factor in studying future changes in ENSO is the difficulty in accurately separating the anthropogenic response of ENSO into its transient and equilibrium components. Analysis of millennial-scale warming in high emission scenarios from the Long Run Model Intercomparison have shown that the transient response to anthropogenic forcing contains large uncertainties, whereas the equilibrium response manifests a decrease in ENSO amplitude and no change in ENSO frequency96 and the rainfall from the Global Precipitation Climatology Project (GPCP version 2.3)97. The model simulations are taken from a 30-member ensemble simulation of the Community Earth System Model—Large Ensemble Simulation 98. The atmospheric component has 30 vertical levels with a horizontal resolution of 1.25° longitude by 0.94° latitude. The ocean model component has a 1° horizontal resolution with 60 vertical levels. CESM is one of the most skillful models in representing ENSO variability and associated global teleconnections73. We validated all relevant results using the CMIP6 model archive (data freely available at: https://esgf-node.llnl.gov/projects/cmip6/). All CMIP6 models were interpolated to the horizontal resolution of CESM-LENS. See Supplementary Table For observations, we analyze the NOAA Extended Reconstructed Sea Surface Temperature version 5 (ERSST.v5)100, and the Shared Socioeconomic Pathways (SSP585) for the CMIP6 models. The RCP8.5 and SSP585 result in similar radiative forcing levels. Each model/ensemble member has a distinct climate trajectory due to differences in the atmospheric initial conditions. Differences among ensemble members from CESM-LENS are solely due to internal variability, while differences among models from CMIP6 also include model biases. We repeated relevant analyses with 10, 15, 20, and 30 members and the results converge beyond 15-members. Thus, adding more ensembles will not add much to the results qualitatively, beyond increasing the degrees of freedom36.The analysis comprises 16 CMIP6 models and 30 ensemble members from CESM-LENS under historical radiative forcing . The 21 C projection also comprises 30 ensemble members from CESM-LENS for the 2051–2100 period under the Representative Concentration Pathway 8.5 radiative forcing of the CMIP5 design protocolAll models employed here show reasonable representation of the spatio-temporal evolution of El Niño events  due to external forcing as well as CESM model bias. Thus, interannual anomalies for a given ensemble member exclude any trend associated with the increasing GHGs as well as responses of low-latitude volcanic eruptionsWe define an El Niño event following the method used at the NOAA Climate Prediction Center where 3-month averaged SSTAs over the Niño3.4 region  should exceed 0.5 °C for a minimum of five consecutive months. SSTAs are defined by removing the ensemble mean SST and monthly climatology for each ensemble member. The monthly climatology is defined for the period of 1951–2000 for the observations and historical model runs (20 C), and from 2051 to 2100 for the future projections (21 C).T denotes the mixed layer temperature, and u and w are the zonal and vertical components of velocity, respectively, which are evaluated in an Eulerian reference frame on the model grid. H = 75 m is the mixed layer depth, taken here to be constant throughout the tropical Pacific20. We have tested these results using different mixed layer depths  and found that the main conclusion is consistent and independent on the mixed layer depth. The entrainment velocity is taken to be the vertical velocity at the base of the mixed layer. Bars and primes represent the climatological mean and monthly anomalies, respectively, computed independently for the 20 C and 21 C. The residual term is composed of the surface net heat fluxes, meridional heat advection, non-linear advection  represents the wind stress anomaly associated with WWBs, which is a function of longitude x, which is centered at xo, and time t. Note that the Kelvin wave forcing is the integral of the WWB forcing from the central longitude xo to the eastern boundary xe along the characteristics  possible combinations for CESM-LENS (CMIP6) respectively.A Monte Carlo bootstrapping method is employed to determine confidence intervals by subsampling the dataset. For example, all composite analyses presented are obtained by randomly selecting Supplementary InformationPeer Review File


Published maps identifying archaeological sites in the Amazon basin show a paucity of sites in western Amazonia compared to the Brazilian Amazon. Whereas fewer than two dozen are identified for the Peruvian Amazon on basin-wide maps, a thorough review of unpublished archival material held by the Ministry of Culture of Peru and other sources revealed more than 400 known but unpublished sites in the Department of Loreto, challenging the notion that the region was sparsely occupied in prehistory. Our database provides the geolocation of each site and corresponding references for use by scientists seeking to better understand regional Pre-Columbian human occupation and settlement, cultural change, resource use and their landscape legacies. These data are foundational not only to the development of a richer understanding of prehistory and historical ecology of the Amazon basin but importantly for informing current land use, forest conservation and development policies as well as initiatives to support indigenous land and cultural rights in Amazonia. Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.16750639 The discovery of extensive anthropic soils (terra preta)7, the enrichment of forests with useful and semi-domesticated species12, and the presence of landscape-scale fisheries infrastructure13 together suggest enduring landscape transformations by purposeful human action over millennia19. Still, some scientists remain sceptical of the extensive human modification thesis, pointing to contrary evidence drawn often from beyond Brazil, in the outer Amazon basin [e.g.22].An important ongoing debate in Amazonian studies is the extent to which indigenous peoples occupied and transformed their environment in prehistory. Evidence from the Brazilian Amazon – from Pre-Columbian geoglyphs, settlement sites, raised fields, and causeways – points to large complex polities in nucleated and interconnected settlements along the rivers and interfluves23. Published maps identify fewer than two dozen sites in the Peruvian Amazon .Western Amazonia remains far less studied by using controlled archaeological investigative methods than Brazilin situ conservation of cultural material in humid forest tropical soils, the lowlands of the Peruvian Amazon have some of the most active meandering rivers in the world31, making it difficult to locate and preserve archeological sites. In an influential article, Donald Lathrap identified two primary threats to prehistoric sites along the major rivers – floodplain aggradation which drowns sites; and, rapid river meandering destroys floodplain sites and erodes river bluffs32. Lathrap’s view of the salience of site instability due to river dynamics has been echoed by his students to explain the paucity of prehistoric settlement33 and terra preta soils27, and may have dampened international interest in the pursuit of archaeological sites in the Peruvian Amazon. Nevertheless, many propitious locations remain, on river terraces or bluffs34. Two recent reviews of archaeological evidence along the Napo River35 and Lower Ucayali River36 identify many more sites than previously reported in the literature.In addition to the typical challenges to 2–and is the largest department by area in the Peruvian Amazon. For each site we provide the longitude and latitude of the site location and the corresponding key reference(s). We have summarized and mapped the distribution of sites in Loreto  as will indigenous peoples and the groups that support them through initiatives to buttress indigenous land and cultural rights in Amazonia.Ministerio de Cultura  in Iquitos and Lima and other institutions. These sites were progressively catalogued by Santiago Rivas Panduro , an archaeologist who worked in Iquitos for the Ministerio de Cultura during the early 2000s and later as a consulting archaeologist. Very few of the sites have yet been subjected to controlled investigation and most references are found in unpublished site visit and reconnaissance reports, environmental impact statements, conference presentations, and oral testimonies. Many sites were encountered by accident, often during road building and petroleum exploration activities including the running of seismic lines, road construction, and well drilling. SRP was responsible for documenting many of the sites reported through field reconnaissance and this database represents the culmination of his career’s work.The archaeological site database was constructed based on a thorough review of published reports in the international and national literatures as well as unpublished materials held by the 37. Each record corresponds to one archaeological site and comprises 12 fields: (1) Map site number; (2) Site name; (3) Site code; (4) Department; (5) Province; (6) District; (7) Longitude; (8) Latitude; (9) Elevation (Google Earth); (10) Elevation (Recorded); (11) Site Location notes (Satellite imagery 2020); and (12) Reference(s). The “Map site number” corresponds to the number we assigned to identify the site on our provincial maps , river , and a site number. Unregistered sites retain the code given by the reporting archaeologist . “Department”, “Province”, and “District” record the administrative units in which the site is located . “Longitude” and “Latitude” are recorded in decimal degrees and are approximate only, except where indicated as being measured on-site; “On-site Measurement” indicates whether longitude and latitude were measured with a GPS on site (yes/no). “Elevation (Google Earth)” is recorded in metres above sea level (asl) according to Google Earth and as such are approximate. “Elevation (recorded)” captures the elevation as measured on-site with a GPS. “Site Location notes (Satellite imagery 2020)” refers to any observations made regarding site location based on verification using Google Earth imagery in November 2020. “Reference(s)” refers to the documents that correspond to the site, typically a project report, impact statement, or publication. We present citations in the original language of the text.The database is stored at figshare as an Excel worksheetaps Fig. . The “SiMinisterio de Cultura and an additional 13% have a formal site code. In November 2020, the accuracy of each site location was checked using Google Earth imagery. Of the 415 sites, 22 sites (5%) were found now to lie in the active channel of the nearby river, reflecting changes in the river course since the site was originally reported; 29 sites are now located on the river’s edge. A total of 163 sites were documented as part of impact assessments and field monitoring of oil exploration and road building activities, at least some of which may have been destroyed in the development process.The data were compiled over a period of nearly 20 years by a professional archaeologist (SRP) who was considered by his international peers to be the leading archaeologist in the Department of Loreto of Peru. Each site reported was confirmed with a corresponding citation to a published or unpublished work(s). Of the 415 sites, 36% are registered with the Archaeology. The database will advance the field of Amazonian archaeology by saving archaeologists’ considerable time and effort in locating sites and locales of potential interest and significance. The location data can be used to guide future archaeological investigations using remote sensing analyses  and controlled field excavations to document extant and undocumented archaeological sites; in the development of a more complete cultural chronology and understanding of the historical ecology of Amazonia; to protect and preserve archaeological sites under threat of destruction; to inspire, guide and train a new generation of Peruvian archaeologists and stimulate archaeological research in western Amazonia; and, to valorise the cultural heritage of indigenous peoples in this less studied but extensive region of the Amazon basin. The database could serve as a template for the development of similar compilations for other Amazonian countries as well as a basin-wide database of documented archaeological sites.Development activity impacts and land use planning. The site location data can be used to assess the potential impacts of development activities in the Peruvian Amazon, a resource frontier region with significant exploration and production of oil, gas, gold and timber and attendant road building. Knowledge of where archaeological sites are located will inform decision makers as to the need for impact assessments and protective/mitigative measures. Regional and local governments as well as local communities can use these data in the formulation of land use planning policy, conservation and development plans in the Peruvian Amazon. Location data will also be central to the Ministry of Culture’s efforts to protect and preserve archaeological sites from immanent development and environmental threats.Indigenous land claims and cultural rights. Indigenous peoples and advocacy groups can use the data to legitimize and buttress land claims and cultural rights in Amazonia. The paucity of documented archaeological sites is often used as evidence of a lack of indigenous occupation and thus (pre)historical rights to land and other resources. Indigenous federations, NGOs, scientists and scholars (including indigenous scholars) will benefit significantly by knowledge of the location of the many archaeological sites referenced in the database. These data may also be used to empower individual communities in their struggle to protect their lands from invasion.Our database provides high quality geolocational data for scientists, researchers, planners, policy makers, government agencies, and indigenous peoples to locate over 400 unpublished archaeological sites in the Peruvian Amazon. Locational data contained in this database are intended for re-use in at least three realms.Potential site destruction. Some sites identified in the database are prone to destruction by fluvio-geomorphological change and/or development activities and thus may no longer exist. Most archaeological sites located along or near rivers which vary in their exposure to riverbank erosion and aggradation. Of the 415 sites verified in November of 2020, 22 sites (5%) now lie in the active channel of a river, reflecting changes in the river course since the site was originally reported; 29 sites are currently located on the river’s edge. Site instability means that reported sites may not persist in the future. The same can be said of sites documented as part of impact assessments and field monitoring conducted for oil exploration and road building activities (n = 163). Although one of the purposes of assessments and monitoring is to identify archaeological sites for preservation/conservation, it is possible that a small number of sites may have been further disturbed by subsequent development activities or destroyed. Publication of the database is urgently needed to protect and preserve known sites.Un-documented sites. The list of archaeological sites reported in the database for the Peruvian Amazon is partial only, as we anticipate that more sites remain to be documented through further field reconnaissance and excavation. Still, the current listing of georeferenced unpublished sites reported is the most comprehensive to date; is much more extensive than records available in the published literature from the Peruvian Amazon; demonstrates clearly how the region is far from impoverished in terms of archaeological sites and cultural prehistorical heritage; and, suggests the promise for new sites remain to be encountered and documented.Limited site descriptive information. Limited information is provided in the database of site characteristics, archaeological tradition or phase, or material culture which would be a valuable supplementary addition through future work. By providing the site location, name and registry information, database users can access more detailed site information from the corresponding citations reported for each site and pursue further site exploration and excavation as might be of interest. Of the 415 sites, 36% are registered with the Ministry of Culture and additional 13% have a formal site code. Database users can refer to the offices of the Ministry of Culture in Lima and Iquitos for access to corresponding documentation for sites registered with the Ministry.This database is limited in three respects that are important to acknowledge but which do not diminish the quality or re-use value of the data.


Mobile edge computing (MEC) represents an enabling technology for prospective Internet of Vehicles (IoV) networks. However, the complex vehicular propagation environment may hinder computation offloading. To this end, this paper proposes a novel computation offloading framework for IoV and presents an unmanned aerial vehicle (UAV)-aided network architecture. It is considered that the connected vehicles in a IoV ecosystem should fully offload latency-critical computation-intensive tasks to road side units (RSUs) that integrate MEC functionalities. In this regard, a UAV is deployed to serve as an aerial RSU (ARSU) and also operate as an aerial relay to offload part of the tasks to a ground RSU (GRSU). In order to further enhance the end-to-end communication during data offloading, the proposed architecture relies on reconfigurable intelligent surface (RIS) units consisting of arrays of reflecting elements. In particular, a dual-RIS configuration is presented, where each RIS unit serves its nearby network nodes. Since perfect phase estimation or high-precision configuration of the reflection phases is impractical in highly mobile IoV environments, data offloading via RIS units with phase errors is considered. As the efficient energy management of resource-constrained electric vehicles and battery-enabled RSUs is of outmost importance, this paper proposes an optimization approach that intends to minimize the weighted total energy consumption (WTEC) of the vehicles and ARSU subject to transmit power constraints, timeslot scheduling, and task allocation. Extensive numerical calculations are carried out to verify the efficacy of the optimized dual-RIS-assisted wireless transmission. In the forthcoming Internet of Vehicles (IoV) era, where multiple automobile terminals are interconnected, innovative applications will emerge, including autonomous driving, ultra-high-quality video streaming, and augmented reality (AR) . As new In recent years, there have been various contributions in the MEC-enabled IoV ecosystem. In , a stochWhile fruitful results have been described in previous work on MEC in IoV, the highly dynamic network topologies of IoV drastically influence the data offloading process. More importantly, the communication links between vehicles and ground RSUs (GRSUs) can be blocked in propagation environments with large obstacles and dispersed nodes. In this direction, hovering aerial RSUs (ARSUs) relying on unmanned aerial vehicles (UAVs) have great potential to attain a higher chance of line-of-sight (LoS) communication across different terrains thus sufficiently extending the radio coverage between vehicles and MEC servers ,14,15. IOn the other hand, with the rapid evolution of radio frequency (RF) micro electro-mechanical systems (MEMs), the programmable and reconfigurable meta-surfaces have emerged, among which the reconfigurable intelligent surface (RIS) technology has recently received unprecedented attention ,31. MoreA novel dual-MEC IoV architecture is proposed, where a rapidly deployed and dynamically repositioned UAV-based ARSU equipped with a MEC server facilitates the computation offloading and also acts as an intermediate decode-and-forward (DF) aerial relay enabling the communication between vehicles and a GRSU. Full offloading is applied and a trade-off between energy consumption and delay is obtained by efficiently using the computing resources at both ARSU and GRSU.In practice, the direct communication links between vehicles (ARSU) and ARSU (GRSU) may be vulnerable to fading and blockage effects due to large objects in the propagation environment. Thus, the proposed architecture leverages a dual-RIS deployment strategy to assist the direct communication. It is considered that one RIS unit is positioned close to the vehicles and a second RIS unit is positioned towards GRSU. Owing to the dynamic and highly mobile vehicular environment, imperfect estimation of the reflection phases is introduced. Hence, wireless transmission via the RIS units with phase errors is assumed. In order to obtain a 3-D realistic geometrical positioning of the vehicles, ARSU, GRSU, and RIS units, while accurately modeling the mobility characteristics, velocity and distance vectors are utilized.Moreover, this paper formulates a multi-variable optimization problem to minimize the weighted total energy consumption (WTEC) from both the vehicles and ARSU perspective and elongate their endurance. In this respect, the Lagrange dual method along with a subgradient-based algorithm are leveraged to provide optimal solutions for the transmit power allocation, timeslot scheduling, and task allocation. Moreover, an asymptotic analysis of the WTEC is included as the number of reflecting elements increases. The numerical results illustrate the total computation-based and communication-based delay (TCCD) and WTEC, focus on the benefits of the dual-RIS-based data offloading, and affirm the efficiency of the optimization method.To the best of the authors’ knowledge, the area of computation offloading for RIS-based UAV-aided IoV is unexplored. As newer network architectures are indispensable, this paper proposes an IoV framework, which includes a UAV-based ARSU and relies on RIS units. This framework may find practical application in beyond fifth generation (B5G) mission-critical scenarios, where multiple resource-limited vehicles should execute computationally intensive tasks by using the processing capabilities of MEC servers. As the communication links between vehicles and GRSUs may be blocked, an ARSU can bring flexibility, additional computing resources, and extended radio coverage. RIS units are also employed, in order to further enhance the connectivity and reliability by reshaping the propagation environment in favor of signal transmission. More specifically, the main contributions of this paper can be summarized as follows:The rest of this paper is organized as follows. In K vehicles moving along a unidirectional road segment, where the distribution of the vehicles follows a Poisson distribution [k-th vehicle with k-th vehicle (ARSU) and ARSU (GRSU).In this paper, a MEC-enabled IoV is considered consisting of ribution . The latk, A, G, and k-th vehicle, ARSU, 1st RIS, GRSU, and 2nd RIS, respectively. It is considered that k-th vehicle, ARSU, 1st RIS, GRSU, and 2nd RIS, respectively. Let a and b. Then, k-th vehicle and ARSU and k-th vehicle and ARSU are moving with velocities k-th vehicle and ARSU, respectively. In practice, the ARSU should not notably draw away from its initial position, since its movement may affect the connectivity with the vehicles and GRSU. It is assumed that the initial locations of the vehicles are known to the ARSU for designing its trajectory, whereas the fixed locations of the 1st RIS and 2nd RIS are known as well. For convenience, we use a sufficiently small constant T into N timeslots.  its task. Thus, It is considered that K equal durations k-th vehicle to ARSU and k-th vehicle and ARSU, respectively, for data offloading in the n-th timeslot can be expressed as: k-th vehicle and ARSU, respectively, for bits offloading in the n-th timeslot. Moreover, the energy consumption for ARSU computing in the n-th timeslot can be written as [In order to implement the computation offloading, the TDMA protocol is adopted. This protocol has been widely used in IoV networks  and MEC itten as (6)Ek,cA at ARSU  and κA>0k-th vehicle, the ARSU, and the GRSU are equipped with single omni-directional antennas, whereas the RIS units employ multiple reflecting elements as well as a wireless controller for the dynamic adjustment of the phase shift of each element. Without loss of generality, it is assumed that the 1st and 2nd RIS units have the same number L of reflecting elements. It is also assumed that the channel gain remains unchanged in each timeslot, since the k-th vehicle and the ARSU shift over an insignificantly short distance. Thus, during the flying period, the wireless radio channel can be represented by a series of channel snapshots, where each snapshot is associated with a particular position of the k-th vehicle and ARSU.It is considered that the m distributions, have been previously used [m distribution was experimentally validated in UAV-based scenarios [k-th vehicle (ARSU) and ARSU (GRSU) is subjected to Nakagami-m fading conditions. Then, the cumulative distribution function (CDF) of the instantaneous SNR received at the ARSU can be expressed as [m fading parameter, k-th vehicle and ARSU. Fγth,function , eq.  and the l-th element of 1st RIS (ARSU) is modeled as a Rician fading channel accounting for both the LoS and non-line-of-sight (NLoS) components. Each RIS element should be designed to maximize the reflection strength and steer the reflection angle towards the ARSU (or GRSU). However, it is assumed that the phase shifts induced by the channels cannot be perfectly evaluated and/or the desired phases cannot be precisely set. Quantization phase errors are considered and thus only a discrete set of q is the number of quantization bits. It is assumed that the phase error k-th vehicle and ARSU via the 1st RIS is equivalent to a direct channel with Nakagami scalar fading and can be expressed asn-th timeslot for the link between the k-th vehicle (l-th element of the 1st RIS) and the l-th element of the 1st RIS (ARSU). It is assumed that the phase errors m fading parameter and average SNR, respectively, of the composite channel. Then, the CDF of the instantaneous SNR received at ARSU is expressed as [k-th vehicle (1st RIS) and 1st RIS (ARSU), k-th vehicle (1st RIS) and 1st RIS (ARSU). Using (7) and (10), the CDF of the instantaneous SNR received at ARSU accounting for both the direct link as well as the link via the 1st RIS can be expressed as follows [The channel between a UAV and a RIS unit is mostly dominated by LoS links, since the UAV usually flies at high altitudes and the RIS unit is mounted on the facade of a building. However, multipath propagation may also exist in urban and dense-urban environments with tall buildings acting as effective scatterers. In addition, local scattering effects may influence the channels between an RIS unit and vehicles, whereas an additional LoS link can be also established ,33. Thusshown in , the com moments , with |φessed as (10)Fγthfunction , eq.  threshold, in order to maintain an acceptable QoS. In this paper, maximal-ratio combining (MRC) is adopted. Thus, the requirement atisfied . Using tL increases. As In order to support a massive number of vehicles in future MEC-enabled IoV scenarios, a vast number of discrete reflecting elements at each RIS unit is required. Thus, this paper derives the asymptotic rate, as e obtain , eq. , timeslot scheduling, and task allocation.k-th vehicle and ARSU, respectively, k-th vehicle and ARSU, respectively, andn-th timeslot. The weights can be modified according to energy demands and tradeoffs of an envisioned IoV application and also provide priority/fairness among the vehicles. Thus, k-th vehicle’s (ARSU’s) battery is running low. It is noted that the constraints (26b) and (26c) specify the range of transmit power of the k-th vehicle and ARSU, the constraints (26d), (26e), and (26g) indicate the transmission delay limitations, the constraint (26f) designates the range of the task assignment ratio, and the constraints (26h) and (26i) describe the data offloading limitations. In general, the propulsion energy consumption, which is defined in (1), is remarkable and is significantly affected by the ARSU’s trajectory, i.e., the time-variant location of the ARSU during the flight period. However, in this paper, a pre-determined ARSU’s trajectory is considered and the optimization of the trajectory, which can further decrease the WTEC, is left as a future work. Thus, the propulsion energy consumption is excluded from the optimization process.The optimization problem can be formulated as:Lemma 1.Problem (P1) is a convex problem.Proof. From (4)–(6), (26a), and (27), it follows that the objective function of problem (P1) is convex with respect to itten as , eq. (7.r symbol  (p. 256) As This paper leverages the Lagrangian dual method to solve Problem (P1). First, the non-negative dual variables KN independent subproblems and these sub-problems can be further decomposed into three subproblems as  Since problem (P1) is convex, it satisfies the Slater’s condition . As a stk-th vehicle can be obtained by applying KKT conditions, setting the derivative of the Lagrangian of subproblem (L1) with respect to The aforementioned subproblems are convex. Hence, the Karush–Kuhn–Tucker (KKT) conditions may be imposed on these subproblems for finding their optimal solutions. The optimal transmit power L increases.To derive a closed-form solution and provide insights into problem (L1), we present an asymptotic analysis as Proposition 1. The optimal transmit power of the k-th vehicle and the offloading time, when whereand function .Proof. As Next, we provide a recommendation for the energy-efficient offloading task assignment ratio. By solving subproblem (L3) with the aid of KKT conditions, the following optimal solution is obtainedOne observes that ARSU processes fewer task-input data, as  is not unique, the following linear programming problem is formulated:As arbitrary dual variables are considered heretofore, the optimal dual variables can be obtained by solving problem P1-dual. Since problem P1-dual is generally non-differentiable, the iterative ellipsoid method  is adoptAlgorithm 1: Optimal Solution to Problem (P1).1.Set the values of IoV parameters and the value of the tolerant threshold 2.Initialize the iteration index, the dual variables Then, calculate the achievable rate using (18).3.Repeat4.Solve subproblems (L1) and (L2) with KKT conditions and obtain Then, use (39) and obtain 5.Solve problem P1-dual and calculate the subgradients of the objectivefunction and the constraints.6.Update 7.End Repeat until convergence.8.Let 9.Update Use (39) and obtain Then, derive WTEC.In order to obtain the optimal solution to principal problem (P1), problem (P2) should be solved. In this regard, the subgradient-based Algorithm 1 is proposed to derive an optimal solution. The complexity of Algorithm 1 is due to Steps 4 to 6, the complexity of which is nd OK2N2 , respect) by CVX .AlgoritThis section provides results to demonstrate the impact of the key network parameters on the TCCD gramming . Figure  of UAVs . In thisIn s (e.g., ,20,24,25q increases, more energy is consumed with a fixed number of reflecting elements. However, the WTEC is remarkably robust against phase errors for large values of reflecting elements. It can be also seen that the convergence of the asymptotic WTEC directly depends on the number of quantization bits and up to 90 reflecting elements are required for an accurate approximation of the analytical results.The effect of the number of quantization bits on the WTEC is investigated in x-axis for different values of the Rician factors IS units  suggestex-axis for varying Rician factor k-th vehicle and the 1st RIS unit improves mainly owing to the increase in the average SNR of the composite channel. On the other hand, the fading conditions also affect the effective rate and thus the WTEC. Hence, the vehicles should move towards the 1st RIS unit, as long as the LoS component is weak.In order to ascertain how the distance between the 1st RIS unit and the vehicles influences the WTEC, T and Finally, This paper leveraged a UAV to provide additional computational resources and ubiquitous connectivity in future IoV networks. As RIS units constitute an emerging technology for reduced latency as well as improved energy efficiency, this paper also presented a dual-RIS network configuration and proposed a novel UAV-aided dual-RIS MEC-enabled IoV network architecture. In this direction, this paper introduced a 3-D geometrical representation of the entire network, provided an asymptotic WTEC analysis, and formulated a convex WTEC-aware optimization problem, which is subjected to several practical constraints. Based on the mathematical derivations and the convenient form of the closed-form solutions, indicative results are provided, in order to investigate the effect of the key network parameters on the non-optimized and optimized WTEC. These results underline that the number of supported vehicles is determined by the number of reflecting elements and the size of offloaded data. It is also demonstrated that the dual-RIS MEC deployment significantly outperforms other MEC deployments operating with a single RIS unit or without RIS units. Moreover, the results revealed that the impact of phase errors on the WTEC becomes less influential as the number of reflecting elements increases. Since the weight factor of ARSU and its velocity adjust the propulsion energy consumption, the results pointed out that using RIS units not only shortens the transmission delay, but also averts purposeless mobility of ARSU.Several fertile research areas can be identified to expand this work. For instance, multiple ARSUs can be deployed to extend the network range, whereas RIS-aided WPT for flight time prolongation constitutes another interesting research direction. Furthermore, cooperative multi-RIS transmission with inter-RIS signal reflection can further improve the beamforming gain.


Pedicle screws are the gold standard in spine surgery, allowing a solid tricolumnar fixation which is unmatched by hooks and wires. The freehand technique is the most widely adopted for pedicle screws placing. While freehand technique has been classically performed with manual tools, there has been a recent trend toward the use of power tools. The aim of this review is to summarize and expose potential risks and advantages of power pedicle screws placing. The literature showed that the use of power tools offers an acceptable safety profile, comparable to manual technique. With an adequate training, the power technique may speed up the screw placing, reduce the fluoroscopy time and the physical stress to the spine surgeon. Regarding differences in pull-out strength between power and manual techniques, the literature is still uncertain and inconsistent, both in clinical and preclinical studies. The choice between the use of power and manual freehand pedicle screws placing is still based on the surgeon’s own preference. Pedicle screws were first introduced by Boucher  in the 1Pedicle screws placing, regardless of the technique adopted, follows these fundamental steps: hole preparation, palpation, hole tapping, re-palpation, screw insertion. Classically, the traditional freehand technique has been performed with manual tools: a Gearshift for hole preparation, a manual tap for tapping and a manual screwdriver for insertion. While the principles of freehand pedicle screws placing have remained the same , there has been a recent trend toward the use of power tools, considering some critical issues. Firstly, it has been demonstrated that spine surgeons are at greater risk of musculoskeletal overuse injuries . SecondlThe aim of this study is to review the literature about freehand power pedicle screws placing technique, assessing associated risks and benefits compared to the manual technique.The aspect that could really make a difference in clinical outcomes is the pull-out strength and the consequent risk of screw failure. In this regard, there are uncertain and inconsistent information regarding any difference between power and manual technique.George et al.  performeAbraho et al.  registerOikonomidis et al.  carried p = 0.024). When including all patients, regardless of the follow-up length, the difference in failure rate increased and the revision rate owing to screw failure was also statistically higher in the manual group (p = 0.022). However, it needs to be underlined that constructs in the power group got a higher screw density, which could itself lead to a reduction in the mechanical complications rate and represent a possible bias of the study.Considering the wide spread of pedicle screws and of the use of power tools in other districts, it is surprising that the first retrospective study about this topic has been written by Seehausen et al.  only in Theoretically, the probe insertion leads to a compaction of the cancellous bone around the probe , 19, creWhen talking about pedicle screws placing, safety and reliability are a major concern, considering the possible catastrophic consequences that a misplaced screw may have.Allen et al.  carried p < 0.05) [In terms of accuracy, a reduced screw wobble (where wobble is defined as the deviation of the screw from its intended trajectory) has been recorded with power screw insertion by Skaggs et al.  and Maha < 0.05) . LookingIn their study comparing manual versus power-assisted screw placement on 442 cases, Seehausen et al.  found onp < 0.0001). They recorded a non-significative trend toward decreased operative times and blood loss in the FPA cohort. Most importantly, no safety differences have been recorded, with comparable misplacement rates and patterns between the two techniques. This is the most crucial aspect, especially in AIS, since pedicle screw placing may be particularly challenging due to rotation and dysplasia of the pedicles. Interestingly, the rate of anterior cortex perforation was unexpectedly lower in the FPA group (10.6 vs. 15.3%), yet without statistical significance. The strengths of this study are its prospective RCT design and the homogeneity of patients (only AIS) and of constructs . One possible confounding factor is the fact that surgeries were performed by three different surgeons.Yan et al.  designedKojima et al.  performeThe use of fluoroscopy, although it improves the confidence in pedicle screws placing, poses the spine surgeon, and only marginally the patient, to radiation-related risks –14.p < 0.001), resulting in a reduced radiological risk both for the surgeon and patients.Seehausen et al.  found thAs already stated, a recent survey  of the SIn this regard, the only study focusing on the possible role of power tools in screw placement was carried out by Skaggs et al. . They shAt our division, pedicle screws are routinely placed using power-assisted technique since more than 10 years –28. SurpFirstly, a careful identification of correct entry points should be carried on, using anatomical landmarks for each section of the spine. In the lumbar spine, the entry point is located at the junction between the pars interarticularis and the transverse process immediately lateral to the mammillary process or at the bisection of a vertical line through the facet joints and a horizontal line through the transverse process . In the After the entry points identification, the cortical bone over it is removed with a rongeur, exposing cancellous bone. This helps the surgeon to find the pedicle and prevents the drill tip from sliding medially on the hard cortex, which may result in an unwanted trajectory deviation. In the thoracic spine, we remove the inferior articular facet with an osteotome, exposing the superior articular process (SAP) which we use as a reference point for pedicle trajectory. In fact, it has been demonstrated that there is a constant angular relationship with the SAP and the pedicle axis: the line perpendicular to the SAP can act as a trajectory . TherefoFor pedicle tract preparation, the Authors use a power drill, set in ream mode, with a 2.7 mm tip, following a funnel trajectory. Some others Authors prefer to use a 2 mm bit , 23, 32 After the pedicle tract preparation, we routinely tap the tract, because it reduces the risk of misalignment of the screw with respect to its pilot hole trajectory . We use The literature specifically focusing on power-assisted screw placement is poor and does not provide strength evidence. This literature overview seemed to show that, both in clinical and preclinical studies, the power-assisted technique allows to place screws with an acceptable safety profile, even in the most challenging pedicle anatomies like in AIS. Pedicle screws accuracy seems more surgeon dependent than technique dependent. With adequate training, the power technique may speed up the screw placing and reduce the physical stress to the spine surgeon, making the screw phase more effortless and allowing to save surgeon’s focus for the next, often more critical, surgical steps. Additionally, it could reduce fluoroscopy time, lowering both surgeons’ and patient’s radiation exposure. However, these benefits may not be sufficient to make the switch from the safe and reliable manual technique. The aspect that could really make the difference in clinical outcomes is pull-out strength: unfortunately, information regarding any difference in pull-out strength between power and manual techniques is still uncertain and inconsistent. Therefore, scientific evidence is still not strong enough to guide the surgeon’s choice.