To deliver the most wide-ranging set of antimicrobial resistance (AMR) burden estimates for Croatia to date.A complex modeling approach with five broad modeling components was used to estimate the disease burden for 12 main infectious syndromes and one residual group, 23 pathogenic bacteria, and 88 bug–drug combinations. This was represented by two relevant counterfactual scenarios: deaths/disability-adjusted life years (DALYs) that are attributable to AMR considering a situation where drug-resistant infections are substituted with sensitive ones, and deaths/DALYs associated with AMR considering a scenario where people with drug-resistant infections would instead present without any infection. The 95% uncertainty intervals (UI) were based on 1000 posterior draws in each modeling step, reported at the 2.5% and 97.5% of the draws’ distribution, while out-of-sample predictive validation was pursued for all the models.Escherichia coli, Staphylococcus aureus, Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa (ordered by the number of deaths). Trimethoprim/sulfamethoxazole-resistant E coli and methicillin-resistant S. aureus were dominant pathogen-drug combinations in regard to mortality associated with and attributable to AMR, respectively.The total burden associated with AMR in Croatia was 2546 (95% UI 1558–3803) deaths and 46 958  DALYs, while the attributable burden was 614 (365–943) deaths and 11 321  DALYs. The highest number of deaths was established for bloodstream infections, followed by peritoneal and intra-abdominal infections and infections of the urinary tract. Five leading pathogenic bacterial agents were responsible for 1808 deaths associated with resistance: We showed that AMR represented a substantial public health concern in Croatia, which reflects global trends; hence, our detailed country-level findings may fast-track the implementation of multipronged strategies tailored in accordance with leading pathogens and pathogen-drug combinations. Antimicrobial resistance (AMR) belongs to the most pressing public health hazards worldwide and demands the commitment of all countries in determining priorities and framing adequate policies . The mosCroatia has been aware of the importance of this hazard for several decades. AMR surveillance in this country was inaugurated in 1996 with the establishment of the Croatian Committee for Antibiotic Resistance Surveillance at the Croatian Academy of Medical Sciences . This stHowever, previous ECDC reports focused on prevalence surveillance of resistant invasive strains  and covered only eight bacterial species that were deemed of public health significance in Europe ,9, an efNotwithstanding such an established history in resistance tracking and participation in the burden of AMR assessment, there is also an issue of whether the publication and dissemination of these results actually informed health care providers and influenced prescription patterns in Croatia. Croatia is placed among European countries that have a rather high total consumption of antimicrobial agents , which, consequently, translates to high resistance rates of many pathogenic species . In CroaAccordingly, there is a need for even better indicators of country-level AMR burden that would offer precise insights to health care professionals, the scientific community, and the general public to inform policy decisions. In this study, we aimed to present the most complete and wide-ranging country-level estimates of the bacterial AMR burden in 2019 for Croatia to date, showing the proportion of deaths and DALYs caused by antibiotic-resistant microorganisms across different infectious syndromes, and covering a comprehensive set of bacterial agents and pathogen-drug combinations with the use of two innovative counterfactual scenarios.This study used the methodological approach and robust estimation process of overall and age-specific deaths/DALYs from the global burden of AMR framework  to provihttps://ghdx.healthdata.org/record/ihme-data/global-bacterial-antimicrobial-resistance-burden-estimates-2019).More specifically, the majority of microbial data came from the SENTRY Antimicrobial Surveillance Program, Pfizer ATLAS Programme, European Antimicrobial Resistance Surveillance Network, Study for Monitoring Antimicrobial Resistance Trends, Global Antimicrobial Resistance Surveillance System by the World Health Organization (WHO), and specific country-level resistance data for tuberculosis and the Gonococcal Antimicrobial Surveillance Programme. More details on the data sources and systematic reviews that were used for the estimation process can be found in the Appendix of the article by Murray et al on the global burden of AMR , and datWe estimated the AMR disease burden for 12 main infectious syndromes and one residual group, 23 pathogenic bacteria, and 88 bug–drug combinations. Our overall approach consisted of five components: 1) mortality count where infection was implicated, 2) infectious deaths (proportion) that are attributable to a specific infectious syndrome, 3) infectious syndrome deaths (proportion) attributable to a specific pathogen, 4) pathogens that are resistant to an antimicrobial drug of interest in percentage terms, and 5) the excess death or infection duration risk associated with this resistance. These components enabled us to estimate disease burden based on two plausible counterfactual scenarios : deaths that are attributable to AMR considering an alternative scenario where drug-resistant infections are substituted with sensitive ones, and deaths that are associated with AMR considering an alternative scenario where individuals with drug-resistant infections would instead be without any infection.Across these five modeling components, there were ten broad estimation steps. Estimation steps 1-2 defined the death counts where infection was implicated by referring to the Global Burden of Disease (GBD) 2019 cause of death estimates , taking Advanced statistical techniques including the Bayesian meta-regression tool MR-BRT, a network analysis using multinomial estimation with partial and composite observations , a two-stage spatiotemporal modeling framework , and spatiotemporal Gaussian process regression were used in the process. More details on our modeling approach and major methodological innovations can be found in the AMR global burden  and the In Croatia in 2019 there were 5333 deaths (95% UI 3378–8010) associated with one of 11 infectious syndromes  as an underlying or an intermediate cause of death. Bacterial pathogens of interest  caused 4160 (2582–6237) of such deaths. The burden of associated and attributable mortality due to bacterial AMR was 2546 (1558–3803) and 614 (365–943) deaths, respectively. Among the estimated syndromes, bloodstream infections had the highest total burden with 1067 (529–1804) deaths associated with and 264 (132–460) deaths attributable to any resistant pathogen-drug combination, followed by peritoneal/intra-abdominal infections, infections of the urinary tract, and lower respiratory infections (by order of number of deaths). These four syndromes were behind more than 90% of fatal outcomes associated with and attributable to AMR in Croatia in 2019. A complete breakdown by infectious syndrome for deaths and DALYs is shown in Escherichia coli (694 [443–1017] deaths), Staphylococcus aureus (335 [198–522] deaths), Acinetobacter baumannii (288 [142–510] deaths), Klebsiella pneumoniae (281 [174–420] deaths), and Pseudomonas aeruginosa (210 [130–322] deaths)  were 59.9 (95% UI 36.7–89.5) and 28.9 (17.4–43.6) per 100 000 people, respectively, while the overall crude and age-standardized associated DALY rates were 1105.4 (659.9–1686.2) and 629.7 (369.4–971.9) per 100 000 people, respectively. The burden of AMR among children younger than 5 years of age was low, accounting for only 0.34% and 1.67% of total infectious deaths and DALYs associated with bacterial resistance, respectively. Five pathogens dominated the landscape of mortality associated with AMR:  deaths) . Each ofths each .S. aureus was the leading combination for the overall mortality attributable to AMR , while E coli resistant to trimethoprim/sulfamethoxazole (co-trimoxazole) was responsible for most deaths associated with AMR  (S. aureus and co-trimoxazole-resistant E coli were responsible for 1092 (421–2046) and 10 273  DALYs, respectively  . These tectively . When coA. baumannii, fluoroquinolone-resistant E coli, and fluoroquinolone-resistant E. faecium  were among the top pathogen-drug combinations by attributable AMR burden for each infectious syndrome. In addition to co-trimoxazole-resistant E coli, there were three more pathogen-drug combinations among the leading combinations of associated AMR burden (both deaths and DALYs) that included E coli: those resistant to aminopenicillin, beta-lactam/beta-lactamase-inhibitor (co-amoxiclav), and fluoroquinolones. Interestingly, these three specific pathogen-drug combinations had comparatively different fatal and nonfatal burdens when assessed across infectious syndromes, as the highest number of deaths (jointly) was estimated for bloodstream infections , whereas the highest number of DALYs (jointly) was estimated for peritoneal and intra-abdominal infections .In addition to these two pathogen-drug combinations, carbapenem-resistant To our knowledge, this is the most detailed study thus far that reports the burden of mortality and DALYs due to AMR for Croatia, and the first one to use two measures – burden attributable to and associated with AMR – for a wide-ranging list of pathogens and pathogen-drug combinations. We demonstrated that bacterial resistance played a considerable role in excess mortality in 2019, as more than 2500 deaths could have been fended off if all resistant infections had been substituted by no infection, whereas more than 600 lives could have been saved if all drug-resistant infections had been substituted by drug-sensitive ones. These exhaustive, country-level estimates are novel and, thus, hold immense value for progress in this field.E coli, P. aeruginosa, or A. baumannii as a result of data scarcity regarding colistin resistance , while multidrug resistance (MDR) estimation in P. aeruginosa or A. baumannii was not assessed due to our approach to MDR infections , particularly in bloodstream infections, where this pathogen-drug combination was responsible for 28 (10–61) and 109 (53–190) deaths in 2019 attributable to and associated with AMR, respectively. After 2008, MRSA rates decreased, with resistance rates falling to 12% by 2014; however, since 2015 MRSA rates started to increase again and reached 16% in 2019  may be explained by the use of the higher-valent pneumococcal vaccines, which substantially reduced the prevalence of multidrug-resistant strains, and in turn the rate of invasive pneumococcal disease  and 0.19 (0.09–0.36), respectively, and those associated with AMR were 73 (42–117) and 0.84 (0.48-1.37), respectively. However, these metrics were much higher for E. faecium resistant to fluoroquinolones, with 35 (10–68) deaths and 0.40 (0.11-0.79) ASMR attributable to AMR, as well as 191 (113–290) deaths and 2.21 (1.28-3.4) ASMR associated with AMR.Gram-negative bacteria dominated the resistance burden in Croatia; however, andscape . A recenandscape  showed aThis is another warning signal about the importance of adequately addressing fluroquinolone prescription habits in Croatia. A recent survey involving 12 urology departments in Croatia showed that fluoroquinolones were by far the most commonly prescribed class of antibiotics (accounting for 84% of prescriptions), and the authors have emphasized how the lack of uniform guidelines contributes to varying protocols, ultimately leading to a concerning escalation in antibiotic resistance .We would like to state several limitations of this study, primarily a relatively low number of microbiological data points linked to clinical outcomes; this can be viewed as a general problem that will have to be addressed by improving and expanding systematic data collection approaches . AdditioIn conclusion, we showed that the burden of AMR in Croatia was considerable, which means there is a need for a rigorous systems approach that will address the complexities and nuance surrounding AMR as a public health threat. Although Croatia is committed to meticulous resistance tracking, tireless monitoring is of utmost importance  in order to close the gap between research and policy. National data serve as the foundation for monitoring trends, evaluating interventions, and guiding decision-making to effectively address the challenges posed by AMR. Without consistent and accurate data, the pursuit of research endeavors in this critical field would be hindered. This makes it crucial for countries like Croatia to prioritize and invest in enhancing their data-collection capabilities. We believe that our estimates represent an important step toward that goal.


It is undoubtedly worth spreading the news that AI researchers can rely on the help of chemists and biotechnologists to reach the ambitious goals of building intelligent systems from scratch. This article reports the first attempt at building a Chemical Artificial Intelligence knowledge map and describes the basic intelligent functions that can be implemented through molecular and supramolecular chemistry. Chemical Artificial Intelligence provides new tools and concepts to mimic human intelligence because it shares, with biological intelligence, the same principles and materials. It enables peculiar dynamics, possibly not accessible in software and hardware domains. Moreover, the development of Chemical Artificial Intelligence will contribute to a deeper understanding of the strict link between intelligence and life, which are two of the most remarkable emergent properties shown by the Complex Systems we call biological organisms.Chemical Artificial Intelligence (CAI) is a brand-new research line that exploits molecular, supramolecular, and systems chemistry in  Humanity is experiencing a fourth technological revolution, altering how we live, work, and relate to one another . Cuttingwetware  to imitate some performances of biological intelligence—at a minimal but organizationally significant level—and promote unconventional robotics, based on molecular assemblies.A brand-new idea for mimicking intelligence (intended in the broadest sense) has been recently sparked by three factors. Firstly, the relentless miniaturisation of the transistors , has been pushed to the limit, whereby a few atoms or single molecules become the basic switching elements . SecondlThis article is the first of two papers series, which aim to present our viewpoints on the current strategies for developing CAI, its paradigms, and its scope, also called the problems domain. Our opinions about its perspectives are also expressed. This first part focuses on Molecular and Supramolecular Chemistry. The second contribution will focus on Systems Chemistry.It is undoubtedly worth spreading the news that AI researchers can rely on the help of chemists and biotechnologists to reach the ambitious goals of building intelligent systems from scratch. We expect that, in the following years, the collaboration among chemists, biotechnologists, computer scientists, mathematicians, engineers, and physicists, will boost the development of chemical AI and chemical robotics. From a technological viewpoint, CAI will contribute by providing new tools and concepts to the sciences of the artificial because it shares, with the intelligence of biological systems, the same principles and materials, enabling peculiar dynamics not accessible in software and hardware domains . Moreover, we suggest that CAI will also contribute to generating basic scientific knowledge by allowing a deeper understanding of the strict link between intelligence and life, which are two of the most astounding emergent properties shown by the Complex Systems we call biological organisms .Before presenting the strategies proposed so far to develop CAI and its domains of application, it is paramount to neatly outline its scope. First of all, the burgeoning research field of CAI must be distinguished from the already impactful and still tremendously soaring field of AI in chemistry , in whicThere is more, however. The features of CAI allow starting new investigation directions, in particular those inspired to lower and more basic, but nevertheless relevant, forms of intelligence, e.g., the one referred to uni- or pauci-cellular organisms. The biologically-inspired molecular systems of CAI are complex fluid mixtures, usually made of soft matter, likewise living cells. As it happens in living cells, the molecular elements literally transform into each other, blurring the difference between the “computer” and “computed” elements of the circuit. The result of these dynamics is a sort of computation that can be interpreted in the classical manner (input/output) or according to systemic perspectives: Indeed, these systems can display linear and circular causalities, and all perform parallel computations.x-axis reports the CAI domains that are split, for convenience, into two parts: Molecular and Supramolecular Chemistry and Systems Chemistry, respectively. The y-axis reports the CAI paradigms, which are the main components of the Human Nervous System (HNS), i.e., the Sensory System (SS), the Central Nervous System (CNS), and the Effector System (ES). We use these terms here because of their importance in human-centered descriptions of intelligence, but it is clear that functionally similar parts or modules can also be found in other organisms, down to unicellular ones. The problems CAI faces are properly distributed between the two coordinates of the graph. The SS, which includes the sensory cells catching physical and chemical stimuli, allows for collecting data. The ability to transform raw sensorial inputs into usable information is perception and requires the brain (included in the CNS). The brain also allows computing and reasoning, i.e., solving problems. Knowledge is generated by the ability to understand and represent the world. Planning is the capability of fixing goals. The ES, made of muscles and glands, allows working, communicating, and acting, which means pursuing and achieving the planned goals to maximize the expected utility. The principal results achieved in mimicking human intelligence through Molecular and Supramolecular chemistry are highlighted in this manuscript, along with their perspectives. The results and perspectives related to Systems Chemistry will be presented in the second part of this series.The behavior of molecules and how they can be employed to develop CAI depend primarily on their structure. The molecular structure is defined by specifying i) the type and number of the atomic elements that are present  ii) how the constitutive atoms are reciprocally bound , and iii) how the groups of atoms are arranged in the three-dimensional space. operties . Figure 23), the outputs are macroscopic variables that can be monitored through proper instruments, which often are spectroscopic. Every output is a function of the inputs, the molecular structure, and the features of the surrounding microscopic environment. Such chemical compounds are sensors of the molecular world , they are employed to implement quantum computing, which is alluring for its parallelism . When th0, MC1, MC2, MC3, and MC4. MC0 is obtained as soon as the C-O bond of the spiro-oxazine (SpO) is broken. It is a sort of matrix of the other conformers that are in chemical equilibrium (represented by two opposite arrows) and are obtained by mutually rotating the two-halves of the molecule. Each conformer exists as a superposition  of two or more structures that differ in how the electrons are distributed across the molecular skeleton. The features of MC conformational distribution, which are the number of conformers and their relative weights  or is embedded in micro-heterogeneous environments  can be uMany of the molecules employed to compute respond to the stimuli by changing their skeleton through relative movements of some of its molecular fragments, which can be assimilated to the movement of parts of a macroscopic machine. In this case, the molecules are also called Molecular Machines. Some of them carry out useful work within a cycle, and they are named Motors. Some others are simple switches because they go back and forth between two states . MoleculMolecular and supramolecular chemistry is clearly contributing to the development of CAI. Responsive molecules and supramolecules are valuable for mimicking basic functions of the human nervous system and any other biological system, such as sensing, computing, communicating, and working. The chemical compounds that play these roles assist and augment humans because they establish a direct link between our macroscopic world and the microscopic molecular world. Among all the possible physicochemical variables that can help to link the two worlds, the optical ones are particularly appealing . As inpu


Almost 25% of schizophrenia patients suffer from obsessive-compulsive symptoms (OCS) considered a transdiagnostic clinical continuum. The presence of symptoms pertaining to both schizophrenia and obsessive-compulsive disorder (OCD) may complicate pharmacological treatment and could contribute to lack or poor response to the therapy. Despite the clinical relevance, no reviews have been recently published on the possible neurobiological underpinnings of this comorbidity, which is still unclear. An integrative view exploring this topic should take into account the following aspects: (i) the implication for glutamate, dopamine, and serotonin neurotransmission as demonstrated by genetic findings; (ii) the growing neuroimaging evidence of the common brain regions and dysfunctional circuits involved in both diseases; (iii) the pharmacological modulation of dopaminergic, serotoninergic, and glutamatergic systems as current therapeutic strategies in schizophrenia OCS; (iv) the recent discovery of midbrain dopamine neurons and dopamine D1- and D2-like receptors as orchestrating hubs in repetitive and psychotic behaviors; (v) the contribution of N-methyl-D-aspartate receptor subunits to both psychosis and OCD neurobiology. Finally, we discuss the potential role of the postsynaptic density as a structural and functional hub for multiple molecular signaling both in schizophrenia and OCD pathophysiology. Almost 25% of schizophrenia patients suffer from obsessive-compulsive symptoms (OCS), while approximately 12% meet the diagnostic criteria for obsessive-compulsive disorder (OCD) ,4,5,6. N(1)Do schizophrenia core symptoms  share common dysfunctional brain networks with OCD relevant to dopamine–glutamate–serotonin interplay?(2)Do schizophrenia and OCD pathophysiology share some presynaptic and postsynaptic mechanisms and do genetic findings support a potential overlapping?(3)How does dopamine–glutamate–serotonin interaction support translational research to identify new therapeutic strategies?In this scenario, some challenging hypotheses have been raised, and the present review has been proposed to address a critical appraisal of the following issues:We will attempt to provide a molecular framework of OCS presentation in schizophrenia patients and possibly relevant inferences for their treatment, especially for those patients not responding to available antipsychotics.OCS have been described at different stages during the clinical trajectory of schizophrenia : (i) befThe differentiation of obsession and compulsion, the core symptomatology of OCD, from delusions and delusionally guided repetitive behaviors is decisive to define a potential subgroup of patients affected by schizophrenia and referred to as schizo-obsessive . Based oThe possible interrelationship between schizophrenia and OCD has been explored by considering, in both preclinical and clinical settings, the possibility of common genetic factors underpinning the two disorders.solute transporter family (SLC1A1) gene on chromosome 9p24, which encodes the neuronal excitatory amino acid glutamate transporter 1 (EAAC1), and susceptibility to SGA-induced OCS MDL, a selective 5-HT2A antagonist, in the polar, dorsolateral, and medial frontal cortex as well as in the parietal and temporal associative cortex of OCD patients, with a significant correlation between the availability of 5-HT2A in the OFC and dorsolateral frontal cortex and the severity of clinical symptoms. In addition, the results showed a reduction in the uptake of [11C]Raclopride, a selective D2R antagonist, in the entire striatum, particularly in the ventral portion, possibly reflecting endogenous dopaminergic overactivity [Brain abnormalities as unveiled by imaging studies may involve common regions in schizophrenia and OCD: the frontal lobe, the basal ganglia, the thalamus, and the cerebellum . Functio factors  Table 21H-MRS st factors ,67  [These observations are important as the authors suggested that the strong antagonism at serotonin receptors and simultaneous blockade action on dopaminergic receptors may constitute a key mechanism involved in the induction of OCS ,74. In t= 0.027) . Althoug= 0.027) . Of inte= 0.027) ,103, sug= 0.027) ,104.SSRIs have been found beneficial in some cases for treating OCS in schizophrenia and may be considered in augmentation with antipsychotics ,105. SomThe above-mentioned studies support the involvement of glutamatergic, dopaminergic, and serotoninergic neurotransmissions in both the occurrence and possible treatment options of OCS in schizophrenia patients. However, molecular studies on this complex interaction are still lacking. Evidence from preclinical studies may provide some key suggestions on the interplay of these three neurotransmitters in OCS overlapping schizophrenia symptoms. OCS, when part of OCD, responds selectively to SSRIs; however, despite the efficacy of SSRIs in the treatment of OCD, little and sparse evidence underlying serotonin deficit or variants of serotonergic genes in the developing of disease symptomatology is available ,128,129.Several clinical and preclinical studies focus their attention on dopamine–serotonin-glutamate neurotransmission convergence points. Intracellular molecules, as well as receptor heterodimerization, are responsible for integrating different types of signaling in response to extracellular stimuli and drugs .and postmortem studies on schizophrenia brains [2A associated with clozapine resistance in humans, exhibit a reduced capacity to form this type of heterodimers [2A is also able to constitute heterodimers with metabotropic glutamate receptor 2 (mGluR2), resulting in the potentiation of mGluR2-Gi signaling and inhibition of 5-HT2A-Gq signaling, restored by clozapine [2+ release, whereas D2R activation inhibits NMDAR neurotransmission that could be implicated in the hypoglutamatergic transmission reported in schizophrenia and in restoring cortical–striatal connectivity and synaptic plasticity, relevant for cognitive processes [The cyclic adenosine monophosphate (cAMP)-regulated phosphoprotein, 32 kDa (DARPP-32), is a common point of convergence of glutamate and dopamine neurotransmission. It is localized in the mid-spiny neurons of the striatum ,151 thata brains ,158,159;a brains ,161. It a brains ,164,165.a brains ,167. Thia brains . Dopamina brains . Biolumia brains ,171,172 a brains ,174. Introdimers . 5-HT2A lozapine . The prelozapine ,178. Finrocesses ,180.Taken together, these findings may partially emphasize the complexity of the interplay between dopamine, glutamate, and serotonin and could allow OCS to be read in the context of schizophrenia as a dysregulation of the circuits canonically involved in the disorder, with an imbalance that could be responsible for the simultaneous occurrence of both compulsive and psychotic symptoms as a psychopathological and endophenotypic continuum.The canonical hypothesis of OCS is based on the dysregulation of the CSTC loops  that conHowever, based on the assumption that in the ventral part of the prefrontal cortex (PFC) a difference between ventral and dorsal circuits exists in terms of functional meaning, new and more detailed modeling is proposed to explain the neural circuits involved in the compulsivity. In this regard, two new circuits are defined: ventral–emotional and dorsal–cognitive pathways. The two circuits have different timings of neurodevelopment, and it could be related to their function; ventromedial areas of the PFC  are involved in the control of emotional behaviors and develop relatively early, whereas lateral regions of the PFC  develop later and are implicated in executive functions .-The affective circuit, from ventromedial-PFC and ACC to the nucleus accumbens (NAc) and the thalamus, relevant for affective and reward processing.-The dorsal cognitive circuit, from the dorsolateral-PFC to the caudate nucleus and the thalamus, relevant for executive functions.-The ventral cognitive circuit, from the anterolateral OFC to the anterior part of the putamen and thalamus, relevant for motor preparation and response inhibition .Coherent with the above-mentioned evidence, Milad and Rauch  have sugOn the other hand, the change in nosographic categorization of OCD with the shift from “anxiety disorders” to “obsessive-compulsive and related disorders”  has suggGrowing evidence also points to the amygdala and limbic system activation that appears to be associated with the experience of OCS ,197,198 On the other hand, a disrupted CSTC loop is also involved in schizophrenia dysfunction, as demonstrated in a recent neuroimaging study . SeveralNetwork connectivity has contributed to explore the differential activation of ACC and OFC in schizophrenia and OCD. A recent study found that projections from the right anterior insula to the right medial OFC are reduced, whereas those between the right anterior insula and left dorsal ACC are increased in the OCD group with poor insight . On the Szechtman H. and colleagues  investigOverall, these data suggest that D2R is a key component in midbrain dopamine pathways with regard to locomotor sensitization and compulsivity , likely Other evidence suggests a hyperdopaminergic state in the ventral striatum that may be particularly relevant to OCS because of its involvement in excessive appraisal or the choice of appealing behavior . In acco1B receptor as responsible for inducing OCD-like symptoms in mice and concluding that SSRIs reduced OCD-like behavior by desensitizing these receptors [1A receptor [The observation that patients affected by OCD are responsive to SSRIs led to the assumption that the serotonin system could be involved in the neurobiological basis of the disease. Although SSRI demonstrates efficacy, there is surprisingly little evidence of a serotonin deficit as a primary causal role in OCD’s biological underpinnings . Differeeceptors . The samreceptor ,243, butreceptor . Althougreceptor . Meanwhireceptor ,145. Theselection of goal-directed behavior evaluated in a recent preclinical study in a rat model [While serotoninergic neurons of the dorsal raphe receive input from the PFC whose function is associated with motivation in a mice animal model , subcortat model . In addiat model . In contat model . Severalat model .2A receptor and mGluR2 may result in the formation of heteromeric complexes relevant to the mechanism of action of hallucinogens as well as for antipsychotics [2A/Gq11 and mGluR2/Gi/o pathways is responsible for the different effects of molecules at 5HT2A/mGluR2 that act as pro- or antipsychotic drugs [2A and nuclear factor kappa-light-chain-enhancer of activated B cells that are involved in the in regulation of histone deacetylase 2 [A structural and functional interplay between the 5HTychotics . In addiic drugs . Serotonic drugs . These tic drugs  via 5HT2tylase 2 ,253.Glutamate neurotransmission is also under reciprocal dopaminergic regulation, probably via NMDAR, considering that antagonists at these sites -5-methyl-10,11-dihydroxy-5H-dibenzocyclohepten-5,-10-imine; dizocilpine-MK-801) are responsible for increased dopamine function and metabolism ,255,256.The interplay among these neurotransmitter systems remains to be investigated and is likely to be closely related to cell types, brain regions, timing of stimulation, and phase of psychiatric disorder. From this perspective, OCS in schizophrenia could occur as an imbalance of neurotransmission or even cell typology during the disorder or the neurodevelopmental process.The synaptic interactions between dopamine and glutamate signaling can take place at several levels of the synaptic structure, including the postsynaptic density (PSD). The PSD is detectable as a dense electronic microscopy disk-shaped structure beneath the postsynaptic membrane ,261. It NMDAR represents the core of PSD, together with AMPAR and mGluR type I (mGluR 1 and mGluR 5) ; the locNo direct findings are available regarding the above-mentioned proteins for the neurobiological basis of OCD except for SAPAP3, a PSD protein, that could represent a possible mechanism shared by OCD and schizophrenia ,283,284 The SAPAP family includes four postsynaptic scaffold proteins, resulting from different splicing, that are highly concentrated at the PSD and relevant for maintaining the structure and functioning of synapsis  Figure . Due to The SAPAP family is a group of proteins characterized by direct interaction with PSD-95 (via the GK domain)  and ShanDuring the postnatal period, the SAPAP isoforms are expressed differently in the neurodevelopmental process. The spatiotemporal expression pattern of the isoform SAPAP3 is characterized by a peak expression observed around 2–3 weeks after birth in the cortex, striatum, and thalamus ,300. ThiSAPAP3 is also involved in monoaminergic system modulation. SAPAP3 KO mice exhibit an upregulation of the serotonin metabolite 5-hydroxyindoleacetic acid and the 5-hydroxyindoleacetic acid/serotonin ratio in all cortical and striatal regions  and respEmerging evidence points to neuromodulation techniques, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), as promising methods for the treatment of both schizophrenia and OCD ,313,314.The rTMS and tDCS, each with its own specificities, are both techniques that are well tolerated and relatively feasible even in complex patients. The contraindications are few, , and there is evidence of safety in all age groups, with specific safety guidelines being available ,316. Eve(a) the impact of both techniques of neuromodulation on multiple neurotransmitter systems, including serotonin, dopamine, and glutamate, in preclinical modeling ,318; (b)Evidence has accumulated on the possible efficacy of brain stimulation techniques both for positive and negative symptoms of schizophrenia, as well as for the potential improvement of neurocognition. Regarding positive symptoms, the effectiveness of inhibitory stimulation—cathodal tDCS and low-frequency repetitive rTMS (LF-rTMS)—has been demonstrated for the treatment of auditory hallucinations, using as a target the left temporo-parietal junction, a brain area that results in hyperactivity during auditory hallucinations ,323. Reg2-mGluR [2A, and D2R, as demonstrated by multiple in vitro techniques, in particular fluorescence resonance energy transfer [The co-occurrence of OCS in schizophrenia is not a rare condition, making even more complex both the behavioral manifestations and the outcome of schizophrenia, as well as contributing to the TRS condition, characterized by a severe clinical complication affecting cognition and functioning . Therefo2-mGluR , 5HT2A, transfer . Finallytransfer , especiatransfer ,266,335.Despite the findings on dopamine–glutamate–serotonin interplay in schizophrenia and OCD, the conceptualization of its prominent role has unveiled several limitations that should be acknowledged. First, beyond the three major neurotransmitters here addressed and their reciprocal interactions, the proposed framework is a reductionism by itself. Other neurotransmitters, such as norepinephrine , GABA 3, opioidsThe presence of OCS in schizophrenia is a relevant clinical challenge whose neurobiological underpinnings remain for the most part obscure; however, findings from genetics, imaging, and preclinical modeling are emerging. The interaction between dopamine, serotonin, and glutamate may represent a possible molecular scalpel to better identify the molecular pathophysiology and putative strategies of this complex clinical condition. Nevertheless, the involvement and fine tuning of synaptic proteins especially at the glutamatergic dendritic spine may represent a novel possibility to explore the biological basis of this clinical manifestation and must be considered for further investigation.


Self-assembly of particle-like dissipative solitons, in the presence of mutual interactions, emphasizes the vibrant concept of soliton molecules in varieties of laser resonators. Controllable manipulation of the molecular patterns, held by the degrees of freedom of internal motions, still remains challenging to explore more efficient and subtle tailoring approaches for the increasing demands. Here, we report a new phase-tailored quaternary encoding format based on the controllable internal assembly of dissipative soliton molecules. Artificial manipulation of the energy exchange of soliton-molecular elements stimulates the deterministic harnessing of the assemblies of internal dynamics. Self-assembled soliton molecules are tailored into four phase-defined regimes, thus constituting the phase-tailored quaternary encoding format. Such phase-tailored streams are endowed with great robustness and are resistant to significant timing jitter. All these results experimentally demonstrate the programmable phase tailoring and exemplify the application of the phase-tailored quaternary encoding, prospectively promoting high-capacity all-optical storage. Here the elementary pulse entity, termed ‘dissipative solitons’ in contrast to the ‘pure solitons’ formed in conservative systems, originates from the dual interplays between the dispersion/nonlinearity and gain/loss9. Intriguingly, these ultrashort soliton entities can behave like particles and self-assemble into bound states of complex structures, endowed by the balanced interaction forces13. The parallel concept of ‘matter molecules’ is transferred into the multisoliton complexes, and many unveiled internal motions emphasize this light-matter analogy, which spreads the profound concept of dissipative soliton molecules (DSMs)14. Considering the increased complexity beyond the single entity, soliton molecules display more plentiful internal dynamics in the presence of energy exchange between each constituent, as well as would allow enhanced coding of optical-soliton bits19. Recent use of time-stretch dispersive Fourier transform (TS-DFT) based real-time spectral interferometry enables long-lasting studies on the transient multisoliton dynamics19. The degrees of freedom of molecular internal motions are anticipated by resolving the temporal separations and relative phases, in response to how far the molecular analogy reaches26. For applied stimuli, dynamic soliton molecules can support high-order encoding formats of all-optical information processing beyond the pulse-counting formats. This foresight of alternative encoding scheme is held by the precise switching between each bound state, arousing one striking question of programmable generation and control of molecular dynamics27.Streams of ultrashort light pulses delivered from mode-locked laser resonators stimulate potential applications in ultrafast science and information technology28. Soliton constituents can be globally ordered and locally spaced to form a supramolecular structure by tailoring long-range soliton interactions of different origins10. This panoramic scenario allows for the assemblies of soliton–soliton, soliton–molecule or molecule–molecule under controllable intra-molecular dynamics, with respect to the time scales ranging from tens of picoseconds to hundreds of picoseconds. While staring at the solitonic bound states down to several picoseconds even sub-picoseconds, precise manipulation of intra-molecular dynamics emerges into the scientific spotlight, echoing the degrees of freedom towards temporal separations and relative phases29. In consideration of the energy exchange within molecular structures, direct pump modulation is exploited to harness the multisoliton interactions for a rapid switching between discrete binding states, principally referring to the temporal separations30. Recent parallel work further performs on-demand harnessing of soliton molecules between each predetermined value of the temporal separation by varying the second-order group-velocity dispersion and dispersion losses32. Quaternary encoding and switching of soliton molecules are proposed beyond the binary format. These temporal-separation-switched intra-molecular manipulations would make these ‘potential applications’ realizable, as well as appealing to explore subtler assembly and control of soliton molecules, fueled by the degrees of freedom of internal dynamics, especially applicable to multiple encoding formats for all-optical storages.Temporal optomechanical lattice induced trapping potentials enable an all-optical assembly of large soliton sequences in a photonics crystal fiber-based fiber laser resonator39. Intrinsic insights into the mutual interactions reveal the scenarios of energy exchange within the binding structures, which emphasizes the inevitable routes for controlling the assembly of molecular patterns. Viewed from the real-time spectral interferometry, which is regarded as the ‘eyes’ in controllable laser systems, the fringe pattern is modified by external perturbations, generally indicating the beginnings of temporal-separation variations, synthesis and dissociation processes40. With regard to the superiority of the dynamic indicator and the applied foresights, the programmable tailoring of molecular phases is expected to be fuel debate; however, it is barely experimentally achievable for laser resonators. In this paper, we pursue a new quaternary encoding format based on the programmable tailoring of the internal dynamics of DSMs. Controllable manipulation on the energy exchange enables deterministic harnessing of soliton assemblies, accordingly developing four phase-defined regimes. By implementing electronic modulation of the gain supply, continuous switching among these regimes is realized, validating the reversibility and high fidelity of the programmable tailoring. In addition, the recorded real-time streams exemplify the availability of this phase-tailored encoding, which is highly desirable for multiple encoding and switching.The on-going discovery of internal molecular dynamics, via using the advanced spectral observations, in essence, can enrich the manipulation mechanism of soliton molecules14. Versatile internal motions are governed by the energy exchange between two adjacent constituents, which is important for phase-dominated soliton dynamics11. A real-time monitoring module is utilized to identify these particle-like behaviors by retrieving the temporal distributions and internal motions. Such particle-like behaviors can be harnessed by the tunable intracavity gain supply. High-speed electronic modulation of the gain supply is introduced to stimulate the artificial manipulation on the temporal assembly and internal assembly of DSMs   Fig. .Fig. 2PhφNP, φSP, φPP) indicate the different pulse intensity relations between the two constituents   Fig. . In partSequentially, programmable electronic modulations of the gain supply are implemented to harness the phase-tailored assemblies of the DSMs. These internal phase dynamics are mainly affected by the gain dynamics, pulse intensity relations and energy exchanges between the two adjacent constituents Fig. . To illu5,31. Programmable tailoring of the molecular phase is implemented for multiple encoding. Beyond the pulse-counting-based binary encoding , including a 100-μs for valid data and another 100-μs for the hysteresis process Fig. . The speTo verify the availability of this phase-tailored quaternary encoding, an exemplary ‘fiber’ is encoded into real-time streams and decoded by retrieving the molecular phase Fig. . In eachg0 actuate the deterministic harnessing of the molecular phase of DSMs. The simulation results reveal the exact relations between the phase evolutions and the pulse intensities. In practice, the exemplary string {f|i|b|e|r} is presented to experimentally validate the availability of this phase-tailored quaternary encoding.The controllable manipulation of the molecular patterns still remains challenging to explore more efficient and subtle tailoring approaches for satisfying the increasing demands. Apart from the temporal-separation-based harnessing of the molecular patterns, the molecular phase of DSMs is also expected to be harnessed. Recent studies of transient soliton dynamics provide strong supports for guiding the artificial manipulation on the molecular phase. Here, inspired by advanced applications of ultrafast optics in all-optical storage and optical computations, we develop an ultrafast laser-based manipulation system for the programmable tailoring of the molecular phase by implementing precise electronic modulations of the gain supply. The energy exchange within the molecular structures is manipulated to stimulate the deterministic harnessing of the phase-tailored soliton assemblies. Self-assembled soliton molecules are tailored into four phase-defined regimes, thus constituting the phase-tailored quaternary encoding format. Numerical simulations of the switching among different phase-defined regimes are conducted to confirm and interpret the physical mechanism of the programmable phase tailoring  and the accurate identification of the encoded formats. In particular, this direct electronic modulation can be improved by upgrading the electronic modulation signals to avoid the common recoil voltage and unstable voltage. The well-set voltages for these four phase-defined regimes can optimize the hysteresis of the continuous switching and the fidelity of the phase-tailored encoding. For increasing the speed of the quaternary encoding, faster phase-evolving velocities of the NP and PP regimes can be taken into account. Thus, we believe that the electronic modulation of the gain supply is considered as a direct and efficient way to realize the programmable tailoring of the molecular phase of the DSMs, and desirable for the applications in practical occasions.41, the extended temporal-phase evolutions may accommodate more information for high-capacity all-optical storage. Naturally, the released degrees of freedom of the on-demand harnessing will bring about significant challenges for both the ‘eyes’ of the real-time characterization and the ‘hands’ of the precise manipulation. We consider two major avenues for the future investigations. One is to introduce the joint temporal-spectral analysis of the time-stretch dispersive Fourier transform and the time-lens measurements. The real-time full-field characterization can provide new insights into the internal motions, especially for the complex molecular patterns. ‘Hands’ can help control the laser parameters such as the gain, dissipation, dispersion, nonlinearity and polarization to drive the artificial manipulation. The released degrees of freedom of harnessing and the technical advances are expected to fuel this research topic and extend the application scenarios in the near future.For the moment, the topic of on-demand harnessing is currently driving considerable attentions. Based on the research thought that the transient dynamics guide the artificial manipulation on DSMs, we expect the lasting investigations by releasing the harnessing degrees of freedom. Particularly, more internal motions can be anticipated for enabling the artificial manipulation. The phase-evolving velocity can be quantified to encode information beyond the four phase-defined regimes. Moreover, the programmable tailoring of the temporal assemblies and the internal assemblies of DSMs allows for the higher-order encoding formats. While considering the molecular patterns with increased number of solitons such as the tri-soliton assembly and the quartic-soliton assemblyβ2 = +0.061 ps2 m−1, EDF 80, OFS) as the gain medium and a 2.9-m single-mode fiber . The cavity repetition rate of the fiber laser resonator is about 54.86 MHz. The NPR based mode-locking module is composed of a polarizer and two polarization controllers (PCs). The ultrafast fiber laser resonator with near-zero dispersion provides an abundant platform for investigating the phase-tailored soliton assemblies and the quaternary encoding.We investigate the programmable tailoring of the molecular phase of DSMs, which are generated from the ultrafast fiber laser resonator. The pump energy is programmed by implementing electronic modulations of a 980-nm semiconductor laser diode and is then injected into the laser resonator through a hybrid module, which is integrated by a wavelength division multiplexer (WDM), a 10:90 output optical coupler (OC) and an isolator (ISO). The emitted optical pulses are extracted from the 10% output port. The total length of laser resonator is 3.7 m, including a 0.8-m erbium-doped fiber  is used as a dispersive medium with a total dispersion of −220 ps2 for the time-stretch process. For soliton pairs with a temporal separation τ, the spectral modulation period 1/τ of the optical spectrum is mapped into the time domain and stretched to −1, Teledyne LeCroy) are utilized to detect the successive spectral evolution of DSMs. And an optical spectral analyzer  is used to monitor the optical spectrum for comparison. The first-order autocorrelation traces are calculated from the successive spectral interferograms by performing fast Fourier transform. The separation information and phase information (imaginary part) are extracted from the peaks of the first-order autocorrelation traces. However, the extracted phase information is in the range of  and cannot represent the real internal phase evolution. The phase unwrapping is introduced to make the extracted phase information continuous by adding 2kπ. If the variation of two phases is over π rad, it is regarded as phase jump. The retrieved molecular phase should be consistent with the evolution of the spectral fringes in successive spectra interferograms. In particular, phase ambiguity is also important in the phase retrieval, especially during the switching between different soliton assemblies. The assembly and dissociation of soliton assemblies follow very complex dynamics and are represented by the rapid spectral evolution and unstable temporal separation, consequently resulting in the phase ambiguity10. Recent study has reported on machine learning strategies to reconstruct the multisoliton dynamics without the phase ambiguity, which have potential applications in ultrafast science18.A 10-km SMF (−1. Appropriate voltages related to the four phase-defined regimes are set to realize the high fidelity of the phase-tailored encoding. The direct electronic modulation can be upgraded to avoid the uncontrollable fluctuations of the gain supply, which is commonly induced by the recoil voltage and unstable voltage. Relying on the ASCII-based phase-tailored alphabet, arbitrary encoding can be realized by implementing the precise electronic modulation of the gain supply.An AFG with a modulation bandwidth of 25 MHz is utilized to generate the electronic modulation signals. The emitted pump power is modulated by the electronic signal with a transfer efficiency of 52 mW Vz, T, β2, γ are the propagation coordinate, pulse duration, second-order dispersion parameter and nonlinear parameter, respectively; Ωg is the gain bandwidth; g is the gain coefficient, modeled by g0 is the small signal gain that is non-zero only for the EDF; Psat is the gain saturation power; Pave is the averaged power of pulses.To confirm and better interpret the mechanism of the phase-tailored soliton assemblies, numerical simulations are executed through a piecewise pulse propagation model in the scalar approach, which takes into account the different segments in the fiber laser resonator. The propagation model follows the extended nonlinear Schrödinger equation:a0, I, Isat, ans are the modulation depth, input intensity, saturation intensity and non-saturable absorbance, respectively. We emulate the experimental situation by adjusting the parameters of the fiber laser resonator. The internal phase evolution is retrieved from the successive spectral evolution.The saturable absorber in the fiber laser resonator is modeled by a transmission function: Supplementary Information


The study of fermentation and brewing has a long history of pioneering discoveries that continue to influence modern industrial food production. Since then, numerous research endeavors have yielded conventional criteria that guide contemporary brewing practices. However, the intricate open challenges faced today necessitate a more exhaustive understanding of the process at the molecular scale. We have developed an ultra-high-resolution mass spectrometric analysis (FT-ICR-MS) of the brewing process that can rapidly and comprehensively resolve thousands of molecules. This approach allows us to track molecular fluctuation during brewing at the level of chemical compositions. Employing biological triplicates, our investigation of two brewing lines that are otherwise identical except for the malt used revealed over 8,000 molecular descriptors of the brewing process. Metabolite imprints of both the similarities and differences arising from deviating malting temperatures were visualized. Additionally, we translated traditional brewing attributes such as the EBC-value, free amino nitrogen, pH-value, and concentration curves of specific molecules, into highly correlative molecular patterns consisting of hundreds of metabolites. These in-depth molecular imprints provide a better understanding of the molecular circumstances leading to various changes throughout the brewing process. Such chemical maps go beyond the observation of traditional brewing attributes and are of great significance in the investigation strategies of current open challenges in brewing research. The molecular base of knowledge, along with advancements in technological and data integration schemes, can facilitate the efficient monitoring of brewing and other productions processes. FermentSince then, our understanding of the brewing process has improved significantly. Sophisticated brewing attributes that describe and guide the process have been established and standardized , 8. HoweParallel to the evolution of brewing, new techniques and methodologies have been established in the field of analytical chemistry. Targeted univariate measurements are complemented by non-targeted approaches, which promise to reveal a large part of the molecular world of beer and make it accessible through rapid profiling measurements . ParticuContrary to mentioned studies, the focus of the presented research is not on the bottled beer but on the entire brewing process from the grain to the finished beer. With the help of ultrahigh-resolution analytics, we aim to make the molecular diversity and complexity of the brewing process visible and establish deep chemical imprints for the decisive process steps. In addition, multivariate statistics  will be used to correlate the relationship of classical brewing attributes with molecular profiles comprising hundreds of metabolites. A molecular base of knowledge will be unveiled through a defined and reproducible experimental design. The investigations will focus on two brewing series that differ solely in the kilning temperature applied to the same barley, while maintaining uniform conditions for all other aspects of the brewhouse process. This approach enables the evaluation of the impact of Maillard reaction during kilning on the overall molecular composition of subsequent stages of the brewing process. Moreover, it provides a means to characterize the inherent molecular processes that remain consistent during brewing, independent of the influence of the Maillard reaction. We aim to demonstrate the potential of ultrahigh-resolution mass spectrometry to address the convoluted questions in brewing research and facilitate efficient monitoring and control of the brewing process in the future.2.2.1.Hordeum vulgare L. variety Accordine in biological triplicates of 25 liter for each sample series. One set of triplicates was carried out with Pilsner malt (indicated by a _P suffix) and the other with Munich malt (indicated by a _M suffix). A graphical overview of the experimental brewing process and sampling points—resulting in three biological replicates of samples 0 to F_P and 0 to F_M, respectively—is given in Humulus lupulus L. pellets variety Tradition (6.6% α-acids) was added. Fermentation was carried out for about 20 days at 12°C using SafLager™ TUM 34/70 Saccharomyces pastorianus dry yeast, resulting in an ethanol concentration by volume of 4.8–4.9 (M), and 4.7–4.9 (P), and an apparent degree of fermentation of 78.3–79.5% (M), and 82.9–83.5% (P), respectively. Maturation was considered complete at a diacetyl  content of less than 0.1 mg/L, and the beers with EBC values of 14.8–15.9 (M), and 5.9–6.3 (P) were subsequently bottled.The beers were brewed with 2.2.The content of amino acids (LS-HPLC001 2018–07), free amino nitrogen   or after (I) the respective process step in both brewing lines, hundreds of characteristic metabolite signals were found to be specific. Nonetheless, it should be noted that as an intrinsic tenet of instrumental analytics, the absence of a molecule signal merely signifies a concentration lower than what is detectable. The presence of 1,195 degraded compositions and 1,596 newly formed compositions within the metabolic mass range substantiate the assertion made by unsupervised statistics, highlighting the central role of germination as the most critical step in chemical transformation.Germination induces the release and activation of lipases . This ul22H32O5] . During 22H32O5] . While te traced , the ince traced . An intee traced , 30. In In the initial stage of drying, both growth and enzymatic reactions continue similarly to germination. When the enzyme activity is either deactivated due to low water content or inhibited by high temperatures, the reactions of amino components and carbonyls predominate, indicating the occurrence of the Maillard reaction. Both phases are reflected in the molecular signature of kilning, encompassing hundreds of compounds. The degradation of lipids progresses, with nitrogen-containing lipids, such as amino acid conjugates or others, being significantly involved . The res20H40O7], [C22H40-44O6-8]. Accordingly, the release of phosphatidylcholines/−ethanolamines [C27H44-54NO9-12P] and glycerophospholipids [C19H39O7P], [C21H39-43O7P], [C24H45-47O7-9P] is observed cohumulone [C20H28O5], (iso)lupulone [C26H38O4], and (iso)colupulone [C25H36O4] by orders of magnitude. Particularly, highly oxygenated compounds such as [C20H28O7], [C21H30O7], [C25H36O8], or [C26H38O8] contribute to a total of over 250 derivatives of hop bitter acids  and ending with the finished beer (Sample F_M), is visualized in 3.3.Using OPLS, molecular signatures correlating with traditional brewing attributes given in The intrinsic nature of molecular profiling is that beyond mere correlations, causality is not necessarily explained. However, the OPLS model of the TBI  and EBC-4.In conclusion, the application of FT-ICR-MS analysis in studying the brewing process using Munich and Pilsner malt, derived from the same raw barley, has provided valuable insights into the molecular complexity and diversity inherent in brewing with specific reproducible brewhouse conditions. By systematically sampling key stages from raw barley to finished beer, we were able to annotate over 8,000 molecular compositions, tentatively categorizing them into their respective compound classes. All signals were obtained simultaneously in a 10-min measurement. Our statistical evaluation of the chemical mapping of beer unveiled metabolite signatures, including hundreds of compositions, that reflect significant compositional changes occurring during brewing.The comprehensive molecular analysis revealed a wealth of information regarding the molecular evolution of brewing on the compositional level, offering a multi-dimensional perspective that complements traditional brewing attributes. This expansive molecular imprint, particularly evident in the Maillard reaction products, underscores the chemical complexity that can be unraveled through holistic high-resolution analytical techniques. Moreover, distinct compositional spaces observed allowed us to differentiate between the Pilsner and Munich brewing approaches on a comprehensive molecular scale.By augmenting well-established brewing attributes, the FT-ICR-MS analysis contributes to the broader understanding of the brewing process and open research challenges. It emphasizes the importance of comprehending the molecular circumstances that underlie the diverse changes encountered throughout the brewing process.The aspiration is to extend the test series to encompass beers with additional variations in raw materials or process parameters. Complementary proteomics approaches promise insights into the intricate network of enzymatic reactions involved in brewing. Aroma compound analysis, covering the smallest and volatile molecular fraction, and sensorics could complement a future integrated -omics framework, as well as structure elucidation by Tandem-mass spectrometry or NMR. As technology continues to advance and data integration schemes improve, it is conceivable that comprehensive molecular data will emerge as a fundamental tool for efficient monitoring and guiding of the brewing and other production processes in the future.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.SP, MZ, FA, and PS-K contributed to conception, design, and administration of the study. MZ, FA, and SP organized and conducted the brewing experiments. SP and PS-K designed the methodology of data analysis. SP performed the measurements, data processing, statistical analysis, and data visualization. PS-K, MR, MZ, and MG provided the infrastructure for measurements, data processing, and experimental brewing. SP wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Key Concepts identified from across the CE4AMR portfolio as integral to tackling AMR. We suggest it be used to guide future interventions aimed at addressing AMR via social, participatory, and behavior-change approaches.Antimicrobial resistance (AMR) is a social and biological problem. Although resistance to antimicrobials is a natural phenomenon, many human behaviors are increasing the pressure on microbes to develop resistance which is resulting in many commonly used treatments becoming ineffective. These behaviors include unregulated use of antimicrobial medicines, pesticides and agricultural chemicals, the disposal of heavy metals and other pollutants into the environment, and human-induced climatic change. Addressing AMR thus calls for changes in the behaviors which drive resistance. Community engagement for antimicrobial resistance (CE4AMR) is an international and interdisciplinary network focused on tackling behavioural drivers of AMR at community level. Since 2019 this network has worked within Low-Middle Income Countries (LMICs), predominantly within Southeast Asia, to tackle behavioral drivers of AMR can be mitigated through bottom-up solutions championed by local people. This commentary presents seven  Drug reThe most discussed driver of AMR is repeated human exposure to antimicrobial medicines . This isMany, if not all, drivers of AMR have a behavioural component. Thus, a growing number of research projects have begun to tackle AMR from a social perspective –15. AntiThe growing number of projects, collaborations, and networks exemplifies the importance and complexities of tackling AMR from behavioural and social science perspectives. Their outputs emphasize the imperative to develop equitable partnerships with whole communities, including gatekeepers, and wider stakeholders to address good stewardship around antimicrobials. When attempting to tackle the behavioural drivers of AMR, projects must engage the community within which they are working to support the development of context specific solutions. Messages and modes of communication must be bespoke and meaningful to the people the project wishes to work with, because behavioural changes can only be actioned by the people engaging in the behaviour.The CE4AMR network focuses on CE approaches to address AMR and has previously published methodological articles regarding what constitutes CE, and how CE can be equitably developed to address AMR , 22. TheAll projects are based in LMICs, with in-country co-investigators and research partners designed to maintain long-term connections with community members, wider stakeholders, gatekeepers, and policy makers. This extensive engagement with Nepal and Bangladesh  has allowed CE4AMR team to unpick many of the complexities around communicating on AMR at community level and influencing meaningful behavioural change and actions , 27, 28.This is the first point within many of the CE4AMR behavioural interventions. For communities to connect with the nuances of AMR an essential element within projects is to promote discussion about the often-novel concept of microscopic organisms (microbes) which cause illnesses. This allows reflections that many different microbes cause different illnesses, and that each different microbe will need a different treatment. The understanding of microbes as tiny living things also helps communities understand that microbes can move around in human and animal bodies and faeces, and in the soil and water. In some interventions, CE4AMR discusses ‘good’ microbes that help digest food, as this point helps clarify that taking antimicrobials when one is not sick could be harmful by killing off ‘good’ microbes.antimicrobials save lives’ may not always be contextually appropriate in communities where the timing and cause of death is considered predetermined by a higher power. Rather, CE4AMR emphasises that, when used properly, antimicrobials increase the quality of human and animal lives by maintaining health and productivity. The discussion can then move to how misusing antimicrobials can mean they do not work as effectively. This learning can be contextualised by exemplifying  that there are many different types of illness and many types of medicines, including antimicrobials.The life-saving value of antimicrobial medicines is always emphasized within CE4AMR interventions. This is to prevent harm resulting from assumptions that to prevent AMR one should simply stop using antimicrobials. However, community members have reflected that saying ‘In all interventions the CE4AMR team stresses that communities should seek advice from a healthcare or veterinary professional to understand which medicine they or their animal should use and how. Doing so will mean that the appropriate medicine  is used, and that the infection is fully treated. This is a challenging concept for many reasons. For example, in rural areas access to healthcare centres can be limited or geographically difficult, thus informal drug sellers and traditional healers are regularly consulted. In CE4AMR projects, this point often leads to discussion of finances because many communities believe that the antimicrobials available freely at their local level health facilities, such as health posts in Nepal, are less effective than more expensive options purchased for instance from pharmacies and drug-sellers. Affirming the expertise of health professionals, including vets, is an important message which can challenge this belief and increase engagement with accessible health services for humans and animals. Storytelling is a useful tool to exemplify this point by showing successful health outcomes of visiting government health facilities. That said, this is a point at which community engagement requires support from policy makers to strengthen infrastructure and allow intended behaviours to become actionable. One particular CE4AMR project used video making to share challenges around AMR behaviours with policy makers and highlight the reasons AMR-minimising behaviours are and cannot always be actioned .Point three is emphasized by discussing what could happen if antimicrobials are misused, for example via incorrect drug-bug matching or the taking of an incomplete dosage in humans and animals. In livestock and domesticated animals, antimicrobials are often misused to promote growth or prevent future disease (prophylaxis). In CE4AMR interventions, the discussion continues that if an incorrect antimicrobial medicine is taken to treat sick animals or humans, it may not kill the infection. Instead, this misuse can cause the infecting microbe to find ways to change to avoid the medicine, potentially leading to AMR. Similarly, if humans and animals do not complete a full course of antimicrobial treatment, the infecting microbe can survive. Indeed, a key driver of AMR is repeated exposure to low and incomplete doses of antimicrobials. CE4AMR finds that this message is well-received with regards to human, particularly child, health but can be more difficult in terms of animal health. This is primarily because veterinary professionals may not travel to rural areas, so there may be no other option but to buy antimicrobials without consultation .One of the most important points to communicate is that AMR happens to microbes, not to people or animals. This instils a greater sense of collective responsibility for addressing AMR. For example, individuals do not just need to be thinking about their own health-related behaviours, but also that of others. In terms of the COSTAR community dialogues, which aim to generate collective action and community driven solutions to AMR, this point is crucial.our environment to think about the local surroundings and impacts of AMR. An interactive community mapping exercise often helps people take a holistic view of how closely linked they, their families and animals are to their environment are, and crucially how they have the power to manage and reduce risks of cross contamination within this environment. Again, this can lead to collective action and meaningful local solutions.The concept of AMR happening to microbes helps people understand how AMR spreads. Activities can exemplify living microbes inside people, animals, water, and soil. This is important as it helps conceptualise the idea that microbes move around the environment, and that resistant microbes can also move. This can be difficult to understand without first thinking about microbes as living entities. The cycle diagram Fig.  is oftenAdditionally, because antimicrobial medicines do not fully break down in human and animal bodies, they can pass out in waste and food products , and can remain in meat products. This is important to explore with communities and CE4AMR often uses a second cycle diagram Fig.  to demonclean-cook stove to minimise emissions that contribute to global warming.AMR is likened to other global challenges including the climate crisis  and wateuse antimicrobial medicines carefully to keep them working. If you use them too often and without a diagnosis, they may stop working and this means your illness would be harder to treat and could be more expensive. This is an extremely detailed message with several points that need to be communicated before the conclusion can be realized. For this reason, whilst CE4AMR acknowledges interlinkages between AMR and wider global health challenges the nuances of AMR do require a bespoke approach to CE. CE4AMR projects use locally appropriate storytelling mechanisms within all their interventions because storytelling allows relatable narratives to be developed around AMR.Messaging about cause and consequence in these contexts also tends to be linear: for example, washing hands with soap and water will ensure the removal of harmful microbes from the skin and prevent infection. However, when dealing with AMR, messages tend to be more complex. For example: Key Concepts and suggestions of how to apply them via CE, it is hoped CE4AMR’s storytelling approach may support other interventions that address AMR from a community, behavioural and social science perspective.CE4AMR projects are ongoing, and the network continues to learn and adapt its approaches to tackle AMR at community level. AMR is a dense biological and social problem which requires diverse and interdisciplinary action if it is to be addressed properly at all levels of society. The community level is an appropriate space to deliver behavior-change interventions on AMR but the range of information to be communicated can be overwhelming. By sharing these seven


In this study, Yb2O3 belonging to the lanthanide oxide family was produced as nanofiber forms by using the electrospinning technique, which allows for large-scale production, for the first time. The morphological, structural, optical, and phase properties of the produced nanofibers were investigated via XRD, SEM-Mapping, TEM, FTIR, UV-Vis, and XPS characterization techniques. As a result of these analyses, it was determined that the Yb2O3 nanofibers with a diameter of 125 ± 15 nm have a cubic crystal structure and a bandgap of 3.32 eV. The results of this study have shown that the Yb2O3 nanofibers are capable of performing performance evaluations in many different energy conversion applications and others.Metal oxide nanomaterials are widely used in many applications of renewable energy. Ytterbium oxide (Yb The m eEg) plot  obtainedEg) plot . The m vion type , 32.hυ is photon energy, A is energy-independent constant, Eg is optical band gap and m is exponent a value that determines bandgap types.where ∞)hυ)2 vs photon energy given in The optical band-gap of nanofibers was estimated as 3.32 eV by fitting the linear part of the graph of (F(R2O3 nanofibers. FTIR results of crystalized nanofiber, polymer composite, and PAN are given comparatively in −1 are matched to the bond vibration of organic molecules belonging to PAN. The bands at 2935, 2245, and 1448 cm−1 were attributed to stretching of the C-H of the CH2, the C≡N of the acrylonitrile group, and the C=O of the carbonyl group, respectively. The peak centered at 1448 cm−1 occurred from CH2 tensile vibration, while the peak at 1360 cm−1 was ascribed to the C-H stretching of aliphatic CH groups. Furthermore, the C-H and C-O bond vibrations were observed at 1242 and 1072 cm−1, respectively [−1 which is seen in the FTIR result of Yb2O3 nanofibers was assigned to bond vibration between Yb with O atoms.FTIR spectroscopy was carried out to determine the presence of organic molecules in crystalized Ybectively , 34. Aft2O3 nanofibers were fabricated by the electrospinning technique and presented to the literature for the first time with this study. The produced nanofibers were characterized by various methods such as XRD, SEM, TEM, elemental mapping, EDX, XPS, UV-Vis spectroscopy, and FTIR. As a result of the analyses, it was seen that the nanofibers consist of nanoparticles with 9 ± 2 nm, which have a pure and cubic crystal structure. Moreover, the chemical composition of the nanofibers was calculated as Yb2.19O2.81 by EDX. It was determined with optical measurements and calculations that the nanofibers have a direct band transition type and a band-gap value of 3.32 eV. The obtained characterization results show that the high crystalline Yb2O3 nanofibers can be used in many energy applications such as solar cells, hydrogen production, oxygen evolution-reduction reactions, and fuel cells. Moreover, it is predicted that produced nanofibers may contribute to an increase in application efficiencies because they have a larger contact surface area than other nanomaterials with different morphology used in these applications.Highly crystalline, pure, and homogeneous YbThe percent crystallinity of nanofibers was calculated from the XRD pattern using the following equation.c is the degree of crystallinity, Ac and Aa are the areas of crystalline and amorphous peaks in the XRD pattern, respectively.where XFigure S1.2O3 porous nanofibers.Modified Sherrer method graph of YbFigure S2.2O3 porous nanofibers.Williamson–Hall method graph of YbFigure S3.3+PAN composite nanofibers.Diameter size distribution graph of YbAcFigure S4.2O3 nanofibers.Diameter size distribution graph of Yb