Daphnia. Here, we tested whether this translates into fitness costs in terms of lower starvation resistance in offspring. We exposed Daphnia magna mothers to aqueous dopamine (2.3 or 0 mg/L for the control) at two food levels (ad libitum vs. 30% ad libitum) and recorded a range of maternal life history traits. The longevity of their offspring was then quantified in the absence of food. In both control and dopamine treatments, mothers that experienced restricted food ration had lower somatic growth rates and higher age at maturation. Maternal food restriction also resulted in production of larger offspring that had a superior starvation resistance compared to ad libitum groups. However, although dopamine exposed mothers produced smaller offspring than controls at restricted food ration, these smaller offspring survived longer under starvation. Hence, maternal dopamine exposure provided an improved offspring starvation resistance. We discuss the relative importance of proximate and ultimate causes for why D. magna may not evolve toward higher endogenous dopamine levels despite the fitness benefits this appears to have.The neurotransmitter dopamine has been shown to play an important role in modulating behavioral, morphological, and life history responses to food abundance. However, costs of expressing high dopamine levels remain poorly studied and are essential for understanding the evolution of the dopamine system. Negative maternal effects on offspring size from enhanced maternal dopamine levels have previously been documented in  Costs of expressing high dopamine levels remain poorly studied and are essential for understanding the evolution of the dopamine system. Here, we tested whether enhanced maternal dopamine levels translate into offspring fitness costs, but found an opposite effect, with increased longevity under starvation for their offspring. Thus, it remains unclear what constrains the evolution of higher endogenous dopamine levels. Based on the previous findings of Issa et al. , northern Norway. Ephippial eggs were hatched in the laboratory and propagated clonally. For the current experiment, juveniles of a single clone (clone 49) of D. magna were asexually propagated for 10 successive generations prior to use. A maximum of 30 individuals of D. magna were cultured in 2.5‐L aquaria at 20°C in a modified “Aachener Daphnien Medium” (ADaM)  at a final concentration of 3.2 × 105 cells/ml.As previously outlined in Issa et al. , ephippi2.20 generation, a similar experimental design as in Issa et al.  three times a week, and the animals were fed at each renewal event with Shellfish Diet 1800® at a final concentration of 2.88 × 105 cells/ml (ad lib at 20°C) for the high food ration and 8.6 × 104 cells/ml (30% ad lib at 20°C) for the restricted food ration.For the Fa et al.  was useda et al. . Ten neoDaphnia, maturity can be determined by visual inspection of the brood chamber  through the transparent carapace, into which fully developed eggs are oviposited. Mature individuals were removed from the beakers, photographed for size measurements (see Section 1 generation), two individuals were randomly sampled from each well, photographed for size measurements . Individual measurements of body length at first reproduction for the F0 generation (after releasing their first clutch of eggs) and at birth for the F1 generation were measured in the same way. All body length measurements (mm) were converted into dry mass (mg) using the equation by Yashchenko et al.  at the neonatal stage (day 0), dry mass end is the individual dry mass (in mg) at maturation, and duration is the number of days between the two stages.Immediately prior to dopamine exposure on day 0 of the experiment, a random sample of 30 Fo et al. : Dry masN = 4; two samples collected in total from each of the dopamine and control treatments). Simultaneously, the new exposure solutions and ADaM medium were sampled for dopamine analysis .As in Issa et al. , conductD. magna, according to OECD guidelines  prior to dopamine analysis. Two complementary sample preparation protocols were used: (1) dilute‐and‐shoot; and (2) liquid–liquid extraction. Subsequent analysis was performed by ultra‐performance liquid chromatography coupled to a triple quadrupole mass analyzer (UPLC‐MS/MS). This analysis was done as described in Issa et al. , where ses OECD, . The con2.4lme functions in the package nlme, Pinheiro et al., glmer function in the package lme4, Bates et al., nlme package was used to allow residual variance to differ among treatments, food ration, and the two‐way interaction between these  of models that included all fixed factors but differed in their random effects structure. Once the appropriate random structure was determined, fits of alternative models with different fixed effects structures were compared, again using AICc.All statistical analyses and graphic illustrations were performed in R v. 3.6.3  when food was restricted, without any apparent costs to fitness. The higher dopamine exposure resulted, however, in smaller offspring, which could potentially perform worse particularly when facing restrictions in food availability  to food abundance as well as the starvation resistance of their offspring (F1).In a previous study, Issa et al.  investigGliwicz, . Since oDaphnia , such as Daphnia, respond to stressful environments by accelerating their life cycle . Hence, further understanding of the evolution of the dopamine signaling system may require a combined investigation of ultimate and proximate causes.In summary, maternal dopamine exposure boosted The authors have no conflict of interest to declare.Semona Issa: Conceptualization ; investigation (lead); writing – original draft (lead); writing – review and editing (lead). Safa Chaabani: Investigation (supporting); writing – review and editing (supporting). Alexandros G. Asimakopoulos: Investigation (supporting); methodology (supporting); writing – review and editing (supporting). Veerle L. B. Jaspers: Methodology ; writing – review and editing (supporting). Sigurd Einum: Conceptualization ; methodology ; resources (supporting); supervision (supporting); writing – review & editing (supporting).Supplementary MaterialClick here for additional data file.


Cutibacterium modestum is one of the five species of the genus Cutibacterium. While C. acnes has been reported as an important pathogen in bone and joint infections, the clinical characteristics of C. modestum infections remain unclear. Moreover, thus far, there has been no clinical case report regarding C. modestum infections.Staphylococcus aureus. The patient’s condition did not improve; thereafter, anaerobic culture bottles revealed Gram-positive rods on day 11 of incubation. There was no evidence of infective endocarditis upon transthoracic echocardiography. Needle aspiration from the L4–L5 intervertebral disc was performed on day 13 that also showed the presence of Gram-positive rods. The patient was diagnosed with vertebral osteomyelitis caused by C. modestum using a combination of characteristic peak analysis with matrix-assisted laser desorption ionization (MALDI), microbial biochemistry examinations, and 16S rRNA gene sequencing from the blood and pus cultures. He was successfully treated with alternative intravenous ampicillin, followed by oral amoxicillin for 10 weeks, according to the tests for ampicillin susceptibility, with a minimum inhibitory concentration of 0.016 μg/mL using E-test® under aerobic conditions.An 82-year-old man with a history of repeated trigger point injections for lumbago at the L4 level presented with fever and an exacerbation of lumbago. Physical examination indicated knocking pain at the L4–L5 levels; magnetic resonance imaging showed irregular bone destruction of the L4 vertebral body, and low T1 and high T2 intensity lesions at the L4–L5 intervertebral disc. Two sets of blood cultures (two aerobic and two anaerobic) were performed. Intravenous cefazolin was administered, considering the common pathogens of vertebral osteomyelitis, such as Cutibacterium modestum is a microorganism that is difficult to identify. A combination of characteristic peaks with MALDI, appropriate microbial biochemical examinations, and 16S rRNA gene sequencing may serve as an efficient guide for the identification of C. modestum. Cutibacterium are Gram-positive, non-spore forming, non-motile rods, which were reclassified from Propionibacterium species, based on whole-genome sequencing results [Cutibacterium modestum, which was previously known as Propionibacterium humerusii, is one of the five species of the genus Cutibacterium; it was first reported in 2011 [C. modestum infections, and the clinical characteristics of C. modestum infections remain unclear. However, C. acnes, which belongs to the same subspecies as C. modestum, is well recognized as an important pathogen in bone and joint infections, especially in joints with implants [C. modestum microbiologically [C. modestum.Bacterial species from the genus  results , 2. Cuti in 2011 . There iimplants , 5. Therogically ; howeverAn 82-year-old Japanese man, with a history of repeated trigger point injections for lumbago at the L4 level for the past 6 months, presented with fever and exacerbation of his lumbago within the previous month.Physical examination indicated knocking pain at the L4–L5 levels. The laboratory findings were as follows: C-reactive protein, 20.4 mg/L; and white blood cell count, 7200/µL with 57.1% neutrophils. Magnetic resonance imaging (MRI) showed irregular bone destruction at the L4 vertebral body endplate and a lesion with low T1 and high T2 intensity at the L4 vertebral body and the L4–L5 intervertebral disc  and 100%  similarity to C. modestum, (GenBank accession no. LC466959), respectively [Two sets of blood cultures (two aerobic and anaerobic) were performed, and intravenous cefazolin 1 g) was administered every 12 h, considering possible infection with  g was adC. modestum, and cefazolin was replaced with intravenous ampicillin (2 g) administration every 6 h, based on the result of the susceptibility test on day 26  methods to identify C. modestum and the potential of heterogeneity of C. modestum, and (3) clinical management of vertebral osteomyelitis caused by C. modestum.There are three clinical issues: (1) the possibility of vertebral osteomyelitis caused by Cutibacterium acnes is widely recognized as a post-operatively contracted causative agent of vertebral osteomyelitis [C. modestum is an anaerobic, aerotolerant, and non-spore-forming Gram-positive rod [C. modestum is a skin commensal, similar to C. acnes; therefore, C. modestum could also cause infections via contaminated skin surfaces [C. modestum could be misidentified as C. acnes, based on the low score value of ≤ 1.70 when using matrix-assisted laser desorption ionization (MALDI) [C. modestum [C. modestum shows 98.0% similarity to C. acnes in 16S rRNA gene sequencing [C. acnes infections in previously published case reports could have been C. modestum infections.myelitis . C. modetive rod . The isotive rod . C. modesurfaces , 6. Our C. modestum. First, the dominant peaks in the MALDI spectrum of C. modestum are present at 3493, 3712, 6986, and 7424 m/z, which are absent in that of C. acnes [C. modestum in cases with other Cutibacterium species, based on the low scores in MALDI. In our case, the isolates from blood and pus showed a low score value of 1.55 and 1.45, respectively, to C. acnes with MALDI biotyper® (Bruker). However, the MALDI spectrum of isolates from blood and pus exhibited dominant peaks of 3494, 3713, 6989, and 7427 m/z and 3495, 3714, 6991, and 7429 m/z, respectively  shows negative results for hydrolysis of N-acetyl-β-glucosaminidase, indole, phenylalanine arylamidase, leucine arylamidase, pyrazinamidase, β-glucuronidase, β-galactosidase, and gelatin and for ribose fermentation; the other Cutibacterium species show variable results [C. modestum. In our case, the isolates were positive for indole hydrolysis and negative for hydrolysis of other test substrates. This suggests that C. modestum could comprise heterogeneous strains.Third, the microbial biochemistry of estum LC46959 showC. modestum, even in cases without 16S rRNA gene sequencing.These characteristics, in addition to the culture period, characteristic colonies, and the finding of Gram staining, contribute to the rapid identification of C. acnes vertebral osteomyelitis [C. modestum vertebral osteomyelitis. In our case, the anaerobic culture bottles revealed positive results after 11 days of incubation with no preceding antimicrobial administration. Additionally, the needle-aspirated sample from the infected intervertebral disc, obtained on day 13, yielded a positive culture result. The review of 29 C. acnes vertebral osteomyelitis cases indicated that the incubation time for the blood cultures was unknown in cases of negative blood cultures [C. modestum vertebral osteomyelitis, these findings suggest the importance of prolonged cultures and local needle aspiration in cases of negative blood cultures for identifying C. modestum.Clinically, blood cultures are often negative in myelitis . Therefocultures . AlthougC. modestum vertebral osteomyelitis is uncertain. In vitro, C. acnes could survive on Schaedler medium for 8 months under anaerobic conditions; the conditions are similar in the vertebrae or intervertebral discs [C. acnes vertebral osteomyelitis [The optimal duration of antimicrobial therapy for al discs . Our patmyelitis . This suC. modestum is a difficult-to-identify pathogen mimicking C. acnes with regard to its microbiological characteristics. However, a combination of characteristic peak analysis with MALDI, appropriate microbial biochemistry examinations, and 16S rRNA gene sequencing may serve as a reliable and efficient guide for identifying and diagnosing C. modestum infections.In conclusion,


After the development of Web 2.0 and social networks, analyzing consumers’ responses and opinions in real-time became profoundly important to gain business insights. This study aims to identify consumers’ preferences and perceptions of genderless fashion trends by text-mining, Latent Dirichlet Allocation-based topic modeling, and time-series linear regression analysis. Unstructured text data from consumer-posted sources, such as blogs and online communities, were collected from January 1, 2018 to December 31, 2020. We examined 9722 posts that included the keyword “genderless fashion” with Python 3.7 software. Results showed that consumers were interested in fragrances, fashion, and beauty brands and products. In particular, 18 topics were extracted: 13 were classified as fashion categories and 5 were derived from beauty and fragrance sectors. Examining the genderless fashion trend development among consumers from 2018 to 2020, “perfume and scent” was revealed as the hot topic, whereas “bags,” “all-in-one skin care,” and “set-up suit” were cold topics, declining in popularity among consumers. The findings contribute to contemporary fashion trends and provide in-depth knowledge about consumers’ perceptions using big data analysis methods and offer insights into product development strategies. Consumers’ blogs and social network opinions have become a valuable resource for gaining marketing insights and relationship management —the largest web search engine in South Korea. We then examined consumers’ perceptions of genderless fashion over the past 3 years by collecting their texts from blogs and online communities. After the data cleansing and preprocessing procedures, we specified the top keywords to extract the topics. Then, an n-gram analysis  was used to build the model. Consumers’ posting date, platform type, title, contents, and link information were gathered; the text-mining objects were title and content. Data were pre-processed to cleanse them of undesirable words, special characters, non-Korean words, and punctuation. Afterward, word tokenization was lemmatized and converted into the minimal unit of meaning formats such as nouns, adjectives, verbs, or adverbs in their dictionary forms. These words were accumulated in the bag-of-words model  and a Durbin–Watson value greater than 1.5 and less than 2.5, if the regression coefficient value was positive, were classified as a “hot topic”; while, if negative, they were classified as a “cold topic,” and topics for which no meaningful result could be derived were classified as a “neutral topic”  were cold topics, indicating that consumers’ interest in these gradually declined. The remaining topics were classified as neutral topics because they were non-significant in the time-series analysis , items , and cosmetic and perfume products  related to genderless fashion. This indicates that consumers’ recommended products and styles of genderless fashion are affected by the diverse fashion labels collection. Consumers are interested in the coordination and design details of certain brand items related to the gender-neutral concept. In particular, beauty cosmetics and fragrances, which are dominated by female-oriented stereotypes, are now being highlighted, regardless of gender division, owing to the influence of genderless fashion trends among consumers. Kim  stated tSecond, 18 topics were analyzed from LDA-based algorithms and 13 topics were classified as fashion categories , while 5 topics were classified as beauty and fragrance categories . The fashion industry has provided designs and services differently according to gender Szmydke, ; howeverThird, our time-series linear regression analysis revealed a hot topic (“perfume and scent”) and three cold topics , while the rest were presented as neutral topics. The topic that has continuously grown among consumers in relation to the genderless fashion trend in the last 3 years has been “perfume and scent.” Certain brands of seasonal perfumes  and scents  were mentioned among the consumers. As “gift” suggests in the topic, genderless fragrances have a sensuous and soft scent, which are easy to give as a present regardless of gender. According to BBC’s report, gender fluid fragrances have surged in popularity, increasing to 51% as compared to 17% in 2010  or fashion week collection . Yoo  explaineExisting research on genderless fashion trends has focused on the style characteristics shown in collections and advertisements (Hong & Joo, This study has managerial implications for product planners who develop merchandise based on recent trends. We found that consumers have a high interest in brands and products related to perfume, fashion, and cosmetics in terms of genderless fashion trends that can make their individuality stand out despite gender division. Therefore, when a product planner plans a merchandising product group targeting consumers, these product categories can be prioritized. In particular, given that the topic of “perfume and scent” has been on the rise among consumers, strategic promotions and collaboration with genderless fragrance brands can also be conceived.The limitations of this study and suggestions for future research are as follows.This study collected the text documents from consumers postings of blogs and online communities, therefore it is not focused solely on a specific generation. Because the genderless fashion is popularly accepted by Millennials and Generation Z Anyanwu, , it woul


Pharmaceutical cocrystal provides an alternative modification strategy for the formulation development of drugs owning to their potential ability to improve the physicochemical properties of active pharmaceutical ingredients (APIs) efficiently by changing inter-molecular interactions between raw materials. Isoniazid (INH) is an indispensable main drug for the treatment of tuberculosis, but its tablet formulation is unstable and prone to degradation. In the present study, the monohydrate cocrystal of INH and protocatechuic acid (PA) was prepared by solvent evaporation using PA as cocrystal former to optimize the properties of INH. The parent materials and corresponding 1:1 molar ratio INH-PA monohydrate cocrystal have been characterized by the terahertz time-domain (THz-TDS) and Raman spectroscopy. The THz absorption spectra displayed that there were obvious differences between the peaks of experimental cocrystal and the parent materials, and the same situation was found in Raman vibrational spectra. In addition, density functional theory (DFT) was applied to simulating and optimizing the structure of INH-PA monohydrate cocrystal and supplied corresponding vibrational modes. Our results provided a unique method to characterize the formation of INH-PA monohydrate cocrystal at the molecular-level and a lot of information about cocrystal structure and intra-molecular and/or inter-molecular hydrogen bond interactions in the emerging pharmaceutical cocrystal fields. Tuberculosis (TB) is a global emergency case announced by the World Health Organization (WHO) and among the top 10 causes of death . The IntCocrystal is generally defined as the crystalline single-phase materials  formed bIn the past few years, many new solid forms involving INH have been studied, especially the cocrystallization of INH and different co-forms. Pawel Grobelny et al.  firstly Most of the studies of cocrystals relating to INH above are implemented by a few traditional ways such as differential scanning calorimetry (DSC), X-ray diffraction (XRD), which are time-consuming in some cases or not detailed enough about the structures of molecules and the influence of intra-molecular and/or inter-molecular interactions within the cocrystals . Thus, tIn the present work, the monohydrate cocrystal between INH and PA was synthesized by slow solvent evaporation and THz and Raman spectral techniques were used to observe the fingerprint information from INH, PA, their physical mixture and cocrystal. The terahertz spectrum is composed of a mixture of hydrogens, weak covalent bonds, ionic bonds and van der Waals force in the solid states . These cAnhydrous solid-state INH (purity 98%) and sample PA (purity 99%) were acquired by J&K Chemical Company . Methanol was purchased from Hangzhou Gaojing Fine Chemical Company . All chemicals were used as received without further purification. The physical mixture of parent materials was obtained by mixing the two compounds at a molar ratio of 1:1 in a glass vial by using a vortex mixer. The cocrystal was obtained by slow solvent crystallization, which was commonly used in the preparation of cocrystal. INH  and PA  were respectively dissolved in a mixture of 20 mL methanol and de-ionized water  solid-state laser was selected as the near-infrared light source with 150 mW operating power and the total analysis time for each sample was of the order of 5 min intervals.THz spectra of INH, PA, their physical mixture and cocrystal were detected by THz-TDS Z2 system , which was applied to investigate the THz transmission spectra of target substances based on photoconductive switches. The optical pulse sequence was from Ti: Sapphire oscillator ultrafast laser pulse system  with the frequency 75 MHz, the pulse width 100 fs and the center wavelength 780 nm. Due to the strong absorption of THz radiation by water, nitrogen gas with high purity was continuously flushed into the detector during the experiment. Three measurements for each set of sample and reference were carried out and took the average value as the ultimate spectral data. Since the outputs of the experiment were time domain spectra of the electric field intensity of THz, they need to be converted into corresponding frequency domain spectra by fast Fourier transform (FFT) process, and the THz absorption spectra were acquired by dividing the sample frequency response by that of the reference. The Raman spectra of the above substances were detected by the Fourier transform Raman (FT-Raman) spectrometer  after over 500 scans at 2 cm−1 was used to convolute the Lorentzian line shapes into the calculated vibrational modes.The crystal engineering method of supramolecular heterosynthesis between the API and the coformer is an effective strategy for the rational selection of suitable coformers and the design of new pharmaceutical cocrystals. It is important to understand the hydrogen bond interactions, which lead to strong heterosynthons in the cocrystal compared to homosynthons in individual components . TherefoThe low frequency vibrational spectra of molecules provide many useful values for molecular vibration, rotation modes, and some weak inter-molecular interactions such as hydrogen bond interactions, van der Waals forces and so on. THz spectroscopy can be used to obtain such low frequency vibrational information of crystalline compounds, which makes it a vigorous analytical tool for studying the structure and inter-molecular interaction of various molecules . The THzThree possible theoretical cocrystal forms were simulated in this paper. In form I, the hydrogen bond was formed by pyridine N–carboxylic acid synthons of two raw materials , not only because of its sensitivity to structural changes, but also its rapidity, non-destruction, no sample preparation and capability of characterization in the water environment . Differe−1 in the experimental Raman spectrum, theoretical form II and theoretical form III are in good agreement, while theoretical form I lacks the relevant characteristic peak. Comparing the theoretical form II with the theoretical form III, the characteristic peak of the theoretical form III at 1442 cm−1 is well matched with that of experiment, but the theoretical form II is short of such characteristic peak. Additionally, located in the high frequency region of 1610 cm−1, the number of characteristic peaks of form III is more consistent with the experimental spectrum. Therefore, the Raman spectrum from theoretical form III is in better agreement with the experimental results, which is consistent with the above THz spectrum results and proves the formation of cocrystal. In addition, the distinct vibrational modes of INH-PA monohydrate cocrystal are assigned in −1 is mainly attributed to the scissoring vibration of O33-C22-C21-H26, deformation vibration of PA ring and the out of plane rocking vibration of H36-O35. Another characteristic peak with high resolution at 1318 cm−1 is mainly formed by the in-plane rocking vibration of H17-N13-C12, the out of plane rocking vibration of H15-N14-H16 and stretching vibration of N14-N13. In addition, two obvious characteristic peaks located in the high frequency region are accompanied by the vibration of the water molecule during the crystal vibration. For instance, the characteristic peak at 1632 cm−1 can be considered as the result of deformation vibration of INH ring and the scissoring vibration of water (H36-O35-H37). Additionally, the characteristic peak at 1655 cm−1 can be attributed to the deformation vibration of PA ring and the scissoring vibration of H34-O33-C22 and water (H36-O35-H37). Among them, O35-H36... O33 and O35-H37... O11 are the two important hydrogen bonds forming the cocrystal structure. By analyzing the vibrational modes of the four Raman characteristic peaks with high resolution, it can be seen that most of the vibrations of INH-PA hydrate cocrystal are influenced by inter-molecular interactions, especially the effect of inter-molecular hydrogen bonds between INH, PA and water molecule. Therefore, the hydrogen bonds play an important role in the formation of INH-PA monohydrate cocrystal.The Raman spectra of the experimental results compared with the theoretical calculation are shown in −1 in the above Raman spectra, which also confirms the important influence of inter-molecular hydrogen bonding on the formation of cocrystal. Combining the results of chemical bond length variations with THz and Raman spectra, it can help us better understand the offset, emergence and vanishing of characteristic peaks in the spectrum of INH-PA monohydrate cocrystal and provides us with abundant information about the molecular structure and inter-molecular interactions (particularly the hydrogen bonds between raw substances).It is well known that the change of bond length between different atoms is the most direct reason for the characteristic vibration mode information exhibited in the Raman spectra of various compounds ,42. TherIn this paper, the vibrational spectra of solid-state INH, PA, physical mixtures and INH-PA monohydrate cocrystal were obtained by THz and Raman spectra. It can be perceived that there are some differences between the vibrational spectra of INH-PA monohydrate cocrystal and those of original materials. Three possible theoretical cocrystal forms were simulated by DFT so as to compare with the experimental spectra, then the vibrational modes at different absorption peaks were assigned according to the above simulation results. According to the above analysis results, it can be concluded that the monohydrate cocrystal between INH and PA is formed on the score of non-covalent bond interactions between molecules, particularly the influence from inter-molecular hydrogen bonds. Through the comparison of three theoretical cocrystal forms, the theoretical cocrystal form III  is more consistent with the experimental results. In addition, the study on typical hydrogen bond length also confirmed the important role of hydrogen bonds in the formation of cocrystal. Raman and terahertz spectroscopic techniques are complementary to the investigation into vibrational modes and micro-molecular structure of INH-PA monohydrate cocrystal. The study shows the superiority of vibrational spectroscopy adequately certifying the molecular structure and inter-molecular hydrogen bond interactions in the study of specific cocrystals, which provides theoretical and experimental basis for the structural research of emerging pharmaceutical cocrystal fields at the micro-molecular level.


On January 8, 2021, newborns around the world lost one of their greatest advocates: Ann-Marie Widström died at age 85, in the presence of her dearest family. Health care professionals and families alike are deeply saddened by her passing. I had the privilege to have Ann-Marie as an outstanding mentor and a long-time cherished friend. I write this to honor her memory and remind the world of her great legacy.the innate sequence of the human mammal at birth” or “the nine stages of newborn instinctual behaviour” leading the newborn to self-regulate at birth and find the breast to breastfeed for the first time.As a visionary researcher, Ann-Marie Widström observed, described, studied, and validated what is now called “Breastfeeding-Baby’s Choice, which is now a CD under the same title, translated into many languages, and well utilized throughout the world. She then extensively published her findings in many scientific periodicals, each time further defining and explaining the nine stages, and the importance of implementing this sequence at clinical and research levels.All mammals have their own innate sequence at birth leading to survival, self-regulation, and feeding. Ann-Marie described the human sequence beginning in 1993 with a short video called Ann-Marie was a very meticulous and even perfectionist researcher and writer. She taught us well. Many junior and senior researchers from different countries were inspired and moved by her charisma, her simplicity, and her deep humaneness. She was always open to receiving them in Stockholm, at the Karolinska Institutet, for a few hours, days, or even years, enthusiastically sharing her knowledge, and her curiosity about everything related to newborns. Discussions were always animated and with touches of humor.As a friend, she was extremely present, open, attentive, warm, lively, and funny. She much enjoyed good meals with friends, with lots of discussion, jokes, and sharing of memories. Ann-Marie, rest in peace. The world has become a better place because of who you were, and because of your work. It was an honor and a pleasure to work with you for more than 10 years and to cherish you as our friend.


The MYC oncoprotein and its family members N-MYC and L-MYC are known to drive a wide variety of human cancers. Emerging evidence suggests that MYC has a bi-directional relationship with the molecular clock in cancer. The molecular clock is responsible for circadian (~24 h) rhythms in most eukaryotic cells and organisms, as a mechanism to adapt to light/dark cycles. Disruption of human circadian rhythms, such as through shift work, may serve as a risk factor for cancer, but connections with oncogenic drivers such as MYC were previously not well understood. In this review, we examine recent evidence that MYC in cancer cells can disrupt the molecular clock; and conversely, that molecular clock disruption in cancer can deregulate and elevate MYC. Since MYC and the molecular clock control many of the same processes, we then consider competition between MYC and the molecular clock in several select aspects of tumor biology, including chromatin state, global transcriptional profile, metabolic rewiring, and immune infiltrate in the tumor. Finally, we discuss how the molecular clock can be monitored or diagnosed in human tumors, and how MYC inhibition could potentially restore molecular clock function. Further study of the relationship between the molecular clock and MYC in cancer may reveal previously unsuspected vulnerabilities which could lead to new treatment strategies. MYC), N-MYC (MYCN), and L-MYC (MYCL) are members of the basic helix-loop-helix (bHLH) family of transcription factors [The MYC family of proto-oncogenes is a group of protein-coding transcription factors whose effects extend to various biological processes, including cell cycle progression and metabolic control. C-MYC , downregulation of their inhibitors p21gression . This abgression ,4,5. In ARNTL)—control the molecular clock in cells, which leads to circadian rhythms in cellular and organismal activity [Three other members of the bHLH family—CLOCK, NPAS2, and BMAL1  and ROR  proteins, both of which are nuclear hormone receptors that regulate BMAL1 [What is referred to as the ‘molecular clock’ is a regulatory mechanism consisting of a group of cooperative proteins with oscillatory expression that follows a circadian rhythm and has influence on several different biological functions A. The mote BMAL1 . RORs, ote BMAL1 . The REVte BMAL1 , have bete BMAL1 ,21. CLOCMYC locus is perturbed to allow for unrestricted expression. Chromosomal translocations place MYC under the control of novel promoter and regulatory elements. These translocation events are primary drivers in B cell cancers such as Burkitt’s lymphoma (where they occur with up to 80% frequency), diffuse large B-cell lymphoma, and multiple myeloma (where they occur in each with up to 15% frequency) [MYC under the control of the IGH promoter, leading to both loss of normal transcriptional control of MYC, and massive overexpression [MYC and its family members are instead subject to focal amplification, where the MYC locus appears dozens to hundreds of times throughout the genome in inappropriate locations. In a recent study that queried genomic cancer patient data from The Cancer Genome Atlas, MYC or one of its paralogues was found to be amplified in 28% of all cancers. However, this number is much higher in specific cancers; for instance, in ovarian cancer, one of the three MYC paralogues is amplified in nearly 100% of cases [MYC is amplified or rearranged in the genome, or where cell line or mouse models simulate this amplification.The MYC family of proteins is upregulated in a large number of human cancers, but the manner of this upregulation, and whether it is direct or indirect, varies. In many cancers, the equency) ,24,25. Iof cases . In suchof cases . ThroughMYC can be upregulated by the BCR-ABL fusion protein in chronic myelogenous leukemia, mutant Notch in T cell acute lymphoblastic leukemia, PTEN loss in breast cancer, and EGFR mutation in non-small-cell lung cancer [MYC regulation and expression are intact when it is upregulated downstream of other mutations. The manner of MYC upregulation in cancer, whether it be genomically altered, or upregulated downstream of other oncogenic mutations, is important to consider in the context of this review. MYC and the molecular clock extensively cross-talk, and the outcome of this relationship in cancer may depend on how MYC is deregulated.In contrast, MYC can be stabilized or upregulated downstream of other oncogenic mutations. To illustrate a few examples, g cancer ,31,32,33ARNTL), CLOCK, and the CLOCK paralogue NPAS2 [Drosophila bound to molecular clock gene promoters, and elevated dMYC ablated behavioral and metabolic rhythms [Emerging data suggest that MYC and the molecular clock have a fascinating bidirectional relationship which is likely perturbed in many cancers. Several recent studies across multiple organisms and model systems have addressed the interplay of oncogenic MYC and circadian rhythm, and these studies have overwhelmingly suggested that deregulated MYC disrupts or fully ablates oscillation of the molecular clock. These mechanisms are summarized in ue NPAS2 ,37,38. Wue NPAS2 ,37,38. Tue NPAS2 ,36,37,38ue NPAS2 . Intriguue NPAS2 . The abi rhythms . It is aThe role of endogenous MYC in regulating the molecular clock is far less clear, and largely remains to be uncovered. MYC is upregulated when cells are stimulated with mitogens to enter the cell cycle , and oneMYC.A link between circadian disruption, tumorigenesis, and patient outcomes in cancer has long been suspected. Analysis of the Nurses Health Study I and II, each representing more than 70,000 volunteers, was performed observing women who worked third/night shifts, causing a them to develop a disrupted circadian rhythm. Through the study, it was noted that these women with disrupted circadian rhythms had increased incidence of breast and lung cancer compared to their counterparts ,44,45. IMYC expression. What we know of molecular clock regulation of MYC comes mostly from tumorigenesis studies; the role of the molecular clock in regulating endogenous MYC in normal and healthy cells remains to be determined. Nonetheless, the consensus amongst multiple studies is that genetic disruption of the molecular clock tends to de-repress and upregulate MYC. A study in mouse liver revealed that Myc exhibits circadian oscillation, and was upregulated up to 25-fold (but remained oscillatory) when a dominant-negative PER2 mutant was expressed [Per2 mutation and Arntl (BMAL1) deletion in lung tumors both resulted in upregulated Myc [Myc expression and activity [Cry1 or Cry2 had little effect on Myc mRNA expression or MYC protein levels, Cry1/Cry2 double knockout  instead led to MYC repression. The authors attributed this to CLOCK-BMAL1 being locked in an active state without the negative feedback of the PER-CRY complex, which indirectly led to Myc suppression [The molecular circadian clock and MYC have a bi-directional relationship: while oncogenic MYC can disrupt the molecular clock, it appears that the molecular clock itself can regulate xpressed . Similarated Myc . These ractivity ,58. Howeactivity , as seenpression .MYC expression, but the molecular clock exerts control over MYC in other ways as well. Studies in synchronized neuroblastoma cell lines showed that histone modifications control oscillatory MYC expression, and that MYC protein oscillation was modulated by circadian control of protein stability [Cry2 led to elevated MYC protein in transformed mouse fibroblasts, human lung cancer and colon cancer cell lines, and a mouse model of lymphoma [Cry2 deletion, MYC still retained circadian oscillation in mouse fibroblasts. CRY2′s role in regulating MYC protein stability may be cell type and context specific, as Cry2 deletion in mouse spleen did not affect MYC protein levels, despite components of the SCF E3-ubiquitin ligase complex being present in this tissue [These studies suggest that CLOCK-BMAL1 may repress tability ,65. It wlymphoma . Importas tissue . More stCry2 deletion in mouse fibroblasts [Per2 mutation nor Cry2 deletion ablated the molecular clock, MYC continued to oscillate [MYC oncogenes themselves may be critical in determining its role in circadian oscillation.A unifying theme emerges from the above studies: even though MYC was elevated due to behavioral or genetic clock disruption, when oscillation of the molecular clock was intact, MYC continued to oscillate as well. This can be seen most clearly in PER2-mutant overexpression in the liver, and roblasts ,61. In bscillate ,61. Intescillate ,37,39,40MYC is known to be a critical factor for maintenance of stem cells in general and GSCs in particular [MYC in GSCs [MYC oscillated, which may be an intriguing topic of future study.A parallel field of studies suggests that in some cancers distinct from the types discussed above, the molecular clock may promote, rather than restrain tumorigenesis. This was demonstrated chiefly in cancers that have a distinct stem cell component, such as skin cancer, acute myelogenous leukemia, and glioblastoma ,67,68. Trticular ,70, it ibHLH transcription factors such as MYC and CLOCK-BMAL1 directly influence chromatin state and pause release. The interaction between MYC and CLOCK-BMAL1 in controlling chromatin and pause release in healthy cells is unknown; however, evidence suggests that their mutual regulation of these processes is out of balance in cancer. MYC may play a role in global chromatin remodeling, such as during B cell activation ,72; howeOncogenic MYC has a role not just in transcriptional initiation, but also in RNA polymerase II (Pol II) pause release. Pause release is the process whereby Pol II ‘pauses’ shortly after initiating transcription, and is later released by external factors to complete transcriptional elongation of the target gene . Recent Histone modifications  have long been known to oscillate , and morThe relationship between the molecular clock and polymerase II pause release is somewhat less clear, and still a highly active area of research. It has long been appreciated that CLOCK and BMAL1 rhythmically recruit Pol II and associated factors to promoters; this was thought be a principal driver of rhythmic transcription ,96. HoweThe ability of oncogenic MYC to shape global chromatin organization and transcriptional elongation may also impact the ability of the molecular clock to govern these same processes, which could lead to competition between these two sets of transcriptional machinery. Given that oncogenic MYC is reliant on chromatin state for specificity, circadian regulation of chromatin state may impact which genes MYC can upregulate, and when. In cancer cells where the molecular clock is retained, oscillation of chromatin state, availability of chromatin-binding proteins like WDR5, and higher-level chromatin organization may still occur ,90. We sMYC genomic amplification, and using computational approaches to assess the functionality of the molecular clock in tumor cells (discussed in more detail below) will be required to fully appreciate the role of MYC in modulating circadian rhythms in human cancer cells.In contrast, in settings where oncogenic MYC ablates the molecular clock, the entire chromatin landscape may change, allowing for MYC to enact an even more transformative program in tumor cells. MYC’s ability to statically (irrespective of time-of-day) upregulate proteins like REV-ERBα and suppress BMAL1 may suppress or even eliminate the ability of the molecular clock to rhythmically regulate chromatin accessibility and higher-level organization. This, along with MYC’s ability to promote global pause release, may unleash a novel transcriptional program quite unlike that in cells with a functional molecular clock. These conjectures suggest that simply quantifying MYC expression in a given tumor may not be enough to properly diagnose MYC’s potential impact on the molecular clock in human cancer. Assessing potential Cell-autonomous control of metabolism is a key node where MYC and the molecular clock may compete for control of cell physiology. MYC is well known to rewire metabolism to promote a constantly proliferative state. The role of MYC in rewiring metabolism has been previously reviewed ; but briIn contrast to the well-known role of MYC in driving proliferative metabolism in cells, the role of the molecular clock in cell-autonomous metabolism has only been addressed recently. It has been known for decades that the circadian clock strongly controls whole body metabolism, particularly pancreatic endocrine and liver functions ; howeverIf amplified MYC disrupts molecular clock oscillation, it may also disrupt cell-autonomous metabolic oscillations; indeed, it was demonstrated that intracellular glucose oscillations are ablated by MYC overexpression in cancer cells . MYC-driMetabolic pathways, such as glutamine and arginine uptake and catabolism, likely oscillate in non-transformed cells as well as some cancer cells with an intact clock . These lTumors must escape detection by the immune system as foreign bodies in order to successfully develop and progress . Immune While it is clear that oncogenic MYC can affect the molecular clock of tumor cells, it is less clear how MYC can influence the clock of tumor-infiltrating immune cells. A full discussion of the extent of circadian control of immune responses, and the implications of circadian disruption in immune cells is beyond the scope of this paper, but has been covered in several comprehensive reviews ,131. In A more subtle and indirect mechanism whereby MYC may disrupt the clock of neighboring immune cells could be due to metabolic competition and metabolic waste in the tumor (reviewed in ) FigureC. BecausMYC expression and destabilize MYC protein [In this final section, we will briefly consider novel strategies to target MYC in cancer  protein ,162,163. protein . Finally protein ,152,164.Disruption of the molecular circadian clock is a common feature of MYC amplification across several kinds of cancer, so it stands to reason that inhibition of MYC in cancer may re-activate the molecular clock, or more precisely, allow the molecular clock of cancer cells to again respond to external entrainment signals. This raises several interesting questions: first, why would this be important, and second, how would this clock reactivation be assessed? As to the first question, whole-body circadian rhythms are known to strongly influence time-dependent drug delivery and metabolism, a field known as chronotherapeutics ,166. ChrDespite the importance of assessing the health and function of the molecular circadian clock in human cancers, it is quite difficult to actually conduct these measurements. Thus, with current technology, it would be challenging to determine if MYC inhibition restored circadian oscillations in a patient tumor. Ideally, to properly assess a circadian oscillation , a researcher conducts serial measurements in 2–4 h increments across several days, and then tests for oscillations in these time-series data. Indeed, this technique is quite feasible with serial sampling of human blood from volunteers, and has revealed that night shift work may be a risk factor for DNA damage that can lead to cancer ,171. HowAn alternate approach may be to assess the state of the circadian clock before and after MYC inhibition not in the tumor, but in a more easily accessed part of the body such as the blood. There is evidence from mouse models that primary tumors may distally disrupt circadian clocks throughout the body ,174. In While MYC has been the subject of numerous studies investigating its multiple different interactions and effects in cancer, there is still much to be elucidated about its interplay with the molecular circadian clock. MYC disruption of the molecular clock is likely to influence metabolic reprogramming, chromatin state and accessibility, and immune infiltrate. There are still a wide range of discoveries to be made within the field, from further elucidating the role of MYC in affecting the circadian clock of cells in the tumor microenvironment to establishing the clinical value of MYC inhibition and further developing methods to assess patient circadian rhythms. Research on the MYC oncoproteins spans a variety of disciplines, and their further study is key to understanding and rationally treating MYC-driven cancers.


Antimicrobial resistance (AMR) is a major threat to both human and animal health since it significantly diminishes the therapeutic options available. Significant amounts of the antimicrobials used in humans and animals are excreted into the environment essentially unchanged, or as metabolites that still retain antimicrobial activity. They reach the environment via direct excretion by pasture animals, from discharges from wastewater treatment plants, via application of manure and sludge to agricultural fields, or direct application of antimicrobials in aquaculture. The release of antimicrobials into the environment can exert a selective pressure on environmental microbiota, leading to the selection of antimicrobial resistance genes (ARGs) in a variety of ecosystems. Thus, the microbiota of plants, wild animals and the environmental microbiota in general can be affected. Another way of dissemination of ARGs into the environmental ecosystems is via AMR bacteria in animal and human faeces. The resulting pool of ARGs in the environment can be considered as self-replicating genetic pollutants, with the possibilities of horizontal transfer, recombination, and generation of a broader diversity of ARGs. From this pool, ARGs can be reintroduced back to human and animal pathogens, thus contributing to the global problem of AMR.Antimicrobial residues and AMR determinants have been reported in soils, surface and groundwater, glaciers, air, agricultural produce, wildlife and other urban, agricultural and natural environments. The main aim of this Research Topic was to uncover the role of AMR in wildlife and the environment for better understanding of AMR epidemiology in a globalised world. Within this topic, 11 articles have been published that complemented our knowledge on the occurrence and diversity of antimicrobial residues, AMR bacteria and ARGs in the environment and wildlife.Mbanga et al. characterised genomic diversity of environmental E. coli isolates from a wastewater treatment plant and surrounding receiving waters in South Africa using phylogenomic analysis. They concluded that these isolates mainly clustered with clinical isolates, thus highlighting their importance for public health. Continuous surveillance of AMR bacteria in wastewater and associated surface waters could serve as a proxy for local AMR and its dynamic over time. Such a surveillance strategy may be highly relevant in low-resource settings, where clinical surveillance of AMR is too costly. The dissemination of AMR bacteria from river water to vegetables irrigated by this water was studied by Díaz-Gavidia et al. in Central Chile. They isolated Enterobacterales strains that were resistant to four antibiotic classes, with some of them demonstrating multi-drug resistant (MDR) phenotypes. The occurrence of MDR Enterobacterales during the rainy season was less frequent compared to the dry season. Association of AMR frequency with season and vegetable type contributes to a better understanding of a potential public health impact of AMR/MDR bacteria present in irrigation water and vegetables.Jauregi et al. evaluated the potential risks associated with antibiotic residues, ARGs and mobile genetic elements (MGEs) introduced into soil and crops via cow manure application. Authors compared different treatments  and crops (wheat and lettuce) but no single treatment could be identified as superior to the others to reduce the potential resistome risks. The authors concluded that the treatments should be specific and take into consideration the amendment, soil and crop types.Salmonella enterica strains was investigated by Donoso et al. They isolated 15 S. enterica strains, 14 of which belonged to the Infantis serotype, with the carriage of pESI plasmid and MDR phenotype.AMR can be also exchanged between humans and animals through pests and wild animals. The role of common pests in poultry such as the lesser mealworms to serve as a potential reservoir of zoonotic Haenni et al. investigated 424 wild birds and 16 wild mammals in a rescue centre in France for the presence of AMR bacteria. They demonstrated a wide dissemination of Enterobacteriaceae with an IncHI2/ST1 plasmid carrying the blaCTX–M−9, blaSHV−12 and mcr-9 genes. Interestingly, these clones are not bona fide microbiota of birds but, similarly to nosocomial infections in hospitals, represent dissemination of clones within the rescue centre. These findings suggest a potential dissemination of ESBL-positive clones to the natural environments from rescue centres. Plaza-Rodríguez et al. investigated the occurrence and AMR patterns of several bacterial species in certain wild animals in Germany, including wild boars, roe deer, and wild ducks and geese. In general, the prevalence of AMR bacteria was low. However, resistance was identified against clinically relevant drugs such as third-generation cephalosporins, fluoroquinolones and colistin. Skarzyńska et al. characterised the AMR status of 71 E. coli isolates from free-living birds in Poland using phenotypic assessment and WGS. Multiple resistance types were found, including those towards cephalosporins, quinolones, polymyxins, aminoglycosides, as well as fosfomycin. Molecular epidemiological analyses revealed that the E. coli strains were of the global lineages ST131, ST10, and ST224 as well as the three novel STs, 11104, 11105, and 11194. O'Hagan et al. investigated the AMR prevalence in E. coli, Salmonella spp., and methicillin resistant Staphylococcus aureus (MRSA) isolates from European badgers and red foxes in Northern Ireland. No MRSA were detected, while ESBLs were detected in 8.90% of badger and 11.53% of fox faecal E. coli isolates, which, in addition, also displayed MDR phenotype. AmpC type resistance was found only in the S. enterica subsp. arizonae isolate. Detection and quantification of ARGs in the gut of kelp gulls and Magellanic penguins revealed that AMR profiles differ between these two bird species , which could be reflective of differential biology, ecology and proximity to human-impacted areas. In another study, the distribution and resistance to third-generation cephalosporins in E. cloacae complex members and their relationship between wild anoles and human activities  was investigated. No relation was identified. The authors suggested that the high level of resistance in wild anoles was probably due to environmental factors that favour the selection of these resistant strains.Wildlife may also contribute to the dissemination of genes conferring resistance to clinically relevant antimicrobials. They could serve as reservoirs of AMR bacteria and also represent epidemiological links between human, livestock and natural environments, especially in the case of long-distance haulers such as migratory birds. Several articles in the Research Topic addressed this issue. Streptomyces that occur naturally in the environment can be active again pathogenic fungi, and constitute an alternative to chemical fungicide treatment and might participate to reduce the burden of phytopharmaceuticals .Other antibiosis factors like polyene produced by In conclusion, it is currently rather difficult to make generalisations because available data are fragmentary and insufficient. More comprehensive and larger-scale studies are necessary to evaluate the occurrence and diversity of antimicrobials and AMR in wildlife and the environment. Within the One Health framework, it is crucial to understand the role played by wildlife and environment in the development and transmission of antimicrobial resistance, and to evaluate its impact.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


The effect of the chemical and phase composition of silicoaluminophosphate gels on the physicochemical properties of SAPO-11 molecular sieves was shown. The secondary structural units that the AEL lattice is composed of were found to be formed at the initial stage of preparation involving aluminum isopropoxide. Several approaches to control their morphology and secondary porous structure are also proposed.The formation of silicoaluminophosphate gels using boehmite, Al isopropoxide, and di-n-propylamine as a template of silicoaluminophosphate gels as well as their subsequent crystallization into SAPO-11 molecular sieves was studied in detail using X-ray fluorescence spectroscopy (XRF), powder X-ray diffraction (XRD), Raman spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and N The current progress in oil refining and petrochemical industries is largely associated with the use of zeolites in the development of modern catalysts and adsorbents ,2. The wIn 1984, Wilson et al. first reported on the synthesis of SAPO-n silicoaluminophosphate molecular sieves ,6. SAPO-Currently, molecular sieves based on SAPO-n silicoaluminophosphates are already used in industry. In particular, UOP and the Dalian Institute of Chemical Physics (DICP) have developed and implemented industrial processes on the basis of SAPO-34 to obtain lower olefins from methanol . Chevron7+ n-paraffins [Among the wide variety of SAPO-n, SAPO-11 molecular sieves (AEL structure) are of particular interest due to the presence of a one-dimensional channel system with elliptical pores of 4.0 × 6.5 Å, which are comparable to the molecular sizes of various practically important compounds and moderately strong acid sites. SAPO-11 molecular sieves are the most selective catalysts for hydroisomerization of Caraffins ,13, isomaraffins  and cyclaraffins ,16 as wearaffins ,18.Despite some success achieved in the synthesis and application of SAPO-11 molecular sieves in catalysis, the issues of formation and the relation between the results of subsequent crystallization of reaction gels and their physicochemical properties have been poorly studied thus far. Addressing these issues will make it possible to specify SAPO-11 crystallization and proceed to the development of these materials with the desired properties, which is one of the current challenges in the field of synthesis and research of molecular sieves.4-11 were not studied in this work.Already in , phosphoIt was shown in  that, up4-11 molecular sieves.Earlier ,21,22, wThe research results prove the importance of the gel formation stage during subsequent crystallization of the above materials. Therefore, we carried out a detailed study of the relation between the chemical and phase composition of silicoaluminophosphate gels prepared using various sources of aluminum and different contents of the template, and the morphology and porous structure of SAPO-11 molecular sieves formed during crystallization.2O3 ratio of 1.5.It should be noted that the pH value of the gels strongly depends on the reactivity of the Al source and the content of the template. Thus, when preparing gels using the more reactive Al isopropoxide, when aluminophosphate is formed already at the initial stages of their formation, the pH value exceeds ~7. When using a less reactive boehmite, it is ~5, even at a DPA/AlDifferences in the phase composition of gels affect the phase composition of the products of their crystallization . The SAP2O3 ratio = 1.0. When it increases to 1.5, the conditions favorable for the formation of SAPO-41 are achieved. It is important to note that in the amorphous and layered phase, the sources of aluminum and phosphorus almost completely reacted with each other with the formation of bonds of the Al–O–P type, in contrast to gels prepared using boehmite.Thus, crystallization of SAPO-11 of high phase purity is possible only from amorphous SAPO-11-iAl-1.0 gel under DPA/Al4-n and SAPO-n molecular sieves, signals at 270 and 500 cm−1 are associated with 10R and 4R rings [−1, linked by 10R rings. Thus, future fragments of the SAPO-11 structure are formed at the initial stage of the preparation of the silicoaluminophosphate gel at room temperature.As noted above, the gels prepared using aluminum isopropoxide are characterized by the presence of the Al–O–P type bonds. Raman spectroscopy is known to be very sensitive to ring structures forming the molecular sieve lattice. For AlPO4R rings ,24. The In summary, the above results revealed that to prepare molecular sieves of high phase purity of the AEL structure, it is necessary that the main phases in the initial gels are aluminophosphates, which have already preformed the Al–O–P type bonds, contributing to the formation of crystals of the SAPO-11 molecular sieve.The solution to the problem of synthesizing SAPO-11 of high phase purity from initial gels prepared using such sources of Al as hydrated aluminum oxides (boehmite and pseudoboehmite) can be the introduction of an additional aging stage, which will preliminarily form a higher content of aluminophosphates.4·2H2O in the gels. Introduction of the aging stage at 90 and 120 °C therefore provides formation of predominantly aluminophosphate phases in the initial gels.It is important to note that the results of crystallization significantly depend on the chemical and phase composition of the gels, which determine the pH value. Thus, SAPO-iAl-1.0 SAPO-PB-1.0(120) gel samples and SAPO-PB-1.5 SAPO-PB-1.0(90) gel samples were characterized by pH values of ~7 and ~5, respectively, while the results of their crystallization were significantly different from each other. As will be shown below, both the morphology of the crystals and the characteristics of their porous structure differed significantly.Thus, the results obtained suggest that by regulating the chemical and phase composition of silicoaluminophosphate gels by using various sources of aluminum in their preparation and changing the content of the template in the reaction mixture as well as by introducing the aging stage, it is possible to control the morphology of primary crystals and secondary aggregates of SAPO-11 molecular sieves.2O3 = 1.0–1.5), and as of the temperature (25–120 °C) aging stage on the chemical and phase composition as well as properties of the porous structure of silicoaluminophosphate gels and products of their subsequent crystallization are detailed in the present work by applying the methods of XRD, Raman spectroscopy, SEM, TEM, and N2 adsorption–desorption.The influence of various sources of aluminum , the content of the template in the reaction mixture DPA·40H2O. To prepare the gels, Al isopropoxide  or boehmite , Sasol SB, Hamburg, Germany), SiO2 sol, orthophosphoric acid , and di-n-propylamine  were used as sources of Al, P, Si, and a template, respectively. Silicoaluminophosphate gels were prepared as follows: 10.0 g of orthophosphoric acid was added to 27.0 g of distilled water and 17.3 g of Al isopropoxide or 5.6 g of boehmite was added under vigorous stirring to form alumophosphate, then 4.4 or 6.6 g of di-n-propylamine was added to the gel. After DPA was added, the calculated amount of the SiO2 source was slowly introduced into the resulting gel, and then the reaction mixture was intensively stirred for 1 h.For the crystallization of SAPO-11 molecular sieves, we used silicoaluminophosphate gels with the following composition: 1.0AlThe samples of SAPO-PB-1.0 silicoaluminophosphate gel were kept in a thermostat at 60, 90, or 120 °C for 24 h. After aging, the gel samples were assigned an additional index (60), (90), and (120), respectively .SAPO-11 molecular sieves were crystallized from the corresponding silicoaluminophosphate gels at 200 °C for 24 h. Preliminary experiments have shown that crystallization for more than 24 h results in the formation of cristobalite. The chemical composition of the obtained silicoaluminophosphate gels and crystallization products was characterized by X-ray fluorescence spectroscopy recorded on a Shimadzu EDX 7000P spectrometer  by the fundamental parameter method.Powder X-ray diffraction patterns of silicoaluminophosphate gels and the uncalcined SAPO-11 samples were recorded on a Bruker D8 Advance diffractometer  in CuKα radiation. The patterns were collected over a 2θ range from 5 to 40° with a scanning speed of 1° min. The phase analysis of the obtained X-ray diffraction patterns was performed by the DIFFRAC.EVA program using the PDF2 database. The crystallinity degree was assessed by the content of an amorphous halo in the range from 20 to 30°(2θ). −1 with a resolution of 2 cm−1. An Nd:YVO4 laser with a wavelength of 1064 nm and a power up to 1.5 W was used as an excitation source.Raman spectra of the silicoaluminophosphate gels were obtained on a FT-Raman Thermo Scientific Nicolet NXR 9650 Fourier spectrometer  in the range of 70–3800 cmThe size and morphological features of silicoaluminophosphate gels and SAPO-11 were detailed by field emission scanning electron microscopy (FE-SEM) with a Hitachi Regulus SU8220 scanning electron microscope . The images were taken in the mode of registration of secondary electrons at 2 kV accelerating voltage. The microstructure of the samples was also examined by transmission electron microscopy (TEM) on a Hitachi HT 7700 electron microscope . The images were recorded in the light field mode at an accelerating voltage of 100 kV.t-Plot approach. The pore size distribution was calculated by the BJH  model from the desorption branch. Prior to the analysis, fresh samples were calcined at 600 °C for 6 h.The BET surface area, the volume of micro- and mesopores were measured by the method of low-temperature nitrogen adsorption–desorption with a Nova 1200e sorptometer . The specific surface area was calculated by the multipoint BET method. The micropore volumes in the presence of mesopores were derived from a


XN), first observed in symmetric mesogenic dimers of the CB-n-CB series with an odd number of methylene spacers (n), as a twist–bend nematic (TBN). We show that the XN is unrelated to any of the elastic deformations  stipulated by the continuum elasticity theory of nematics. Results from molecular theory and computer simulations are used to illuminate the local symmetry and physical origins of the nanoscale modulations in the XN phase, a spontaneously chiral and locally polar nematic. We emphasize and contrast the differences between the XN and theoretically conceivable nematics exhibiting spontaneous modulations of the elastic modes by presenting a coherent formulation of one-dimensionally modulated nematics based on the Frank–Oseen elasticity theory. The conditions for the appearance of nematic phases presenting true elastic modulations of the twist–bend, splay–bend, etc., combinations are discussed and shown to clearly exclude identifications with the nanoscale-modulated nematics observed experimentally, e.g., the XN phase. The latter modulation derives from packing constraints associated with nonlinear molecules—a chiral, locally-polar structural organization indicative of a new type of nematic phase.The nature of the nanoscale structural organization in modulated nematic phases formed by molecules having a nonlinear molecular architecture is a central issue in contemporary liquid crystal research. Nevertheless, the elucidation of the molecular organization is incomplete and poorly understood. One attempt to explain nanoscale phenomena merely “shrinks down” established macroscopic continuum elasticity modeling. That explanation initially (and mistakenly) identified the low temperature nematic phase ( XN [Unexpectedly, nonlinear (“bent-core”) dimer molecules exhibit two distinct nematic phases. The lower-temperature nematic, initially termed NX , exhibitNX ,3.XN is driven by nematic elasticity . The id in ref.  when R.BXN has a single polar director m which is a C2 symmetry axis that roto-translates, generating a molecular length-scale 1-D modulation which confers form-chirality to the microstructure, i.e., it implies a new type of nematic organization, the so-called polar-twisted nematic, PTN.Forcing the applicability of continuum elasticity theory on the molecular scale constitutes a grave conflation of structure scales that renders the concept of the nematic director—its symmetries and canonical distortions—ill-defined, if not totally wrong. Moreover, it obscures the underlying physics responsible for the modulation. On the other hand, both molecular theory  and simuXN, focusing on the underlying physics of the molecular organization and the symmetries thereof. Results from molecular theory and simulations are used to highlight the distinguishing features of this new nematic phase and its successful description within the framework of the PTN model. In order to emphasize that the new phase is not an elastically modulated state of the conventional uniaxial nematic phase—TBN or otherwise—we present a systematic description of the 1-D spontaneously modulated states that derive from the classical Frank–Oseen theory of elasticity [XN.In this work we consider the nanoscale modulation observed in the asticity ,22, strePTN model is outlined in 7-CB dimers, supporting the PTN picture, are presented in XN phase; the conclusions are drawn in Terminology: For the clarity of the exposition to follow it is useful to stress some distinctions regarding the terminology used for the various nematic phases and states involved:TBN): This is a theoretical model, first formulated by R.B. Meyer [elastic deformations can be stabilized, under certain conditions, in a uniaxial nematic phase (UN). The twist–bend nematic (B. Meyer  on the bSBN): Another theoretical model, also first presented by R.B. Meyer, simultaneously with the TBN [UN developing stable states with spontaneous splay and bend elastic deformations is considered. The necessity for the formation of domains in the SBN model was pointed out in the original work.The splay–bend nematic : A theoretical model formulated on the basis of molecular interactions [m which, in turn, undergoes periodic roto-translation modulations over molecular length scales, thereby eliminating macroscopic polarity. This model has been proposed for the description of the experimental XN phase [The polar-twisted nematic  has the simplest supramolecular organization: As in ordinary liquids, there is no positional order in the UN. However, the molecules have long-range orientational order defining the UN’s “nematic director” n, an apolar local axis of complete rotational symmetry  . This suOseen and Zocher used continuum mechanics to describe such macroscopic deformations ,25. The n(r), by identifying three fundamental bulk distortions of n(r) that contribute to the total free energy density. These distortions, called splay, twist and bend  accounts for spatial deformations of the nematic director field, and bend , span man-field from the magnitudes of the elastic constants, typically on the order 10−8 Pa [11 Pa). One can infer the delicate nature of the forces involved in deforming the  10−8 Pa ; the elaUN nematics; different elastic contributions emerge in phases having lower point symmetries. This expression for the bulk elastic free energy density is often supplemented by two “surface terms” (see ref [Equation (1) is strictly valid for (see ref ), namelynsity P⊥  couples (i)The deformations extend over regions of spatial dimension (ii)The curvatures of the nematic director field are “soft” ((iii)The (iv)S shows negligible spatial variation in the presence of the elastic distortions.The principal value of the nematic order paramater (v)The changes in mass density, induced by the elastic distortions, are also negligible.The FOt, from which twist, bend and splay immerge as the three fundamental deformations of a uniaxial nematic continuum, is based on a number of assumptions regarding the local symmetry of the nematic medium and the length-scale of the director-field deformations. These are listed below (see for example ):(i)Theb, perpendicular to the nematic director n  that can possibly be induced by the splay or bend deformations has, within the FOt formulation, a necessarily negligible effect on the local symmetry of the molecular ordering and is sometimes referred to as phantom polarity. Similarly, a twist deformation would induce a chiral influence on the molecular conformations, whose magnitude is on the order of Regarding the symmetry condition (iii), it should be noted that a bend deformation introduces the bend vector or n see ; similarZ-axis, the director X-Y) perpendicular to Z and can vary only from plane to plane on moving along Z, i.e., We seek the possible stable states in which one or more of the elastic deformation elements X-Y plane. Thus, the modulation along the Z-axis can be monitored by the variations of both the magnitude and the direction of X-Y plane to another. Obviously, the unperturbed state (uniform Z. The deviation of the direction of (1)X-Y plane, the constant A comes with a positive sign.A quadratic contribution associated the magnitude of (2)A scalar coupling of (3)A pseudoscalar coupling, There are also quadratic combinations which can be represented by the set of two independent terms Proceeding in the framework of the FOt, the free energy is to be formulated in terms of the elastic deformation elements B and D are not fixed by any obvious physical considerations; in fact, the signs of these terms will be shown not to be critical to the 1-D modulations considered below.The sign of the pseudoscalar coupling constants Lastly, there are quadratic invariants of the form n(Z) and their couplings with n) state. An expression whose bulk part, in the 1-D modulated case, is essentially identical to the above expression  are broken locally but preserved globally in the spontaneously deformed states. It is worth noting here that s is a local axis of full rotational symmetry , and b is a local C2 axis preserving the symmetry (1)ψ; equivalently at constant ψ. Such modulations exclude the possibility of splay deformations.Modulations at constant magnitude of (2)ψ confined to oscillate along a single fixed axis in the X-Y plane. In this case the director reorients periodically while remaining on a fixed plane containing the Z-axis. Such modulations exclude twist deformations.Modulations with (3)ψ confined to oscillate along a single axis whose orientation is rotated on moving along the Z-axis. A combination of the previous two modes, i.e., We will limit our attention to periodic modulations of externally unbiased samples, implying that the spatially averaged bend, ions see :(1)ModuIn this case n along Z i.e., the UN. At the other end of the acceptable range of n perpendicular to Z. Minimization of T)N is stable relative to UN for t) of the modulation in this purely twisted nematic state has a lower bound given by Obviously, the state with TBN states—may be explored when TBN state, with equilibrium values n(Z). The latter lies within the acceptable range The stability of periodic states with intermediate values of TN and TBN states can be summarized as follows:In terms of the dimensionless parameters TN: stability relative to UN for modulation wavenumber TBN: stability relative to UN for modulation wavenumber g 1 range over which both the TBN and TN solutions exist and are stable relative to the UN. It is straightforward to show that, in that common range, the TBN is stable over the TN due to the condition ρ 1.Note that there is a common TN and the TBN states. In physical terms, the existence of some chiral aspect at the molecular level, and the strength of its coupling to the twist elastic deformation is a determining factor for the appearance of these states. Specifically, for the TBN state, there is no particular requirement regarding the bend elastic constant A 0, a negative value of Clearly, the pseudoscalar coupling parameter g and of the elastic constant ratio ρ. One might naively deduce from the relation TBN pitch.In down see . In otheTBN) was first demonstrated by R.B. Meyer [0P. More than two decades later, a twist–bend state was derived starting from the FOt but assuming a negative bend elastic constant, which makes it necessary to include higher order curvatures of the nematic director in the free energy [The possibility of an elastically modulated state of constant twist and bend . Note that the director modulations of Equation (5) lead to vanishing average splay and bend over a repeat length of the modulation. However, the singling out of a plane, in this case defined as the Z-independent expression in Equation (4), this form of the free energy density has a periodic Z-dependence of repeat length Z-range we consider the integrated free energy over a full repeat length of the free energy density. Assuming constant molecular density and degree of ordering, as dictated by the conditions (iv) and (v) in Unlike the UN domains. Note that the K13 and B terms do not contribute to the integrated free energy, but they do influence the free energy over fragments of SBN−UN domains will not be further considered here. Different mechanisms for the stabilization of SBN states are discussed in [Therefore, the modulated phase cannot be continuously stabilized for any finite ussed in .TSBN). Such a state, showing simple harmonic Z-dependence of the director components can be represented by the following parameterization:This can be equivalently viewed as a twist–bend modulation with periodically varying “cone angle”. The latter variation generates a splay deformation and the resulting total modulation can be termed as twist–splay–bend , the free energy density in this case reduces to:q is identified with the fundamental wavenumber k is an even multiple of q, i.e., Z-integration over the latter length yields:Obviously, for l, a continuous SBTN state can be stabilized for finite wavenumber q, under certain conditions for the parameters l, indicating that, unless specific boundary conditions favoring a finite l are imposed, the most stable state is the one for which TBN. Of course, as in the case of the SBN, stabilization of alternating domains over fragments of the repeat length are not in principle ruled out and in this case the overall stability is influenced also by the terms involving K13, B and D together with the free energy density at the interface of the alternating domains.It is apparent from this expression that for given TN and TBN are associated with a Z-independent free energy density (compare Equation (4) with Equations (6) and (8)), and these are the only states that can in principle be stable continuously over an arbitrary Z-range without the need of particular stabilizing boundary conditions. In summary, for the simple harmonic 1-D elastic modulations considered in this section, only the Z-range as well as the transverse X-Y sample dimensions are finite, implying that the stability will, in any case, be somehow influenced by boundary conditions. This has to be taken into account particularly in relation to the length scale of the modulations: Since the validity of the nematic elasticity FOt is restricted to modulations typically on the order of 1 μm or larger (see condition (i) in X, Y and Z dimensions of the sample should be orders of magnitude larger in order for the periodicity along the Z-direction to be allowed to develop and, furthermore, in order for the 1-D character of the modulation to avoid inhibition by lateral, boundary-surface-induced deformations. These considerations are of particular relevance to experimental attempts at stabilizing, identifying and characterizing states of truly elastic 1-D spontaneous modulations, such as the TBN or the SB.NNaturally, in actual samples, the modulation molecular order modulations with emphasis on the fundamental differences in the methodology and in the underlying physics vis a vis the elastic deformations of the director field n(r). These are quite distinct from the elastic modulations of the previous section, primarily in that the modulation length-scale is not restricted to macroscopic lengths but can extend down to molecular dimensions. Nanoscale modulations have been long known in smectic liquid crystals; these include the molecular density modulations characteristic of SmA and SmC (synclinic)  as well s and orientation ω relative to a phase-fixed macroscopic frame X, Y and Z. The orientation is often conveniently described in two steps, with the help of the so called “director frame” in which the distribution of molecular orientations is subject to specific symmetries. Thus the orientation of the molecular axes relative to the director frame is denoted by Z as the modulation axis and X, Y remaining arbitrary, the orientation Z-coordinate, X-Y plane and its axes can only change direction on moving along the Z-axis. Accordingly, the distribution function in this case is written as The modulations of molecular order in a nematic phase are directly reflected on the single-molecule distribution function via a statistical mechanical approximation for the evaluation of the average potential energy of a dimer molecule [To formulate molecule   formed by a variety of LC dimers with bent average structure, the CB-n-CB with odd-n  distance d and maintaining a (“bent-core”) configuration that confers to the overall molecule significant deviation from linearity. The crucial contribution to the effective potential comes from a term [Z axis), C2 axis of the phase), C2 axis and k is set by the intramolecular distance d. Finally, the effective potential is obtained by applying the mean field approximation. Despite the extreme simplicity of the molecular modeling and of the statistical mechanical treatment, the resulting effective potential m a term  of the fmolecule b. Note tI) fluid, the uniaxial nematic (UN) and the so called polar-twisted nematic (PTN) in which there is polar order along the director m, which roto-translates along the modulation direction Z at wavenumber k of the order of 1/d. The local symmetry of the phase is C2 while the global symmetry of the phase  is uniaxial about Z and apolar. Due to the molecular achirality, domains of opposite twisting sense  are thermodynamically equivalent. The thermodynamic stability of the PTN phase extends over reasonably broad ranges of the geometrical parameters of the molecular model and, depending on the particular values of these parameters, the PTN can be obtained, on lowering the temperature, either from the sequence PTN phase shows very strong polar ordering of the y-molecular (C2) axis along the polar director m, quantified by the order parameter For reasonable bend-angles P and of the modulation wave vector k (in units of 1/d) are shown in β. It is apparent that the transition temperature and the phase sequence leading to the TPN (either directly from the isotropic or Uvia N) are sensitive to the angle β; above a critical value of β, the UN is eliminated from the stable-phase sequence and the transition takes place directly from the isotropic fluid. Similarly, the polar order parameter P is sensitive to the angle β, as expected from the sensitivity of the molecular-shape-polarity to variations of that angle. The temperature dependence of P shows a gradual or abrupt increase at the onset of the modulated phase, depending on whether the transition is from the UN or directly from the isotropic fluid. Notably, k shows marginal dependence on the angle β as well as on the reduced temperature, aside from a rapid or abrupt (in the case of direct transition from the isotropic) rise at the onset of the modulated phase. This is in accord with the notion that the modulation is generated by the molecular packing and therefore k is essentially determined by the molecular geometry. The situation here is in marked contrast with the elastic modulation wave number The temperature dependences of the polar order parameter ants see .PTN phase. In marked contrast with the UN, the mesogenic units show strong polar ordering, m. The local quadrupolar ordering is also significantly different: the ordering tensor m; the other two, denoted by Z. Of course, neither of It is interesting to examine the ordering of the mesogenic units of the symmetric dimer molecule in the n under the respective twist and bend deformation. Whilst TBN state, each molecular segment M has its own principal axis frame in the PTN phase  and therefore the angle XN phase [L).Obviously, the angle NX phase ,39. In Faxes see b, i.e., PTN is parameterized in terms of a wave vector k and a variety of deviation angles TBk and TBN state of modulated uniaxial nematic elastic continua. These distinct differences have often been overlooked PTN phase, relative to the isotropic fluid and the UN phase, found over a range of the model parameters, does not exclude the possibility that, over the same parameter range, some other LC phase  or even a solid, would be more stable than the PTN.The thermodynamic stability of the (2)PTN phase be influenced if the primitive molecular model were enriched by realistic features of the actual molecules, e.g., the CB-n-CB dimers of odd n, forming the experimental XN phase? Such features include the extensive flexibility of the spacer chain and the related partition of the molecular interactions into successions of aromatic–aliphatic–aromatic zones which are thought to promote structural microsegregation.How would the stability and the main structural characteristics of the The results regarding the structure and stability of the Molecular simulations provide a fairly reliable means of elucidating such points as the stable phase under given conditions is produced by the simulation and the molecular structure can accommodate considerable complexity, as opposed to the molecular theory approach wherein the various phases are predetermined, their relative stability is assessed on the basis of a postulated form of the free energy  and computational tractability restricts the modeling of the molecular structure and interactions to levels of minimal complexity. 7-CB dimer molecules [Indeed, both of the above issues were addressed by molecular simulations using a fairly realistic parameterization see c of the olecules . The resk is done with respect to the conformationally averaged distance P is obtained from the simulations as the averaged projection of the molecular y-axis of m. It is apparent from Although the molecular models in XN phase with the TBN model were pointed out in a recent paper, The twist bend nematic: a case of mistaken identity [XN with elasticity models—have chosen  to broaden the notion of the twist–bend nematic. Thus, they directly advocate that there is no unique TBN model but an evolving cluster of different TBN models, not necessarily based on elasticity, into which even the PTN model is subsumed. In essence, the authors trivialize the question of the structure and underlying physics operative in the XN to mere nomenclature: The XNis defined as TBN, therefore, whatever it takes to describe correctly the XN is by definition included in their evolving cluster of TBN models.The discrepancies resulting from identifying the identity . Since tidentity ,42 appeaidentity ; a detaiidentity ). BrieflXN phase is two or more orders of magnitude below the length scale for the applicability of the FOt of elasticity, thus pointing directly to a different underlying physical mechanism. Moreover, the scale difference is reflected in the magnitude of the bend-induced polarity in the TBN .Aside from the length-scale and symmetry discrepancies, the mix up of continuum with microscopic concepts leads to flawed conclusions on well-established matters. For example, what are termed in  as twistden (see ). Anotheden  down to the nanoscale. The length-scale, structure, and symmetry differences between the elasticity-based TBN and the molecular packing-based PTN models are enormous. These are graphically summarized in Of course, we do not adopt the view of an evolving “cluster of TBN and PTN models share two common features: (i) both phases are positionally disordered  and (ii) both present a 1-D modulation of the orientational order, and this introduces a fundamental wave number k. However, the respective values for this wave number, The PTN and the TBN models are summarized in TBN and PTN are mutually exclusive, leaving no room for physical consistency in descriptions which arbitrarily combine features from both macro- and microscopic regimes to produce hybrid interpretations.The main differences between the XN phase of odd-n-linked CB-n-CB dimers was discovered in 1991 [XN phase was branded TBN, despite the incongruency of modulation length scales—continuum versus molecular. One might reasonably ask, “on what length scales might continuum descriptions of soft matter apply?” A minimal answer for fluid phases would be, “At scales larger than those showing structure in its radial distribution function”. For simple liquids that distance is multiple molecular dimensions. The experimental helical pitch exhibited by the XN phase of the CB-n-CB dimers (PTL ~8 nm) [UN—the high-temperature, apparently uniaxial phase above the lower temperature XN exhibited by nonlinear mesogens—could transform directly into the nanometer-scale, modulated structure in the XN. Interestingly, there are experimental indications [XN phase of the CB-n-CB is in fact not obtained from a UN phase on lowering the temperature but from a phase consisting of fragments of XN-like aggregates (cybotactic groups) of opposite handedness exhibiting global uniaxial symmetry and achirality on the NMR time-scale. The transition to the XN phase in that case proceeds via the self-assembly of aggregates of the same handedness to form macroscopic XN domains. Molecular shape and local packing ultimately determine the nature of the long range supramolecular organization found in LCs, and when new molecular shapes are explored, unexpected phases are discovered . This wa in 1991 . Two decT ~8 nm) ,44,45,46T ~8 nm) . It remaications  supportin in the continuum approximation (macroscopic) are often mistakenly combined in the literature [XN phase have nothing to do with elasticity and are generated by molecular organization at the nanoscale, i.e., that bent-core molecules exhibit a genuinely different nematic state and not a spontaneous elastic deformation of the conventional UN phase. Despite the large disparity between length scales and phase symmetries, the elastic deformations of terature  with polTBN state , consider the implications of the analysis in Lastly, regarding the possibility of preparing and identifying experimentally a true TBN model to account for the experimentally-established fundamental properties of the XN phase, similar length-scale and symmetry considerations apply to other dubious identifications [SBN. In summary, as is generally the case in condensed matter, macroscopic physical models break down at the nanoscale.Although the present discussion focused on the inappropriateness of using an elasticity-based ications ,19,47 of


Africa is challenged by the emergence of antimicrobial resistance (AMR). In order to improve patient management and to optimise approaches to curb the spread of antimicrobial resistance, we examined knowledge and perceptions of AMR and antibiotics prescription practices of HCW  in Lambaréné, Gabon.We conducted a self-administered, questionnaire-based survey in HCW at the regional referral hospital, a medical research centre, and peripheral health care facilities. The proportions of correct responses to questions were determined and compared between physicians and nurses using Fisher’s Exact test.p = 0.028).A total of 47 HCW took part in the survey. Of those, 64% (30/47) recognised antibiotic resistance as a major public health issue in Gabon, but only 14/47 (30%) recognised it as a problem in their health facility. Of note, 37/47 (79%) recognised excessive use of antibiotics without microbiological confirmation in case of infection, and buying antibiotics without a prescription, as possible cause of antimicrobial resistance. Some HCW  reported having prescribed antibiotics because the patients asked for them; and a total of 15/47 (32%) responded that antibiotics could help patients recover faster when added to malaria treatment. Compared to nurses, most of the physicians recognised that excessive use of antibiotics without microbiological confirmation of infection could contribute to AMR spread (18/19 (95%) vs 19/28 (68%); Most HCW recognised AMR as public health issue. However, a quarter of the participants did not know about the causes fostering the emergence of antimicrobial resistance. There is a need to perform regular HCW training in antimicrobial prescription, and to set up an antimicrobial stewardship program.The online version contains supplementary material available at 10.1186/s13756-022-01079-x. Antimicrobial resistance (AMR) is challenging in low-income countries (LMICs) because of the high prevalence of infections and irrational use of antimicrobials –3. Poor Klebsiella spp. were gentamicin-resistant; 30%, were resistant to tazobactam, and 18–79% were resistant to commonly-used cephalosporin antibiotics .There was a high fluoroquinolone resistance rate, ranging from 18% ciprofloxacin to 54% nalidixic acid resistance  years.p = 0.89), the type of health facility (p = 0.45), the professional category (p = 0.38), and the length of service (p = 0.15) were not associated with a better awareness of AMR. The overall knowledge about possible causes of antimicrobial resistance spread was limited. The attitudes most frequently selected by HCW to be associated with AMR spreading were ‘excessive use of antibiotics without microbiological confirmation of infection’  and ‘buying antibiotics without a prescription’ . In general, the proportion of appropriate responses to the questions related to possible cause of AMR spread was higher among physicians than among nurses  of the prescribers responded that antimicrobial resistance is a problem in Gabon, while 30% 14/47) responded that it is a problem in their health facilities. A total of 70% (33/47) of health workers responded that there is uncoordinated antimicrobial prescription in their health facility; and 81% (38/47) responded that self-medication of antimicrobials could contribute to antimicrobial resistance. Educational level (4/47 respp = 0.023), reported that antibiotics, when added to malaria treatment, help the patients recover more quicker; 19/19 (100%) of physicians vs. 20/28(71%) nurses (p = 0.02) reported that antibiotics are always required for treating diarrhoea  of participants across all professional groups prescribed at least three different groups of antibiotics during the week prior to the survey; 28% (13/47) reported to have prescribed antibiotics because the patients asked for them. The majority  of prescribers did not receive a recent training in antimicrobial prescription during the last year. Most of the HCW  referred to their own experience to choose the antibiotic to be prescribed to the patient; 21% (10/47) requested microbiological culture and antimicrobial susceptibility testing before prescribing antibiotics  respondents strongly agreed that it would be very useful to perform regular training on antimicrobial prescriptions; and to have guidelines for antibiotic prescription; as well as that the vast majority agreed to determine the local antimicrobial resistance profile to guide empirical prescription 90% (42/47) Table . Across As per our knowledge, this is the first study assessing AMR knowledge and antibiotics prescription practice among HCW in Gabon.Similar to other studies, the prescribers responded that antimicrobial resistance is a global and national public health challenge –19. HoweRegarding potential interventions to combat AMR based on our findings, most favourite measures include: (1) to establish a national AMR surveillance program; and (2) to avail clinical microbiology laboratory capacity and local guidelines for rational use of antibiotics Table ; (3) to Escherichia coli/Shigella spp. (30.2%), enterotoxigenic Escherichia coli (24.6%), followed by G. lamblia (13.7%), Cryptosporidium spp. (12.9%), and rotavirus (9.5%) [As expected, most physicians had a good attitude concerning the prescription of antimicrobials, compared to nurses. However, all of the physicians reported that antibiotics are always required for diarrhoea. This is an unexpected finding, which can be possibly explained by the fact that the most-frequently isolated pathogens in diarrhoea of children under five years in Lambaréné and surroundings were entero-invasive s (9.5%) .The strength of this study is that we included all level of health facilities in the Lambaréné region. Furthermore, this study provides valuable information on AMR and antimicrobial prescription, that could help to design appropriate local antimicrobial stewardship measures. Gabon has no formal AMR surveillance system as recommended by WHO . It is iAs with most surveys, our study does have certain limitations; for example, there is a possibility that respondents gave what was perceived as socially most acceptable answers. Furthermore, the sample size in our study is low compared with other studies conducted earlier in Africa reflecting the lack of HCW particularly outside the capitals in sub-Saharan Africa. We invited all HCW in the target health facilities to participate without restrictions. The small sample size of our study may limit the generalisability of our findings to national level, and the interpretation of our study results should be done with caution. There is a need to search for funding to conduct a national survey to further understand the issue of AMR in Gabon and to take appropriate actions to reduce its spread.Prescribers in Lambaréné recognise the AMR as a public health challenge in health facilities and in Gabon. Prescribers strongly believed that antimicrobial stewardship should be implemented in their health facilities to reduce the spread of AMR. There is a need to set up regular (re)training programs in antimicrobial prescription across health facilities in Lambaréné, Gabon.Additional file 1. Study questionnaire in English.