bluuebunny/crossref_metadata_2025 huggingface dataset:
Isolation, phytochemistry, characterization, biological activity, and application of Morinda officinalis How oligosaccharide: a review
Authors: Yue Jiahui , Xia Wenxin , Wang Yushu , Zhang Yuanyuan , Zhang Yan , Li Yuxin , Wang Lulu , Li Cunbing , Li Tingting , Fu Xueyan
Published: November 2023

Morinda officinalis How oligosaccharide (MOO) stands as one of the principal active constituents of M. officinalis How, widely employed in traditional Chinese medicine. The methods for MOO extraction predominantly encompass hot water extraction, ethanol extraction, ultrasonic-assisted extraction, and microwave-assisted extraction. Distinct extraction techniques yield varying MOO quantities. MOO encompasses a diversity of oligosaccharides, including bajijiasu, sucrose, 1-kestose, nystose, mannose, 1F-fructofuranosylnystose, 1,1,1,1-kestohexose, fructoheptasaccharide, inulin-type hexasaccharide, inulin-type heptasaccharide, inulotriose, inulotetraose, inulopentaose, and mannose. MOO exhibits a wide spectrum of biological activities, exerting specific effects on the nervous system, cardiovascular system, motor system, reproductive system, and immune system. It demonstrates antidepressant properties, offers potential in mitigating Alzheimer’s disease, stimulates angiogenesis, and possesses anti-osteoporotic and other pharmacological effects. Clinically, when combined with various antidepressants, MOO exhibits specific therapeutic efficacy across multiple forms of depression. As a naturally occurring plant oligosaccharide, MOO holds diverse pharmaceutical applications. This article conducts a review of the latest extraction and purification methodologies, structural characterization analysis, biological activity assessment, and clinical applications of MOO. Such a comprehensive analysis yields innovative insights for advancing the research and application of MOO in the future.
Synchronous colonal and jejunal adenocarcinomas leading to intussusception in an adult female suffering from celiac disease
Authors: Sadeghi Mirsalim Seyyed , Haghshenas Negin , Khanghah Ali Samady
Published: November 2023

Coeliac disease, a relatively rare gluten-sensitive enteropathy, correlates with small intestinal malignancies, especially lymphoma and adenocarcinoma. Any kind of masses, whether malignant or benign, in the way of natural peristaltic action may increase the probability of intussusception, telescoping invagination of the proximal segment into the distal one causing an obstruction. We report a case of synchronous adenocarcinomas of the colon and jejunum in a 3-year-old female presenting as bowel obstruction. She also had coeliac disease. During laparotomy, the surgical team encountered jejunojejunal intussusception as the cause of obstruction. There are direct relationships among coeliac disease, increased risk of adenocarcinoma, and repeated intussusceptions in the absence of mass in adults. The intussusception phenomenon in an adult necessitates investigating a more severe lead point than simple mesenteric lymphadenopathy.
Multiband cross-correlated radio variability of the blazar 3C 279
Authors: Mohana A Krishna , Gupta Alok C , Marscher Alan P , Sotnikova Yulia V , Jorstad S G , Wiita Paul J , Cui Lang , Aller Margo F , Aller Hugh D , Kovalev Yu A , Kovalev Y Y , Liu Xiang , Mufakharov T V , Popkov A V , Mingaliev M G , Erkenov A K , Nizhelsky N A , Tsybulev P G , Zhao Wei , Weaver Z R , Morozova D A
Published: November 2023

We present the results of our study of cross-correlations between long-term multiband observations of the radio variability of the blazar 3C 279. More than a decade (2008–2022) of radio data were collected at seven different frequencies ranging from 2 to 230 GHz. The multiband radio light curves show variations in flux, with the prominent flare features appearing first at higher-frequency and later in lower-frequency bands. This behaviour is quantified by cross-correlation analysis, which finds that the emission at lower-frequency bands lags that at higher-frequency bands. Lag versus frequency plots are well fit by straight lines with negative slope, typically ∼−30 day GHz−1. We discuss these flux variations in conjunction with the evolution of bright moving knots seen in multiepoch Very Long Baseline Array maps to suggest possible physical changes in the jet that can explain the observational results. Some of the variations are consistent with the predictions of shock models, while others are better explained by a changing Doppler beaming factor as the knot trajectory bends slightly, given a small viewing angle to the jet.
High temperatures are associated with reduced cognitive performance in wild southern pied babblers
Authors: Soravia Camilla , Ashton Benjamin J. , Thornton Alex , Ridley Amanda R.
Published: November 2023

Global temperatures are increasing rapidly. While considerable research is accumulating regarding the lethal and sublethal effects of heat on wildlife, its potential impact on animal cognition has received limited attention. Here, we tested wild southern pied babblers (
Turdoides bicolor
) on three cognitive tasks (associative learning, reversal learning and inhibitory control) under naturally occurring heat stress and non-heat stress conditions. We determined whether cognitive performance was explained by temperature, heat dissipation behaviours, individual and social attributes, or proxies of motivation. We found that temperature, but not heat dissipation behaviours, predicted variation in associative learning performance. Individuals required on average twice as many trials to learn an association when the maximum temperature during testing exceeded 38°C compared with moderate temperatures. Higher temperatures during testing were also associated with reduced inhibitory control performance, but only in females. By contrast, we found no temperature-related decline in performance in the reversal learning task, albeit individuals reached learning criterion in only 14 reversal learning tests. Our findings provide novel evidence of temperature-mediated cognitive impairment in a wild animal and indicate that its occurrence depends on the cognitive trait examined and individual sex.
Dispersal modes affect Rhamnaceae diversification rates in a differentiated manner
Authors: Chen Yong-Sheng , Muellner-Riehl Alexandra N. , Yang Yi , Liu Jian , Dimitrov Dimitar , Luo Ao , Luo Yuan , Sun Hang , Wang Zhi-Heng
Published: November 2023

The evolution of dispersal modes has been proposed to promote the diversification of angiosperms. However, little is known about the relative impact of different dispersal modes on plant diversification. We test the association between dispersal modes and diversification rates using Rhamnaceae, the cosmopolitan buckthorn family, as a model. We found that species with diplochory have the highest diversification rates followed by those with myrmecochory and ballistic dispersal, while lineages dispersed by vertebrates and wind have relatively low diversification rates. The difference in diversification rates may be closely linked to the difference in dispersal distance and ecological interactions implied by each dispersal mode. Species which disperse over larger geographical distances may have much higher speciation rates due to the increased chance of establishing isolated populations due to geological barriers or habitat fragmentation. However, long-distance dispersal may also increase the chance of extinction. By contrast, species with short-distance dispersal modes may have low speciation rates. Complex interactions with the surrounding environment may, however, impact diversification rates positively by increasing plant survival and reproductive success.
Vibrio chanodichtyis sp. nov., isolated from the intestine of swordfish Chanodichthys dabryi
Authors: Wu Ningning , Liu Le , Liu Kai , Shao Jiahui , Nie Zhijuan , He Jian , Shen Qirong
Published: November 2023

A Gram-stain-negative, facultatively anaerobic, motile, curved-rod-shaped flagellated bacterium, designated DSL-7T, was isolated from the intestine of Chanodichthys dabryi in the Yangtze river, PR China. The strain grew optimally in tryptone soy broth medium at 37 °C, pH 7.0 and with 1 % (w/v) NaCl. Strain DSL-7T showed less than 96.2 % 16S rRNA gene sequence similarity to type strains of the genus

Vibrio

. Phylogenetic analysis based on genomes indicated that strain DSL-7T belonged to the genus

Vibrio

and formed a subclade with

Vibrio mimicus

NCTC 11435T,

Vibrio metoecus

OP3HT,

Vibrio cholerae

ATCC 14035T,

Vibrio albensis

ATCC14547T,

Vibrio paracholerae

OP3HEDC-792T and Vibrio tarriae 2521-89T. The average nucleotide identity (ANI) and in digital DNA–DNA hybridization (dDDH) values between DSL-7T and closely related type strains were below the accepted threshold to delineate a new species of 95 and 70 %, respectively. The major cellular fatty acids were summed feature 3 (C16 : 1
 ω7c and/or C16 : 1
 ω6c), C16 : 0, summed feature 8 (C18 : 1
 ω7c and/or C18 : 1
 ω6c) and C14 : 0. The genomic DNA G+C content was 47.6 mol%. Based on the phenotypic, chemotaxonomic, phylogenetic and genomic data, strain DSL-7T represents a novel species of the genus

Vibrio

, for which the name Vibrio chanodichtyis sp. nov. is proposed, with strain DSL-7T (=KCTC 92851T=CCTCC AB 2022396T) as the type strain.
Yamadazyma sisaketensis f.a., sp. nov. and Yamadazyma koratensis f.a., sp. nov., two novel ascomycetous yeast species from mushrooms and cocoa leaves in Thailand, and reassignment of Candida andamanensis, Candida jaroonii and Candida songkhlaensis to the genus Yamadazyma
Authors: Khunnamwong Pannida , Nualthaisong Panadda , Sakolrak Baramee , Nutaratat Pumin , Limtong Savitree
Published: November 2023

Six strains representing two novel ascomycetous yeast species were isolated from mushroom fruiting bodies and cocoa leaves collected in Thailand. Analysis of the internal transcribed spacer (ITS) regions and the D1/D2 domains of the large subunit rRNA gene sequences showed that the six strains were divided into two groups. The first group consisted of four strains (DMKU-SSK46, DMKU-SK1, SCCL3-5 and SCCL19-3), that were closely related to the type strains of Candida conglobata, Candida insectorum, Yamadazyma dushanensis, Yamadazyma mexicana and Yamadazyma riverae, but with 12–14 (2.5–2.9 %) and 28–50 (5.4–8.8 %) nucleotide substitutions in the D1/D2 domains and the ITS regions, respectively. However, two strains (DMKU-KMY40 and DMKU-KO18) of the second group differed from a group of described species, Candida diddensiae, Candida dendronema, Candida germanica, Candida kanchanaburiensis, Candida naeodendra, Candida vaughaniae and Yamadazyma siamensis by 8–15 (1.5–2.8 %) and 45–53 (8.2–9.6 %) nucleotide substitutions in the D1/D2 domains and the ITS regions, respectively. Phylogenetic analysis based on the concatenated sequences of the ITS regions and D1/D2 domains showed that these strains represented two species of the Yamadazyma clade that were distinct from the other related species. Based on the phylogenetic analysis and phenotypic characteristics, these six strains were assigned to two novel species of the genus Yamadazyma, although formation of ascospores was not observed. Yamadazyma sisaketensis f.a., sp. nov., is proposed for the first group (four strains). The holotype is TBRC 17139T (ex-type culture: PYCC 9797). The MycoBank number is MB 849637. Yamadazyma koratensis f.a., sp. nov. is proposed for the second group (two strains). The holotype is TBRC 14868T (ex-type culture: PYCC 8907). The MycoBank number is MB 849638. In addition, it is proposed that Candida andamanensis, Candida jaroonii and Candida songkhlaensis are reassigned to the genus Yamadazyma as Yamadazyma andamanensis comb. nov., Y. jaroonii comb. nov. and Y. songkhlaensis comb. nov., respectively.
Hematologic abnormalities after COVID-19 vaccination: A large Korean population-based cohort study
Authors: Choi Hye Sook , Kim Min-Ho , Choi Myeong Geun , Park Joo Hun , Chun Eun Mi
Published: November 2023

Adverse hematologic events have been reported after COVID-19 vaccination. The objective of this study was to investigate whether hematologic abnormalities develop after COVID-19 vaccination. Retrospective cohort analyses of data from the Korean National Health Insurance Service (KNHIS) database were conducted from July 2022 to August 2023. We randomly selected data of half of those living in Seoul City as of January 1, 2021 with their diagnostic records up to December 31, 2021. The included participants were vaccinated and nonvaccinated persons aged 20 years or older (n= 4,203,887). Hematologic abnormalities after COVID-19 vaccination were identified as nutritional anemia, hemolytic anemia, aplastic anemia, coagulation defects, and neutropenia using International Classification of Diseases, Tenth Revision codes after index date. Incidence rates of hematologic abnormalities in the vaccination group 3 months after vaccination were significantly higher than those in the nonvaccinated group: 14.79 vs. 9.59 (P<.001) for nutritional anemia, 7.83 vs. 5.00 (P<.001) for aplastic anemia, and 4.85 vs. 1.85 (P<.001) for coagulation defects. COVID-19 mRNA vaccine was associated with higher development of nutritional anemia (odds ratio [OR], 1.230 [95% CI, 1.129-1.339], P<.001) and aplastic anemia (OR, 1.242 [95% CI, 1.110-1.390], P<.001) than the viral vector vaccine. The risk of coagulation defects was increased (OR, 1.986 [95% CI, 1.523-2.589], P<.001) after vaccination, and there was no risk difference between mRNA vaccine and viral vector vaccine (OR, 1.075 [95% CI, 0.936-1.233], P=.306). In conclusions, COVID-19 vaccination increased the risk of hematologic abnormalities. When administering the COVID-19 vaccine, careful observation will be necessary after vaccination.
ERBB2 R599C variant is associated with left ventricular outflow tract obstruction defects in human
Authors: Ampuja M , Selenius S , Paatero I , Chowdhury I , Villman J , Broberg M , Ranta A , Ojala T , Chong JX , Bamshad M , Priest JR , Varjosalo M , Kivelä R , Helle E
Published: November 2023

Background and aims

Non-syndromic congenital heart defects (CHD) are occasionally familial and left ventricular out flow tract obstruction (LVOTO) defects are among the subtypes with the highest hereditability. The aim of this study was to evaluate the pathogenicity of a heterozygousERBB2variant R599C identified in three families with LVOTO defects.

Methods

Variant detection was done with exome sequencing. Western blotting, digital PCR, mass spectrometry (MS), MS-microscopy and flow cytometry were used to study the function of theERBB2variant R599C. Cardiac structure and function were studied in zebrafish embryos expressing humanERBB2WT or R599C. Patient-derived human induced pluripotent stem cell cardiomyocytes (hiPS-CM) and endothelial cells (hiPS-ECs) were used for transcriptomic analyses.

Results

While phosphorylation of the ERBB2 R599C receptor was not altered, the variant affected dramatically the binding partners of the protein and lead to mislocalization of ERBB2 from plasma membrane to ER and mitochondria. Expression of human ERBB2 R599C in zebrafish embryos resulted in cardiomyocyte hypertrophy, increased cardiac wall thickness, and impaired fractional shortening, demonstrating that the mutant receptor induces functional and structural defects during heart development. Transcriptomic analyses of hiPS-ECs and hiPS-CMs from a patient with the R599C variant indicated aberrant expression of genes related to cardiovascular system development and abnormal response to oxidative stress in both cell types.

Conclusion

The heterozygous variantERBB2R599C leads to abnormal cellular localization of the ERBB2 receptor inducing structural changes and dysfunction in the zebrafish embryo heart. This evidence suggests ERBB2 as a novel disease gene for CHD.
Phenotype Execution and Modelling Architecture (PhEMA) to support disease surveillance and real-world evidence studies: English sentinel network evaluation
Authors: Jamie Gavin , Elson William , de Lusignan Simon , Kar Debasish , Wimalaratna Rashmi , Hoang Uy , Meza-Torres Bernardo , Forbes Anna , Hinton Will , Anand Sneha , Ferreira Filipa , Ordonez-Mena Jose , Agrawal Utkarsh , Byford Rachel
Published: November 2023

Objective

To evaluate Phenotype Execution and Modelling Architecture (PhEMA), to express sharable phenotypes using Clinical Query Language (CQL) and intensional SNOMED CT Fast Healthcare Interoperability Resources (FHIR) valuesets, for exemplar chronic disease, sociodemographic risk factor and surveillance phenotypes.

Method

We curated three phenotypes: Type 2 diabetes (T2DM), excessive alcohol use and incident influenza-like illness (ILI) using CQL to define clinical and administrative logic. We defined our phenotypes with valuesets, using SNOMED’s hierarchy and expression constraint language (ECL), and CQL, combining valuesets and adding temporal elements where needed. We compared the count of cases found using PhEMA with our existing approach using convenience datasets.

Results

The T2DM phenotype could be defined as two intensionally defined SNOMED valuesets and a CQL script. It increased the prevalence from 7.2% to 7.3%. Excess alcohol phenotype was defined by valuesets that added qualitative clinical terms to the quantitative conceptual definitions we currently use; this change increased prevalence by 58%, from 1.2% to 1.9%. We created an ILI valueset with SNOMED concepts, adding a temporal element using CQL to differentiate new episodes. This increased the weekly incidence in our convenience sample (weeks 26 to 38) from 0.95 cases to 1.11 cases per 100,000 people.

Conclusions

Phenotypes for surveillance and research can be described fully and comprehensibly using CQL and intensional FHIR valuesets. Our use case phenotypes identified a greater number of cases, whilst anticipated from excessive alcohol this was not for our other variable. This may have been due to our use of SNOMED CT hierarchy.
An electronic cigarette pod system delivering 6-methyl nicotine, a synthetic nicotine analog, marketed in the United States as “PMTA exempt”
Authors: Jordt Sven E. , Jabba Sairam V. , Silinski Peter , Berman Micah L.
Published: November 2023

As of April 14, 2022, the United States Food and Drug Administration (FDA) has been authorized to regulate tobacco products containing nicotine from any source, including synthetic, requiring manufacturers to submit a premarket tobacco product application (PMTA). A recent report by the World Health Organization (WHO) warned that non-nicotine tobacco alkaloids or other synthetic nicotine analogs could be used by manufacturers to bypass regulatory schemes focusing on nicotine alone. From October 2023 on, vape stores in the United States started selling a new electronic cigarette pod system, named Spree Bar, advertised as “PMTA exempt”, with youth-appealing flavors and advertising. The products are marketed as containing “Metatine”, a trademarked name for 6-methyl nicotine, a synthetic nicotine analog patented by a Chinese electronic cigarette manufacturer. Here we used liquid chromatography-mass spectrometry (LCMS) to confirm the presence of a chemical species with the molecular weight of 6-methyl nicotine in Spree Bar e-liquids. The FDA needs to determine whether, in its view, 6-methyl nicotine is a form of “nicotine” within the meaning of the Tobacco Control Act, or whether 6-methyl nicotine can be regulated as a drug under the Federal Food, Drug, and Cosmetic Act (FDCA).
Hi-C2B: Optimised detection of chromosomal contacts within synchronised meioticS. cerevisiaecells
Authors: Wright Ellie M. , Schalbetter S. , Neale Matthew J.
Published: November 2023

Hi-C, a genome-wide chromosome conformation capture assay is a powerful tool used to study three-dimensional genome organisation by converting physical pairwise interactions into counts of pairwise interaction. To study the many temporally regulated facets of meiotic recombination inS. cerevisiaethe Hi-C assay must be robust such that fine- and wide-scale comparisons between genetic datasets can be made. Here we describe an updated protocol for Hi-C (Hi-C2B) that generates reproducible libraries of interaction data with low noise and for a relatively low cost.
One-pot Golden Gate Assembly of an avian infectious bronchitis virus reverse-genetics system
Authors: Bilotti Katharina , Keep Sarah , Sikkema Andrew P. , Pryor John M. , Kirk James , Foldes Katalin , Doyle Nicole , Wu Ge , Freimanis Graham , Dowgier Giulia , Adeyemi Oluwapelumi , Tabatabaei S. Kasra , Lohman Gregory J.S. , Bickerton Erica
Published: November 2023

Avian infectious bronchitis is an acute respiratory disease of poultry of particular concern for global food security. Investigation of Infectious Bronchitis Virus (IBV), the causative agent of avian infectious bronchitis, via reverse genetics enables deeper understanding of virus biology and a rapid response to emerging variants. Classic methods of reverse genetics for IBV can be time consuming, rely on recombination for the introduction of mutations, and, depending on the system, can be subject to genome instability and unreliable success rates. In this study, we have applied data-optimized Golden Gate Assembly design to create a rapidly executable, flexible, and faithful reverse genetics system for IBV. The IBV genome was divided into 12 fragments at high-fidelity fusion site breakpoints. All fragments were synthetically produced and propagated inE. coliplasmids, amenable to standard molecular biology techniques for DNA manipulation. The assembly can be carried out in a single reaction, with the products used directly in subsequent viral rescue steps. We demonstrate the use of this system for generation of point mutants and gene replacements. This Golden Gate Assembly-based reverse genetics system will enable rapid response to emerging variants of IBV, particularly important to vaccine development for controlling spread within poultry populations.
Identification and characterization of new structural scaffolds modulating the activity ofMycobacterium tuberculosisdihydroneopterin aldolase (FolB)in vitro
Authors: Falcão Virginia Carla de Almeida , Czeczot Alexia de Matos , Alam Mohammad Maqusood , Park Kyu-Ho Paul , Heo Jinyeong , Woo Minjeong , Camini Ana Micaela , Timmers Luis Fernando Saraiva Macedo , Shum David , Perelló Marcia Alberton , Basso Luiz Augusto , Machado Pablo , Bizarro Cristiano Valim , Delorme Vincent
Published: November 2023

Antifolates were among the first broad-spectrum compounds used as antimycobacterial agents and can still be of use when no other therapeutic options are available. The discovery of compounds targeting this essential pathway could lead to new therapeutic agents to treat tuberculosis (TB). In particular, the enzyme required for the conversion of 7,8-dihydroneopterin (DHNP) to 6-hydroxymethyl-7,8-dihydropterin (HP) and glycolaldehyde (GA) in the folate pathway (MtbFolB, a dihydroneopterin aldolase - DHNA, EC 4.1.2.25), has received little attention as a potential drug target. Here, we conducted a small-scale diversity screening to identifyMtbFolB inhibitors using a microplate-based enzyme inhibition assay. About 6,000 compounds were assembled for the screening and 19 hits were identified, spanning 5 independent clusters. These compounds were tested in dose-response studies and active compounds selected for kinetic inhibition and time-dependent inhibition studies, leading to compounds with IC50values ranging from 2.6 to 47 µM. A preliminary structure activity analysis was performed, revealing that bi-sulfonamide compounds could be explored for further optimizations. Docking studies highlighted two modes of binding for pyrazol-3-one compounds and, for the sulfonamide series, indicated several interactions with the catalytic Tyrosine-54 (Tyr54D) and Lysine-99 (Lys99A) residues ofMtbFolB. The sulfonamide compound13represents the first identified compound directed againstMtbFolB with an antimycobacterial activity.
CD56/NCAM mediates cell migration of human NK cells by promoting integrin-mediated adhesion turnover
Authors: Martinez Amera L. , Shannon Michael J. , Sloan Tyler , Mace Emily M.
Published: November 2023

Natural killer (NK) cells patrol tissue to mediate lysis of virally infected and tumorigenic cells. Human NK cells are typically identified by their expression of neural cell adhesion molecule (NCAM, CD56), yet, despite its ubiquitous expression on NK cells, CD56 remains a poorly understand protein on immune cells. CD56 has been previously demonstrated to play roles in NK cell cytotoxic function and cell migration. Specifically, CD56-deficient NK cells have impaired cell migration on stromal cells and CD56 is localized to the uropod of NK cells migrating on stroma. Here, we show that CD56 is required for NK cell migration on ICAM-1 and is required for the establishment of persistent cell polarity and unidirectional actin flow. The intracellular domain of CD56 (NCAM-140) is required for its function, and the loss of CD56 leads to enlarged actin foci and sequestration of phosphorylated Pyk2, accompanied by increased size and frequency of activated LFA-1 clusters. Together, these data identify a role for CD56 in regulating human NK cell migration through modulation of actin dynamics and integrin turnover.
Stable long-term individual variation in chimpanzee technological efficiency
Authors: Berdugo S. , Cohen E. , Davis A. J. , Matsuzawa T. , Carvalho S.
Published: November 2023

Using tools to access hard-to-reach and high-quality resources, such as termites, honey, and nuts, initiated a fundamental adaptive shift in human and nonhuman primate cognitive and behavioural evolution. Variation in the efficiency of extracting calorie-rich and nutrient-dense resources directly impacts energy expenditure, and potentially has significant repercussions for cultural transmission where model selection biases are employed during skill acquisition. Assessing variation in efficiency is key to understanding the evolution of complex behavioural traits in primates. Yet, individual-level differences beyond age- and sex-class in primate extractive foraging efficiency have never been investigated. Here, we used 25 years (1992– 2017) of video data of the Bossou chimpanzee community (Guinea), to investigate whether individual differences in nut-cracking efficiency exist across the life span of chimpanzees aged ≥ 6 years. Data from 3,882 oil-palm nut-cracking bouts from over 800 hours of observation were collected. We found long-term stable and reliable individual differences in four (out of five) measures of efficiency. We found no sex effect, challenging previous research on a female bias in chimpanzee tool use. These life-long differences in extractive foraging impacts daily energy budgets, which potentially have significant individual fitness and life history consequences. Additionally, the establishment of long-term individual variation in chimpanzee stone tool use has implications for interpreting archaeological records of hominins. Our findings highlight the importance of longitudinal data from long-term field sites when investigating underlying cognitive and behavioural diversity across individual lifespans and between populations.
The transcriptomic and proteomic ramifications of segmental amplification
Authors: Fritts Ryan K. , Ebmeier Christopher C. , Copley Shelley D.
Published: November 2023

Gene amplification can drive adaptation by rapidly increasing the cellular dosage of critical gene products. Segmental amplifications often encompass large genomic regions surrounding the gene(s) under selection for higher dosage. Overexpression of co-amplified neighboring genes imposes a substantial metabolic burden. While compensatory mutations can decrease inappropriate overexpression of co-amplified genes, it takes time for such mutations to arise. The extent to which intrinsic regulatory mechanisms modulate expression of co-amplified genes in the immediate aftermath of segmental amplification is largely unknown. To address the collateral effects of segmental amplification, we evolved replicate cultures of anEscherichia colimutant under conditions that select for higher dosage of an inefficient enzyme whose weak activity limits growth rate. Segmental amplifications encompassing the gene encoding the weak-link enzyme arose in all populations. Amplicons ranged in size (9 to 125 kb) and copy number (2 to 12 copies). We performed RNA-seq and label-free proteomics to quantify expression of amplified genes present at 2, 6, and 12 copies. mRNA expression generally scales with gene copy number, but protein expression scales less well with both gene copy number and mRNA expression. We characterize the molecular mechanisms underlying discrepancies between gene copy number and expression for several cases. We also show that segmental amplifications can have system-wide consequences by indirectly altering expression of non-amplified genes. Our findings indicate that the fitness benefit derived from segmental amplification depends on the combined effects of amplification size, gene content, and copy number as well as collateral effects on non-amplified genes.

Significance Statement

Gene amplification frequently drives rapid adaptation when organisms are challenged by harsh conditions. However, gene amplification rarely amplifies only the gene(s) under selection for higher dosage. Segmental amplifications often include many co-amplified neighbor genes. Because segmental amplifications can reach very high copy number, overexpression of co-amplified genes can impose an energetic burden and perturb physiology, yet this aspect of gene amplification has received little attention. Here, we performed transcriptomic and proteomic analysis of laboratory-evolvedEscherichia colistrains containing large, high-copy-number amplifications. We found that mRNA levels, but often not protein levels, scale well with gene copy number. We identified amplified genes that exhibit discrepancies between gene copy number and mRNA/protein expression and examine the molecular mechanisms underlying these discrepancies.
Epstein-Barr virus-encoded BART9 and BART15 miRNAs are elevated in exosomes of cerebrospinal fluid from relapsing-remitting multiple sclerosis patients
Authors: Mohammadinasr Mina , Montazersaheb Soheila , Hosseini Vahid , Kahroba Houman , Talebi Mahnaz , Molavi Ommoleila , Ayromlou Hormoz , Hejazi Mohammad Saeid
Published: November 2023

Epstein-Barr virus (EBV) infection is approved as the main environmental trigger of multiple sclerosis (MS). In this path, we quantified EBV-encoded BART9-3p and BART15 miRNAs in exosomes of cerebrospinal fluid (CSF) of untreated relapsing-remitting MS (RRMS) patients in comparison with the control group. Interestingly, patients displayed significant upregulation of BART9-3p (18.4-fold) and BART15 (3.1-fold) expression in CSF exosomes. Moreover, the expression levels of miR-21-5p and miR-146a-5p were found to be significantly elevated in the CSF samples obtained from the patient group in comparison to those obtained from the HC group. The levels of Interferon gamma (IFN-γ), interleukin-1β (IL-1β), interleukin- 6 (IL-6), interleukin-17 (IL-17), interleukin-23 (IL-23), transforming growth factor beta (TGF- β), and tumor necrosis factor alpha (TNF-α) were observed to be significantly elevated in the serum and CSF exosomes of the patients. The highest increase was observed in TGF-β (8.5- fold), followed by IL-23 (3.9-fold) in CSF exosomes. These findings are in agreement with the association between EBV infection and inflammatory cytokines induction. Furthermore, the ratios of TGF-β:TNF-α and TGF-β:IFN-γ attained values of 4 to 16.4 and 1.3 to 3.6, respectively, in the CSF exosomes of the patients, in comparison to those of the control group. Remarkable stimulation of EBV BART9-3p, BART15 miRNAs, and inflammatory cytokines expression in CSF exosomes confers a substantial link between EBV in MS onset and also the infection-to-MS transition.
FrameDiPT: SE(3) Diffusion Model for Protein Structure Inpainting
Authors: Zhang Cheng , Leach Adam , Makkink Thomas , Arbesú Miguel , Kadri Ibtissem , Luo Daniel , Mizrahi Liron , Krichen Sabrine , Lang Maren , Tovchigrechko Andrey , Lopez Carranza Nicolas , Şahin Uğur , Beguir Karim , Rooney Michael , Fu Yunguan
Published: November 2023

Protein structure prediction field has been revolutionised by deep learning with protein folding models such as AlphaFold 2 and ESMFold. These models enable rapidin silicoprediction and have been integrated intode novoprotein design and protein-protein interaction (PPI) prediction. However, biologically relevant features dependent on conformational distributions cannot be estimated with these models. Diffusion models, a novel class of generative models, have been developed to learn conformational distributions and applied tode novoprotein design. Limited work has been done on protein structure inpainting, where a masked section is recovered by simultaneously conditioning on its sequence and the rest of the structure. In this work, we proposeFrameDiffinPainTing (FrameDiPT), a generalised model for protein inpainting. This is important for T-cells given the hyper-variability of the complementarity determining region (CDR) loops. We evaluated the model on CDR loop design for T-cell receptors and achieved comparable prediction accuracy to ProteinGenerator and RFdiffusion with limited training data and learnable parameters. Different from deterministic structure prediction models, FrameDiPT captures the conformational distribution at different regions and binding states, highlighting a key advantage of generative models. The model and inference code have been released1.
Exploring TAS2R46 Biomechanics through Molecular Dynamics and Network Analysis
Authors: Cannariato Marco , Fanunza Riccardo , Zizzi Eric A. , Miceli Marcello , Di Benedetto Giacomo , Deriu Marco A. , Pallante Lorenzo
Published: November 2023

Understanding the intricate interplay between structural features and signal-processing events is crucial for unravelling the mechanisms of biomolecular systems. G protein-coupled receptors (GPCRs), a pervasive protein family in humans, serve a wide spectrum of vital functions. TAS2Rs, a subfamily of GPCRs, play a primary role in recognizing bitter molecules and triggering events leading to the perception of bitterness, a crucial defence mechanism against spoiled or poisonous food. Beyond taste, TAS2Rs function is associated with many diseases as they are expressed in several extra-oral tissues. Since the precise mechanism of TAS2R activation is poorly understood, this work aims to characterize the mechanisms underlying the signal transduction on the recently experimentally solved human TAS2R46 bitter taste receptor using molecular dynamics simulations coupled with network-based analysis. The results show that the allosteric activation of the receptor is associated with more correlated dynamics of the receptor and the formation of an interaction between two helices which mainly convey the signal transferring from the extracellular to the intracellular region. By elucidating the hallmarks of the allosteric network of TAS2R46 under varying conditions (ligand-bound, ligand-free, and transition states), this study has enabled the identification of the unique functional mechanisms of this receptor, thereby establishing a foundation for a more profound characterisation of this intriguing class of receptors.

Highlights

The dynamics of TAS2R46 in different states were studied through molecular dynamics and network analysis.

The presence of the bitter agonist increases intra-protein correlations.

TM3 and TM6 helices mediate the allosteric network in Holo TAS2R46.

The rotation of Y2416.48residue is pivotal in the allosteric network for the Holo TAS2R46.
AOPWIKI-EXPLORER: An Interactive Graph-based Query Engine leveraging Large Language Models
Authors: Kumar Saurav , Deepika Deepika , Slater Luke T , Kumar Vikas
Published: November 2023

Background

Adverse Outcome Pathways (AOPs) provide a basis for non-animal testing, by outlining and encoding the cascade of molecular and cellular events initiated upon stressor exposure, leading to adverse effects. AOPs are therefore considered an integral part of the New Approach Methodology (NAMs) to human health risk assessment. Over the last few years, the scientific community has shown immense interest in developing AOPs with crowdsourcing, with the results of those efforts being archived in the AOP wiki: a centralized repository coordinated by the OECD, which hosts nearly 512 AOPs. However, the AOP-wiki platform currently lacks a versatile querying system, which would enable developers to integrate and explore the AOP network data in a manner that would permit their practical use in risk assessment.

Implementation

This work proposes to expose the full potential of the AOP wiki archive by adapting its data into a Labeled Property Graph (LPG) database. In addition, the solution provides both database-specific query and natural language query interfaces to support retrieval and integration of the graph data, including the ability to chain stepwise queries. To evaluate the platform, a case study is presented, with three levels of use case scenarios (simple, moderate, and complex query). This tool is freely available on GitHub (InSilicoVida/AOPWiki-explorer) for wider community usability and further enhancement.

Conclusions

The presented query engine increases the potential of AOP exploration, by reducing the time, human resources, and technical ability needed to make practical use of the data they contain. Also, its dynamic prompt generation capability, will lead to precise query generation as the interaction increases. We, therefore, anticipate that the approach will be integral to the future realisation of new approach methodologies in chemical risk assessment.
A deep-learning-based screening platform in aging-relevant human motor neurons to identify therapeutic compounds for amyotrophic lateral sclerosis
Authors: Jalnapurkar Bhagawati , Le David , Shainin William , Zarcone Ryan , Bhatnagar Rajat , Chin Joshua , Corbin Conor , Curt Charles , Hodge Brian , Martinez Fernando , Mikita Thomas , Pipathsouk Anne , Rosen Jesse , Rando Thomas A. , Rodgers Joseph T. , Linsley Jeremy W.
Published: November 2023

Age is the primary risk factor for most neurodegenerative diseases including amyo-trophic lateral sclerosis (ALS). Despite the clear importance of age on the development and progression of ALS, age is rarely considered a factor in cellular or animal models of ALS. The recent advent of direct reprogramming methodologies, whereby somatic cells such as fibroblasts can be converted into neurons while retaining the age signature of the host, has facilitated the study of age-relevant human cellsin vitrofor the first time. Despite the promise of this technology, age is a complex, multidimensional, and dy-namic phenotype that makes the interpretation of the interplay between age and dis-ease a great challenge. To circumvent these challenges, we developed a screening platform for directly reprogrammed neurons in an age-relevant human cellular model to better model and identify disease-modifying targets and pathways for ALS. This plat-form uses deep learning image analysis to screen compounds for efficacy against ALS-associated cellular phenotypes and efficiently classifies ALS-like phenotypic signatures as well as predicts the age of the original fibroblast donor. Notably, our work identified NCB-0846, a TNIK/MAP4K7 inhibitor, as a novel compound with the ability to revert ALS-like phenotypes. Moreover, we show that chronic dosing of NCB-0846 in the SOD1G93A mouse model of ALS significantly reduced serum neurofilament-L levels. Our findings establish the power of a platform that combines direct reprogramming of human cells and deep learning as a powerful tool for combatting aging and age-related diseases.
Modulation of Biophysical Properties of Nucleocapsid Protein in the Mutant Spectrum of SARS-CoV-2
Authors: Nguyen Ai , Zhao Huaying , Myagmarsuren Dulguun , Srinivasan Sanjana , Wu Di , Chen Jiji , Piszczek Grzegorz , Schuck Peter
Published: November 2023

Genetic diversity is a hallmark of RNA viruses and the basis for their evolutionary success. Taking advantage of the uniquely large genomic database of SARS-CoV-2, we examine the impact of mutations across the spectrum of viable amino acid sequences on the biophysical phenotypes of the highly expressed and multifunctional nucleocapsid protein. We find variation in the physicochemical parameters of its extended intrinsically disordered regions (IDRs) sufficient to allow local plasticity, but also exhibiting functional constraints that similarly occur in related coronaviruses. In biophysical experiments with several N-protein species carrying mutations associated with major variants, we find that point mutations in the IDRs can have nonlocal impact and modulate thermodynamic stability, secondary structure, protein oligomeric state, particle formation, and liquid-liquid phase separation. In the Omicron variant, distant mutations in different IDRs have compensatory effects in shifting a delicate balance of interactions controlling protein assembly properties, and include the creation of a new protein-protein interaction interface in the N-terminal IDR through the defining P13L mutation. A picture emerges where genetic diversity is accompanied by significant variation in biophysical characteristics of functional N-protein species, in particular in the IDRs.
Unicellular life balances asymmetric allocation and repair of somatic damage representing the origin of r/K selection
Authors: Biba Dmitry A. , Wolf Yuri I. , Koonin Eugene V. , Rochman Nash D.
Published: November 2023

Over the course of multiple divisions, cells accumulate diverse non-genetic, somatic damage including misfolded and aggregated proteins and cell wall defects. If the rate of damage accumulation exceeds the rate of dilution through cell growth, a dedicated mitigation strategy is required to prevent eventual population collapse. Strategies for somatic damage control can be divided into two categories, asymmetric allocation and repair, which are not, in principle, mutually exclusive. Through mathematical modelling, we identify the optimal strategy, maximizing the total cell number, over a wide range of environmental and physiological conditions. The optimal strategy is primarily determined by extrinsic (damage-independent) mortality and the physiological model for damage accumulation that can be either independent (linear) or increasing (exponential) with respect to the prior accumulated damage. Under the linear regime, the optimal strategy is either exclusively repair or asymmetric allocation whereas under the exponential regime, the optimal strategy is mixed. Repair is preferred when extrinsic mortality is low, whereas at high extrinsic mortality, asymmetric damage allocation becomes the strategy of choice. We hypothesize that optimization over somatic damage repair and asymmetric allocation in early cellular life forms gave rise to therandKselection strategies.
Identification of a highly drought-resistantpp7l hda6mutant
Authors: Xu Duorong , Leister Dario , Kleine Tatjana
Published: November 2023

Plants have evolved efficient strategies to cope with drought stress, including stomata closure, significant changes in nuclear gene expression, and epigenetic mechanisms. Previously, we identifiedArabidopsis thalianaPROTEIN PHOSPHATASE7-LIKE (PP7L) as an extrachloroplastic protein that promotes chloroplast development and high light, and salt tolerance. Here, we demonstrate that thepp7lmutant can withstand prolonged periods of drought stress. Interestingly, chloroplast development inpp7lrecovers under drought conditions, despite growth of the mutant is impaired under normal growth conditions. To assess the (post)transcriptional changes occurring in thepp7lmutant under different durations of drought exposure, we used long non-coding RNA-sequencing. Compared to the previously reported drought-responsive changes in the wild type, the drought-responsive changes detected in thepp7lmutant were negligible. Our analysis of data generated in this study and previously motivated us to create app7l hda6mutant, which exhibits remarkable drought resistance. Notably, the growth penalty associated withpp7lwas alleviated in the double mutant, ruling out a dwarf effect on the drought-tolerant trait of this genotype.
Role of auditory feedback for vocal production learning in the Egyptian fruit-bat
Authors: Elie Julie E. , Muroy Sandra E. , Genzel Daria , Na Tong , Beyer Lisa A. , Swiderski Donald L. , Raphael Yehoash , Yartsev Michael M.
Published: November 2023

Some species have evolved the ability to use the sense of hearing to modify existing vocalizations, or even create new ones. This ability corresponds to various forms of vocal production learning that are all possessed by humans, and independently displayed by distantly related vertebrates. Among mammals, a few species, including the Egyptian fruit-bat, would possess such vocal production learning abilities. Yet the necessity of an intact auditory system for the development of the Egyptian fruit-bat typical vocal repertoire has not been tested. Furthermore, a systematic causal examination of learned and innate aspects of the entire repertoire has never been performed in any vocal learner. Here we addressed these gaps by eliminating pups’ sense of hearing at birth and assessing its effects on vocal production in adulthood. The deafening treatment enabled us to both causally test these bats vocal learning ability and discern learned from innate aspects of their vocalizations. Leveraging wireless individual audio recordings from freely interacting adults, we show that a subset of the Egyptian fruit-bat vocal repertoire necessitates auditory feedback. Intriguingly, these affected vocalizations belong to different acoustic groups in the vocal repertoire of males and females. These findings open the possibilities for targeted studies of the mammalian neural circuits that enable sexually dimorphic forms of vocal learning.
SARS-CoV-2 infects neurons, astrocytes, choroid plexus epithelial cells and pericytes of the human central nervous system
Authors: Haverty Ruth , McCormack Janet , Evans Christopher , Purves Kevin , O’Reilly Sophie , Gautier Virginie , Rochfort Keith , Fabre Aurelie , Fletcher Nicola F.
Published: November 2023

SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, is associated with a range of neurological manifestations including haemorrhage, thrombosis and ischaemic necrosis and encephalitits. However, the mechanism by which this occurs is unclear. Neurological disease associated with SARS-CoV-2 infection has been proposed to occur following direct infection of the central nervous system and/or indirect sequelae as a result of peripheral inflammation. We profiled ACE2 and TMPRSS2 in brain tissue from five healthy human donors, and observed expression of these proteins in astrocytes, neurons and choroid plexus epithelium within frontal cortex and medulla. Primary human astrocytes, neurons and choroid plexus epithelial cells supported productive SARS-CoV-2 infection in an ACE2- dependent manner. Infected cells supported the full viral lifecycle, releasing infectious virus particles. In contrast, primary brain microvascular endothelial cells, pericytes and microglia were refractory to SARS-CoV-2 infection. These data support a model whereby SARS-CoV-2 is neurotropic, and this may in part explain the neurological sequelae of infection.

Importance

A subset of patients with COVID-19 develop neurological symptoms, but the underlying cause is poorly understood. We observed that cells within normal human brain express the SARS-CoV-2 entry factors ACE-2 and TMPRRS2, with expression mainly observed within astrocytes, neurons and choroid plexus epithelium. Primary human astrocytes, neurons and choroid plexus epithelial cells culturedin vitrosupported the full SARS-CoV-2 life cycle with a range of SARS-CoV-2 variants. This study demonstrates that cells of the human central nervous system express SARS-CoV-2 entry factorsin vivoand support viral infectionin vitro, thus supporting a model where neurological symptoms seen in some COVID-19 patients may be as a result of direct viral infection of the central nervous system. Furthermore, these data highlight the importance of investigating the ability of therapeutics to clear virus from this potential reservoir of infection.