bluuebunny/crossref_metadata_2025_split huggingface dataset:
Running ahead of evolution - AI based simulation for predicting future high-risk SARS-CoV-2 variants
Authors: Chen Jie , Nie Zhiwei , Wang Yu , Wang Kai , Xu Fan , Hu Zhiheng , Zheng Bing , Wang Zhennan , Song Guoli , Zhang Jingyi , Fu Jie , Huang Xiansong , Wang Zhongqi , Ren Zhixiang , Wang Qiankun , Li Daixi , Wei Dongqing , Zhou Bin , Yang Chao , Tian Yonghong , Gao Wen 
Published: November 2022

AbstractThe never-ending emergence of SARS-CoV-2 variations of concern (VOCs) has challenged the whole world for pandemic control. In order to develop effective drugs and vaccines, one needs to efficiently simulate SARS-CoV-2 spike receptor binding domain (RBD) mutations and identify high-risk variants. We pretrain a large protein language model with approximately 408 million protein sequences and construct a high-throughput screening for the prediction of binding affinity and antibody escape. As the first work on SARS-CoV-2 RBD mutation simulation, we successfully identify mutations in the RBD regions of 5 VOCs and can screen millions of potential variants in seconds. Our workflow scales to 4096 NPUs with 96.5% scalability and 493.9× speedup in mixed precision computing, while achieving a peak performance of 366.8 PFLOPS (reaching 34.9% theoretical peak) on Pengcheng Cloudbrain-II. Our method paves the way for simulating coronavirus evolution in order to prepare for a future pandemic that will inevitably take place. Our models are released athttps://github.com/ZhiweiNiepku/SARS-CoV-2_mutation_simulationto facilitate future related work.JustificationWe develop a novel multi-constraint variation prediction framework to simulate SARS-CoV-2 RBD mutations, reaching a peak performance of 366.8 PFLOPS with 96.5% scalability and achieving 493.9× speedup. Our method facilitates the prediction and prioritization of future high-risk variants for the early deployment of drugs and vaccines.Performance attributesOverview of the problemCoronavirus Disease 2019 (COVID-19) has spread rapidly to more than 200 countries or regions since December 2019. Due to its high infectivity, there have been over 645 million confirmed cases, including approximately 6.6 million deaths, reported by the World Health Organization (WHO) as of December 20221. In addition to being a serious threat to human health, COVID-19 has had a catastrophic impact on the global economy.
Mammary epithelium permeability during established lactation: Associations with cytokine levels in human milk
Authors: Kivlighan Katie T. , Schneider Sallie S. , Browne Eva P. , Pentecost Brian T. , Anderton Douglas L. , Arcaro Kathleen F. 
Published: November 2022

AbstractObjectiveThe cytokine profile of human milk may be a key indicator of mammary gland health and has been linked to infant nutrition, growth, and immune system development. The current study examines the extent to which mammary epithelium permeability (MEP) is associated with cytokine profiles during established lactation among a diverse group of US mothers.MethodsParticipants were drawn from a previous study of human milk cytokines. The present analysis includes 162 participants (98 Black women, 64 White women) with infants ranging from 1-18 months of age. Levels of cytokines were determined previously. Here we measure milk sodium (Na) and potassium (K) levels with ion-selective probes.Elevated MEPwas defined and evaluated by both Na levels > 10 mmol/L and Na/K ratios greater than 0.6. Bivariate associations, principal components analysis, and multivariable logistic regression models were used to examine associations between maternal-infant characteristics, twelve cytokines (IL-6, IL8, TNFα, IL-1β, FASL, VEGFD, FLT1, bFGF, PLGF, EGF, leptin, adiponectin), and elevated MEP.ResultsElevated MEP was observed in 12% and 15% of milk samples as defined by Na and Na/K cutoffs, respectively. The odds of experiencing elevated MEP (defined by Na > 10 mmol/L) were higher among Black participants and declined with older infant age. All cytokines, except leptin, were positively correlated with either Na or the Na/K ratio. A pro-inflammatory factor (IL-6, IL-8, TNFα, IL-1β, EGF) was more strongly correlated with the Na/K ratio, while a tissue remodeling factor (FASL, VEGFD, FLT1, bFGF, PLGF, adiponectin) was more strongly correlated with Na. The pro-inflammatory and tissue remodeling factors each contributed uniquely to raising the odds of elevated MEP as defined by either Na or the Na/K ratio.ConclusionThis exploratory analysis of MEP and cytokine levels during established lactation indicates that elevated MEP among US women may be more common than previously appreciated and that Black women may have increased odds of experiencing elevated MEP based on current definitions. Research aimed at understanding the role of MEP in mammary gland health or infant growth and development should be prioritized.
A New Variant of Hepatitis A Virus Causing Transient Liver Enzyme Elevations in Mauritius-origin Laboratory-housed Cynomolgus macaques
Authors: Mecklenburg Lars , Ducore Rebecca , Boyle Molly , Newell Andrew , Boone Laura , Luft Joerg , Romeike Annette , Haverkamp Ann-Kathrin , Mansfield Keith , Baczenas JJ , Minor Nick , O’Connor Shelby L. , O’Connor David H. 
Published: November 2022

ABSTRACTHepatitis A virus (HAV) infects humans and non-human primates causing an acute self-limited illness. Three HAV genotypes have been described for humans and three genotypes have been described for non-human primates. We observed transiently elevated liver enzymes in Mauritius-origin laboratory-housed macaques in Germany and were not able to demonstrate HAV by serology and PCR. Using deep sequencing, we have identified a new HAV genotype with 86% nucleotide sequence homology to HAV genotype IV capsid proteins and approximately 80% nucleotide homology to other HAV genotypes. In situ hybridization indicates persistence in the biliary epithelium up to 3 months after liver enzymes were elevated. Vaccination using a commercial vaccine against human HAV prevented reoccurrence of liver enzyme elevations. Since available assays for HAV did not detect this new variant, knowledge of its existence may ameliorate potential significant epidemiological and research implications in laboratories globally.Article Summary LineA new genotype of hepatitis A virus, that was not identifiable by available diagnostic assays, caused liver enzyme elevations in laboratory-housed Mauritius-origin Cynomolgus macaques.
Structural dynamics of E6AP E3 ligase HECT domain and involvement of flexible hinge loop in ubiquitin chain synthesis mechanism
Authors: Takeda Kazusa , Muro Ikumi , Kobayashi Fuminori , Flechsig Holger , Kodera Noriyuki , Ando Toshio , Konno Hiroki 
Published: November 2022

AbstractUbiquitin (Ub) ligases E3 are an important factor in selecting target proteins for ubiquitination and determining the type of polyubiquitin chains on the target proteins. In the HECT (homologous to E6AP C-terminus)-type E3 ligases, the HECT domain is composed of an N-lobe containing the E2-binding site and a C-lobe containing the catalytic Cys residue that forms a thioester bond with Ub. These two lobes are connected by a flexible hinge loop. The large conformational rearrangement of the HECT domain via the flexible hinge loop is essential for HECT-type E3-mediated Ub transfer from E2 to a target protein. However, detailed insights into the structural dynamics of this type of E3 ligases remain unclear. Here, we provide the first direct demonstration of structural dynamics of the E6AP HECT domain using high-speed atomic force microscopy. We also investigated structural dynamics of hinge loop flexibility restricted HECT domain, and we found that flexibility of the E6AP hinge loop has a great impact not only on its structural dynamics but also on the formation of free Ub chains mediated by E3-E3 interactions.
Hungry for compliments? Ghrelin is not associated with neural responses to social rewards or their pleasantness
Authors: Sailer Uta , Riva Federica , Lieberz Jana , Campbell-Meiklejohn Daniel , Scheele Dirk , Pfabigan Daniela M. 
Published: November 2022

AbstractThe stomach-derived hormone ghrelin motivates food search and stimulates food consumption, with highest plasma concentrations before a meal and lowest shortly after. However, ghrelin also appears to affect the value of non-food rewards such as interaction with rat conspecifics, and monetary rewards in humans. The present pre-registered study investigated how nutritional state and ghrelin concentrations are related to the subjective and neural responses to social and non-social rewards.In a cross-over feed-and-fast design, 67 healthy volunteers (20 women) underwent functional magnetic resonance imaging (fMRI) in a hungry state and after a meal with repeated plasma ghrelin measurements. In task 1, participants received social rewards in the form of approving expert feedback, or non-social computer reward. In task 2, participants rated the pleasantness of compliments and neutral statements.Nutritional state and ghrelin concentrations did not affect the response to social reward in task 1. In contrast, ventromedial prefrontal cortical activation to non-social rewards was reduced when the meal strongly suppressed ghrelin. In task 2, fasting increased activation in the right ventral striatum during all statements, but ghrelin concentrations were neither associated with brain activation nor with experienced pleasantness. Complementary Bayesian analyses provided moderate evidence for a lack of correlation between ghrelin concentrations and behavioral and neural responses to social rewards, but moderate evidence for an association between ghrelin and non-social rewards.This suggests that ghrelin’s influence may be restricted to non-social rewards. Social rewards implemented via social recognition and affirmation may be too abstract and complex to be susceptible to ghrelin’s influence. In contrast, the non-social reward was associated with the expectation of a material object that was handed out after the experiment. This may indicate that ghrelin might be involved in anticipatory rather than consummatory phases of reward.
Repurposing of the multiciliation gene regulatory network in fate specification of Cajal-Retzius neurons
Authors: Moreau Matthieu X , Saillour Yoann , Elorriaga Vicente , Bouloudi Benoît , Delberghe Elodie , Guerrero Tanya Deutsch , Ochandorena-Saa Amaia , Maeso-Alonso Laura , Marques Margarita M , Marin Maria C , Spassky Nathalie , Pierani Alessandra , Causeret Frédéric 
Published: November 2022

SUMMARYCajal-Retzius (CR) neurons are key players of cortical development that display a very unique transcriptomic identity. However, little is known about the mechanisms involved in their fate specification. Here we use scRNAseq to reconstruct the differentiation trajectory of hem-derived CR cells (CRs) and unravel the transient expression of a complete gene module previously known to control the cellular process of multiciliogenesis. However, we find that CRs do not undergo centriole amplification or multiciliation. We show that upon genetic disruption ofGmnc, the master regulator of the multiciliation cascade, CRs are initially produced but fail to reach their normal identity and lean towards an aberrant fate resulting in their massive apoptosis. We further dissect the contribution of multiciliation effector genes and identifyTrp73as a key determinant. Finally, we usein uteroelectroporation to demonstrate that the intrinsic competence of hem progenitors as well as the heterochronic expression ofGmncprevent centriole amplification in the CR lineage. Our work exemplifies how the co-option of a complete gene module, repurposed to control a completely distinct process, may contribute to the emergence of novel cell identities.
Neuroprotective potential of anAyurvediccompound “Ras-Sindoor” onDrosophila melanogastermodel of Parkinson’s disease
Authors: Narwal Sonia , Rai Arushi , Iyer Shreyas , Tare Kirti , Tare Meghana 
Published: November 2022

AbstractParkinson’s Disease (PD) is the second most common neurodegenerative disease affecting 1-2% of the global population with no cure to date. PD is characterized by accumulation of Lewy Bodies (LBs), which are caused due to aggregation of incorrectly folded α-Synuclein, (SNCA). Another form of PD manifestation is characterized by loss of function ofparkin, which encodes an E3 ubiquitin ligase. Despite extensive research, the cause for onset and progression of PD remains unknown and current therapeutics mainly help manage the disease. An alternative line of treatment can be useful.In this study, we have employed two different genetic models ofDrosophilato screen forAyurvediccompounds and found anAyurvedicmercury based organo-metallic drug Ras-Sindoor has neuroprotective function. Our data indicate that characteristic locomotory dysfunction phenotype of PD is restored upon administration of the compound. Interestingly, RS fed flies also exhibit reduced transcript levels of initiator caspasedronc, which possibly prevents cell death in dopaminergic neurons. Additionally, RS fed PD model flies exhibit an enhanced life span. Our studies emphasize beneficial use of traditionalAyurvediccompounds as a holistic cure for PD like multifactorial diseases.
Structural basis for Fc receptor recognition of immunoglobulin M
Authors: Chen Qu , Menon Rajesh , Tolar Pavel , Rosenthal Peter B. 
Published: November 2022

AbstractFcμR is the IgM-specific Fc receptor involved in the survival and activation of B cells. Using cryo-EM, we reveal eight binding sites for the human FcμR Ig domain on the IgM pentamer, one of which overlaps with the receptor binding site for the transcytosis receptor pIgR, but a different mode of binding explains Ig isotype specificity. The complex explains engagement with polymeric serum IgM and the monomeric IgM B cell receptor.
Pyruvate-conjugation of PEGylated liposomes effectively enhances their uptake in retinal photoreceptors
Authors: Christensen Gustav , Chen Yiyi , Urimi Dileep , Schipper Nicolaas , Paquet-Durand François 
Published: November 2022

AbstractDespite several promising candidates there is a paucity of drug treatments available for patients suffering from retinal diseases. An important reason for this is the lack of suitable delivery systems that can achieve sufficiently high drug uptake in the retina and its photoreceptors. A promising and versatile method for drug delivery to specific cell types involves liposomes, surface-coated with substrates for transporter proteins highly expressed on the target cell.We identified strong lactate transporter (monocarboxylate transporter, MCT) expression on photoreceptors as a potential target for drug delivery vehicles. To evaluate MCT suitability for drug targeting, we used PEG-coated liposomes and conjugated these with different monocarboxylates, including lactate, pyruvate, and cysteine. Monocarboxylate-conjugated dye-loaded liposomes were tested on both human-derived cell-lines and murine retinal explant cultures. We found that liposomes conjugated with pyruvate consistently displayed higher cell uptake than unconjugated liposomes or liposomes conjugated with lactate or cysteine. Pharmacological inhibition of MCT1 and MCT2 reduced internalization, suggesting an MCT-mediated uptake mechanism. Pyruvate-conjugated liposomes loaded with the drug candidates CN03 and CN04 reduced photoreceptor cell death in murinerd1andrd10retinal degeneration models.Overall, this study proposes pyruvate-conjugated liposomes as a vehicle for drug delivery specifically to photoreceptors. Notably, in retinal degeneration models, free drug solutions could not achieve the same therapeutic effect. Our study thus highlights pyruvate-conjugated liposomes as a promising system for drug delivery to retinal photoreceptors, as well as other neuronal cell types displaying high expression of MCT-type proteins.
Steroidogenesis and androgen/estrogen signaling pathways are altered inin vitromatured testicular tissues of prepubertal mice
Authors: Moutard Laura , Goudin Caroline , Jaeger Catherine , Duparc Céline , Louiset Estelle , Pereira Tony , Fraissinet François , Delessard Marion , Saulnier Justine , Rives-Feraille Aurélie , Delalande Christelle , Lefebvre Hervé , Rives Nathalie , Dumont Ludovic , Rondanino Christine 
Published: November 2022

AbstractChildren undergoing cancer treatments are at risk for impaired fertility. Cryopreserved prepubertal testicular biopsies could theoretically be later maturedin vitroto produce spermatozoa for assisted reproductive technology. A completein vitrospermatogenesis has been obtained from mouse prepubertal testicular tissue, although with low efficiency. Steroid hormones being essential for the progression of spermatogenesis, the aim of this study was to investigate steroidogenesis and steroid signaling in organotypic cultures. Histological, RT-qPCR, western blot analyses and steroid hormone measurements were performed onin vitrocultured mouse prepubertal testicular tissues and age-matchedin vivocontrols. Despite a conserved density of Leydig cells after 30 days of culture (D30), transcript levels of adult Leydig cell and steroidogenic markers were decreased. Increased amounts of progesterone and estradiol and reduced androstenedione levels were observed at D30, together with decreased transcript levels of steroid metabolizing genes and steroid target genes. hCG was insufficient to facilitate Leydig cell differentiation, restore steroidogenesis and improve sperm yield. In conclusion, this study reports the failure of adult Leydig cell development and altered steroid production and signaling in tissue cultures. The organotypic culture system will need to be further improved before it can be translated in clinics for childhood cancer survivors.
DNA bridging explains sub-diffusive movement of chromosomal loci in bacteria
Authors: Subramanian Srikanth , Murray Seán M. 
Published: November 2022

Chromosomal loci in bacterial cells show a robust sub-diffusive scaling of the mean square displacement, MSD(τ) ∼τα, withα< 0.5. On the other hand, recent experiments have also shown that DNA-bridging Nucleoid Associated Proteins (NAPs) play an important role in chromosome organisation and compaction. Here, using polymer simulations we investigate the role of DNA bridging in determining the dynamics of chromosomal loci. We find that bridging compacts the polymer and reproduces the sub-diffusive elastic dynamics of monomers at timescales shorter than the bridge lifetime. Consistent with this prediction, we measure a higher exponent in a NAP mutant (ΔH-NS) compared to wild-typeE. coli. Furthermore, bridging can reproduce the rare but ubiquitous rapid movements of chromosomal loci that have been observed in experiments. In our model the scaling exponent defines a relationship between the abundance of bridges and their lifetime. Using this and the observed mobility of chromosomal loci, we predict a lower bound on the average bridge lifetime of around 5 seconds.Significance StatementThe bacterial chromosome exhibits dynamics that cannot be explained by simple polymer models. In particular, the mean square displacement of individual chromosomal loci exhibits a power law scaling with an exponent less than that predicted by polymer theory. Here, we use polymer simulations and experiments to show that DNA bridging by Nucleoid Associated Proteins can explain these anomalous dynamics. Consistent with this, we show that in the absence of the bridging protein H-NS, the scaling exponent increases. Chromosomal loci also display rare rapid movements not explainable by polymer theory, even accounting for the viscoelasticity of the cytoplasm. Our simulations show that bridging can additionally explain this behaviour. Finally, we predict a lower bound on the average bridge lifetime within cells.
A stochastic compartmental model to simulate intra- and inter-species influenza transmission in an indoor swine farm
Authors: Kontowicz Eric , Moreno-Madriñan Max , Ragland Darryl , Beauvais Wendy 
Published: November 2022

AbstractCommon in swine production worldwide, influenza causes significant reductions in feed efficiency and potential transmission to the workforce. Swine vaccines are not universally used in swine production, partly due to their limited efficacy because of continuously evolving influenza viruses. We evaluated the effects of vaccination, quarantine of infected pigs, and changes to workforce routine (ensuring workers moved from younger pig batches to older pig batches). A Susceptible-Exposed-Infected-Recovered model was used to simulate stochastic influenza transmission during a single production cycle on an indoor hog growing unit containing 4000 pigs and two workers. The absence of control practices resulted in 3,958 pigs [1 – 3972] being infected and a 0.61 probability of workforce infection. Quarantine of infected pigs the same day they became infectious was the single effective control practice, reducing the number of infected pigs to 3 [1 - 3961] and the probability of workforce infection to 0.27. The second-best control practice was mass pig vaccination (80% effective vaccine), which reduced the number of infected pigs to 23.5 [1 - 635] and the probability of workforce infection to 0.07. The third-best control practice was changing the worker routine by starting with younger to older pig batches, which reduced the number of infected pigs to 997 [1 - 1984] and the probability of workforce infection (0.22). All other control practices, when considered alone, showed little improvement in reducing total infected pigs and the probability of workforce infection. Combining all control strategies reduced the total number of infected pigs to 1 or 2 with a minimal probability of workforce infection (0.03 – 0.01). These findings suggest that non-pharmaceutical interventions can reduce the impact of influenza on swine production and reduce the risk of interspecies transmission when efficacious vaccines are unavailable. Therefore, these results can help prevent the emergence of influenza strains with pandemic potential.
Finding Consensus miRNAs Silencing KLF1 Expression as A Promising Therapeutic Option of Sickle Cell Anemia
Authors: Al-Madhagi Haitham Ahmed 
Published: November 2022

1AbstractSickle cell anemia (SCA) is the almost the severest hemoglobinopathy known with no cure till date. Patients with SCA has a shorter lifespan and suffer from painful crises and end-organ damages. The goal of this in silico work is to find the consensus miRNAs targeting KLF1 gene, responsible for HbF-to-HbA switching followed by generating the corresponding miRNA sponge for gene silencing purposes. 3 publicly available databases were searched, miRDB, miRWalk and TargetScan. Afterwards, the hybridization examination of the predicted miRNAs was evaluated. Finally, the design of miRNA sponge as a means to target miRNA was performed. In conclusion, hsa-miR-330-5p was the best miRNA targeting KLF1 gene in many aspects and its miRNA sponge sequence was provided.