bluuebunny/crossref_metadata_2025_split huggingface dataset:
Common and rare variant analyses reveal novel genetic factors underlying Idiopathic Pulmonary Fibrosis and shared aetiology with COVID-19
Authors: Kousathanas Athanasios , Odhams Christopher A. , Cook James , Hu Yao , Klee Stephan , Erzurumluoglu A. Mesut , Ramirez Fidel , Mayr Christoph , Schäfer Dennis , Beck Lara , Christ Ingrid , Lee Taekyu , Tarr James Christopher , Fesik Steven W. ,   Boehringer Ingelheim – Global Computational Biology and Digital Sciences, Duboff James , Wirtz-Peitz Frederik , Moutsianas Loukas , Brown Matthew A. , Kriegl Jan , Okafo Goerge , Jensen Jan N , Thomas Matthew J. , Ding Zhihao 
Published: August 2024

AbstractIdiopathic pulmonary fibrosis (IPF) is a progressive and debilitating respiratory disease with limited therapeutic options. We carried out genome-wide association (GWAS), post-GWAS and rare variant analyses utilising the whole genome sequencing data (WGS) from the 100,000 Genomes Project (100kGP) of a cohort of IPF participants (n=586) to identify novel associations and potential drug targets. Meta-analysis combining 100kGP and published GWASs of IPF (total 11,746 cases and 1,416,493 controls) identified a novel association signal at the 1q21.2 locus (rs16837903, OR[95%CI]=0.88[0.85, 0.92],P=9.54×10−9) which was also successfully replicated with independent data and linked to the probable effector geneMCL1. MCL1showed increased expression levels in IPF patients versus controls in alveolar epithelial type I cells. Despite its known antiapoptotic role, inhibition ofMCL1 in vitrodid not selectively deplete senescent cells, hinting at the complexity involved in targetingMCL1. Rare variant burden analysis identifiedANGPTL7, a secreted glycoprotein involved in the regulation of angiogenesis, as a novel IPF candidate gene (OR[95%CI]=28.79 [8.51-97.43],P=6.73×10−8). Transcriptome-wide association analysis (TWAS) revealed that overexpression of cell cycle regulatorSERTAD2and nuclear importerTPNO3were associated with increased IPF risk. We also investigated shared genetic mechanisms between IPF with severe COVID-19 and expanded the list of shared genetic loci with three novel colocalised signals at 1q21.2, 6p24.3 and 16p13.3 with probable effector genesMCL1,DSP and RHBDF1, implicating regulation of apoptosis, cell adhesion and epidermal growth factor signalling, respectively. By leveraging the genetic correlation between IPF and severe COVID-19 (rg[95% CI]) = 0.39 [0.25-0.53]) through multi-trait meta-analysis, we further identified and replicated an additional novel candidate IPF signal at 2p16.1 with probable effector geneBCL11A, a regulator of haematopoiesis and lymphocyte development. Based on prioritized genes across analyses, we propose mechanisms mediating IPF disease risk and shared mechanisms between IPF and severe COVID-19, thereby expanding the potential for developing common treatments.
Distinct contributions of the dorsal and ventral hippocampus to spatial working memory and spatial coding in the prefrontal cortex
Authors: Babl Susanne S. , Sigurdsson Torfi 
Published: August 2024

AbstractThe hippocampus (HPC) supports spatial working memory (SWM) through its interactions with the prefrontal cortex (PFC). However, it is not clear whether and how the dorsal (dHPC) and ventral (vHPC) poles of the HPC make distinct contributions to SWM and whether they differentially influence the PFC. To address this question, we optogenetically silenced the dHPC or the vHPC while simultaneously recording from the PFC of mice performing a SWM task. We found that whereas both HPC subregions were necessary during the encoding phase of the task, only the dHPC was necessary during the choice phase. Silencing of either subregion altered the spatial firing patterns of PFC neurons. However, only silencing of the vHPC affected their coding of spatial goals. These results thus reveal distinct contributions of the dorsal and ventral HPC poles to SWM and the coding of behaviorally-relevant spatial information by PFC neurons.
Shifts in vernalization and phenology at the rear edge hold insight into adaptation of temperate plants to future milder winters
Authors: Perrier Antoine , Turner Megan C. , Galloway Laura F. 
Published: August 2024

SummaryTemperate plants often regulate reproduction through winter cues, such as vernalization, that may decrease under climate change. Studies of rear-edge populations, glacial relicts that persist in environments that have warmed since last glaciation, can provide insight into adaptive potential to milder winters.We studied how rear-edge populations have adapted to shorter winters and compared them to the rest of the range in the herbCampanula americana. Using citizen science, climate data and experimental climate manipulation, we characterize variation in vernalization requirements and reproductive phenology across the range and their potential climatic drivers.Rear-edge populations experienced little to no vernalization in nature. In climate manipulation experiments, these populations also had a reduced vernalization requirement, weaker response to changes in vernalization length, and flowered later compared to the rest of the range.Our results suggest shifts in phenology and its underlying regulation at the rear edge to compensate for unreliable vernalization cues. Thus, future milder winters may be less detrimental to these populations than more northern ones. Furthermore, our results showcase strong adaptive shifts at the rear edge of temperate plants’ ranges, highlighting the importance of these areas in studies of predicted future climates.
Assessing white matter plasticity in a randomized controlled trial of early literacy training in preschoolers
Authors: Caffarra Sendy , Karipidis Iliana I. , Kruper John , Kubota Emily , Richie-Halford Adam , Takada Megumi , Rokem Ariel , Yeatman Jason D. 
Published: August 2024

AbstractReading is a cognitive skill that requires our brain to go through a myriad of changes during learning. While many studies have described how reading acquisition shapes children’s brain function, less is known about the impact of reading on brain structure. Here we examined short-term causal effects of reading training on preschoolers’ behavior and white matter structure. Forty-eight English-speaking preschoolers (4y10m to 6y2m) participated in a randomized controlled trial where they were randomly assigned to two training programs: the Letter training program was focused on key skills for reading (e.g., decoding and letter knowledge), while the Language training program strengthened oral language comprehension skills without exposure to text. Longitudinal behavioral data showed that only the Letter Training group increased letter knowledge and decoding skills after the two-week training. Diffusion MRI measures (FA and MD) of eighteen white matter pathways (including the left arcuate and the left inferior longitudinal fasciculus) did not reveal any statistically significant changes for either group despite high degrees of scan-rescan reliability across sessions. These findings suggest that a two- week reading training program can cause changes in preschoolers’ letter knowledge and decoding abilities, without being accompanied by measurable changes in the diffusion properties of the major white matter pathways of the reading network. We conclude highlighting possible constraints (i.e., age, training onset and duration, cognitive profile) to reading-related white matter plasticity.
Ultrahigh-throughput discovery of modified aptamers as specific and potent enzyme inhibitors
Authors: Husser Claire , Hoetzel Janis , Cubi Roger , Lebars Isabelle , Kraus Leon , Di Primo Carmelo , Baudrey Stephanie , Proschak Ewgenij , Kieffer Bruno , Suess Beatrix , Ryckelynck Michael 
Published: August 2024

AbstractEnzymes are instrumental to life and key actors of pathologies, making them relevant drug targets. Most enzyme inhibitors consist of small molecules. Although efficient, their development is long, costly and can come with unwanted off-targeting. Substantial gain in specificity and discovery efficiency is possible using biologicals. Best exemplified by antibodies, these drugs derived from living systems display high specificity and their development is eased by harnessing natural evolution. Aptamers are nucleic acids sharing functional similarities with antibodies while being deprived of many of their limitations. Yet, the success rate of inhibitory aptamer discovery remained hampered by the lack of an efficient discovery pipeline. In this work, we addressed this issue by introducing an ultrahigh-throughput strategy combiningin vitroselection, microfluidic screening and bioinformatics. We demonstrate its efficiency by discovering a modified aptamer that specifically and strongly inhibits SPM-1, a beta-lactamase that remained recalcitrant to the development of potent inhibitors.Graphical Abstract
Placental and fetal microbiota in rhesus macaque: a case study using metagenomic sequencing
Authors: Du Qiao , Liu Xu , Zhang Rusong , Hu Gang , Liu Qinghua , Ma Wen , Hu Ying , Fan Zhenxin , Li Jing 
Published: August 2024

AbstractRecent evidence challenging the notion of a sterile intrauterine environment has sparked research into the origins and effects of fetal microbiota on immunity development during gestation. Rhesus macaques (RMs) serve as valuable non-human primate (NHP) models due to their similarities to humans in development, placental structure, and immune response. In this study, metagenomic analysis was applied to the placenta, umbilical cord, spleen, gastrointestinal (GI) tissues of an unborn RM fetus, and the maternal intestine, revealing the diversity and functionality of microbes in these tissues. We observed substantial microbial sharing between the mother and fetus, with the microbial composition of the placenta and umbilical cord more closely resembling that of the fetal organs than the maternal intestine. Notably, compared with other adult RMs, there was a clear convergence between maternal and fetal microbiota, alongside distinct differences between the microbiota of adults and the fetus, which underscores the unique microbial profiles in fetal environments. Furthermore, the fetal microbiota displayed a less developed carbohydrate metabolism capacity than adult RMs. It also shared antibiotic resistance genes (ARGs) with both maternal and adult RM microbiomes, indicating potential vertical transmission. Comparative analysis of the metagenomes between the RM fetus and a human fetus revealed significant differences in microbial composition and genes, yet also showed similarities in certain abundant microbiota. Collectively, our results contribute to a more comprehensive understanding of the intrauterine microbial environment in macaques.
Study of excess manganese stress response highlights the central role of manganese exporter Mnx for holding manganese homeostasis in the cyanobacteriumSynechocystis sp.PCC 6803
Authors: Reis Mara , Zenker Sanja , Viehöver Prisca , Niehaus Karsten , Bräutigam Andrea , Eisenhut Marion 
Published: August 2024

ABSTRACTCellular levels of the essential micronutrient manganese (Mn) need to be carefully balanced within narrow boarders. In cyanobacteria, sufficient Mn supply is critical for assuring the function of the oxygen-evolving complex as central part of the photosynthetic machinery. However, Mn accumulation is fatal for the cells. The reason for the observed cytotoxicity is unclear. To understand the causality behind Mn toxicity in cyanobacteria, we investigated the impact of excess Mn on physiology and global gene expression in the model organismSynechocystissp. PCC 6803. We compared the response of the wild type and the knock-out mutant in the manganese exporter (Mnx), Δmnx,which is disabled in the export of surplus Mn and thus functions as model for toxic Mn overaccumulation. While growth and pigment accumulation in Δmnxwas severely impaired 24 h after addition of 10-fold Mn, the wild type was not affected and thus mounted an adequate transcriptional response. RNA-seq data analysis revealed that the Mn stress transcriptomes were partly resembling an iron limitation transcriptome. However, the expression of iron limitation signature genesisiABDCwas not affected by the Mn treatment, indicating that Mn excess is not accompanied by iron limitation inSynechocystis.We suggest that the Ferric uptake regulator, Fur, gets partially mismetallated under Mn excess conditions and thus interferes with an iron-dependent transcriptional response. To encounter mismetallation and other Mn-dependent problems on protein level, the cells invest into transcripts of ribosomes, proteases, and chaperones. In case of the Δmnxmutant the consequences of the disability to export excess Mn from the cytosol manifest in additionally impaired energy metabolism and oxidative stress transcriptomes with fatal outcome. This study emphasizes the central importance of Mn homeostasis and the transporter Mnx’s role in restoring and holding it.
Protective threshold of a potent neutralizing Zika virus monoclonal antibody in rhesus macaques
Authors: Nkolola Joseph P. , Hope David , Guan Ruaron , Colarusso Alessandro , Aid Malika , Carnahan Robert H. , Crowe James E. , Barouch Dan H. 
Published: August 2024

AbstractZika virus (ZIKV) is a mosquito-borne flavivirus that caused a global pandemic in 2016-2017 with continued ongoing transmission at low levels in several countries. In the absence of an approved ZIKV vaccine, neutralizing monoclonal antibodies (mAbs) provide an option for the prevention and treatment of ZIKV infection. Previous studies identified a potent neutralizing human mAb ZIKV-117 that reduced fetal infection and death in mice following ZIKV challenge. In this study, we report exquisite potency of ZIKV-117 in a titration study in rhesus macaques to protect against ZIKV challenge. We show complete protection at a dose of 0.016 mg/kg ZIKV-117, which resulted in median serum concentrations of 0.13 µg/mL. The high potency of this mAb supports its potential clinical development as a novel biotherapeutic intervention for ZIKV.ImportanceIn this study, we report the potency of the ZIKV-specific neutralizing antibody ZIKV-117 against ZIKV challenge in a titration study rhesus macaques. This high potency supports the further development of this mAb for ZIKV.
P(all-atom) Is Unlocking New Path For Protein Design
Authors: Qu Wei , Guan Jiawei , Ma Rui , Zhai Ke , Wu Weikun , Wang Haobo 
Published: August 2024

AbstractWe introduce Pallatom, an innovative protein generation model capable of producing protein structures with all-atom coordinates. Pallatom directly learns and models the joint distribution P(structure, seq) by focusing on P(all-atom), effectively addressing the interdependence between sequence and structure in protein generation. To achieve this, we propose a novel network architecture specifically designed for all-atom protein generation. Our model employs a dual-track framework that tokenizes proteins into residue-level and atomic-level representations, integrating them through a multi-layer decoding process with “traversing” representations and recycling mechanism. We also introduce theatom14representation method, which unifies the description of unknown side-chain coordinates, ensuring high fidelity between the generated all-atom conformation and its physical structure. Experimental results demonstrate that Pallatom excels in key metrics of protein design, including designability, diversity, and novelty, showing significant improvements across the board. Our model not only enhances the accuracy of protein generation but also exhibits excellent training efficiency, paving the way for future applications in larger and more complex systems.
A Single Mutation in an Enteric Virus Alters Tropism and Sensitivity to Microbiota
Authors: Erickson Andrea K. , Sutherland Danica M. , Welsh Olivia L. , Maples Robert W. , Dermody Terence S. , Pfeiffer Julie K. 
Published: August 2024

SUMMARYMany enteric viruses benefit from the microbiota, and depletion of the microbiota reduces infection of noroviruses and picornaviruses in mice. However,Reoviralesviruses are outliers among enteric viruses. Rotavirus infection is inhibited by bacteria, and we determined that several reovirus strains have enhanced replication following microbiota depletion. We found that an isogenic pair of reoviruses have opposing infection outcomes after microbiota depletion. Microbiota depletion reduces infection of reovirus strain T3SA+ but increases infection of strain T3SA−. These strains differ by a single amino acid polymorphism in the σ1 attachment protein, which confers sialic acid binding to T3SA+. Sialic acid binding facilitates T3SA+ infection of intestinal endothelial cells, while T3SA− inefficiently infects intestinal epithelial cells due to restriction by microbiota-driven, host-derived type III interferon responses. This study enhances an understanding of the complex interactions of enteric viruses, the microbiota, intestinal tropism, and antiviral responses.HighlightsMicrobiota enhance infection of a sialic acid (SA)-binding reovirus strain but inhibit infection of an isogenic non-SA-binding reovirus strain that differs by a single amino acid change.SA binding facilitates viral infection of intestinal endothelial cells in a microbiota-dependent manner.A non-SA-binding reovirus strain inefficiently infects intestinal epithelial cells due to microbiota-driven type III interferon responses.
Dissociable patterns of dopamine dynamics and causal contributions to stimulus-response behaviors across striatal subregions
Authors: Princz-Lebel Oren , Skirzewski Miguel , Rai Harleen , Panjwani Samina , Chu Anthony , Lemieux Claire A. , Palmer Daniel , Machado Meira M.F. , Prado Vania F. , Prado Marco A.M. , Saksida Lisa M. , Bussey Timothy J. 
Published: August 2024

SummaryStriatal dopaminergic dynamics exhibit regional variation, yet are usually studied in isolation, with interpretations often extrapolated to the striatum as a whole. Here we used fiber photometry to characterize DA dynamics across the nucleus accumbens, dorsomedial, and dorsolateral striatum in parallel in mice performing a striatum-dependent stimulus-response (S-R) learning task. We found that transients in all regions varied dynamically across task events but differed significantly across regions in their timing of peak responding, presence of pre-choice ramping, and stability across learning. Next, manipulations of reward probability revealed that DA transients in all regions tracked reward delivery and omission, but not choice. Lastly, we used inhibitory chemogenetics to test the necessity of these signals for cognition, revealing that nigrostriatal DA, but not mesolimbic striatal DA, was necessary for the acquisition of S-R contingencies. These findings demonstrate heterogeneity of DA signals across the striatum and reveal their distinct, causal roles in cognition.
Functional investigation of a putative calcium-binding site involved in the inhibition of inositol 1,4,5-trisphosphate receptor activity
Authors: Arige Vikas , Wagner Larry E. , Malik Sundeep , Baker Mariah R. , Fan Guizhen , Serysheva Irina I. , Yule David I. 
Published: August 2024

AbstractA wide variety of factors influence inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) activity resulting in modulation of intracellular Ca2+release. This regulation is thought to define the spatio-temporal patterns of Ca2+signals necessary for the appropriate activation of downstream effectors. The binding of both IP3and Ca2+are obligatory for IP3R channel opening, however, Ca2+regulates IP3R activity in a biphasic manner. Mutational studies have revealed that Ca2+binding to a high-affinity pocket formed by the ARM3 domain and linker domain promotes IP3R channel opening without altering the Ca2+dependency for channel inactivation. These data suggest a distinct low-affinity Ca2+binding site is responsible for the reduction in IP3R activity at higher [Ca2+]. We determined the consequences of mutating a cluster of acidic residues in the ARM2 and central linker domain reported to coordinate Ca2+in cryo-EM structures of the IP3R type 3. This site is termed the “CD Ca2+binding site” and is well-conserved in all IP3R sub-types. We show that the CD site Ca2+binding mutants where the negatively charged glutamic acid residues are mutated to alanine exhibited enhanced sensitivity to IP3-generating agonists. Ca2+binding mutants displayed spontaneous elemental Ca2+events (Ca2+puffs) and the number of IP3-induced Ca2+puffs was significantly augmented in cells stably expressing Ca2+binding site mutants. When measured with “on-nucleus” patch clamp, the inhibitory effect of high [Ca2+] on single channel-open probability (Po) was reduced in mutant channels and this effect was dependent on [ATP]. These results indicate that Ca2+binding to the putative CD Ca2+inhibitory site facilitates the reduction in IP3R channel activation when cytosolic [ATP] is reduced and suggest that at higher [ATP], additional Ca2+binding motifs may contribute to the biphasic regulation of IP3-induced Ca2+release.
The threat of contagious diseases: when consumers avoid human presence in product packaging
Authors: Park Jane , Kim Chaeyeong , Park Sehoon 
Published: August 2024

PurposePostulating that individuals exposed to the threat of contagious diseases respond oversensitively toward other people, the current research aims to investigate its impact on consumers’ preferences for human images—human presence—in product packaging.Design/methodology/approachFive independent online and offline experiments were conducted. Studies 1, 2a, and 2b employed a three-group (threat: contagious vs. control vs. noncontagious) between-subjects design to investigate the main effect and its underlying mechanism. To further examine the moderation effects, Study 3 used a 2 (threat: contagious vs. control) × 2 (product feature: basic vs. antibacterial) between-subjects design, and Study 4 employed a 2 (threat: contagious vs. control) × 3 (human type: non–human vs. human–adult vs. human–baby) between-subjects design.FindingsStudies 1, 2a, and 2b demonstrate that consumers facing the threat of contagious diseases tend to avoid social interaction, leading to a lower preference for products featuring human presence (vs. non-human presence). Studies 3 and 4 contribute to our hypothesized process by providing boundary conditions. Specifically, when the product incorporates an antibacterial function (Study 3) and the packaging depicts a baby (Study 4), the existing effect can be attenuated.Originality/valueDespite the prevalence of experiencing epidemics and pandemics, little work has examined how threatened consumers respond to product packaging. The present research addresses this gap by exploring consumers' preferences for products featuring human presence on their packaging. Furthermore, this research contributes to the practical understanding of consumer choices by identifying product features and human types as moderating factors.