bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of the Okvik/Old Bering Sea culture of the Bering Strait as a major transition
Authors: Prentiss Anna Marie , Laue Cheyenne , Gjesfjeld Erik , Walsh Matthew J. , Denis Megan , Foor Thomas A. 
Published: January 2023

Great transitions are thought to embody major shifts in locus of selection, labour diversification and communication systems. Such expectations are relevant for biological and cultural systems as decades of research has demonstrated similar dynamics within the evolution of culture. The evolution of the Neo-Inuit cultural tradition in the Bering Strait provides an ideal context for examination of cultural transitions. The Okvik/Old Bering Sea (Okvik/OBS) culture of Bering Strait is the first representative of the Neo-Inuit tradition. Archaeological evidence drawn for settlement and subsistence data, technological traditions and mortuary contexts suggests that Okvik/OBS fits the definition of a major transition given change in the nature of group membership (from families to political groups with social ranking), task organization (emergent labour specialization) and communication (advent of complex art forms conveying social and ideological information). This permits us to develop a number of implications about the evolutionary process recognizing that transitions may occur on three scales: (1) ephemeral variants, as for example, simple technological entities; (2) integrated systems, spanning modular technology to socio-economic strategies; and (3) simultaneous change across all scales with emergent properties.
This article is part of the theme issue ‘Human socio-cultural evolution in light of evolutionary transitions’.
An explainable spatial-temporal graphical convolutional network to score freezing of gait in parkinsonian patients
Authors: Kwon Hyeokhyen , Clifford Gari D. , Genias Imari , Bernhard Doug , Esper Christine D. , Factor Stewart A. , McKay J. Lucas 
Published: January 2023

AbstractFreezing of gait (FOG) is a poorly understood heterogeneous gait disorder seen in patients with parkinsonism which contributes to significant morbidity and social isolation. FOG is currently measured with scales that are typically performed by movement disorders specialists (ie. MDS-UPDRS), or through patient completed questionnaires (N-FOG-Q) both of which are inadequate in addressing the heterogeneous nature of the disorder and are unsuitable for use in clinical trials The purpose of this study was to devise a method to measure FOG objectively, hence improving our ability to identify it and accurately evaluate new therapies. We trained interpretable deep learning models with multi-task learning to simultaneously score FOG (cross-validated F1 score 97.6%), identify medication state (OFF vs. ON levodopa; cross-validated F1 score 96.8%), and measure total PD severity (MDS-UPDRS-III score prediction error ≤ 2.7 points) using kinematic data of a well-characterized sample of N=57 patients during levodopa challenge tests. The proposed model was able to identify kinematic features associated with each FOG severity level that were highly consistent with the features that movement disorders specialists are trained to identify as characteristic of freezing. In this work, we demonstrate that deep learning models’ capability to capture complex movement patterns in kinematic data can automatically and objectively score FOG with high accuracy. These models have the potential to discover novel kinematic biomarkers for FOG that can be used for hypothesis generation and potentially as clinical trial outcome measures.
Principal-stretch-based constitutive neural networks autonomously discover a subclass of Ogden models for human brain tissue
Authors: St. Pierre Sarah R. , Linka Kevin , Kuhl Ellen 
Published: January 2023

AbstractThe soft tissue of the brain deforms in response to external stimuli, which can lead to traumatic brain injury. Constitutive models relate the stress in the brain to its deformation and accurate constitutive modeling is critical in finite element simulations to estimate injury risk. Traditionally, researchers first choose a constitutive model and then fit the model parameters using tension, compression, or shear experiments. In contrast, constitutive artificial neural networks enable automated model discovery without having to choosing a specific model a priori before learning the model parameters. Here we reverse engineer a constitutive artificial neural network that uses the principal stretches, raised to a wide range of exponential powers, as activation functions for the hidden layer. Upon training, the network autonomously discovers a subclass of models with multiple Ogden terms that outperform popular constitutive models including neo Hooke, Blatz Ko, and Mooney Rivlin. While invariant-based networks fail to capture the pronounced tension-compression asymmetry of brain tissue, our principal-stretch-based network can simultaneously explain tension, compression, and shear data for the cortex, basal ganglia, corona radiata, and corpus callosum. Without fixing the number of terms a priori, our model self-selects the best subset of terms out of more than a million possible combinations, while simultaneously discovering the best model parameters and best experiment to train itself. Eliminating user-guided model selection has the potential to induce a paradigm shift in soft tissue modeling and democratize brain injury simulations.Our source code, data, and examples are available athttps://github.com/LivingMatterLab/CANN.
Genotype-specific variation in seasonal body condition at a large-effect maturation locus
Authors: House Andrew H. , Debes Paul V. , Kurko Johanna , Erkinaro Jaakko , Primmer Craig R. 
Published: January 2023

AbstractOrganisms utilize varying lipid resource allocation strategies as a means to survive seasonal environmental changes and life-history stage transitions. In Atlantic salmon, a certain lipid threshold is needed to initiate sexual maturation. Because of this, an individual’s maturation schedule may be affected by changes in temperature and food availability across the seasons that create natural fluctuations of lipid reserves.Recent studies have found a genome region, including the genevgll3,that explains a large proportion of variation for size and age at maturity. Vgll3encodes a transcription co-factor that acts as an inhibitor of adipogenesis in mice and also affects condition factor and other phenotypes in juvenile salmon. However, even with many studies investigating varying temperature effects, there is a lack of temporal studies examining the effects of seasonality on such phenotypes, nor have the effects ofvgll3genotype on condition factor and maturation in different temperatures at different life stages.Here, we investigate the influence of different larval and juvenile incubation temperatures,vgll3genotype and their interactions on juvenile salmon phenotypes including body condition, and sexual maturation rate. We reared Atlantic salmon for 2 years in varying temperatures with an average 1.76 °C difference between warm and cold treatments in four different larval-juvenile phase treatment groups (Warm-Warm, Warm-Cold, Cold-Warm, and Cold-Cold) until the first occurrence of maturation in males.We found no effect of larval temperature on the measured phenotypes or maturation rate, suggesting the occurrence of growth compensation over the course of the experiment. Agreeing with previous studies, an increased maturation rate was observed in individuals of the warm juvenile temperature treatment.In addition, we observed differences in condition factor associated withvgll3genotype, wherebyvgll3*EEindividuals (the genotype associated with early maturation) had a less variable condition factor across the seasons compared to thevgll3*LL(associated with late maturation) individuals.This result suggests avgll3influence on resource acquisition and allocation strategies, possibly linked with the early maturation process, with individuals carrying the early maturationvgll3genotype having a higher early maturation rate and a higher condition factor in the spring.
Cross-Species Protection to Innate Immunity Mediated by A Bacterial Pigment
Authors: Liu Yiwei , McQuillen Eleanor A. , Rana Pranav S. J. B. , Gloag Erin. S. , Wozniak Daniel J. 
Published: January 2023

AbstractBacterial infections are often polymicrobial.Pseudomonas aeruginosaandStaphylococcus aureuscause chronic co-infections, which are more problematic than mono-species infections. We found that the production ofS. aureusmembrane-bound pigment staphyloxanthin (STX), was induced by theP. aeruginosaexoproduct, 2-heptyl-4-hydroxyquinoline N-oxide (HQNO). The induction phenotype was conserved inP. aeruginosaandS. aureusclinical isolates examined. When subjected to hydrogen peroxide or human neutrophils,P. aeruginosasurvival was significantly higher when mixed with wild-type (WT)S. aureus, compared to a mutant deficient in STX production orP. aeruginosaalone. In a murine wound model, co-infection with WTS. aureus, but not the STX-deficient mutant, enhancedP. aeruginosaburden and disease compared to mono-infection. In conclusion, we discovered a novel role forP. aeruginosaHQNO mediating polymicrobial interactions withS. aureusby inducing STX production, which consequently promotes resistance of both pathogens to innate immune effectors. These results further our understanding of how different bacterial species cooperatively cause co-infections.
High-throughput quantification of camelid cytokine mRNA expression in PBMCs by microfluidic qPCR technology
Authors: Rodon Jordi , Te Nigeer , Ballester Maria , Segalés Joaquim , Vergara-Alert Júlia , Bensaid Albert 
Published: January 2023

ABSTRACTCamelids are economically and socially important in several parts of the world and might carry pathogens with epizootic or zoonotic potential. However, biological research in these species is limited due to lack of reagents. Here, we developed RT-qPCR assays to quantify a panel of camelid innate and adaptive immune response genes, which can be monitored in a single run. Validation of the assays was performed with PHA, PMA-ionomycin, and Poly I:C-stimulated PBMCs from alpaca, dromedary camel and llama, including normalization by multiple reference genes. Further, comparative gene expression analyses for the different camelid species were performed by a unique microfluidic qPCR assay. Compared to unstimulated samples, PHA and PMA-ionomycin stimulation elicited robust Th1 and Th2 responses in PBMCs from camelid species. Additional activation of type I and type III IFN signalling pathways was described exclusively in PHA-stimulated dromedary lymphocytes, in contrast to those from alpaca and llama. We also found that PolyI:C stimulation induced robust antiviral response genes in alpaca PBMCs. The proposed methodology should be useful for the measurement of immune responses to infection or vaccination in camelid species.
Deep Learning Dynamic Allostery of G-Protein-Coupled Receptors
Authors: Do Hung N. , Wang Jinan , Miao Yinglong 
Published: January 2023

AbstractG-protein-coupled receptors (GPCRs) are the largest superfamily of human membrane proteins and represent primary targets of ∼1/3 of currently marketed drugs. Allosteric modulators have emerged as more selective drug candidates compared with orthosteric agonists and antagonists. However, many X-ray and cryo-EM structures of GPCRs resolved so far exhibit negligible differences upon binding of positive and negative allosteric modulators (PAMs and NAMs). Mechanism of dynamic allosteric modulation in GPCRs remains unclear. In this work, we have systematically mapped dynamic changes in free energy landscapes of GPCRs upon binding of allosteric modulators using the Gaussian accelerated molecular dynamics (GaMD), Deep Learning (DL) and free energy prOfiling Workflow (GLOW). A total of 18 available high-resolution experimental structures of allosteric modulator-bound class A and B GPCRs were collected for simulations. A number of 8 computational models were generated to examine selectivity of the modulators by changing their target receptors to different subtypes. All-atom GaMD simulations were performed for a total of 66 µs on 44 GPCR systems in the presence/absence of the modulator. DL and free energy calculations revealed significantly reduced conformational space of GPCRs upon modulator binding. While the modulator-free GPCRs often sampled multiple low-energy conformational states, the NAMs and PAMs confined the inactive and active agonist-G protein-bound GPCRs, respectively, to mostly only one specific conformation for signaling. Such cooperative effects were significantly reduced for binding of the selective modulators to “non-cognate” receptor subtypes in the computational models. Therefore, comprehensive DL of extensive GaMD simulations has revealed a general dynamic mechanism of GPCR allostery, which will greatly facilitate rational design of selective allosteric drugs of GPCRs.
Multiplepalsgene modules control a balance between immunity and development inCaenorhabditis elegans
Authors: Lažetić Vladimir , Blanchard Michael J. , Bui Theresa , Troemel Emily R. 
Published: January 2023

ABSTRACTThe immune system continually battles against pathogen-induced pressures, which often leads to the evolutionary expansion of immune gene families in a species-specific manner. For example, thepalsgene family expanded to 39 members in theCaenorhabditis elegansgenome, in comparison to a single mammalianpalsortholog. Our previous studies have revealed that two members of this family,pals-22andpals-25, act as antagonistic paralogs to control the Intracellular Pathogen Response (IPR). The IPR is a protective transcriptional response, which is activated upon infection by two molecularly distinct natural intracellular pathogens ofC. elegans– the Orsay virus and the fungusNematocida parisiifrom the microsporidia phylum. In this study, we identify a previously uncharacterized member of thepalsfamily,pals-17, as a newly described negative regulator of the IPR.pals-17mutants show constitutive upregulation of IPR gene expression, increased immunity against intracellular pathogens, as well as impaired development and reproduction. We also find that two other previously uncharacterizedpalsgenes,pals-20andpals-16, are positive regulators of the IPR, acting downstream ofpals-17. These positive regulators reverse the effects caused by the loss ofpals-17on IPR gene expression, immunity and development. We show that the negative IPR regulator protein PALS-17 and the positive IPR regulator protein PALS-20 colocalize inside intestinal epithelial cells, which are the sites of infection for IPR-inducing pathogens. In summary, our study demonstrates that severalpalsgenes from the expandedpalsgene family act as ON/OFF switch modules to regulate a balance between organismal development and immunity against natural intracellular pathogens inC. elegans.AUTHOR SUMMARYImmune responses to pathogens induce extensive rewiring of host physiology. In the short term, these changes are generally beneficial as they can promote resistance against infection. However, prolonged activation of immune responses can have serious negative consequences on host health, including impaired organismal development and fitness. Therefore, the balance between activating the immune system and promoting development must be precisely regulated. In this study, we used genetics to identify a gene in the roundwormCaenorhabditis eleganscalledpals-17that acts as a repressor of the Intracellular Pathogen Response (IPR), a defense response against viral and microsporidian infections. We also found thatpals-17is required for the normal development of these animals. Furthermore, we identified two otherpalsgenes,pals-20andpals-16, as suppressors ofpals-17mutant phenotypes. Finally, we found that PALS-17 and PALS-20 proteins colocalize inside intestinal cells, where viruses and microsporidia invade and replicate in the host. Taken together, our study demonstrates a balance between organismal development and immunity that is regulated by several genetic ON/OFF switch ‘modules’ inC. elegans.
Comprehensive analysis of primary immune thrombocytopenia clinical trials in the ClinicalTrials.gov database
Authors: Wang Yacan , Bi Hui , Yang Wen , Wang Honghui , Wang Xiuli , Xie Dongmei , Li Huiting , Zhou Zeping 
Published: January 2023

AbstractObjectiveThe purpose is to clarify the overall situation of clinical related to primary immune thrombocytopenia (ITP), to evaluate the difference between published clinical trials and unpublished trials, and to evaluate the relevant information of trial publication.MethodsSearch theClinicalTrials.govdatabase on March 20, 2022 to identify ITP clinical trials and obtain relevant data. Publications in PubMed were searched using standardized methods to identify the publication of completed clinical trials.ResultsOf 341 trials identified, interventional trials were the most common (74.2%, n=253). Interventional trials and observational trials differ in the main research content (odds ratio (OR) 0.06, 95% confidence interval (CI) 0.03-0.015, P=0.000). In terms of published articles, there are few trials involving non drugs (OR 0.23, CI 0.08-0.64, P = 0.005). There were fewer trials with less than 10 participants (OR 1.52, CI 1.06-2.20, P = 0.024). Of the 167 completed trials, 93 (55.7%) were published and 48 (28.7%) uploaded results.ConclusionIf the main research content involves drugs, trials with a larger number of people are more likely to be published. The publication rate of ITP clinical trials is high, but the submission rate of database results is low. Therefore, more attention should be paid to the submission of clinical trial results in the later stage.
SARS-CoV-2 evolution in the absence of selective immune pressures, results in antibody resistance, interferon suppression and phenotypic differences by lineage
Authors: Willett Julian Daniel Sunday , Gravel Annie , Dubuc Isabelle , Gudimard Leslie , dos Santos Pereira Andrade Ana Claudia , Lacasse Émile , Fortin Paul , Liu Ju-Ling , Cervantes Jose Avila , Galvez Jose Hector , Djambazian Haig Hugo Vrej , Zwaig Melissa , Roy Anne-Marie , Lee Sally , Chen Shu-Huang , Ragoussis Jiannis , Flamand Louis 
Published: January 2023

AbstractThe persistence of COVID-19 is partly due to viral evolution reducing vaccine and treatment efficacy. Serial infections of Wuhan-like SARS-CoV-2 in Balb/c mice yielded mouse-adapted strains with greater infectivity and mortality. We investigated if passaging unmodified B.1.351 (Beta) and B.1.617.2 (Delta) 20 times in K18-ACE2 mice, expressing human ACE2 receptor, in a BSL-3 laboratory without selective pressures, would drive human health-relevant evolution and if evolution was lineage-dependent. Late-passage virus caused more severe disease, at organism and lung tissue scales, with late-passage Delta demonstrating antibody resistance and interferon suppression. This resistance co-occurred with ade novospike S371F mutation, linked with both traits. S371F, an Omicron-characteristic mutation, was co-inherited at times with spike E1182G per Nanopore sequencing, existing in different quasi-species at others. Both are linked to mammalian GOLGA7 and ZDHHC5 interactions, which mediate viral-cell entry and antiviral response. This study demonstrates SARS-CoV-2’s tendency to evolve with phenotypic consequences, its evolution varying by lineage, and suggests non-dominant quasi-species contribute.
In situarchitecture of Opa1-dependent mitochondrial cristae remodeling
Authors: Fry Michelle Y. , Navarro Paula P. , Hakim Pusparanee , Ananda Virly Y. , Qin Xingping , Landoni Juan C. , Rath Sneha , Inde Zintis , Lugo Camila Makhlouta , Luce Bridget E. , Ge Yifan , McDonald Julie L. , Ali Ilzat , Ha Leillani L. , Kleinstiver Benjamin P. , Chan David C. , Sarosiek Kristopher A. , Chao Luke H. 
Published: January 2023

AbstractCristae membrane state plays a central role in regulating mitochondrial function and cellular metabolism. The protein Optic atrophy 1 (Opa1) is an important crista remodeler that exists as two forms in the mitochondrion, a membrane-anchored long form (l-Opa1) and a processed short form (s-Opa1). The mechanisms for how Opa1 influences cristae shape have remained unclear due to lack of native three-dimensional views of cristae. We performin situcryo-electron tomography of cryo-focused ion beam milled mouse embryonic fibroblasts with defined Opa1 states to understand how each form of Opa1 influences cristae architecture. In our tomograms, we observe a variety of cristae shapes with distinct trends dependent on s-Opa1:l-Opa1 balance. Increased l-Opa1 levels promote cristae stacking and elongated mitochondria while increased s-Opa1 levels correlated with irregular cristae packing and round mitochondria shape. Functional assays indicate a role for l-Opa1 in wild-type apoptotic and calcium handling responses, and compromised respiratory function under Opa1 imbalance. In summary, we provide three-dimensional visualization of cristae architecture to reveal relationships between mitochondrial ultrastructure and cellular function dependent on Opa1-mediated membrane remodeling.HighlightsIn situultrastructural characterization of mitochondrial cristae with different forms of Opa1.Mitochondria with predominantly l-Opa1 show crista stacking, longer cristae, reduced globular cristae and an absence of tubular cristae.Mitochondria with mostly s-Opa1 showed irregular cristae packing with wider cristae junctions and narrower cristae.l-Opa1 expressing cells with WT-like cristae junction properties, show wild-type apoptotic response and calcium handling.Imbalance in Opa1 processing show compromised respiratory function and an increase in amorphous cristae.
In vitroproduction of cat-restrictedToxoplasmapre-sexual stages by epigenetic reprogramming
Authors: Antunes Ana Vera , Shahinas Martina , Swale Christopher , Farhat Dayana C. , Ramakrishnan Chandra , Bruley Christophe , Cannella Dominique , Corrao Charlotte , Couté Yohann , Hehl Adrian B. , Bougdour Alexandre , Coppens Isabelle , Hakimi Mohamed-Ali 
Published: January 2023

Summary paragraphSexual reproduction ofToxoplasma gondii, which is restricted to the small intestine of felids, is sparsely documented, due to ethical concerns surrounding the use of cats as model organisms. Chromatin modifiers dictate the developmental fate of the parasite during its multistage life cycle, but their targeting to stage-specific cistromes is poorly described1. In this study, we found that transcription factors AP2XII-1 and AP2XI-2, expressed in tachyzoite stage that causes acute toxoplasmosis, can silence genes necessary for merozoites, a developmental stage critical for sexual commitment and transmission to the next host, including humans. Their conditional and simultaneous depletion leads to a drastic change in the transcriptional program, promoting a complete transition from tachyzoites to merozoites. Pre-gametes producedin vitrounder these conditions are characterized by specific protein markers and undergo typical asexual endopolygenic division cycles. In tachyzoites, AP2XII-1 and AP2XI-2 bind DNA as heterodimers at merozoite promoters and recruit the epigenitors MORC and HDAC31, which in turn restrict the accessibility of chromatin to the transcriptional machinery. Thus, the commitment to merogony stems from a profound epigenetic rewiring orchestrated by AP2XII-1 and AP2XI-2. This effectivein vitroculture of merozoites paves the way to exploreToxoplasmasexual reproduction without the need to infect kittens and has potential for the development of therapeutics to block parasite transmission.