bluuebunny/crossref_metadata_2025_split huggingface dataset:
Friction patterns guide actin network contraction
Authors: Colin Alexandra , Orhant-Prioux Magali , Guérin Christophe , Savinov Mariya , Scarfone Ilaria , Roux Aurelien , De La Cruz Enrique M. , Mogilner Alex , Théry Manuel , Blanchoin Laurent 
Published: December 2022

AbstractThe shape of cells is the outcome of the balance of inner forces produced by the actomyosin network and the resistive forces produced by cell adhesion to their environment. The specific contributions of contractile, anchoring and friction forces to network deformation rate and orientation are difficult to disentangle in living cells where they influence each other. Here, we reconstituted contractile acto-myosin networksin vitroto study specifically the role of the friction forces between the network and its anchoring substrate. To modulate the magnitude and spatial distribution of friction forces, we micropatterned actin nucleation promoting factors on glass or on a lipid bilayer. We adapted their concentrations on each surface to induce the assembly of actin networks of similar densities, and compare the deformation of the network toward the centroid of the pattern shape upon myosin-induced contraction. We found that actin network deformation was faster and more coordinated on lipid bilayers than on glass, showing the resistance of friction to network contraction. To further study the role of the spatial distribution of these friction forces, we designed heterogeneous micropatterns made of glass and lipids. The deformation upon contraction was no longer symmetric but biased toward the region of higher friction. Furthermore, we showed that the pattern of friction could robustly drive network contraction and dominate the contribution of asymmetric distributions of myosins. Therefore, we demonstrate that during contraction both the active and resistive forces are essential to direct the actin network deformation.Significance statementCell shape changes are controlled by complex sets of mechanical forces of various origins. Numerous studies have been dedicated to the role of active forces, originating from molecular motors and filament polymerization, but much less is known about the guiding role of resistive forces. Here we show that a non-uniform distribution of friction forces between a contracting acto-myosin network and its underlying substrate can direct its deformation as it contracts. Our results suggest that the contribution of resistive forces, such as anchoring forces but also less specific viscous forces along cell surface, can be as significant as those of active forces in driving network deformation and should be considered in mechanical models describing the regulation of cell shape and movements.
SARS-CoV-2 Variant-Specific Differences in Inhibiting the Effects of the PKR-Activated Integrated Stress Response
Authors: Christ Wanda , Klingström Jonas , Tynell Janne 
Published: December 2022

SummaryThe integrated stress response (ISR) is a eukaryotic cell pathway that triggers translational arrest and the formation of stress granules (SGs) in response to various stress signals, including those caused by viral infections. The SARS-CoV-2 nucleocapsid protein has been shown to disrupt SGs, but SARS-CoV-2 interactions with other components of the pathway remains poorly characterized. Here, we show that SARS-CoV-2 infection triggers the ISR through activation of the eIF2α-kinase PKR while inhibiting a variety of downstream effects. In line with previous studies, SG formation was efficiently inhibited and the induced eIF2α phosphorylation only minimally contributed to the translational arrest observed in infected cells. Despite ISR activation and translational arrest, expression of the stress-responsive transcripts ATF4 and CHOP was not induced in SARS-CoV-2 infected cells. Finally, we found variant-specific differences in the activation of the ISR between ancestral SARS-CoV-2 and the Delta and Omicron BA.1 variants in that Delta infection induced weaker PKR activation while Omicron infection induced higher levels of p-eIF2α and greatly increased SG formation compared to the other variants. Our results suggest that different SARS-CoV-2 variants can affect normal cell functions differently, which can have an impact on pathogenesis and treatment strategies.
Diagnosis with Confidence: Deep Learning for Reliable Classification of Squamous Lesions of the Upper Aerodigestive Tract
Authors: Lubrano Mélanie , Bellahsen-Harrar Yaëlle , Berlemont Sylvain , Atallah Sarah , Vaz Emmanuelle , Walter Thomas , Badoual Cécile 
Published: December 2022

AbstractBackgroundDiagnosis of head and neck (HN) squamous dysplasias and carcinomas is critical for patient care cure and follow-up. It can be challenging, especially for grading intraepithelial lesions. Despite recent simplification in the last WHO grading system, the inter- and intra-observer variability remains substantial, particularly for non-specialized pathologists, exhibiting the need for new tools to support pathologists.MethodsIn this study we investigated the potential of deep learning to assist the pathologist with automatic and reliable classification of HN lesions following the 2022 WHO classification system. We created, for the first time, a large-scale database of histological samples (>2000 slides) intended for developing an automatic diagnostic tool. We developed and trained a weakly supervised model performing classification from whole slide images (WSI). We evaluated our model on both internal and external test sets and we defined and validated a new confidence score to assess the predictions which can be used to identify difficult cases.ResultsOur model demonstrated high classification accuracy across all lesion types on both internal and external test sets (respectively average AUC: 0.878 (95% CI:[0.834-0.918]) and 0.886 (95% CI: [0.813-0.947])) and the confidence score allowed for accurate differentiation between reliable and uncertain predictions.ConclusionsOur results demonstrate that the model, associated with confidence measurements, can help in the difficult task of classifying head and neck squamous lesions by limiting variability and detecting ambiguous cases, taking us one step closer to a wider adoption of AI-based assistive tools.
Viability of carcass removal as an option for offsetting the incidental take of golden eagles (Aquila chrysaetos) at wind energy facilities
Authors: Lonsdorf Eric V. , Gerber James S. , Ray Deepak , Slater Steven J. , Allison Taber D. 
Published: December 2022

ABSTRACTAs wind energy expands to achieve the United States’ net zero emission goals, compensatory mitigation will be required to offset negative impacts to birds and bats. The golden eagle (Aquila chrysaetos) is particularly susceptible to collision with wind turbines but only one option for offsetting mortalities has been approved by the U.S. Fish and Wildlife Service despite many sources of anthropogenic-caused mortality. Here, we update a previously developed vehicle-collision model with empirical data and integrate a resource equivalency analysis so that removal of road-killed game animals can be used as mitigation to offset incidental mortality. We parameterized the golden eagle behavior parameters using camera-traps placed at roadside carcasses. We quantified the effects of different carcass-removal schemes based on vehicle and carcass characteristics observed for the state of Wyoming. Our model results indicate that while eagles saved per carcass removed depends on removal interval and vehicle traffic volume, carcass removal is a viable mitigation strategy; up to seven eagles could be saved per year in some counties. While some uncertainty remains about the precise credit received from each carcass removed, delaying the inclusion of additional mitigation methods prevents opportunities for conservation action. An adaptive management program could be a way forward where management and monitoring are combined to further improve estimates of mitigation credit.
Decorrelation Time Mapping as an Analysis Tool for Nanobubble-Based Contrast Enhanced Ultrasound Imaging
Authors: Wegierak Dana , Cooley Michaela , Perera Reshani , Wulftange William J. , Gurkan Umut A. , Kolios Michael C. , Exner Agata A. 
Published: December 2022

AbstractNanobubbles (NBs) are nanoscale (∼100-500 nm diameter) ultrasound (US) contrast agents that enable new robust applications of contrast enhanced US and US-mediated therapy. Due to their sub-micron size, high particle density, and highly deformable shell, NBs exhibit unique properties. In pathological states of heightened vascular permeability, such as in tumours, NBs can extravasate, enabling extravascular applications not currently possible with clinically available microbubbles (∼1000-10,000 nm diameter). This ability can be explored to develop imaging biomarkers to improve tumour detection. There is a need for an imaging method that can rapidly and effectively separate intravascular versus extravascular NB signal when imaged using nonlinear dynamic contrast enhanced US. Herein, we demonstrated the use of decorrelation time (DT) mapping to achieve this goal. Twoin vitromodels were used to explore the roles of NB velocity and diffusion on DTs. Mice bearing prostate specific membrane antigen (PSMA) expressing flank tumours (n = 7) were injected with bubble agents to evaluate thein vivopotential of this technique. The DT was calculated at each pixel of nonlinear contrast videos to produce DT maps. Across all models, long DT correlated with slowly moving or entrapped NBs while short DT correlated with flowing NBs. DT maps were sensitive to NBs in tumour tissue with high average DT in tumour regions (∼10 s) compared to surrounding normal tissue (∼1 s). Molecular NB targeting to PSMA extended DT (17 s) compared to non-targeted NBs (12 s), demonstrating sensitivity to NB adherence dynamics. Overall, DT mapping ofin vivoNB dynamics produced detailed information of tumour tissue and showed potential for quantifying extravascular NB kinetics. This new NB-contrast enhanced US-based biomarker can be useful in molecular ultrasound imaging, with improved sensitivity and specificity of target tissue detection and potential for use as a predictor of vascular permeability and the enhanced permeability and retention (EPR) effect in tumours.
An improved reference of the grapevine genome supports reasserting the origin of the PN40024 highly-homozygous genotype
Authors: Velt Amandine , Frommer Bianca , Blanc Sophie , Holtgräwe Daniela , Duchêne Éric , Dumas Vincent , Grimplet Jérôme , Hugueney Philippe , Lahaye Marie , Kim Catherine , Matus José Tomás , Navarro-Payá David , Orduña Luis , Tello-Ruiz Marcela K. , Vitulo Nicola , Ware Doreen , Rustenholz Camille 
Published: December 2022

AbstractThe genome sequence assembly of the diploid and highly homozygousV. viniferagenotype PN40024 serves as the reference for many grapevine studies. Despite several improvements of the PN40024 genome assembly, its current version PN12X.v2 is quite fragmented and only represents the haploid state of the genome with mixed haplotypes. In fact, despite the PN40024 genome is nearly homozygous, it still contains various heterozygous regions. Taking the opportunity of the improvements that long-read sequencing technologies offer to fully discriminate haplotype sequences and considering that severalVitissp. genomes have recently been assembled with these approaches, an improved version of the reference, called PN40024.v4, was generated.Through incorporating long genomic sequencing reads to the assembly, the continuity of the 12X.v2 scaffolds was highly increased. The number of scaffolds decreased from 2,059 to 640 and the number of N bases was reduced by 88%. Additionally, the full alternative haplotype sequence was built for the first time, the chromosome anchoring was improved and the amount of unplaced scaffolds were reduced by half. To obtain a high-quality gene annotation that outperforms previous versions, a liftover approach was complemented with an optimized annotation workflow forVitis. Integration of the gene reference catalogue and its manual curation have also assisted in improving the annotation, while defining the most reliable estimation to date of 35,230 genes. Finally, we demonstrate that PN40024 resulted from selfings of cv. ‘Helfensteiner’ (cross of cv. ‘Pinot noir’ and ‘Schiava grossa’) instead of a single ‘Pinot noir’. These advances will help maintaining the PN40024 genome as a gold-standard reference also contributing in the eventual elaboration of the grapevine pangenome.
Dysfunctional Hippocampal-Prefrontal Network Underlies a Multidimensional Neuropsychiatric Phenotype following Early-Life Seizure
Authors: Ruggiero Rafael Naime , Marques Danilo Benette , Rossignoli Matheus Teixeira , De Ross Jana Batista , Prizon Tamiris , Beraldo Ikaro Jesus Silva , Bueno-Junior Lezio Soares , Kandratavicius Ludmyla , Peixoto-Santos Jose Eduardo , Aguiar Cleiton Lopes , Leite João Pereira 
Published: December 2022

AbstractBrain disturbances during development can have a lasting impact on neural function and behavior. Seizures during this critical period are linked to significant long-term consequences such as neurodevelopmental disorders, cognitive impairments, and psychiatric symptoms, resulting in a complex spectrum of multimorbidity. The hippocampus-prefrontal cortex (HPC-PFC) circuit emerges as a potential common link between such disorders. However, the mechanisms underlying these outcomes and how they relate to specific behavioral alterations are unclear. We hypothesized that specific dysfunctions of hippocampal-cortical communication due to early-life seizure would be associated with distinct behavioral alterations observed in adulthood. Here, we performed a multilevel study to investigate behavioral, electrophysiological, histopathological, and neurochemical long-term consequences of early-lifeStatus epilepticusin male rats. We show that adult animals submitted to early-life seizure (ELS) present working memory impairments and sensorimotor disturbances, such as hyperlocomotion, poor sensorimotor gating, and sensitivity to psychostimulants despite not exhibiting neuronal loss. Surprisingly, cognitive deficits were linked to an aberrant increase in the HPC-PFC long-term potentiation (LTP) in a U-shaped manner, while sensorimotor alterations were associated with heightened neuroinflammation, as verified by glial fibrillary acidic protein (GFAP) expression, and altered dopamine neurotransmission. Furthermore, ELS rats displayed impaired HPC-PFC theta-gamma coordination and an abnormal brain state during active behavior resembling rapid eye movement (REM) sleep oscillatory dynamics. Our results point to impaired HPC- PFC functional connectivity as a possible pathophysiological mechanism by which ELS can cause cognitive deficits and psychiatric-like manifestations even without neuronal loss, bearing translational implications for understanding the spectrum of multidimensional developmental disorders linked to early-life seizures.
Plasma concentrations of anti-inflammatory cytokine TGF-β are associated with hippocampal structure related to explicit memory performance in older adults
Authors: Raschick Matthias , Richter Anni , Fischer Larissa , Knopf Lea , Schult Annika , Yakupov Renat , Behnisch Gusalija , Guttek Karina , Düzel Emrah , Dunay Ildiko Rita , Seidenbecher Constanze I. , Schraven Burkhart , Reinhold Dirk , Schott Björn H. 
Published: December 2022

AbstractHuman cognitive abilities, and particularly hippocampus-dependent memory performance typically decline with increasing age. Immunosenescence, the age-related disintegration of the immune system, is increasingly coming into the focus of research as a considerable factor contributing to cognitive decline. In the present study, we investigated potential associations between plasma levels of pro- and anti-inflammatory cytokines and learning and memory performance as well as hippocampal anatomy in young and older adults. Plasma concentrations of the inflammation marker CRP as well as the pro-inflammatory cytokines IL-6 and TNF-α and the anti-inflammatory cytokine TGF-β1were measured in 142 healthy adults (57 young, 24.47 ± 4.48 years; 85 older, 63.66 ± 7.32 years) who performed tests of explicit memory (Verbal Learning and Memory Test, VLMT; Wechsler Memory Scale, Logical Memory, WMS) with an additional delayed recall test after 24 hours. Hippocampal volumetry and hippocampal subfield segmentation were performed using FreeSurfer, based on T1-weighted and high-resolution T2-weighted MR images. When investigating the relationship between memory performance, hippocampal structure, and plasma cytokine levels, we found that TGF- β1concentrations were positively correlated with the volumes of the hippocampal CA4-dentate gyrus region in older adults. These volumes were in turn positively associated with better performance in the WMS, particularly in the delayed memory test. Our results support the notion that endogenous anti-inflammatory mechanisms may act as protective factors in neurocognitive aging.
Deep learning-enabled design of synthetic orthologs of a signaling protein
Authors: Lian Xinran , Praljak Niksa , Subramanian Subu K. , Wasinger Sarah , Ranganathan Rama , Ferguson Andrew L. 
Published: December 2022

AbstractEvolution-based deep generative models represent an exciting direction in understanding and designing proteins. An open question is whether such models can represent the constraints underlying specialized functions that are necessary for organismal fitness in specific biological contexts. Here, we examine the ability of three different models to produce synthetic versions of SH3 domains that can support function in a yeast stress signaling pathway. Using a select-seq assay, we show that one form of a variational autoencoder (VAE) recapitulates the functional characteristics of natural SH3 domains and classifies fungal SH3 homologs hierarchically by function and phylogeny. Locality in the latent space of the model predicts and extends the function of natural orthologs and exposes amino acid constraints distributed near and far from the SH3 ligand-binding site. The ability of deep generative models to specify orthologous functionin vivoopens new avenues for probing and engineering protein function in specific cellular environments.
Lateral compression of lipids drives transbilayer coupling of liquid-like protein condensates
Authors: Lee Yohan , Park Sujin , Yuan Feng , Hayden Carl C. , Choi Siyoung Q. , Stachowiak Jeanne C. 
Published: December 2022

AbstractLiquid-liquid phase separation of proteins has recently been observed on the surfaces of biological membranes, where it plays a role in diverse cellular processes, from assembly of focal adhesions and the immunological synapse, to biogenesis of trafficking vesicles. Interestingly in each of these cases, proteins on both surfaces of the membrane are thought to participate, suggesting that protein phase separation could be coupled across the membrane. To explore this possibility, we used an array of freestanding planar lipid membranes to observe protein phase separation simultaneously on both surfaces of lipid bilayers. When proteins known to engage in phase separation bound to the surfaces of these membranes, two-dimensional, protein-rich phases rapidly emerged. These phases displayed the hallmarks of a liquid, coarsening over time by fusing and re-rounding. Interestingly, we observed that protein-rich domains on one side of the membrane colocalized with those on the other side, resulting in transbilayer coupling. How do liquid-like protein phases communicate across the lipid bilayer? Our results, based on lipid probe partitioning and the differential mobility of proteins and lipids, collectively suggest an entropic coupling mechanism, which relies on the ability of protein phase separation to locally reduce the entropy of the underlying lipid membrane, most likely by increasing lipid packing. Regions of reduced entropy then colocalize across the bilayer to minimize the overall free energy of the membrane. These findings suggest a previously unknown mechanism by which cellular signals originating from one side of the membrane, triggered by protein phase separation, can be transferred to the opposite side.
Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 locus mismatches associated with long-term renal transplant survival
Authors: Sun Zeguo , Zhang Zhongyang , Banu Khadija , Gibson Ian , Colvin Robert , Yi Zhengzi , Zhang Weijia , De Kumar Bony , Pell John , Djamali Arjang , Gallon Lorenzo , O’Connell Philip , He Cijiang , Pober Jordan , Heeger Peter , Menon Madhav C 
Published: December 2022

AbstractBackgroundLong-term kidney allograft survival remains suboptimal. Emerging evidence indicates donor-recipient (D-R) mismatches outside of human leukocyte antigens (HLA) contribute to graft survival but mechanisms remain unclear, specifically for those mismatches within intronic regions.MethodsWe analyzed genome-wide SNP data of D-R pairs from two well-phenotyped kidney transplant cohorts (median follow-up ~1800 days), Genomics of Chronic Allograft Rejection (GoCAR; n=385) and Clinical Trials in Organ Transplantation 1/17 (CTOT1/17; n=146), quantifying genetic mismatches outside of HLA for every D-R pair at variant, gene, and genome-wide scales.ResultsUnbiased genome-wide screen of GoCAR D-R pairs uncovered the LIMS1 locus as the topranked candidate where D-R mismatches associated with death censored graft loss (DCGL). Independent of HLA, a previously unreported relationship between mismatches at a highly linked, intronic haplotype of 30 SNPs was seen as associated with DCGL, with confirmatory association in intra-ancestry D-Rs. Validation testing within the CTOT-01/17 showed similar associations with DCGL. Haplotype D-R mismatches showed a dosage effect, and the introduction of minor alleles in the donor to major allele-carrying recipients showed a greater risk of DCGL. Both the new LIMS1 haplotype and the previously reported LIMS1 SNP rs893403 are expression quantitative trait loci (eQTL) for the gene GCC2 in recipient immune cells, without alterations in GCC2 or LIMS1 coding sequences. Transcriptome enrichment analyses performed on whole blood and within multiple T cell subsets demonstrated significant associations of GCC2 gene, and of either allelic locus, with regulation of TGF-beta-SMAD signaling, implying a role in Treg function and association with rejection.ConclusionsOur analysis unravels intronic non-HLA SNP mismatches within LIMS1 that do not induce protein sequence variation but associate with DCGL. By acting as cis-eQTLs for GCC2 expression, these SNPs modulates TGF-beta signaling and T cell function, associating with immune events and graft outcomes. The findings have clinical implications for risk assessment and individualized therapy in kidney transplant recipients.