bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Monoclonal Antibody Targeting a Large Surface of the Receptor Binding Motif Shows Pan-neutralizing SARS-CoV-2 Activity Including BQ.1.1 Variant
Authors: de Campos-Mata Leire , Trinité Benjamin , Modrego Andrea , Vaquero Sonia Tejedor , Pradenas Edwards , Melero Natalia Rodrigo , Carlero Diego , Marfil Silvia , Pons-Grífols Anna , Bueno-Carrasco María Teresa , Santiago César , Tarrés-Freixas Ferran , Urrea Victor , Izquierdo Nuria , Riveira-Muñoz Eva , Ballana Ester , Pérez Mónica , Vergara-Alert Júlia , Segalés Joaquim , Carolis Carlo , Arranz Rocío , Blanco Julià , Magri Giuliana 
Published: January 2023

SummaryIn the present study we report the functional and structural characterization of 17T2, a new highly potent pan-neutralizing SARS-CoV-2 human monoclonal antibody (mAb) isolated from a convalescent COVID-19 individual infected during the first wave of the COVID-19 pandemic. 17T2 is a class 1 VH1-58/κ3-20 antibody, derived from a receptor binding domain (RBD)-specific IgA memory B cell and developed as a human recombinant IgG1. Functional characterization revealed that 17T2 mAb has a high and exceptionally broad neutralizing activity against all SARS-CoV-2 spike variants tested, including BQ.1.1. Moreover, 17T2 mAb hasin vivoprophylactic activity against Omicron BA.1.1 infection in K18-hACE2 transgenic mice. 3D reconstruction from cryogenic-electron microscopy (cryo-EM) showed that 17T2 binds the Omicron BA.1 spike protein with the RBD domains in “up” position and recognizes an epitope overlapping with the receptor binding motif, as it is the case for other structurally similar neutralizing mAbs, including S2E12. Yet, unlike S2E12, 17T2 retained its high neutralizing activity against all Omicron sublineages tested, probably due to a larger contact area with the RBD, which could confer a higher resilience to spike mutations. These results highlight the impact of small structural antibody changes on neutralizing performance and identify 17T2 mAb as a potential candidate for future therapeutic and prophylactic interventions.
Reliable imputation of spatial transcriptome with uncertainty estimation and spatial regularization
Authors: Qiao Chen , Huang Yuanhua 
Published: January 2023

AbstractImputation of missing features in spatial transcriptomics is urgently demanded due to technology limitations, while most existing computational methods suffer from moderate accuracy and cannot estimate the reliability of the imputation. To fill the research gaps, we introduce a computational model, TransImp, that imputes the missing feature modality in spatial transcriptomics by mapping it from single-cell reference. Uniquely, we derived a set of attributes that can accurately predict imputation uncertainty, hence enabling us to select reliably imputed genes. Also, we introduced a spatial auto-correlation metric as a regularization to avoid overestimating spatial patterns. Multiple datasets from various platforms have demonstrated that our approach significantly improves the reliability of downstream analyses in detecting spatial variable genes and interacting ligand-receptor pairs. Therefore, TransImp offers a way towards a reliable spatial analysis of missing features for both matched and unseen modalities, e.g., nascent RNAs.
Safety of bivalent omicron-containing mRNA-booster vaccines: a nationwide cohort study
Authors: Andersson Niklas Worm , Thiesson Emilia Myrup , Vinsløv Hansen Jørgen , Hviid Anders 
Published: January 2023

ABSTRACTBackgroundSafety data to support bivalent omicron-containing mRNA-booster vaccination are lacking.MethodsIn a Danish nationwide cohort study from 1 January 2021 to 10 December 2022, we examined the association between bivalent omicron-containing mRNA-booster vaccination as a fourth Covid-19 vaccine dose and risk of adverse events in individuals aged ≥50 years. Using incidence rate ratios estimated with Poisson regression, we compared the rates of hospital visits for 27 different adverse events in a 28-day main risk period following vaccination with a bivalent omicron-containing mRNA-booster vaccine as a fourth dose to reference period rates from day 29 after the third or fourth vaccine dose and onward. Secondary analyses included stratifying by sex, age, and vaccine type and assessing the associations using self-controlled case series and observed vs. expected cohort analyses.Results1,740,417 individuals (mean age 67.8 years, standard deviation 10.7) received a bivalent omicron-containing mRNA-booster vaccine as a fourth dose. Fourth dose vaccination with a bivalent omicron-containing booster did not statistically significantly increase the rate of any of the 27 adverse outcomes within 28 days, nor when analyzed according to age, sex, vaccine type, or using alternative analytical approaches. However, post-hoc analysis detected signals for myocarditis (statistically significantly so in females), although the outcome was very rare and findings were based on few cases. No risk of cerebrovascular infarction was found.ConclusionsBivalent omicron-containing mRNA-booster vaccination as a fourth dose was not associated with an increased risk of 27 different adverse events in 50+-year-olds.
Human scalp hair as a thermoregulatory adaptation
Authors: Lasisi Tina , Smallcombe James W , Kenney W. Larry , Shriver Mark D. , Zydney Benjamin , Jablonski Nina G. , Havenith George 
Published: January 2023

AbstractHumans are unique among mammals in having a functionally naked body with a hair-covered scalp. Scalp hair is exceptionally variable across populations withinHomo sapiens. Neither the function of human scalp hair nor the consequences of variation in its morphology have been studied within an evolutionary framework. A thermoregulatory role for human scalp hair has been previously suggested. Here, we present experimental evidence on the potential evolutionary function of human scalp hair and variation in its morphology. Using a thermal manikin and human hair wigs at different wind speeds in a temperature and humidity-controlled environment, with and without simulated solar radiation, we collected data on the convective, radiative, and evaporative heat fluxes to and from the scalp in relation to properties of a range of hair morphologies, as well as a naked scalp. We find evidence for a significant reduction in solar radiation influx to the scalp in the presence of hair. Maximal evaporative heat loss potential from the scalp is reduced by the presence of hair, but the amount of sweat required on the scalp to balance the incoming solar heat (i.e. zero heat gain) is reduced in the presence of hair. Particularly, we find that hair that is more tightly curled offers increased protection against heat gain from solar radiation.SignificanceThe evolution of human scalp hair might be explained by thermoregulation pressures experienced in hot and arid environments. Bipedal posture and a hairless body may have necessitated the development of scalp hair to minimize heat gain from solar radiation, particularly in hominins with large brains. We used a thermal manikin and human-hair wigs to examine this thermoregulatory hypothesis. We found that scalp hair reduces heat gain from solar radiation; tightly curled hair is most protective. Specifically, our results show that hair protects the scalp from solar radiation while minimizing the amount of sweat required to offset heat gain, with tightly curled hair providing the most protection.
Sustained release Resolvin D1 liposomes are effective in the treatment of osteoarthritis in obese mice
Authors: Dravid Ameya A. , Dhanabalan Kaamini M. , Naskar Soumyadeep , Vashistha Akshi , Agarwal Smriti , Padhan Bhagyashree , Dewani Mahima , Agarwal Rachit 
Published: January 2023

AbstractOsteoarthritis (OA) is the most common joint disorder and currently affects > 500 million patients worldwide, with ~60% of them also suffering from obesity. There is no drug approved for human use that changes the course of OA progression. OA is one of the most common comorbidities of obesity, and obesity-related OA (ObOA) is a serious health concern because it shows heightened severity of tissue damage and also predominantly affects the working population. Unresolved inflammation is a major driver of ObOA, thus, resolving disease-associated inflammation is a viable strategy to treat ObOA. Resolvins are highly potent molecules that play a role in the resolution of inflammation and promote tissue healing. However, small molecules (like Resolvin D1; RvD1) have to be administered frequently or prior to injury because they lose theirin vivoactivity rapidly either by lymphatic clearance, or oxidation-mediated deactivation. In this study, we have encapsulated RvD1 in liposomes and established its efficacy in the mouse model of ObOA at much lower dosages than freely administered RvD1. Liposomal RvD1 (lipo-RvD1) acted as a source of the RvD1 molecules for ~11 daysin vitroin synovial fluid derived from patients. When administered prophylactically or therapeutically, lipo-RvD1 suppressed cartilage damage in male C57BL/6 mice compared to untreated and free RvD1 treatments. This efficacy was achieved by increasing the proportion of the proresolution M2 macrophages over proinflammatory M1 macrophages in the synovial membrane. These results show the potential of lipo-RvD1 as an anti-OA agent.Graphical abstract:Mechanism of working of lipo-RvD1 in ObOA joint.
End-to-End Explainable AI: Derived Theory-of-Mind Fingerprints to Distinguish Between Autistic and Typically developing and Social Symptom Severity
Authors: Bhavna Km , Banerjee Romi , Roy Dipanjan 
Published: January 2023

AbstractTheory-of-Mind (ToM) is an evolving ability that significantly impacts human learning and cognition. Early development of ToM ability allow one to comprehend other people’s aims and ambitions, as well as thinking that differs from one’s own. Autism Spectrum Disorder (ASD) is the prevalent pervasive neurodevelopmental disorder in which participants’ brains appeared to be marked by diffuse variations throughout large-scale brain systems made up of functionally connected but physically separated brain areas that got abnormalities in willed action, self-monitoring and monitoring the intents of others, often known as ToM. Although functional neuroimaging techniques have been widely used to establish the neural correlates implicated in ToM, the specific mechanisms still need to be clarified. The availability of current Big data and Artificial Intelligence (AI) frameworks paves the way for systematically identifying Autistics from typically developing by identifying neural correlates and connectome-based features to generate accurate classifications and predictions of socio-cognitive impairment. In this work, we develop an Ex-AI model that quantifies the common sources of variability in ToM brain regions between typically developing and ASD individuals. Our results identify a feature set on which the classification model can be trained to learn characteristics differences and classify ASD and TD ToM development more distinctly. This approach can also estimate heterogeneity within ASD ToM subtypes and their association with the symptom severity scores based on socio-cognitive impairments. Based on our proposed framework, we obtain an average accuracy of more than 90 % using Explainable ML (Ex-Ml) models and an average of 96 % classification accuracy using Explainable Deep Neural Network (Ex-DNN) models. Our findings identify three important sub-groups within ASD samples based on the key differences and heterogeneity in resting state ToM regions’ functional connectivity patterns and predictive of mild to severe atypical social cognition and communication deficits through early developmental stages.
BiFCo: Visualising cohesin assembly/disassembly cycle in living cells
Authors: González-Martín Emilio , Jiménez Juan , Tallada Víctor A. 
Published: January 2023

AbstractCohesin is a ring-shaped protein complex highly conserved in evolution that is composed in all eukaryotes of at least two SMC proteins (Structural Maintenance of Chromosomes) SMC1 and SMC3 in humans (Psm1 and Psm3 in fission yeast), and the kleisin RAD21 (Rad21 in fission yeast). Mutations in its components or its regulators cause genetic syndromes (known as cohesinopathies) and several types of cancer. It has been shown in a number of organisms that only a small fraction of each subunit is assembled into complexes. Therefore, the presence of an excess of soluble components hinders dynamic chromatin loading/unloading studies using fluorescent fusionsin vivo. Here, we present a system based on bimolecular fluorescent complementation in the fission yeastSchizosaccharomyces pombe, named Bi-molecular Fluorescent Cohesin (BiFCo) that selectively excludes signal from individual proteins to allow monitoring the complex assembly/disassembly within a physiological context during a whole cell cycle in living cells. This system may be expanded and diversified in different genetic backgrounds and other eukaryotic models, including human cells.
Tracking coreceptor switch of the transmitted/founder HIV-1 identifies co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting
Authors: Marichannegowda Manukumar Honnayakanahalli , Zemil Michelle , Wieczorek Lindsay , Sanders-Buell Eric , Bose Meera , O’Sullivan Anne Marie , King David , Francisco Leilani , Diaz-Mendez Felisa , Setua Saini , Chomont Nicolas , Phanuphak Nittaya , Ananworanich Jintanat , Hsu Denise , Vasan Sandhya , Michael Nelson L. , Eller Leigh Anne , Tovanabutra Sodsai , Tagaya Yutaka , Robb Merlin L. , Polonis Victoria R. , Song Hongshuo 
Published: January 2023

AbstractThe CCR5 (R5) to CXCR4 (X4) coreceptor switch in natural HIV-1 infection is associated with faster progression to AIDS, but the underlying mechanisms remain unclear. The difficulty in capturing the earliest moment of coreceptor switchin vivolimits our understanding of this phenomenon. Here, by tracking the evolution of the transmitted/founder (T/F) HIV-1 in a prospective cohort of individuals at risk for HIV-1 infection identified very early in acute infection, we investigated this process with high resolution. The earliest X4 variants evolved from the R5 tropic T/F strains. Strong X4 usage can be conferred by a single mutation. The mutations responsible for coreceptor switch can confer escape to neutralization and drive X4 variants to replicate mainly in the central memory and naïve CD4+ T cells. We propose a novel concept to explain the co-evolution of virus antigenicity and entry tropism termed “escape by shifting”. This concept posits that for viruses with receptor or coreceptor flexibility, entry tropism alteration represents a mechanism of immune evasionin vivo.
Distinct mutational processes shape selection of MHC class I and class II mutations across primary and metastatic tumors
Authors: Mumphrey Michael B. , Hosseini Noshad , Parolia Abhijit , Geng Jie , Zou Weiping , Raghavan Malini , Chinnaiyan Arul , Cieslik Marcin 
Published: January 2023

AbstractDisruption of antigen presentation via loss of MHC expression is a strategy whereby cancer cells escape immune surveillance and develop resistance to immunotherapy. We developed the personalized genomics algorithm Hapster and accurately called somatic mutations within the MHC genes of 10,001 primary and 2,199 metastatic tumors, creating a catalog of 1663 nonsynonymous mutations that provide key insights into MHC mutagenesis. We found that MHC-I genes are among the most frequently mutated genes in both primary and metastatic tumors, while MHC-II mutations are more restricted. Recurrent deleterious mutations are found within haplotype and cancer-type specific hotspots associated with distinct mutational processes. Functional classification of MHC residues revealed significant positive selection for mutations disruptive to the B2M, peptide, and T-cell binding interfaces, as well as MHC chaperones. At the cohort level, all cancers with positive selection for MHC mutations are responsive to immune checkpoint inhibitors, underscoring the translational relevance of our findings.
Knocking out CD70 rescues CD70-specific nanoCAR T cells from antigen induced exhaustion
Authors: De Munter Stijn , Buhl Juliane , De Cock Laurenz , Van Parys Alexander , Daneels Willem , Pascal Eva , Deseins Lucas , Ingels Joline , Goetgeluk Glenn , Billiet Lore , Pille Melissa , Vandamme Niels , Van Dorpe Jo , Offner Fritz , Depla Erik , Tavernier Jan , Kerre Tessa , Drost Jarno , Vandekerckhove Bart 
Published: January 2023

AbstractCD70 is an attractive target for chimeric antigen receptor (CAR) T cell therapy as treatment for both solid and liquid malignancies. However, functionality of CD70-specific CARs is only modest. Here, we optimized a CD70-specific VHH based CAR (nanoCAR). We evaluated the nanoCARs in clinically relevant modelsin vitro, using co-cultures of CD70-specific nanoCAR T cells with malignant rhabdoid tumor organoids, andin vivoby using a diffuse large B cell lymphoma (DLBCL) patient-derived xenograft (PDX) model. Whereas the nanoCAR T cells were highly efficient in organoid co-cultures, they showed only modest efficacy in the PDX model. Knocking out CD70 expression by the nanoCAR T cells resulted in dramatically enhanced functionality in the PDX model, suggesting that endogenous CD70 interaction with the nanoCAR induces exhaustion. Through single-cell transcriptomics, we obtained evidence that CD70KO CD70-specific nanoCAR T cells are protected from antigen induced exhaustion. Our data shows that CARs targeted to endogenous T cell antigens, negatively affect CAR T cell functionality by inducing an exhausted state which can be overcome by knocking out the specific target, in this case CD70.
ApTOLL, a new therapeutic aptamer for cytoprotection and (re)myelination after Multiple Sclerosis
Authors: Fernández-Gómez Beatriz , Marchena Miguel A. , Piñeiro David , Gómez-Martín Paula , Sánchez Estefanía , Laó Yolanda , Valencia Gloria , Nocera Sonia , Benítez-Fernández Rocío , Castaño-León Ana M. , Lagares Alfonso , Hernández-Jiménez Macarena , de Castro Fernando 
Published: January 2023

ABSTRACTApTOLL is an aptamer specifically designed to antagonize Toll-Like Receptor 4 (TLR4), a relevant actor for innate immunity involved in inflammatory responses in multiple sclerosis (MS) and other diseases. MS is a primary demyelinating, chronic, inmune and neurodegenerative disease of the central nervous system that normally debuts in young adults. The currently available therapeutic arsenal to treat MS is composed of immunomodulators but, to date, there are no (re)myelinating drugs available in clinics. Our present study shows cells expressing TLR4 in demyelinating lesions of MS patients (postmortemsamples from cerebral cortex) and, as a derivative, we studied the effect of TLR4 inhibition with ApTOLL in animal models of MS (experimental autoimmune encephalomyelitis -EAE- and the cuprizone). The treatment with ApTOLL positively impacted the clinical symptomatology, and this was associated with better preservation plus restoration of myelin and oligodendrocytes in the demyelinated lesions of these animals, which suggests not only an immunomodulatory but also a remyelinating effect of the treatment with ApTOLL. This latter was corroborated on purified cultures of rodent and adult human oligodendrocyte precursor cells (OPCs), confirming the expression of TLR4 in this cell type. Altogether, the molecular nature of ApTOLL and its mechanism/s of action strongly supports this compound as a novel candidate to treat MS and other demyelinating scenarios.
Genomic and Proteomic Analysis of Patients with Reoccurring Discrete Subaortic Stenosis
Authors: Birla Ravi K. , Singampalli Kavya L. , Nieuwsma Asela , Brimmer Sunita , Kaul Aditya , Wadhwa Lalita , Jung Sung Y. , Mezquita Dereck , Grimm Sandra , Balaji Swathi , Coarfa Cristian , Caldarone Christopher , Grande-Allen Jane , Keswani Sundeep G. 
Published: January 2023

AbstractDiscrete subaortic stenosis (DSS) is a pediatric condition in which a fibrotic membrane forms within the left ventricular outflow track. The fibrotic membrane is removed surgically; however, there is a high rate of reoccurrence which requires a second surgery. There are currently no tools available to predict the risk of reoccurrence in DSS patients, a limitation addressed by this study. In this study, we analyzed resected fibrotic membranes for DSS patients at the time of first surgery for non-recurrent and recurrent patients, and at the time of second surgery for recurrent patients. RNA-sequencing was conducted to obtain a global screen of changes in RNA expression while mass spectrometry was used to obtain a global screen of changes in protein expression. The results from the RNA-sequencing and mass spectrometry provide valuable insight into genes and the proteins that are differentially regulated in recurrent vs non-recurrent DSS patients.
Distinct neural components of visually guided grasping during planning and execution
Authors: Klein Lina K. , Maiello Guido , Stubbs Kevin M. , Proklova Daria , Chen Juan , Paulun Vivian C. , Culham Jody C. , Fleming Roland W. 
Published: January 2023

AbstractSelecting suitable grasps on three-dimensional objects is a challenging visuomotor computation, which involves combining information about an object (e.g., its shape, size, and mass) with information about the actor’s body (e.g., the optimal grasp aperture and hand posture for comfortable manipulation). Here we used functional magnetic resonance imaging to investigate brain networks associated with these distinct aspects during grasp planning and execution. Human participants viewed and then executed preselected grasps on L-shaped objects made of wood and/or brass. By leveraging a computational approach that accurately predicts human grasp locations, we selected grasp points that disentangled the role of multiple grasp-relevant factors: grasp axis, grasp size, and object mass. Representational Similarity Analysis revealed that grasp axis was encoded along dorsal-stream regions during grasp planning. Grasp size was first encoded in ventral-stream areas during grasp planning, then in premotor regions during grasp execution. Object mass was encoded in ventral-stream and (pre)motor regions only during grasp execution. Premotor regions further encoded visual predictions of grasp comfort, whereas the ventral stream encoded grasp comfort during execution, suggesting its involvement in haptic evaluation. These shifts in neural representations thus capture the sensorimotor transformations that allow humans to grasp objects.Significance StatementGrasping requires integrating object properties with constraints on hand and arm postures. Using a computational approach that accurately predicts human grasp locations by combining such constraints, we selected grasps on objects that disentangled the relative contributions of object mass, grasp size, and grasp axis during grasp planning and execution in a neuroimaging study. Our findings reveal a greater role of dorsal-stream visuomotor areas during grasp planning, and surprisingly, increasing ventral stream engagement during execution. We propose that during planning, visuomotor representations initially encode grasp axis and size. Perceptual representations of object material properties become more relevant instead as the hand approaches the object and motor programs are refined with estimates of the grip forces required to successfully lift the object.