bluuebunny/crossref_metadata_2025_split huggingface dataset:
SPIRED-Fitness: an end-to-end framework for the prediction of protein structure and fitness from single sequence
Authors: Chen Yinghui , Xu Yunxin , Liu Di , Xing Yaoguang , Gong Haipeng 
Published: February 2024

AbstractSignificant research progress has been made in the field of protein structure and fitness prediction. Particularly, single-sequence-based structure prediction methods like ESMFold and OmegaFold achieve a balance between inference speed and prediction accuracy, showing promise for many downstream prediction tasks. Here, we propose SPIRED, a novel single-sequence-based structure prediction model that exhibits comparable performance to the state-of-the-art methods but with approximately 5-fold acceleration in inference and at least one order of magnitude reduction in training consumption. By integrating SPIRED with downstream neural networks, we compose an end-to-end framework named SPIRED-Fitness for the rapid prediction of both protein structure and fitness from single sequence. SPIRED-Fitness and its derivative SPIRED-Stab achieve state-of-the-art performance in predicting the mutational effects on protein fitness and stability metrics, respectively.
mTORC1 Activation In Presumed Classical Monocytes: Observed Correlates With Human Size Variation and Neuropsychiatric Disease
Authors: Berner Karl , Oz Naci , Kaya Alaattin , Acharjee Animesh , Berner Jon 
Published: February 2024

ABSTRACTBackgroundGain of function disturbances in nutrient sensing are likely the largest component in human age-related disease. Mammalian target of rapamycin complex 1 (mTORC1) activity affects health span and longevity. The drugs ketamine and rapamycin are effective against chronic pain and depression, and both affect mTORC1 activity. Our objective was to measure phosphorylated p70S6K, a marker for mTORC1 activity, in individuals with psychiatric disease to determine whether phosphorylated p70S6K could predict medication response.MethodsTwenty-seven females provided blood samples in which p70S6K and phosphorylated p70S6K were analyzed. Chart review gathered biometric measurements, clinical phenotypes, and medication response. Questionnaires assessed anxiety, depression, autism traits, and mitochondrial dysfunction, to determine neuropsychiatric disease profiles. Univariate and multivariate statistical analyses were used to identify predictors of medication response.ResultsmTORC1 activity correlated highly with both classical biometrics (height, macrocephaly, pupil distance) and specific neuropsychiatric disease profiles (anxiety and autism). Across all cases, phosphorylated p70S6K was the best predictor for ketamine response, and also the best predictor for rapamycin response in a single instance.ConclusionsThe data illustrates the importance of mTORC1 activity in both observable body structure and medication response. This report suggests that a simple assay may allow cost-effective prediction of medication response.
Grb7,Grb10andGrb14,encoding the growth factor receptor-bound 7 family of signalling adaptor proteins have overlapping functions in the regulation of fetal growth and post-natal glucose metabolism
Authors: Moorwood Kim , Smith Florentia M. , Garfield Alastair S. , Cowley Michael , Holt Lowenna J. , Daly Roger J. , Ward Andrew 
Published: February 2024

AbstractBackgroundThe growth factor receptor bound 7 (Grb7) family of signalling adaptor proteins comprises Grb7, Grb10 and Grb14. Each can interact with the insulin receptor and other receptor tyrosine kinases, where Grb10 and Grb14 inhibit insulin receptor activity. In cell culture studies they mediate functions including cell survival, proliferation, and migration. Mouse knockout (KO) studies have revealed physiological roles forGrb10andGrb14in glucose-regulated energy homeostasis. BothGrb10KO andGrb14KO mice exhibit increased insulin signalling in peripheral tissues, with increased glucose and insulin sensitivity and a modestly increased ability to clear a glucose load. In addition,Grb10strongly inhibits fetal growth such that at birthGrb10KO mice are 30% larger by weight than wild type littermates.ResultsHere, we generate aGrb7KO mouse model. We show that during fetal development the expression patterns of Grb7 and Grb14 each overlap with that of Grb10. Despite this,Grb7andGrb14did not have a major role in influencing fetal growth, either alone or in combination withGrb10. At birth, in most respects bothGrb7KO andGrb14KO single mutants were indistinguishable from wild type, whileGrb7:Grb10double knockout (DKO) were near identical toGrb10KO single mutant andGrb10:Grb14DKO mutants slightly smaller. In the developing kidneyGrb7had a subtle positive influence on growth. An initial characterisation ofGrb7KO adult mice revealed sexually dimorphic effects on energy homeostasis, with females having significantly smaller white adipose tissue (WAT) depots and an enhanced ability to clear glucose from the circulation, compared to wild type littermates. Males had elevated fasted glucose levels with a trend towards smaller WAT depots, without improved glucose clearance.ConclusionsGrb7andGrb14do not have significant roles as inhibitors of fetal growth, unlikeGrb10, and insteadGrb7may promote growth of the developing kidney. In adulthood,Grb7contributes subtly to glucose mediated energy homeostasis, raising the possibility of redundancy between all three adaptors in physiological regulation of insulin signalling and glucose handling.
Thermodynamics determines the coupling between growth and byproduct production
Authors: Oftadeh Omid , Hatzimanikatis Vassily 
Published: February 2024

AbstractGenetic manipulation of cells to couple byproduct production and growth rate is important in bioengineering and biotechnology. In this way, we can use growth rate as a selective pressure, where the mutants with higher growth have higher production capacity. Computational methods have been proposed to find knockouts that couple growth and byproduct production. However, none of these methods consider the energetic and thermodynamic feasibility of such knockout strategies. Furthermore, there is no computational study of how variations in metabolite concentrations affect the coupling between growth and byproduct formation. One of the computational methods to find knockouts that couple growth and byproduct formation is OptKnock. OptKnock is a bi-level optimization problem. Here, we integrated thermodynamic constraints into the bilevel formulation of OptKnock to create TOptKnock. We show that the computational efficiency of TOptKnock is comparable to that of OptKnock. TOptKnock can account for the thermodynamic viability of the knockouts and examine how variations in metabolite concentrations affect the coupling. We have shown that the coupling between growth and byproduct formation can change in response to variations in concentrations. Thus, a knockout strategy might be optimal for one intracellular condition but suboptimal for another. If metabolomics data are available, TOptKnock can search for optimal knockout interventions under the given condition. We also envision that the TOptKnock framework will help develop strategies for manipulating metabolite concentrations to couple growth and byproduct formation.
A pipeline for facile cloning of antibody Fv domains and their expression, purification, and characterization as recombinant His-tagged IgGs
Authors: Sinha Akesh , Park Jinha M. , Gulzar Naveed , Pandya Darpan N. , Wadas Thaddeus J. , Scott Jamie K. 
Published: February 2024

AbstractWe report a functional pipeline for facile conversion of variable Fv domains, typically discovered in antibody discovery programs, into chimeric monoclonal antibodies (mAbs). Often, in initial screenings, a set of candidate mAbs is produced in small volumes and purified from supernatant for testing. Our pipeline also simplifies purification of mAbs by using an extended histidine tag (His-10) fused to the C-terminus of the light chain. Both the length of the His-10 and its location have been shown to affect the efficacy of mAb purification using an inexpensive nickel-based resin at neutral pH. Our antibody cloning and purification pipeline, when followed together with detection and affinity measurements, can be smoothly incorporated into an antibody discovery workflow.
Host-pathogen Coadaptation by running with PAR protein
Authors: Zhu Sucheng , Zhou Xinyi , Qi Bin 
Published: February 2024

SummaryHost-pathogen coadaptation is mutually beneficial for the survival of both organisms. Embryo development is a crucial aspect of animal evolution as it ensures the continuation of their offspring. However, there is little understanding of the coadaptation mechanisms underlying embryo developmental factors in host-pathogen interactions. Here, by using aC. elegans-P. aeruginosainfection model, we demonstrate that PAR-5, essential for the establishment of anterior-posterior polarity within the single cellC. eleganszygote, acts as a mediator in regulating host-pathogen co-evolution. We discover thatPseudomonas aeruginosa-PA14 infection induces PAR-5 expression, which accelerates animal embryo development and ensures the continuity of their offspring. Moreover, PA14 stimulates host PAR-5 secretion, which reduces the virulence of PA14. Both functions of PAR-5 are beneficial for host survival. Meanwhile, pathogens utilize PAR-5 to inhibit host immunity/UPRERby bypassing the core PMK-1-mediated innate immunity and activating mTOR by interacting with LET-363, promoting pathogen spread. Therefore, our study uncovers an unexpected mechanism in host-pathogen co-evolution that targets a host embryo developmental factor, promoting coexistence and facilitating the adaptation of both hosts and pathogens.
DNA metabarcoding diet analysis in ruminants is quantitative and integrates feeding over several weeks
Authors: Kamenova Stefaniya , Meyer Pernille , Brysting Anne Krag , Rescia Leo , Folkow Lars P. , Sundset Monica Alterskjær , Coissac Éric , Gussarova Galina 
Published: February 2024

AbstractDietary DNA metabarcoding is an established method, especially useful for resolving the diverse diets of large mammalian herbivores (LMH). However, despite longstanding research interest on the topic, we still lack unequivocal evidence on the potential of DNA metabarcoding to reflect proportions of ingested dietary plants in LMH. One major aspect to consider is the time window during which ingested diet remains detectable in faecal samples. This parameter is currently unknown for LMH, thus potentially hindering the scope of ecological conclusions. Another unknown factor is quantitative performance, i.e. the extent to which the amount of ingested biomass can be assessed based on sequence read abundances. We assessed DNA metabarcoding quantitative performance and DNA half-life detectability for plants with different digestibilities in a controlled feeding experiment with three female Eurasian tundra reindeer (Rangifer tarandus tarandus). Reindeer were fed birch twigs (Betula pubescens) and increasing biomass of lichen (mainlyCladonia stellaris). Relative read abundance positively correlated with ingested lichen biomass, suggesting potential for deriving dietary proportions in free-ranging reindeer on natural pastures. Dietary DNA was consistently detected within a few hours upon ingestion, with a mean half-life detectability of 30 and 14 hours for birch and lichen, respectively. However, dietary DNA remained detectable in faeces for at least 26 days post-feeding, indicating that a single faecal sample can provide an unsuspectedly integrative estimate of diet in ruminants. Together, our findings provide novel empirical validation of DNA metabarcoding as a tool for diet analysis in LMH.
A multipleArc(mArc) tagging system to uncover the organizational principles of multiple memories
Authors: Stackmann Michelle , Yelhekar Tushar D. , Meng Meizhen , Sun Xiaochen , Nthumba Joseph , Bulthuis Nicholas E. , Vaughan Nick , Zhu Elaine , Lin Yingxi , Denny Christine A. 
Published: February 2024

SUMMARYEngrams or memory traces are the neuronal ensembles that collectively store individual experiences. Genetic strategies based on immediate early genes (IEGs), such asArc/Arg3.1, allow us to tag the ensembles active during memory encoding and compare them to those active during retrieval. However, these strategies only allow for the tagging of one neural ensemble. Here, we developed a multipleArc(mArc) system that allows for the tagging of twoArc+ensembles. We validated this system by investigating how context, time, and valence influence neuronal ensemble reactivation in the dentate gyrus (DG). We show that similar contextual and valenced experiences are encoded in overlapping DG ensembles. We also find that ensembles are modulated by time, where experiences closer in time are encoded in more similar ensembles. These results highlight the dynamic nature of DG ensembles and show that the mArc system provides a powerful approach for investigating multiple memories in the brain.HIGHLIGHTSThe mArc system allows for the tagging of twoArc+ensembles in the same mouseDG ensembles labeled by the mArc system receive increased excitatory inputContext, valence, and time influence DG ensemble reactivationDG neural ensembles are reactivated less with increasing time
Quality of life in head and neck cancer survivors: the Big Data for Quality of Life study
Authors: Moreira-Soares Mauricio , Fossen Erlend I. F. , Taylor Katherine J. , Singer Susanne , Hurley Katrina , Thomas Steve , Pring Miranda , Ness Andrew , Cavalieri Stefano , Vener Claudia , Lopez-Perez Laura , Cabrera-Umpierrez Maria Fernanda , Fico Giuseppe , Frigessi Arnoldo , Licitra Lisa , LeBlanc Marissa 
Published: February 2024

AbstractBackgroundThe Big Data for Quality of Life (BD4QoL) study investigates quality of life (QoL) in head and neck cancer (HNC) survivors, focusing on survivorship and characterizing survivor demographics.MethodsWe screened data from 5 studies across Europe (N=7276) and included patients with a diagnosis of squamous cell carcinoma (oral cavity, hypopharynx, larynx, oropharynx, nasal cavity and paranasal sinuses), treated with curative intent, alive after treatment, TNM 7thed. stages I, II, III, IVa and IVb, with availability of QoL questionnaires.ResultsThe cohort of 4448 HNC survivors primarily includes men (78%) with median age 61 years. Most received radiotherapy (75%) and had a history of smoking (78%). Survivors’ scores on EORTC QLQ-C30 functioning scales indicated high functioning, with prevalent symptoms of fatigue, pain, and insomnia. Lower rates of missing data were observed in older patients, those with higher education and income levels, nonsmokers, married individuals, and patients not treated with radiotherapy. The odds ratios ranged from 0.47 to 0.99, indicating these factors may predict more consistent QoL data reporting in HNC survivors.ConclusionsThese data support the development and validation of clinical prediction models for QoL in HNC survivors in a multicentre randomized controlled trial.
WITHDRAWN: Comparison of Leucocyte Telomere Length, Atherosclerotic Cardiovascular disease risk and the output of a Deep learning Cardiac BioAge risk prediction tool: A UK Biobank Cohort study
Authors: Vaghefi Ehsan , An Songyang , Corbett Rini , Squirrell David 
Published: February 2024

Withdrawal Statement“The authors have withdrawn their manuscript owing to major updates that will be made prior to resubmission. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.”
Recapitulating memory B cell responses in a Lymphoid Organ-Chip to evaluate mRNA vaccine boosting strategies
Authors: Jeger-Madiot Raphaël , Planas Delphine , Staropoli Isabelle , Kervevan Jérôme , Mary Héloïse , Collina Camilla , Fonseca Barbara F. , Debarnot Hippolyte , Robinot Rémy , Gellenoncourt Stacy , Schwartz Olivier , Ewart Lorna , Bscheider Michael , Gobaa Samy , Chakrabarti Lisa A. 
Published: February 2024

ABSTRACTPredicting the immunogenicity of candidate vaccines in humans remains a challenge. To address this issue, we developed a Lymphoid Organ-Chip (LO chip) model based on a microfluidic chip seeded with human PBMC at high density within a 3D collagen matrix. Perfusion of the SARS-CoV-2 Spike protein mimicked a vaccine boost by inducing a massive amplification of Spike-specific memory B cells, plasmablast differentiation, and Spike-specific antibody secretion. Features of lymphoid tissue, including the formation of activated CD4+ T cell/B cell clusters and the emigration of matured plasmablasts, were recapitulated in the LO chip. Importantly, myeloid cells were competent at capturing and expressing mRNA vectored by lipid nanoparticles, enabling the assessment of responses to mRNA vaccines. Comparison of on-chip responses to Wuhan monovalent and Wuhan/Omicron bivalent mRNA vaccine boosts showed equivalent induction of Omicron neutralizing antibodies, pointing at immune imprinting as reportedin vivo. The LO chip thus represents a versatile platform suited to the preclinical evaluation of vaccine boosting strategies.
Independent regulation of early trafficking of NMDA receptors by ligand-binding domains of the GluN1 and GluN2A subunits
Authors: Netolicky Jakub , Zahumenska Petra , Misiachna Anna , Kolcheva Marharyta , Kucera Tomas , Fibigar Jakub , Rehakova Kristyna , Hemelikova Katarina , Kortus Stepan , Langore Emily , Ladislav Marek , Korabecny Jan , Horak Martin 
Published: February 2024

AbstractThe essential role of N-methyl-D-aspartate receptors (NMDARs) in excitatory neurotransmission is underscored by numerous pathogenic variants in the GluN subunits, including those identified in their ligand-binding domains (LBDs). The prevailing hypothesis postulates that the endoplasmic reticulum (ER) quality control machinery verifies the agonist occupancy of NMDARs; however, whether it controls the structure of LBDs or the functionality of NMDARs is unknown. Using alanine substitutions combined with microscopy and electrophysiology, we found that surface expression of GluN1/GluN2A receptors, the primary NMDAR subtype in the adult forebrain, strongly correlates with EC50values for glycine and L-glutamate. Interestingly, co-expression of both GluN1 and GluN2A subunits with alanine substitutions led to an additive reduction in the surface number of GluN1/GluN2A receptors, as did co-expression of both GluN1 and GluN2A subunits containing closed cleft conformation of LBDs. The synchronized ER release confirmed the altered regulation of early trafficking of GluN1/GluN2A receptors bearing alanine substitutions in the LBDs. Furthermore, the human versions of GluN1/GluN2A receptors containing pathogenic GluN1-S688Y, GluN1-S688P, GluN1-D732E, GluN2A-S511L, and GluN2A-T690M variants exhibited distinct surface expression compared to the corresponding alanine substitutions. Mutant cycles of GluN1-S688, GluN1-D732, GluN2A-S511, and GluN2A-T690 residues revealed, in most cases, a weak correlation between surface expression of the mutant GluN1/GluN2A receptors and their EC50values for glycine or L-glutamate. Consistent with our experimental data, molecular modeling and dynamics showed that the ER quality control machinery likely perceives structural changes of the LBDs but not the functionality of GluN1/GluN2A receptors.Significant statementOur study showed that structural changes in LBDs independently regulate the early trafficking of GluN1/GluN2A receptors and that the surface numbers of mutant GluN1/GluN2A receptors do not necessarily correlate with their agonist sensitivity. In addition, we validated a novel system of synchronized release of GluN1/GluN2A receptors from the ER. Together, our experimental andin silicofindings support the urgency of further detailed research on the regulation of early trafficking of NMDARs, as it may open the avenue to targeted therapeutic intervention of CNS disorders associated with pathogenic variants in GluN subunits.
Taurine pangenome uncovers a segmental duplication upstream ofKITassociated with depigmentation in white-headed cattle
Authors: Milia Sotiria , Leonard Alexander S. , Mapel Xena Marie , Ulloa Sandra Milena Bernal , Drögemüller Cord , Pausch Hubert 
Published: February 2024

AbstractCattle have been selectively bred for coat color, spotting, and depigmentation patterns. The assumed autosomal dominant inherited genetic variants underlying the characteristic white head of Fleckvieh, Simmental, and Hereford cattle have not been identified yet, although the contribution of structural variation upstream theKITgene has been proposed. Here, we construct a graph pangenome from 24 haplotype assemblies representing seven taurine cattle breeds to identify and characterize the white head-associated locus for the first time based on long-read sequencing data and pangenome analyses. We introduce a pangenome-wide association mapping approach which examines assembly path similarities within the graph to reveal an association between two most likely serial alleles of a complex structural variant 66 kb upstreamKITand facial depigmentation. The complex structural variant contains a variable number of tandemly duplicated 14.3 kb repeats, consisting of LTRs, LINEs, and other repetitive elements, leading to misleading alignments of short and long reads when using a linear reference. We align 250 short-read sequencing samples spanning 15 cattle breeds to the pangenome graph, further validating that the alleles of the structural variant segregate with head depigmentation. We estimate an increased count of repeats in Hereford relative to Simmental and other white-headed cattle breeds from the graph alignment coverage, suggesting a large under-assembly in the current Hereford-based cattle reference genome which had fewer copies. We show that exploiting assembly path similarities within graph pangenomes can reveal trait-associated complex structural variants.
Wheat NAC transcription factorNAC5-1is a positive regulator of senescence
Authors: Evans Catherine , Mogg Sophie Louise , Soraru Charline , Wallington Emma , Coates Juliet , Borrill Philippa 
Published: February 2024

ABSTRACTWheat (Triticum aestivumL.) is an important source of both calories and protein in global diets, but there is a trade-off between grain yield and protein content. The timing of leaf senescence could mediate this trade-off as it is associated with both decline in photosynthesis and nitrogen remobilisation from leaves to grain. NAC transcription factors play key roles in regulating senescence timing. In rice,OsNAC5expression is correlated with earlier senescence, but the role of the wheat ortholog in senescence had not been characterised. We verified thatNAC5-1is the ortholog ofOsNAC5and that it is expressed in senescing flag leaves in wheat. To characteriseNAC5-1,we combined missense mutations inNAC5-A1andNAC5-B1from a TILLING mutant population and overexpressedNAC5-A1in wheat. Mutation inNAC5-1was associated with delayed onset of flag leaf senescence, while overexpression ofNAC5-A1was associated with slightly earlier onset of leaf senescence. DAP-seq was performed to locate transcription factor binding sites ofNAC5-1.Analysis of DAP-seq and comparison with other studies identified putative downstream target genes ofNAC5-1which could be associated with senescence. This work showed thatNAC5-1is a positive transcriptional regulator of leaf senescence in wheat. Further research is needed to test the effect ofNAC5-1on yield and protein content in field trials, to assess the potential to exploit this senescence regulator to develop high-yielding wheat while maintaining grain protein content.