bluuebunny/crossref_metadata_2025_split huggingface dataset:
PTPRC, KDM5C, GABBR1 and HDAC1 are the major targets of valproic acid in regulation of its anticonvulsant pharmacological effects
Authors: Kumar Arun HS 
Published: December 2022

AbstractBackgroundValproic acid (VPA) is a small molecule which is the 3rdmost prescribed drug among anticonvulsant therapeutics. Understanding of the pharmacology of VPA targets will help optimally rationalise the therapeutic effects and also minimise the undesired outcomes. Hence this study analysed the human specific targets of VPA and assessed the affinity of VPA to these targets to interpret potential safe therapeutic range for VPA.Materials and MethodsThe targets of VPA were identified from the SwissTargetPrediction server and STITCH database and analysed for their affinity with VPA using Autodock vina 1.2.0. The volume of distribution (Vd, L) and the dose of VPA reported in the DrugBank database was used for estimation of the plasma and CSF concentration. The plasma and CSF Concentration Affinity (CA) ratio of VPA against each of the high affinity targets was assessed at variable Vd (0.1 to 0.4 L/kg) to identify the therapeutic safety window of VPA.ResultsThe plasma/CSF concentration of VPA range from 170 to 7000 µM and 17 to 700 µM respectively. The plasma concentration achieved was within the safety limits (170 to 700 µM) at higher Vd (>10 L), while at lower Vd (<10L), the plasma or CSF concentration achieved was of concern at VPA dose of >1000 mg/day. The plasma concentration at very low Vd (< 2L) was of concern even at dose of 500 mg/day. The affinity of VPA against all its human specific targets ranged from 2.9 to 52.1 mM. The CA ratio of VPA against its high affinity target was observed to be greater than 0.8, indicating potentially significant modulation of these targets. The following four targets showed CA ratio of over 1: PTPRC, KDM5C, GABBR1 and HDAC1, indicating their preferential targeting by VPA. CES1 and SLC22A12 are high affinity targets of VPA which can contribute to its undesired pharmacological effects (CNS oedema and hepatotoxicity).ConclusionThis study offers a novel insight into the anticonvulsant and undesired pharmacology of VPA by specifically identifying the targets involved and recommends an evidence based approach to personalise dose titration of VPA to achieve optimal therapeutic benefits.
Structural and Mechanistic Basis of Substrate Transport by the Multidrug Transporter MRP4
Authors: Bloch Magnus , Raj Isha , Pape Tillmann , Taylor Nicholas M.I. 
Published: December 2022

SUMMARYMultidrug resistance-associated protein 4 (MRP4) is an ATP-binding cassette (ABC) transporter expressed at multiple tissue barriers where it actively extrudes a wide variety of drug compounds. Overexpression of MRP4 provides resistance to clinically used antineoplastic and antiviral agents, making it a highly attractive therapeutic target for countering multidrug resistance.Here we report the cryo-EM structures of multiple physiologically relevant states of membrane-embedded human MRP4, including complexes between MRP4 and two widely used chemotherapeutic agents and a complex between MRP4 and its native substrate. The structures display clear similarities and distinct differences in the coordination of these chemically diverse substrates and, in combination with functional and mutational analysis, reveal molecular details of the transport mechanism. Our study provides key insights regarding the basis of the unusually broad substrate specificity of MRP4 and constitutes an important contribution towards a general understanding of the versatile ensemble of multidrug transporters.
Activity-based proteomics uncovers suppressed hydrolases and aneo-functionalised antibacterial enzyme at the plant-pathogen interface
Authors: Sueldo Daniela J. , Godson Alice , Kaschani Farnusch , Krahn Daniel , Kessenbrock Till , Buscaill Pierre , Schofield Christopher J. , Kaiser Markus , van der Hoorn Renier A. L. 
Published: December 2022

ABSTRACTThe extracellular space of plant tissues contains hundreds of hydrolases that might harm colonizing microbes. Successful pathogens may suppress these hydrolases to enable disease. Here, we report the dynamics of extracellular hydrolases in leaves upon infection withPseudomonas syringae.Using activity-based proteomics with a cocktail of biotinylated probes we simultaneously monitored 171 active hydrolases, including 109 serine hydrolases (SHs), 49 glycosidases (GHs) and 13 cysteine proteases (CPs). The activity of 82 of these hydrolases (mostly SHs) increases during infection, whilst the activity of 60 hydrolases (mostly GHs and CPs) is suppressed during infection. Active β-galactosidase-1 (BGAL1) is amongst the suppressed hydrolases, consistent with production of the BGAL1 inhibitor byP. syringae. One of the other suppressed hydrolases, the pathogenesis-relatedNbPR3, decreases bacterial growth when transiently overexpressed. This is dependent on its active site, revealing a role forNbPR3 activity in antibacterial immunity. Despite being annotated as a chitinase,NbPR3 does not possess chitinase activity, and contains a E112Q active site substitution that is essential for antibacterial activity and is conserved only inNicotianaspecies.This study introduces a powerful approach to reveal novel components of extracellular immunity, exemplified by the discovery of the suppression of neo-functionalisedNicotiana-specificantibacterialNbPR3.
Distinct Subsets of Multi-Lymphoid Progenitors Support Ontogeny-Related Changes in Human Lymphopoiesis
Authors: Keita Seydou , Diop Samuel , Lekiashvili Shalva , Chabaane Emna , Nelson Elisabeth , Strullu Marion , Arfeuille Chloé , Guimiot Fabien , Domet Thomas , Duchez Sophie , Evrard Bertrand , Darde Thomas , Larghero Jerome , Verhoeyen Els , Cumano Ana , Macintyre Elizabeth A. , Jouen François , Goodhardt Michele , Garrick David , Chalmel Frederic , Hussen Kutaiba Alhaj , Canque Bruno 
Published: December 2022

SUMMARYChanges in lymphocyte production patterns occurring across human ontogeny remain poorly defined. In this study, we demonstrate that human lymphopoiesis is supported by three waves of embryonic, fetal, and postnatal multi-lymphoid progenitors (MLPs) differing in CD7 and CD10 expression and their output of CD127-/+early lymphoid progenitors (ELP). Our results reveal that, like the fetal-to-adult switch in erythropoiesis, transition to postnatal life coincides with a shift from multilineage to B lineage-biased lymphopoiesis and an increase in production of CD127+ELPs which persists until puberty. A further developmental transition is observed in elderly individuals where B-cell differentiation bypasses the CD127+compartment and branches directly from CD10+MLPs. Functional analyses indicate that these changes are determined at the level of the hematopoietic stem cell. Besides reconciling controversies about the identity and function of human MLPs, these results may shed light on the causes of age-related differences in the incidence of lymphoblastic leukemia.
Class background reverses the effect of a polygenic index of cognitive performance on economic ideology
Authors: Ahlskog Rafael 
Published: December 2022

AbstractVariation in political preferences is increasingly understood to stem from both environmental influences and genetics. Research has argued that a possible pathway for genetic effects on ideology is via cognitive performance, showing a genetic overlap between the traits. Yet, an unambiguous link between cognitive performance and economic policy preferences remains elusive, with results ranging from negative to positive effects on economic conservatism. In this study, I argue that this heterogeneity reflects an underlying gene-by-environment interaction. I depart from the assumption that cognitive performance, rather than being directly connected to a set of policy preferences, influences the capacity to correctly optimize those preferences. Combined with insights from standard models in political economics, this leads to the proposal that genetics associated with cognitive performance should cause more left-wing economic preferences if you grow up in relative poverty, but more right-wing preferences if you grow up in relative affluence. Utilizing variation in a polygenic index of cognitive performance within dizygotic twin pairs, coupled with unique register data on economic conditions for both the twins, their parents, and their childhood neighborhood, I show that the effect of the PGI on a finegrained measure of economic conservatism is zero on average, but indeed sizable and sign-discordant by class background. To my knowledge, this represents the first sign-discordant GxE finding for a socially relevant outcome, which has implications for future social science research using PGIs.
Long COVID: G Protein-Coupled Receptors (GPCRs) responsible for persistent post-COVID symptoms
Authors: Das Sanisha , Kumar Suresh 
Published: December 2022

ABSTRACTAs of early December 2022, COVID-19 had a significant impact on the lives of people all around the world, with over 630 million documented cases and over 6 million deaths. A recent clinical analysis revealed that under certain conditions, a patient’s disease symptoms are more likely to persist. Long COVID is characterised by many symptoms that continue long after the SARS-CoV-2 infection has resolved. This work utilised computational methods to analyse the persistence of COVID symptoms after recovery and to identify the relevant genes. Based on functional similarity, differentially expressed genes (DEGs) of SARS-CoV-2 infection and 255 symptoms of long covid were examined, and potential genes were identified based on the rank of functional similarity. Then, hub genes were identified by analysing the interactions between proteins. Using the identified key genes and the drug-gene interaction score, FDA drugs with potential for possible alternatives were identified. Also discovered were the gene ontology and pathways for 255 distinct symptoms. A website (https://longcovid.omicstutorials.com/) with a list of significant genes identified as biomarkers and potential treatments for each symptom was created. All of the hub genes associated with the symptoms, GNGT1, GNG12, GNB3, GNB4, GNG13, GNG8, GNG3, GNG7, GNG10, and GNAI1, were discovered to be associated with G-protein coupled receptors. This demonstrates that persistent COVID infection affects various organ systems and promotes chronic inflammation following infection. CTLA4, PTPN22, KIT, KRAS, NF1, RET, and CTNNB1 were identified as the common genes that regulate T-cell immunity via GPCR and cause a variety of symptoms, including autoimmunity, cardiovascular, dermatological, general symptoms, gastrointestinal, pulmonary, reproductive, genitourinary, and endocrine symptoms (RGEM). Among other functions, they were found to be involved in the positive regulation of protein localization to the cell cortex, the regulation of triglyceride metabolism, the binding of G protein-coupled receptors, the binding of G protein-coupled serotonin receptors, the heterotrimeric G-protein complex, and the cell cortex region. These biomarker data, together with the gene ontology and pathway information that accompanies them, are intended to aid in determining the cause and improving the efficacy of treatment.
GENERALIST: An efficient generative model for protein sequence families
Authors: Akl Hoda , Emison Brooke , Zhao Xiaochuan , Mondal Arup , Perez Alberto , Dixit Purushottam D. 
Published: December 2022

AbstractGenerative models of protein sequence families are an important tool in the repertoire of protein scientists and engineers alike. However, state-of-the-art generative approaches face inference, accuracy, and overfitting-related obstacles when modeling moderately sized to large proteins and/or protein families with low sequence coverage. To that end, we present a simple to learn, tunable, and accurate generative model, GENERALIST:GENERAtive nonLInear tenSor-factorizaTionfor protein sequences. Compared to state-of-the-art methods, GENERALIST accurately captures several high order summary statistics of amino acid covariation. GENERALIST also predicts conservative local optimal sequences which are likely to fold in stable 3D structure. Importantly, unlike other methods, the density of sequences in GENERALIST-modeled sequence ensembles closely resembles the corresponding natural ensembles. GENERALIST will be an important tool to study protein sequence variability.
Mycorrhizal status impacts the genetic architecture of mineral accumulation in field grown maize (Zea maysssp.maysL.)
Authors: Li Meng , Perez-Limón Sergio , Ramírez-Flores M. Rosario , Barrales-Gamez Benjamín , Meraz-Mercado Marco Antonio , Ziegler Gregory , Baxter Ivan , Olalde-Portugal Víctor , Sawers Ruairidh J. H. 
Published: December 2022

SUMMARYArbuscular mycorrhizal fungi (AMF) establish symbioses with major crop species, providing their hosts with greater access to mineral nutrients and promoting tolerance to heavy metal toxicity. There is considerable interest in AMF as biofertilizers and for their potential in breeding for greater nutrient efficiency and stress tolerance. However, it remains a challenge to estimate the nutritional benefits of AMF in the field, in part due to a lack of suitable AMF-free controls. Here we evaluated the impact of AMF on the concentration of 20 elements in the leaves and grain of field grown maize using a custom genetic mapping population in which half of the families carry the AMF-incompatibility mutationcastor. By comparing AMF-compatible and AMF-incompatible families, we confirmed the benefits of AMF in increasing the concentration of essential mineral nutrients (e.g., P, Zn, and Cu) and reducing the concentration of toxic elements (e.g., Cd and As) in a medium-input subtropical field. We characterised the genetic architecture of element concentration using quantitative trait mapping and identified loci that were specific to AMF-compatible or AMF-incompatible families, consistent with their respective involvement in mycorrhizal or direct nutrient uptake. Patterns of element covariance changed depending on AMF status and could be used to predict variation in mycorrhizal colonisation. We comment on the potential of AMF to drive genotype-specific differences in the host ionome across fields and to impact the alignment of biofortification breeding targets. Our results highlight the benefits of AMF in improving plant access to micronutrients while protecting from heavy metals, and indicate the potential benefits of considering AMF in biofortification programs.
Breeding the phenylketonuria mouse: novel dietary regimen enables breeding of female C57BL/6J mice homozygous for thePahenu2mutation without fostering
Authors: Durrer Katherine E. , Mancilla Viviana J. , Allen Michael S. 
Published: December 2022

AbstractThePahenu2mutation in C57BL/6J mice is a well characterized model for studying phenylketonuria (PKU), withPahenu2homozygotes displaying heightened blood phenylalanine and other characteristics of PKU.Pahenu2homozygous females do not successfully rear young on any conventional diet due to their disease status. The most commonly used successful breeding strategy is crossingPahenu2heterozygous females with homozygous mutant males; producing litters of 50% homozygous and 50% heterozygous animals. In many treatment studies the heterozygous pups produced are not useable, but add to experimental costs and total animals used. To this end our lab created a dietary regimen with reduced phenylalanine and increased large neutral amino acid content, enabling homozygous mating. Phenylalanine levels in homozygous females and males on the new diet are significantly lower than that of homozygous females and males on traditional diets (p= 1.35×10-4andp= 1.5×10-5respectively). Litters born toPahenu2homozygous mothers on this diet demonstrate no significant difference in litter size compared to litters born to heterozygous mothers (p> 0.75). No observable defects were noted in litters born from homozygous crosses. This dietary regimen enables litter production of 100%Pahenu2homozygous animals for investigators who wish to rapidly expand theirPahenu2mouse colony size or do not require heterozygous littermate controls in their PKU studies.
Interactive auditory task reveals complex sensory-action integration in mouse primary auditory cortex
Authors: Liu Ji , Kanold Patrick O. 
Published: December 2022

AbstractPredictive coding theory postulates that the brain achieves perception by actively making predictions about the incoming sensory information and correcting them if errors signals arise. These signals are likely the most relevant when the individual is actively interacting with the environment and where the sensory outcome determines the ongoing action. In addition, the cerebral cortex is thought to play a key role in generating these signals. Thus, to study the representation of error signals in the primary sensory cortex, we trained mice to perform an interactive auditory task that coupled their actions to the generated sound and perturbed this coupling to evoke putative error responses. We imaged Layer 2/3 (L2/3) and Layer 4 (L4) neurons in the mouse primary auditory cortex, and we identified not only neurons that mainly encoded action related information but also neurons encoding the mismatch between the action and the sound. These results show that a subset of A1 neurons encode the nonlinear interactions between the sound and the action. Furthermore, more L2/3 neurons encoded action related information than L4, indicating that action-sound integration emerges hierarchically in A1 circuits. Together, our results show that complex interactions between action and sound happen in A1 and that some A1 neurons responses reflect the violation of the learnt relationship between the action and sound feedback. Thus, primary sensory cortices not only encode sensory driven activity but also represent the complex interplay between sensory inputs, expectations, and errors.
Composition of minor ampullate silk makes its properties different from those of major ampullate silk
Authors: Nakamura Hiroyuki , Kono Nobuaki , Mori Masaru , Masunaga Hiroyasu , Numata Keiji , Arakawa Kazuharu 
Published: December 2022

ABSTRACTSpider’s minor ampullate silk, or MI-silk, exhibits distinct mechanical properties and water resistance compared to its major ampullate counterpart (MA-silk). The principal protein constituent of MI-silk is known as minor ampullate spidroin, or MiSp, and while its sequence has been deciphered and is thought to underlie the differences in properties with MA-silk, the composition of MI-silk and the relationship between its composition and properties remain elusive. In this study, we set out to investigate the mechanical properties, water resistance, and proteome of MA-silk and MI-silk fromAraneus ventricosusandTrichonephila clavata. We also synthesized artificial fibers from major ampullate spidroin, MaSp1 and 2, and MiSp to compare their properties. Our proteomic analysis reveals that the MI-silk of both araneids is composed of MiSp, MaSp1, and spidroin constituting elements (SpiCEs). The absence of MaSp2 in the MI-silk proteome and the comparison of the water resistance of artificial fibers suggest that the presence of MaSp2 is the reason for the disparity in water resistance between MI-silk and MA-silk.
Intention to breastfeed and association with subsequent breastfeeding duration, a linked population level routine data study - The Born in Wales cohort 2018-2021
Authors: Jones H , Seaborne M , Mhereeg M , James M , Kennedy N , Bandyopadhyay A , Brophy S 
Published: December 2022

AbstractObjectiveThe World Health Organisation recommends exclusive breastfeeding for the first six months of life. This study aimed to examine 1) If intention to breastfeed is associated with higher levels of breastfeeding, and 2) If the pandemic impacted the intention to breastfeed and the breastfeeding rates in Wales.MethodsThis was a cohort study utilising routinely collected, linked healthcare data from the Secure Anonymised Information Linkage databank (SAIL). SAIL combines data from the National Community Child Health (NCCH) and Maternal Indicators (MIDS) datasets. All women that gave birth between 2018 and 2021 recorded in the NCCH dataset and MIDS dataset were included.ResultsIntention to breastfeed was associated with being 27.5 times more likely to continue to breastfeed for six months compared to those who did not intend to breastfeed (OR 27.5, 95% CI: 24.8-30.5). 57.8% of expectant mothers intended to breastfeed pre-pandemic and 58.7% intended to breastfeed in 2020. Exclusive breastfeeding rates to six months were 16.6% pre-pandemic, 20.5% in 2020 and 19.7% in 2021. Those aged 30-39 were 3.91 times more likely to breastfeed.ConclusionThe biggest predictor of exclusive breastfeeding at six months was intention to breastfeed. During the pandemic those who intended to breastfeed were more likely to breastfeed exclusively for six months compared to before and after the pandemic, suggesting time at home may facilitate breastfeeding. Therefore, targeted interventions during pregnancy planning and early pregnancy to promote and encourage intention to start breastfeeding and promoting home working could improve breastfeeding rates and duration.
Internal limiting membrane disruption facilitates engraftment of transplanted human stem cell derived retinal ganglion cells
Authors: Aguzzi Erika A , Zhang Kevin Y , Nagalingam Arumugam , Quillen Sarah , Hariharakumar Shreya , Chetla Nitin , Madhoun Salaheddine , Edwards Malia M , Quigley Harry A , Zack Donald J , Johnson Thomas V 
Published: December 2022

AbstractRetinal ganglion cell (RGC) death causes irreversible vision loss in patients with glaucoma and other forms of optic neuropathy because the mammalian retina and optic nerve lack endogenous regenerative capacity. RGC transplantation and optic nerve regeneration represent a potential translational approach to vision restoration in glaucoma secondary to RGC loss. Functional RGC replacement requires that 1) donor RGCs integrate into the recipient retina and receive synaptic input from afferent bipolar and amacrine cells and that 2) donor RGCs extend their axons and establish synaptic connections to appropriate neurons in the brain. Here, in an effort to address retinal integration, we demonstrate that the internal limiting membrane (ILM) acts as a physical barrier to the integration of transplanted human stem cell-derived RGCs (hRGCs) into the recipient retina following intravitreal transplantationin vivo. To circumvent the ILM barrier, we intravitreally injected the nonspecific protease pronase-E in immunosuppressed adult C57BL/6J mice prior to transplantation of hRGCs. Separately, we also transplanted hRGCs into adultLama1nmf223mice, which harbor a point mutation in theirLama-α1gene that causes developmental ILM dysgenesis. We assessed donor hRGC survival and engraftment using 3D reconstructions of confocal z-stacks in retinal flatmounts. Migration of surviving donor RGC somas into the recipient RGC layer significantly increased after proteolytic or developmental ILM disruption. Moreover, lamination of dendritic arbors into the recipient inner plexiform layer was observed exclusively following ILM disruption. To assess the clinical translatability of this finding, we transplanted hRGCs onto postmortem organotypic human retinal explant cultures and observed significantly increased engraftment following proteolytic ILM digestion. These findings enhance our understanding of the barriers faced by transplanted hRGCs in the adult murine and human retina and provide an avenue for clinically translatable regenerative medicine approaches to vision restoration in optic neuropathy.