bluuebunny/crossref_metadata_2025_split huggingface dataset:
Developing a safe 15-hour preservation protocol of donor kidneys using normothermic machine perfusion
Authors: Stone John P , Cowey William R , Bowers Corban JT , Stewart Amy F , Armstrong Erin R , Clancy Marc , Entwistle Timothy R , Pozo Jorge del , Amin Kavit , Fildes James E 
Published: September 2023

AbstractIntroductionBackgroundNormothermic machine perfusion (NMP) offers a superior alternative to existing hypothermic preservation strategies but is currently limited to 1-3 hours. Extending the time a kidney can be sustained using this technology could electivise transplantation, and enable physiological assessments of renal function. We aimed to develop a protocol that allows the safe preservation of donor kidneys for 12 hours using this technique.MethodsPorcine kidneys (n=20) were retrieved and flushed with 1L preservation solution before being stored on ice. Following a cold ischaemic time of 3.5 hours, kidneys were placed onto a NMP circuit and perfused for 12 hours. Renal haemodynamics, biochemistry and urine output were recorded and analysed. At the end of perfusion, kidneys were scored based on the clinical assessment score and their suitability for transplant determined. Biopsies were collected at the end for histological assessment.ResultsAll kidneys were successfully perfused with immediate recordable renal blood flow (RBF). RBF continually improved over the course of the perfusions, peaking at 12 hours, and negatively correlated with intra-renal resistance. Perfusate sodium concentrations remained stable and within physiological parameters. Sodium bicarbonate increased over time with a corresponding decrease in lactate concentrations, demonstrating active renal gluconeogenesis and Cori cycle processes. Urine production began immediately in all kidneys and was sustained throughout, indicating active renal function. Under the clinical perfusion assessment score, all kidneys received a score of 1 and would be considered suitable for transplantation. Histological assessment revealed kidneys were injury free with REMUZZI scores of 0 in all samples.ConclusionWe have developed an NMP protocol that safely preserves donor kidneys for over 15 hours. Successful perfusion was achieved with stable haemodynamics, blood-perfusate biochemistry, and maintained urine output. Importantly, kidneys remained in optimal health, with no evidence of injury. This protocol may enable the electivisation of transplantation, while reducing ischaemic injury associated with static cold storage.
Bumblebee occupancy responds to complex interactions between local and landscape land use, climatic niche properties and climate change
Authors: Newbold Tim , Kerr Jeremy , Soroye Peter , Williams Jessica J. 
Published: September 2023

AbstractInsect biodiversity is changing rapidly, driven by a complex suite of pressures, foremost among which are human land use, land-use intensification, and increasingly climate change. Bumblebees deliver important pollination services to wild plants and human crops, but we lack large-scale empirical evidence on how land use and climate change interact to drive bumblebee biodiversity changes. We assess bumblebee occupancy responses to interactive effects of land use and climate pressures across North America and Western Europe. Occupancy increases with landscape natural habitat and decreases with the duration of human use of landscapes. Responses to historical climate warming are negative in natural habitats but positive in human land uses, while human land use reduces occupancy most in the centre of species’ temperature niches. We estimate that the combined pressures have reduced bumblebee occupancy by 61% across sampled natural habitats, and 65% across human land uses, suggesting that treating present-day natural habitats as an undisturbed reference is misleading. Our results can inform efforts to conserve bumblebee biodiversity in the face of ongoing land-use changes and accelerating climatic changes.One-sentence summaryLand use and climate change interact to drive large declines in bumblebee occupancy in both natural and human-modified habitats
Powerful and accurate detection of temporal gene expression patterns from multi-sample multi-stage single cell transcriptomics data with TDEseq
Authors: Fan Yue , Li Lei , Sun Shiquan 
Published: September 2023

ABSTRACTWe present a non-parametric statistical method called TDEseq that takes full advantage of smoothing splines basis functions to account for the dependence of multiple time points, and uses hierarchical structure linear additive mixed models to model the correlated cells within an individual. As a result, TDEseq demonstrates powerful performance in identifying four potential temporal expression patterns within a specific cell type. Extensive simulation studies and the analysis of four published scRNA-seq datasets show that TDEseq can produce well-calibrated p-values and up to 20% power gain over the existing methods for detecting temporal gene expression patterns.
TAPIR: a T-cell receptor language model for predicting rare and novel targets
Authors: Fast Ethan , Dhar Manjima , Chen Binbin 
Published: September 2023

AbstractT-cell receptors (TCRs) are involved in most human diseases, but linking their sequences with their targets remains an unsolved grand challenge in the field. In this study, we present TAPIR (T-cell receptor and Peptide Interaction Recognizer), a T-cell receptor (TCR) language model that predicts TCR-target interactions, with a focus on novel and rare targets. TAPIR employs deep convolutional neural network (CNN) encoders to process TCR and target sequences across flexible representations (e.g., beta-chain only, unknown MHC allele, etc.) and learns patterns of interactivity via several training tasks. This flexibility allows TAPIR to train on more than 50k either paired (alpha and beta chain) or unpaired TCRs (just alpha or beta chain) from public and proprietary databases against 1933 unique targets. TAPIR demonstrates state-of-the-art performance when predicting TCR interactivity against common benchmark targets and is the first method to demonstrate strong performance when predicting TCR interactivity against novel targets, where no examples are provided in training. TAPIR is also capable of predicting TCR interaction against MHC alleles in the absence of target information. Leveraging these capabilities, we apply TAPIR to cancer patient TCR repertoires and identify and validate a novel and potent anti-cancer T-cell receptor against a shared cancer neoantigen target (PIK3CA H1047L). We further show how TAPIR, when extended with a generative neural network, is capable of directly designing T-cell receptor sequences that interact with a target of interest.
UNNT: A novel Utility for comparing Neural Net and Tree-based models
Authors: Gutta Venkata Vineeth , Ganakammal Satish Ranganathan , Jones Sara , Beyers Matthew , Chandrasekaran Sunita 
Published: September 2023

AbstractUsing deep learning in cancer research to tackle scientific challenges is becoming an increasingly popular technique. Advances in enhanced data generation, machine learning algorithms, and compute infrastructure have led to an acceleration in the use of deep learning in various domains of cancer research such as drug response problems. In our study, we explored tree-based models to improve the accuracy of a single drug response model and demonstrate that tree-based models such as XGBoost have advantages over deep learning models, such as a convolutional neural network (CNN), for single drug response problems. However, comparing models is not a trivial task. To make training and comparing CNNs and XGBoost (eXtreme Gradient Boosting) more accessible to users, we developed an open-source library called UNNT (A novel Utility for comparing Neural Net and Tree-based models). The case studies, in this manuscript, focus on cancer drug response datasets however the application can be used on datasets from other domains, such as chemistry.Author summaryAdvancement in data science, machine learning (ML), and artificial intelligence (AI) methods has enabled extraction of meaningful information from large and complex datasets that has assisted in better understanding, diagnosing, and treating cancer. The understanding of the drug response domain in cancer research has been accelerated with developing ML models to aid in predicting the effectiveness of the drugs based on a specific genomic molecular feature. In this study we developed a novel robust framework called UNNT (A novel Utility for comparing Neural Net and Tree-based models) that trains and compares deep learning method such as CNN and tree-based method such as XGBoost on the user input dataset. We applied this software to single drug response problem in cancer to identify the best performing ML method based on the National Cancer Institute 60 (NCI60) dataset. In addition, we studied the computational aspects of training each of these models where our results show that neither is evidently superior on both CPUs and GPUs while training. This shows that when both models have similar error rates for a dataset the hardware available determines the model choice for training as discussed in tables 7 and 11. UNNT:https://github.com/vgutta/UNNT.git
Tuning Interdomain Conjugation Towardin situPopulation Modification in Yeast
Authors: Stindt Kevin R , McClean Megan N 
Published: September 2023

AbstractThe ability to modify and control natural and engineered microbiomes is essential for biotechnology and biomedicine. Fungi are critical members of most microbiomes, yet technology for modifying the fungal members of a microbiome has lagged far behind that for bacteria. Interdomain conjugation (IDC) is a promising approach, as DNA transfer from bacterial cells to yeast enablesin situmodification. While such genetic transfers have been known to naturally occur in a wide range of eukaryotes, and are thought to contribute to their evolution, IDC has been understudied as a technique to control fungal or fungal-bacterial consortia. One major obstacle to widespread use of IDC is its limited efficiency. In this work, we utilize interactions between genetically tractableEscherichia coliandSaccharomyces cerevisiaeto control the incidence of IDC. We test the landscape of population interactions between the bacterial donors and yeast recipients to find that bacterial commensalism leads to maximized IDC, both in culture and in mixed colonies. We demonstrate the capacity of cell-to-cell binding via mannoproteins to assist both IDC incidence and bacterial commensalism in culture, and model how these tunable controls can predictably yield a range of IDC outcomes. Further, we demonstrate that these lessons can be utilized to lastingly alter a recipient yeast population, by both “rescuing” a poor-growing recipient population and collapsing a stable population via a novel IDC-mediated CRISPR/Cas9 system.
Plant diversity darkspots for global collection priorities
Authors: Ondo Ian , Dhanjal-Adams Kiran L. , Pironon Samuel , Silvestro Daniele , Colli-Silva Matheus , Deklerck Victor , Grace Olwen M. , Monro Alexandre K. , Nicolson Nicky , Walker Barnaby , Antonelli Alexandre 
Published: September 2023

SummaryMore than 15% of all vascular plant species may remain scientifically undescribed, and many of the >340,000 described species have no or few geographic records documenting their distribution. Identifying and understanding taxonomic and geographic knowledge shortfalls is key to prioritising future collection and conservation efforts.Using extensive data for 343,523 vascular plant species and time-to-event analyses, we conducted multiple tests related to plant taxonomic and geographic data shortfalls, and identified 32 global diversity darkspots (regions predicted to lack most information about their species diversity and distribution). We defined priority regions for future collection according to several socio-economic and environmental scenarios.Most plant diversity darkspots are found within biodiversity hotspots, except New Guinea. We identify New Guinea, the Philippines, Borneo, Myanmar, India, Turkey, Colombia, Ecuador, and Peru, as global collection priorities under all environmental and socio-economic conditions considered.Our study provides a framework to accelerate plant species documentation for the implementation of conservation actions. As digitisation of the world’s herbaria progresses, collection and conservation priorities may soon be identifiable at finer scales.
GPR35 inhibits TRPA1-mediated colonic afferent hypersensitivity through suppression of Substance P release
Authors: Gupta Rohit A , Higham James P , Urriola-Muñoz Paulina , Barker Katie H , Paine Luke , Ghooraroo Joshua , Hockley James RF , Rahman Taufiq , Smith Ewan St John , Brown Alistair JH , Suzuki Rie , Bulmer David C 
Published: September 2023

AbstractThe development of non-opioid analgesics for the treatment of chronic abdominal pain is a pressing area of unmet clinical need. To address this, we examined the expression of Gi/o-coupled receptors in colonic sensory neurons, which, like opioid receptors, have the potential to inhibit nociceptor activation due to their inhibitory G protein coupling. This led to the identification of the orphan receptor GPR35 as a visceral analgesic drug target due to its marked co-expression with TRPA1, a mediator of noxious mechanotransduction in the bowel. Consistent within silicodocking studies which identified binding sites for the mast cell stabiliser cromolyn and phosphodiesterase inhibitor zaprinast at GPR35, we demonstrated, using GPR35 knockout mice, that the antinociceptive effects of these drugs on TRPA1-mediated colonic nociceptor activation and mechanosensitisation were GPR35-dependent. Further work showed these antinociceptive effects occurred through the inhibition of substance P (SP) release. This confirmed both the pronociceptive effect of SP on colonic afferents, and the contribution of SP to TRPA1-mediated colonic nociceptor activation and sensitisation. We also found that TRPA1-induced contraction of the colon was mediated by SP signalling and could be inhibited by cromolyn in a GPR35-dependent manner. Our data identify GPR35, through its inhibition of SP-mediated colonic contractility and nociceptor activation and sensitisation, as a putative mechanism for the reported clinical efficacy of cromolyn in the treatment of irritable bowel syndrome. These findings highlight the potential utility of GPR35 agonists to deliver non-opioid analgesia for the treatment of abdominal pain associated with gastrointestinal diseases such as irritable bowel syndrome and inflammatory bowel disease.
Extracellular matrix scaffold-assisted tumor vaccines induce tumor regression and long-term immune memory
Authors: Pal Sanjay , Chaudhari Rohan , Baurceanu Iris , Hill Brenna J. , Nagy Bethany A. , Wolf Matthew T. 
Published: September 2023

AbstractInjectable scaffold delivery is an immune engineering strategy to enhance the efficacy and reliability of cancer vaccine immunotherapy. The composition and structure of the biomaterial scaffold determines both vaccine release kinetics and inherent immune stimulation via the scaffold host response. Extracellular matrix (ECM) scaffolds prepared from decellularized tissues initiate an acute alternative inflammatory response following implantation, which facilitates wound healing following tumor resection and promotes local cancer immune surveillance. However, it remains unknown whether this environment is compatible with generating protective anti-tumor cytotoxic immunity with local immunotherapy delivery. Here, we engineered an ECM scaffold-assisted therapeutic cancer vaccine that maintained an immune microenvironment consistent with tissue reconstruction. Immune adjuvants MPLA, GM-CSF, and CDA were screened in a cancer vaccine formulated for decellularized small intestinal submucosa (SIS) ECM scaffold co-delivery. Though MPLA and GM-CSF showed the greatest increase in local myeloid cell infiltration, we found that the STING pathway adjuvant CDA was the most potent inducer of cytotoxic immunity with SIS-ECM scaffold delivery. Further, CDA did not diminish hallmark ECM immune responses needed in wound healing such as highIl4cytokine expression. SIS scaffold delivery enhanced therapeutic vaccine efficacy using CDA and the antigen ovalbumin, curing greater than 50% of established EG.7 tumors in young mice and 75% in 24-week-old mature mice, compared to soluble components alone (0% cured). SIS-ECM scaffold assisted vaccination extended antigen exposure, was dependent on CD8+cytotoxic T cells, and generated long term anti-tumor memory at least 7 months post-vaccination in both young and mature-aged mice. This study shows that an ECM scaffold is a promising delivery vehicle to enhance cancer vaccine efficacy while being orthogonal to characteristics of pro-healing immune hallmarks.
Soybean RIN4 represents a mechanistic link between plant immune and symbiotic signaling
Authors: Tóth Katalin , Kim Daewon , Cho Sung-Hwan , Nguyen Cuong T. , Nguyen Tran H. N. , Hartanto Christopher , Michno Jean-Michel , Stec Adrian O. , Stupar Robert M. , Stacey Gary 
Published: September 2023

AbstractThe legume-rhizobium symbiosis represents a unique and beneficial interaction between legumes and nitrogen-fixing soil bacteria, called rhizobia. The initiation and development of this symbiosis is complex and begins with recognition of key molecular signals, produced by the plant and its symbiont, which determine symbiotic compatibility. Current data suggest that the invading symbiont initially triggers plant immune responses that are subsequently suppressed. Hence, there is growing evidence that features of plant immunity may be relevant to symbiotic establishment. RIN4 is a key immune regulator in plants, regulating basal immunity and it is also targeted by pathogen effector proteins that either confer susceptibility or resistance, depending on the presence of the appropriate resistance protein. Surprisingly, we found that RIN4 was rapidly phosphorylated upon rhizobial inoculation of soybean root hairs. RNAi silencing and mutant studies indicate that RIN4 expression is essential for effective nodulation of soybean. RIN4 phosphorylation occurs within a fifteen amino acid motif, which is highly conserved within the Fabales (legumes) and Rosales orders, that comprise species capable of nitrogen-fixing endosymbiosis with rhizobia. RIN4 proteins mutated in this conserved phosphorylation site failed to support efficient soybean nodulation. Phosphorylation of this site is mediated by the symbiotic receptor-like kinase, SymRK, a well-studied member of the symbiotic signaling pathway. The data implicate RIN4 phosphorylation as a key mediator of rhizobial compatibility, interconnecting symbiotic and immune signaling pathways.SignificanceThe nitrogen fixing legume-rhizobium symbiosis is a cornerstone of sustainable agriculture, with ongoing efforts to transfer this unique ability to non-leguminous crop plants. Plants are surrounded by a myriad of microbes in the soil, and, therefore, require constant surveillance in order to distinguish between a pathogen or symbiont. Plants monitor for specific molecular signals that indicate pathogen or symbiont presence. We show that RIN4, a key immune regulator, plays an essential role in promoting the development of the symbiotic nitrogen-fixing relationship between soybean and its compatible symbiontBradyrhizobium japonicum. Therefore, RIN4 is likely a key player in mediating the appropriate response upon infection by friend or foe.
Lipid network of plasma extracellular vesicles reveals sex-based differences in the lipidomic profile from patients with alcohol use disorder
Authors: Perpiñá-Clérigues Carla , Mellado Susana , Galiana-Roselló Cristina , Fernández-Regueras María , Marcos Miguel , García-García Francisco , Pascual María 
Published: September 2023

AbstractAlcohol use disorder (AUD) is one of the most common psychiatric disorders, and the consumption of this substance is considered one of the main causes of preventable deaths worldwide. Lipids play a crucial functional role in cell membranes, however little is known about the role of lipids containing extracellular vesicles (EVs), as regulatory molecules and biomarkers. In this study, a highly sensitive lipidomic strategy is employed to characterize plasma EV lipid species from individuals with AUD, to evaluate differential functional roles and enzymatic activity networks to improve the knowledge of lipid metabolism in the alcohol consumption. Plasma EV lipids from female and male patients with AUD and healthy individuals were analyzed to obtain lipid differential abundance, as well as biological interpretation of LINEX2lipidomics data, evaluating enzymatic dysregulation through an enrichment algorithm. Our results showed for the first time that females with AUD exhibit greater substrate-product changes in LPC and PC lipids, as well as phospholipases and acyltransferases activity, potentially linked to cancer progression and neuroinflammation. Conversely, males with AUD showed dysregulation in Cer and SM lipid, involving sphingomyelinases, sphingomyelin phosphodiesterase, and sphingomyelin synthase, which could be related with hepatotoxicity. Notably, females with AUD showed LION-terms associated with “positive intrinsic curvature”, while males exhibited “negative intrinsic curvature, contributing to vesicle fusion processes. These methodological developments allow a better understanding of lipid metabolism and its regulatory mechanisms, which contributes not only to identify novel lipid targets, but also the discovery of sex-specific clinical biomarkers in the AUD.
Evolutionary origin of morphologically cryptic species imprints co-occurrence and sympatry patterns
Authors: Delić Teo , Borko Špela , Premate Ester , Rexhepi Behare , Alther Roman , Knüsel Mara , Malard Florian , Weber Dieter , Stoch Fabio , Flot Jean-François , Fišer Cene , Altermatt Florian 
Published: September 2023

AbstractAimMorphologically cryptic species are an important part of global biodiversity, yet it remains unclear how these species contribute to and integrate into communities at different geographic scales. It is especially unclear at which scales they co-occur, and if and how their ranges overlap. To adequately protect biodiversity, an accurate understanding of the underlying processes and adequate level of protection is needed, in particularly for often overlooked cryptic species.QuestionWe analyzed patterns of syntopies (local co-occurrences) and sympatries (range overlap) to test how the evolutionary origin of cryptic species shapes biodiversity patterns at different geographic scales. We hypothesized i) that syntopies are more common among phylogenetically deeply divergent cryptic species than among close relatives, and ii) that sympatries are an outcome of phylogenetic relatedness and dispersal, with range size as a proxy of dispersal ability.LocationWestern Europe.TaxonSubterranean amphipod crustaceans of the polyphyleticNiphargus rhenorhodanensisspecies complex.MethodsUnilocus species delimitations (PTP, ASAP), calibrated multilocus phylogenetic analyses, co-occurrence analyses using a probabilistic model, generalized linear models (GLM).ResultsThe studied species complex comprises 37–48 molecular operational taxonomic units (MOTUs) from nine different clades. Syntopies are random or less frequent than expected, implying an insufficient between-MOTU differentiation allowing stable coexistence. GLM suggested that age of divergence does not predict species sympatries, although they emerge more frequently among MOTUs from different clades. By contrast, sympatries emerge when at least one MOTU disperses over a large geographic range. Biodiversity rich regions were found at the foothills of the Alps, the Jura and the Central Massif, regardless the inference method.Main conclusionsBiodiversity patterns of the herein studied species complex are driven mainly by dispersal and reflect geographic circumstances of speciation. While species richness on a local scale may be the outcome of competition and dispersal, regional biodiversity patterns emerged through biogeographic history on a clade-level.