bluuebunny/crossref_metadata_2025_split huggingface dataset:
dsMTL - a computational framework for privacy-preserving, distributed multi-task machine learning
Authors: Cao Han , Zhang Youcheng , Baumbach Jan , Burton Paul R , Dwyer Dominic , Koutsouleris Nikolaos , Matschinske Julian , Marcon Yannick , Rajan Sivanesan , Rieg Thilo , Ryser-Welch Patricia , Späth Julian ,   The COMMITMENT consortium, Herrmann Carl , Schwarz Emanuel 
Published: August 2021

AbstractMultitask learning allows the simultaneous learning of multiple ‘communicating’ algorithms. It is increasingly adopted for biomedical applications, such as the modeling of disease progression. As data protection regulations limit data sharing for such analyses, an implementation of multitask learning on geographically distributed data sources would be highly desirable. Here, we describe the development of dsMTL, a computational framework for privacy-preserving, distributed multi-task machine learning that includes three supervised and one unsupervised algorithms. dsMTL is implemented as a library for the R programming language and builds on the DataSHIELD platform that supports the federated analysis of sensitive individual-level data. We provide a comparative evaluation of dsMTL for the identification of biological signatures in distributed datasets using two case studies, and evaluate the computational performance of the supervised and unsupervised algorithms. dsMTL provides an easy- to-use framework for privacy-preserving, federated analysis of geographically distributed datasets, and has several application areas, including comorbidity modeling and translational research focused on the simultaneous prediction of different outcomes across datasets. dsMTL is available at https://github.com/transbioZI/dsMTLBase (server-side package) and https://github.com/transbioZI/dsMTLClient (client-side package).
Efficient decoding of large-scale neural population responses with Gaussian-process multiclass regression
Authors: Greenidge C. Daniel , Scholl Benjamin , Yates Jacob L. , Pillow Jonathan W. 
Published: August 2021

AbstractNeural decoding methods provide a powerful tool for quantifying the information content of neural population codes and the limits imposed by correlations in neural activity. However, standard decoding methods are prone to overfitting and scale poorly to high-dimensional settings. Here, we introduce a novel decoding method to overcome these limitations. Our approach, the Gaussian process multi-class decoder (GPMD), is well-suited to decoding a continuous low-dimensional variable from high-dimensional population activity, and provides a platform for assessing the importance of correlations in neural population codes. The GPMD is a multinomial logistic regression model with a Gaussian process prior over the decoding weights. The prior includes hyperparameters that govern the smoothness of each neuron’s decoding weights, allowing automatic pruning of uninformative neurons during inference. We provide a variational inference method for fitting the GPMD to data, which scales to hundreds or thousands of neurons and performs well even in datasets with more neurons than trials. We apply the GPMD to recordings from primary visual cortex in three different species: monkey, ferret, and mouse. Our decoder achieves state-of-the-art accuracy on all three datasets, and substantially outperforms independent Bayesian decoding, showing that knowledge of the correlation structure is essential for optimal decoding in all three species.
Light Potentials of Photosynthetic Energy Storage in the Field: What limits the ability to use or dissipate rapidly increased light energy?
Authors: Kanazawa Atsuko , Chattopadhyay Abhijnan , Kuhlgert Sebastian , Tuitupou Hainite , Maiti Tapabrata , Kramer David M. 
Published: August 2021

SummaryThe responses of plant photosynthesis to rapid fluctuations in environmental conditions are thought to be critical for efficient capture of light energy. Such responses are not well represented under laboratory conditions, but have also been difficult to probe in complex field environments. We demonstrate an open science approach to this problem that combines multifaceted measurements of photosynthesis and environmental conditions, and an unsupervised statistical clustering approach. In a selected set of data on mint (Menthasp.), we show that the “light potential” for increasing linear electron flow (LEF) and nonphotochemical quenching (NPQ) upon rapid light increases are strongly suppressed in leaves previously exposed to low ambient PAR or low leaf temperatures, factors that can act both independently and cooperatively. Further analyses allowed us to test specific mechanisms. With decreasing leaf temperature or PAR, limitations to photosynthesis during high light fluctuations shifted from rapidly-induced NPQ to photosynthetic control (PCON) of electron flow at the cytochromeb6fcomplex. At low temperatures, high light induced lumen acidification, but did not induce NPQ, leading to accumulation of reduced electron transfer intermediates, a situation likely to induce photodamage, and represents a potential target for improving the efficiency and robustness of photosynthesis. Finally, we discuss the implications of the approach for open science efforts to understand and improve crop productivity.
Development of a flexible split prime editor using truncated reverse transcriptase
Authors: Zheng Chunwei , Liang Shun-Qing , Liu Bin , Liu Pengpeng , Kwan Suet-Yan , Wolfe Scot A. , Xue Wen 
Published: August 2021

AbstractPrime Editor (PE) has tremendous promise for gene therapy. However, it remains a challenge to deliver PE (>6.3 kb) in vivo. Although PE can be split into two fragments and delivered using dual adeno-associated viruses (AAVs), choice of split sites within Cas9 – which affects editing efficiency – is limited due to the large size of PE. Furthermore, the potential effect of overexpressing RT in mammalian cells is largely unknown. Here, we developed a compact PE with complete deletion of the RNase H domain of reverse transcriptase (RT), which showed comparable editing to full-length PE. Using compact PE, we tested the effect of 4 different Cas9 split sites and found that the Glu 573 split site supports robust editing (up to 93% of full-length PE). The compact PE, but not PE2, abolished its binding to eRF1 and showed minimal effect on stop codon readthrough, which therefore might reduce the effects on protein biosynthesis. This study identifies a safe and efficient compact PE2 that enables flexible split-PE design to facilitate efficient delivery in vivo and advance the utility of prime editing.
Recurrent de novo single point mutation on the gene encoding Na+/K+ pump results in epilepsy
Authors: Li Hong-Ming , Hu Wen-Bao , Hong Chun-Gu , Duan Ran , Chen Meng-Lu , Cao Jia , Wang Zhen-Xing , Chen Chun-Yuan , Yin Fei , Hu Zhong-Hua , Li Jia-Da , Zhong Li-Hong , Xie Hui , Liu Zheng-Zhao 
Published: August 2021

AbstractThe etiology of epilepsy remains undefined in two-thirds of patients. Here, we identified a de novo mutation of ATP1A2 (c.2426 T>G, p.Leu809Arg), which encodes the α2 subunit of Na+/K+-ATPase, from a family with idiopathic epilepsy. This mutation caused seizures in the study patients. We generated the point mutation mouse model Atp1a2L809R, which recapitulated the epilepsy observed in the study patients. In Atp1a2L809R/WT mice, convulsions were observed and cognitive and memory function was impaired. This mutation affected the potassium binding function of the protein, disabling its ion transport ability, thereby increasing the frequency of nerve impulses. Our work revealed that ATP1A2L809R mutations cause a predisposition to epilepsy. Moreover, we first provide a point mutation mouse model for epilepsy research and drug screening.
Friend or Foe: Hybrid proline-rich proteins determine how plants interact with and respond to beneficial and pathogenic microbes
Authors: Banday Zeeshan Z. , Cecchini Nicolás M. , Scott Allison T. , Hu Ciara T. , Filzen Rachael C. , Agbo Elinam , Greenberg Jean T. 
Published: August 2021

AbstractPlant plastids generate signals, including some derived from lipids, that need to be mobilized to effect signaling. We used informatics to discover potential plastid membrane proteins involved in microbial responses. Among these are proteins co-regulated with the systemic immunity component AZI1, a hybrid proline-rich protein (HyPRP) and HyPRP superfamily members. HyPRPs have a transmembrane domain, a proline-rich region (PRR) and a lipid transfer protein domain. The precise subcellular location(s) and function(s) is unknown for most HyPRP family members. As predicted by informatics, a subset of HyPRPs have a pool of protein that targets plastid outer envelope membranes (OEMs) via a mechanism that requires the PRR. Additionally, two HyPRPs may be associated with thylakoid membranes. Most of the plastid and non-plastid localized family members also have pools that localize to endoplasmic reticulum, plasma membrane or plasmodesmata. HyPRPs with plastid pools regulate, positively or negatively, systemic immunity against the pathogen Pseudomonas syringae. HyPRPs also regulate the interaction with the plant growth promoting rhizobacteria Pseudomonas simiae WCS417 in the roots to influence colonization, root system architecture and/or biomass. Thus, HyPRPs have broad and distinct roles in immune, development and growth responses to microbes and reside at sites that may facilitate signal molecule transport.
Combined use of Oxford Nanopore and Illumina sequencing yields insights into soybean structural variation biology
Authors: Lemay Marc-André , Sibbesen Jonas A. , Torkamaneh Davoud , Hamel Jérémie , Levesque Roger C. , Belzile François 
Published: August 2021

AbstractBackgroundStructural variant (SV) discovery based on short reads is challenging due to their complex signatures and tendency to occur in repeated regions. The increasing availability of long-read technologies has greatly facilitated SV discovery, however these technologies remain too costly to apply routinely to population-level studies. Here, we combined short-read and long-read sequencing technologies to provide a comprehensive population-scale assessment of structural variation in a panel of Canadian soybean cultivars.ResultsWe used Oxford Nanopore sequencing data (∼12X mean coverage) for 17 samples to both benchmark SV calls made from the Illumina data and predict SVs that were subsequently genotyped in a population of 102 samples using Illumina data. Benchmarking results show that variants discovered using Oxford Nanopore can be accurately genotyped from the Illumina data. We first use the genotyped SVs for population structure analysis and show that results are comparable to those based on single-nucleotide variants. We observe that the population frequency and distribution within the genome of SVs are constrained by the location of genes. Gene Ontology and PFAM domain enrichment analyses also confirm previous reports that genes harboring high-frequency SVs are enriched for functions in defense response. Finally, we discover polymorphic transposable elements from the SVs and report evidence of the recent activity of a Stowaway MITE.ConclusionsOur results demonstrate that long-read and short-read sequencing technologies can be efficiently combined to enhance SV analysis in large populations, providing a reusable framework for their study in a wider range of samples and non-model species.
A Human Liver Organoid Screening Platform for DILI Risk Prediction
Authors: Zhang Charles J. , Meyer Sophia R. , O’Meara Matthew J. , Huang Sha , Capeling Meghan M. , Ferrer-Torres Daysha , Childs Charlie J. , Spence Jason R. , Fontana Robert J. , Sexton Jonathan Z. 
Published: August 2021

ABSTRACTBackground and AimsDrug-induced liver injury (DILI), both intrinsic and idiosyncratic, causes frequent morbidity, mortality, clinical trial failures and post-approval withdrawal. This suggests an unmet need for improved in vitro models for DILI risk prediction that can account for diverse host genetics and other clinical factors. In this study, we evaluated the utility of human liver organoids (HLOs) for high-throughput DILI risk prediction and in an organ-on-chip system.MethodsHLOs were derived from 3 separate iPSC lines and benchmarked on two platforms for their ability to model in vitro liver function and identify hepatotoxic compounds using biochemical assays for albumin, ALT, and AST, microscopy-based morphological profiling, and single-cell transcriptomics: 1) HLOs dispersed in 384-well formatted plates and exposed to a library of compounds. 2) HLOs adapted to a liver-on-chip system.ResultsDispersed HLOs derived from the 3 iPSC lines had similar DILI predictive capacity to intact HLOs in a high-throughput screening format allowing for measurable IC50 values of compound cytotoxicity. Distinct morphological differences were observed in cells treated with drugs exerting differing mechanisms of toxicity.On-chip HLOs significantly increased albumin production, CYP450 expression, and ALT/AST release when treated with known DILI drugs compared to dispersed HLOs and primary human hepatocytes. On-chip HLOs were able to predict the synergistic hepatotoxicity of tenofovir-inarigivir and showed steatosis and mitochondrial perturbation via phenotypic and transcriptomic analysis with exposure to FIAU and acetaminophen, respectively.ConclusionsThe high throughput and liver-on-chip system exhibit enhanced in vivo-like function and demonstrate the potential utility of these platforms for hepatotoxicity risk assessment. Tenofovir-inarigivr associated hepatotoxicity was observed and correlates with the clinical manifestation of DILI observed in patients.LAY SUMMARYIdiosyncratic (spontaneous, patient-specific) drug-induced liver injury (DILI) is difficult to study due to the lack of liver models that function as human liver tissue and are adaptable for large-scale drug screening. Human liver organoids grown from patient stem cells respond to known DILI-causing drugs in both a high-throughput and on a physiological “chip” culture system. These platforms show promise in their use as predictive model for novel drugs before entering clinical trials.
Genome-wide local ancestry and direct evidence for mitonuclear coadaptation in African hybrid cattle populations (Bos taurus/indicus)
Authors: Ward James A. , McHugo Gillian P. , Dover Michael J. , Hall Thomas J. , Ismael Ng’ang’a Said , Sonstegard Tad S. , Bradley Daniel G. , Frantz Laurent A. F. , Salter-Townshend Michael , MacHugh David E. 
Published: August 2021

SUMMARYThe phenotypic diversity of African cattle reflects adaptation to a wide range of agroecological conditions, human-mediated selection preferences, and complex patterns of admixture between the humplessBos taurus(taurine) and humpedBos indicus(zebu) subspecies, which diverged 150-500 thousand years ago. Despite extensive admixture, all African cattle possess taurine mitochondrial haplotypes, even populations with significant zebu biparental and male uniparental nuclear ancestry. This has been interpreted as the result of a human-mediated dispersal ultimately stemming from zebu bulls imported from South Asia during the last three millennia. Here we assess whether ancestry at mitochondrially-targeted nuclear genes in African admixed cattle is impacted by mitonuclear functional interactions. Using high-density SNP data, we find evidence for mitonuclear coevolution across hybrid African cattle populations with a significant increase of taurine ancestry at mitochondrially-targeted nuclear genes. Our results, therefore, support the hypothesis of incompatibility between the taurine mitochondrial genome and the zebu nuclear genome.GRAPHICAL SUMMARYHighlights•Using high-density genome-wide SNP data, we present evidence for mitonuclear coevolution in hybrid African cattle.•We observe a significant increase of taurine ancestry across multiple hybrid populations at mitochondrially-targeted nuclear genes.•Our results provide support for the hypothesis of mitonuclear incompatibility between the zebu nuclear genome and the taurine mitochondrial genome.
Methylmalonic acid impairs cell respiration and glutamate uptake in C6 rat glioma cells
Authors: Costa Renata T. , Santos Marcella B. , Alberto-Silva Carlos , Carrettiero Daniel C. , Ribeiro César A.J. 
Published: August 2021

ABSTRACTMethylmalonic acidemia is an organic acidemia caused by deficient activity of L-methylmalonyl-CoA mutase or its cofactor cyanocobalamin and it is biochemically characterized by an accumulation of methylmalonic acid (MMA) in tissue and body fluids of patients. The main clinical manifestations of this disease are neurological and observable symptoms during metabolic decompensation are encephalopathy, cerebral atrophy, coma, and seizures, which commonly appear in newborns. This study aimed to investigate the toxic effects of MMA in a glial cell line presenting astrocytic features. Astroglial C6 cells were exposed to MMA (0.1-10mM) for 24 or 48 hours and cell viability, glucose consumption and oxygen consumption rate, as well as glutamate uptake and ATP content were analyzed. The possible preventive effects of bezafibrate were also evaluated. MMA significantly reduced cell viability after 48-hour period and increased glucose consumption during the same period of incubation. Regarding the energy homeostasis, MMA significantly reduced respiratory parameters of cells after 48-hour exposition, indicating that cell metabolism is compromised at resting and reserve capacity state, which might influence the cell capacity to meet energetic demands. Glutamate uptake and ATP content were also compromised after exposition to MMA, which can be influenced energy metabolism impairment, affecting the functionality of the astroglial cells. Our findings suggest that these effects could be involved in the pathophysiology of neurological dysfunction of this disease.
Cryptococcus neoformans melanization incorporates multiple catecholamines to produce polytypic melanin
Authors: Baker Rosanna P. , Chrissian Christine , Stark Ruth E. , Casadevall Arturo 
Published: August 2021

AbstractMelanin is a major virulence factor in pathogenic fungi that enhances the ability of fungal cells to resist immune clearance. Cryptococcus neoformans is an important human pathogenic fungus that synthesizes melanin from exogenous tissue catecholamine precursors during infection, but the type of melanin made in cryptococcal meningoencephalitis is unknown. We analyzed the efficacy of various catecholamines found in brain tissue in supporting melanization using animal brain tissue and synthetic catecholamine mixtures reflecting brain tissue proportions. Solid-state NMR spectra of the melanin pigment produced from such mixtures yielded more melanin than expected if only the preferred constituent dopamine had been incorporated, suggesting uptake of additional catecholamines. Probing the biosynthesis of melanin using radiolabeled catecholamines revealed that C. neoformans melanization simultaneously incorporated more than one catecholamine, implying that the pigment was polytypic in nature. Nonetheless, melanin derived from individual or mixed catecholamines had comparable ability to protect C. neoformans against ultraviolet light and oxidants. Our results indicate that melanin produced during infection differs depending on the catecholamine composition of tissue and that melanin pigment synthesized in vivo is likely to accrue from the polymerization of a mixture of precursors. From a practical standpoint our results strongly suggest that using dopamine as a polymerization precursor is capable of producing melanin pigment comparable to that produced during infection. On a more fundamental level our findings uncover additional structural complexity for natural cryptococcal melanin by demonstrating that pigment produced during human infection is likely to be composed of polymerized moieties derived from chemically different precursors.
Mitochondrial pyruvate supports lymphoma proliferation by fueling a non-canonical glutamine metabolism pathway
Authors: Wei Peng , Bott Alex J. , Cluntun Ahmad A. , Morgan Jeffrey T. , Cunningham Corey N. , Schell John C. , Ouyang Yeyun , Ficarro Scott B. , Marto Jarrod A. , Danial Nika N. , DeBerardinis Ralph J. , Rutter Jared 
Published: August 2021

SUMMARYThe fate of pyruvate, which is modulated by the activity of the mitochondrial pyruvate carrier (MPC), is a defining metabolic feature in many cancers. Diffuse large B-cell lymphomas (DLBCLs) are a genetically and metabolically heterogeneous cancer. Although MPC expression and activity differed between DLBCL subgroups, mitochondrial pyruvate was uniformly consumed by glutamate pyruvate transaminase 2 (GPT2) to support α-ketoglutarate production as part of glutaminolysis. This led us to discover that glutamine exceeds pyruvate as a carbon source for the tricarboxylic acid (TCA) cycle in DLBCLs. Furthermore, we found that MPC inhibition unexpectedly leads to decreased glutaminolysis, which is contrary to previous observations in other cell types. We also discovered that MPC inhibition and depletion only decreased DLBCL proliferation in an extracellular matrix (ECM) environment and in vivo xenografts, but not in the typical DLBCL suspension environment. We also have found that the metabolic profile of DLBCL cells in ECM is markedly different from cells in suspension environment. Thus, we report that besides the canonical glutamate dehydrogenase (GDH)-mediated glutaminolysis, the non-canonical GPT2 mediated consumption and assimilation of glutamine and pyruvate in DLBCLs enables their proliferation in an extracellular environment-dependent manner.HIGHLIGHTSGlutamine, but not glucose, is a major carbon source for the tricarboxylic acid cycle in diffuse large B-cell lymphomas.Mitochondrial pyruvate supports glutaminolysis in diffuse large B-cell lymphomas by supplying pyruvate for glutamate pyruvate transaminase 2-mediated α -ketoglutarate production.Mitochondrial pyruvate carrier inhibition leads to decreased glutaminolysis in diffuse large B-cell lymphomas.α -ketoglutarate production is important for diffuse large B-cell lymphoma proliferation in a solid extracellular matrix environment.Mitochondrial pyruvate carrier activity supports diffuse large B-cell lymphoma proliferation in a solid extracellular matrix environment and in mouse xenografts.