bluuebunny/crossref_metadata_2025_split huggingface dataset:
A modeling-based approach to optimize COVID-19 vaccine dosing schedules for improved protection
Authors: Dogra Prashant , Schiavone Carmine , Wang Zhihui , Ruiz-Ramírez Javier , Caserta Sergio , Staquicini Daniela I. , Markosian Christopher , Wang Jin , Sostman H. Dirk , Pasqualini Renata , Arap Wadih , Cristini Vittorio 
Published: September 2022

AbstractWhile the development of different vaccines has slowed the dissemination of SARS-CoV-2, the occurrence of breakthrough infections continues to fuel the pandemic. As a strategy to secure at least partial protection, with a single dose of a given COVID-19 vaccine to maximum possible fraction of the population,delayedadministration of subsequent doses (or boosters) has been implemented in many countries. However, waning immunity and emergence of new variants of SARS-CoV-2 suggest that such measures may jeopardize the attainment of herd immunity due to intermittent lapses in protection. Optimizing vaccine dosing schedules could thus make the difference between periodic occurrence of breakthrough infections or effective control of the pandemic. To this end, we have developed a mechanistic mathematical model of adaptive immune response to vaccines and demonstrated its applicability to COVID-19 mRNA vaccines as a proof-of-concept for future outbreaks. The model was thoroughly calibrated against multiple clinical datasets involving immune response to SARS-CoV-2 infection and mRNA vaccines in healthy and immunocompromised subjects (cancer patients undergoing therapy); the model showed robust clinical validation by accurately predicting neutralizing antibody kinetics, a correlate of vaccine-induced protection, in response to multiple doses of mRNA vaccines. Importantly, we estimated population vulnerability to breakthrough infections and predicted tailored vaccination dosing schedules to maximize protection and thus minimize breakthrough infections, based on the immune status of a sub-population. We have identified a critical waiting window for cancer patients (or, immunocompromised subjects) to allow recovery of the immune system (particularly CD4+ T-cells) for effective differentiation of B-cells to produce neutralizing antibodies and thus achieve optimal vaccine efficacy against variants of concern, especially between the first and second doses. Also, we have obtained optimized dosing schedules for subsequent doses in healthy and immunocompromised subjects, which vary from the CDC-recommended schedules, to minimize breakthrough infections. The developed modeling tool is based on generalized adaptive immune response to antigens and can thus be leveraged to guide vaccine dosing schedules during future outbreaks.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and fibromyalgia are indistinguishable by their cerebrospinal fluid proteomes
Authors: Schutzer Steven E. , Liu Tao , Tsai Chia-Feng , Petyuk Vladislav A. , Schepmoes Athena A. , Wang Yi-Ting , Weitz Karl K. , Bergquist Jonas , Smith Richard D. , Natelson Benjamin H 
Published: September 2022

AbstractMyalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and fibromyalgia have overlapping neurologic symptoms particularly disabling fatigue. This has given rise to the question whether they are distinct central nervous system (CNS) entities or is one an extension of the other. To investigate this, we used unbiased quantitative mass spectrometry-based proteomics to examine the most proximal fluid to the brain, cerebrospinal fluid (CSF). This was to ascertain if the proteome profile of one was the same or different from the other. We examined two separate groups of ME/CFS, one with (n=15) and one without (n=15) fibromyalgia. We quantified a total of 2,083 proteins using immunoaffinity depletion, tandem mass tag isobaric labeling and offline two-dimensional liquid chromatography coupled to tandem mass spectrometry, including 1,789 that were quantified in all the CSF samples. ANOVA analysis did not yield any proteins with an adjusted p-value < 0.05. This supports the notion that ME/CFS and fibromyalgia as currently defined are not distinct entities.
Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis
Authors: Mastropasqua Francesca , Oksanen Marika , Soldini Cristina , Alatar Shemim , Arora Abishek , Ballarino Roberto , Molinari Maya , Agostini Federico , Poulet Axel , Watts Michelle , Rabkina Ielyzaveta , Becker Martin , Li Danyang , Anderlid Britt-Marie , Isaksson Johan , Remnelius Karl Lundin , Moslem Mohsen , Jacob Yannick , Falk Anna , Crosetto Nicola , Bienko Magda , Santini Emanuela , Borgkvist Anders , Bölte Sven , Tammimies Kristiina 
Published: September 2022

ABSTRACTGenetic variants affectingHeterogeneous Nuclear Ribonucleoprotein U (HNRNPU)have been identified in several neurodevelopmental disorders (NDDs). HNRNPU is widely expressed in the human brain and shows the highest postnatal expression in the cerebellum. Recent studies have investigated the role ofHNRNPUin cerebral cortical development, but the effects ofHNRNPUdeficiency on cerebellar development remain unknown. Here, we describe the molecular and cellular outcomes ofHNRNPUlocus deficiency duringin vitroneural differentiation of patient-derived and isogenic neuroepithelial stem cells with a hindbrain profile. We demonstrate thatHNRNPUdeficiency leads to chromatin remodeling of A/B compartments, and transcriptional rewiring, partly by impacting exon inclusion during mRNA processing. Genomic regions affected by the chromatin restructuring and host genes of exon usage differences show a strong enrichment for genes implicated in epilepsies, intellectual disability, and autism. Lastly, we show that at the cellular level.HNRNPUdownregulation leads to altered neurogenesis and an increased fraction of neural progenitors in the maturing neuronal population. We conclude that,HNRNPUlocus is involved in delayed commitment of neural progenitors to neuronal maturation in cell types with hindbrain profile.
Quantitative bioactivity signatures of dietary supplements and natural products
Authors: Yasgar Adam , Bougie Danielle , Eastman Richard T. , Huang Ruili , Itkin Misha , Kouznetsova Jennifer , Lynch Caitlin , McKnight Crystal , Miller Mitch , Ngan Deborah K. , Peryea Tyler , Shah Pranav , Shinn Paul , Xia Menghang , Zakharov Alexey V. , Simeonov Anton 
Published: September 2022

AbstractDietary Supplements and Natural Products have minor oversight of their safety and efficacy. We assembled a collection of Dietary Supplements and Natural Products (DSNP) as well as Traditional Chinese Medicinal (TCM) Plant extracts, which were screened against an in vitro panel of assays, including a liver cytochrome p450 enzyme panel, CAR/PXR signaling pathways, and P-gp transporter assays, to assess their activity. This pipeline facilitated the interrogation of Natural Product-Drug Interaction (NaPDI) through prominent metabolizing pathways. In addition, we compared the activity profiles of the DSNP/TCM substances with those of an approved drug collection. Many of the approved drugs have well-annotated mechanisms of action (MOA) while the MOAs for most of the DSNP and TCM samples remain unknown. Based on the premise that compounds with similar activity profiles tend to share similar targets or MOA, we clustered the library activity profiles to identify overlap with the NCATS Pharmaceutical Collection to predict the MOAs of the DSNP/TCM substances. Overall, we highlight four significant bioactivity profiles (measured by p-values) as examples of this prediction. These results can be used as a starting point for further exploration on the toxicity potential and clinical relevance of these substances.
A continental scale analysis reveals widespread root bimodality
Authors: Lu Mingzhen , Wang Sili , Malhotra Avni , Tumber-Dávila Shersingh Joseph , Weintraub-Leff Samantha , McCormack Luke , Wang Xingchen Tony , Jackson Robert B. 
Published: September 2022

Summary paragraphRecent studies of plant fine roots have greatly advanced our understanding of their geometric properties and symbiotic relationships, but knowledge of how these roots are spatially distributed across the soil matrix lags far behind. An improved understanding of broad-scale variability in root vertical distribution is critical for understanding plant-soil-atmosphere interactions and their influence on the land carbon sink. Here we analyze a continental-scale dataset of plant roots reaching 2-meters depth, spanning 19 ecoclimatic domains ranging from Alaskan tundra to Puerto Rican neotropical forest. Contrary to the common expectation that fine root abundance decays exponentially with increasing soil depth, we found surprising root bimodality at ~20% of 44 field sites —a secondary peak of fine root biomass far beneath the soil surface. All of the secondary root peaks were observed deeper than 60cm (with 33% below 1m), far deeper than the sampling depth commonly used in ecosystem studies and forestry surveys. We demonstrate that root bimodality is more likely in places with relatively low total fine root biomass, and is more frequently associated with shrubland vegetation but less with grassland. Further statistical analyses revealed that the secondary peak of root biomass coincided with unexpected high soil nitrogen contents at depth. By linking roots and nutrient distributions, we further demonstrate that deep soil nutrients tend to be underexploited by plant rooting systems, yet root bimodality offers a unique mechanism by which fine roots can tap into soil resources in the deep. Our findings suggest that empirical practices have often systematically overlooked root dynamics in deep soils, and as a result the current-generation global climate and vegetation models have relied on overly simplistic assumptions for plant rooting distribution.
An intragenic FAT1 regulatory element deleted in muscular dystrophy patients drives muscle and mesenchyme expression during development
Authors: Caruso Nathalie , Zimmermann Angela K , Nigam Tarana , Becker Celine , Lipson Karelia , Helmbacher Françoise 
Published: September 2022

SummaryFat1 is an atypical cadherin playing multiple roles that influence tissue morphogenesis. During mouse development Fat1 is required to modulate muscle morphogenesis through complementary activities in myogenic cells, muscle-associated connective tissue, and motor neurons, ablation of which leads to regionalized muscle phenotypes. We previously identified copy number variants (CNV) deleting an intragenic conserved non-coding element (CNE) in the human FAT1 locus, that were enriched among muscular dystrophy patients with symptoms resembling those of Facioscapulohumeral Dystrophy (FSHD), compared to healthy individuals. Since such deletions of a putative cis-regulatory element had the potential to cause tissue-specific depletion of FAT1, they were postulated to act as symptom modifiers. However, activity of this CNE has not been functionally explored so far. To investigate the possible regulatory activity of this Fat1-CNE, we engineered transgenic mice in which it drives expression of a bi-cistronic reporter comprising the CRE-recombinase (Cre) and a myristilated-tdTomato fluorescent protein. The tissue-specific pattern of cre and tomato expression indicates that this enhancer has bipotential character, and drives expression in skeletal muscle and in muscle-associated mesenchymal cells. We extended our analysis of one of the transgenic lines, which exhibits enhanced expression in mesenchymal cells at extremities of subsets of muscles matching the map of Fat1-dependent muscles. This transgenic line exhibits highly selective CRE-mediated excision in scattered cells within the Tomato-positive territory hotspots. This represents a novel tool to genetically explore the diversity of muscle-associated mesenchymal lineages.
Ancient DNA Reveals China as a Historical Genetic Melting Pot in Tiger Evolution
Authors: Sun Xin , Liu Yue-Chen , Tiunov Mikhail P. , Gimranov Dmitry O. , Zhuang Yan , Han Yu , Driscoll Carlos A. , Pang Yu-Hong , Li Chunmei , Pan Yan , Velasco Marcela Sandoval , Gopalakrishnan Shyam , Yang Rui-Zheng , Li Bao-Guo , Jin Kun , Xu Xiao , Uphyrkina Olga , Huang Yan-Yi , Wu Xiao-Hong , Gilbert M. Thomas P. , O’Brien Stephen J. , Yamaguchi Nobuyuki , Luo Shu-Jin 
Published: September 2022

AbstractThe contrast between the tiger’s (Panthera tigris) 2-3 My age and extant tigers’ coalescence approximately 110,000 years ago suggests an ancient demographic bottleneck. Here we collected over 60 extinct specimens across mainland Asia and generated whole genome sequences from a 10,600-year-old Russian Far East (RFE) specimen (RUSA21, 8ξ coverage), 14 South China tigers (0.1-12ξ), three Caspian tigers (4-8ξ), plus 17 new mitogenomes. RUSA21 clustered within modern Northeast Asian phylogroups and partially derived from an extinct Late Pleistocene lineage. While some 8,000-10,000-year-old RFE mitogenomes are basal to all tigers, one 2,000-year-old specimen resembles present Amur tigers. The Caspian tiger likely dispersed from an ancestral Northeast Asian population and experienced gene flow from southern Bengal tigers. Lastly, genome-wide monophyly supported the South China tiger as a distinct subspecies, albeit with mitochondrial paraphyly, hence resolving its longstanding taxonomic controversy. The distribution of mitochondrial haplogroups corroborated by biogeographical modeling suggested Southwest China was a Late Pleistocene refugium for a relic basal lineage. As suitable habitat returned, Eastern China became a genetic melting pot to foster divergent lineages to merge into South China tigers and other subsequent northern subspecies to develop. Genomic information retrieved from ancient tigers hence sheds light on the species’ full evolutionary history leading to nine modern subspecies and resolves the natural history of surviving tigers.
First mitogenome phylogeny of the sun bear Helarctos malayanus reveals a deep split between Indochinese and Sundaic lineages
Authors: Kunde Miriam N. , Barlow Axel , Klittich Achim , Yakupova Aliya , Patel Riddhi P. , Fickel Jörns , Förster Daniel W. 
Published: September 2022

ABSTRACTThe sun bear Helarctos malayanus is one of the most endangered ursids, and to date classification of sun bear populations has been based almost exclusively on geographic distribution and morphology. The very few molecular studies focusing on this species were limited in geographic scope. Using archival and non-invasively collected sample material, we have added a substantial number of complete or near-complete mitochondrial genome sequences from sun bears of several range countries of the species’ distribution. We here report 32 new mitogenome sequences representing sun bears from Cambodia, Thailand, Peninsular Malaysia, Sumatra and Borneo. Reconstruction of phylogenetic relationships revealed two matrilines that diverged ∼290 thousand years ago: one restricted to portions of mainland Indochina (China, Cambodia, Thailand; “Mainland clade”), and one comprising bears from Borneo, Sumatra, Peninsular Malaysia but also Thailand (“Sunda clade”). Generally recent coalescence times in the mitochondrial phylogeny suggest that recent or historical demographic processes have resulted in a loss of mtDNA variation. Additionally, analysis of our data in conjunction with shorter mtDNA sequences revealed that the Bornean sun bear, classified as a distinct subspecies (H. m. euryspilus), does not harbour a distinctive matriline. Further molecular studies of H. malayanus are needed, which should ideally include data from nuclear loci.
DNA methylation supports accelerated biological age in Type 2 Diabetes which can be reversed with pharmacological treatments: Retrospective Cohort Study
Authors: Cortez Briana N. , Pan Hui , Aguayo-Mazzucato Cristina 
Published: September 2022

AbstractBackgroundBiological age (BA) closely depicts age-related changes at a cellular level. Type 2 Diabetes mellitus (T2D) accelerates BA when calculated using clinical biomarkers. However, there is a large spread of individual BA within these groups and it is unclear what clinical biomarkers correlate with different speeds of aging and whether pharmacological treatment of diabetes alter BA. We hypothesized that accelerated BA would be seen at the DNA methylation (DNAm) level, the gold standard to determine BA, and biomarkers and treatments would correlate the rate of BA in T2D.MethodsPublicly available DNAm samples were obtained from the GEO NCBI database and the NHANES 2017-2018 and ACCORD Cohorts were used for our analysis. We used the DNA Methylation Phenotypic Age algorithm and the Klemera and Doubal (KDM) methods to calculate BA with DNA methylation and clinical biomarkers, respectively.ResultsDNAm showed increased BA in whole blood and pancreatic islets in T2D in aging-related pathways, such as DNA damage and inflammation. Using the NHANES and ACCORD Trial cohorts, we found that avoidance of fried and fatty foods, and vigorous activity correlated with decreased BA in T2D. Cardiovascular, glycemic, and inflammatory biomarkers associated with the rate of aging in DM. Intensive blood pressure and T2D treatment associated with a greater deceleration in the speed of aging as compared to the standard.ConclusionsOverall, we show that certain tissues age faster in people with T2D and this strongly associates with blood glucose control, inflammation and cardiovascular health. Effective treatment of the disease can decelerate aging and decrease BA suggesting the latter as a novel and integrated index to evaluate and follow people with T2D.FundingThis study was supported by Institutional Startup Funds to C.A.M. (Joslin Diabetes Center) and NIH grants P30 DK036836 Joslin Diabetes Research Center (Bioinformatic Core).
Rapid learning of neural circuitry from holographic ensemble stimulation enabled by model-based compressed sensing
Authors: Triplett Marcus A. , Gajowa Marta , Antin Benjamin , Sadahiro Masato , Adesnik Hillel , Paninski Liam 
Published: September 2022

AbstractDiscovering how neural computations are implemented in the cortex at the level of monosynaptic connectivity requires probing for the existence of synapses from possibly thousands of presynaptic candidate neurons. Two-photon optogenetics has been shown to be a promising technology for mapping such monosynaptic connections via serial stimulation of neurons with single-cell resolution. However, this approach is limited in its ability to uncover connectivity at large scales because stimulating neurons one-by-one requires prohibitively long experiments. Here we developed novel computational tools that, when combined, enable learning of monosynaptic connectivity from high-speed holographic neural ensemble stimulation. First, we developed a model-based compressed sensing algorithm that identifies connections from postsynaptic responses evoked by stimulation of many neurons at once, considerably increasing the rate at which the existence and strength of synapses are screened. We show that this model-based approach, explicitly incorporating known biophysics of optogenetic mapping experiments, is critical for accurately determining synaptic connectivity using compressed sensing. Second, we developed a deep learning method that isolates the postsynaptic response evoked by each stimulus, allowing stimulation to rapidly switch between ensembles without waiting for the postsynaptic response to return to baseline. We then validated our approach by performing large-scale connectivity mapping experiments in slices from layer 2/3 of mouse primary visual cortex. Together, our system increases the throughput of monosynaptic connectivity mapping by an order of magnitude over existing approaches, enabling the acquisition of connectivity maps at speeds needed to discover the synaptic circuitry implementing neural computations.
Improving 3D Edge Detection for Visual Inspection of MRI Coregistration and Alignment
Authors: Rorden Chris , Newman-Norlund Roger , Drake Chris , Glen Daniel R. , Fridriksson Julius , Hanayik Taylor , Taylor Paul A. 
Published: September 2022

AbstractDetecting and visualizing edges is important in several neuroimaging and medical imaging applications. For example, it is common to use edge maps to ensure the automatic alignment of low-resolution functional MRI images to match a high-resolution structural image has been successful. Specifically, software toolboxes like FSL and AFNI generate volumetric edge maps that can be particularly useful for visually assessing the alignment of datasets, overlaying the edge map of one on the other. Therefore, edge maps play a crucial role in quality assurance. Popular methods for computing edges are based on either the first derivative of the image as in FSL, or a variation of the Canny Edge detection method as implemented in AFNI. The crucial algorithmic parameter for adjustment for each of these methods relates to the image intensity. However, image intensity is relative and can be quite variable in most neuroimaging modalities. Further, the existing approaches do not necessarily generate a closed edge/surface, which can reduce the ability to determine the correspondence between a represented edge and another image. We suggest that using the second derivative (difference of Gaussian, or DoG) of the image to generate edges resolves both these issues. This method primarily operates by specifying a spatial scale of interest (which is typically known in medical imaging) rather than a contrast scale, and creates closed surfaces by definition. We describe some convenient implementation features (for both efficiency and visual quality) developed here, and we provide open source implementations of this method as both online and high performance portable code. Finally, we include this method as part of both the AFNI and FSL software packages.
Optimal energy and redox metabolism in the cyanobacteriumSynechocystissp. PCC 6803
Authors: Kugler Amit , Stensjö Karin 
Published: September 2022

AbstractCyanobacteria represent an attractive platform for the sustainable production of chemicals and fuels. However, the obtained rates, yields, and titers are below those required for commercial application. Carbon metabolism alone cannot achieve maximal accumulation of end-products, since an efficient production of target molecules entails energy and redox balance, in addition to carbon flow. The interplay between cofactor regeneration and heterologous metabolite overproduction in cyanobacteria is not fully explored. Here, we applied stoichiometric metabolic modelling of the cyanobacteriumSynechocystissp. PCC 6803, in order to investigate the optimality of energy and redox metabolism, while overproducing bio-alkenes - isobutene, isoprene, ethylene and 1-undecene. Our network-wide analysis indicates that the rate of NADP+ reduction, rather than ATP synthesis, controls ATP/NADPH ratio, and thereby chemical production. The simulation implies that energy and redox balance necessitates gluconeogenesis, and that acetate metabolism via phosphoketolase serves as an efficient carbon- and energy-recycling pathway. Furthermore, we show that an auxiliary pathway, composed of serine, one-carbon and glycine metabolism, supports cellular redox homeostasis and ATP cycling, and that theSynechocystismetabolism is controlled by few key reactions carrying a high flux. The study also revealed non-intuitive metabolic pathways to enhance isoprene, ethylene and 1-undecene production. We conclude that metabolism of ATP and NAD(P)H is entwined with carbon and nitrogen metabolism, and cannot be assessed in isolation. We envision that the presented here in-depth metabolic analysis will guide the a priori design ofSynechocystisas a host strain for an efficient manufacturing of target products.