bluuebunny/crossref_metadata_2025_split huggingface dataset:
3D modeling of CpG DNA binding with matrix lumican shows leucine-rich repeat motif involvement as in TLR9- CpG DNA interactions
Authors: Choi Tansol , Maiti George , Chakravarti Shukti 
Published: August 2023

AbstractLumican is an extracellular matrix proteoglycan, known to regulate toll-like receptor (TLR) signaling in innate immune cells. In experimental settings, lumican suppresses TLR9 signaling by binding to, and sequestering its synthetic ligand, CpG-DNA, in non-signal permissive endosomes. However, the molecular details of lumican interactions with CpG-DNA are obscure. Here, the 3-D structure of the 22 base-long CpG-DNA (CpG ODN_2395) bound to lumican or TLR9 were modeled using homology modeling and docking methods. Some of the TLR9-CpG ODN_2395 features predicted by our model are consistent with the previously reported TLR9-CpG DNA crystal structure, substantiating our current analysis. Our modeling indicated a smaller buried surface area for lumican-CpG ODN_2395 (1803 A2) compared to that of TLR9-CpG ODN_2395 (2094 A2), implying a potentially lower binding strength for lumican and CpG-DNA than TLR9 and CpG-DNA. The docking analysis identified 32 amino acids in lumican LRR1-11 interacting with CpG ODN_2395, primarily through hydrogen bonding, salt-bridges and hydrophobic interactions. Our study provides molecular insights into lumican and CpG-DNA interactions that may lead to molecular targets for modulating TLR9 mediated inflammation and autoimmunity.
Segment Anything for Microscopy
Authors: Archit Anwai , Nair Sushmita , Khalid Nabeel , Hilt Paul , Rajashekar Vikas , Freitag Marei , Gupta Sagnik , Dengel Andreas , Ahmed Sheraz , Pape Constantin 
Published: August 2023

AbstractWe present Segment Anything for Microscopy, a tool for interactive and automatic segmentation and tracking of objects in multi-dimensional microscopy data. Our method is based on Segment Anything, a vision foundation model for image segmentation. We extend it by training specialized models for microscopy data that significantly improve segmentation quality for a wide range of imaging conditions. We also implement annotation tools for interactive (volumetric) segmentation and tracking, that speed up data annotation significantly compared to established tools. Our work constitutes the first application of vision foundation models to microscopy, laying the groundwork for solving image analysis problems in these domains with a small set of powerful deep learning architectures.
Prospective Fecal Microbiomics Biomarkers for Chronic Wasting Disease
Authors: Didier Adam , Bourner Maureen , Kleks Guy , Zolty Avihai , Kumar Brajendra , Nichols Tracy , Durynski Karie , Bender Susan , Gibison Michelle , Murphy Lisa , Ellis Julie C. , Dong Dawei W. , Kashina Anna 
Published: August 2023

AbstractChronic wasting disease (CWD) is a naturally occurring prion disease in cervids that has been rapidly proliferating in the US. Here we investigated a potential link between CWD infection and gut microbiome by analyzing 50 fecal samples obtained from CWD-positive animals of different sexes from various regions in the US, compared to 50 CWD-negative controls using high throughput sequencing of the 16S ribosomal RNA and targeted metabolomics. Our analysis reveals promising trends in the gut microbiota that could potentially be CWD-dependent, including several bacterial taxa at each rank level, as well as taxa pairs, that can differentiate between CWD-negative and CWD-positive deer. At each rank level, these taxa and taxa pairs could facilitate identification of around 70% of both the CWD-negative and the CWD-positive samples. Our results provide a potential tool for diagnostics and surveillance of CWD in the wild, as well as conceptual advances in our understanding of the disease.ImportanceThis is a comprehensive study that tests the connection between the composition of the gut microbiome in deer in response to Chronic Wasting Disease (CWD). We analyzed 50 fecal samples obtained from CWD-positive animals compared to 50 CWD-negative controls to identify CWD-dependent changes in the gut microbiome, matched with the analysis of fecal metabolites. Our results show promising trends suggesting that fecal microbial composition can directly correspond to CWD disease status. These results point to microbial composition of the feces as a potential tool for diagnostics and surveillance of CWD in the wild, including non-invasive CWD detection in asymptomatic deer and deer habitats, and enable conceptual advances in our understanding of the disease.
Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms
Authors: Lai Louis Tung Faat , Balaraman Jayashree , Zhou Fei , Matthies Doreen 
Published: August 2023

AbstractMagnesium ions (Mg2+) play an essential role in cellular physiology. In mitochondria, protein and ATP synthesis and various metabolic pathways are directly regulated by Mg2+. MRS2, a magnesium channel located in the inner mitochondrial membrane, mediates the influx of Mg2+into the mitochondrial matrix and regulates Mg2+homeostasis. Knockdown of MRS2 in human cells leads to reduced uptake of Mg2+into mitochondria and disruption of the mitochondrial metabolism. Despite the importance of MRS2, the Mg2+translocation and regulation mechanisms of MRS2 are still unclear. Here, using cryo-EM we determined the structure of human MRS2 in the presence and absence of Mg2+at 2.8 Å and 3.3 Å, respectively. From the homo-pentameric structures, we identified R332 and M336 as major gating residues, which were then tested using mutagenesis and two cellular divalent ion uptake assays. A network of hydrogen bonds was found connecting the gating residue R332 to the soluble domain, potentially regulating the gate. Two Mg2+-binding sites were identified in the MRS2 soluble domain, distinct from the two sites previously reported in CorA, a homolog of MRS2 in prokaryotes. Altogether, this study provides the molecular basis for understanding the Mg2+translocation and regulatory mechanisms of MRS2.
Human Immunodeficiency Virus 1 Capsid Uncoating in the Nucleus Progresses Through Defect Formation in the Capsid Lattice
Authors: Gifford Levi B. , Melikyan Gregory B. 
Published: August 2023

AbstractThe HIV-1 core consists of a cone-shaped capsid shell made of ∼250 capsid protein (CA) hexamers and 12 pentamers encapsulating the viral genome. HIV-1 capsid disassembly, referred to as uncoating, is a highly regulated process that is important for productive infection, however, the location, timing, and regulation of uncoating remain controversial. Here, we employ amber codon suppression to directly label CA and visualize capsid trafficking and uncoating in live cells. In addition to direct CA labeling, a fluid phase fluorescent probe is incorporated into the viral core to detect the formation of small defects in the capsid lattice. This double-labeling strategy does not significantly impact HIV-1 infectivity, maturation, nuclear import, or capsid stability. Single virus tracking reveals nuclear import of intact cores defined as complexes containing both the fluid phase marker and robust CA signal. Subsequent uncoating of HIV-1 cores in the nucleus is manifested by a sequential loss of both fluorescent markers. This two-step uncoating – release of the core content marker followed by loss of CA – is observed in different cells, including a macrophage line. Importantly, the lag between the two steps of uncoating (∼30 min) appears independent of the cell type and is much longer than upon uncoating of cell-free viruses. These data suggest that HIV- 1 uncoating in the nucleus is initiated through a localized defect in the capsid lattice that precedes a global loss of CA. Our results imply that intact HIV-1 cores enter the cell nucleus and uncoat in a stepwise fashion, before integrating into the host genome.
Hypothetical geneRv0495cregulates redox homeostasis inMycobacterium tuberculosis
Authors: Pal Rahul , Talwar Sakshi , Pandey Manitosh , Nain Vaibhav , Sharma Taruna , Tyagi Shaifali , Barik Vishawjeet , Chaudhary Shweta , Gupta Sonu Kumar , Kumar Yashwant , Nanda Ranjan , Singhal Amit , Pandey Amit Kumar 
Published: August 2023

AbstractMycobacterium tuberculosis(Mtb) has evolved sophisticated surveillance mechanisms to regulate and neutralize redox imbalances and associated lethal consequences. Failing this, the accumulated ROS induces toxicity by oxidizing a variety of biological molecules including proteins, nucleic acids and lipids. In the present study we identified Mtb’sRv0495cgene as an important regulator of oxidized cytosolic environment. Compared to wild type Mtb strain lackingthe Rv0495cgene, ΔRv0495c, had increased ROS and NAD+/NADH ratio creating a highly oxidized intracellular environment. ΔRv0495cstrain demonstrated slow growth phenotype underin vitroandex-vivogrowth conditions and demonstrated enhanced susceptibility to drugs, oxidative, nitrosative and hypoxic growth conditions. In addition, the increase in the superoxide radicals triggered a Fenton-like reaction rendering the ΔRv0495csusceptible to free iron. The increase in the intracellular ROS levels of the ΔRv0495cwas further corroborated by an increase in the expression of proteins involved in antioxidant defense and enhanced ROS-mediated oxidation and degradation of mycobacterial lipids. This superoxide-induced lipid degradation resulted in altered colony morphology and loss of membrane integrity in the ΔRv0495c. Surprisingly, despite showing a growth defect phenotype in anex-vivomacrophage infection model, the absence of theRv0495cgene in Mtb enhanced the pathogenicity and augmented the ability of the Mtb to grow inside the host. Gene expression analysis revealed a Rv0495c mediated immunomodulation of the host controls inflammation and helps creates a favorable niche for long-term survival of Mtb inside the host. In summary, the current study underscores the fact that the truce in the war between the host and the pathogen favors long-term disease persistence in tuberculosis. We believe targeting Rv0495c could potentially be explored as a strategy to potentiate the current anti-TB regimen.
Gate keeping the sebaceous gland
Authors: Sachdeva Suveer , Ahmed Araz , Proctor Gordon , Miletich Isabelle 
Published: August 2023

AbstractSebaceous gland (SG) secretions are pivotal to skin and eye health. At the SG-epidermis confluence is an overlooked epidermal collar we named the follicular epidermis (FE). Here, we show that the FE is similar among different SG types and contains unique Axin2+ stem cells in a niche at its basal FE-perpendicular flexure (FE-PF). Lineage tracing and ablation assays demonstrate Axin2+ cells as integral for FE homeostasis. Wnt-secretion arrest experiments resulted in FE-obstruction via hyperproliferation and inhibited differentiation inferring FE-PF Axin2+ cells are Wnt-producers maintaining FE-patency. Upon constitutive Axin2+ cell Wnt signalling, FE-PF-specific cell proliferation with early-stage signs of malignancy formed alongside a keratin-plugging FE-obstruction type. While keratin-based obstructions are recognized, inhibited differentiation obstructions are not, which suggests a one-size-fits-all therapeutic approach is not optimal. We offer a molecular identification toolkit to aid anti-obstruction advances in dermatology/ophthalmology and highlight the FE-PF as a skin tumorigenic site.SummaryThis work characterises a novel site in the skin, it’s stem cells and niche, a site prone to cancer. Obstructions can occur at this site by two mechanisms, one of which is novel, bringing into question current therapy and prompting a rethink of disease in dermatology and ophthalmology to account for this novel site.Graphical Abstract
Real-time identification of epistatic interactions in SARS-CoV-2 from large genome collections
Authors: Innocenti Gabriel , Galardini Marco 
Published: August 2023

AbstractThe emergence and rapid spread of the SARS-CoV-2 virus has highlighted the importance of genomic epidemiology in understanding the evolution of pathogens and for guiding public health interventions. In particular, the Omicron variant underscored the role of epistasis in the evolution of lineages with both higher infectivity and immune escape, and therefore the necessity to update surveillance pipelines to detect them as soon as they emerge. In this study we applied a method based on mutual information (MI) between positions in a multiple sequence alignment (MSA), which is capable of scaling up to millions of samples. We showed how it could reliably predict known experimentally validated epistatic interactions, even when using as little as 10,000 sequences, which opens the possibility of making it a near real-time prediction system. We tested this possibility by modifying the method to account for sample collection date and applied it retrospectively to MSAs for each month between March 2020 and March 2023. We could detect a cornerstone epistatic interaction in the Spike protein between codons 498 and 501 as soon as 6 samples with a double mutation were present in the dataset, thus demonstrating the method’s sensitivity. Lastly we provide examples of predicted interactions between genes, which are harder to test experimentally and therefore more likely to be overlooked. This method could become part of continuous surveillance systems tracking present and future pathogen outbreaks.
DEBBIES to compare life history strategies across ectotherms
Authors: Smallegange Isabel M. , Lucas Sol 
Published: August 2023

AbstractDemographic models are used to explore how life history traits structure life history strategies across species. This study presents the DEBBIES dataset that contains estimates of eight life history traits (length at birth, puberty and maximum length, maximum reproduction rate, fraction energy allocated to respiration versus reproduction, von Bertalanffy growth rate, mortality rates) for 185 ectotherm species. The dataset can be used to parameterise dynamic energy budget integral projection models (DEB-IPMs) to calculate key demographic quantities like population growth rate and demographic resilience, but also link to conservation status or biogeographical characteristics. Our technical validation shows a satisfactory agreement between observed and predicted longevity, generation time, age at maturity across all species. Compared to existing datasets, DEBBIES accommodates (i) easy cross-taxonomical comparisons, (ii) many data-deficient species, and (iii) population forecasts to novel conditions because DEB-IPMs include a mechanistic description of the trade-off between growth and reproduction. This dataset has the potential for biologists to unlock general predictions on ectotherm population responses from only a few key life history traits.
SC2Spa: a deep learning based approach to map transcriptome to spatial origins at cellular resolution
Authors: Liao Linbu , Madan Esha , Palma António M. , Kim Hyobin , Kumar Amit , Bhoopathi Praveen , Winn Robert , Trevino Jose , Fisher Paul , Brakebusch Cord Herbert , Gogna Rajan , Won Kyoung Jae 
Published: August 2023

AbstractIntegrating single cell RNAseq (scRNAseq) and spatial transcriptomics (ST) data is still challenging especially when the spatial resolution is poor. For cellular resolution spatial mapping, we have developed deep learning-based SC2Spa to learn the intricate spatial mapping rules from the transcriptome to its location from ST data. Benchmarking tests show that SC2Spa uniquely recapitulates tissue architecture from scRNAseq. SC2Spa successfully mapped scRNAseq even to various low resolution Visium data. SC2Spa identified spatially variable genes and suggested negative regulatory relationships between genes. SC2Spa armored with deep learning provides a new way to map the transcriptome to its spatial location and perform subsequent analyses.
Source tracing ofLeishmania donovaniin emerging foci of visceral leishmaniasis in West Nepal
Authors: Monsieurs Pieter , Cloots Kristien , Uranw Surendra , Banjara Megha Raj , Ghimire Prakash , Burza Sakib , Hasker Epco , Dujardin Jean-Claude , Domagalska Malgorzata Anna 
Published: August 2023

AbstractWe sequencedLeishmania donovanigenomes in blood samples collected in emerging foci of Visceral Leishmaniasis, in West Nepal. We detected lineages which are very different from pre-elimination main parasite population: a new lineage and a rare one previously reported once in East Nepal. We highlight the need for genomic surveillance.
A mathematical theory of relational generalization in transitive inference
Authors: Lippl Samuel , Kay Kenneth , Jensen Greg , Ferrera Vincent P. , Abbott L.F. 
Published: August 2023

AbstractHumans and animals routinely infer relations between different items or events and generalize these relations to novel combinations of items. This allows them to respond appropriately to radically novel circumstances and is fundamental to advanced cognition. However, how learning systems (including the brain) can implement the necessary inductive biases has been unclear. Here we investigated transitive inference (TI), a classic relational task paradigm in which subjects must learn a relation (A>BandB>C) and generalize it to new combinations of items (A>C). Through mathematical analysis, we found that a broad range of biologically relevant learning models (e.g. gradient flow or ridge regression) perform TI successfully and recapitulate signature behavioral patterns long observed in living subjects. First, we found that models with item-wise additive representations automatically encode transitive relations. Second, for more general representations, a single scalar “conjunctivity factor” determines model behavior on TI and, further, the principle of norm minimization (a standard statistical inductive bias) enables models with fixed, partly conjunctive representations to generalize transitively. Finally, neural networks in the “rich regime,” which enables representation learning and has been found to improve generalization, unexpectedly show poor generalization and anomalous behavior. We find that such networks implement a form of norm minimization (over hidden weights) that yields a local encoding mechanism lacking transitivity. Our findings show how minimal statistical learning principles give rise to a classical relational inductive bias (transitivity), explain empirically observed behaviors, and establish a formal approach to understanding the neural basis of relational abstraction.
A chromosome-scale assembly for ‘d’Anjou’ pear
Authors: Yocca Alan , Akinyuwa Mary , Bailey Nick , Cliver Brannan , Estes Harrison , Guillemette Abigail , Hasannin Omar , Hutchison Jennifer , Jenkins Wren , Kaur Ishveen , Khanna Risheek Rahul , Loftin Madelene , Lopes Lauren , Moore-Pollard Erika , Olofintila Oluwakemisola , Oyebode Gideon Oluwaseye , Patel Jinesh , Thapa Parbati , Waldinger Martin , Zhang Jie , Zhang Qiong , Goertzen Leslie , Carey Sarah B. , Hargarten Heidi , Mattheis James , Zhang Huiting , Jones Teresa , Boston LoriBeth , Grimwood Jane , Ficklin Stephen , Honaas Loren , Harkess Alex 
Published: August 2023

AbstractCultivated pear consists of severalPyrusspecies withP. communis(European pear) representing a large fraction of worldwide production. As a relatively recently domesticated crop and perennial tree, pear can benefit from genome-assisted breeding. Additionally, comparative genomics within Rosaceae promises greater understanding of evolution within this economically important family. Here, we generate a fully-phased chromosome-scale genome assembly ofP. communiscv. ‘d’Anjou’. Using PacBio HiFi and Dovetail Omni-C reads, the genome is resolved into the expected 17 chromosomes, with each haplotype totalling nearly 540 Megabases and a contig N50 of nearly 14 Mb. Both haplotypes are highly syntenic to each other, and to theMalus domestica‘Honeycrisp’ apple genome. Nearly 45,000 genes were annotated in each haplotype, over 90% of which have direct RNA-seq expression evidence. We detect signatures of the known whole-genome duplication shared between apple and pear, and we estimate 57% of d’Anjou genes are retained in duplicate derived from this event. This genome highlights the value of generating phased diploid assemblies for recovering the full allelic complement in highly heterozygous crop species.
C5aR1 antagonism suppresses inflammatory glial gene expression and alters cellular signaling in an aggressive Alzheimer’s model
Authors: Schartz Nicole D. , Liang Heidi Y. , Carvalho Klebea , Chu Shu-Hui , Mendoza-Arvilla Adrian , Petrisko Tiffany J. , Gomez-Arboledas Angela , Mortazavi Ali , Tenner Andrea J. 
Published: August 2023

AbstractAlzheimer’s disease (AD) is the leading cause of dementia in older adults, and the need for effective, sustainable therapeutic targets is imperative. Pharmacologic inhibition of C5aR1 reduces plaque load, gliosis and memory deficits in animal models. However, the cellular basis underlying this neuroprotection and which processes were the consequence of amyloid reduction vs alteration of the response to amyloid were unclear. In the Arctic model, the C5aR1 antagonist PMX205 did not reduce plaque load, but deficits in short-term memory in female mice were prevented. Hippocampal single cell and single nucleus RNA-seq clusters revealed C5aR1 dependent and independent gene expression and cell-cell communication. Microglial clusters containing neurotoxic disease-associated microglial genes were robustly upregulated in Arctic mice and drastically reduced with PMX205 treatment, while genes in microglia clusters that were overrepresented in the Arctic-PMX205 vs Arctic group were associated with synapse organization and transmission and learning. PMX205 treatment also reduced some A-1 astrocyte genes. In spite of changes in transcript levels, overall protein levels of some reactive glial markers were relatively unchanged by C5aR1 antagonism, as were clusters associated with protective responses to injury. C5aR1 inhibition promoted signaling pathways associated with cell growth and repair, such as TGFβ and FGF, in Arctic mice, while suppressing inflammatory pathways including PROS, Pecam1, and EPHA. In conclusion, pharmacologic C5aR1 inhibition prevents cognitive loss, limits microglial polarization to a detrimental inflammatory state and permits neuroprotective responses, as well as leaving protective functions of complement intact, making C5aR1 antagonism an attractive therapeutic strategy for individuals with AD.One Sentence SummaryPharmacologic inhibition of C5aR1 suppresses disease-enhancing processes and promotes disease mitigating pathways in an aggressive model of Alzheimer’s disease.