bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integration of single-cell multiomic measurements across disease states with genetics identifies mechanisms of beta cell dysfunction in type 2 diabetes
Authors: Wang Gaowei , Chiou Joshua , Zeng Chun , Miller Michael , Matta Ileana , Han Jee Yun , Kadakia Nikita , Okino Mei-Lin , Beebe Elisha , Mallick Medhavi , Camunas-Soler Joan , Santos Theodore dos , Dai Xiao-Qing , Ellis Cara , Hang Yan , Kim Seung K. , MacDonald Patrick E. , Kandeel Fouad R. , Preissl Sebastian , Gaulton Kyle J , Sander Maike 
Published: January 2023

AbstractAltered function and gene regulation of pancreatic islet beta cells is a hallmark of type 2 diabetes (T2D), but a comprehensive understanding of mechanisms driving T2D is still missing. Here we integrate information from measurements of chromatin activity, gene expression and function in single beta cells with genetic association data to identify disease-causal gene regulatory changes in T2D. Using machine learning on chromatin accessibility data from 34 non-diabetic, pre-T2D and T2D donors, we robustly identify two transcriptionally and functionally distinct beta cell subtypes that undergo an abundance shift in T2D. Subtype-defining active chromatin is enriched for T2D risk variants, suggesting a causal contribution of subtype identity to T2D. Both subtypes exhibit activation of a stress-response transcriptional program and functional impairment in T2D, which is likely induced by the T2D-associated metabolic environment. Our findings demonstrate the power of multimodal single-cell measurements combined with machine learning for identifying mechanisms of complex diseases.
Additive energetic contributions of multiple peptide positions determine the relative promiscuity of viral and human sequences for PDZ domain targets
Authors: Tahti Elise F. , Blount Jadon M. , Jackson Sophie N. , Gao Melody , Gill Nicholas P. , Smith Sarah N. , Pederson Nick J. , Rumph Simone N. , Struyvenberg Sarah A. , Mackley Iain G. P. , Madden Dean R. , Amacher Jeanine F. 
Published: January 2023

AbstractProtein-protein interactions that include recognition of short sequences of amino acids, or peptides, are critical in cellular processes. Protein-peptide interaction surface areas are relatively small and shallow, and there are often overlapping specificities in families of peptide-binding domains. Therefore, dissecting selectivity determinants can be challenging. PDZ domains are an example of a peptide-binding domain located in several intracellular signaling and trafficking pathways, which form interactions critical for the regulation of receptor endocytic trafficking, tight junction formation, organization of supramolecular complexes in neurons, and other biological systems. These domains are also directly targeted by pathogens, and a hallmark of many oncogenic viral proteins is a PDZ-binding motif. However, amidst sequences that target PDZ domains, there is a wide spectrum in relative promiscuity. For example, the viral HPV16 E6 oncoprotein recognizes over double the number of PDZ domain-containing proteins as the cystic fibrosis transmembrane conductance regulator (CFTR) in the cell, despite similar PDZ targeting-sequences and identical motif residues. Here, we determine binding affinities for PDZ domains known to bind either HPV16 E6 alone or both CFTR and HPV16 E6, using peptides matching WT and hybrid sequences. We also use energy minimization to model PDZ-peptide complexes and use sequence analyses to investigate this difference. We find that while the majority of single mutations had a marginal effect on overall affinity, the additive effect on the free energy of binding accurately describes the selectivity observed. Taken together, our results describe how complex and differing PDZ interactomes can be programmed in the cell.
Autophagy collaborates with apoptosis pathways to control myelination specificity and function
Authors: Zhang Tingxin , Bae Han-Gyu , Bhambri Aksheev , Zhang Yihe , Barbosa Daniela , Xue Jumin , Wazir Sabeen , Mulinyawe Sara B. , Kim Jun Hee , Sun Lu O. 
Published: January 2023

SUMMARYOligodendrocytes are the sole myelin producing cells in the central nervous system. Oligodendrocyte numbers are tightly controlled across diverse brain regions to match local axon type and number, but the underlying mechanisms and functional significance remain unclear. Here, we show that autophagy, an evolutionarily conserved cellular process that promotes cell survival under canonical settings, elicits premyelinating oligodendrocyte apoptosis during development and regulates critical aspects of nerve pulse propagation. Autophagy flux is increased in premyelinating oligodendrocytes, and its genetic blockage causes ectopic oligodendrocyte survival throughout the entire brain. Autophagy acts in the TFEB-Bax/Bak pathway and elevatesPUMAmRNA levels to trigger premyelinating oligodendrocyte apoptosis cell-autonomously. Autophagy continuously functions in the myelinating oligodendrocytes to limit myelin sheath numbers and fine-tune nerve pulse propagation. Our results providein vivoevidence showing that autophagy promotes apoptosis in mammalian cells under physiological conditions and reveal key intrinsic mechanisms governing oligodendrocyte number.HIGHLIGHTSAutophagy flux increases in the premyelinating and myelinating oligodendrocytesAutophagy promotes premyelinating oligodendrocyte (pre-OL) apoptosis to control myelination location and timingAutophagy acts in the TFEB-PUMA-Bax/Bak pathway and elevatesPUMAmRNA levels to determine pre-OL fateAutophagy continuously functions in the myelinating oligodendrocytes to limit myelin sheath thickness and finetune nerve pulse propagation
New mega dataset combined with deep neural network makes a progress in predicting impact of mutation on protein stability
Authors: Pak Marina A , Dovidchenko Nikita V , Sharma Satyarth Mishra , Ivankov Dmitry N 
Published: January 2023

AbstractPrediction of proteins stability change (ΔΔG) due to single mutation is important for biotechnology, medicine, and our understanding of physics underlying protein folding. Despite the recent tremendous success in 3D protein structure prediction, the apparently simpler problem of predicting the effect of mutations on protein stability has been hampered by the low amount of experimental data. With the recent high-throughput measurements of mutational effects in ‘mega’ experiment for ~850,000 mutations [Tsuboyama et al., bioRxiv, 2022] it becomes possible to apply the state-of-the-art deep learning methods. Here we explore the ability of ESM2 deep neural network architecture with added Light Attention mechanism to predict the change of protein stability due to single mutations. The resulting method ABYSSAL predicts well the data from the ‘mega’ experiment (Pearson correlation 0.85) while the prediction of ΔΔG values from previous experiments is more modest (Pearson correlation 0.50). ABYSSAL also shows a perfect satisfaction of the antisymmetry property. The ABYSSAL training demonstrated that the dataset should contain around ~100,000 data points for taking advantage of the state-of-the-art deep learning methods. Overall, our study shows great perspectives for developing the deep learning ΔΔG predictors.
F-actin and Myosin F control apicoplast elongation dynamics which drive apicoplast-centrosome association inToxoplasma gondii
Authors: Devarakonda Parvathi Madhavi , Sarmiento Valeria , Heaslip Aoife T. 
Published: January 2023

ABSTRACTToxoplasma gondiicontains an essential plastid organelle called the apicoplast that is necessary for fatty acid, isoprenoid, and heme synthesis. Perturbations affecting apicoplast function or inheritance lead to parasite death. The apicoplast is a single copy organelle and therefore must be divided so that each daughter parasite inherits an apicoplast during cell division. In this study we identify new roles for F-actin and an unconventional myosin motor, TgMyoF, in this process. First, loss of TgMyoF and actin lead to an accumulation of apicoplast vesicles in the cytosol indicating a role for this actomyosin system in apicoplast protein trafficking or morphological integrity of the organelle. Second, live cell imaging reveals that during division the apicoplast is highly dynamic, exhibiting branched, U-shaped and linear morphologies that are dependent on TgMyoF and actin. In parasites where movement was inhibited by the depletion of TgMyoF, the apicoplast fails to associate with the parasite centrosomes. Thus, this study provides crucial new insight into mechanisms controlling apicoplast-centrosome association, a vital step in the apicoplast division cycle, which ensures that each daughter inherits a single apicoplast.
On the correspondence between the transcriptomic response of a compound and its effects on its targets
Authors: Engler Hart Chloe , Ence Daniel , Healey David , Domingo-Fernández Daniel 
Published: January 2023

AbstractBetter understanding the transcriptomic response produced by a compound perturbing its targets can shed light on the underlying biological processes regulated by the compound. However, establishing the relationship between the induced transcriptomic response and the target of a compound is non-trivial, partly because targets are rarely differentially expressed. Thus, connecting both modalities requires orthogonal information (e.g., pathway or functional information). Here, we present a comprehensive study aimed at exploring this relationship by leveraging thousands of transcriptomic experiments and target data for over 2,000 compounds. Firstly, we confirmed that compound-target information does not correlate as expected with the transcriptomic signatures induced by a compound. However, we demonstrate how the concordance between both modalities can be increased by connecting pathway and target information. Additionally, we investigated whether compounds that target the same proteins induce a similar transcriptomic response and conversely, whether compounds with similar transcriptomic responses share the same target proteins. While our findings suggest that this is generally not the case, we did observe that compounds with similar transcriptomic profiles are more likely to share at least one protein target, as well as common therapeutic applications. Lastly, we present a case scenario on a few compound pairs with high similarity to demonstrate how the relationship between both modalities can be exploited for mechanism of action deconvolution.
Arginine limitation causes a directed DNA sequence evolution response in colorectal cancer cells
Authors: Hsu Dennis J. , Gao Jenny , Yamaguchi Norihiro , Pinzaru Alexandra , Mandayam Nandan , Liberti Maria , Heissel Søren , Alwaseem Hanan , Tavazoie Saeed , Tavazoie Sohail F. 
Published: January 2023

AbstractUtilization of specific codons varies significantly across organisms. Cancer represents a model for understanding DNA sequence evolution and could reveal causal factors underlying codon evolution. We found that across human cancer, arginine codons are frequently mutated to other codons. Moreover, arginine restriction—a feature of tumor microenvironments—is sufficient to induce arginine codon-switching mutations in human colon cancer cells. Such DNA codon switching events encode mutant proteins with arginine residue substitutions. Mechanistically, arginine limitation caused rapid reduction of arginine transfer RNAs and the stalling of ribosomes over arginine codons. Such selective pressure against arginine codon translation induced a proteomic shift towards low arginine codon containing genes, including specific amino acid transporters, and caused mutational evolution away from arginine codons—reducing translational bottlenecks that occurred during arginine starvation. Thus, environmental availability of a specific amino acid can influence DNA sequence evolution away from its cognate codons and generate altered proteins.
Early infection response of the first trimester human placenta at single-cell scale
Authors: Hoo Regina , Ruiz-Morales Elias R. , Kelava Iva , Sancho-Serra Carmen , Mazzeo Cecilia Icoresi , Chelaghma Sara , Tuck Elizabeth , Predeus Alexander V. , Fernandez-Antoran David , Waller Ross F. , Lee Marcus , Vento-Tormo Roser 
Published: January 2023

AbstractPlacental infections are a major worldwide burden, particularly in developing countries. The placenta is a transient tissue located at the interface between the mother and the fetus. Some pathogens can access the placental barrier resulting in pathological transmission from mother to fetus, which may have a profound impact on the health of the developing fetus. Limited tissue accessibility, critical differences between humans and mice, and, until recently, lack of properin vitromodels, have hampered our understanding of the early placental response to pathogens. Here we use single-cell transcriptomics to describe the placental primary defence mechanisms against three pathogens that are known to cause fetal and maternal complications during pregnancy -Plasmodium falciparum, Listeria monocytogenesandToxoplasma gondii. We optimiseex vivoplacental explants of the first-trimester human placenta and show that trophoblasts (the epithelial-like cells of the placenta), and Hofbauer cells (placental macrophages) orchestrate a coordinated inflammatory response after 24 hours of infection. We show that hormone biosynthesis and transport are downregulated in the trophoblasts, suggesting that protective responses are promoted at the expense of decreasing other critical functions of the placenta, such as the endocrine production and the nourishment of the fetus. In addition, we pinpoint pathogen-specific effects in some placental lineages, including a strong mitochondrial alteration in the Hofbauer cells in response toT. gondii. Finally, we identify adaptive strategies and validate nutrient acquisition employed by theP. falciparumduring placental malaria infection. This study provides the first detailed cellular map of the first-trimester placenta upon infection and describes the early events that may lead to fetal and placental disorders if left unchecked.
Early life drought predicts components of adult body size in wild female baboons
Authors: Levy Emily J. , Lee Anna , Siodi I. Long’ida , Helmich Emma C. , McLean Emily M. , Malone Elise J. , Pickard Maggie J. , Ranjithkumar Riddhi , Tung Jenny , Archie Elizabeth A. , Alberts Susan C. 
Published: January 2023

AbstractObjectivesIn many taxa, adverse early-life environments are associated with reduced growth and smaller body size in adulthood. However, in wild primates, we know very little about whether, where, and to what degree trajectories are influenced by early adversity, or which types of early adversity matter most. Here, we use parallel-laser photogrammetry to assess inter-individual predictors of three measures of body size (leg length, forearm length, and shoulder-rump length) in a population of wild female baboons studied since birth.Materials and MethodsUsing >2,000 photogrammetric measurements of 127 females, we present a cross-sectional growth curve of wild female baboons (Papio cynocephalus) from juvenescence through adulthood. We then test whether females exposed to three important sources of early-life adversity - drought, maternal loss, or a cumulative measure of adversity – were smaller for their age than females who experienced less adversity. Using the ‘animal model’, we also test whether body size is heritable in this study population.ResultsProlonged early-life drought predicted shorter limbs but not shorter torsos (i.e., shoulder-rump lengths). Our other two measures of early-life adversity did not predict any variation in body size. Heritability estimates for body size measures were 36%-58%. Maternal effects accounted for 13%-22% of the variance in leg and forearm length, but no variance in torso length.DiscussionOur results suggest that baboon limbs, but not torsos, grow plastically in response to maternal effects and energetic early-life stress. Our results also reveal considerable heritability for all three body size measures in this study population.
Structural insights into ubiquitin chain cleavage byLegionellaovarian tumor deubiquitinases
Authors: Kang Sangwoo , Kim Gyuhee , Choi Minhyung , Jeong Minwoo , van der Heden van Noort Gerbrand J. , Roh Soung-Hun , Shin Donghyuk 
Published: January 2023

ABSTRACTAlthough ubiquitin is found only in eukaryotes, several pathogenic bacteria and viruses possess proteins that hinder the host ubiquitin system.Legionella, a gram-negative intracellular bacterium, possesses an ovarian tumor (OTU) family of deubiquitinases (Lot DUBs). Herein, we describe the molecular characteristics of Lot DUBs. We elucidated the structure of LotA OTU1 domain and revealed that entire Lot DUBs possess a characteristic extended helical lobe (EHL) that is not found in other OTU-DUBs. The structural topology of EHL is the same throughout the Lot family, and it provides an S1′ ubiquitin-binding site. Moreover, the catalytic triads of Lot DUBs resemble those of the A20-type OTU-DUBs. Furthermore, we revealed a unique mechanism by which LotA OTU domains cooperate together to distinguish the length of the chain and preferentially cleaves longer K48-linked polyubiquitin chains. The LotA OTU1 domain itself cleaves K6-linked ubiquitin chains, while it is also essential for assisting the cleavage of longer K48-linked polyubiquitin chains by the OTU2 domain. Thus, this study provides novel insights into the structure and mechanism of action of Lot DUBs.
Genomics of the “tumorigenes” clade of the familyRhizobiaceaeand description ofRhizobium rhododendrisp. nov.
Authors: Kuzmanović Nemanja , diCenzo George C. , Bunk Boyke , Spröer Cathrin , Frühling Anja , Neumann-Schaal Meina , Overmann Jörg , Smalla Kornelia 
Published: January 2023

AbstractTumorigenic members of the familyRhizobiaceae, known as agrobacteria, are responsible for crown and cane gall diseases of various agricultural crops worldwide. Tumorigenic agrobacteria are commonly found in the generaAgrobacterium,Allorhizobium, andRhizobium. In this study, we analyzed a distinct “tumorigenes” clade of the genusRhizobium, which includes the tumorigenic speciesRhizobium tumorigenes, as well as strains causing crown gall disease on rhododendron. Here, high quality, closed genomes of representatives of the “tumorigenes” clade were generated, followed by comparative genomic and phylogenomic analyses. Additionally, phenotypic characteristics of representatives of the “tumorigenes” clade were analyzed. Our results showed that the tumorigenic strains isolated from rhododendron represent a novel species of the genusRhizobiumfor which the nameRhizobium rhododendrisp. nov. is proposed. This species also includes additional strains originating from blueberry and Himalayan blackberry in USA, whose genome sequences were retrieved from GenBank. BothR. tumorigenesandR. rhododendricontain multipartite genomes, including a chromosome, putative chromids, and megaplasmids. Synteny and phylogenetic analyses indicated that a large putative chromid ofR. rhododendriresulted from the cointegration of an ancestral megaplasmid and two putative chromids, following its divergence fromR. tumorigenes. Moreover, gene clusters specific for both species of the “tumorigenes” clade were identified, and their biological functions and roles in ecological diversification ofR. rhododendriandR. tumorigeneswere predicted and discussed.
CAS12e (CASX2) CLEAVAGE OF CCR5: IMPACT OF GUIDE RNA LENGTH AND PAM SEQUENCE ON CLEAVAGE ACTIVITY
Authors: Armstrong David A. , Hudson Taylor R. , Hodge Christine A. , Hampton Thomas H. , Howell Alexandra L. , Hayden Matthew S. 
Published: January 2023

ABSTRACTCRISPR/Cas is under development as a therapeutic tool for the cleavage, excision, and/or modification of genes in eukaryotic cells. While much effort has focused on CRISPR/Cas fromStreptococcus pyogenes(SpCas9) andStaphylococcus aureus(SaCas9), alternative CRISPR systems have been identified using metagenomic datasets from non-pathogenic microbes, including previously unknown class 2 systems, adding to a diverse toolbox of gene editors. The Cas12e (CasX1, CasX2) endonucleases from non-pathogenic Deltaproteobacteria (DpeCas12e) and Planctomycetes (PlmCas12e) are more compact than SpCas9, have a more selective protospacer adjacent motif (PAM) requirement, and deliver a staggered cleavage cut with 5-7 base overhangs. We investigated varying guide RNA (spacer) lengths and alternative PAM sequences to determine optimal conditions for PlmCas12e cleavage of the cellular geneCCR5(CC-Chemokine receptor-5).CCR5encodes one of two chemokine coreceptors required by HIV-1 to infect target cells, and a mutation ofCCR5(delta-32) is responsible for HIV-1 resistance and reported cures following bone marrow transplantation. Consequently,CCR5has been an important target for gene editing utilizing CRISPR, TALENs, and ZFNs. We determined thatCCR5cleavage activity varied with the target site, guide RNA length, and the terminal nucleotide in the PAM sequence. Our analyses demonstrated a PlmCas12e PAM preference for purines (A, G) over pyrimidines (T, C) in the fourth position of the CasX2 PAM (TTCN). These analyses have contributed to a better understanding of CasX2 cleavage requirements and will position us more favorably to develop a therapeutic that creates the delta-32 mutation in theCCR5gene in hematopoietic stem cells.
Productivity determinants in the service industry: differences between high and low knowledge intensive sectors
Authors: Guevara-Rosero Grace , Carrión-Cauja Cristian , Simbaña-Landeta Lizbeth , Camino-Mogro Segundo 
Published: January 2023

PurposeThe service industry has become an important sector for the economic growth, particularly in developing countries. In this context, the aim of this article is to compare the productivity determinants across firms operating in low and high knowledge intensity service sectors (low knowledge intensive sectors (LKIS) and high knowledge intensive sectors (HKIS)) in Ecuador.Design/methodology/approachThe authors use a two-step estimation method. The firm productivity is estimated in the first step and the productivity determinants in the second step. To achieve the objective, the authors use an unbalanced panel database on the financial statements from formal Ecuadorian firms for the period 2007–2018.FindingsThe authors’ results show that LKIS firms are slightly more labor-intensive compared to HKIS firms. Productivity determinants are similar across HKIS and LKIS firms, except for exports and market concentration. HKIS firms are more productive when the competition level is low, indicating that higher market power is associated with higher productivity. The influence of taxes on productivity depends on firm size. Small and medium-sized firms are more negatively affected than large firms.Practical implicationsTaxes should be designed considering the size of the companies, since these could affect their productivity. Thus, lower taxes to small and medium firms may reduce firm size inequality. In addition, the acquired knowledge of HKIS should be spread to other firms becoming a positive externality instead of an entry barrier.Originality/valueDespite the productivity determinants of the service sector has been recently explored, in contrast to the manufacturing sector, individual and contextual determinants are less identified. In this paper the authors use a large set of firm characteristics that might affect productivity in service firms.