bluuebunny/crossref_metadata_2025_split huggingface dataset:
SOD1is a synthetic lethal target inPPM1D-mutant leukemia cells
Authors: Zhang Linda , Hsu Joanne I. , Braekeleer Etienne D. , Chen Chun-Wei , Patel Tajhal D. , Martell Alejandra G. , Guzman Anna G. , Wohlan Katharina , Waldvogel Sarah M. , Urya Hidetaka , Tovy Ayala , Callen Elsa , Murdaugh Rebecca , Richard Rosemary , Jansen Sandra , Vissers Lisenka , de Vries Bert B.A. , Nussenzweig Andre , Huang Shixia , Coarfa Cristian , Anastas Jamie N. , Takahashi Koichi , Vassiliou George , Goodell Margaret A. 
Published: September 2023

AbstractThe DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase, Mg2+/Mn2+ dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications ofPPM1Dare found across several human cancers making it a relevant pharmacologic target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies ofPPM1D,uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress inPPM1D-mutant cells. Altogether, our results demonstrate the protective role of SOD1 against oxidative stress inPPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy againstPPM1D-mutant cancers.
Cryo-EM structures of Tau filaments from the brains of mice transgenic for human mutant P301S Tau
Authors: Schweighauser Manuel , Murzin Alexey G. , Macdonald Jennifer , Lavenir Isabelle L. , Crowther R. Anthony , Scheres Sjors H.W. , Goedert Michel 
Published: September 2023

ABSTRACTMice transgenic for human mutant P301S tau are widely used as models for human tauopathies. They develop neurodegeneration and abundant filamentous inclusions made of human mutant four-repeat tau. Here we used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments from the brains of Tg2541 and PS19 mice. Both lines express human P301S tau (0N4R for Tg2541 and 1N4R for PS19) on mixed genetic backgrounds and downstream of different promoters (murineThy1for Tg2541 and murinePrnpfor PS19). The structures of tau filaments from Tg2541 and PS19 mice differ from each other and those of tau filaments from human brains. However, they share a substructure at the junction of repeats 2 and 3, which comprises residues I297-V312 of tau and includes the P301S mutation. The filament core from the brainstem of Tg2541 mice consists of residues K274-H329 of tau and two disconnected protein densities. Two non-proteinaceous densities are also in evidence. The filament core from the cerebral cortex of line PS19 extends from residues G271-P364 of tau. One strong non-proteinaceous density is also present. Unlike the tau filaments from human brains, the sequences following repeat 4 are missing from the cores of tau filaments from the brains of Tg2541 and PS19 mice.
A Two-Step Activation Mechanism Enables Mast Cells to Differentiate their Response between Extracellular and Invasive Enterobacterial Infection
Authors: von Beek Christopher , Fahlgren Anna , Geiser Petra , Di Martino Maria Letizia , Lindahl Otto , Prensa Grisna I. , Mendez-Enriquez Erika , Eriksson Jens , Hallgren Jenny , Fällman Maria , Pejler Gunnar , Sellin Mikael E. 
Published: September 2023

AbstractMast cells (MCs) localize to mucosal tissues and contribute to innate immune defenses against infection. How MCs sense, differentiate between, and respond to bacterial pathogens remains a topic of ongoing debate. Using the prototype enteropathogenSalmonellaTyphimurium (S.Tm) and other closely related enterobacteria, we here demonstrate that MCs can regulate their cytokine secretion response to distinguish between extracellular and invasive bacterial infection. Tissue-invasiveS.Tm and MCs colocalize in theSalmonella-infected mouse gut. Toll-like Receptor 4 (TLR4) sensing of extracellularS.Tm, or pure LPS, causes a slow and modest induction of MC cytokine transcripts and proteins, including IL-6, IL-13, and TNF. By contrast, type-III-secretion-system-1 (TTSS-1)-dependentS.Tm invasion of both mouse and human MCs triggers rapid and potent inflammatory gene expression and >100-fold elevated cytokine secretion. TheS.Tm TTSS-1 effectors SopB, SopE, and SopE2 here elicit a second activation signal, including Akt phosphorylation downstream of effector translocation, which combines with TLR activation to promote the full-blown MC response. Supernatants fromS.Tm-infected MCs boost macrophage survival and maturation from bone-marrow progenitors. Taken together, this study shows that MCs can differentiate between extracellular and host-cell invasive enterobacteria via a two-step activation mechanism and tune their inflammatory output accordingly.
In-situ Single-Molecule Investigations of the Impacts of Biochemical Perturbations on Conformational Intermediates of Monomeric α-Synuclein
Authors: Huang Wenmao , Le Shimin , Yao Mingxi , Shi Yi , Yan Jie 
Published: September 2023

Abstractα-Synuclein aggregation is a common trait in synucleinopathies, including Parkinson’s disease. Being an unstructured protein, α-synuclein exists in several distinct conformational intermediates, contributing to both its function and pathogenesis. However, the regulation of these monomer conformations by biochemical factors and potential drugs has remained elusive. In this study, we devised an in-situ single-molecule manipulation approach to pinpoint kinetically stable conformational intermediates of monomeric α-synuclein and explore the effects of various biochemical factors and drugs. We uncovered a partially folded conformation located in the non-amyloid-β component (NAC) region of monomeric α-synuclein, which is regulated by preNAC region. This conformational intermediate is sensitive to biochemical perturbations and small-molecule drugs that influencing α-synuclein’s aggregation tendency. Our findings reveal that this partially folded intermediate may play a role in α-synuclein aggregation, offering fresh perspectives for potential treatments aimed at the initial stage of higher-order α-synuclein aggregation. The single-molecule approach developed here can be broadly applied to the study of disease-related intrinsically disordered proteins.
Transcriptome-wide meta-analysis of codon usage inEscherichia coli
Authors: Sutradhar Anima , Pointon Jonathan , Lennon Christopher , Stracquadanio Giovanni 
Published: September 2023

AbstractThe preference for synonymous codons, termed codon usage bias (CUB), is a fundamental feature of coding sequences, with distinct preferences being observed across species, genomes and genes. Accurately quantifying codon usage frequencies is useful for a range of applications, from guiding mRNA vaccine design, to elucidating protein folding and uncovering co-evolutionary relationships. However, current methods are either based on a single genome assembly, lack functional stratification, or are extremely outdated. To address this, we adopted a data-driven approach and developed Codon Usage Bias estimation from RNA-sequencing data (CUBSEQ), a fully automatic meta-analysis pipeline to estimate CUB at the trascriptome-level and for gene panels. Here, we used CUBSEQ to perform, to our knowledge, the largest and most comprehensive CUB analysis of the transcriptome and highly expressed genes inEscherichia coli, using RNA sequencing data from 6,763 samples across 72 strains. By capturing sequence variants of these genes through variant calls, we constructed a per-sample representation of theE. colitranscriptome revealing a rich mutational landscape. We then identified a set of 81 highly expressed genes with consistent expression patterns across strains, sample library size and experimental conditions, and found significant differences in CUB compared to transcriptome-wide genes and alternative codon usage tables. Finally, we found codons with a high relative frequency were often associated with a larger repertoire of isoaccepting tRNAs and not necessarily high tRNA abundance.
The Alzheimer’s disease risk gene CD2AP functions in dendritic spines by remodelling F-actin
Authors: Mirfakhar Farzaneh S. , Castanheira Jorge , Domingues Raquel , Ramalho José S. , Almeida Cláudia Guimas 
Published: September 2023

AbstractCD2AP was identified as a genetic risk factor for late-onset Alzheimer’s disease (LOAD). However, how CD2AP contributes to LOAD synaptic dysfunction underlying AD memory deficits is unclear. We have shown that CD2AP loss-of-function increases β-amyloid (Aβ) endocytic production, but whether it contributes to synapse dysfunction is unknown. Because CD2AP is an actin-binding protein, it may also function in F-actin-rich dendritic spines, the excitatory postsynaptic compartment. Here, we demonstrate that CD2AP colocalises with F-actin in dendritic spines. Cell-autonomous depletion of CD2AP specifically reduces spine density and volume, with a functional decrease in synapse formation and neuronal network activity. Post-synaptic reexpression of CD2AP but not blocking Aβ-production is sufficient to rescue spine density. CD2AP overexpression increases spine density, volume, and synapse formation, while a rare LOAD CD2AP mutation induces aberrant F-actin spine-like protrusions without synapses. CD2AP controls postsynaptic actin turnover, with the LOAD mutation in CD2AP decreasing F-actin dynamicity. Our data support that CD2AP risk variants could contribute to LOAD synapse dysfunction by disrupting spine formation and growth by deregulating actin dynamics.Graphical abstract
Multifractal signatures in ossification reveal a disordered-to-ordered transition in mineral patterns
Authors: Bahadorian Mohammadreza , Lattner Johanna , Tabler Jacqueline M. , Modes Carl D. 
Published: September 2023

AbstractDeveloping biological systems can exhibit both dynamic pattern formation and cross-scale interactions. Multiscale relationships are critical in the establishment of these patterns but remain poorly understood. Classification of mineral pattern in bone is a quintessential example. One approach to quantifying these patterns relies upon statistical self-similarity and, in particular, monofractal analysis. However, simple monofractal characterisations fail to capture the complexity of multiscale interactions in developing biological systems. Here we show that multifractal techniques, effectively capture the complex patterns of self-similarity in a dimensionally reduced, usable way. Further, we show that a simple generative model of ossification in the mouse skull, coupled with multifractal methods indicates a primary role of collagen density in pattern establishment and predicts the existence of a sharp boundary in pattern complexity.
Gene expression analysis suggests immunosuppressive roles of endolysosomes in glioblastoma
Authors: Sun Michael A , Yao Haipei , Yang Qing , Pirozzi Christopher J. , Chandramohan Vidyalakshmi , Ashley David M. , He Yiping 
Published: September 2023

AbstractTargeting endolysosomes is a strategy extensively pursued for treating cancers, including glioblastomas (GBMs), mainly on the basis that the intact function of these subcellular organelles is key to tumor cell autophagy and survival. Here, by gene expression analyses and cell type abundance estimation in GBMs, we showed that genes associated with the endolysosomal machinery are more prominently featured in non-tumor cells in GBMs than in tumor cells, and that tumor-associated macrophages represent the primary immune cell type that contributes to this trend. Further analyses found an enrichment of endolysosomal pathway genes in immunosuppressive (pro-tumorigenic) macrophages, such as M2-like macrophages or those associated with worse prognosis in glioma patients, but not in those linked to inflammation (anti-tumorigenic). Specifically, genes critical to the hydrolysis function of endolysosomes, including progranulin and cathepsins, were among the most positively correlated with immunosuppressive macrophages, and elevated expression of these genes is associated with worse patient survival in GBMs. Together, these results implicate the hydrolysis function of endolysosomes in shaping the immunosuppressive microenvironment of GBM. We propose that targeting endolysosomes, in addition to its detrimental effects on tumor cells, can be leveraged for modulating immunosuppression to render GBMs more amendable to immunotherapies.
The Dynamics of the Female Microbiome: Unveiling Abrupt Changes of Microbial Domains across Body Sites from Preconception to Perinatal Phase
Authors: Neumann Charlotte J , Pausan Manuela-Raluca , Haid Victoria , Weiss Eva-Christine , Kolovetsiou-Kreiner Vassiliki , Amtmann Bettina , Winkler Petra , Mahnert Alexander , Jantscher-Krenn Evelyn , Moissl-Eichinger Christine 
Published: September 2023

AbstractThe microbial ecosystem of women undergoes enormous changes during pregnancy and the perinatal period. Little is known about the extent of changes in the maternal microbiome beyond the vaginal cavity and its recovery after birth. In this study, we followed pregnant women (mpre,n= 30) into the postpartum period (1 month postpartum, mpost,n= 30). We profiled their oral, urinary, and vaginal microbiome, archaeome, mycobiome and urinary metabolome and compared them with nonpregnant women (np,n= 29).Overall, pregnancy status (np, mpre, mpost) had a smaller effect on the microbiomes than body site, but massive transitions were observed for the oral and urogenital (vaginal and urinary) microbiomes. While the oral microbiome fluctuates during pregnancy but stabilizes rapidly within the first month postpartum, the urogenital microbiome is characterized by a major remodeling caused by a massive loss ofLactobacillusand thus a shift from vaginal community state type (CST) I (40% of women) to CST IV (85% of women). The urinary metabolome rapidly reached an np-like composition after delivery, apart from lactose and oxaloacetic acid, which were elevated during active lactation. Fungal and archaeal profiles were indicative of pregnancy status.Methanobacteriumsignatures were found exclusively in np women, andMethanobrevibactershowed opposite behavior in oral cavity (increased) and vagina (decreased) during pregnancy.Our findings suggest that the massive remodeling of the maternal microbiome and metabolome needs more attention and that potential interventions could be envisioned to optimize recovery and avoid long-term effects on maternal health and subsequent pregnancies.
SMAD4 promotes somatic-germline contact during murine oocyte growth
Authors: Granados-Aparici Sofia , Yang Qin , Clarke Hugh 
Published: September 2023

AbstractDevelopment of the mammalian oocyte requires physical contact with the surrounding granulosa cells of the follicle, which provide it with essential nutrients and regulatory signals. This contact is achieved through specialized filopodia, termed transzonal projections (TZPs), that extend from the granulosa cells to the oocyte surface. Transforming growth factor (TGFβ) family ligands produced by the oocyte increase the number of TZPs, but how they do so is unknown. Using an inducible Cre recombinase strategy together with expression of green fluorescent protein to verify Cre activity in individual granulosa cells, we examined the effect of depleting the canonical TGFβ mediator, SMAD4. We observed a 20-50% decrease in the total number of TZPs in SMAD4-depleted granulosa cell-oocyte complexes, and a 50% decrease in the number of newly generated TZPs when the granulosa cells were reaggregated with granulosa cell-free wild-type oocytes. Three-dimensional image analysis revealed that TZPs of SMAD4-depleted cells were also longer than controls and more frequently oriented towards the oocyte. Strikingly, the transmembrane proteins, N-cadherin and Notch2, were reduced by 50% in these cells. SMAD4 may thus modulate a network of cell adhesion proteins that stabilize the attachment of TZPs to the oocyte, thereby amplifying signalling between the two cell types.Impact statementGenetic deletion of SMAD4 in the granulosa cells of growing ovarian follicles reduces the number of transzonal projections that contact the oocyte, implicating TGFβ-family signaling in maintaining soma-germ line communication.
What is the best method for estimating ancestral states from discrete characters?
Authors: Keating Joseph N 
Published: September 2023

AbstractAncestral state estimation is a formal phylogenetic method for inferring the nature of ancestors and performing tests of character evolution. As such, it is among the most important tools available to evolutionary biologists. However, there are a profusion of methods available, the accuracy of which remains unclear. Here I use a simulation approach to test between parsimony and likelihood methods for estimating ancestral states from discrete binary characters. I simulate 500 characters using 15 different Markov generating models, a range of tree sizes (8-256 tips) and three topologies representing end members of tree symmetry and branch length heterogeneity. Simulated tip states were subjected to ancestral state estimation under the Equal Rates (ER) and All-Rates-Different (ARD) models, as well as under parsimony assuming accelerated transformations (ACCTRAN). The results demonstrate that both parsimony and likelihood approaches obtain high accuracy applied to trees with more tips. Parsimony performs poorly when trees contain long branches, whereas the ER model performs well across simulations and is reasonably robust to model violation. The ER model frequently outperforms the ARD model, even when data are simulated using unequal rates. Furthermore, the ER model exhibits less transition rate error when compared to ER models. These results suggest that ARD models may be overparameterized when character data is limited. Surprisingly, the difference in likelihood-based information criteria between models was found to be a poor predictor of difference in model error; better fitting models are not necessarily more accurate. However, there is a strong correlation between model uncertainty and model error; likelihood models with more certain ancestral state estimates are typically more accurate. Using empirical morphological datasets, I demonstrate that applying different methods often results in substantively different ancestral state estimates. The results of the simulation study highlight the importance of incorporating fossils in ancestral state estimation. Fossils increase the total number of tips, break long branches and are closer to internal nodes, thereby lowering average branch length and overall branch length heterogeneity of trees. These factors will all contribute to increasing the accuracy of ancestral state estimates, irrespective of the method used.
Optimization of RNAi efficiency in PVD neuron ofC. elegans
Authors: Singh Pallavi , Selvarasu Kavinila , Ghosh-Roy Anindya 
Published: September 2023

AbstractPVD neuron ofC. eleganshas become an attractive model for the study of dendrite development and regeneration due to the elaborate and stereotype dendrite morphology in this neuron. The molecular basis for dendrite maintenance and regeneration is poorly understood. RNA interference (RNAi) by feedingE. coliexpressing dsRNA has been the basis of several genome wide screens performed usingC. elegans. However, the feeding method often fails when it comes to nervous system. Using an optimal induction condition for the dsRNA expression inE coli, we fed the worm strains with HT115 bacteria expressing dsRNA against genes likemec-3, hpo-30,andtiam-1, whose loss of function are known to show dendrite morphology defects in PVD neuron. We found that RNAi of these genes in the strains such asnre-1(-) lin-15b(-), lin-15b(-)andsid-1(-); lin-15b(-); Punc-119::sid-1[+]resulted in significant reduction of dendrite branching. However, the phenotypes were significantly modest compared to the respective loss of function mutants. To obtain stronger phenotype for PVD specific genes, we have made a strain, which strongly expressessid-1undermec-3promoter specific for PVD. WhenPmec-3::sid-1is expressed in eithernre-1(-);lin-15b(-)orlin-15b(-)background, the higher order branching phenotype after RNAi ofmec-3, hpo-30,andtiam-1was significantly enhanced as compared tonre-1(-);lin-15b(-)andlin-15b(-)background alone. Next we tested thenre-1(-) lin-15b(-),Pmec-3-sid-1[+]strain for the knockdown of genes playing role in dendrite regeneration process. We found that whenaff-1andced-10genes were knocked down in thenre-1(-) lin-15b(-),Pmec-3-sid-1[+]background, the dendrite regeneration was significantly reduced and the extent of reduction was comparable to that of the mutants ofaff-1andced-10. Essentially, our strain expressingsid-1in PVD neuron optimizes the condition for RNAi for high throughput screening for PVD development, maintenance and regeneration.
Sequential early-life viral infections modulate the microbiota and adaptive immune responses to systemic and mucosal vaccination
Authors: Li Yuhao , Molleston Jerome M. , Kim Andrew H. , Ingle Harshad , Aggarwal Somya , Nolan Lila S. , Hassan Ahmed O. , Foster Lynne , Diamond Michael S. , Baldridge Megan T. 
Published: September 2023

AbstractIncreasing evidence points to the microbial exposome as a critical factor in maturing and shaping the host immune system, thereby influencing responses to immune challenges such as infections or vaccines. To investigate the effect of early-life viral exposures on immune development and vaccine responses, we inoculated mice with six distinct viral pathogens in sequence beginning in the neonatal period, and then evaluated their immune signatures before and after intramuscular or intranasal vaccination against SARS-CoV-2. Sequential viral infection drove profound changes in all aspects of the immune system, including increasing circulating leukocytes, altering innate and adaptive immune cell lineages in tissues, and markedly influencing serum cytokine and total antibody levels. Beyond these immune responses changes, these exposures also modulated the composition of the endogenous intestinal microbiota. Although sequentially-infected mice exhibited increased systemic immune activation and T cell responses after intramuscular and intranasal SARS-CoV-2 immunization, we observed decreased vaccine-induced antibody responses in these animals. These results suggest that early-life viral exposures are sufficient to diminish antibody responses to vaccination in mice, and highlight their potential importance of considering prior microbial exposures when investigating vaccine responses.