bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generation of an inflammatory niche in an injectable hydrogel depot through recruitment of key immune cells improves efficacy of mRNA vaccines
Authors: Meany Emily L. , Klich John H. , Jons Carolyn K. , Mao Tianyang , Chaudhary Namit , Utz Ashley , Baillet Julie , Song Ye E. , Saouaf Olivia M. , Ou Ben S. , Williams Shoshana C. , Eckman Noah , Irvine Darrell J. , Appel Eric 
Published: July 2024

AbstractMessenger RNA (mRNA) delivered in lipid nanoparticles (LNPs) rose to the forefront of vaccine candidates during the COVID-19 pandemic due in part to scalability, adaptability, and potency. Yet there remain critical areas for improvements of these vaccines in durability and breadth of humoral responses. In this work, we explore a modular strategy to target mRNA/LNPs to antigen presenting cells with an injectable polymer-nanoparticle (PNP) hydrogel depot technology which recruits key immune cells and forms an immunological niche in vivo. We characterize this niche on a single cell level and find it is highly tunable through incorporation of adjuvants like MPLAs and 3M-052. Delivering commercially available SARS-CoV-2 mRNA vaccines in PNP hydrogels improves the durability and quality of germinal center reactions, and the magnitude, breadth, and durability of humoral responses. The tunable immune niche formed within PNP hydrogels effectively skews immune responses based on encapsulated adjuvants, creating opportunities to precisely modulate mRNA/LNP vaccines for various indications from infectious diseases to cancers.
Osmotic Stress Influences Microtubule Drug Response Via WNK1 Kinase Signaling
Authors: Monfort-Vengut Ana , Sanz-Gómez Natalia , Ballesteros-Sánchez Sandra , Ortigosa Beatriz , Cambón Aitana , Ramos Maria , Lorenzo Ángela Montes-San , Rosa-Rosa Juan Manuel , Martínez-López Joaquín , Sánchez-Prieto Ricardo , Sotillo Rocío , de Cárcer Guillermo 
Published: July 2024

ABSTRACTIon homeostasis is critical for numerous cellular processes, and disturbances in ionic balance underlie diverse pathological conditions, including cancer progression. Targeting ion homeostasis is even considered as a strategy to treat cancer. However, very little is known about how ion homeostasis may influence anticancer drug response. In a genome-wide CRISPR-Cas9 resistance drug screen, we identified and validated the master osmostress regulator WNK1 kinase as a modulator of the response to the mitotic drug rigosertib. Osmotic stress and WNK1 inactivation lead to an altered response not only to rigosertib treatment but also to other microtubule-related drugs, minimizing the prototypical mitotic arrest produced by these drugs. This effect is due to an alteration in microtubule stability and polymerization dynamics, likely maintained by fluctuations in intracellular molecular crowding upon WNK1 inactivation. This promotes resistance to microtubule depolymerizing drugs, and increased sensitivity to microtubule stabilizing drugs. In summary, our data proposes WNK1 osmoregulation activity as a biomarker for microtubule-associated chemotherapy response.
Chronic wounds and adaptivePseudomonas aeruginosa: A phenotypic and genotypic characterization
Authors: Buchholtz Kasandra , Jønsson Rie , Marvig Rasmus L. , Mojsoska Biljana , Krogfelt Karen Angeliki 
Published: July 2024

AbstractPhenotypic and genetic diversity is found in varying prevalence in clinical populations where beneficial adaptations enable the bacteria to avoid recognition and eradication by the host immune system. This study aimed to investigate the presence ofPseudomonas aeruginosain chronic venous leg ulcers wounds over an 8-week time course. This was performed using genomic and phenotypic approaches to understand the survival and persistence ofPseudomonasstrains. The findings of this study show that the two patients were colonized with a recurringP. aeruginosagenotype with only minor phenotypic differences and few SNP differences, suggesting that thePseudomonasisolates present in the wound can survive and proliferate in the host’s hostile environment. The results provided from this study will allow us to understand clinically important traits inP. aeruginosaand provide insight into the dynamics and adaptations (or the lack thereof) in chronic wounds.HighlightsEach patient is colonised overtime with a unique MLSTThe total number of detected SNPs was 18 and 20 within each patient, respectivelyOne MLST belonged to the sequence type ST132, often observed in clinical isolates, whereas the other belonged to ST3244, previously seen inenvironmental isolates
microGWAS: a computational pipeline to perform large scale bacterial genome-wide association studies
Authors: Burgaya Judit , Damaris Bamu F. , Fiebig Jenny , Galardini Marco 
Published: July 2024

AbstractIdentifying genetic variants associated with bacterial phenotypes, such as virulence, host preference, and antimicrobial resistance, has great potential for a better understanding of the mechanisms involved in these traits. The availability of large collections of bacterial genomes has made genome-wide association studies (GWAS) a common approach for this purpose. The need to employ multiple software tools for data pre- and post-processing limits the application of these methods by experienced bioinformaticians. To address this issue, we have developed a pipeline to perform bacterial GWAS from a set of assemblies and annotations, with multiple phenotypes as targets. The associations are run using five sets of genetic variants: unitigs, gene presence/absence, rare variants (i.e. gene burden test), gene cluster specific k-mers, and all unitigs jointly. All variants passing the association threshold are further annotated to identify overrepresented biological processes and pathways. The results can be further augmented by generating a phylogenetic tree and by predicting the presence of antimicrobial resistance and virulence associated genes. We tested the microGWAS pipeline on a previously reported dataset onE. colivirulence, successfully identifying the causal variants, and providing further interpretation on the association results. The microGWAS pipeline integrates the state-of-the-art tools to perform bacterial GWAS into a single, user-friendly, and reproducible pipeline, allowing for the democratization of these analyses. The pipeline can be accessed, together with its documentation, at:https://github.com/microbial-pangenomes-lab/microGWAS.
Targeting NOTCH2-JAG1 juxtacrine signaling reverses macrophage-mediated tumor resistance to taxol
Authors: Yu Fazhi , Zhou Qin , Zhou Tong , Xie Yijia , Zhang Peng , He Wei , Yu Weiqiang , Cheng Aoxing , Liu Hanyuan , Wu Qingfa , Ma Xiaopeng , Guo Jing , Zhou Ying , Shi Jue , Yang Zhenye 
Published: July 2024

AbstractTaxanes are widely used in chemotherapy, but primary and acquired resistance limit the clinical efficacy. Studies have shown tumor interaction with macrophages in the tumor microenvironment (TME) plays a significant role in taxane resistance, yet therapeutic strategies that directly deplete or repolarize macrophages are challenging and with considerable risk of side effects. Here we uncovered that tumor-macrophage interaction can be selectively targeted by inhibiting post-mitotic NOTCH2-JAG1 juxtacrine signaling in the TME, which strongly sensitizes paclitaxel response. Using translatome profiling, we found significant NOTCH2 upregulation during paclitaxel-induced prolonged mitosis. NOTCH2 was subsequently activated in the post-mitotic G1 phase by JAG1 expressed on the neighboring macrophages and tumor cells, which promoted tumor cell survival and upregulated cytokines that recruited JAG1-expressing macrophages, thus generating a positive feedback loop that further enhanced the pro-tumor NOTCH2 activity. By targeting this NOTCH2-JAG1 axis using NOTCH2 shRNA or a pan-NOTCH inhibitor, macrophage recruitment and paclitaxel resistance were significantly attenuated in multiple mouse tumor models of ovarian cancer. Clinical samples from paired primary and recurrent ovarian cancer patients also showed significant correlation of higher NOTCH2 expression with worse prognosis. Our results thus point to combining NOTCH2 inhibitor with taxane as an effective therapeutic strategy to selectively disrupt tumor-macrophage interaction in the TME and overcome macrophage-mediated taxane resistance in NOTCH2-positive tumors.
Short-Term Warming Induces Cyanobacterial Blooms and Antibiotic Resistance in a Freshwater Lake as Revealed by Metagenomics Analysis
Authors: Manna Bharat , Jay Emma , Zhang Wensi , Zhou Xueyang , Lyu Boyu , Thomas Gevargis Muramthookil , Singhal Naresh 
Published: July 2024

AbstractClimate change poses significant risks to freshwater ecosystems, potentially exacerbating harmful cyanobacterial blooms and antibiotic resistance. We investigated these dual threats in Cosseys Reservoir, New Zealand, by simulating short-term warming scenarios and assessing the role of oxidative stress. Microcosms were subjected to Base (22°C), Normal (24°C), and projected Future (27°C) temperatures, with additional treatments including reactive oxygen species (ROS). Metagenomic analysis revealed substantial restructuring of microbial communities under warming conditions. Cyanobacterial abundance increased from 6.11% (initial) to 20.53% at 24°C and 10.66% at 27°C. Notably, ROS addition mimicked the effects of temperature increase on cyanobacterial proliferation. Toxin-producing families, includingMicrocystaceaeandNostocaceae, proliferated significantly. The microcystin synthesis gene (mcy) showed a strong positive association (R² = 0.88) with cyanobacterial abundance. Moreover, cyanobacteria exhibited enhanced nutrient acquisition (pstSgene, R² = 0.69) and upregulated nitrogen metabolism pathways under warming conditions. Concurrently, we observed a marked increase in antibiotic resistance gene (ARG) abundance with rising temperatures. The relative abundance of multidrug resistance genes was consistently high across all conditions (50.82 % of total ARGs). ROS stress further intensified ARG proliferation, particularly for efflux pump genes (e.g.,acrB,adeJ,ceoB,emrB,MexK,muxB). Co-association network analysis identified key antibiotic-resistant bacteria (e.g.,Streptococcus pneumoniae,Acinetobacter baylyi) and ARGs (e.g.,acrB,MexK,rpoB2,bacA) central to resistance dissemination under warming conditions. This study demonstrates that even modest temperature increases (2-5°C) can promote both cyanobacterial blooms and antibiotic resistance in freshwater ecosystems over short time scales. The synergistic effects of temperature and oxidative stress underscore the complex challenges posed by climate change to water quality and public health.HighlightsShort-term warming promotes toxic cyanobacteria and antibiotic resistance in freshwater.Harmful cyanobacteria and their metabolic potential increase under warming conditions.Reactive oxygen species mimic and exacerbate temperature effects.Oxidative stress response genes strongly correlate with ARG abundance.Co-association networks identify key host pathogen central to resistance spread.
Reproducibly oriented cell divisions pattern the first flat body structures to set up dorsoventrality and de novo meristem formation inMarchantia polymorpha
Authors: Wallner Eva-Sophie , Dolan Liam 
Published: July 2024

AbstractLand plant bodies develop from stem cells located in meristems. However, we know little about how meristems initiate from non-meristematic cells. The haploid body of bryophytes develops from unicellular spores in isolation from the parental plant, which allows all stages of development to be observed. We discovered that the Marchantia spore undergoes a series of precisely oriented cell divisions to generate a flat prothallus on which a meristem later develops de novo. The young sporeling comprises an early cell mass. One cell of the early cell mass elongates and undergoes a formative division that produces the prothalloblast, which initiates prothallus formation. A symmetric division of the prothalloblast followed by two transverse divisions generate a four-celled plate that expands into a flat disc through oblique divisions in three of the four plate cell-derived quadrants. One quadrant gives rise to a flat flabellum. A notch with a meristem and apical stem cell develops at the margin of the flabellum. The transcription factor MpC3HDZ is a marker of the first flat prothallus structure and polarises to the dorsal tissues of flabella and meristems. Mpc3hdzmutants are defective in setting up dorsoventrality and thallus body flatness. We report how a regular set of cell divisions forms the prothallus – the first dorsoventral structure – and how cells on the margin of the prothallus develop a dorsoventralised meristem de novo.
Oncogenic NOVA1 expression dysregulates alternative splicing in breast cancer
Authors: Moakley Daniel F , Zhang Chaolin 
Published: July 2024

AbstractNeuro-Oncological Ventral Antigen 1 (NOVA1) is best known for its role in mediating an alternative splicing (AS) program in neurons, yet was first discovered as an antigen expressed in breast tumors, causing rare autoimmune reactions and paraneoplastic neurological disorders (PNDs). The PND model suggests a plausible role of the tumor antigen expression in tumor suppression, whereas it has emerged that NOVA may function as an oncogene in a variety of cancers. In addition, whether NOVA mediates AS in breast cancer remains unanswered. Here we examine the AS profiles of breast invasive carcinoma (BRCA) tumor samples and demonstrate that ectopicNOVA1expression led to the activation of neuron-like splicing patterns in many genes, including exons targeted by NOVA in the brain. The splicing dysregulation is especially prevalent in cell periphery and cytoskeleton genes related to cell-cell communication, actin-based movement, and neuronal functions. We find that NOVA1-mediated AS is most prominent in Luminal A tumors and highNOVA1expression in this subtype is associated with poorer prognosis. Our results suggest that ectopic NOVA1 in tumors has regulatory activity affecting pathways with high relevance to tumor progression and that this might be a more general mechanism for PND antigens.
TgATG9 is required for autophagosome biogenesis and maintenance of chronic infection inToxoplasma gondii
Authors: Thaprawat Pariyamon , Zhang Zhihai , Rentchler Eric C. , Wang Fengrong , Chalasani Shreya , Giuliano Christopher J. , Lourido Sebastian , Di Cristina Manlio , Klionsky Daniel J. , Carruthers Vern B. 
Published: July 2024

AbstractToxoplasma gondiiis a ubiquitous protozoan parasite that can reside long-term within hosts as intracellular tissue cysts comprised of chronic stage bradyzoites. To perturb chronic infection requires a better understanding of the cellular processes that mediate parasite persistence. Macroautophagy/autophagy is a catabolic and homeostatic pathway that is required forT. gondiichronic infection, although the molecular details of this process remain poorly understood. A key step in autophagy is the initial formation of the phagophore that sequesters cytoplasmic components and matures into a double-membraned autophagosome for delivery of the cargo to a cell’s digestive organelle for degradative recycling. WhileT. gondiiappears to have a reduced repertoire of autophagy proteins, it possesses a putative phospholipid scramblase, TgATG9. Through structural modeling and complementation assays, we show herein that TgATG9 can partially rescue bulk autophagy inatg9Δyeast. We demonstrated the importance of TgATG9 for proper autophagosome dynamics at the subcellular level using three-dimensional live cell lattice light sheet microscopy. Conditional knockdown of TgATG9 inT. gondiiafter bradyzoite differentiation resulted in markedly reduced parasite viability. Together, our findings provide insights into the molecular dynamics of autophagosome biogenesis within an early-branching eukaryote and pinpoint the indispensable role of autophagy in maintainingT. gondiichronic infection.
Structural Basis for the Activation of Proteinase-Activated Receptors (PARs) by Endogenous Ligands
Authors: Lyu Zongyang , Lyu Xiaoxuan , Xia Guliang , Carney Daniel , Alves Vinicius M. , Falk Mathew , Arora Nidhi , Zou Hua , McGrath Aaron , Kang Yanyong 
Published: July 2024

AbstractThe proteinase-activated receptor (PAR) subfamily of G protein-coupled receptors (GPCRs) include four members, PAR1-PAR4, that play critical roles in hemostasis, thrombosis, embryonic development, wound healing, inflammation, and cancer progression. The PARs share a unique activation mechanism driven by proteinase cleavage at a specific site within the extracellular amino-terminus, exposing a ‘tethered ligand’ that self-activates the receptor. Subsequent activation allows PAR family members to initiate complex intracellular signaling networks via traditional G protein-mediated pathways and beta-arrestin signaling and, in this way, the PARs link extracellular protease signaling molecules to cellular functions. Despite a primary reliance on biochemical studies for understanding tethered ligand recognition, direct structural visualization of these ligand-receptor complexes has been elusive. Here, we present structural snapshots of activated PAR1 and PAR2 bound to their endogenous tethered ligands, revealing, for the first time, shallow and constricted orthosteric binding pockets and highlighting critical residues involved in ligand recognition and receptor activation. Surprisingly, comparisons with antagonist-bound structures show minimal conformational changes in the TM6 helix, a typical signature of GPCR activation, with large movements of TM7 observed upon activation. These insights lead to the identification of a common mechanism for PAR1 and PAR2 activation and provide a structural template for designing novel antagonists targeting the orthosteric binding site, potentially opening new avenues for therapeutic interventions.
Differential circulating proteomic responses associated with ancestry during severe COVID-19 infection
Authors: Zheng Thomas M , Ilboudo Yann , Lu Tianyuan , Butler-Laporte Guillaume , Nakanishi Tomoko , Morrison David , Adra Darin , Cuddeback Lena , Brent Richards J. 
Published: July 2024

AbstractBackgroundCOVID-19 led to a disruption in nearly all aspects of society, yet these impacts were not the same across populations. During the pandemic, it became apparent that ancestry was associated with COVID-19 severity and morbidity, such that individuals of African descent tended to have worse outcomes than other populations. One factor that may influence COVID-19 outcomes is the circulating proteomic response to infection. This study examines how different ancestries had differential circulating protein levels in response to severe COVID-19 infection.Methods4,979 circulating proteins from 1,272 samples were measured using the SomaScan platform. We used a linear mixed model to assess the ancestry-specific association between the level of each protein and severe COVID-19 illness, accounting for sex, age, and days since symptom onset. We then compared each ancestry-specific effect size of severe COVID-19 illness on protein level to one another in a pairwise manner to generate Z-scores. These Z-scores were then converted into p-values and corrected for multiple comparisons using a Benjamini-Hochberg false discovery rate of 5%.ResultsComparing ancestries, we found that 62% of the tested proteins are associated with severe COVID-19 in European-ancestry individuals, compared to controls. We found that 45% and 22% of the tested proteins were different between COVID-19 infected and control individuals in people of African and East Asian ancestry, respectively. There was a strong correlation in effect size between ancestries. We found that individuals of European and African ancestry had the most similar response with a Pearson correlation of 0.868, 95% CI [0.861, 0.875] while European and East Asian ancestries had a Pearson correlation of 0.645, 95% CI [0.628, 0.661] and, East Asian and African ancestries had a Pearson correlation of 0.709, 95% CI [0.695, 0.722]. However, we found 39 unique proteins that responded differently (FDR < 0.05) between the three ancestries.ConclusionsExamining 4,979 protein levels in 1,272 samples, we identified that the majority of measured proteins had similar responses to infection across individuals of European, African and East Asian ancestry. However, there were 39 proteins that may have a differential response to infection, when stratified by ancestry. These proteins could be investigated to assess whether they explain the differences in observed severity of COVID-19 between ancestral populations.
Performance of LFSPROTP53germline carrier risk predictions compared to standard genetic counseling practice on prospectively collected probands
Authors: Corredor Jessica L. , Dodd-Eaton Elissa B. , Woodman-Ross Jacynda , Woodson Ashley , Nguyen Nam H. , Peng Gang , Green Sierra , Gutierrez Angelica M. , Arun Banu K. , Wang Wenyi 
Published: July 2024

AbstractPurposeCurrent clinical guidelines for genetic testing for Li-Fraumeni Syndrome (LFS) have many limitations, primarily the criteria don’t consider detailed personal and family history information and may miss many individuals with LFS. A personalized risk assessment tool, LFSPRO, was created to estimate a proband’s risk for LFS based on personal and family history information. The purpose of this study is to compare LFSPRO to existing clinical criteria to determine if LFSPRO can outperform these tools. Additionally, we gauged genetic counselors’ (GCs) experience using LFSPRO for their patients.MethodsBetween December 2021 and March 2024, GCs identified patients concerning for LFS based on the patients’ personal and family history information. This information was entered into LFSPRO to predict the risk to have a pathogenic/pathogenic (LP/P) germlineTP53variant. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) was compared between LFSPRO and Chompret criteria. Select GCs were asked to fill out surveys regarding their experience using LFSPRO following their genetic counseling appointments.ResultsLFSPRO’s sensitivity and specificity were 0.529 and 0.781 compared to Chompret’s respective 0.235 and 0.677. Additionally, LFSPRO had a positive predictive value (PPV) of 0.30 compared to Chompret’s 0.114. LFSPRO’s risk prediction was concordant with genetic testing results in 75% of probands. Eighty-one percent of GC surveys reported LFSPRO being concordant with the GC’s expectations and 75% would feel comfortable sharing the results with patients.ConclusionLFSPRO showed improved sensitivity and specificity compared to Chompret criteria and GCs report a positive experience with LFSPRO. LFSPRO can be used to increase access to genetic testing for patients at risk for LFS and could help healthcare providers give more direct risk assessments regarding LFS testing and management for patients.