bluuebunny/crossref_metadata_2025_split huggingface dataset:
Laboratory-confirmed respiratory viral infection triggers for acute myocardial infarction and stroke: systematic review protocol
Authors: Nguyen Tu Q , Vlasenko Diana , Shetty Aishwarya N , Reid Christopher M , Clothier Hazel J , Buttery Jim P 
Published: April 2024

AbstractBackgroundCardiovascular disease contributes substantially to global mortality and morbidity. Respiratory tract infections, particularly influenza, may trigger an increase in the short-term risk of acute myocardial infarction and stroke. Recent studies have also linked this risk to other respiratory viruses, including respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the pathogen-specific relative contributions, the strength of their associations, and overall public health significance are poorly understood. Assuming causal links, understanding, quantifying, and comparing the effects of different pathogens as triggering factors for acute cardiovascular events is critical to guide future research and prevention. Our aim is to conduct a systematic review to examine the relative effects of laboratory-confirmed respiratory virus infections as triggers for acute myocardial infarction and stroke.MethodsWe will conduct a comprehensive search of Ovid MEDLINE, PubMed, Ovid Embase, Cochrane Library Central Register of Controlled Trials, and Web of Science, from inception to the end of March 2024. We will include the following analytical epidemiological study types: randomised controlled trials, cohort and case-control studies, self-controlled case series, and case-crossover designs. We will not impose restrictions on the date, language, geographical region, or sample size, to minimise the risk of introducing biases. Search results will be screened for eligibility by two independent reviewers, and discrepancies resolved by consensus and/or arbitration by a third reviewer. We will assess the risk of bias among the included studies by adopting the Cochrane Collaboration tools for randomised and non-randomised studies. The overall quality of studies will be assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. We will examine sources of heterogeneity, and if studies are sufficiently homogeneous, a meta-analysis will be conducted to calculate the pooled effect sizes. Reporting will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.RegistrationInternational Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD42024494997
Folate receptor alpha protein expression in ovarian serous cystadenocarcinoma tumors of The Cancer Genome Atlas: exploration beyond single-agent therapy
Authors: Persenaire Christianne , Bitler Benjamin G. , Corr Bradley R. 
Published: April 2024

AbstractEpithelial ovarian cancer (EOC) can be highly lethal, with limited therapeutic options for patients with non-homologous recombination deficient (HRD) disease. Folate receptor alpha (FOLR1/FRα)-targeting agents have shown promise both alone and in combination with available therapies, but the relationship of FRα to other treatment-driving biomarkers is unknown. The Cancer Genome Atlas (TCGA) was queried to assess protein and mRNA expression and mutational burden in patients with differential FRα protein-expressing ovarian tumors, and the results referenced against the standard 324 mutations currently tested through FoundationOne Companion Diagnostics to identify targets of interest. Of 585 samples within TCGA, 121 patients with serous ovarian tumors for whom FRα protein expression was quantified were identified. FRα protein expression significantly correlated with FOLR1 mRNA expression (p=7.19×10-14). Progression free survival (PFS) for the FRα-high group (Q1) was 20.7 months, compared to 16.6 months for the FRα-low group (Q4, Logrank, p=0.886). Overall survival (OS) was 54.1 months versus 36.3 months, respectively; however, this result was not significant (Q1 vs. Q4, Logrank, p=0.200). Mutations more commonly encountered in patients with high FRα-expressing tumors included PIK3CA and FGF family proteins. Combinations of FRα-targeting agents with PI3K, mTOR, FGF(R) and VEGF inhibitors warrant investigation to evaluate their therapeutic potential.Simple SummaryEpithelial ovarian cancer can be highly lethal, with limited therapeutic options for patients without BRCA mutations or non-homologous recombination deficient disease. Folate receptor alpha (FRα)-targeting agents have shown promise in the setting of platinum-sensitive and platinum-resistant ovarian cancer, both alone and in combination with available therapies, but the relationship of FRα to other treatment-driving biomarkers is unknown. This study identifies potential targetable mutations in FRα-expressing tumors, including PIK3CA and FGF/R family proteins, and provides a basis for future investigations of novel combinations of FRα-targeting agents with PIK3CA, mTOR, FGF/R, and VEGF inhibitors.
Sex-Specific Regulation of Stress Susceptibility by the Astrocytic GeneHtra1
Authors: Parise Eric M. , Gyles Trevonn M. , Godino Arthur , Sial Omar K. , Browne Caleb J. , Parise Lyonna F. , Torres-Berrío Angélica , Salery Marine , Durand-de Cuttoli Romain , Rivera Matthew T. , Cardona-Acosta Astrid M. , Holt Leanne , Markovic Tamara , van der Zee Yentl Y. , Lorsch Zachary S. , Cathomas Flurin , Garon Juliet B. , Teague Collin , Issler Orna , Hamilton Peter J. , Bolaños-Guzmán Carlos A. , Russo Scott J. , Nestler Eric J. 
Published: April 2024

AbstractMajor depressive disorder (MDD) is linked to impaired structural and synaptic plasticity in limbic brain regions. Astrocytes, which regulate synapses and are influenced by chronic stress, likely contribute to these changes. We analyzed astrocyte gene profiles in the nucleus accumbens (NAc) of humans with MDD and mice exposed to chronic stress.Htra1, which encodes an astrocyte-secreted protease targeting the extracellular matrix (ECM), was significantly downregulated in the NAc of males but upregulated in females in both species. ManipulatingHtra1in mouse NAc astrocytes bidirectionally controlled stress susceptibility in a sex-specific manner. SuchHtra1manipulations also altered neuronal signaling and ECM structural integrity in NAc. These findings highlight astroglia and the brain’s ECM as key mediators of sex-specific stress vulnerability, offering new approaches for MDD therapies.
Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage
Authors: Huber Nadine , Hietanen Tomi , Heikkinen Sami , Shakirzyanova Anastasia , Hoffmann Dorit , Rostalski Hannah , Dhingra Ashutosh , Rodriguez-Nieto Salvador , Kärkkäinen Sari , Koskuvi Marja , Korhonen Eila , Hartikainen Päivi , Pylkäs Katri , Krüger Johanna , Malm Tarja , Takalo Mari , Hiltunen Mikko , Koistinaho Jari , Portaankorva Anne M. , Solje Eino , Haapasalo Annakaisa 
Published: April 2024

AbstractFrontotemporal dementia (FTD) is the second most common cause of dementia in patients under 65 years, characterized by diverse clinical symptoms, neuropathologies, and genetic background. Synaptic dysfunction is suggested to play a major role in FTD pathogenesis. Disturbances in the synaptic function can also be associated with theC9orf72repeat expansion (C9-HRE), the most common genetic mutation causing FTD. C9-HRE leads to distinct pathological hallmarks, such asC9orf72haploinsufficiency and development of toxic RNA foci and dipeptide repeat proteins (DPRs). FTD patient brains, including those carrying the C9-HRE, are also characterized by neuropathologies involving accumulation of TDP-43 and p62/SQSTM1 proteins. This study utilized induced pluripotent stem cell (iPSC)-derived cortical neurons from C9-HRE-carrying or sporadic FTD patients and healthy control individuals. We report that the iPSC neurons derived from C9-HRE carriers developed typical C9-HRE-associated hallmarks, including RNA foci and DPR accumulation. All FTD neurons demonstrated increased TDP-43 nucleus-to-cytosolic shuttling and p62/SQSTM1 accumulation, and changes in nuclear size and morphology. In addition, the FTD neurons displayed reduced number and altered morphologies of dendritic spines and significantly altered synaptic function indicated by a decreased response to stimulation with GABA. These structural and functional synaptic disturbances were accompanied by upregulated gene expression in the FTD neurons related to synaptic function, including synaptic signaling, glutamatergic transmission, and pre- and postsynaptic membrane, as compared to control neurons. Pathways involved in DNA repair were significantly downregulated in FTD neurons. Only one gene,NUPR2,potentially involved in DNA damage response, was differentially expressed between the sporadic and C9-HRE-carrying FTD neurons. Our results show that the iPSC neurons from FTD patients recapitulate pathological changes of the FTD brain and strongly support the hypothesis of synaptic dysfunction as a crucial contributor to disease pathogenesis in FTD.
soibean: High-resolution Taxonomic Identification of Ancient Environmental DNA Using Mitochondrial Pangenome Graphs
Authors: Vogel Nicola Alexandra , Rubin Joshua Daniel , Pedersen Anders Gorm , Sackett Peter Wad , Pedersen Mikkel Winther , Renaud Gabriel 
Published: April 2024

AbstractAncient environmental DNA (aeDNA) is becoming a powerful tool to gain insights about past ecosystems. However, several methodological challenges remain, particularly for classifying the DNA to species level and conducting phylogenetic placement. Current methods, primarily tailored for modern datasets, fail to capture several idiosyncrasies of aeDNA, including species mixtures from closely related species and ancestral divergence. We introducesoibean, a novel tool that utilises pangenomic graphs for identifying species from ancient environmental mitochondrial reads. It outperforms existing methods in accurately identifying species from multiple sources within a sample, enhancing phylogenetic analysis for aeDNA.soibeanemploys a damage-aware likelihood model for precise identification at low-coverage with high damage rate, demonstrating effectiveness through simulated data tests and empirical validation. Notably, our method uncovered new empirical results in published datasets, including using porpoise whales as food in a Mesolithic community in Sweden, demonstrating its potential to reveal previously unrecognised findings in aeDNA studies.
Functions of the Bloom Syndrome Helicase N-terminal Intrinsically Disordered Region
Authors: Bereda Colleen C. , Dewey Evan B. , Nasr Mohamed A. , Sekelsky Jeff 
Published: April 2024

AbstractBloom Syndrome helicase (Blm) is a RecQ family helicase involved in DNA repair, cell-cycle progression, and development. Pathogenic variants in humanBLMcause the autosomal recessive disorder Bloom Syndrome, characterized by predisposition to numerous types of cancer. Prior studies ofDrosophila Blmmutants lacking helicase activity or protein have shown sensitivity to DNA damaging agents, defects in repairing DNA double-strand breaks (DSBs), female sterility, and improper segregation of chromosomes in meiosis. Blm orthologs have a well conserved and highly structured RecQ helicase domain, but more than half of the protein, particularly in the N-terminus, is predicted to be unstructured. Because this region is poorly conserved across multicellular organisms, we compared closely related species to identify regions of conservation, potentially indicating important functions. We deleted two of theseDrosophila-conserved regions inD. melanogasterusing CRISPR/Cas9 gene editing and assessed the effects on different Blm functions. Each deletion had distinct effects on different Blm activities. Deletion of either conserved region 1 (CR1) or conserved region 2 (CR2) compromised DSB repair through synthesis-dependent strand annealing and resulted in increased mitotic crossovers. In contrast, CR2 is critical for embryonic development but CR1 is not as important. CR1 deletion allows for proficient meiotic chromosome segregation but does lead to defects in meiotic crossover designation and patterning. Finally, deletion of CR2 does not lead to significant meiotic defects, indicating that while each region has overlapping functions, there are discreet roles facilitated by each. These results provide novel insights into functions of the N-terminal disordered region of Blm.
Neural dynamics of visual working memory representation during sensory distraction
Authors: Degutis Jonas Karolis , Weber Simon , Soch Joram , Haynes John-Dylan 
Published: April 2024

AbstractRecent studies have provided evidence for the concurrent encoding of sensory percepts and visual working memory contents (VWM) across visual areas; however, it has remained unclear how these two types of representations are concurrently present. Here, we reanalyzed an open-access fMRI dataset where participants memorized a sensory stimulus while simultaneously being presented with sensory distractors. First, we found that the VWM code in several visual regions did not fully generalize between different time points, suggesting a dynamic code. A more detailed analysis revealed that this was due to shifts in coding spaces across time. Second, we collapsed neural signals across time to assess the degree of interference between VWM contents and sensory distractors, specifically by testing the alignment of their encoding spaces. We find that VWM and feature-matching sensory distractors are encoded in coding spaces that do not fully overlap, but the separation decreases when distractors negatively impact behavioral performance in recalling the target. Together, these results indicate a role of dynamic coding and temporally stable coding spaces in helping multiplex perception and VWM within visual areas.
Chemogenetic stimulation of phrenic motor output and diaphragm activity
Authors: Benevides Ethan S. , Thakre Prajwal P. , Rana Sabhya , Sunshine Michael D. , Jensen Victoria N. , Oweiss Karim , Fuller David D. 
Published: April 2024

ABSTRACTImpaired respiratory motor output contributes to morbidity and mortality in many neurodegenerative diseases and neurologic injuries. We investigated if expressing designer receptors exclusively activated by designer drugs (DREADDs) in the mid-cervical spinal cord could effectively stimulate phrenic motor output to increase diaphragm activation. Two primary questions were addressed: 1) does effective DREADD-mediated diaphragm activation require focal expression in phrenic motoneurons (vs. non-specific mid-cervical expression), and 2) can this method produce a sustained increase in inspiratory tidal volume? Wild type (C57/bl6) and ChAT-Cre mice received bilateral intraspinal (C4) injections of an adeno-associated virus (AAV) encoding the hM3D(Gq) excitatory DREADD. In wild-type mice, this produced non-specific DREADD expression throughout the mid-cervical ventral horn. In ChAT-Cre mice, a Cre-dependent viral construct was used to drive neuronal DREADD expression in the C4 ventral horn, targeting phrenic motoneurons. Diaphragm EMG was recorded in isoflurane-anesthetized spontaneously breathing mice at 4-9 weeks post-AAV delivery. The DREADD ligand JHU37160 (J60) caused a bilateral, sustained (>1 hour) increase in inspiratory EMG bursting in both groups; the relative increase was greater in ChAT-Cre mice. Additional experiments in ChAT-Cre rats were conducted to determine if spinal DREADD activation could increase inspiratory tidal volume (VT) during spontaneous breathing, assessed using whole-body plethysmography without anesthesia. Three-to-four months after intraspinal (C4) injection of AAV driving Cre-dependent hM3D(Gq) expression, intravenous J60 resulted in a sustained (>30 min) increase in VT. Subsequently, phrenic nerve recordings performed under urethane anesthesia confirmed that J60 evoked a > 200% increase in inspiratory output. We conclude that targeting mid-cervical spinal DREADD expression to the phrenic motoneuron pool enables ligand-induced, sustained increases in phrenic motor output and VT. Further development of this technology may enable application to clinical conditions associated with impaired diaphragm activation and hypoventilation.
Metastasis of colon cancer requires Dickkopf-2 to generate cancer cells with Paneth cell properties
Authors: Shin Jae Hun , Park Jooyoung , Lim Jaechul , Jeong Jaekwang , Dinesh Ravi K. , Maher Stephen E. , Kim Jeonghyun , Park Soyeon , Hong Jun Young , Wysolmerski John , Choi Jungmin , Bothwell Alfred L. M. 
Published: April 2024

AbstractMetastasis is the leading cause of cancer-related mortality. Paneth cells provide stem cell niche factors in homeostatic conditions, but the underlying mechanisms of cancer stem cell niche development are unclear. Here we report that Dickkopf-2 (DKK2) is essential for the generation of cancer cells with Paneth cell properties during colon cancer metastasis. Splenic injection ofDkk2-knockout (KO) cancer organoids into C57BL/6 mice resulted in a significant reduction of liver metastases. Transcriptome analysis showed reduction of Paneth cell markers such as lysozymes in KO organoids. Single cell RNA sequencing analyses of murine metastasized colon cancer cells and patient samples identified the presence of lysozyme positive cells with Paneth cell properties including enhanced glycolysis. Further analyses of transcriptome and chromatin accessibility suggested Hepatocyte nuclear factor 4-alpha (HNF4A) as a downstream target of DKK2. Chromatin immunoprecipitation followed by sequencing analysis revealed that HNF4A binds to the promoter region ofSox9, a well-known transcription factor for Paneth cell differentiation. In the liver metastatic foci, DKK2 knockout rescued HNF4A protein levels followed by reduction of lysozyme positive cancer cells. Taken together, DKK2-mediated reduction of HNF4A protein promotes the generation of lysozyme positive cancer cells with Paneth cell properties in the metastasized colon cancers.
How does plant chemodiversity evolve? Testing five hypotheses in one population genetic model
Authors: Wittmann Meike J. , Bräutigam Andrea 
Published: April 2024

SummaryPlant chemodiversity, the diversity of plant specialized metabolites, is an important dimension of biodiversity. However, there are so far few quantitative models to test verbal hypotheses on how chemodiversity evolved. Here we develop such a model to test predictions of five hypotheses: the “fluctuating selection hypothesis”, the “dominance reversal hypothesis”, the interaction diversity hypothesis, the synergy hypothesis, and the screening hypothesis.We build a population genetic model of a plant population attacked by herbivore species whose occurrence fluctuates over time. We study the model using mathematical analysis and individual-based simulations.As predicted by the “dominance reversal hypothesis”, chemodiversity can be maintained if alleles conferring a defense metabolite are dominant with respect to the benefits, but recessive with respect to costs. However, even smaller changes in dominance can maintain polymorphism. Moreover, our results underpin and elaborate predictions of the synergy and interaction diversity hypotheses, and, to the extent that our model can address it, the screening hypotheses. By contrast, we found only partial support for the “fluctuating selection hypothesis”.In summary, we have developed a flexible model and tested various verbal models for the evolution of chemodiversity. Next, more mechanistic models are needed that explicitly consider the organization of metabolic pathways.
Top-down Mass Spectrometric Analysis of a Lipooligosaccharide from the Human CommensalBacteroides fragilis
Authors: Yang Tiandi , Daugherty Jason , Kasper Dennis L. 
Published: April 2024

AbstractLipopolysaccharides (LPS) and lipooligosaccharides (LOS) are ubiquitous structures found on the outer membrane of gram-negative bacteria.Bacteroides fragilis, is a gram-negative anaerobe commonly inhabiting the human colon. The LOS of this organism is known to trigger a type I interferon response in dendritic cells. However, detailed structural analysis of this LOS has been largely elusive. Using top-down mass spectrometry, we have unraveled the comprehensive fine structure ofB. fragilisLOS. Our analysis reveals that this LOS has a poly-galactose-rhamnose-KDO-lipid A architecture, which can be modified by hexuronic acid and ethanolamine via phosphodiester linkages. The lipid moiety typically includes three to five acyl chains of varying length on a glucosamine disaccharide. This investigation lays the groundwork for deeper immunological exploration ofB. fragilisLOS and underscores the efficacy of top-down mass spectrometry in characterizing intact LOS/LPS structures and their modifications.
Transcatheter versus Surgical Interventions for Severe Aortic Stenosis: A Contemporary Evaluation against Conservative Management
Authors: Ma Zhiyuan , Shadman Shahrad , Maddahi Yaniv , Krishnamurthy Mahesh , Puleo Peter , Shirani Jamshid 
Published: April 2024

AbstractBackgroundAortic valve replacement (AVR), through transcatheter (TAVR) or surgical (SAVR) means, serves as a pivotal therapeutic approach for severe aortic stenosis (AS). While both modalities show advantages over conservative management, the long-term mortality benefits post-AVR, especially when comparing TAVR with SAVR, remain uncertain.ObjectivesThis study aimed to perform an in-depth meta-analysis of randomized controlled trials (RCT) comparing TAVR versus SAVR, as well as their outcomes against conservative management.MethodsElectronic databases were searched up to December 7, 2023. Individual patient data extracted from Kaplan-Meier plots, underwent pooling and modeling with stratification by surgical risk. The primary endpoint was all-cause mortality at 5 years.ResultsThe study included eleven RCTs and twelve non-RCTs, encompassing 4215 patients undergoing TAVR, 4017 undergoing SAVR and comparing 11,285 AVR patients with 23,358 receiving conservative management. TAVR exhibited significantly lower all-cause mortality at 6 months (HR 0.62, 95% CI: 0.52-0.74) compared to SAVR, with no significant difference beyond 6 months (HR 1.08, 95% CI: 0.98-1.19). Additionally, over a 5-year period, there were no significant disparities in cardiovascular mortality (HR 0.98, 95% CI: 0.83-1.16) or stroke (HR 1.02, 95% CI: 0.75-1.38) between TAVR and SAVR, while TAVR exhibited a notable advantage with a markedly reduced risk of cardiovascular mortality in the initial 6 months (HR 0.64, 95% CI: 0.46-0.87) and stroke within the first month post-procedure (HR 0.31, 95% CI: 0.19-0.51). Furthermore, the mean aortic valve area and pressure gradient remained comparable between TAVR and SAVR, exhibiting stability throughout the 5-year follow-up period. AVR markedly reduced all-cause mortality compared to medical therapy (P < 0.001), with 5-year crude mortality rates of 31.6% versus 49.3%, and a difference in restricted mean survival time of 8.9 months. Similar outcomes were observed across high, intermediate, and low surgical risk categories.ConclusionsWhile TAVR demonstrated early mortality reduction compared to SAVR, no distinctions emerged in the overall 5-year follow-up, regardless of surgical risk. AVR notably improved survival over conservative therapy. This study advocates for the preference of TAVR or SAVR in severe AS patients when feasible.