bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cisplatin promotes pyroptosis of gastric cancer cells by activating GSDME
Authors: Jiang Xianglai , Wang Yongfeng , Wang Chenyu , Ma Haizhong , Yu Miao , Cai Hui 
Published: September 2023

ABSTRACTAccording to studies, numerous chemotherapeutic drugs can facilitate programmed cell death via pyroptosis. Clarifying the mechanism by which cisplatin kills gastric cancer cells is crucial for enhancing gastric cancer’s sensitivity to chemotherapy and elucidating the mechanism of drug resistance in gastric cancer. The differentially expressed genes following cisplatin treatment were identified using second-generation sequencing technology. Bioinformatics was used to investigate the functional enrichment of differentially expressed genes and core genes in tumor cells killed by cisplatin. Cox regression analyses were used to examine the pyroptosis core genes that worked as independent prognostic factors for patients with gastric cancer. The expression of core genes in gastric cancer cells was silenced by siRNA, and the changes in the proliferation of gastric cancer cells were observed. The expression of related genes and the survival of gastric cancer cells after the addition of cisplatin were observed. The second-generation sequencing, RT-PCR and Western blotting showed that the pyroptosis core gene was significantly highly expressed after cisplatin treatment. The results of differential gene enrichment of cisplatin-treated gastric cancer cells showed that differential genes were mainly concentrated in biological processes and signaling pathways related to pyroptosis. GSDME protein is highly expressed after cisplatin treatment, and it is also a poor prognostic factor for gastric cancer patients and an independent prognostic factor. After the same dose of cisplatin treatment, the survival rate of siGSDME gastric cancer cells was significantly higher than that of GSDME regular expression gastric cancer cells. After acting on gastric cancer cells, cisplatin triggers pyroptosis by stimulating the activation of genes such as GSDME, resulting in the death of gastric cancer cells. GSDME is an independent prognostic factor for gastric cancer patients and is significantly linked with a shorter OS. In gastric cancer cells, silencing GSDME can substantially reduce cisplatin’s cytotoxicity.
Prognostic models predicting transition to psychotic disorder using blood-based biomarkers: a systematic review and critical appraisal
Authors: Byrne Jonah F. , Mongan David , Murphy Jennifer , Healy Colm , Fӧcking Melanie , Cannon Mary , Cotter David R. 
Published: September 2023

AbstractBackgroundAccumulating evidence suggests individuals with psychotic disorder show abnormalities in metabolic and inflammatory processes. Recently, several studies have employed blood-based predictors in models predicting transition to psychotic disorder in risk-enriched populations. A systematic review of the performance and methodology of prognostic models using blood-based biomarkers in the prediction of psychotic disorder from risk-enriched populations is warranted.MethodsDatabases (PubMed, EMBASE and PsycINFO) were searched for eligible texts from 1998 to 15/05/2023 which detailed model development or validation studies. The checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS) was used to guide data extraction from eligible texts and the Prediction Model Risk of Bias Assessment Tool (PROBAST) was used to assess risk of bias and applicability of the studies. A narrative synthesis of included studies was performed.Results17 eligible studies were identified: 16 eligible model development studies and one eligible model validation study. A wide range of biomarkers were assessed including nucleic acids, proteins, metabolites and lipids. The range of C-index (area under the curve) estimates reported for the models was 0.67-1.00. No studies assessed model calibration. According to PROBAST criteria, all studies were at high risk of bias in the analysis domain.DiscussionWhile a wide range of potentially predictive biomarkers were identified in the included studies, most studies did not account for overfitting in model performance estimates, no studies assessed calibration, and all models were at high risk of bias according to PROBAST criteria. External validation of the models is needed to provide more accurate estimates of their performance. Future studies which follow the latest available methodological and reporting guidelines and adopt strategies to accommodate required sample sizes for model development or validation will clarify the value of including blood-based biomarkers in models predicting psychosis.
Prevalence and predictors of self-medication for COVID-19 among slum dwellers in Jinja City, Uganda
Authors: Nakito Prossy , Kisakye Angela N. , Walekhwa Abel Wilson , Tumukunde Gloria , Mutesi Charity , Muhumuza Nicholas , Nyamor Carolyne , Musoke David , Musinguzi Geofrey , Byonanebye Dathan M. 
Published: September 2023

AbstractIntroductionSelf-medication is a serious public health concern globally and is more prevalent in underserved populations, especially in resource limited settings. The lack of effective treatment for COVID-19 and poor access to healthcare were drivers of self-medication. We investigated the prevalence and associated factors with self-medication for COVID-19 among slum dwellers in a Ugandan slum.Methods and materialsWe conducted a cross-sectional study using randomly selected respondents from slums in Jinja city, Uganda. Households were proportionately selected from the slums and one participant with confirmed or self-reported COVID-19 during 2021 was recruited. Poisson regression with robust standard errors was used to determine the crude (CPR) and adjusted prevalence ratios (APR) (95% CI) of factors associated with self-medication. Variables were selected apriori and backward elimination approach used to fit the final multivariate model in which variables with aP≤ 0.05 were included.ResultsOverall, 517 respondents were recruited, median age (years) was 31 (26-40), and 59% were male. The prevalence of self-medication for COVID-19 was 87.23% (451/517), 95% CI: [84.00%-90.00%] and 56% knew that self-medication was dangerous. Age≥50 years, compared to 20-29 years [APR: 1.12, 95% CI:1.05, 1.20], being female [APR: 1.07, 95% CI: 1.02, 1.13], minor [APR: 1.62, 95% CI: 1.25, 2.11], and severe symptoms [APR: 1.51, 95% CI: 1.16, 1.96], access to internet [APR: 1.13, 95% CI: 1.07, 1.20]. Having medical insurance [APR: 0.63, 95% CI: 0.46, 0.87] and awareness about laws against self-medication [APR: 0.89, 95% CI: 0.81, 0.97] were associated with a lower risk of self-medication.ConclusionThe prevalence of self-medication in slum dwellers in Uganda was high despite high awareness about its dangers. Self-medication was common in those with severe symptoms and those access to internet. There is need to control infodemia and improve health insurance cover in informal settlements within Uganda.
Local G-quadruplexes are not a major determinant of altered gene expression in BLM-deficient cells
Authors: Lobo Thamar Jessurun , Lansdorp Peter M , Guryev Victor 
Published: September 2023

AbstractMutations in theBlmgene can cause Bloom Syndrome, a genetic disorder characterized by genome instability and cancer predisposition.Blmencodes a helicase which was reported to resolve G-quadruplex DNA structuresin vitro. The G-quadruplex resolving activity of the BLM helicase has been previously implicated in altering gene expression. However, the exact mechanisms of how G-quadruplex structures may affect gene expression remain to be elucidated. We employed experimentally defined G-quadruplex forming DNA sequences and generated transcriptomes for several Bloom Syndrome patient-derived cell lines and BLM-deficient mouse embryonic stem cells to further investigate the effect of G-quadruplexes on gene expression. Our results do not support the previous findings that G-quadruplexes located within a gene play a major role in altering its expression in BLM-deficient cells. We found concerted large-scale changes in transcript abundance, splicing, nucleosome occupancy, and phasing, that cannot be linked to the local presence of G-quadruplex sequences in either gene bodies or promotors. The investigation of genomic features associated with large-scale differences in nucleosome density highlights the rDNA locus and active enhancers as the most strongly affected regions. We hypothesize that global changes in chromatin structure rather than local G4s might mediate the transcriptome changes in the absence of BLM.
NSUN5 is essential for proper Hippo signaling in mouse preimplantation development
Authors: Liu Dan , Yamamoto Takuto , Minami Naojiro , Honda Shinnosuke , Ikeda Shuntaro 
Published: September 2023

AbstractNOL1/NOP2/Sun domain family, member 5 (NSUN5) is an enzyme belonging to the 5-methylcytosine (m5C) writer family that modifies rRNA and mRNA. By re-analyzing published RNA-sequencing data, we found thatNsun5expression was increased at the 2-cell stage during mouse preimplantation development. It has been reported that m5C regulates the stability of rRNA and mRNA. Therefore, NSUN5 may affect the expression of genes required for the development and differentiation of early mouse embryos via its role in modifying RNA. The Hippo signaling pathway has been identified as a critical regulator of the segregation of inner cell mass and trophectoderm lineages during mouse embryogenesis. According to these findings, we hypothesized that NSUN5 controls cell differentiation by regulating the expression of components of the Hippo signaling pathway in mouse early embryos. UsingNsun5-specific small interfering RNAs, we efficiently knocked downNsun5expression in mouse preimplantation embryos, resulting in impairments in early development, including reduced blastocyst formation, smaller size, and impaired hatching from the zona pellucida.Nsun5depletion also led to decreased cell numbers, suggesting impaired cell proliferation. Furthermore,Nsun5knockdown embryos exhibited reduced yes-associated protein 1 (YAP1) nuclear translocation during the morula stage, potentially affecting cell differentiation. The imbalance in pluripotent and trophectoderm lineages was evident with a significant reduction in the ratio of CDX2-positive cells to OCT4-positive cells.Nsun5depletion impacted the Hippo signaling pathway, increasing the expression of the key genesLats1andLats2during the morula stage. Our findings underscore the essential role ofNsun5in early embryonic development by affecting cell proliferation, YAP1 nuclear translocation, and the Hippo pathway. Understanding the roles ofNsun5in mouse early embryos will provide insights into complex regulatory networks in development, with implications for reproductive medicine and fertility research.
Thermal and Nutrient Stress Drove Permian-Triassic Marine Extinctions
Authors: Foster William J. , Frank Anja B. , Li Qijan , Danise Silvia , Wang Xia , Peckmann Jörn 
Published: September 2023

AbstractThe Permian-Triassic mass extinction coincides with extensive environmental changes (i.e., thermal stress, deoxygenation and potentially ocean acidification), but the primary drivers of extinction in them marine realm are currently unknown. To understand which factors caused extinctions, we quantitatively investigated the relationship between geochemical proxies and fossil record at the most intensively-studied locality for this event, the Meishan section, China. We found that δ18Oapatite(paleotemperature proxy) and δ114Cd (primary productivity proxy) best explain changes in species diversity and composition at Meishan’s paleoequatorial setting. These findings suggest that the physiological stresses induced by ocean warming and nutrient availability played a predominant role in driving equatorial marine extinctions during the Permian-Triassic event. This research enhances our understanding of the interplay between environmental changes and extinction dynamics during a past climate crisis.One-Sentence SummaryOcean warming and nutrient availability were key drivers of equatorial marine extinctions during the Permian-Triassic mass extinction.
CCG-1423-derived compounds reduce global RNA synthesis and inhibit transcriptional responses
Authors: Prajapati Bina , Sokolova Maria , Sidorenko Ekaterina , Kyriacou Mikael , Kyheröinen Salla , Vihervaara Anniina , Vartiainen Maria K. 
Published: September 2023

AbstractMyocardin-related transcription factors (MRTFs) are coactivators of serum response factor (SRF), and thereby regulate cytoskeletal gene expression in response to actin dynamics. MRTFs have also been implicated in heat shock protein (hsp) transcription in fly ovaries, but the mechanisms remain unclear. Here we demonstrate that in mammalian cells, MRTFs are dispensable forhspgene induction. However, the widely used small molecule inhibitors of MRTF/SRF transcription pathway, derived from CCG-1423, efficiently inhibithspgene transcription in both fly and mammalian cells also in absence of MRTFs. Quantifying RNA synthesis and RNA polymerase distribution demonstrates that CCG-1423-derived compounds have a genome-wide effect on transcription. Indeed, tracking nascent transcription at nucleotide resolution reveals that CCG-1423-derived compounds reduce RNA polymerase II elongation, and severely dampen the transcriptional response to heat shock. The effects of CCG-1423-derived compounds therefore extend beyond the MRTF/SRF pathway into nascent transcription, opening novel opportunities for their use in transcription research.
Molecular control of cellulosic fin morphogenesis in ascidians
Authors: LANOIZELET Maxence , ELKHOURY YOUHANNA Christel , DARRAS SébasBen 
Published: September 2023

AbstractThe tunicates form a group of filter-feeding marine animals closely related to vertebrates. They share with them a number of features such as a notochord and a dorsal neural tube in the tadpole larvae of ascidians, one of the three groups that make tunicates. However, a number of typical chordate characters have been lost in different branches of tunicates, a diverse and fast-evolving phylum. Consequently, the tunic, a sort of exoskeleton made of extracellular material including cellulose secreted by the epidermis, is the unifying character defining the tunicate phylum. In the larva of ascidians, the tunic differenBates in the tail into a median fin (with dorsal and ventral extended blades) and a caudal fin. Here we have performed experiments in the ascidianPhallusia mammillatato address the molecular control of tunic 3D morphogenesis. We have demonstrated that the tail epidermis medio-lateral paaerning essenBal for peripheral nervous system specificaBon also controls tunic elongaBon into fins. More specifically, when tail epidermis midline idenBty was abolished by BMP signaling inhibiBon, or CRISPR/Cas9 inacBvaBon of the transcripBon factor coding genesMsxorKlf1/2/4/17, median fin did not form. We postulated that this geneBc program should regulate effectors of tunic secreBon. We thus analyzed the expression and regulaBon in different ascidian species of two genes acquired by horizontal gene transfer (HGT) from bacteria,CesAcoding for a cellulose synthase andGh6coding for a cellulase. Although we have uncovered an unexpected dynamic history of these genes in tunicates, and high levels of variability in gene expression and regulaBon among ascidians, we showed thatGh6has a regionalized expression in the epidermis, and that it is a regulator of caudal fin formaBon. Our study consBtutes an important step in the study of the integraBon of HGT-acquired genes into developmental networks, and a cellulose-based morphogenesis of extracellular material in animals.
Proteome partitioning constraints on long-term laboratory evolution
Authors: Mori Matteo , Patsalo Vadim , Williamson James R. , Scott Matthew 
Published: September 2023

AbstractAdaptive laboratory evolution experiments provide a controlled context in which the dynamics of selection and adaptation can be followed in real-time at the single-nucleotide level1. And yet this precision introduces hundreds of degrees-of-freedom as genetic changes accrue in parallel lineages over generations2. On short timescales, physiological constraints have been leveraged to provide a coarse-grained view of bacterial gene expression characterized by a small set of phenomenological parameters3–5. Here, we ask whether this same framework, operating at a level between genotype and fitness, informs physiological changes that occur on evolutionary timescales. Using Lenski’s Ara-1 lineage adapted to growth in glucose minimal medium6, we find that the proteome is substantially remodeled over 40 000 generations. We apply our existing quantitative proteomics analysis to partition hundreds of expressed proteins into six sectors with shared metabolic function and physiological response4. To accommodate the increased growth rates in the evolved strains, expression of metabolic enzymes undergoes sector-specific adaptation to enable increased fluxes. We find that catabolic proteins adapt by increasing the total enzyme abundance, whereas anabolic and glycolytic proteins exhibit decreased free-enzyme pools. We propose that flux-dependent regulation7and substrate saturation8can account for the sector-specific remodeling.
In-vitroreconstitution of Herpes Simplex Virus 1 fusion identifies low pH as a fusion co-trigger
Authors: Ramirez J. Martin , Calderon-Zavala Ariana , Balaram Ariane , Heldwein Ekaterina E. 
Published: September 2023

ABSTRACTMembrane fusion mediated by Herpes Simplex virus 1 (HSV-1) is a complex, multi-protein process that is receptor-triggered and can occur both at the cell surface and in endosomes. To deconvolute this complexity, we reconstituted HSV-1 fusion with synthetic lipid vesiclesin vitro. Using this simplified, controllable system, we discovered that HSV-1 fusion required not only a cognate host receptor but also low pH. On the target membrane side, efficient fusion required cholesterol, negatively charged lipids found in the endosomal membranes, and an optimal balance of lipid order and disorder. On the virion side, the four HSV-1 entry glycoproteins gB, gD, gH, and gL were sufficient for fusion. We propose that low pH is a biologically relevant co-trigger for HSV-1 fusion. The dependence of fusion on low pH and endosomal lipids could explain why HSV-1 enters most cell types by endocytosis. We hypothesize that under neutral pH conditions, other, yet undefined, cellular factors may serve as fusion co-triggers. Thein-vitrofusion system established here can be employed to systematically investigate HSV-1-mediated membrane fusion.IMPORTANCEHerpes simplex virus 1 (HSV-1) causes life-long, incurable infections and diseases ranging from mucocutaneous lesions to fatal encephalitis. Fusion of viral and host membranes is a critical step in HSV-1 infection of target cells that requires multiple factors on both the viral and host sides. Due to this complexity, many fundamental questions remain unanswered, such as the viral and host factors that are necessary and sufficient for HSV-1-mediated membrane fusion and the nature of the fusion trigger. Here, we developed a simplifiedin-vitrofusion assay to examine the fusion requirements and identified low pH as a co-trigger for virus-mediated fusionin vitro.We hypothesize that low pH has a critical role in cell entry and, potentially, pathogenesis.
A cell atlas of the larvalAedes aegyptiventral nerve cord
Authors: Yin Chang , Morita Takeshi , Parrish Jay Z. 
Published: September 2023

AbstractMosquito-borne diseases account for nearly one million human deaths annually, yet we have a limited understanding of developmental events that influence host-seeking behavior and pathogen transmission in mosquitoes. Mosquito-borne pathogens are transmitted during blood meals, hence adult mosquito behavior and physiology have been intensely studied. However, events during larval development shape adult traits, larvae respond to many of the same sensory cues as adults, and larvae are susceptible to infection by many of the same disease-causing agents as adults. Hence, a better understanding of larval physiology will directly inform our understanding of physiological processes in adults. Here, we use single cell RNA sequencing (scRNA-seq) to provide a comprehensive view of cellular composition in theAedes aegyptilarval ventral nerve cord (VNC), a central hub of sensory inputs and motor outputs which additionally controls multiple aspects of larval physiology. We identify more than 35 VNC cell types defined in part by neurotransmitter and neuropeptide expression. We also explore diversity among monoaminergic and peptidergic neurons that likely control key elements of larval physiology and developmental timing, and identify neuroblasts and immature neurons, providing a view of neuronal differentiation in the VNC. Finally, we find that larval cell composition, number, and position are preserved in the adult abdominal VNC, suggesting studies of larval VNC form and function will likely directly inform our understanding adult mosquito physiology. Altogether, these studies provide a framework for targeted analysis of VNC development and neuronal function inAedeslarvae.
Peripheral insulin resistance attenuates cerebral glucose metabolism and impairs working memory in healthy adults
Authors: Deery Hamish A. , Liang Emma , Di Paolo Robert , Voigt Katharina , Murray Gerard , Siddiqui M. Navyaan , Egan Gary F. , Moran Chris , Jamadar Sharna D. 
Published: September 2023

AbstractPeople with insulin resistance are at increased risk for cognitive decline. Insulin resistance has previously been considered primarily a condition of ageing but it is increasingly seen in younger adults. Here, we explore the question that changes in insulin function in early adulthood have both proximal effects, and moderate or even accelerate changes in cerebral metabolism in ageing. Thirty-six younger (mean 27.8 years) and 43 older (mean 75.5) participants completed a battery of tests, including blood sampling, cognitive assessment and a simultaneous PET/MR scan. Cortical thickness and cerebral metabolic rate of glucose were derived for 100 regions and 17 functional networks. Older adults had lower rates of regional cerebral glucose metabolism than younger adults across the brain even after adjusting for lower cortical thickness in older adults. In younger adults, higher insulin resistance was associated with attenuated rates of regional cerebral glucose metabolism, but this was not seen in older adults. The largest effects of insulin resistance in younger adults were in prefrontal, parietal and temporal regions; and in the control, salience ventral attention, default and somatomotor networks. Higher rates of network glucose metabolism were associated with lower reaction time and psychomotor speed. Higher levels of insulin resistance were associated with lower working memory. Our results underscore the importance of insulin sensitivity to brain health and cognitive function across the adult lifespan, even in early adulthood.Significance StatementWe show that preventing insulin resistance in early adulthood is important for ensuring efficient fuel supply for the brain and the maintenance of cognitive health across the adult lifespan. Glucose is the primary source of energy for the brain. Decreased glucose metabolism in the brain due to clinically significant levels of insulin resistance is associated with cognitive impairment. Although sub-clinical levels of insulin resistance have also been associated with brain changes, their impact on cerebral metabolism in healthy individuals is unclear. We showed for the first time that – while older adults have lower rates of cerebral metabolism - peripheral insulin resistance attenuates cerebral metabolism more so in healthy younger than healthy older adults, and impairs working memory.