bluuebunny/crossref_metadata_2025_split huggingface dataset:
FGF12 Modulates Cardiomyocyte Hypertrophy by Inhibiting GATA4-ERK1/2 Phosphorylation Through Altered Intracellular Localization
Authors: Zhang Taojun , Yin Kunlun , Yang Fangfang , Li Tianjiao , Wang Shuiyun , Zhou Zhou 
Published: December 2023

AbstractBackgroundHypertrophic cardiomyopathy (HCM) is a heritable pathological condition resulting from mutations in sarcomere-related proteins, leading to severe structural abnormalities without effective treatment options. Although reducedfibroblast growth factor 12(FGF12) expression is observed in HCM patients, its functional role remains unclear.MethodsEmploying immunoprecipitation (IP)-mass spectrometry (MS) and CUT&Tag sequencing, we investigated FGF12-interacting proteins in myocardial samples from healthy volunteers and HCM patients. CRISPR-Cas9 was utilized to explore the function and interaction partners of FGF12 in cardiomyocytes induced from human pluripotent stem cells (hiPSCs-CMs), other cell lines, and mouse models (MYH7R403Qand MYBPC3c.790G>A, transverse aortic constriction (TAC)). During hypertrophy, FGF12 localizes intranuclearly, prompting investigations into its binding to gene promoter regions through CUT&Tag sequencing and dual-luciferase experiments using myocardial tissues from patients. The beating frequency of hiPS-CMs was assessed using the CardioExcyte 96 real-time label-free cardiomyocyte functional analysis system.ResultsFGF12 was found to associate with proteins involved in energy metabolism, predominantly localizing to the perinuclear space under physiological conditions but shifting into the nucleus of hypertrophic cardiomyocytes. Co-IP-MS revealed significant interactions between FGF12 and metabolism-associated proteins, particularly GATA binding protein 4 (GATA4) and mitogen-activated protein kinase 1/3 (MAPK1/3) in the perinuclear space. In a hypertrophic state, FGF12 bound to the GATA4 promoter region, increasing its expression upon nuclear translocation. Bothin vitroandin vivomodels demonstrated that FGF12 interaction with GATA4 inhibited GATA4 and MAPK1/3 phosphorylation, inducing the expression of hypertrophy-associated genes. Overexpression of FGF12-NLS-del (nuclear localization signal deletion) resulted in decreased GATA4 phosphorylation, suggesting inhibition in the perinuclear region.ConclusionsThis study elucidates a pathological mechanism of HCM involving FGF12, where its nuclear localization enhances phosphorylation, GATA4 expression, and activation of the ERK1/2-pGATA4 pathway genes associated with hypertrophy. Beyond advancing our understanding of HCM, these findings propose FGF12 as a potential therapeutic target for HCM, warranting further exploration to potentially alleviate this condition affecting millions of individuals.
Association of poultry vaccination with the interspecies transmission and molecular evolution of H5 subtype avian influenza virus
Authors: Li Bingying , Raghwani Jayna , Hill Sarah C. , François Sarah , Lefrancq Noémie , Liang Yilin , Wang Zengmiao , Dong Lu , Lemey Phillipe , Pybus Oliver G. , Tian Huaiyu 
Published: December 2023

AbstractThe effectiveness of vaccinating poultry in preventing the transmission of highly pathogenic avian influenza viruses (AIVs) has been questioned for years and its impact on wild birds is uncertain1–3. Here we reconstruct movements of H5 subtype AIV lineages among vaccinated poultry, unvaccinated poultry, and wild birds, worldwide from 1996 to 2023. We find that lineage transitions among host types are lagged and that movements from wild birds to unvaccinated poultry were more frequent than those from wild birds to vaccinated poultry. However, we also find that the HA gene of the AIV lineage that circulated predominately among Chinese poultry with high vaccination coverage underwent faster evolution and greater nonsynonymous divergence than other lineages. Further, this Chinese poultry lineage contained more codons inferred to be under positive selection, including at known antigenic sites, and its rates of nonsynonymous divergence and adaptative fixation increased after mass poultry vaccination began. Our results indicate that the epidemiological, ecological and evolutionary consequences of widespread AIV vaccination in poultry may be linked in complex ways, and that much work is needed to better understand how such interventions may affect AIV transmission to, within and from wild birds.
Concerted SUMO-targeted ubiquitin ligase activities of TOPORS and RNF4 are essential for stress management and cell proliferation
Authors: Liu Julio C.Y. , Ackermann Leena , Hoffmann Saskia , Gál Zita , Hendriks Ivo A. , Jain Charu , Morlot Louise , Tatham Michael H. , McLelland Gian-Luca , Hay Ronald T. , Nielsen Michael Lund , Brummelkamp Thijn , Haahr Peter , Mailand Niels 
Published: December 2023

SummaryProtein SUMOylation provides a principal driving force for cellular stress responses including DNA-protein crosslink (DPC) repair and arsenic-induced PML body degradation. In genome-scale screens, we identified the human E3 ligase TOPORS as a key effector of SUMO-dependent DPC resolution. We demonstrate that TOPORS promotes DPC repair by functioning as a SUMO-targeted ubiquitin ligase (STUbL) for DPCs, combining ubiquitin ligase activity through its RING domain with poly-SUMO chain binding via a cluster of SUMO-interacting motifs, analogous to the STUbL RNF4. Surprisingly, the STUbL activities of TOPORS and RNF4 are both required for SUMO-dependent DPC repair, PML degradation and other stress responses, making overlapping and distinct contributions to ubiquitin chain formation on SUMOylated targets to enable p97/VCP unfoldase recruitment. Combined loss of TOPORS and RNF4 is synthetic lethal even in unstressed cells, leading to defective clearance of SUMOylated proteins from chromatin accompanied by cell cycle arrest and apoptosis. Together, our findings establish TOPORS as a novel STUbL whose concerted action with RNF4 defines a general mechanistic principle in crucial cellular processes governed by direct SUMO-ubiquitin crosstalk.HighlightsThe RING E3 ligase TOPORS is required for SUMO-dependent DPC repairTOPORS is a novel SUMO-targeted ubiquitin ligase (STUbL)TOPORS promotes multiple STUbL-driven processes in conjunction with RNF4Combined TOPORS and RNF4 loss is synthetic lethal in human cells
Association between electrophysiological phenotypes and Kv2.1 potassium channel expression explained by geometrical analysis
Authors: Reyes-Garibaldi Julio César , Herrera-Valdez Marco Arieli 
Published: December 2023

AbstractExcitable cells exhibit different electrophysiological profiles while responding to current stimulation in current-clamp experiments. In theory, the differences could be explained by changes in the expression of proteins mediating transmembrane ion transport. Experimental verification by performing systematic, controlled variations in the expression of proteins of the same type (e.g. voltage-dependent, noninactivating Kv2.1 channels) is difficult to achieve in the absence of other changes. However, biophysical models enable this possibility and allows us to assess and characterise the electrophysiological phenotypes associated to different levels of expression of non-inactivating voltage-dependent K-channels of type Kv2.1. To do so, we use a 2-dimensional biophysical model of neuronal membrane potential and study the phase plane geometry and bifurcation structures associated with different levels of Kv2.1 expression with the input current as bifurcation parameter. We find that increasing the expression of Kv2.1 channels reduces the size of the region of the phase plane from which action potentials can be initiated. The changes in expression can also be related to different transitions between rest and repetitive firing in current clamp experiments. For instance, increasing the number of Kv2.1 channels shifts the rheobase current to higher levels, but also expands the dynamic range in which excitatory external current produces repetitive spiking. Our analysis shows that changes in the responses to increasing input currents can be associated to different sequences of fixed point bifurcations. In general, the fixed points are attracting, then repulsive, and later become attracting again as the input current increases, but the bifurcation sequences also include changes in fixed point type, and change qualitatively with the expression of Kv2.1 channels. In the non-repetitive spiking regime with low current stimulation, low expression of Kv2.1 channels yields bifurcation sequences that include transitions between 3 and 1 fixed points, and repetitive firing starts with delays that decrease with increasing current (aggregation). For higher expression of Kv2.1 channels there is only one fixed point that changes in type and attractivity as the input current increases, convergence to rest tends to be oscillatory (resonance), and repetitive spiking starts without noticeable delays. Our models explain how the same neuron is theoretically be capable of including both aggregating and resonant modes of integration for synaptic input, as shown in current clamp experiments.
Increased1H-NMR metabolomics-based health score associates with declined cognitive performance and functional independence in older adults at risk of cardiovascular disease
Authors: Zonneveld Michelle H. , Kuhaili Nour Al , Mooijaart Simon P. , Slagboom P. Eline , Jukema J. Wouter , Noordam Raymond , Trompet Stella 
Published: December 2023

AbstractBackgroundThe 1-HMR metabolomics-based MetaboHealth score, comprised of 14 serum metabolic markers, associates with disease-specific mortality, but it is unclear whether the score also reflects cognitive changes and functional impairment.ObjectivesAssess the associations between the MetaboHealth score with cognitive and daily functioning, and cognitive and functional decline in older people at increased cardiovascular risk.Methods5292 older people free of dementia at baseline with mean age 75.3 years (standard deviation=3.4) from the Prospective Study of Pravastatin in the Elderly (PROSPER). MetaboHealth score was measured at baseline, and cognitive function and functional independence were measured at baseline and every 3 months during up to 2.5-years follow-up. Cognitive function was assessed using the Stroop test (selective attention), the Letter Digit Coding test (LDCT) (processing speed), and the two versions of the Picture Learning test (delayed and immediate; memory). Two tests of functional independence were used: Barthel Index (BI) and instrumental activities at daily living (IADL).ResultsA higher MetaboHealth score was associated with worse cognitive function (in all domains) and with worse functional independence. For example, after full adjustments, a 1-SD higher MetaboHealth score was associated with 9.02 (95%CI 7.29, 10.75) seconds slower performance on the Stroop test and 2.79 (-3.26,-2.21) less digits coded on the LDCT. During follow-up, 1-SD higher MetaboHealth score was associated with an additional decline of 0.53 (0.23,0.83) seconds on the Stroop test and -0.08 (-0.11,-0.06) points on the IADL.ConclusionMetabolic disturbance, as reflected by an increased metabolomics-based health score, may mark future cognitive and functional decline.
Evaluation of non-contact infrared thermometers for COVID-19 fever screening in healthcare workers: A prospective observational study in a tertiary care hospital
Authors: Kumar D. Suresh , Ratheesh R. , Poojadharshini M. , Kalyani P. , Pooja S. 
Published: December 2023

ABSTRACTBackgroundIn the fight against COVID-19, efficient fever screening was essential to curb transmission. Fever served as a cardinal symptom, aiding early and timely identification of fever among healthcare workers (HCWs) was crucial. While non-contact infrared thermometers (NCITs) offered non-invasive screening, existing data gaps were present. This study aimed to assess the NCIT effectiveness in HCW fever screening by comparing results with serology and RT-PCR tests, ascertaining their utility in healthcare settings for COVID-19 detection.MethodsThis prospective observational study was conducted at a dedicated COVID-19 tertiary care hospital with 250 beds in South India. The study population comprised 736 healthcare workers (HCWs) working in the hospital, and the study was carried out between April 2020 and December 2020. Daily fever screening using non-contact infrared thermometers (NCITs) was performed on all HCWs upon their entry to the hospital. Additionally, serological tests were offered to all HCWs starting from November 2020 to assess prior COVID-19 infection exposure. COVID-19 admissions were closely monitored during the study period to identify hospitalized HCWs with symptoms who subsequently tested positive for COVID-19 using RT-PCR.ResultsIn this study cohort of 736 HCWs, 44,836 NCIT screenings revealed no fever cases. The serological analysis identified prior COVID-19 exposure in 229 HCWs. McNemar’s test (χ2= 26.27, p < 0.05) emphasized discordance between NCIT and serology. ROC analysis yielded an AUC of 0.500, indicating NCIT’s challenge in distinguishing febrile cases. Additionally, 68 symptomatic HCWs tested COVID-19 positive through RT-PCR, highlighting the role of complementary diagnostics.ConclusionThe failure of NCIT to identify fever cases in our study highlights the importance of incorporating supplementary screening methods and comprehensive strategies in future pandemic preparedness.
Whole genome and transcriptome sequencing in neuromuscular disorders: a diagnostic and health economic analysis
Authors: Yang Ziying , Yang Xiaoru , Chen Yunmei , Wang Zhonghua , Fu Xiangke , Song Lijie , Yang Xunzhe , Peng Zhiyu , Dai Yi 
Published: December 2023

AbstractBackgroundA considerable number of patients suffering from neuromuscular disorders (NMD) are unable to receive an accurate diagnosis through initial genetic testing. It is imperative to develop a cost-effective diagnostic strategy that incorporates appropriate multi-omics techniques.MethodsThis study included 33 NMD patients with negative results from whole-exome sequencing (WES). Whole-genome sequencing (WGS) and RNA sequencing (RNA-seq) were performed concurrently to evaluate clinical utility. Additionally, eight diagnostic pathways were compared in terms of diagnostic rate, turnaround time, and cost.ResultsOur implementation of parallel WGS and RNA-seq testing successfully validated the clinical utility of this strategy in the cohort of 33 NMD patients initially yielding negative results from WES. The combined utilization of both methods resulted in an additional diagnosis for 42% (15/33) of the patients, with WGS contributing to 36% and RNA-seq contributing to 6% of the diagnoses. The Integration of alternative splicing results derived from RNA-seq data into variant filtering significantly reduced the number of rare intronic variants requiring interpretation and provided compelling evidence to support the classification of variant pathogenicity based on functional impact. Our comprehensive analysis, comparing eight different diagnostic pathways, revealed the cost-effectiveness of parallel WGS and RNA-seq testing as a diagnostic approach for patients. Moreover, the analysis of rare genomic findings within our cases showcased their potential to inform patient care, aid treatment decisions, and expand the range of NMD mutations in diagnosing rare NMD cases.ConclusionThe integration of parallel WGS and RNA-seq testing represents a transformative diagnostic approach for NMD patients. The cost-effectiveness of this approach, coupled with its ability to improve diagnostic yield and interpretation efficiency, makes it a highly recommended strategy for clinical implementation to enhance the management and care of NMD patients.
Alterations in gamma frequency oscillations correlate with cortical tau deposition in Alzheimer’s disease
Authors: Nencha Umberto , Rigoni Isotta , Ribaldi Federica , Altomare Daniele , Seeck Margitta , Garibotto Valentina , Vulliémoz Serge , Frisoni Giovanni B. 
Published: December 2023

AbstractWe assessed the relationship of gamma oscillations with tau deposition in Alzheimer’s disease (AD) and other cognitive diseases, as both are altered during the disease course and relate to neurodegeneration. We retrospectively analyzed data from 7 AD, tau positive patients and 9 tau negative patients, that underwent amyloid PET, and cerebral tau PET and EEG within 12 months. Relative gamma power was higher in tau positive (AD) patients than in tau negative patients (p<.05) and tau burden was associated with a linear increase in gamma power (p<.001), while no association was present with amyloid-β burden. Thus, increase in the gamma power might represent a novel biomarker for tau driven neurodegeneration.
Deep immune profiling of chronic rhinosinusitis in allergic and non-allergic cohorts using mass cytometry
Authors: Kidane Fana Alem , Müller Lena , Rocha-Hasler Marianne , Tu Aldine , Stanek Victoria , Campion Nicholas , Bartosik Tina , Zghaebi Mohammed , Stoshikj Slagjana , Gompelmann Daniela , Spittler Andreas , Idzko Marco , Schneider Sven , Eckl-Dorna Julia 
Published: December 2023

ABSTRACTBackgroundChronic rhinosinusitis (CRS) is characterized by persistent nasal and paranasal sinus mucosa inflammation. It comprises two phenotypes, namely CRS with nasal polyps (CRSwNP) and without (CRSsNP). CRSwNP can be associated with asthma and hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) in a syndrome known as NSAID-exacerbated respiratory disease (N-ERD). Furthermore, CRS frequently intertwines with respiratory allergies.ObjectiveThis study investigated the phenotypic characteristics of peripheral blood mononuclear cells (PBMCs) within cohorts of CRS patients, additionally examining the influence of comorbid respiratory allergies on these parameters.Methods24 participants were grouped into controls, CRSsNP, CRSwNP, and N-ERD (n=6/group), with half of the patients in each group having respiratory allergies. Levels of cytokines were quantified in nasal secretions and sera. The abundance and phenotypic features of immune cells in PBMCs were evaluated through mass cytometry and clustering methods.ResultsN-ERD patients showed heightened type 2 nasal cytokine levels. Mass cytometry analysis revealed increased activated naive B cell levels in CRSwNP and N-ERD, while resting naive B cells were higher in CRSsNP. Th2a cell levels did not differ between CRS subtypes but were significantly elevated in allergic subjects. In CRSwNP and N-ERD patients, naive B cells had a lower CXCR5 and higher CD45RA expression, while NK cells displayed reduced CD56 levels.ConclusionsThere are distinct immunological features in PBMCs of CRS phenotypes and allergy, characterized by elevated resting naive B cells in CRSsNP, increased activated naive B cells in CRSwNP and N-ERD, and higher Th2a cell levels in allergic subjects.Capsule summaryThis study examines immunological profiles in different phenotypes of CRS with and without comorbid allergy patients, highlighting immune cell intricacies in CRS subtypes and immune differences in CRS and respiratory allergy.
Role of the metallo-reductase FADING and vacuolinos in anthocyanin degradation in flowers and fruits
Authors: Passeri Valentina , Li Shuangjiang , Strazzer Pamela , i Calvó’ Enric Martínez , Senden Esther , Guzzo Flavia , Commisso Mauro , Spelt Cornelis , Vandenbussche Michiel , Bliek Mattijs , Verweij Walter , Koes Ronald , Quattrocchio Francesca M. 
Published: December 2023

AbstractAnthocyanins are vacuolar pigments that confer red-violet colors to plant tissues. Pigmentation patterns result from spatio-temporally regulated anthocyanin synthesis and degradation. Mutational inactivation of a conserved MYB-bHLH-WDrepeat-WRKY transcriptional complex (MBWW) causes degradation of anthocyanins and ‘fading’ of flower color via a pathway that involvesFADING (FA). Here we show thatFAencodes a vacuolar membrane Fe-reductase-oxidase that promotes anthocyanin degradation. In wild type petals anthocyanins in the central vacuole (CV) are stable, because FA-GFP is upheld in small vacuoles (vacuolinos) and kept away from the CV, indicating that vacuolinos act as gatekeepers in protein trafficking. In cells lacking vacuolinos, includingmbww-mutant petals, FA-GFP reaches the CV and triggers anthocyanin degradation. Virus-induced gene silencing (VIGS) of an FA-homolog in pepper fruits prevented the “fading” of anthocyanins during fruit maturation. These findings provide new insights to breed ornamental and food crops with increased anthocyanin-content and enhanced nutritional value of edible parts.
Maximizing glycoproteomics results through an integrated PASEF workflow
Authors: Baerenfaenger Melissa , Post Merel A , Zijlstra Fokje , van Gool Alain J , Lefeber Dirk J , Wessels Hans JCT 
Published: December 2023

ABSTRACTGlycoproteins play important roles in numerous physiological processes and are often implicated in disease. Analysis of site-specific protein glycobiology through glycoproteomics is evolving rapidly in recent years thanks to hardware and software innovations. Particularly, the introduction of Parallel Accumulation Serial Fragmentation (PASEF) on hybrid trapped ion mobility time-of-flight mass spectrometry instruments combined deep proteome sequencing with separation of (near-)isobaric precursor ions or converging isotope envelopes through ion mobility separation. However, reported use of PASEF in integrated glycoproteomics workflows to comprehensively capture the glycoproteome is still limited. To this end, we developed an integrated methodology using the timsTOF Pro 2 to enhance N-glycopeptide identifications in complex mixtures. We systematically optimized the ion optics tuning, collision energies, mobility isolation width and the use of do-pant-enriched nitrogen gas (DEN). Thus, we obtained a marked increase in unique glycopeptide identification rates compared to standard proteomics settings showcasing our results on a large set of glycopeptides. With short liquid chromatography gradients of 30 minutes, we increased the number of unique N-glycopeptide identifications in human plasma samples from around 100 identifications under standard proteomics condition to up to 1500 with our optimized glycoproteomics approach, highlighting the need for tailored optimizations to obtain comprehensive data.Abstract Figure