bluuebunny/crossref_metadata_2025_split huggingface dataset:
Histopathology and proteomics are synergistic for High-Grade Serous Ovarian Cancer platinum response prediction
Authors: Kilim Oz , Olar Alex , Biricz András , Madaras Lilla , Pollner Péter , Szállási Zoltán , Sztupinszki Zsofia , Csabai István 
Published: June 2024

AbstractPatients with High-Grade Serous Ovarian Cancer (HGSOC) exhibit varied responses to treatment, with 20-30% showingde novoresistance to platinum-based chemotherapy. While hematoxylin-eosin (H&E) pathological slides are used for routine diagnosis of cancer type, they may also contain diagnostically useful information about treatment response. Our study demonstrates that combining H&E-stained Whole Slide Images (WSIs) with proteomic signatures using a multimodal deep learning framework significantly improves the prediction of platinum response in both discovery and validation cohorts. This method outperforms the Homologous Recombination Deficiency (HRD) score in predicting platinum response and overall patient survival. The study sets new performance benchmarks and explores the intersection of histology and proteomics, highlighting phenotypes related to treatment response pathways, including homologous recombination, DNA damage response, nucleotide synthesis, apoptosis, and ER stress. This integrative approach has the potential to improve personalized treatment and provide insights into the therapeutic vulnerabilities of HGSOC.
Using Simulated Encounters with Standardized Patients to Teach Medical Students to Address Implicit Biases and Microaggressions in the Clinical Setting
Authors: Thommen Rachel , Weber Harli , Lo Katherine , Ayhan Deelan , Vellek John , Levy Lior , Smith Sarah , Hoke Christopher , Alnifaidy Redab , Vargas Danielle , Yamulla Katharine , Liberatos Penny , Etienne Mill , Ludmer Pamela 
Published: June 2024

AbstractPurposeStructural obstacles in healthcare related to social, economic, and political factors contribute to inequities in patient care. Combined didactic and experiential learning may be more effective to teach medical students how to address implicit bias and microaggression in the clinical setting.MethodsRising third year medical students at New York Medical College participated in a student-led implicit bias and microaggression training program, including experiential learning through standardized patient (SP) encounters and self-reflection via student-led debrief sessions. The SP encounters simulated instances of xenophobia and perceived language barriers in a hospital setting, in which students were expected to address microaggressions in real time utilizing the VITALS (Validate, Inquire, Take time, Assume the best, Leave opportunities, Speak up for others) framework.Results200 students participated in the program. Survey responses on attitudes regarding implicit bias and microaggressions were collected prior to participating in the program (T1), after the VITALS video presentation (T2), and after the SP encounter and debrief sessions (T3). Students felt more likely to interrupt a microaggression from T1 to T3.ConclusionsOur implicit bias training, equipped students with the tools and practice needed to interrupt microaggressions in the clinical setting.Practice PointsCombined didactic and experiential learning may be more effective than didactics alone for teaching medical students how to address implicit bias and microaggression in the clinical setting.Students overestimated their comfort level to interrupt a microaggression after watching the training video alone, underscoring the importance of experiential learning.Students valued the opportunity to practice interrupting microaggressions in a safe space with the SPs.The SP encounter positively impacted students’ likelihood to interrupt a microaggression in the future.Students felt more comfortable interrupting a microaggression from a peer than from a person in power.
ACKR5/GPR182 is a scavenger receptor for the atypical chemokine CXCL17, GPR15L and various endogenous peptides
Authors: Meyrath Max , Palmer Christie B. , Plesseria Jean-Marc , Darcis Joy , Nesheva Desislava , Thelen Marcus , Legler Daniel F. , Leurs Rob , Hanson Julien , Szpakowska Martyna , Chevigné Andy 
Published: June 2024

AbstractGPR182/ACKR5, the most recently deorphanized chemokine receptor, is mainly expressed on endothelial cells and was proposed to act as a scavenger regulating the availability of a large set of chemokines. In this study, we first established the exact profiles and ranking of the chemokines binding to the human and mouse GPR182. We confirmed the high promiscuity of GPR182 towards XC, CC and CXC chemokines and a clear difference in the chemokine repertoires of the human and mouse orthologues. We next demonstrated that, beyond classical chemokines, GPR182 exhibits potent binding to the chemoattractant protein GPR15L/C10orf99, the atypical chemokine CXCL17 and various endogenous peptides, mainly from the opioid, apelin, and PACAP families. We also showed that these newly identified ligands engage GPR182 through varied binding modes. While GPR15L, just like classical chemokines, predominantly engages GPR182 via its N terminus, conversely to the C terminus-dependent binding to its cognate receptor GPR15, CXCL17 exhibits a more complex interaction, relying on both the N and C terminus. The binding mode of the newly identified peptide ligands also differ from the interactions with their cognate receptors. Our findings establish the first scavenger receptor for CXCL17 and GPR15L and advance the understanding of GPR182 ligand interactions, suggesting a regulatory role beyond chemokines.
Chromosome-level reference genome assembly for the protected resource plant,Zenia insignis
Authors: Chen Si-Yun , Yang Zhi-Yun , Zhang Rong , Liu Hui , Yi Ting-Shuang 
Published: June 2024

AbstractZenia insignisChun, from the subfamily Dialioideae of Fabaceae, is a tree species of significant economic and ecological values. It is a threatened species as per the IUCN Red List. The absence of a reference genome has impeded research onZ. insignisdespite its importance. In this study, we generated a reference genome forZ. insig n,iwsith a contig N50 of 6.02Mb, a total length of 361.11 Mb, and 97.71% of the sequences assembled into 14 pseudo-chromosomes. The BUSCO assessment score for completeness is 97.30%, and the LAI index assessment score for continuity is 14.57. To our knowledge, this is the first reported nuclear genome of a species belonging to subfamily Dialioideae. The reference genome will provide a valuable resource for the phylogenomic studies of the Fabaceae family and facilitate further research onZ. insignis.
Blood to Biomarker Quantitation in Under One Hour with Rapid Proteomics using a Hyperthermoacidic Protease
Authors: Yannone Steven M. , Tuteja Vikas , Goleva Olena , Leung Donald Y.M. , Stotland Aleksandr , Keoseyan Angel J. , Hendricks Nathan G. , Van Eyk Jennifer E. , Kreimer Simion 
Published: June 2024

AbstractMulti-step multi-hour tryptic proteolysis has limited the utility of bottom-up proteomics for cases that require immediate quantitative information. The recently available hyperthermoacidic (HTA) protease “Krakatoa” digests samples in a single 5 to 30-minute step at pH 3 and >80 °C; conditions that disrupt most cells and tissues, denature proteins, and block disulfide reformation. The combination of quick single-step sample preparation with high throughput dual trapping column single analytical column (DTSC) liquid chromatography-mass spectrometry (LC-MS) achieves “Rapid Proteomics” in which the time from sample collection to actionable data is less than 1 hour. The presented development and systematic evaluation of this methodology found reproducible quantitation of over 160 proteins from just 1 microliter of whole blood. Furthermore, the preference of the HTA-protease for intact proteins over peptides allows for sensitive targeted quantitation of the Angiotensin I and II bioactive peptides in under half an hour. With these methods we analyzed serum and plasma from 53 individuals and quantified Angiotensin and proteins that were not detected with trypsin. This assessment of Rapid Proteomics suggests that concentration of circulating protein and peptide biomarkers could be measured in almost real-time by LC-MS.TOC FigureRapid proteomics enables near real-time monitoring of circulating blood biomarkers. One microliter of blood is collected every 8 minutes, digested for 20 minutes, and then analyzed by targeted mass spectrometry for 8 minutes. This results in a 30-minute delay with datapoints every 8 minutes.
HCV infection activates the proteasome via PA28γ acetylation and heptamerization to facilitate the degradation of RNF2, a catalytic component of polycomb repressive complex 1
Authors: Kasai Hirotake , Yamashita Atsuya , Akaike Yasunori , Tanaka Tomohisa , Matsuura Yoshiharu , Moriishi Kohji 
Published: June 2024

ABSTRACTWe previously reported that hepatitis C virus (HCV) infection or HCV core protein expression induces HOX gene expression by impairing histone H2A monoubiquitination via a proteasome-dependent reduction in the level of RNF2, a key catalytic component of polycomb repressive complex 1 (PRC1) (J. Virol, 2021, 95, e01784-20). In this study, we aimed to investigate the mechanism by which HCV infection accelerates RNF2 degradation. Yeast two-hybrid screening and an immunoprecipitation assay revealed that RNF2 is a PA28γ-binding protein. The proteasome activator PA28γ destabilized the RNF2 protein in a proteasome-dependent manner, since RNF2 degradation was impaired by PA28γ knockout or MG132 treatment. HCV infection or core protein expression reduced the levels of RNF2 and histone H2A K119 monoubiquitination and induced the expression of HOX genes in the presence of PA28γ, while PA28γ knockout reversed these changes. Treatment with a lysine acetyltransferase inhibitor inhibited the acetylation of PA28γ at K195 and the degradation of the RNF2 protein, while treatment with a lysine deacetylase inhibitor accelerated these events in a PA28γ-dependent manner. RNF2 protein degradation was increased by expression of the acetylation mimetic PA28γ mutant but not by expression of the acetylation-defective mutant or the proteasome activation-defective mutant. Furthermore, HCV infection or core protein expression facilitated the interaction between PA28γ and the lysine acetyltransferase CBP/p300 and then accelerated PA28γ acetylation and heptamerization to promote RNF2 degradation. These data suggest that HCV infection accelerates the acetylation-dependent heptamerization of PA28γ to increase the proteasomal targeting of RNF2.IMPORTANCEHCV is a causative agent of HCV-related liver diseases, including hepatic steatosis, cirrhosis and hepatocellular carcinoma. PA28γ, which, in heptameric form, activates the 20S core proteasome for the degradation of PA28γ-binding proteins, is responsible for HCV-related liver diseases. HCV core protein expression or HCV infection accelerates RNF2 degradation, leading to the induction of HOX gene expression via a decrease in the level of H2Aub on HOX gene promoters. However, the mechanism of RNF2 degradation in HCV-infected cells has not been clarified. The data presented in this study suggest that PA28γ acetylation and heptamerization are promoted by HCV infection or by core protein expression to activate the proteasome for the degradation of RNF2 and are responsible for HCV propagation. This study provides novel insights valuable for the development of therapies targeting both HCV propagation and HCV-related diseases.
Identification of ABHD6 as a regulator of lysophosphatidylserines in the mammalian liver and kidneys
Authors: Chakraborty Arnab , Punnamraju Prajwal , Sajeevan Theja , Kaur Arshdeep , Kolthur-Seetharam Ullas , Kamat Siddhesh S. 
Published: June 2024

SUMMARYLysophosphatidylserine (lyso-PS) is a potent hormone-like signaling lysophospholipid, which regulates many facets of mammalian biology and dysregulation in its metabolism is associated with several human neurological and autoimmune diseases. Despite the physiological importance and causal relation with human pathophysiology, little is known about the metabolism of lyso-PS in tissues other than the nervous and immune systems. To address this problem, here, we attempted to identify one (or more) lipase(s) capable of degrading lyso-PS in different mammalian tissues. We found that the membrane proteomic fraction of most mammalian tissues possess lyso-PS lipase activity, yet interestingly, the only bona fide lyso-PS lipase ABHD12 displays this enzymatic activity and has control over lyso-PS metabolism only in the mammalian brain. Using anin vitroinhibitor screen against membrane proteomic fractions of different tissues, we find that another lipase from the metabolic serine hydrolase family, ABHD6, is a putative lyso-PS lipase in the mouse liver and kidney. Finally, using pharmacological tools, we validate the lyso-PS lipase activity of ABHD6in vivo, and functionally designate this enzyme as a major lyso-PS lipase in primary hepatocytes, and the mammalian liver and kidneys.HIGHLIGHTSLyso-PS lipase enzymatic activity is present in the membrane proteomic fraction of most mammalian tissuesAnin vitroinhibitor screen identifies ABHD6 as a putative lyso-PS lipase in the liver and kidneyABHD6 functions as a lyso-PS lipase in primary hepatocytesABHD6 also performs lyso-PS lipase activityin vivoand regulates lyso-PS levels in the liver and kidney
Functional and Clinical Implications of Extrachromosomal Circular DNA in the Human Germline
Authors: Evans Melanie , Rajachandran Shreya , Zhang Xin , Zhang Yanfeng , Saner Karla , Xu Lin , Orwig Kyle E. , Bukulmez Orhan , Chen Haiqi 
Published: June 2024

AbstractExtrachromosomal circular DNA (eccDNA) originates from linear chromosomal DNA and can be found in various human cell types including the male germline. However, the functional effects and biogenesis mechanisms of the eccDNA in the human male germline are not well understood. Here, we developed a sequencing approach to extract eccDNA sequence information and the paired transcriptome information from the same cells. By applying this approach to human samples, we found evidence of transcriptional activities of germline eccDNAs. We also showed that patients with chronic diseases such as hypertension and diabetes had a significantly higher number of eccDNAs in the sperm than their healthy counterparts. This was, at least partly, due to an increased apoptosis signaling in the germline. Analysis of single cell RNA sequencing data of spermatogenic cells from diabetic patientsvs. healthy individuals suggested that a dysregulation in the expression levels of multiple poly (ADP-ribose) polymerases may contribute to the increased amount of germline eccDNAs in diseased patients. In addition, we identified a potential horizontal transfer mechanism through which healthy sperm can take up eccDNAs from their surrounding microenvironment. Together, our results suggest that eccDNA may have functional effects on the germline, and it may serve as a non-invasive clinical biomarker for human health.
Uncontrolled glycemia and PTSD in diabetic patients living in high conflict zones: A cross-sectional study
Authors: Bleibel Mohammad , Nasser Bilal , Dorra Lana El , Jomaa Leya Al , Deek Hiba 
Published: June 2024

AbstractBackgroundLocal conflicts such as those occurring in Palestinian camps in Lebanon have led to detrimental effects on the physical and psychological aspects of the people living in these regions. PTSD and uncontrolled glycemia are expected to be the consequences of these events.AimTo determine the impact of the Ein El Helwe events on blood glycemic levels and the possibility of developing post-traumatic stress disorders.DesignA cross-sectional questionnaire with self-administered questionnaires.MethodsParticipants were identified from the community of South Lebanon in the area surrounding, or inside, the Ein El Helwe Camp during the time of the events. The participants completed an electronic questionnaire which included sociodemographic data, diabetes condition and the DSM-IV symptoms of PTSD and its level. The Scale is a validated scale that had previously been translated to Arabic.ResultsA total of 234 participants were included in the final analysis of the study with almost 30% having uncontrolled glycemia. The mean age of the study participants was 53.49+13.09 years with more female than male participants and more living around rather than inside the camp. Glycemic control was associated with gender, educational level, living in or outside the camp and the body mass index. Multivariate analysis confirmed the impact of educational level, living area and PTSD on the glycemic control. The relationship between glycemic control and PTSD was based on some of the latter’s symptoms.ConclusionThe study highlighted the impact of conflicts and wars on the development of uncontrolled glycemia among participants living in and around Ein El Helwe Camp. Multiple factors contributed to the findings including sociodemographic, lifestyle factors and cultural aspects which should further be analysed in future studies. Additionally, glycemia levels should be monitored for more reliable findings in future studies.
YAP dysregulation triggers hypertrophy by CCN2 secretion and TGFβ uptake in human pluripotent stem cell-derived cardiomyocytes
Authors: Chirikian Orlando , Faynus Mohamed A. , Merk Markus , Singh Zachary , Muray Christopher , Pham Jeffrey , Chialastri Alex , Vander Roest Alison , Goldstein Alex , Pyle Trevor , Lane Kerry V. , Roberts Brock , Smith Jacqueline E. , Gunawardane Ruwanthi N. , Sniadecki Nathan J. , Mack David L. , Davis Jennifer , Bernstein Daniel , Streichan Sebastian J. , Clegg Dennis O. , Dey Siddharth S. , Wilson Maxwell Z. , Pruitt Beth L. 
Published: June 2024

AbstractHypertrophy Cardiomyopathy (HCM) is the most prevalent hereditary cardiovascular disease – affecting >1:500 individuals. Advanced forms of HCM clinically present with hypercontractility, hypertrophy and fibrosis. Several single-point mutations in b-myosin heavy chain (MYH7) have been associated with HCM and increased contractility at the organ level. Different MYH7 mutations have resulted in increased, decreased, or unchanged force production at the molecular level. Yet, how these molecular kinetics link to cell and tissue pathogenesis remains unclear. The Hippo Pathway, specifically its effector molecule YAP, has been demonstrated to be reactivated in pathological hypertrophic growth. We hypothesized that changes in force production (intrinsically or extrinsically) directly alter the homeostatic mechano-signaling of the Hippo pathway through changes in stresses on the nucleus. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we asked whether homeostatic mechanical signaling through the canonical growth regulator, YAP, is altered 1) by changes in the biomechanics of HCM mutant cardiomyocytes and 2) by alterations in the mechanical environment. We use genetically edited hiPSC-CM with point mutations in MYH7 associated with HCM, and their matched controls, combined with micropatterned traction force microscopy substrates to confirm the hypercontractile phenotype in MYH7 mutants. We next modulate contractility in healthy and disease hiPSC-CMs by treatment with positive and negative inotropic drugs and demonstrate a correlative relationship between contractility and YAP activity. We further demonstrate the activation of YAP in both HCM mutants and healthy hiPSC-CMs treated with contractility modulators is through enhanced nuclear deformation. We conclude that the overactivation of YAP, possibly initiated and driven by hypercontractility, correlates with excessive CCN2 secretion (connective tissue growth factor), enhancing cardiac fibroblast/myofibroblast transition and production of known hypertrophic signaling molecule TGFβ. Our study suggests YAP being an indirect player in the initiation of hypertrophic growth and fibrosis in HCM. Our results provide new insights into HCM progression and bring forth a testbed for therapeutic options in treating HCM.Graphical Abstract
CDK12 controls transcription at damaged genes and prevents MYC-induced transcription-replication conflicts
Authors: Curti Laura , Rohban Sara , Bianchi Nicola , Croci Ottavio , Andronache Adrian , Barozzi Sara , Mattioli Michela , Ricci Fernanda , Pastori Elena , Sberna Silvia , Bellotti Simone , Accialini Anna , Ballarino Roberto , Crosetto Nicola , Wade Mark , Parazzoli Dario , Campaner Stefano 
Published: June 2024

ABSTRACTOncogene-induced replicative stress is a potent tumor-suppressive mechanism that must be kept in check for cancer cells to thrive. Thus, the identification of genes and pathways involved in replicative stress is key to understand cancer evolution and to identify prospective therapeutic targets. Here, we investigated factors that modulate replicative stress upon deregulation of the MYC oncogene. We identified the cyclin-dependent kinase CDK12 as selectively required to prevent transcription-replication conflicts and the activation of a cytotoxic DNA-damage response (DDR). At the mechanistic level, CDK12 was recruited to damaged genes by PARP-dependent DDR-signaling and elongation-competent RNAPII. Once recruited, CDK12 repressed transcription by preventing the association of CDK9 with RNAPII. Either loss or chemical inhibition of CDK12 led to DDR-resistant transcription at damaged genes. Genome-wide profiling revealed that loss of CDK12 exacerbated transcription-replication conflicts in MYC-overexpressing cells and led to the accumulation of double-strand DNA breaks (DSBs), occurring preferentially between early- replicating regions and transcribed genes, organized in a co-directional head-to-tail orientation. Overall, our data demonstrate that CDK12 protects genome integrity by repressing transcription of damaged genes, which is required for proper resolution of DSBs at oncogene-induced transcription-replication conflicts. This provides a rationale that explains both how CDK12 deficiency can promote tandem duplications of early-replicated regions during tumor evolution, and how CDK12 targeting can exacerbate replicative-stress in tumors.