bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased ambulance attendances related to suicide and self-injury in response to the pandemic in Australia
Authors: John James , Synn Ei Phyu , Winata Teresa , Eapen Valsamma , Lin Ping-I 
Published: May 2022

AbstractInvestigating the change in the trend of ambulance service utilization for suicide in response to the COVID-19 pandemic can clarify the impact of the pandemic on acute health services. To determine whether the trends of the ambulance attendances related to self-injury and suicide changes in response to the COVID-19 pandemic. We extracted the data from the National Ambulance Surveillance System in Australia between March 2018 and March 2021 to examine the trajectory of the ambulance attendances related to self-injury and suicide. The results indicate that the number of ambulance attendances related to self-injury, suicidal ideation and suicidal attempt increased immediately during the first quarter since the outbreak and stayed higher over the at least 12 months. Notably, the post-outbreak surge in ambulance attendances associated with these mental health crises did not continue to escalate further. To sum up, the overall increase in ambulance attendances may reflect increased distress in the community, but also signify disruptions of other non-emergency health services. In contrast to recent evidence for the suicide rate being unchanged during the pandemic, our findings provide a different perspective on the impact of the pandemic on mental health services. This warrants a re-assessment of resources for mental health services in the post-COVID era.
Molecular consequences of PQBP1 deficiency, involved in the X-linked Renpenning syndrome
Authors: Courraud Jérémie , Engel Camille , Quartier Angélique , Drouot Nathalie , Houessou Ursula , Plassard Damien , Sorlin Arthur , Brischoux-Boucher Elise , Van Maldergem Lionel , Gouy Evan , Rossi Massimiliano , Edery Patrick , Putoux Audrey , Gilbert-Dussardier Brigitte , Kalscheuer Vera , Mandel Jean-Louis , Piton Amélie 
Published: May 2022

AbstractMutations in the PQBP1 gene (polyglutamine-binding protein 1) are responsible for a syndromic X-linked form of intellectual disability (XLID), the Renpenning syndrome. PQBP1 encodes a protein that plays a role in the regulation of gene expression, splicing and mRNA translation. To investigate the consequences of variants in PQBP1, we performed transcriptomic studies in 1) patients’ lymphoblastoid cell lines (LCL) carrying pathogenic variants in PQBP1 and 2) in human neural stem cells (hNSC) knocked-down (KD) for PQBP1. This led to the identification of a hundred dysregulated genes. In particular, we identified an increase in the expression of a non-canonical isoform of another XLID gene, UPF3B. UPF3B plays a crucial role during neurodevelopment by coding for an important actor of the nonsense mRNA mediated decay (NMD) system involved in regulation of protein translation, however, the exact function of the non-canonical isoform,UPF3B_S, is currently unknown. In order to investigate the role of UPF3B_S isoform, we compared the protein interactome of UPF3B_S to the canonical isoform (UPF3B_L). We confirmed that, on the contrary to UPF3B_L, UPF3B_S does not interact with the UPF2/UPF1 complex while it still interacts with exon junction complexes (EJC). However, no notable decrease of NMD pathways was observed in patient’s LCL or in hNSC KD for PQBP1. We identified several additional protein interactors specific to UPF3B_S. Moreover, we used the increase of UPF3B_S mRNA as a molecular marker to test the pathogenicity of variants of unknown clinical significance identified in individuals with ID in PQPB1. We analyzed patients’ LCL mRNA as well as blood mRNA samples and performed complementation studies in HeLa cells by overexpressing Wild-type and mutant PQBP1 cDNA. We showed that all these three approaches were efficient to test the effect of variants, at least for variants affecting the CTD domain of the protein. In conclusion, our study provides information on how PQBP1 deficiency may affect the expression of genes and isoforms, such as UPF3B. This informs about the pathological mechanisms involved in Renpenning syndrome but also allows to propose a functional test for variants of unknown significance identified in PQBP1.
HAPLN1 is a driver for peritoneal carcinomatosis in pancreatic cancer
Authors: Wiedmann Lena , De Angelis Rigotti Francesca , Vaquero-Siguero Nuria , Donato Elisa , Espinet Elisa , Moll Iris , Alsina-Sanchis Elisenda , Mülfarth Ronja , Vacca Margherita , Gerwing Jennifer , Trumpp Andreas , Fischer Andreas , Rodriguez-Vita Juan 
Published: May 2022

AbstractPancreatic ductal adenocarcinoma (PDAC) frequently metastasizes into the peritoneum, which contributes to poor prognosis. Metastatic spreading is promoted by cancer cell plasticity, yet its regulation by the microenvironment is incompletely understood. Here we show that the presence of hyaluronan and proteoglycan link protein-1 (HAPLN1) in the extracellular matrix enhances tumor cell plasticity and PDAC metastasis. Bioinformatic analysis showed that HAPLN1 expression is enriched in the basal PDAC subtype and associated with worse overall patient survival. In a mouse model for peritoneal carcinomatosis, HAPLN1-induced immunomodulation favored a more permissive microenvironment, which accelerated the peritoneal spread of tumor cells. Mechanistically, HAPLN1, via hyaluronic acid synthesis and signaling, promoted adoption of a highly plastic cancer cell state, facilitating EMT, stemness, invasion and immunomodulation in a paracrine manner. Extracellular HAPLN1 modifies cancer cells as well as fibroblasts, rendering them immunomodulatory. We identify HAPLN1 as a prognostic marker and a driver for peritoneal metastasis in PDAC.
Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity
Authors: Lei Yuanjiu , VanPortfliet Jordyn J. , Chen Yi-Fan , Bryant Joshua D. , Li Ying , Fails Danielle , Torres-Odio Sylvia , Ragan Katherine B. , Deng Jingti , Mohan Armaan , Wang Bing , Brahms Olivia N. , Yates Shawn D. , Spencer Michael , Tong Carl W. , Bosenberg Marcus W. , West Laura Ciaccia , Shadel Gerald S. , Shutt Timothy E. , Upton Jason W. , Li Pingwei , West A. Phillip 
Published: May 2022

SUMMARYMitochondrial DNA (mtDNA) is a potent agonist of the innate immune system; however, the exact immunostimulatory features of mtDNA and the kinetics of mtDNA detection by cytosolic nucleic acid sensors remain poorly defined. Here, we show that mitochondrial genome instability leads to Z-form mtDNA accumulation. Z-DNA Binding Protein 1 (ZBP1) stabilizes Z-form mtDNA and nucleates a cytosolic complex containing cGAS, RIPK1, and RIPK3 to sustain STAT1 phosphorylation and type I interferon (IFN-I) signaling. Increased mitochondrial Z-DNA, ZBP1 expression, and IFN-I responses are observed in cardiomyocytes after exposure to Doxorubicin, a first-line chemotherapeutic agent that induces frequent cardiotoxicity in cancer patients. Strikingly, mice lacking ZBP1 or IFN-I signaling are protected from Doxorubicin-induced cardiotoxicity. Our findings reveal ZBP1 as a cooperative partner for cGAS that sustains IFN-I responses to mitochondrial genome instability and highlight ZBP1 as a potential target in heart failure and other disorders where mtDNA stress contributes to interferon-related pathology.
Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities
Authors: Zhang Yuxiang , Remillard David , Onubogu Ugoma , Karakyriakou Barbara , Asiaban Joshua N. , Ramos Anissa R. , Bowland Kirsten , Bishop Timothy R. , Ott Christopher J. , Janiszewska Michalina , Cravatt Benjamin F. , Erb Michael A. 
Published: May 2022

AbstractHistone deacetylases (HDACs) have been widely pursued as targets for anti-cancer therapeutics. However, many of these targets are universally essential for cell survival, which may limit the therapeutic window that can be achieved by drug candidates. By examining large collections of CRISPR/Cas9-based essentiality screens, we discovered a genetic interaction between HDAC1 and HDAC2 wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal translocations that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic deletion or dTAG-mediated degradation, we show that HDAC2 disruption suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the degradation of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2/NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Furthermore, we reveal that several of the degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, providing motivation to develop paralog-selective HDAC1 or HDAC2 degraders. Altogether, we identify HDAC1/2 collateral synthetic lethality as a new therapeutic target and reveal a novel mechanism for exploiting NuRD-associated cancer dependencies.
Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing
Authors: Kessler Nina , Viehmann Susanne F. , Krollmann Calvin , Mai Karola , Kirschner Katharina Maria , Luksch Hella , Kotagiri Prasanti , Böhner Alexander M.C. , Huugen Dennis , de Oliveira Mann Carina C. , Otten Simon , Weiss Stefanie A. I. , Zillinger Thomas , Dobrikova Kristiyana , Jenne Dieter E. , Ablasser Andrea , Bartok Eva , Hartmann Gunther , Hopfner Karl-Peter , Lyons Paul A. , Boor Peter , Rösen-Wolff Angela , Teichmann Lino , Heeringa Peter , Kurts Christian , Garbi Natalio 
Published: May 2022

AbstractAutoimmune vasculitis is a group of life-threatening diseases, whose underlying pathogenic mechanisms are incompletely understood, hampering development of targeted therapies. Here, we demonstrate that patients suffering from anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) showed increased activity of the DNA sensor cGAS and enhanced IFN-I signature. To identify potential therapeutic targets, we developed a mouse model for pulmonary AAV that mimics severe disease in patients. Immunogenic DNA accumulated during disease onset, triggering cGAS/STING/IRF3-dependent IFN-I release that promoted endothelial damage, pulmonary hemorrhages, and lung dysfunction. Macrophage subsets played dichotomic roles in disease. While recruited monocyte-derived macrophages were major disease drivers by producing most IFN-β, resident alveolar macrophages contributed to tissue homeostasis by clearing red blood cells and limiting infiltration of IFN-β-producing macrophages. Moreover, pharmacological inhibition of STING, IFNAR-I or its downstream JAK/STAT signaling reduced disease severity and accelerated recovery. Our study unveils the importance of STING/IFN-I axis in promoting pulmonary AAV progression and identifies cellular and molecular targets to ameliorate disease outcome.Graphical abstractSummaryKessler et al. identify aberrant DNA recognition by cGAS/STING axis and IFN-I production by inflammatory macrophages as a major driver of severe ANCA-associated vasculitis (AAV). Pharmacological interventions blocking this pathway ameliorate disease and accelerate recovery, identifying potential targets for therapeutic intervention in patients.
T Cell-to-Stroma Enrichment (TSE) score: a gene expression metric that predicts response to immune checkpoint inhibitors in patients with urothelial cancer
Authors: Rijnders Maud , Alberto Nakauma-González J. , Robbrecht Debbie G.J. , Gil-Jimenez Alberto , Balcioglu Hayri E. , Oostvogels Astrid A.M. , Aarts Maureen J.B. , Boormans Joost L. , Hamberg Paul , van der Heijden Michiel S. , Szabados Bernadett E. , van Leenders Geert J.L.H. , Mehra Niven , Voortman Jens , Westgeest Hans M. , de Wit Ronald , van der Veldt Astrid A.M. , Debets Reno , Lolkema Martijn P. 
Published: May 2022

AbstractImmune checkpoint inhibitors (ICIs) improve overall survival in patients with metastatic urothelial cancer (mUC). To identify predictive markers of response, whole-genome DNA (n=70) and RNA-sequencing (n=41) were performed using fresh metastatic biopsies prior to treatment with pembrolizumab. PD-L1 combined positivity score did not, whereas tumor mutational burden and APOBEC mutagenesis modestly predicted response. Using gene expression analysis, we defined the T cell-to-stroma enrichment (TSE) score, a signature-based metric that captures the relative abundance of T cells and stromal cells. Patients with a positive and negative TSE score show progression-free survival rates at 6 months of 67 and 0%, respectively. The TSE score was captured by immunofluorescence in tumor tissue, and validated in two independent ICI-treated cohorts of patients with mUC (IMvigor210) and muscle-invasive UC (ABACUS). In conclusion, the TSE score represents a clinically applicable marker that potentially aids in prospectively selecting patients with mUC for ICI treatment.
Chromatin remodeler Chd7 regulates photoreceptor development and outer segment length
Authors: Krueger Laura A. , Bills Jessica D. , Lim Zun Yi , Skidmore Jennifer M. , Martin Donna M. , Morris Ann C. 
Published: May 2022

AbstractMutations in the chromatin remodeling factor CHD7 are the predominant cause of CHARGE syndrome, a congenital disorder that frequently includes ocular coloboma. Although CHD7 is known to be required for proper ocular morphogenesis, its role in retinal development has not been thoroughly investigated. Given that individuals with CHARGE syndrome can experience visual impairment even in the absence of coloboma, a better understanding of CHD7 function in the retina is needed. In this study, we characterized the expression pattern of Chd7 in the developing zebrafish and mouse retina and documented ocular and retinal phenotypes in Chd7 loss-of-function mutants. Zebrafish Chd7 was expressed throughout the retinal neuroepithelium when retinal progenitor cells were actively proliferating, and later in subsets of newly post-mitotic retinal cells. At stages of retinal development when most retinal cell types had terminally differentiated, Chd7 expression remained strong in the ganglion cell layer and in some cells in the inner nuclear layer. Intriguingly, strong expression of Chd7 was also observed in the outer nuclear layer where it was co-expressed with markers of post-mitotic cone and rod photoreceptors. Expression of mouse CHD7 displayed a similar pattern, including expression in the ganglion cells, subsets of inner nuclear layer cells, and in the distal outer nuclear layer as late as P15. Two different mutant chd7 zebrafish lines were characterized for ocular and retinal defects. These mutants displayed microphthalmia, reduced numbers of cone photoreceptors, and truncated rod and cone photoreceptor outer segments. Reduced cone photoreceptor number and abnormal outer segments were also observed in heterozygous Chd7 mutant mice. Taken together, our results in zebrafish and mouse reveal a conserved, previously undescribed role for Chd7 in retinal development and photoreceptor outer segment morphogenesis. Moreover, our work suggests an avenue of future investigation into the pathogenesis of visual system defects in CHARGE syndrome.HighlightsChd7 is expressed in both retinal progenitor cells and in differentiated retinal neurons, including post-mitotic rod and cone photoreceptors.Loss of Chd7 results in a significant decrease in cone photoreceptors in both zebrafish and mouse.Cone and rod photoreceptor outer segments are truncated in chd7 mutants, suggesting a heretofore unappreciated role for Chd7 in outer segment morphogenesis.
CRISPR-Cas effector specificity and target mismatches determine phage escape outcomes
Authors: Schelling Michael A. , Nguyen Giang T. , Sashital Dipali G. 
Published: May 2022

AbstractCRISPR-mediated interference relies on complementarity between a guiding CRISPR RNA (crRNA) and target nucleic acids to provide defense against bacteriophage. Phages escape CRISPR-based immunity mainly through mutations in the PAM and seed regions. However, previous specificity studies of Cas effectors, including the class 2 endonuclease Cas12a, have revealed a high degree of tolerance of single mismatches. The effect of this mismatch tolerance has not been extensively studied in the context of phage defense. Here, we tested defense against lambda phage provided by Cas12a-crRNAs containing pre-existing mismatches against the genomic targets in phage DNA. We observe a correlation between Cas12a mismatch tolerance in vitro and phage defense on solid media. However, in liquid media, we find that most pre-existing crRNA mismatches lead to phage escape and lysis, regardless of whether the mismatches ablate Cas12a cleavage in vitro. We used high-throughput sequencing to examine the target regions of phage genomes following CRISPR challenge. Mismatches at all locations in the target accelerated emergence of mutant phage, including mismatches that greatly slowed cleavage in vitro. Mutations arose near the existing mismatch, in some cases resulting in multiple PAM-distal mismatches allowing for phage escape. Similar experiments with Cas9 showed the location of emergent target mutations was unaffected by pre-existing crRNA-target mismatches. Expression of multiple mismatched crRNAs prevented new mutations from arising in multiple targeted locations, allowing Cas12a mismatch tolerance to provide stronger and longer term protection. These results demonstrate that Cas effector mismatch tolerance and existing target mismatches strongly influence phage evolution.
Mitochondrially targeted proximity biotinylation and proteomic analysis in Plasmodium falciparum
Authors: Lamb Ian M. , Rios Kelly T. , Shukla Anurag , Ahiya Avantika I. , Morrisey Joanne , Mell Joshua C. , Lindner Scott E. , Mather Michael W. , Vaidya Akhil B. 
Published: May 2022

AbstractDespite ongoing efforts to control malaria infection, progress in lowering the number of deaths and infections appears to have stalled. The continued high incidence of malaria infection and mortality is in part due to emergence of parasites resistant to frontline antimalarials. This highlights the need for continued identification of novel protein drug targets. Mitochondrial functions in Plasmodium falciparum, the deadliest species of human malaria parasite, are targets of validated antimalarials including atovaquone and proguanil (Malarone). Thus, there has been great interest in identifying other essential mitochondrial proteins as candidates for novel drug targets. Garnering an increased understanding of the proteomic landscape inside the P. falciparum mitochondrion will also allow us to learn about the basic biology housed within this unique organelle. We employed a proximity biotinylation technique and mass spectrometry to identify novel P. falciparum proteins putatively targeted to the mitochondrion. We fused the leader sequence of a mitochondrially targeted chaperone, Hsp60, to the promiscuous biotin ligase TurboID. Through these experiments, we generated a list of 122 “putative mitochondrial” proteins. To verify whether these proteins were indeed mitochondrial, we chose five candidate proteins of interest for localization studies using ectopic expression and tagging of each full-length protein. This allowed us to localize four candidate proteins of unknown function to the mitochondrion, three of which have previously been assessed to be essential. We suggest that phenotypic characterization of these and other proteins from this list of 122 could be fruitful in understanding the basic mitochondrial biology of these parasites and aid antimalarial drug discovery efforts.
A map of cis-regulatory modules and constituent transcription factor binding sites in 80% of the mouse genome
Authors: Ni Pengyu , Wilson David , Su Zhengchang 
Published: May 2022

ABSTRACTMouse is probably the most important model organism to study mammal biology and human diseases. A better understanding of the mouse genome will help understand the human genome, biology and diseases. However, despite the recent progress, characterization of the regulatory sequences in the mouse genome is still far from complete, limiting its use to understand the regulatory sequences in the human genome. Here, by integrating binding peaks in 9,060 transcription factor (TF) ChIP-seq datasets that cover 79.9% of the mouse mappable genome using an efficient pipeline, we were able to partition these binding peak-covered genome regions into a cis-regulatory module (CRM) candidate (CRMC) set and a non-CRMC sets. The CRMCs contain 912,197 putative CRMs and 38,554,729 TF binding sites (TFBSs) islands, covering 55.5% and 24.4% of the mappable genome, respectively. The CRMCs tend to be under strongly evolutionary constraints, indicating that they are likely cis-regulatory; while the non-CRMCs are largely selectively neutral, indicating that they are unlikely cis-regulatory. Based on evolutionary profiles of the genome positions, we further estimated that 63.8% and 27.4% of the mouse genome might code for CRMs and TFBSs, respectively. Validation using experimental data suggests that at least most of the CRMCs are authentic. Thus, this unprecedentedly comprehensive map of CRMs and TFBSs can be a good resource to guide experimental studies of regulatory genomes in mice and humans.
Comprehensive Comparative Genomic revels:Bacteroides fragilisis a reservoir of antibiotic resistance genes in the gut microbiota
Authors: Evanovich Eliane , de Souza Mendonça Mattos Patricia Jeanne , Guerreiro João Farias 
Published: May 2022

AbstractBacteroides fragilisare commensal bacteria of the gut microbiota of mammals and may cause severe infection in a susceptible host. Treatment can be cumbersome if multidrug resistant strains are present in the affected tissue. The principal aim of this study was to provide new insights into the genomic properties ofB. fragilisthrough different approaches in comparative genomics. Results revealed that the pan-genome is opened, and an intense exchange of genetic material reinforces this inference. The Don complex, responsible for extraintestinal adaptation, is present in all strains, suggesting a crucial role forB. fragilisadaptation. CRISPR-Cas system is at 76% of the samples, but it apparently has low accuracy against prophage. Multidrug resistance genes are in 80% of strains. Conjugative transposons and integrative and conjugative elements (ICE) are the main spreaders of genes for antimicrobial resistance. We also reported evidence for horizontal gene transfer (HGT) of antimicrobial resistance genes among theB. fragilisstrains and Bacteriodales. At least 398 genes are under positive selection, including genes for antimicrobial resistance and transport of toxins and nutrients.