bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dampened inflammatory signalling and myeloid-derived suppressor-like cell accumulation reduces circulating monocytic HLA-DR density and associates with malignancy risk in long-term renal transplant recipients
Authors: Bottomley Matthew J , Harden Paul N , Wood Kathryn J , Hester Joanna , Issa Fadi 
Published: March 2022

AbstractBackgroundMalignancy is a major cause of morbidity and mortality in transplant recipients. Identification of those at highest risk could facilitate pre-emptive intervention such as reduction of immunosuppression. Reduced circulating monocytic HLA-DR density is a marker of immune depression in the general population and associates with poorer outcome in critical illness. It has recently been used as a safety marker in adoptive cell therapy trials in renal transplantation. Despite its potential as a marker of dampened immune responses, factors that impact upon monocytic HLA-DR density and the long-term clinical sequelae of this have not been assessed in transplant recipients.MethodsA cohort study of stable long-term renal transplant recipients was undertaken. Serial circulating monocytic HLA-DR density and other leucocyte populations were quantified by flow cytometry. Gene expression of monocytes was performed using the Nanostring nCounter platform, and 13-plex cytokine bead array used to quantify serum concentrations. The primary outcome was malignancy development during one-year follow-up. Risk of malignancy was calculated by univariate and multivariate proportionate hazards modelling with and without adjustment for competing risks.ResultsMonocytic HLA-DR density was stable in long-term renal transplant recipients (n=135) and similar to non-immunosuppressed controls (n=29), though was suppressed in recipients receiving prednisolone. Decreased mHLA-DRd was associated with accumulation of CD14+CD11b+CD33+HLA-DRlo monocytic myeloid-derived suppressor-like cells. Pathway analysis revealed downregulation of pathways relating to cytokine and chemokine signalling in monocytes with low HLA-DR density; however serum concentrations of major cytokines did not differ between these groups. There was an independent increase in malignancy risk during follow-up with decreased HLA-DR density.ConclusionsDampened chemokine and cytokine signalling drives a stable reduction in monocytic HLA-DR density in long-term transplant recipients and associates with subsequent malignancy risk. This may function as a novel marker of excess immunosuppression. Further study is needed to understand the mechanism behind this association.
Elevated T-cell exhaustion and urinary tumor DNA levels are associated with BCG failure in patients with non-muscle invasive bladder cancer
Authors: Strandgaard Trine , Lindskrog Sia Viborg , Nordentoft Iver , Christensen Emil , Birkenkamp-Demtröder Karin , Andreasen Tine Ginnerup , Lamy Philippe , Kjær Asbjørn , Ranti Daniel , Wang Yuan-Sho , Bieber Christine , Prip Frederik , Rasmussen Julie , Steiniche Torben , Birkbak Nicolai , Sfakianos John , Horowitz Amir , Jensen Jørgen Bjerggaard , Dyrskjøt Lars 
Published: March 2022

AbstractBackgroundThe functional status of immune cells within the tumor microenvironment and tumor characteristics may explain Bacillus Calmette-Guérin (BCG)-failure in high-risk non-muscle invasive bladder cancer (NMIBC).ObjectiveTo characterize molecular correlates of BCG-failure using a multiomics approach.Design, Setting, and ParticipantsBCG-treated NMIBC patients (n=156) were included. Metachronous tumors were analyzed using RNA-sequencing (n=170) and whole exome sequencing (n=198). Urine samples were analyzed for immune-oncology related proteins (n=190), and tumor-derived DNA (tdDNA; n=192).Outcome Measurement and Statistical AnalysisPrimary endpoint was BCG-failure. Cox regression, Wilcoxon Rank Sum test, t-test or Fisher’s exact test were used.Results and LimitationsBCG caused activation of the immune system regardless of clinical response; however, immune-inhibitory proteins were observed in the urine of BCG-unresponsive patients post-treatment (CD70, PD1, CD5). BCG-failure was associated with post-BCG T-cell exhaustion (p=0.0021). Pre-BCG tumors from patients with post-BCG T-cell exhaustion were characterized by high expression of cell division and immune-related genes. A high post-BCG exhaustion prediction score in pre-BCG tumors was associated with worse post-BCG high-grade recurrence free survival (HGRFS), reflecting BCG-failure (p=0.0084). Pre-BCG tumors of class 2a and 2b were likewise associated with worse post-BCG HGRFS(p=0.0023). Post-BCG exhaustion was observed in patients with high pre-BCG neoantigen load (p=0.023) and mutations in MUC4 (p=0.0007). Finally, absence of post-BCG tdDNA clearance identified patients at high risk of recurrence (p=0.028). The retrospective design, lack of maintenance BCG, and partial overlap in analyses are limitations to the study.ConclusionsBCG failure may be caused by T-cell exhaustion. Tumor subtype and Pre-BCG tumor characteristics may identify patients at high risk of BCG-failure prior to treatment. Urinary measurements have the potential to be used as a real-time assessment of treatment response.Patient SummaryA dysfunctional immune response to BCG therapy may explain lack of response to the treatment.
Proof-of-concept: SCENTinel 1.1 rapidly discriminates COVID-19 related olfactory disorders
Authors: Hunter Stephanie R. , Hannum Mackenzie E. , Pellegrino Robert , O’Leary Maureen A. , Rawson Nancy E. , Reed Danielle R. , Dalton Pamela H. , Parma Valentina 
Published: March 2022

AbstractIt is estimated that 20-67% of those with COVID-19 develop olfactory disorders, depending on the SARS-CoV-2 variant. However, there is an absence of quick, population-wide olfactory tests to screen for olfactory disorders. The purpose of this study was to provide a proof-of-concept that SCENTinel 1.1, a rapid, inexpensive, population-wide olfactory test, can discriminate between anosmia (total smell loss), hyposmia (reduced sense of smell), parosmia (distorted odor perception), and phantosmia (odor sensation without a source). Participants were mailed a SCENTinel 1.1 test, which measures odor detection, intensity, identification, and pleasantness, using one of four possible odors. Those who completed the test (N = 381) were divided into groups based on their self-reported olfactory function: quantitative olfactory disorder (anosmia or hyposmia, N = 135), qualitative olfactory disorder (parosmia and/or phantosmia; N = 86), and normosmia (normal sense of smell; N = 66). SCENTinel 1.1 accurately discriminates quantitative olfactory disorders, qualitative olfactory disorders, and normosmia groups. When olfactory disorders were assessed individually, SCENTinel 1.1 discriminates between hyposmia, parosmia and anosmia. Participants with parosmia rated common odors less pleasant than those without parosmia. We provide proof-of-concept that SCENTinel 1.1, a rapid smell test, can discriminate quantitative and qualitative olfactory disorders, and is the only direct test to rapidly discriminate parosmia.
Association of COVID-19 with risks of hospitalization and mortality from other disorders post-infection: A study of the UK Biobank
Authors: Xiang Yong , Zhang Ruoyu , Qiu Jinghong , So Hon-Cheong 
Published: March 2022

AbstractObjectiveTo study whether COVID-19 infection may be associated with increased hospitalization and mortality from other diseases.DesignCohort study.SettingThe UK Biobank.ParticipantsAll subjects in the UK Biobank with available hospitalization records and alive as of 31-Jan-2020 (N= 412,096; age 50-87).Main outcome measuresWe investigated associations of COVID-19 with hospitalization and mortality due to different diseases post-infection. We conducted a comprehensive survey on disorders from all systems (up to 135 disease categories). Multivariable Cox and Poisson regression was conducted controlling for main confounders. For sensitivity analysis, we also conducted separate analysis for new-onset and recurrent cases, and other analysis such as the prior event rate adjustment(PERR) approach to minimize effects of unmeasured confounders. We also performed association analyses stratified by vaccination status. Time-dependent effects on subsequent hospitalization and mortality were also tested.ResultsCompared to individuals with no known history of COVID-19, those with severe COVID-19 (requiring hospitalization) exhibited higher hazards of hospitalization and/or mortality due to multiple disorders (median follow-up=608 days), including disorders of respiratory, cardiovascular, neurological, gastrointestinal, genitourinary and musculoskeletal systems. Increased hazards of hospitalizations and/or mortality were also observed for injuries due to fractures, various infections and other non-specific symptoms. These results remained largely consistent after sensitivity analyses. Severe COVID-19 was also associated with increased all-cause mortality (HR=14.700, 95% CI: 13.835-15.619).Mild (non-hospitalized) COVID-19 was associated with modestly increased risk of all-cause mortality (HR=1.237, 95% CI 1.037-1.476) and mortality from neurocognitive disorders, as well as hospital admission from a few disorders such as aspiration pneumonitis, musculoskeletal pain and other general signs/symptoms.All-cause mortalities and hospitalizations from other disorders post-infection were generally higher in the pre-vaccination era. The deleterious effect of COVID-19 was observed to wane over time, with maximum HR in the initial phase.ConclusionsIn conclusion, this study revealed increased risk of hospitalization and mortality from a wide variety of pulmonary and extra-pulmonary diseases after COVID-19, especially for severe infections. Mild disease was also associated with increased all-cause mortality. Causality however cannot be established due to observational nature of the study. Further studies are required to replicate our findings.
Vaccine Equity in Low and Middle Income Countries: A Systematic Review and Meta-analysis
Authors: Ali Huda , Hartner Anna-Maria , Echeverria-Londono Susy , Roth Jeremy , Li Xiang , Abbas Kaja , Portnoy Allison , Vynnycky Emilia , Woodruff Kim , Ferguson Neil M , Toor Jaspreet , Gaythorpe Katy AM 
Published: March 2022

AbstractBackgroundEvidence to date has shown that inequality in health, and vaccine coverage in particular, can have ramifications to wider society. However, whilst individual studies have sought to characterise these heterogeneities in immunisation coverage at national level, few have taken a broad and quantitative view of the contributing factors to heterogeneity in vaccine coverage and impact. This systematic review aims to highlight these geographic, demographic, and sociodemographic characteristics through a qualitative and quantitative approach, vital to prioritise and optimise vaccination policies.MethodsA systematic review of two databases (PubMed and Web of Science) was undertaken using Medical Subject Headings (MeSH) and keywords to identify studies examining factors on vaccine inequality and heterogeneity in vaccine coverage. Inclusion criteria were applied independently by two researchers. Studies including data on key characteristics of interest were further analysed through a meta-analysis to produce a pooled estimate of the risk ratio using a random effects model for that characteristic.ResultsOne hundred and eight studies were included in this review. We found that inequalities in wealth, education, and geographic access can affect vaccine impact and vaccine dropout. We estimated those living in rural areas were not significantly different in terms of full vaccination status compared to urban areas but noted considerable heterogeneity between countries. We found that females were 3% (95%CI[1%, 5%]) less likely to be fully vaccinated than males. Additionally, we estimated that children whose mothers had no formal education were 28% (95%CI[18%,47%]) less likely to be fully vaccinated than those whose mother had primary level, or above, education. Finally, we found that individuals in the poorest wealth quintile were 27% (95%CI [16%,37%]) less likely to be fully vaccinated than those in the richest.ConclusionsWe found a nuanced picture of inequality in vaccine coverage and access with wealth disparity dominating, and likely driving, other disparities. This review highlights the complex landscape of inequity and further need to design vaccination strategies targeting missed subgroups to improve and recover vaccination coverage following the COVID-19 pandemic.RegistrationProspero CRD42021261927
True-to-scale DNA-density maps correlate with major accessibility differences between active and inactive chromatin
Authors: Gelléri Márton , Chen Shih-Ya , Szczurek Aleksander , Hübner Barbara , Sterr Michael , Neumann Jan , Kröger Ole , Sadlo Filip , Imhoff Jorg , Markaki Yolanda , Hendzel Michael J. , Cremer Marion , Cremer Thomas , Strickfaden Hilmar , Cremer Christoph 
Published: March 2022

SummaryChromatin compaction differences may have a strong impact on accessibility of individual macromolecules and macromolecular assemblies to their DNA target sites. Estimates based on fluorescence microscopy with conventional resolution, however, suggested only modest compaction differences (∼2-10x) between active and inactive nuclear compartments (ANC and INC). Here, we present maps of nuclear landscapes with true-to-scale DNA-densities, ranging from <5 Mbp/µm3 to >300 Mbp/µm3. Maps were generated from individual human and mouse cell nuclei with single-molecule localization microscopy at ∼20 nm lateral and ∼100 nm axial resolution and supplemented by electron spectroscopic imaging. Microinjection of fluorescent nanobeads with sizes corresponding to macromolecular assemblies for transcription and replication into nuclei of living cells, demonstrated their localization and movements within the ANC and exclusion from the INC.
Cryo-EM structures of human zinc transporter ZnT7 reveal the mechanism of Zn2+uptake into the Golgi apparatus
Authors: Han Bui Ba , Watanabe Satoshi , Nomura Norimichi , Liu Kehong , Uemura Tomoko , Inoue Michio , Tsutsumi Akihisa , Fujita Hiroyuki , Kinoshita Kengo , Iwata So , Kikkawa Masahide , Inaba Kenji 
Published: March 2022

AbstractZinc ions (Zn2+) are vital to most cells, with the intracellular concentrations of Zn2+being tightly regulated by multiple zinc transporters located at the plasma and organelle membranes. We herein present the 2.8-2.9 Å-resolution cryo-EM structures of a Golgi-localized human Zn2+/H+antiporter ZnT7 (hZnT7) in its outward- and inward-facing forms. Cryo-EM analyses showed that hZnT7 exists as a homodimer via tight interactions in both the cytosolic and transmembrane (TM) regions of two protomers, each of which contains a single Zn2+-binding site in its TM domain. hZnT7 undergoes a TM-helix rearrangement to create a negatively charged cytosolic cavity for Zn2+entry in the inward-facing form and a widened luminal cavity for Zn2+release in the outward-facing form. An exceptionally long cytosolic histidine-rich loop characteristic of hZnT7 can bind at least two Zn2+ions, likely facilitating Zn2+recruitment from the cytosol. Unique mechanisms of hZnT7-mediated Zn2+uptake into the Golgi are proposed.
Testing the Drosophila maternal haploid gene for functional divergence and a role in hybrid incompatibility
Authors: Castillo Dean M , Kean Connor M , McCormick Benjamin , Natesan Sahana , Barbash Daniel A 
Published: March 2022

AbstractCrosses between D. simulans females and D. melanogaster males produce viable F1 sons and poorly viable F1 daughters. Unlike most hybrid incompatibilities, this hybrid incompatibility violates Haldane’s rule, the observation that incompatibilities preferentially affect the heterogametic sex. Further, it is important to understand fully the genetic basis of this incompatibility because the causal allele in D. melanogaster is a large species-specific block of complex satellite DNA on its X chromosome known as the 359-bp satellite, rather than a protein-coding locus. The causal allele(s) in D. simulans are unknown but likely involve maternally expressed genes or factors since the F1 females die during early embryogenesis. The maternal haploid (mh) gene is an intriguing candidate because it is expressed maternally and its protein product localizes to the 359-bp repeat. We found that this gene has diverged extensively between D. melanogaster and D. simulans. This observation led to the hypothesis that D. melanogaster mh may have co-evolved with the 359-bp repeat, and that hybrid incompatibility thus results from the absence of a co-evolved mh allele in D. simulans. We tested for functional divergence of mh by creating matched transformants of D. melanogaster and D. simulans orthologs in both D. melanogaster and D. simulans strains. Surprisingly, we find that D. simulans mh fully complements the female sterile phenotype of D. melanogaster mh mutations. Contrary to our hypothesis, we find no evidence that adding a D. melanogaster mh gene to D. simulans increases hybrid viability.
Measuring plant diversity in a two-stage sampling design by Bayesian updated relative abundances
Authors: Damgaard Christian , Pedersen Malthe Holst , Bendsen Nikolaj Bjerg , Mikkelsen Ditte Lønborg , Ehlers Bodil K. , Bataillon Thomas 
Published: March 2022

AbstractThe two-stage sampling design provides good local estimates of both the number of plant species and the relative abundances. However, it is a problem to calculate Hill diversity indices at the local scale, because some of the species found in the large plot are not present in the small plot and such species should then incorrectly be weighted with zero relative abundance. A new method for calculating local Hill diversity indices from species richness and relative abundances data is therefore needed. We suggest to replace the local relative abundances with Bayesian updated relative abundance estimates, where the prior probability distribution of the relative abundances are empirically estimated from all plots of the same habitat types. The method is applied on Danish Nardus grasslands.
Full-length transcriptomic analysis in murine and human heart reveals diversity of PGC-1α promoters and isoforms regulated distinctly in myocardial ischemia and obesity
Authors: Oehler Daniel , Spychala André , Gödecke Axel , Lang Alexander , Gerdes Norbert , Ruas Jorge , Kelm Malte , Szendroedi Julia , Westenfeld Ralf 
Published: March 2022

AbstractBackgroundPeroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) acts as a transcriptional coactivator and regulates mitochondrial function. Various isoforms are generated by alternative splicing and differentially regulated promoters. In the heart, total PGC-1α deficiency knockout leads to dilatative cardiomyopathy, but knowledge on the complexity of cardiac isoform expression of PGC-1α remains sparse. Thus, this study aims to generate a reliable dataset on cardiac isoform expression pattern by long-read mRNA sequencing, followed by investigation of differential regulation of PGC-1α isoforms under metabolic and ischemic stress, using high-fat-high-sucrose-diet-induced obesity and a murine model of myocardial infarction.Methods and ResultsMurine (C57Bl/6J) or human heart tissue (obtained during LVAD-surgery), was used for long-read mRNA sequencing, resulting in full-length transcriptomes including 58,000 mRNA isoforms with 99% sequence accuracy. Automatic bioinformatic analysis as well as manual similarity search against exonic sequences lead to identification of putative coding PGC-1α isoforms, validated by PCR and Sanger-Sequencing. Thereby, 12 novel transcripts generated by hitherto unknown splicing events were detected. In addition, we postulate a novel promoter with homologous and strongly-conserved sequence in human heart. High-fat-diet as well as ischemia/reperfusion (I/R) injury transiently reduced cardiac expression of PGC-1α-isoforms, with the most pronounced effect in the infarcted area. Recovery of PGC-1α-isoform expression was even more decelerated when I/R was performed in diet-induced obese mice.ConclusionsWe deciphered for the first time a complete full-length-transcriptome of the murine and human heart, identifying novel putative PGC-1α coding transcripts including a novel promoter. These transcripts are differentially regulated in I/R and obesity suggesting transcriptional regulation and alternative splicing that may modulate PGC-1α function in the injured and metabolically challenged heart.
An open source 16-channel fluidics system for automating sequential fluorescent in situ hybridization (FISH)-based imaging
Authors: Deng Zhaojie , Beliveau Brian J. 
Published: March 2022

AbstractFluorescent in situ hybridization (FISH) can provide spatial information about DNA/RNA targets in fixed cells and tissues. However, the workflows of multiplexed FISH-based imaging that use sequential rounds of hybridization quickly become laborious as the number of rounds increases because of liquid handling demands. Here, we present an open-source and low-cost fluidics system that is purpose built for automating the workflows of sequential FISH-based imaging. Our system features a fluidics module with 16 addressable channels in which flow is positive pressure-driven and switched on/off by solenoid valves in order to transfer FISH reagents to the sample. Our system also includes a controller with a main printed circuit board that can control up to 120 solenoid valves and allows users to control the fluidics module via serial communication. We demonstrate the automatic and robust fluid exchange with this system by targeting the alpha satellite repeat in HeLa cell with 14 rounds of sequential hybridization and imaging. We anticipate that this simple and flexible system will be of utility to researchers performing multiplexed in situ assays in a range of experimental systems.Abstract FigureSpecifications table
An optimized method for high-quality RNA extraction from distinctive intrinsic laryngeal muscles in the rat model
Authors: Kemfack Angela M. , Hernández-Morato Ignacio , Moayedi Yalda , Pitman Michael J. 
Published: March 2022

AbstractChallenges related to high-quality RNA extraction from post-mortem tissue have limited RNA-sequencing (RNA-seq) application in certain skeletal muscle groups, including the intrinsic laryngeal muscles (ILMs). The present study identified critical factors contributing to substandard RNA extraction from the ILMs and established a suitable method that permitted high-throughput analysis. Here, standard techniques for tissue processing were adapted, and an effective means to control confounding effects during specimen preparation was determined. The experimental procedure consistently provided sufficient intact total RNA (N = 68) and RIN ranging between 7.0 and 8.6, which was unprecedented using standard RNA purification protocols. This study confirmed the reproducibility of the workflow through repeated trials at different postnatal time points and across the distinctive ILMs. High-throughput diagnostics from 90 RNA samples indicated no sequencing alignment scores below 70%, validating the extraction strategy. Significant differences between the standard and experimental conditions suggest circumvented challenges and broad applicability to other skeletal muscles. This investigation remains ongoing given the prospect of therapeutic insights to voice, swallowing, and airway disorders. The present methodology supports pioneering global transcriptome investigations in the larynx previously unfounded in literature.