bluuebunny/crossref_metadata_2025_split huggingface dataset:
A proof-of-concept study for the pathogenetic role of enhancer hypomethylation of MYBPHL in multiple myeloma
Authors: Wong Kwan Yeung , Morgan Gareth J. , Boyle Eileen M. , Cheng Alfred Sze Lok , Yip Kevin Yuk-Lap , Chim Chor Sang 
Published: March 2021

AbstractEnhancer DNA methylation and expression of MYBPHL was studied in multiple myeloma (MM). By bisulfite genomic sequencing, among the three CpGs inside the MYBPHL enhancer, CpG1 was significantly hypomethylated in MM cell lines (6.7–50.0%) than normal plasma cells (37.5–75.0%) (P = 0.007), which was negatively correlated with qPCR-measured MYBPHL expression. In RPMI-8226 and WL-2 cells, bearing the highest CpG1 methylation, 5-azadC caused enhancer demethylation and expression of MYBPHL. In primary samples, higher CpG1 methylation was associated with lower MYBPHL expression. By luciferase assay, luciferase activity was enhanced by MYBPHL enhancer compared with empty vector control, but reduced by site-directed mutagenesis of each CpG. RNA-seq data of newly diagnosed MM patients showed that MYBPHL expression was associated with t(11;14). MOLP-8 cells carrying t(11;14) express the highest levels of MYBPHL, and its knockdown reduced cellular proliferation and increased cell death. Herein, as a proof-of-concept, our data demonstrated that the MYBPHL enhancer, particularly CpG1, was hypomethylated and associated with increased MYBPHL expression in MM, which was implicated in myelomagenesis.
A pioneering study indicate role of GABRQ rs3810651 in ASD severity of Indo-Caucasoid female probands
Authors: Saha Sharmistha , Chatterjee Mahasweta , Sinha Swagata , Mukhopadhyay Kanchan 
Published: March 2021

AbstractAlteration in gamma aminobutyric acid (GABA), the principal inhibitory neurotransmitter, is speculated to be a potential risk factor for Autism Spectrum Disorder (ASD) due to an altered expression in the brain. Sensory, social, and emotional deficits of subjects with ASD were reported to be caused by an imbalance between excitatory and inhibitory neurotransmission as well as GABAergic dysfunction caused by inadequate receptor function. We for the first time studied association between ASD and a missense coding variant rs3810651 (I478F) in the GABRQ gene, encoding for one of the subunits of GABAA receptors. Stratified analysis on families with ASD probands (N = 251) and ethnically matched control subjects (N = 250) revealed marginally higher frequency of “A” allele and “AA” genotype in female ASD probands as compared to gender matched controls. Female probands demonstrated higher severity for Verbal communication (χ2 = 5.75, P = 0.01), Activity level (χ2 = 7.26, P  = 0.007), as well as Level and consistency of intellectual response (χ2 = 7.83 P = 0.005) in presence of “A/AA” warranting further in-depth investigation on the role of rs3810651 in ASD.
Intestinal helminth co-infection is an unrecognised risk factor for increased pneumococcal carriage density and invasive disease
Authors: Law Alice E. , Shears Rebecca K. , Lopez Rodas Andrea A. , Grencis Richard K. , Cooper Philip J. , Neill Daniel R. , Kadioglu Aras 
Published: March 2021

AbstractInfection with Streptococcus pneumoniae is the leading cause of death in children and burden of disease is greatest where helminth infections are also common. We investigated the impact of intestinal helminth co-infection on pneumococcal carriage; a risk factor for invasive disease. We used a mouse co-infection model and clinical data to assess the impact of co-infection on carriage density. Co-infection in mice was associated with increased pneumococcal carriage density and dissemination into lungs. Helminth-infected children also exhibited increased carriage density as compared to uninfected children. Anthelmintic treatment may be a cost-effective method of reducing pneumococcal disease burden in lower-income countries.
Association of antidiabetic therapies with lower extremity amputation, mortality and healthcare cost from a nationwide retrospective cohort study in Taiwan
Authors: Chang Hsien-Yen , Chou Ying-Yi , Tang Wenze , Chang Guann-Ming , Hsieh Chi‐Feng , Singh Sonal , Tung Yu-Chi 
Published: March 2021

AbstractWe compared risks of clinical outcomes, mortality and healthcare costs among new users of different classes of anti-diabetic medications. This is a population-based, retrospective, new-user design cohort study using the Taiwan National Health Insurance Database between May 2, 2015 and September 30, 2017. An individual was assigned to a medication group based on the first anti-diabetic prescription on or after May 1, 2016: SGLT-2 inhibitors, DPP-4 inhibitors, GLP-1 agonists or older agents (metformin, etc.). Clinical outcomes included lower extremity amputation, peripheral vascular disease, critical limb ischemia, osteomyelitis, and ulcer. We built three Cox proportional hazards models for clinical outcomes and mortality, and three regression models with a log-link function and gamma distribution for healthcare costs, all with propensity-score weighting and covariates. We identified 1,222,436 eligible individuals. After adjustment, new users of SGLT-2 inhibitors were associated with 73% lower mortality compared to those of DPP-4 inhibitors or users of older agents, while 36% lower total costs against those of GLP-1 agonists. However, there was no statistically significant difference in the risk of lower extremity amputation across medication groups. Our study suggested that SGLT-2 inhibitors is associated with lower mortality compared to DPP 4 inhibitors and lower costs compared to GLP-1 agonists.
Preoperative immune landscape predisposes adverse outcomes in hepatocellular carcinoma patients with liver transplantation
Authors: Yoon Sang-Ho , Choi Seo-Won , Nam Suk Woo , Lee Kyoung Bun , Nam Jin-Wu 
Published: March 2021

AbstractImmune class in hepatocellular carcinoma (HCC) has been shown to possess immunogenic power; however, how preestablished immune landscapes in premalignant and early HCC stages impact the clinical outcomes of HCC patients remains unexplored. We sequenced bulk transcriptomes for 62 malignant tumor samples from a Korean HCC cohort in which 38 patients underwent total hepatectomy, as well as for 15 normal and 47 adjacent nontumor samples. Using in silico deconvolution of expression mixtures, 22 immune cell fractions for each sample were inferred, and validated with immune cell counting by immunohistochemistry. Cell type-specific immune signatures dynamically shifted from premalignant stages to the late HCC stage. Total hepatectomy patients displayed elevated immune infiltration and prolonged disease-free survival compared to the partial hepatectomy patients. However, patients who exhibited an infiltration of regulatory T cells (Tregs) during the pretransplantation period displayed a high risk of tumor relapse with suppressed immune responses, and pretreatment was a potential driver of Treg infiltration in the total hepatectomy group. Treg infiltration appeared to be independent of molecular classifications based on transcriptomic data. Our study provides not only comprehensive immune signatures in adjacent nontumor lesions and early malignant HCC stages but also clinical guidance for HCC patients who will undergo liver transplantation.
Effectiveness of a digital therapeutic as adjunct to treatment with medication in pediatric ADHD
Authors: Kollins Scott H. , Childress Ann , Heusser Andrew C. , Lutz Jacqueline 
Published: March 2021

AbstractSTARS-Adjunct was a multicenter, open-label effectiveness study of AKL-T01, an app and video-game-based treatment for inattention, as an adjunct to pharmacotherapy in 8–14-year-old children with attention-deficit/hyperactivity disorder (ADHD) on stimulant medication (n = 130) or not on any ADHD medication (n = 76). Children used AKL-T01 for 4 weeks, followed by a 4-week pause and another 4-week treatment. The primary outcome was change in ADHD-related impairment (Impairment Rating Scale (IRS)) after 4 weeks. Secondary outcomes included changes in IRS, ADHD Rating Scale (ADHD-RS). and Clinical Global Impressions Scale—Improvement (CGI-I) on days 28, 56, and 84. IRS significantly improved in both cohorts (On Stimulants: −0.7, p < 0.001; No Stimulants: −0.5, p < 0.001) after 4 weeks. IRS, ADHD-RS, and CGI-I remained stable during the pause and improved with a second treatment period. The treatment was well-tolerated with no serious adverse events. STARS-Adjunct extends AKL-T01’s body of evidence to a medication-treated pediatric ADHD population, and suggests additional treatment benefit.
The digital scribe in clinical practice: a scoping review and research agenda
Authors: van Buchem Marieke M. , Boosman Hileen , Bauer Martijn P. , Kant Ilse M. J. , Cammel Simone A. , Steyerberg Ewout W. 
Published: March 2021

AbstractThe number of clinician burnouts is increasing and has been linked to a high administrative burden. Automatic speech recognition (ASR) and natural language processing (NLP) techniques may address this issue by creating the possibility of automating clinical documentation with a “digital scribe”. We reviewed the current status of the digital scribe in development towards clinical practice and present a scope for future research. We performed a literature search of four scientific databases (Medline, Web of Science, ACL, and Arxiv) and requested several companies that offer digital scribes to provide performance data. We included articles that described the use of models on clinical conversational data, either automatically or manually transcribed, to automate clinical documentation. Of 20 included articles, three described ASR models for clinical conversations. The other 17 articles presented models for entity extraction, classification, or summarization of clinical conversations. Two studies examined the system’s clinical validity and usability, while the other 18 studies only assessed their model’s technical validity on the specific NLP task. One company provided performance data. The most promising models use context-sensitive word embeddings in combination with attention-based neural networks. However, the studies on digital scribes only focus on technical validity, while companies offering digital scribes do not publish information on any of the research phases. Future research should focus on more extensive reporting, iteratively studying technical validity and clinical validity and usability, and investigating the clinical utility of digital scribes.
A role for Dynlt3 in melanosome movement, distribution, acidity and transfer
Authors: Aktary Zackie , Conde-Perez Alejandro , Rambow Florian , Di Marco Mathilde , Amblard François , Hurbain Ilse , Raposo Graça , Delevoye Cédric , Coscoy Sylvie , Larue Lionel 
Published: March 2021

AbstractSkin pigmentation is dependent on cellular processes including melanosome biogenesis, transport, maturation and transfer to keratinocytes. However, how the cells finely control these processes in space and time to ensure proper pigmentation remains unclear. Here, we show that a component of the cytoplasmic dynein complex, Dynlt3, is required for efficient melanosome transport, acidity and transfer. In Mus musculus melanocytes with decreased levels of Dynlt3, pigmented melanosomes undergo a more directional motion, leading to their peripheral location in the cell. Stage IV melanosomes are more acidic, but still heavily pigmented, resulting in a less efficient melanosome transfer. Finally, the level of Dynlt3 is dependent on β-catenin activity, revealing a function of the Wnt/β-catenin signalling pathway during melanocyte and skin pigmentation, by coupling the transport, positioning and acidity of melanosomes required for their transfer.
The metabolic network of the last bacterial common ancestor
Authors: Xavier Joana C. , Gerhards Rebecca E. , Wimmer Jessica L. E. , Brueckner Julia , Tria Fernando D. K. , Martin William F. 
Published: March 2021

AbstractBacteria are the most abundant cells on Earth. They are generally regarded as ancient, but due to striking diversity in their metabolic capacities and widespread lateral gene transfer, the physiology of the first bacteria is unknown. From 1089 reference genomes of bacterial anaerobes, we identified 146 protein families that trace to the last bacterial common ancestor, LBCA, and form the conserved predicted core of its metabolic network, which requires only nine genes to encompass all universal metabolites. Our results indicate that LBCA performed gluconeogenesis towards cell wall synthesis, and had numerous RNA modifications and multifunctional enzymes that permitted life with low gene content. In accordance with recent findings for LUCA and LACA, analyses of thousands of individual gene trees indicate that LBCA was rod-shaped and the first lineage to diverge from the ancestral bacterial stem was most similar to modern Clostridia, followed by other autotrophs that harbor the acetyl-CoA pathway.
Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice
Authors: Voisin Maud , Shrestha Elina , Rollet Claire , Nikain Cyrus A. , Josefs Tatjana , Mahé Mélanie , Barrett Tessa J. , Chang Hye Rim , Ruoff Rachel , Schneider Jeffrey A. , Garabedian Michela L. , Zoumadakis Chris , Yun Chi , Badwan Bara , Brown Emily J. , Mar Adam C. , Schneider Robert J. , Goldberg Ira J. , Pineda-Torra Inés , Fisher Edward A. , Garabedian Michael J. 
Published: March 2021

AbstractAtherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα plays a central role in the transcription of inflammatory and metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRα phosphorylation, bone marrow from LXRα WT and S196A mice was transplanted intoLdlr−/−mice, which were fed a western diet prior to evaluation of atherosclerosis and obesity. Plaques from S196A mice showed reduced inflammatory monocyte recruitment, lipid accumulation, and macrophage proliferation. Expression profiling of CD68+and T cells from S196A mouse plaques revealed downregulation of pro-inflammatory genes and in the case of CD68+upregulation of mitochondrial genes characteristic of anti-inflammatory macrophages. Furthermore, S196A mice had lower body weight and less visceral adipose tissue; this was associated with transcriptional reprograming of the adipose tissue macrophages and T cells, and resolution of inflammation resulting in less fat accumulation within adipocytes. Thus, reducing LXRα pS196 in hematopoietic cells attenuates atherosclerosis and obesity by reprogramming the transcriptional activity of LXRα in macrophages and T cells to promote an anti-inflammatory phenotype.
MED15 prion-like domain forms a coiled-coil responsible for its amyloid conversion and propagation
Authors: Batlle Cristina , Calvo Isabel , Iglesias Valentin , J. Lynch Cian , Gil-Garcia Marcos , Serrano Manuel , Ventura Salvador 
Published: March 2021

AbstractA disordered to β-sheet transition was thought to drive the functional switch of Q/N-rich prions, similar to pathogenic amyloids. However, recent evidence indicates a critical role for coiled-coil (CC) regions within yeast prion domains in amyloid formation. We show that many human prion-like domains (PrLDs) contain CC regions that overlap with polyQ tracts. Most of the proteins bearing these domains are transcriptional coactivators, including the Mediator complex subunit 15 (MED15) involved in bridging enhancers and promoters. We demonstrate that the human MED15-PrLD forms homodimers in solution sustained by CC interactions and that it is this CC fold that mediates the transition towards a β-sheet amyloid state, its chemical or genetic disruption abolishing aggregation. As in functional yeast prions, a GFP globular domain adjacent to MED15-PrLD retains its structural integrity in the amyloid state. Expression of MED15-PrLD in human cells promotes the formation of cytoplasmic and perinuclear inclusions, kidnapping endogenous full-length MED15 to these aggregates in a prion-like manner. The prion-like properties of MED15 are conserved, suggesting novel mechanisms for the function and malfunction of this transcription coactivator.
INPP4B protects from metabolic syndrome and associated disorders
Authors: Zhang Manqi , Ceyhan Yasemin , Kaftanovskaya Elena M. , Vasquez Judy L. , Vacher Jean , Knop Filip K. , Nathanson Lubov , Agoulnik Alexander I. , Ittmann Michael M. , Agoulnik Irina U. 
Published: March 2021

AbstractA high fat diet and obesity have been linked to the development of metabolic dysfunction and the promotion of multiple cancers. The causative cellular signals are multifactorial and not yet completely understood. In this report, we show that Inositol Polyphosphate-4-Phosphatase Type II B (INPP4B) signaling protects mice from diet-induced metabolic dysfunction. INPP4B suppresses AKT and PKC signaling in the liver thereby improving insulin sensitivity. INPP4B loss results in the proteolytic cleavage and activation of a key regulator in de novo lipogenesis and lipid storage, SREBP1. In mice fed with the high fat diet, SREBP1 increases expression and activity of PPARG and other lipogenic pathways, leading to obesity and non-alcoholic fatty liver disease (NAFLD). Inpp4b−/− male mice have reduced energy expenditure and respiratory exchange ratio leading to increased adiposity and insulin resistance. When treated with high fat diet, Inpp4b−/− males develop type II diabetes and inflammation of adipose tissue and prostate. In turn, inflammation drives the development of high-grade prostatic intraepithelial neoplasia (PIN). Thus, INPP4B plays a crucial role in maintenance of overall metabolic health and protects from prostate neoplasms associated with metabolic dysfunction.
CENP-A overexpression promotes distinct fates in human cells, depending on p53 status
Authors: Jeffery Daniel , Gatto Alberto , Podsypanina Katrina , Renaud-Pageot Charlène , Ponce Landete Rebeca , Bonneville Lorraine , Dumont Marie , Fachinetti Daniele , Almouzni Geneviève 
Published: March 2021

AbstractTumour evolution is driven by both genetic and epigenetic changes. CENP-A, the centromeric histone H3 variant, is an epigenetic mark that directly perturbs genetic stability and chromatin when overexpressed. Although CENP-A overexpression is a common feature of many cancers, how this impacts cell fate and response to therapy remains unclear. Here, we established a tunable system of inducible and reversible CENP-A overexpression combined with a switch in p53 status in human cell lines. Through clonogenic survival assays, single-cell RNA-sequencing and cell trajectory analysis, we uncover the tumour suppressor p53 as a key determinant of how CENP-A impacts cell state, cell identity and therapeutic response. If p53 is functional, CENP-A overexpression promotes senescence and radiosensitivity. Surprisingly, when we inactivate p53, CENP-A overexpression instead promotes epithelial-mesenchymal transition, an essential process in mammalian development but also a precursor for tumour cell invasion and metastasis. Thus, we uncover an unanticipated function of CENP-A overexpression to promote cell fate reprogramming, with important implications for development and tumour evolution.
Near-unity broadband omnidirectional emissivity via femtosecond laser surface processing
Authors: Reicks Andrew , Tsubaki Alfred , Anderson Mark , Wieseler Jace , Khorashad Larousse Khosravi , Shield Jeffrey E. , Gogos George , Alexander Dennis , Argyropoulos Christos , Zuhlke Craig 
Published: March 2021

AbstractIt is very challenging to achieve near perfect absorption or emission that is both broadband and omnidirectional while utilizing a scalable fabrication process. Femtosecond laser surface processing is an emerging low-cost and large-scale manufacturing technique used to directly and permanently modify the surface properties of a material. The versatility of this technique to produce tailored surface properties has resulted in a rapidly growing number of applications. Here, we demonstrate near perfect, broadband, omnidirectional emissivity from aluminum surfaces by tuning the laser surface processing parameters including fluence, pulse count, and the ambient gas. Full-wave simulations and experimental results prove that the obtained increase in emissivity is mainly a result of two distinct features produced by femtosecond laser surface processing: the introduction of microscale surface features and the thick oxide layer. This technique leads to functionalized metallic surfaces that are ideal for emerging applications, such as passive radiative cooling and thermal management of spacecraft.
Vegetation and microbes interact to preserve carbon in many wooded peatlands
Authors: Wang Hongjun , Tian Jianqing , Chen Huai , Ho Mengchi , Vilgalys Rytas , Bu Zhao-Jun , Liu Xingzhong , Richardson Curtis J. 
Published: March 2021

AbstractPeatlands have persisted as massive carbon sinks over millennia, even during past periods of climate change. The commonly accepted theory of abiotic controls (mainly anoxia and low temperature) over carbon decomposition cannot fully explain how vast low-latitude shrub/tree dominated (wooded) peatlands consistently accrete peat under warm and seasonally unsaturated conditions. Here we show, by comparing the composition and ecological traits of microbes between Sphagnum- and shrub-dominated peatlands, that slow-growing microbes decisively dominate the studied shrub-dominated peatlands, concomitant with plant-induced increases in highly recalcitrant carbon and phenolics. The slow-growing microbes metabolize organic matter thirty times slower than the fast-growing microbes that dominate our Sphagnum-dominated site. We suggest that the high-phenolic shrub/tree induced shifts in microbial composition may compensate for positive effects of temperature and/or drought on metabolism over time in peatlands. This biotic self-sustaining process that modulates abiotic controls on carbon cycling may improve projections of long-term, climate-carbon feedbacks in peatlands.
Environmentally persistent free radicals are ubiquitous in wildfire charcoals and remain stable for years
Authors: Sigmund Gabriel , Santín Cristina , Pignitter Marc , Tepe Nathalie , Doerr Stefan H. , Hofmann Thilo 
Published: March 2021

AbstractGlobally landscape fires produce about 256 Tg of pyrogenic carbon or charcoal each year. The role of charcoal as a source of environmentally persistent free radicals, which are precursors of potentially harmful reactive oxygen species, is poorly constrained. Here, we analyse 60 charcoal samples collected from 10 wildfires, that include crown as well as surface fires in forest, shrubland and grassland spanning different boreal, temperate, subtropical and tropical climate. Using electron spin resonance spectroscopy, we measure high concentrations of environmentally persistent free radicals in charcoal samples, much higher than those found in soils. Concentrations increased with degree of carbonization and woody fuels favoured higher concentrations. Moreover, environmentally persistent free radicals remained stable for an unexpectedly long time of at least 5 years. We suggest that wildfire charcoal is an important global source of environmentally persistent free radicals, and therefore potentially of harmful reactive oxygen species.