bluuebunny/crossref_metadata_2025_split huggingface dataset:
Remote patient monitoring and digital therapeutics in heart failure: lessons from the Continuum pilot study
Authors: Marier-Tétrault Emmanuel , Bebawi Emmanuel , Béchard Stéphanie , Brouillard Philippe , Zuchinali Priccila , Remillard Emilie , Carrier Zoé , Jean-Charles Loyda , Nguyen John , Lehoux Pascale , Pomey Marie-Pascale , Ribeiro Paula A. B. , Tournoux François 
Published: December 2022

AbstractIntroductionThe increasing use of digital health solutions to monitor heart failure (HF) outpatients has been driven by the COVID-19 pandemic. An ideal technology should answer the specific needs of a public healthcare system: easy integration and proof of clinical benefit to justify investment in its long-term use. Through a consortium bringing together patients, physicians, industry, and hospital organizations, we developed a digital solution called “Continuum,” targeting patients with HF and other comorbidities.HypothesisA digital health solution combining remote patient monitoring (RPM) and digital therapeutics (DTx) was developed to ensure a better follow-up of patients and to rapidly optimize their medication and subsequently avoid future severe adverse events.MethodsA pilot intervention/control study with a three-month follow-up was conducted. Patients in the intervention group (remote patient monitoring group, RPM+) had a smartphone or tablet and entered in their mobile app their vital signs, weight, and HF symptoms daily. HF patients who either did not have a mobile device or the skills to use the app were enrolled in the control group (RPM-). The HealthCare Professionals (HCPs) used a web-based dashboard to follow the RPM+patients. They could access the results of a DTx solution to help them optimize the HF treatment according to Canadian guidelines.Results52 HF patients were enrolled in this study, 32 in the RPM+: 69±9y age, 75% male, ejection fraction 42 ± 14%. In the RPM-group, more patients had at least one hospitalization (all-cause) compared to the RPM+group (35% versus 6% respectively; p=0.008). Similarly, the number of patients with at least one HF hospitalization was more significant in the RPM+group compared to the RPM-(25% versus 6%, p=0.054). Finally, the intervention showed a medium effect on HF treatment optimization (w=0.26) and quality of life for the most compliant patients to the intervention (g=0.48).ConclusionThe results of this pilot study demonstrated the feasibility of an intervention combining RPM and DTx solutions for HF patients. Preliminary results suggest promising impacts on quality of life, hospitalizations, and patients’ medication optimization. However, they need to be confirmed in a more extensive study.
Deprivation and Segregation in Ovarian cancer survival among African American Women: a mediated analysis
Authors: Lawson Andrew B. , Kim Joanne , Johnson Courtney , Hastert Theresa , Bandera Elisa V. , Alberg Anthony J. , Terry Paul , Akonde Maxwell , Mandle Hannah , Cote Michele L. , Bondy Melissa , Marks Jeffrey , Peres Lauren , Schildkraut Joellen , Peters Edward S. 
Published: December 2022

AbstractBackgroundDeprivation and segregation indices are often examined as possible explanations for observed health disparities in population-based studies. In this study we assessed the role of recognized deprivation and segregation indices specifically as they affect survival in a cohort of self-identified Black women diagnosed with ovarian cancer who enrolled in the African American Cancer Epidemiology Study (AACES).MethodsMediation analysis was used to examine the direct and indirect effects between deprivation or segregation and overall survival, via a Bayesian structural equation model with Gibbs variable selection.ResultsThe results suggest that high SES -related indices have an association with increased survival, ranging from 25%-56%. In contrast, ICE-race does not have a significant impact on overall survival. In many cases, the indirect effects have very wide credible intervals, consequently the total effect is not well estimated despite the estimation of the direct effect.ConclusionsOur results show that black women living in higher SES neighborhoods are associated with increased survival with ovarian cancer, using area-level economic indices such as Yost or ICE-income. In addition, the KOLAK urbanization index has a similar impact, and the highlights importance of area-level deprivation and segregation as potentially modifiable social factors in ovarian cancer survival.
Increased Tryptophan, But Not Increased Glucose Metabolism, Predict Resistance of Pembrolizumab in Stage III/IV Melanoma
Authors: Oldan Jorge D. , Giglio Benjamin C. , Smith Eric , Zhao Weiling , Bouchard Deeanna M. , Ivanovic Marija , Lee Yueh Z. , Collichio Frances A. , Meyers Michael , Wallack Diana E. , Abernethy-Leinwand Amber , Long Patricia K. , Trembath Dimitri G. , Googe Paul B. , Kowalski Madeline H. , Ivanova Anastasia , Ezzell Jennifer , Feinberg Nana , Thomas Nancy E. , Wong Terence Z. , Ollila David W. , Li Zibo , Moschos Stergios J. 
Published: December 2022

AbstractClinical trials of combined IDO/PD1 blockade in metastatic melanoma (MM) failed to show additional clinical benefit compared to PD1-alone inhibition. We reasoned that a tryptophan-metabolizing pathway other than the kynurenine one is essential. We immunohistochemically stained tissues along the nevus-to-MM progression pathway for tryptophan-metabolizing enzymes (TMEs; TPH1, TPH2, TDO2, IDO1) and the tryptophan transporter, LAT1. We assessed tryptophan and glucose metabolism by performing baseline C11-labeled α-methyl tryptophan (C11-AMT) and fluorodeoxyglucose (FDG) PET imaging of tumor lesions in a prospective clinical trial of pembrolizumab in MM (clinicaltrials.gov,NCT03089606). We found higher protein expression of all TMEs and LAT1 in melanoma cells than tumor-infiltrating lymphocytes (TILs) within MM tumors (n=68). Melanoma cell-specific TPH1 and LAT1 expression are significantly anti-correlated with TIL presence in MM. High melanoma cell-specific LAT1 and low IDO1 expression were associated with worse overall survival (OS) in MM. Exploratory optimal cut-point survival analysis of pretreatment ‘high’ vs. ‘low’ C11-AMT SUVmaxof the hottest tumor lesion per patient revealed that the ‘low’ C11-AMT SUVmaxwas associated with longer progression-free and OS in our clinical trial (n=26). We saw no such trends with pretreatment FDG PET SUVmax. Treatment of melanoma cell lines with telotristat, a TPH1 inhibitor, increased IDO expression and kynurenine production in addition to suppression of serotonin production. High melanoma tryptophan metabolism is a poor predictor of pembrolizumab response and an adverse prognostic factor. Serotoninergic but not kynurenine pathway activation may be significant. Melanoma cells outcompete adjacent TILs, eventually depriving the latter of an essential amino acid.
The Australian academic STEMM workplace post-COVID: a picture of disarray
Authors: Christian Katherine , Larkins Jo-ann , Doran Michael R. 
Published: December 2022

AbstractIn 2019 we surveyed Australian early career researchers (ECRs) working in STEMM (science, technology, engineering, mathematics and medicine). ECRs almost unanimously declared a “love of research”, however, many reported frequent bullying and questionable research practices (QRPs), and that they intended to leave because of poor career stability. We replicated the survey in 2022 to determine the impact of the COVID-19 pandemic and sought more information on bullying and QRPs. Here, we compare data from 2019 (658 respondents) and 2022 (530 respondents), and detail poor professional and research conditions experienced by ECRs. Job satisfaction declined (62% versus 57%), workload concerns increased (48.6% versus 60.6%), more indicated “now is a poor time to commence a research career” (65% versus 76%) from 2019 to 2022, and roughly half reported experiencing bullying. Perhaps conditions could be tolerable if the ecosystem were yielding well-trained scientists and high-quality science. Unfortunately, there are signs of poor supervision and high rates of QRPs. ECRs detailed problems likely worthy of investigation, but few (22.4%) felt that their institute would act on a complaint. We conclude by suggesting strategies for ECR mentorship, training, and workforce considerations intended to maintain research excellence in Australia and improve ECR career stability.
Disruption offoscauses craniofacial anomalies in developing zebrafish
Authors: Maili Lorena , Tandon Bhavna , Yuan Qiuping , Menezes Simone , Hashmi S. Shahrukh , Letra Ariadne , Eisenhoffer George T. , Hecht Jacqueline T. 
Published: December 2022

AbstractCraniofacial development is a complex and tightly regulated process and disruptions can lead to structural birth defects, the most common being nonsyndromic cleft lip and palate (NSCLP). Previously, we identifiedFOSas a candidate regulator of NSCLP through family-based association studies, yet its specific contributions to oral and palatal formation are poorly understood. This study investigated the role offosduring zebrafish craniofacial development through genetic disruption and knockdown approaches.Foswas expressed in the periderm, olfactory epithelium and other cell populations in the head. Genetic perturbation offosproduced an abnormal craniofacial phenotype with a hypoplastic oral cavity that showed significant changes in midface dimensions by quantitative facial morphometric analysis. Loss and knockdown offoscaused increased cell apoptosis in the head, followed by a significant reduction in cranial neural crest cells (CNCCs) populating the upper and lower jaws. These changes resulted in abnormalities of cartilage, bone and pharyngeal teeth formation. Periderm cells surrounding the oral cavity showed altered morphology and a subset of cells in the upper and lower lip showed disrupted Wnt/β-catenin activation, consistent with modified inductive interactions between mesenchymal and epithelial cells. Taken together, these findings demonstrate that perturbation offoshas detrimental effects on oral epithelial and CNCC-derived tissues suggesting that it plays a critical role in zebrafish craniofacial development and a potential role in NSCLP.Summary statementPerturbation offos, a candidate gene associated with nonsyndromic cleft lip and palate in humans, causes a distinctive orofacial phenotype in zebrafish as a result of abnormal development of craniofacial tissues. Disruption offosin the oral epithelial, cranial neural crest and Wnt responsive cell populations around the oral cavity causes anomalies that suggest a potential role in the etiology of NSCLP.
The Inherited Rate Matrix algorithm for phylogenetic model selection for non-stationary Markov processes
Authors: Tang Yurong , Kaehler Benjamin , Ying Hua , Huttley Gavin 
Published: December 2022

AbstractIn phylogenetic reconstruction, substitution models that assume nucleotide frequencies do not change through time are in very widespread use. DNA sequences can exhibit marked compositional difference. Such compositional heterogeneity implies sequence divergence has arisen from substitution processes that differ between the lineages. Accordingly, there has been considerable interest in exploring the non-stationary model class, which is capable of generating divergent sequence composition. These models are typically parameter rich and this richness is further compounded by the use of time-heterogeneous variants in order to capture compositional heterogeneity. This illuminates two barriers limiting the widespread application of the non-stationary model class: both the compute-time required to fit a model and the risk of model over-fitting increase with the number of parameters and the extent of time-heterogeneity. In this study, we address these issues with a novel model selection algorithm we term the Inherited Rate Matrix algorithm (hereafter IRM). This approach is based on the notion that a species inherits the substitution tendencies of its ancestor. We further present the non-stationary heterogeneous across lineages model (hereafter ns-HAL algorithm) which extends the HAL algorithm of Jayaswal et al. [2014] to the general nucleotide Markov process. The IRM algorithm substantially reduces the complexity of identifying a sufficient solution to the problem of time-heterogeneous substitution processes across lineages. We also address the issue of reducing the computing time with development of a constrained-optimisation approach for the IRM algorithm (fast-IRM). Our algorithms are implemented in Python 3. From a simulation study based on 2nd codon position genome sequences of yeast, we establish that IRM is significantly more accurate than both ns-HAL and heterogeneity in the substitution process across lineages (hereafter HAL) for close and dispersed sequences. IRM is up to 70× faster than ns-HAL while fast-IRM is around 140× faster. fast-IRM also showed a marked speed improvement over a C++ implementation of HAL. Our comparison of the accuracy of IRM with fast-IRM showed no difference with identical inferences made for all data sets. These two algorithms greatly improve the compute time for model selection of a non-stationary process, increasing the suite of problems to which this important substitution model class can be applied.
HexSDF are Required for Synthesis of a Novel Glycolipid that Mediates Daptomycin and Bacitracin Resistance inC. difficile
Authors: Pannullo Anthony G. , Guan Ziqiang , Goldfine Howard , Ellermeier Craig D. 
Published: December 2022

AbstractClostridioides difficileis a Gram-positive opportunistic pathogen that results in 250,000 infections, 12,000 deaths, and $1 billion in medical costs in the US each year. There has been recent interest in using a daptomycin analog, Surotomycin, to treatC. difficileinfections. Daptomycin interacts with both phosphatidylglycerol and Lipid II to disrupt the membrane and halt peptidoglycan synthesis.C. difficilehas an unusual lipid membrane composition as it has no phosphatidylserine or phosphatidylethanolamine, and ∼50% of its membrane is composed of glycolipids, including the uniqueC. difficilelipid aminohexosyl-hexosyldiradylglycerol (HNHDRG). We identified a two-component system (TCS) HexRK that is required forC. difficileresistance to daptomycin. Using RNAseq we found that HexRK regulates a three gene operon of unknown functionhexSDF. Based on bioinformatic predictions,hexSencodes a monogalactosyldiacylglycerol synthase,hexDencodes a polysaccharide deacetylase, andhexFencodes an MprF-like flippase. We find that deletion ofhexRKleads to a 4-fold decrease in daptomycin MIC, and that deletion ofhexSDFleads to an 8-16-fold decrease in daptomycin MIC. The ΔhexSDFmutant is also 4-fold less resistant to bacitracin but no other cell wall active antibiotics. Our data indicate that in the absence of HexSDF the phospholipid membrane composition is altered. In WTC. difficilethe unique glycolipid, HNHDRG makes up ∼17% of the lipids in the membrane. However, in a ΔhexSDFmutant, HNHDRG is completely absent. While it is unclear how HNHDRG contributes daptomycin resistance, the requirement for bacitracin resistance suggests it has a general role in cell membrane biogenesis.ImportanceClostridioides difficileis a major cause of hospital acquired diarrhea and represents an urgent concern due to the prevalence of antibiotic resistance and the rate of recurrent infections. Little is understood aboutC. difficilemembrane lipids, but a unique glycolipid, HNHDRG, has been previously identified inC. difficileand, currently, has not been identified in other organisms. Here we show that HexSDF and HexRK are required for synthesis of HNHDRG, and that production of HNHDRG impacts resistance to daptomycin and bacitracin.
A widespread oscillatory network encodes an aggressive internal state
Authors: Grossman Yael S. , Talbot Austin , Gallagher Neil M. , Thomas Gwenaëlle E. , Fink Alexandra J. , Walder-Christensen Kathryn K. , Russo Scott J. , Carlson David E. , Dzirasa Kafui 
Published: December 2022

AbstractSocial aggression is an innate behavior that can aid an organism in securing access to resources[1], or it can impair group function and survival in behavioral pathology[2-4]. Since many brain regions contribute to multiple social behaviors[5-7], expanded knowledge of how the brain distinguishes between social states would enable the development of interventions that suppress aggression, while leaving other social behaviors intact. Here we show that a murine aggressive internal state is encoded by a widespread network. This network is organized by prominent and synchronized theta (4-11Hz) and beta (14-30Hz) oscillations that relay through the prefrontal cortex, and couples to widespread cellular firing. Strikingly, network activity during social isolation encodes the trait aggressiveness of mice, and causal cellular manipulations known to impact aggression can bidirectionally regulate the network’s activity. Finally, we use closed-loop stimulation of prefrontal cortex and causal mediation analysis to establish that the network is a mediator of aggressive behavior. Thus, we define a widespread network that encodes an aggressive internal state within and across mice.
13C ENDOR Spectroscopy-Guided MD Computations Reveals the Structure of the Enzyme-Substrate Complex of an Active, N-linked Glycosylated Lipoxygenase
Authors: Sharma Ajay , Whittington Chris , Jabed Mohammed , Hill S. Gage , Kostenko Anastasiia , Yu Tao , Li Pengfei , Hoffman Brian M. , Offenbacher Adam R. 
Published: December 2022

AbstractLipoxygenases (LOXs) are enzymes responsible for producing important cell signaling mediators and have been extensively studied for their potential clinical relevance as well as to advance our understanding of enzyme catalysis. The common inability to capture and characterize LOX-substrate complexes by Xray co-crystallography requires the development of alternative structural methods. We previously reported the integration of13C/1H electron nuclear double resonance (ENDOR) spectroscopy and molecular dynamics (MD) to visualize the complex structure of the paradigmatic LOX from soybean, SLO, with substrate linoleic acid (LA). However, this required substitution of the catalytic mononuclear, nonheme iron by the structurally faithful, yet inactive Mn2+ion as a spin-probe. Unlike canonical Fe-LOXs from plants and animals, LOXs from pathogenic fungi contain active mononuclear manganese metallocentres. Here, we report the ground-state active-site structure of the native, fully glycosylated fungal LOX fromM. oryzae, MoLOX complexed with LA obtained through the13C/1H ENDOR-guided MD approach. The Mn-oxygen-to-LA donor carbon distance (DAD) forMoLOX-LA, 3.4 ± 0.3 Å, matches the distance in the single representative X-ray co-structure of an animal 8R-LOX with its natural fatty acid substrate, and slightly elongated from that of the SLO-LA complex, 3.1 ± 0.2 Å, despite its ‘carboxylate-out’ substrate binding orientation versus ‘carboxylate-in’ for SLO. The results provide unique insight into the evolutionary divergence of the ground-state DAD in the LOX family, which influences the activation barrier for hydrogen tunneling, and give a structural basis for guiding development ofMoLOX inhibitors. The work highlights the robustness of ENDOR-guided MD approach to describe LOX-substrate structures that elude conventional X-ray techniques.
Activation of prefrontal cortex and striatal regions in rats after shifting between rules in a T-maze
Authors: Gao Hongying , Oberto Virginie , Biondi Ana , Sara Susan J. , Wiener Sidney I. 
Published: December 2022

AbstractPrefrontal cortical and striatal areas have been identified by inactivation or lesion studies to be required for behavioral flexibility, including selecting and processing of different types of information. In order to identify these networks activated selectively during acquisition of new reward contingency rules, rats were trained to discriminate orientations of bars presented in pseudo-random sequence on two video monitors positioned behind the goal sites on a T maze with return arms. A second group already trained in the visual discrimination task learned to alternate left and right goal arm visits in the same maze while ignoring the visual cues still being presented. In each experimental group, once the rats reached criterion performance, the brains were prepared after a 90 minute delay, for later processing for c-fos immunohistochemistry. While both groups extinguished a prior strategy and acquired a new rule, they differed by the identity of the strategies, and previous learning experience. Among the 28 forebrain areas examined, there were significant increases in the relative density of c-fos immunoreactive cell bodies after learning the second rule in prefrontal cortex cingulate, prelimbic and infralimbic areas, in dorsomedial striatum and the core of nucleus accumbens, in ventral subiculum, and the central nucleus of the amygdala. These largely correspond to structures anatomically identified by previous inactivation studies. The data suggest that this dynamic network may underlie reward-based selection for action, a type of cognitive flexibility.
Characterization of BoHV-4 ORF45
Authors: Russo Luca , Capra Emanuele , Franceschi Valentina , Cavazzini Davide , Sala Roberto , Lazzari Barbara , Cavirani Sandro , Donofrio Gaetano 
Published: December 2022

AbstractBovine herpesvirus 4 (BoHV-4) is aGammaherpesvirusof the genusRhadinovirus, his natural host is the bovine whereas the African Buffalo the natural reservoir. Anyhow, BoHV-4 infection is not associated to a specific disease. Genome structure and genes are well conserved inGammaherpesvirus, andorf45 gene and its product, ORF45, is one of those. BoHV-4 ORF45 has been suggested to be a tegument protein, however, BoHV-4 ORF45 structure and function have not yet been experimentally characterized. In the present study, it is shown that BoHV-4 ORF45, despite its poor homology with other characterizedRhadinovirusORF45s, is structurally related to Kaposi’s sarcoma-associated herpesvirus (KSHV), is a phosphoprotein and localizes in the host cell nuclei. Through the generation of an ORF45-null mutant BoHV-4 and its pararevertant, it was possible to demonstrate that ORF45 is essential for BoHV-4 lytic replication and is associated to the viral particles, as for the other characterizedRhadinovirusORF45s. Finally, the impact of BoHV-4 ORF45 on cellular transcriptome was investigated, an aspect poorly explored or not at all for otherGammaherpesvirus. Many cellular transcriptional pathways were found to be alterate, mainly those involving p90 ribosomal S6 kinase (RSK) and signal-regulated kinase (ERK) complex (RSK/ERK), thus highlighting the authentic character of BoHV-4 ORF45 and paving the way to further investigations.