bluuebunny/crossref_metadata_2025_split huggingface dataset:
C-di-AMP levels modulateStaphylococcus aureuscell wall thickness as well as virulence and contribute to antibiotic resistance and tolerance
Authors: Haunreiter Vanina Dengler , Tarnutzer Andrea , Bär Julian , von Matt Manuela , Hertegonne Sanne , Andreoni Federica , Vulin Clément , Künzi Lisa , Menzi Carmen , Kiefer Patrick , Christen Philipp , Vorholt Julia A. , Zinkernagel Annelies S. 
Published: April 2023

AbstractBeta-lactam antibiotics are widely used to treat infections caused by the important human pathogenStaphylococcus aureus. Resistance to beta-lactams, as found in methicillin-resistantS. aureus(MRSA), renders effective treatment difficult. The second messenger cyclic di-3′,5′- adenosine monophosphate (c-di-AMP) promotes beta-lactam resistance in clinicalS. aureusisolates. C-di-AMP plays a crucial role in the regulation of cellular processes such as virulence, cell wall homeostasis and resistance to beta-lactams in many bacterial species. InS. aureus,c-di-AMP synthesis is mediated by the diadenylate cyclase DacA, while its degradation is carried out by the phosphodiesterases GdpP and Pde2.In this work, we assessed the effect of altered c-di-AMP levels due to mutations incacA,gdpPorgdpP/pde2on virulence determinants. We report that a previously described growth defect in bacteria producing high c-di-AMP levels is mainly attributable to smaller cell size. High c-di-AMP levels also led to decreased survival upon oxidative stress, reduced production of the antioxidant staphyloxanthin, increased oxacillin and fosfomycin resistance and increased cell wall thickness. While resistance to ceftaroline was not affected, high c-di-AMP levels promoted tolerance to this antibiotic. In response to cell wall stress induced by antibiotics, the three-component regulatory system VraTSR mediates an increase in cell wall synthesis via the cell wall stress stimulon (CWSS). Increased c-di-AMP levels led to an activation of the CWSS. Upon deletion ofvraR, resistance to oxacillin and fosfomycin as well as cell wall thickness diminished in the ΔgdpPmutant, indicating a contribution of the VraTSR system to the cell wall related phenotypes.ImportanceAntibiotic resistance and tolerance are substantial health-care related problems, hampering effective treatment of bacterial infections. Mutations in the phosphodiesterase GdpP, which degrades cyclic di-3′, 5′-adenosine monophosphate (c-di-AMP), have recently been associated with resistance to beta-lactam antibiotics in clinicalStaphylococcus aureusisolates. In this study, we show that high c-di-AMP levels decreased the cell size and increased the cell wall thickness inS. aureusmutant strains. As a consequence, an increase in resistance to cell wall targeting antibiotics such as oxacillin and fosfomycin as well as in tolerance to ceftaroline, a cephalosporine used to treat MRSA infections, were observed. These findings underline the importance of investigating the role of c-di-AMP in the development of tolerance and resistance to antibiotics in order to optimize treatment in the clinical setting.
Self-reported effects of classic psychedelics on stuttering
Authors: Gold Noah D. , Goldway Noam , Gerlach-Houck Hope , Jackson Eric S. 
Published: April 2023

AbstractStuttering is a neurodevelopmental communication disorder that can lead to significant social, occupational, and educational challenges. Traditional behavioral interventions for stuttering can be helpful, but effects are often limited. Classic psychedelics hold promise as a complement to traditional interventions, but their impact on stuttering is unknown. We conducted a qualitative content analysis to explore potential benefits and negative effects of psychedelics on stuttering using publicly available Reddit posts. A combined inductive-deductive approach was used whereby meaningful units were extracted and codes were initially assigned inductively. We then deductively applied an established framework to organize the effects (i.e., codes) into five subthemes (Behavioral, Emotional, Cognitive, Belief, and Social Connection), each of which was grouped under an organizing theme (positive, negative, neutral). Results indicated that the effects of psychedelics spanned all subthemes. Nearly 75% of participants reported overall positive effects. Nearly 60% of participants indicated positive behavioral change (e.g., reduced stuttering, increased speech control), 40% reported positive emotional benefit, 15% reported positive cognitive changes, 12% reported positive effects on beliefs, and 7% indicated positive social effects. Approximately 10% of participants reported negative behavioral effects (e.g., increased stuttering, reduced speech control). Psychedelics may help many stutterers improve communication, cultivate a healthier outlook, and promote psychological well-being. These preliminary results indicate that future clinical trials investigating psychedelic-assisted speech therapy for stuttering are warranted.
Monocyte-derived Dll4 is a novel contributor to persistent systemic inflammation in HIV patients
Authors: Wang Shumin , Singh Meera , Yang Hongmei , Morrell Craig N. , Mohamad Laith Awad , Xu Jasmine Jiayuan , Nguyen Tiffany , Ture Sara , Tyrell Alicia , Maggirwar Sanjay B. , Schifitto Giovanni , Pang Jinjiang 
Published: April 2023

AbstractBackgroundIn people living with HIV (PLWH) on combination antiretroviral therapy (cART), persistent systemic inflammation is a driving force for the progression of comorbidities, such as cardiovascular and cerebrovascular diseases. In this context, monocyte- and macrophage-related inflammation rather than T cell activation is a major cause of chronic inflammation. However, the underlying mechanism of how monocytes cause persistent systemic inflammation in PLWH is elusive.Methods and ResultsIn vitro, we demonstrated that lipopolysaccharides (LPS) or tumor necrosis factor alpha (TNFα), induced a robust increase of Delta-like ligand 4 (Dll4) mRNA and protein expression in human monocytes and Dll4 secretion (extracellular Dll4, exDll4) from monocytes. Enhanced membrane-bound Dll4 (mDll4) expression in monocytes triggered Notch1 activation to promote pro-inflammatory factors expression. Dll4 silencing and inhibition of Nocth1 activation diminished the LPS or TNFα -induced inflammation. exDll4 releases in response to cytokines occurred in monocytes but not endothelial cells or T cells. In clinical specimens, we found that PLWH, both male and female, on cART, showed a significant increase in mDll4 expression, activation of Dll4-Notch1 signaling, and inflammatory markers in monocytes. Although there was no sex effect on mDII4 in PLWH, plasma exDll4 was significantly elevated in males but not females compared to HIV uninfected individuals. Furthermore, exDll4 plasma levels paralleled with monocytes mDll4 in male PLWH. Circulating exDll4 was also positively associated with pro-inflammatory monocytes phenotype and negatively associated with classic monocytes phenotype in male PLWH.ConclusionPro-inflammatory stimuli increase Dll4 expression and Dll4-Notch1 signaling activation in monocytes and enhance monocyte proinflammatory phenotype, contributing to persistent systemic inflammation in male and female PLWH. Therefore, monocyte mDll4 could be a potential biomarker and therapeutic target of systemic inflammation. Plasma exDll4 may also play an additional role in systemic inflammation but primarily in men.
Protein language model-based end-to-end type II polyketide prediction without sequence alignment
Authors: Huang Jiaquan , Gao Qiandi , Tang Ying , Wu Yaxin , Zhang Heqian , Qin Zhiwei 
Published: April 2023

AbstractNatural products are important sources for drug development, and the precise prediction of their structures assembled by modular proteins is an area of great interest. In this study, we introduce DeepT2, an end-to-end, cost-effective, and accurate machine learning platform to accelerate the identification of type II polyketides (T2PKs), which represent a significant portion of the natural product world. Our algorithm is based on advanced natural language processing models and utilizes the core biosynthetic enzyme, chain length factor (CLF or KSβ), as computing inputs. The process involves sequence embedding, data labeling, classifier development, and novelty detection, which enable precise classification and prediction directly from KSβwithout sequence alignments. Combined with metagenomics and metabolomics, we evaluated the ability of DeepT2 and found this model could easily detect and classify KSβeither as a single sequence or a mixture of bacterial genomes, and subsequently identify the corresponding T2PKs in a labeled categorized class or as novel. Our work highlights deep learning as a promising framework for genome mining and therefore provides a meaningful platform for discovering medically important natural products.
Cell state-dependent chromatin targeting in NUT carcinoma
Authors: Alekseyenko Artyom A. , Zee Barry M. , Dhoondia Zuzer , Kang Hyuckjoon , Makofske Jessica L. , Kuroda Mitzi I. 
Published: April 2023

ABSTRACTAberrant transcriptional programming and chromatin dysregulation are common to most cancers. Whether by deranged cell signaling or environmental insult, the resulting oncogenic phenotype is typically manifested in transcriptional changes characteristic of undifferentiated cell growth. Here we analyze targeting of an oncogenic fusion protein, BRD4-NUT, composed of two normally independent chromatin regulators. The fusion causes the formation of large hyperacetylated genomic regions or megadomains, mis-regulation ofc-MYC, and an aggressive carcinoma of squamous cell origin. Our previous work revealed largely distinct megadomain locations in different NUT carcinoma patient cell lines. To assess whether this was due to variations in individual genome sequences or epigenetic cell state, we expressed BRD4-NUT in a human stem cell model and found that megadomains formed in dissimilar patterns when comparing cells in the pluripotent state with the same cell line following induction along a mesodermal lineage. Thus, our work implicates initial cell state as the critical factor in the locations of BRD4-NUT megadomains. These results, together with our analysis of c-MYC protein-protein interactions in a patient cell line, are consistent with a cascade of chromatin misregulation underlying NUT carcinoma.
Flux Sampling in Genome-scale Metabolic Modeling of Microbial Communities
Authors: Gelbach Patrick E. , Finley Stacey D. 
Published: April 2023

1.AbstractMicrobial communities play a crucial role in ecosystem function through metabolic interactions. Genome-scale modeling is a promising method to understand these interactions. Flux balance analysis (FBA) is most often used to predict the flux through all reactions in a genome-scale model. However, the fluxes predicted by FBA depend on a user-defined cellular objective. Flux sampling is an alternative to FBA, as it provides the range of fluxes possible within a microbial community. Furthermore, flux sampling may capture additional heterogeneity across cells, especially when cells exhibit sub-maximal growth rates. In this study, we simulate the metabolism of microbial communities and compare the metabolic characteristics found with FBA and flux sampling. We find significant differences in the predicted metabolism with sampling, including increased cooperative interactions and pathway-specific changes in predicted flux. Our results suggest the importance of sampling-based and objective function-independent approaches to evaluate metabolic interactions and emphasize their utility in quantitatively studying interactions between cells and organisms.
Pharmacological chaperones restore proteostasis of epilepsy-associated GABAAreceptor variants
Authors: Wang Ya-Juan , Seibert Hailey , Ahn Lucie Y. , Schaffer Ashleigh E. , Mu Ting-Wei 
Published: April 2023

AbstractRecent advances in genetic diagnosis identified variants in genes encoding GABAAreceptors as causative for genetic epilepsy. Here, we selected eight disease-associated variants in the α1 subunit of GABAAreceptors causing mild to severe clinical phenotypes and showed that they are loss of function, mainly by reducing the folding and surface trafficking of the α1 protein. Furthermore, we sought client protein-specific pharmacological chaperones to restore the function of pathogenic receptors. Applications of positive allosteric modulators, including Hispidulin and TP003, increase the functional surface expression of the α1 variants. Mechanism of action study demonstrated that they enhance the folding and assembly and reduce the degradation of GABAAvariants without activating the unfolded protein response in HEK293T cells and human iPSC-derived neurons. Since these compounds cross the blood-brain barrier, such a pharmacological chaperoning strategy holds great promise to treat genetic epilepsy in a GABAAreceptor-specific manner.
Chronic exposure of mosquito larvae to pesticide residues endangers a new generation of agrochemicals repurposed for malaria prevention
Authors: Ambadiang Marilene M. , Fouet Caroline , Ashu Fred A. , Penlap-Beng Véronique , Kamdem Colince 
Published: April 2023

AbstractAgrochemicals have been successfully repurposed to control mosquitoes worldwide, but pesticides used in agriculture challenge their effectiveness by contaminating surface waters and helping larval populations develop resistance. Thus, knowledge of the lethal and sublethal effects of residual pesticide exposure on mosquitoes is critical for selecting effective insecticides. Here we implemented a new experimental approach to predict the efficacy of agricultural pesticides newly repurposed for malaria vector control. We mimicked insecticide resistance selection as it occurs in contaminated aquatic habitats by rearing field-collected mosquito larvae in water containing a dose of insecticide capable of killing individuals from a susceptible strain within 24 h. We then simultaneously monitored short-term lethal toxicity within 24 h and sublethal effects for 7 days. We found that due to chronic exposure to agricultural pesticides, some mosquito populations are currently pre-adapt to resist neonicotinoids if those were used in vector control. Larvae collected from rural and agricultural areas where neonicotinoid formulations are intensively used for insect pest management were able to survive, grow, pupate and emerge in water containing a lethal dose of acetamiprid, imidacloprid or clothianidin. These results emphasize the importance of addressing exposure of larval populations to formulations applied in agriculture prior to using agrochemicals against malaria vectors.
Systematic review of precision subclassification of type 2 diabetes
Authors: Misra Shivani , Wagner Robert , Ozkan Bige , Schön Martin , Sevilla-Gonzalez Magdalena , Prystupa Katsiaryna , Wang Caroline C. , Kreienkamp Raymond J. , Cromer Sara J. , Rooney Mary R. , Duan Daisy , Thuesen Anne Cathrine Baun , Wallace Amelia S. , Leong Aaron , Deutsch Aaron J. , Andersen Mette K. , Billings Liana K. , Eckel Robert H , Sheu Wayne Huey-Herng , Hansen Torben , Stefan Norbert , Goodarzi Mark O. , Ray Debashree , Selvin Elizabeth , Florez Jose C. ,   ADA/EASD PMDI, Meigs James B. , Udler Miriam S. 
Published: April 2023

AbstractHeterogeneity in type 2 diabetes presentation, progression and treatment has the potential for precision medicine interventions that can enhance care and outcomes for affected individuals. We undertook a systematic review to ascertain whether strategies to subclassify type 2 diabetes are associated with improved clinical outcomes, show reproducibility and have high quality evidence. We reviewed publications that deployed ‘simple subclassification’ using clinical features, biomarkers, imaging or other routinely available parameters or ‘complex subclassification’ approaches that used machine learning and/or genomic data. We found that simple stratification approaches, for example, stratification based on age, body mass index or lipid profiles, had been widely used, but no strategy had been replicated and many lacked association with meaningful outcomes. Complex stratification using clustering of simple clinical data with and without genetic data did show reproducible subtypes of diabetes that had been associated with outcomes such as cardiovascular disease and/or mortality. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into meaningful groups. More studies are needed to test these subclassifications in more diverse ancestries and prove that they are amenable to interventions.
Suicide prevention curriculum development for health and social care students: Protocol for a scoping review
Authors: Gallagher Kerrie , O’ Brien Clíodhna , Dhalaigh Doireann Ní , Corcoran Paul , Griffin Eve 
Published: April 2023

AbstractBackgroundSuicide has become a serious public health concern and international research has shown that the majority of individuals who died by suicide had received healthcare in the year prior to their death. This presents an opportunity for suicide prevention by strategically training healthcare students in suicide prevention knowledge and skills.ObjectiveThe objective of this scoping review is to identify the literature on the development and implementation of suicide prevention curricula for undergraduate and postgraduate students of health and social care degree programmes.Inclusion criteriaStudies will only be considered eligible for inclusion if they describe the development and/or implementation of suicide prevention curricula being taught to health and social care degree students in higher education/university settings. Quantitative, qualitative and mixed method studies published between 2011 and 2023 (inclusive) and in the English language will be considered eligible.MethodsThis scoping review will be conducted according to the PRISMA guidelines for scoping reviews (PRISMA-ScR). The developed search strategy will be implemented across seven databases: Australian Educational Index, British Educational Index, ERIC (Education Resources Information Center), PsycINFO, Embase, Scopus and Web of Science. Several grey literature databases will also be consulted. Further potential results will be located by hand-searching the reference lists of included articles. The search strategy will include variations of the terms ‘university students’, ‘suicide prevention’ and ‘education’. The search terms will be limited to titles, abstracts, and keywords in databases that allow it. Two reviewers will complete the screening using the predefined inclusion criteria. A third reviewer will resolve any conflicts during the screening and eligibility appraisal processes. Results will be presented in the form of tabulated results and an accompanying narrative summary, describing key findings and context related to learning outcomes, methodologies employed and implementation of the identified programmes.
The Epidemiological and Economic Burden of Diabetes in Ghana: A Scoping Review to Inform Health Technology Assessment
Authors: Gad Mohamed , Kazibwe Joseph , Abassah-Konadu Emmanuella , Amankwah Ivy , Owusu Richmond , Gulbi Godwin , Torres-Rueda Sergio , Asare Brian , Vassall Anna , Ruiz Francis 
Published: April 2023

AbstractIntroductionDiabetes remains one of the four major causes of morbidity and mortality globally among non-communicable diseases (NCDs. It is predicted to increase in sub–Saharan Africa by over 50% by 2045. The aim of this study is to identify, map and estimate the burden of diabetes in Ghana, which is essential for optimising NCD country policy and understanding existing knowledge gaps to guide future research in this area.MethodsWe followed the Arksey and O’Malley framework for scoping reviews. We searched electronic databases including Medline, Embase, Web of Science, Scopus, Cochrane and African Index Medicus following a systematic search strategy. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews was followed when reporting the results.ResultsA total of 36 studies were found to fulfil the inclusion criteria. The reported prevalence of diabetes at national level in Ghana ranged between 2.80% – 3.95%. At the regional level, the Western region reported the highest prevalence of diabetes: 39.80%, followed by Ashanti region (25.20%) and Central region at 24.60%. The prevalence of diabetes was generally higher in women in comparison to men. Urban areas were found to have a higher prevalence of diabetes than rural areas. The mean annual financial cost of managing one diabetic case at the outpatient clinic was estimated at GHS 540.35 (2021 US $194.09). There was a paucity of evidence on the overall economic burden and the regional prevalence burden.ConclusionGhana is faced with a considerable burden of diabetes which varies by region and setting (urban/rural). There is an urgent need for effective and efficient interventions to prevent the anticipated elevation in burden of disease through the utilisation of existing evidence and proven priority-setting tools like Health Technology Assessment (HTA).
Assessing awareness of blood cancer symptoms and barriers to symptomatic presentation: Measure development and results from a population survey in the UK
Authors: Boswell Laura , Harris Jenny , Ip Athena , Russell Jessica , Black Georgia , Whitaker Katriina L 
Published: April 2023

AbstractBackgroundLow levels of cancer awareness may contribute to delays in seeking medical help and subsequent delays in diagnosis. For blood cancer this may be a particularly prominent problem due to the high prevalence of undifferentiated symptoms such as bodily pain, weakness, nausea and weight loss, resulting in low symptom awareness. The delay is exacerbated by the dismissal of similar symptoms which are often interpreted as mild disease, resulting in multiple consultations prior to diagnosis. This study describes the development of a Cancer Awareness Measure for Blood Cancer (Blood CAM) and presents results from a population-representative survey using the measure.MethodsA rapid systematic review identified constructs relevant to blood cancer. Items were taken from previous awareness measures and other literature and reviewed by expert groups including health care professionals and patients. Cognitive interviews were conducted with ten members of the public to check comprehension and clarity. A total sample of 434 participants completed the survey at Time 1 and n=302 at Time 2 (two weeks later).ResultsInternal reliability was high across the different constructs included in the questionnaire (>0.70) and test-retest reliability was moderate to good (0.49-0.79). The most commonly recognised blood cancer symptoms were unexplained weight loss (68.9%) and unexplained bleeding (64.9%) and the least commonly recognised symptoms were night sweats (31.3%) breathlessness and rash/itchy skin (both 44%). In terms of symptom experience, fatigue was the most commonly reported symptom (26.7%) followed by night sweats (25.4%).Exploratory factor analysis of barriers to presenting at primary care revealed three distinct categories of barriers; emotional, external/practical and service/healthcare professional related. Service and emotional barriers were most common.ConclusionsWe developed a valid and reliable tool to assess blood cancer awareness and showed variable awareness of blood cancer symptoms which can help target public health campaigns. We also incorporated additional measures (e.g. confidence to re-consult, ability to understand symptoms) that could be used to tailor public messaging for blood cancer and for other harder to suspect and diagnose cancers.