bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving the detection and management of non-communicable diseases among the adult population of the catchment areas of a rural primary healthcare unit in Sidama National Regional State, Ethiopia: A study protocol
Authors: Likka Melaku Haile , Areru Hiwot Abera , Birhanu Betelihem Eshetu , Hibistu Desalegn Tsegaw , Lindtjørn Bernt 
Published: April 2024

AbstractBackgroundThe World Health Organization has designed a package of essential non-communicable diseases (PEN) strategy to improve the detection and management of NCDs. However, the implementation of the PEN in Ethiopia is at an early stage and the readiness of rural primary healthcare units (PHCUs) to implement the strategy is unknown. We, therefore, propose to apply the strategy in the catchment areas of Dobe-Toga Health Center, a rural PHCU in Sidama National Regional State (SNRS), Ethiopia, and improve the NCDs care among adults aged≥45 years.AimWe aim to determine the prevalence of undiagnosed hypertension, pre-T2DM mellitus, T2DM, and comorbidity of hypertension and T2DM among the older adults in the study areas, apply the WHO-PEN- based care model for the participants diagnosed with T2DM and/or hypertension and evaluate its effectiveness in controlling blood glucose and/or pressure. The readiness of PHCUs to implement the WHO-PEN approach in the region will also be determined. Additionally, we examine the influence of diagnosis with hypertension and/or T2DM on the willingness of the study participants to join and/or renew membership in community-based health insurance (CBHI).MethodsThe study will be conducted in catchment areas of Dobe-Toga Health Center from April to November 2024. A cross-sectional survey of 41 health centers and 4 primary hospitals, triangulated with qualitative data, will be employed to assess the readiness of the PHCUs to implement the WHO-PEN interventions while the qualitative data for this study has not been collected yet, the quantitative data was collected through observation checklist of inputs. The remaining studies will be conducted in two phases. In Phase 1, cross- sectional surveys will be conducted to determine the prevalence of undiagnosed hypertension, T2DM, pre- T2DM, and comorbidity of T2DM and hypertension in a randomly selected sample of 3301 older adults. Additionally, the participants’ willingness to pay (WTP) for HbA1c tests will be assessed, and CBHI-related surveys will be conducted. In the second phase, the cohorts will be linked to the health center and will receive the WHO-PEN-based care model. In phase 2, the effects of the care model in controlling blood pressure and glucose will be examined. Furthermore, the adherence to self-care practices of the cohorts will be determined.
Cardiovascular symptoms of PASC are associated with trace-level cytokines that affect the function of human pluripotent stem cell derived cardiomyocytes
Authors: Sinclair Jane E. , Vedelago Courtney , Ryan Feargal J. , Carney Meagan , Lynn Miriam A. , Grubor-Bauk Branka , Cao Yuanzhao , Henders Anjali K. , Chew Keng Yih , Gilroy Deborah , Greaves Kim , Labzin Larisa , Ziser Laura , Ronacher Katharina , Wallace Leanne M. , Zhang Yiwen , Macauslane Kyle , Ellis Daniel J. , Rao Sudha , Burr Lucy , Bain Amanda , Schulz Benjamin L. , Li Junrong , Lynn David J. , Palpant Nathan , Wuethrich Alain , Trau Matt , Short Kirsty R. 
Published: April 2024

ABSTRACTGlobally, over 65 million individuals are estimated to suffer from post-acute sequelae of COVID-19 (PASC). A large number of individuals living with PASC experience cardiovascular symptoms (i.e. chest pain and heart palpitations) (PASC-CVS). The role of chronic inflammation in these symptoms, in particular in individuals with symptoms persisting for >1 year after SARS-CoV-2 infection, remains to be clearly defined. In this cross-sectional study, blood samples were obtained from three different sites in Australia from individuals with i) a resolved SARS-CoV-2 infection (and no persistent symptoms i.e. ‘Recovered’), ii) individuals with prolonged PASC-CVS and iii) SARS-CoV-2 negative individuals. Individuals with PASC-CVS, relative to Recovered individuals, had a blood transcriptomic signature associated with inflammation. This was accompanied by elevated levels of pro-inflammatory cytokines (IL-12, IL-1β, MCP-1 and IL-6) at approximately 18 months post-infection. These cytokines were present in trace amounts, such that they could only be detected with the use of novel nanotechnology. Importantly, these trace-level cytokines had a direct effect on the functionality of pluripotent stem cell derived cardiomyocytesin vitro. This effect was not observed in the presence of dexamethasone. Plasma proteomics demonstrated further differences between PASC-CVS and Recovered patients at approximately 18 months post-infection including enrichment of complement and coagulation associated proteins in those with prolonged cardiovascular symptoms. Together, these data provide a new insight into the role of chronic inflammation in PASC-CVS and present nanotechnology as a possible novel diagnostic approach for the condition.
Molecular architecture of synaptic vesicles
Authors: Kravcenko Uljana , Ruwolt Max , Kroll Jana , Yushkevich Artsemi , Zenkner Martina , Ruta Julia , Lotfy Rowaa , Wanker Erich E. , Rosenmund Christian , Liu Fan , Kudryashev Mikhail 
Published: April 2024

AbstractSynaptic vesicles (SVs) store and transport neurotransmitters to the presynaptic active zone for release by exocytosis. After release, SV proteins and excess membrane are recycled via endocytosis, and new SVs are formed in a clathrin-dependent manner. This process maintains the morphology and complex molecular composition of SVs through multiple recycling rounds. Previous studies explored the molecular composition of SVs through proteomic analysis and fluorescent microscopy, proposing a model for an average SV1,2. However, the structural heterogeneity and molecular architecture of individual SVs are not well described. Here we used cryo-electron tomography to visualize morphological and molecular details of SVs isolated from mouse brains and inside cultured neurons. We describe several classes of small proteins on the SV surface and long proteinaceous densities inside SVs. We identified V-ATPases, determined a structure using subtomogram average, and showed them forming a complex with the membrane-embedded protein synaptophysin. Our bioluminescence assay revealed pairwise interactions between VAMP2 and synaptophysin and V-ATPase Voe1 domains. Interestingly, V-ATPases were randomly distributed on the surface of SVs irrespective of vesicle sizes. A subpopulation of isolated vesicles and vesicles inside neurons contained a partially assembled clathrin coat with a soccer-ball symmetry. We observed a V-ATPase under clathrin cage in several isolated clathrin-coated vesicles. Additionally, from isolated SV preparations and within hippocampal neurons we identified clathrin baskets without vesicles. We determined their preferential location in proximity to the cell membrane. Our analysis advances the understanding of individual SVs’ diversity and their molecular architecture.
Bidirectional dysregulation of synaptic glutamate signaling after transient metabolic failure
Authors: Passlick Stefan , Ullah Ghanim , Henneberger Christian 
Published: April 2024

AbstractIschemia leads to a severe dysregulation of glutamate homeostasis and excitotoxic cell damage in the brain. Shorter episodes of energy depletion, for instance during peri-infarct depolarizations, can also acutely perturb glutamate signaling. It is less clear if such episodes of metabolic failure also have persistent effects on glutamate signaling and how the relevant mechanisms such as glutamate release and uptake are differentially affected. We modelled acute and transient metabolic failure by using a chemical ischemia protocol and analyzed its effect on glutamatergic synaptic transmission and extracellular glutamate signals by electrophysiology and multiphoton imaging, respectively, in the hippocampus. Our experiments uncover a duration-dependent bidirectional dysregulation of glutamate signaling. Whereas short chemical ischemia induces a lasting potentiation of presynaptic glutamate release and synaptic transmission, longer episodes result in a persistent postsynaptic failure of synaptic transmission. We also observed unexpected differences in the vulnerability of the investigated cellular mechanisms. Axonal action potential firing and glutamate uptake were unexpectedly resilient compared to postsynaptic cells, which overall were most vulnerable to acute and transient metabolic stress. We conclude that even short perturbations of energy supply lead to a lasting potentiation of synaptic glutamate release, which may increase glutamate excitotoxicity well beyond the metabolic incident.
Macrolide resistance through uL4 and uL22 ribosomal mutations inPseudomonas aeruginosa
Authors: Goltermann Lise , Laborda Pablo , Irazoqui Oihane , Pogrebnyakov Ivan , Molin Søren , Johansen Helle Krogh , Rosa Ruggero La 
Published: April 2024

AbstractMacrolides are widely used antibiotics for the treatment of bacterial airway infections. Due to its elevated minimum inhibitory concentration in standardized culture media,Pseudomonas aeruginosais considered intrinsically resistant and, therefore, antibiotic susceptibility testing against macrolides is not performed. Nevertheless, due to macrolides’ immunomodulatory effect and suppression of virulence factors, they are used for the treatment of persistentP. aeruginosainfections. Here, we demonstrate that macrolides are, instead, effective antibiotics againstP. aeruginosaairway infections in an air-liquid interface (ALI) infection model system resembling the human airways. Importantly, macrolide treatment in both people with cystic fibrosis and primary ciliary dyskinesia patients leads to the accumulation of uL4 and uL22 ribosomal protein mutations inP. aeruginosawhich causes antibiotic resistance. Consequently, higher concentrations of antibiotics are needed to modulate the macrolide-dependent suppression of virulence. Surprisingly, even in the absence of antibiotics, these mutations also lead to a collateral reduction in growth rate, virulence and pathogenicity in airway ALI infections which are pivotal for the establishment of a persistent infection. Altogether, these results lend further support to the consideration of macrolides asde factoantibiotics againstP. aeruginosaand the need for resistance monitoring upon prolonged macrolide treatment.
The G-Protein-Coupled Receptor Kinase 2 Orchestrates Hair Follicle Homeostasis
Authors: Asensio Alejandro , Sanz-Flores Maria , Liakath-Ali Kif , Palacios-García Julia , Paramio Jesús M , García-Escudero Ramon , Mayor Federico , Ribas Catalina 
Published: April 2024

AbstractTightly regulated cell-cell and cell-niche intercommunications via intertwined signaling networks are involved in maintaining normal hair follicle (HF) homeostasis, cycling and cell fate determination. However, knowledge of specific mechanisms by which hair loss takes place under pathological situations is needed. Using a keratinocyte-specific knockout mouse model, we uncover that the G-protein-coupled receptor kinase 2 (GRK2) signaling node plays a key role in HF homeostasis. Epidermal GRK2 ablation causes alterations during anagen induction, giving rise to abnormal cyst-like structures. HF-linked cysts display aberrant growth and differentiation patterns as well as lineage infidelity, displaying features of abortive HFs unable to fully acquire canonical hallmarks. Cysts triggered by GRK2 deletion displace the dermal papilla away from the bulge and promote irreversible changes in HF stem cell architecture, leading to bulge destruction and hair loss. Our data provide unforeseen roles of GRK2 in epidermal physiology and uncover mechanisms linking dystrophic follicular cysts formation with hair loss, with potential connections to pathogenic processes operating in immune-mediated alopecias.
A Lipidomics-Based Method to Eliminate Negative Urine Culture in General Population
Authors: Nartey Linda K , Mikhael Abanoub , Pětrošová Helena , Yuen Victor , Kibsey Pamela , Ernst Robert K , Chen Michael X , Goodlett David R 
Published: April 2024

ABSTRACTUrinary tract infections (UTIs) pose a significant challenge to human health. Accurate and timely detection remains pivotal for effective intervention. Current urine culture techniques, while essential, often encounter challenges where urinalysis yields positive results, but subsequent culture testing produces a negative result. This highlights potential discrepancies between the two methods and emphasizes the need for improved correlation in urinary tract infection (UTI) detection. Employing advanced lipidomics techniques, we deployed the fast lipid analysis technique (FLAT) on a clinical cohort suspected of having UTIs. Lipid fingerprinting by MALDI-TOF MS, directly from urine samples withoutex vivogrowth, correctly identified the common uropathogens within a 1-hour timeframe when compared to urine culture. FLAT analysis also identified urine samples without culturable pathogens (negative UTIs) with 99% agreement, whereas urinalysis showed 37% agreement with the gold standard urine culture. In 402 urine samples suspected for UTI from out-patients, FLAT assay rapidly ruled out negative urines without the need for culture in 77% of all cases. The potential impact of this innovative lipidomic-based approach extends beyond conventional diagnostic limitations, offering new avenues for early detection and targeted management of urinary tract infections. This research marks a paradigm shift in urine culture methodology, paving the way for improved clinical outcomes and public health interventions.
Plasma pTau181 reveals a pathological signature that predicts cognitive outcomes in Lewy body disease
Authors: Abdelnour Carla , Young Christina B , Shahid-Besanti Marian , Smith Alena , Wilson Edward N. , Ramos Benitez Javier , Vossler Hillary , Plastini Melanie J. , Winer Joseph R. , Kerchner Geoffrey A. , Cholerton Brenna , Andreasson Katrin I. , Henderson Victor W. , Yutsis Maya , Montine Thomas J , Tian Lu , Mormino Elizabeth C. , Poston Kathleen L. 
Published: April 2024

ABSTRACTLewy body disease (LBD) often co-exists with Alzheimer’s disease (AD), influencing disease progression, cognitive decline, and neurodegeneration. This study aims to determine whether plasma phosphorylated-Tau181 (pTau181) could be used as diagnostic biomarker of concurrent Alzheimer’s disease neuropathologic change (ADNC) or amyloidosis alone, as well as a prognostic, monitoring, and susceptibility/risk biomarker for clinical outcomes in LBD. Our sample comprised 565 Stanford research participants: 94 LBD with normal cognition, 83 LBD with abnormal cognition, 114 AD, and 274 who were cognitively normal. We measured plasma pTau181 levels with the LumipulseGplatform. Diagnostic accuracy for concurrent ADNC and amyloidosis was assessed with receiver-operating-characteristic curves in a subset of participants with CSF pTau181/Aβ42, and CSF Aβ42/Aβ40 or amyloid-β PET, respectively. We used linear mixed effects models to examine the associations between baseline and longitudinal plasma pTau181 levels and clinical outcomes. Plasma pTau181 predicted concurrent ADNC and amyloidosis in LBD with abnormal cognition with 87% and 72% accuracy, respectively. In the LBD with abnormal cognition, higher baseline plasma pTau181 was associated with worse baseline MoCA and CDR-SB, as well as accelerated decline in CDR-SB. Additionally, in this group rapid increases in plasma pTau181 over 3 years predicted a faster decline in CDR-SB and memory. In LBD with normal cognition, there was no association between baseline or longitudinal plasma pTau181 levels and clinical outcomes; however, elevated pTau181 at baseline increased the risk of conversion to cognitive impairment. These findings suggest that plasma pTau181 is a promising biomarker for concurrent ADNC and amyloidosis in LBD. Furthermore, plasma pTau181 holds potential as a prognostic, monitoring, and susceptibility/risk biomarker, predicting disease progression in LBD.
Assessing the role of bacterial innate and adaptive immunity as barriers to conjugative plasmids
Authors: Siedentop Berit , Mediavilla Carlota Losa , Kouyos Roger D. , Bonhoeffer Sebastian , Chabas Hélène 
Published: April 2024

AbstractPlasmids are ubiquitous mobile genetic elements, that can be either costly or beneficial for their bacterial host. In response to constant viral threat, bacteria have evolved various immune systems, such as the prevalent restriction modification (RM) (innate immunity) and CRISPR-Cas systems (adaptive immunity). At the molecular level, both systems also target plasmids, but the consequences of these interactions for plasmid spread are unclear. Using a modeling approach, we show that RM and CRISPR-Cas are effective as barriers against the spread of costly plasmids, but not against beneficial ones. Consequently, bacteria can profit from the adaptive advantages that beneficial plasmids confer even in the presence of bacterial immunity. While plasmids that are costly for bacteria may persist for a certain period in the bacterial population, RM and CRISPR-Cas pose a substantial burden for such plasmids, which can eventually drive them to extinction. Finally, we demonstrate that the selection pressure imposed by bacterial immunity on costly plasmids can be circumvented through a diversity of escape mechanisms and highlight how plasmid carriage might be common despite bacterial immunity. In summary, the population-level outcome of interactions between plasmids and defense systems in a bacterial population is closely tied to plasmid cost: Beneficial plasmids can persist at high prevalence in bacterial populations despite defense systems, while costly plasmids may face substantial reduction in prevalence or even extinction.
Essential and virulence-related protein interactions of pathogens revealed through deep learning
Authors: Humphreys Ian R. , Zhang Jing , Baek Minkyung , Wang Yaxi , Krishnakumar Aditya , Pei Jimin , Anishchenko Ivan , Tower Catherine A. , Jackson Blake A. , Warrier Thulasi , Hung Deborah T. , Peterson S. Brook , Mougous Joseph D. , Cong Qian , Baker David 
Published: April 2024

AbstractIdentification of bacterial protein–protein interactions and predicting the structures of the complexes could aid in the understanding of pathogenicity mechanisms and developing treatments for infectious diseases. Here, we developed a deep learning-based pipeline that leverages residue-residue coevolution and protein structure prediction to systematically identify and structurally characterize protein-protein interactions at the proteome-wide scale. Using this pipeline, we searched through 78 million pairs of proteins across 19 human bacterial pathogens and identified 1923 confidently predicted complexes involving essential genes and 256 involving virulence factors. Many of these complexes were not previously known; we experimentally tested 12 such predictions, and half of them were validated. The predicted interactions span core metabolic and virulence pathways ranging from post-transcriptional modification to acid neutralization to outer membrane machinery and should contribute to our understanding of the biology of these important pathogens and the design of drugs to combat them.
Tumor spheroid elasticity estimation using mechano-microscopy combined with a conditional generative adversarial network
Authors: Foo Ken Y. , Shaddy Bryan , Murgoitio-Esandi Javier , Hepburn Matt S. , Li Jiayue , Mowla Alireza , Vahala Danielle , Amos Sebastian E. , Choi Yu Suk , Oberai Assad A. , Kennedy Brendan F. 
Published: April 2024

AbstractTechniques for imaging the mechanical properties of cells are needed to study how cell mechanics influence cell function and disease progression. Mechano-microscopy (a high-resolution variant of compression optical coherence elastography) generates elasticity images of a sample undergoing compression from the phase difference between optical coherence microscopy (OCM) B-scans. However, the existing mechano-microscopy signal processing chain (referred to as the algebraic method) assumes the sample stress is uniaxial and axially uniform, such that violation of these assumptions reduces the accuracy and precision of elasticity images. Furthermore, it does not account for prior information regarding the sample geometry or mechanical property distribution. In this study, we investigate the feasibility of training a conditional generative adversarial network (cGAN) to generate elasticity images from phase difference images of samples containing a cell spheroid embedded in a hydrogel. To train and test the cGAN, we constructed 30,000 elasticity and phase difference image pairs, where elasticity images were generated using a parametric model to simulate artificial samples, and phase difference images were computed using finite element analysis to simulate compression applied to the artificial samples. By applying both the cGAN and algebraic methods to simulated phase difference images, our results indicate the cGAN elasticity images exhibit better spatial resolution and sensitivity. We also evaluated the cGAN on experimental phase difference images of real spheroids embedded in hydrogels and compared the cGAN elasticity with the algebraic elasticity, OCM, and confocal fluorescence microscopy, and found the cGAN elasticity is often more robust to noise, especially within stiff nuclei.
A stress-dependent TDP-43 SUMOylation program preserves neuronal function
Authors: Suk Terry R. , Part Caroline E. , Zhang Jenny L. , Nguyen Trina T. , Heer Meghan M. , Caballero-Gómez Alejandro , Grybas Veronica S. , McKeever Paul M. , Nguyen Benjamin , Callaghan Steve M. , Woulfe John M. , Robertson Janice , Rousseaux Maxime W.C. 
Published: April 2024

AbstractAmyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are overwhelmingly linked to TDP-43 dysfunction. Mutations in TDP-43 are rare, indicating that the progressive accumulation of exogenous factors – such as cellular stressors – converge on TDP-43 to play a key role in disease pathogenesis. Post translational modifications such as SUMOylation play essential roles in response to such exogenous stressors. We therefore set out to understand how SUMOylation may regulate TDP-43 in health and disease. We find that TDP-43 is regulated dynamically via SUMOylation in response to cellular stressors. When this process is blockedin vivo, we note age-dependent TDP-43 pathology and sex-specific behavioral deficits linking TDP-43 SUMOylation with aging and disease. We further find that SUMOylation is correlated with human aging and disease states. Collectively, this work presents TDP-43 SUMOylation as an early physiological response to cellular stress, disruption of which may confer a risk for TDP-43 proteinopathy.