bluuebunny/crossref_metadata_2025_split huggingface dataset:
Symptom Management When Non-Invasive Advanced Respiratory Support is Used During End-of-Life Care: A Systematic Review
Authors: Wenzel David , Bleazard Lucy , Pepper Coral , Faull Christina 
Published: March 2022

ABSTRACTObjectivesto narrate the canon of knowledge around symptom control at end of life for patients using, or having recently used, non-invasive advanced respiratory support (NARS) at end of life for respiratory failure.MethodsA systematic review forming a narrative synthesis from a wide range of sample papers from Medline, Embase, CINAHL, Emcare, Cochrane and OpenGrey databases. A secondary search of grey literature was also performed with hand searching reference lists and author citations. The review was undertaken using the ENTREQ checklist for quality.ResultsIn total 15 studies were included in the synthesis and four themes were generated: NARS as a buoy (NARS can represent hope and relief from the symptoms of respiratory failure), NARS as an anchor (NARS brings significant treatment burden), Impact on Staff (uncertainty over the balance of benefit and burden as well as complex patient care drives distress amongst staff providing care) and the Process of Withdrawal (withdrawal of therapy felt to be futile exists as discrete event in patient care but is otherwise poorly defined).ConclusionNARS represents a complex interplay of hope, symptom control, unnaturally prolonged death and treatment burden. The literature captures the breadth of these issues but further, detailed, research is required in almost every aspect of practice around end-of-life care and NARS – especially how to manage symptoms at the end of life.
Association between central blood pressure, arterial stiffness and low cognitive scores in South African adults
Authors: Mpondo Feziwe , Craig Ashleigh , Kolkenbeck-Ruh Andrea , Soepnel Larske , Crouch Simone , Naidoo Sanushka , Norris Shane A. , Davies Justine , Ware Lisa J. 
Published: March 2022

AbstractBackgroundThe burden of hypertension in South Africa, as well as the successive cardiovascular morbidity and mortality is increasing. Hypertension presents a risk for subsequent cognitive impairment with age. This study sought to determine the association between blood pressure, arterial stiffness, using pulse wave velocity and pulse amplification pressure, and cognitive function in younger and older adults from a 30yr old urban South African birth cohort study.MethodsWe conducted a cross-sectional study among n=93 index children (now age 29yr) and their mothers (all women). We collected peripheral and central blood pressure (BP) variables, and conducted a cognitive assessment using the Montreal Cognitive Assessment (MoCA) instrument and analysed the association of BP variables with global cognitive tests and specific domains.ResultsForty percent of the pooled sample had low MoCA total scores, and 32% of the total sample had hypertension. No associations were found in the regression analysis between BP related variables and total MoCA scores. Also, no associations were found between peripheral and central BP variables with individual cognitive domains when stratified by age. A significant relationship was found between mean pressure and low visual perception (i.e. the ability to interpret information that is seen and give it meaning; p=0.02).ConclusionCentral mean pressure is associated with low visual perception domain among black women. These findings add to the growing evidence which suggests that central BP variables are important to explore as exposure proxies for studying the association of BP and cognitive decline especially at mid-life.
Evaluation of the broth microdilution methodology for susceptibility testing of Mycobacterium tuberculosis in Peru
Authors: Puyen Zully M. , Santos-Lázaro David , Vigo Aiko N. , Coronel Jorge , Alarcón Miriam J. , Cotrina Vidia V. , Moore David A.J. 
Published: March 2022

ABSTRACTPeru is amongst the 30 countries with the highest burden of multidrug-resistant tuberculosis worldwide. In the fight against drug-resistant tuberculosis, the UKMYC6 microtiter plate was developed and validated by the CRyPTIC project. Our objective was to evaluate the use of the broth microdilution UKMYC6 plate for susceptibility testing of drug-resistant Mycobacterium tuberculosis (MTB) strains in Peru. 496 nationally-representative MTB strains determined drug-resistant by the routine agar proportion method (APM) were selected. MICs of 13 anti-tuberculosis drugs were determined for each strain using the microdilution UKMYC6 plates and compared with the APM result. MIC distributions for APM-susceptible and APM-resistant strains were demonstrated for rifampicin, isoniazid, kanamycin, and levofloxacin, with reasonable agreement (0.64≤k≤0.79) for rifampicin, ethambutol, ethionamide and kanamycin and the best agreement for isoniazid and levofloxacin (k>0.8). No strain presented MICs higher than the CRyPTIC Epidemiological cut-off values for the new (bedaquiline, delamanid) or repurposed (clofazimine, linezolid) drugs. The microbroth dilution method using the UKMYC6 microtiter plate allowed the complete susceptibility characterization, through the determination of MICs, of drug-resistant Mycobacterium tuberculosis strains in Peru. This methodology showed a good diagnostic performance for the drugs rifampicin, isoniazid, kanamycin and levofloxacin drugs.
SARS-CoV-2 Omicron neutralization and risk of infection among elderly after a booster dose of Pfizer vaccine
Authors: Bruel Timothée , Pinaud Laurie , Tondeur Laura , Planas Delphine , Staropoli Isabelle , Porrot Françoise , Guivel-Benhassine Florence , Attia Mikaël , Pelleau Stéphane , Woudenberg Tom , Duru Cécile , Koffi Aymar Davy , Castelain Sandrine , Fernandes-Pellerin Sandrine , Jolly Nathalie , De Facci Louise Perrin , Roux Emmanuel , Ungeheuer Marie-Noëlle , Van Der Werf Sylvie , White Michael , Schwartz Olivier , Fontanet Arnaud 
Published: March 2022

AbstractBackgroundThe protective immunity against Omicron following a BNT162b2 Pfizer booster dose among elderly is not well characterized.MethodsThirty-eight residents from three nursing homes were recruited for the study. Antibodies targeting the Spike protein of SARS-CoV-2 were measured with the S-Flow assay. Neutralizing activities in sera were measured as effective dilution 50% (ED50) with the S-Fuse assay using authentic isolates of Delta and Omicron.ResultsAmong the 38 elderly included in the study, with median (inter-quartile range, IQR) age of 88 (81-92) years, 30 (78.9%) had been previously infected. The ED50 of neutralization were lower against Omicron than Delta, and higher among convalescent compared to naive residents. During an Omicron epidemic affecting two of the three nursing homes in December 2021-January 2022, 75% (6/8) of naive residents got infected, compared to 25% (6/24) of convalescents (P=0.03). Antibody levels to Spike and ED50 of neutralization against Omicron after the BNT162b2 booster dose were lower in those with breakthrough infection (n=12) compared to those without (n=20): median of 1256 vs 2523 BAU/mL (P=0.02) and median ED50 of 234 vs 1298 (P=0.0004), respectively.ConclusionThis study confirmed the importance of receiving at least three antigenic exposures to the SARS-CoV-2 Spike protein for achieving satisfactory neutralizing antibody levels. In this population, protection against Omicron infection was increased in individuals who had been previously infected in addition to the three vaccine doses. Thus, a fourth antigenic exposure may be useful in the elderly population to prevent infection with Omicron, a variant known for its high escape immunity properties.
Design, Development, and Usability Evaluation of a Voice App Experience for Heart Failure Management
Authors: Barbaric Antonia , Munteau Cosmin , Ross Heather J. , Tong Kuo-Cheng , Cafazzo Joseph A. 
Published: March 2022

AbstractThe use of digital therapeutics (DTx) in the prevention and management of medical conditions has increased through the years with an estimated 44 million people using one as part of their treatment plan in 2021, nearly double the amount from last year. DTx are commonly accessed through smartphone apps, but offering these treatments through an alternative input can improve the accessibility of these interventions. Voice apps are an emerging technology in the digital health field, and may be an appropriate alternative platform for some patients. This research aimed to identify the acceptability and feasibility of offering a voice app as an alternative input for a chronic disease self-management program. The objective of this project was to design, develop, and evaluate a voice app of an already existing smartphone-based heart failure self-management program, Medly, to be used as a case study. A voice app version of Medly was designed and developed through a user-centered design process. We conducted a usability study and semi-structured interviews with representative end users (n=8) at the Peter Munk Cardiac Clinic in Toronto General Hospital to better understand the user experience. A Medly voice app prototype was built using a software development kit in tandem with a cloud computing platform. Three out of the eight participants were successful in completing the usability session, while the rest of the participants were not due to various errors. Almost all (7 out of the 8) participants were satisfied with the voice app and felt confident using it. Half of the participants were unsure about using the voice app in the future, though. With these findings, design changes were made to better improve the user experience. With rapid advancements in voice user interfaces, we believe this technology will play an integral role when providing access to DTx for chronic disease management.
Orphan nuclear receptors promote alternative lengthening of telomeres (ALT) through ALT-associated PML bodies
Authors: Gaela Venus Marie , Hsia Hsuan-Yu , Boudier Thomas , Chen Liuh-Yow 
Published: March 2022

ABSTRACTAlternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism utilized by about 15% of cancers. Orphan nuclear receptors (NRs), such as COUP-TF1, COUP-TF2, EAR2, TR2, and TR4, associate with telomeres of ALT cells by binding to variant telomeric repeats. However, how these orphan NRs function in the ALT pathway remains to be characterized. Here, we have established an ALT-inducing cell model by tethering orphan NRs to telomeres in non-ALT BJ fibroblast cells. We demonstrate that recruitment of orphan NRs to telomeres is sufficient to initiate formation of ALT-associated promyelocytic leukemia nuclear bodies (APBs) and telomeric DNA synthesis at APBs. We found that the ability of orphan NRs to initiate APB formation and recombination is dependent on the orphan NR AF2 domain, the zinc-finger protein ZNF827, and PML protein. Depletion of orphan NRs in ALT cell lines reduced APB formation and telomeric DNA synthesis, confirming the role of orphan NRs in ALT cells. Furthermore, we found that ATRX/DAXX depletion, together with the telomeric localization of orphan NRs, induces APB formation, telomere clustering, and telomeric DNA synthesis more dramatically in non-ALT cells. Accordingly, we propose that these events in ALT, orphan NR recruitment to telomeres and ATRX/DAXX loss, operate in concert to activate the ALT pathway.
PRMT5 is a therapeutic target in choroidal neovascularization
Authors: Muniyandi Anbukkarasi , Martin Matthew , Sun Mengyao , Sishtla Kamakshi , Jensen Nathan R , Motolani Aishat , Qi Xiaoping , Boulton Michael E , Prabhu Lakshmi , Lu Tao , Corson Timothy W 
Published: March 2022

AbstractOcular neovascular diseases including neovascular age-related macular degeneration (nvAMD) are widespread causes of blindness. Patients’ non-responsiveness to currently used biologics that target vascular endothelial growth factor (VEGF) poses an unmet need for novel therapies. Here, we identify protein arginine methyltransferase 5 (PRMT5) as a novel therapeutic target for nvAMD. PRMT5 is a well-known epigenetic enzyme. We previously showed that PRMT5 methylates and activates a proangiogenic and proinflammatory transcription factor, the nuclear factor kappa B (NF-κB), which has a master role in tumor progression, notably in pancreatic ductal adenocarcinoma and colorectal cancer. We identified a potent and specific small molecule inhibitor of PRMT5, PR5-LL-CM01, that dampens the methylation and activation of NF-κB. Here for the first time, we assessed the antiangiogenic activity of PR5-LL-CM01 in ocular cells. Immunostaining of human nvAMD sections revealed that PRMT5 is highly expressed in the retinal pigment epithelium (RPE)/choroid where neovascularization occurs, while mouse eyes with laser induced choroidal neovascularization (L-CNV) showed PRMT5 is overexpressed in the retinal ganglion cell layer and in the RPE/choroid. Importantly, inhibition of PRMT5 by PR5-LL-CM01 or shRNA knockdown of PRMT5 in human retinal endothelial cells (HRECs) and induced pluripotent stem cell (iPSC)-derived choroidal endothelial cells (iCEC2) reduced NF-κB activity and the expression of its target genes, such as tumor necrosis factor α (TNF-α) and VEGF-A. In addition to inhibiting angiogenic properties of proliferation and tube formation, PR5-LL-CM01 blocked cell cycle progression at G1/S-phase in a dose-dependent manner in these cells. Thus, we provide the first evidence that inhibition of PRMT5 impedes angiogenesis in ocular endothelial cells, suggesting PRMT5 as a potential therapeutic target to ameliorate ocular neovascularization.
ACE2 engagement exposes the fusion peptide to pan-coronavirus neutralizing antibodies
Authors: Low Jun Siong , Jerak Josipa , Tortorici M. Alejandra , McCallum Matthew , Pinto Dora , Cassotta Antonino , Foglierini Mathilde , Mele Federico , Abdelnabi Rana , Weynand Birgit , Noack Julia , Montiel-Ruiz Martin , Bianchi Siro , Benigni Fabio , Sprugasci Nicole , Joshi Anshu , Bowen John E. , Walls Alexandra C. , Jarrossay David , Morone Diego , Paparoditis Philipp , Garzoni Christian , Ferrari Paolo , Ceschi Alessandro , Neyts Johan , Purcell Lisa A. , Snell Gyorgy , Corti Davide , Lanzavecchia Antonio , Veesler David , Sallusto Federica 
Published: March 2022

AbstractCoronaviruses use diverse Spike (S) glycoproteins to attach to host receptors and fuse with target cells. Using a broad screening approach, we isolated from SARS-CoV-2 immune donors seven monoclonal antibodies (mAbs) that bind to all human alpha and beta coronavirus S proteins. These mAbs recognize the fusion peptide and acquire high affinity and breadth through somatic mutations. Despite targeting a conserved motif, only some mAbs show broad neutralizing activity in vitro against alpha and beta coronaviruses, including Omicron BA.1 variant and bat WIV-1, and reduce viral titers and pathology in vivo. Structural and functional analyses show that the fusion peptide-specific mAbs bind with different modalities to a cryptic epitope which is concealed by prefusion-stabilizing ‘2P’ mutations and becomes exposed upon binding of ACE2 or ACE2-mimicking mAbs. This study identifies a new class of pan-coronavirus neutralizing mAbs and reveals a receptor-induced conformational change in the S protein that exposes the fusion peptide region.
Patient-associated mutations inDrosophilaAlk perturb neuronal differentiation and promote survival
Authors: Pfeifer K. , Wolfstetter G. , Anthonydhason V. , Masudi T. , Arefin B. , Bemark M. , Mendoza-Garcia P. , Palmer R.H. 
Published: March 2022

AbstractActivating Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase (RTK) mutations occur in pediatric neuroblastoma and are associated with poor prognosis. To study ALK-activating mutations in a genetically controllable system we employed CRIPSR/Cas9, incorporating orthologues of the human oncogenic mutationsALKF1174LandALKY1278Sin theDrosophila Alklocus.AlkF1251LandAlkY1355SmutantDrosophilaexhibit enhanced Alk signaling phenotypes, but unexpectedly depend on the Jelly belly (Jeb) ligand for activation. BothAlkF1251LandAlkY1355Smutant larval brains display hyperplasia, represented by increased numbers of Alk-positive neurons. Despite this hyperplasic phenotype, no brain tumors were observed in mutant animals. We show that hyperplasia inAlkmutants was not caused by significantly increased rates of proliferation, but rather by decreased levels of apoptosis in the larval brain. Using single-cell RNA sequencing (scRNA-seq), we identify perturbations during temporal fate specification inAlkY1355Smutant mushroom body lineages. These findings shed light on the role of Alk in neurodevelopmental processes and highlight the potential of activating Alk mutations to perturb specification and promote survival in neuronal lineages.
Improved fluorescent Listeria spp. biosensors for analysis of antimicrobials by flow cytometry
Authors: Reich Sebastian J. , Stohr Jonas , Goldbeck Oliver , Fendrich Bastian , Crauwels Peter , Riedel Christian U. 
Published: March 2022

AbstractThe global increase in antibiotic resistances of pathogenic microorganisms require identification and characterization of novel antimicrobials. Bacterial biosensors expressing fluorescent proteins such as pHluorin variants are suitable for high-throughput screenings. Here, we present Listeria spp. pH-sensitive biosensors with improved fluorescence for single cell analysis of antimicrobials by flow cytometry.
Human Digital Twin: Automated Cell Type Distance Computation and 3D Atlas Construction in Multiplexed Skin Biopsies
Authors: Ghose Soumya , Ju Yingnan , McDonough Elizabeth , Ho Jonhan , Karunamurthy Arivarasan , Chadwick Chrystal , Cho Sanghee , Rose Rachel , Corwin Alex , Surrette Christine , Martinez Jessica , Williams Eric , Sood Anup , Al-Kofahi Yousef , Falo Louis D. , Börner Katy , Ginty Fiona 
Published: March 2022

AbstractMapping the human body at single cell resolution in three-dimensions (3D) is an important step toward a “digital twin” model that captures important structure and dynamics of cell-cell interactions. Current 3D imaging methods suffer from low resolution and are limited in their ability to distinguish cell types and their spatial relationships. We present a novel 3D workflow: MATRICS-A (Multiplexed ImageThree-DReconstruction andIntegratedCellSpatial -Analysis) that generates a 3D map of cells from multiplexed images and calculates cell type distance from endothelial cells and other features of interest. We applied this workflow to multiplexed data from sequential skin sections from younger and older donors (n=10; 33-72 years) with biopsies from ten anatomical regions with different sun exposure effects (mild, moderate-marked). Up to 26 sequential sections from each sample underwent multiplexed imaging with 18 biomarkers covering 12 cell types (keratinocytes (granular, spinous, basal), epithelial and myoepithelial cells, fibroblasts, macrophages, T helpers, T killers, T regs, neurons and endothelial cells, markers of DNA damage and repair (p53, DDB2) and cell proliferation (Ki67). Following cell classification, the tissue and classified cells were reconstructed into 3D volumes. A significant inverse correlation between DDB2 positive cells and age was found (corr= -0.78, adj. p=0.047). This suggests reduced capacity for repair in non-cancer older sun-exposed individuals. While absolute immune cell count did not differ by age or sun exposure, the ratio of T Helper/T Killer cells was positively correlated with age (corr=0.82, adj. p=0.048) This is the first such 3D study in skin and paves the way for cataloging more cell types and spatial relationships in aging and disease in skin and other organs.
Constitutive, calcium-independent endoplasmic reticulum-plasma membrane contact site oscillations and its implications in store-operated calcium entry
Authors: Xiong Ding , Tong Cheesan , Yang Yang , Yong Jeffery , Wu Min 
Published: March 2022

AbstractThe endoplasmic reticulum and plasma membrane (ER-PM) contact site dynamics plays a central role for store-operated calcium entry (SOCE). ER localized calcium sensor STIM1 translocates to the contact sites, interacts with Orai and mediates calcium influx from the extracellular environment. Different species of phosphoinositides (PIPs) have been reported to be involved in contact site dynamics as well as STIM1 translocation. However, most of the studies were based on loss-of-function experiments or conditions that generate massive calcium store depletion. The kinetics of ER-PM contact site dynamics during physiological stimuli -induced calcium oscillations are not well understood. Using total internal reflection fluorescence microscopy (TIRFM), we investigated the relationship between dynamics of STIM1 as well as cortical ER (cER) proteins and calcium oscillations in rat basophilic leukemia (RBL) mast cells. Surprisingly, a significant percentage of cells displayed cyclic STIM1 and cER dynamics that were calcium-independent. Using specific lipid sensors, we showed that cyclic ER-PM contact site assembly was in phase with PI(4)P oscillation, but preceded phases of PI(4,5)P2 or PI(3,4,5)P3 oscillation. Optogenetic recruitment of the phosphoinositide 5-phosphatase from INPP5E, which decreased PI(4,5)P2 and increased PI(4)P levels on the plasma membrane, stimulated the translocation of STIM1 and inhibited calcium oscillations. Interestingly, prolonged stable translocation of STIM1 to the plasma membrane had an inhibitory effect on calcium oscillations. Collectively, our findings suggest that ER-PM contact sites formation is PI(4)P-dependent. In addition, reversibility of ER-PM contact sites dynamics and intermediate strength of ER-PM contact are needed for calcium oscillation.
Importin α/β Promote Kif18B Microtubule Association to Spatially Control Microtubule Destabilization
Authors: Shrestha Sanjay , Ems-McClung Stephanie C. , Hazelbaker Mark A. , Yount Amber L. , Shaw Sidney L. , Walczak Claire E. 
Published: March 2022

AbstractTight regulation of microtubule (MT) dynamics is necessary for proper spindle assembly and chromosome segregation. The MT destabilizing Kinesin-8, Kif18B, controls astral MT dynamics and spindle positioning. Kif18B interacts with importin α/β as well as with the plus-tip tracking protein EB1, but how these associations modulate Kif18B is not known. We mapped the key binding sites on Kif18B, made residue-specific mutations, and assessed their impact on Kif18B function. Blocking EB1 interaction disrupted Kif18B MT plus-end accumulation and inhibited its ability to control MT length on monopolar spindles in cells. Blocking importin α/β interaction disrupted Kif18B localization without affecting aster size.In vitro, importin α/β increased Kif18B MT association by increasing the on-rate and decreasing the off-rate from MTs, which stimulated MT destabilization. In contrast, EB1 promoted MT destabilization without increasing lattice bindingin vitro, which suggests that EB1 and importin α/β have distinct roles in the regulation of Kif18B-mediated MT destabilization. We propose that importin α/β-spatially modulate Kif18B association with MTs to facilitate its MT destabilization activity. Our results suggest that Ran-regulation is important not only to control molecular motor function near chromatin but also provides a spatial control mechanism to modulate MT binding of NLS-containing spindle assembly factors.