bluuebunny/crossref_metadata_2025_split huggingface dataset:
The time is now: antimicrobial stewardship in solid organ transplantation
Authors: Hand Jonathan M. 
Published: May 2021

Purpose of review
To provide a summary of complications of antimicrobials and opportunities for antimicrobial stewardship (AS) in solid organ transplant (SOT) patient care.

Recent findings
Personalized, precision antimicrobial prescribing in SOT aiming to avoid negative consequences of antimicrobials is essential to improving patient outcomes. The positive impact AS efforts in transplant care has been recognized and bespoke activities tailored to special interests of transplant patients and providers are evolving. Strategies to optimize stewardship interventions targeting antibacterial, antiviral, and antifungal drug selection and dosing in the transplant population have been recently published though clinical integration using a ‘handshake’ stewardship model is an optimal starting point in transplant care. Other recent studies involving transplant recipients have identified opportunities to shorten duration or avoid antimicrobials for certain commonly encountered clinical syndromes. This literature, informing recent consensus clinical practice guidelines, may help support institutional practice guidelines and protocols. Proposals to track and report stewardship process and outcome measures as a routine facet of programmatic transplant quality reporting have been published. However, developing novel metrics accounting for nuances of transplant patients and programs is critical. Important studies are needed to evaluate organizational transplant prescribing cultures and optimal behavioral science-based interventions relevant to antimicrobial use in this population.

Summary
Consequences of antimicrobial use, such as drug toxicities, and Clostridiodes difficile (CDI) and multidrug-resistant organisms colonization and infection disproportionately affect SOT recipients and are associated with poor allograft and patient outcomes. Stewardship programs encompassing transplant patients aim to personalize antimicrobial prescribing and optimize outcomes. Further studies are needed to better understand optimal intervention strategies in SOT.
Recurrent glomerulonephritis after kidney transplantation: a practical approach
Authors: De Souza Laura , Prunster Janelle , Chan Doris , Chakera Aron , Lim Wai H. 
Published: May 2021

Purpose of review
This review will provide a practical approach in the assessment of kidney failure patients with primary glomerulonephritides (GN) being considered for kidney transplantation, focusing on high-risk subtypes of immunoglobulin A nephropathy, focal segmental glomerulosclerosis, idiopathic membranous glomerulonephritis and membranoproliferative glomerulonephritis.

Recent findings
Recurrent glomerulonephritis remains one of the most common causes of allograft loss in kidney transplant recipients. Although the epidemiology and clinical outcomes of glomerulonephritis recurrence occurring after kidney transplantation are relatively well-described, the natural course and optimal treatment strategies of recurrent disease in kidney allografts remain poorly defined. With a greater understanding of the pathophysiology and treatment responses of patients with glomerulonephritis affecting the native kidneys, these discoveries have laid the framework for the potential to improve the management of patients with high-risk glomerulonephritis subtypes being considered for kidney transplantation.

Summary
Advances in the understanding of the underlying immunopathogenesis of primary GN has the potential to offer novel therapeutic options for kidney patients who develop recurrent disease after kidney transplantation. To test the efficacy of novel treatment options in adequately powered clinical trials requires a more detailed understanding of the clinical and histological characteristics of kidney transplant recipients with recurrent glomerulonephritis.
Unified platform for genetic and serological detection of COVID-19 with single-molecule technology
Authors: Furth Noa , Shilo Shay , Cohen Niv , Erez Nir , Fedyuk Vadim , Schrager Alexander M. , Weinberger Adina , Dror Amiel A. , Zigron Asaf , Shehadeh Mona , Sela Eyal , Srouji Samer , Amit Sharon , Levy Itzchak , Segal Eran , Dahan Rony , Jones Dan , Douek Daniel C. , Shema Efrat 
Published: May 2021

AbstractThe COVID-19 pandemic raises the need for diverse diagnostic approaches to rapidly detect different stages of viral infection. The flexible and quantitative nature of single-molecule imaging technology renders it optimal for development of new diagnostic tools. Here we present a proof-of-concept for a single-molecule based, enzyme-free assay for detection of SARS-CoV-2. The unified platform we developed allows direct detection of the viral genetic material from patients’ samples, as well as their immune response consisting of IgG and IgM antibodies. Thus, it establishes a platform for diagnostics of COVID-19, which could also be adjusted to diagnose additional pathogens.
Comparative transcriptome analysis of noble crayfish and marbled crayfish immune response to Aphanomyces astaci challenges
Authors: Boštjančić Ljudevit Luka , Francesconi Caterina , Rutz Christelle , Hoffbeck Lucien , Poidevin Laetitia , Kress Arnaud , Jussila Japo , Makkonen Jenny , Feldmeyer Barbara , Bálint Miklós , Lecompte Odile , Theissinger Kathrin 
Published: May 2021

AbstractIntroduction of invasive North American crayfish species and their pathogen Aphanomyces astaci has significantly contributed to the decline of European freshwater crayfish populations. In this study, noble crayfish, a susceptible native European species, and marbled crayfish, an invasive disease-resistant species, were challenged with haplogroup A (low virulence) and haplogroup B (high virulence) strain of A. astaci. Hepatopancreatic tissue was isolated 3 and 21 days post-challenge. Our results revealed strong up-regulation in expression levels of the prophenoloxidase cascade immune-related genes in the haplogroup B challenged noble crayfish 3 days post-challenge. In the marbled crayfish, we observed an up-regulation of immune system relevant genes (DSCAM, AP, ALFs, CTLs and hemocyanin) 3 days post-challenge. This response highlights the marbled crayfish capability of building the immune tolerance. Furthermore, we successfully characterised several novel immune related gene groups in both crayfish species, contributing to our current understanding of crayfish immune related genes landscape.Graphical abstracta) Study species noble crayfish (Astacus astacus) in purple and marbled crayfish (Procambarus virginalis) in green challenged with the pathogen Aphanomyces astaci haplogroup A (Hap A) strain of low virulence and haplogroup B (Hap B) strain of high virulence. b) Sampling scheme of the infection experiment: 5 individuals were taken from the experiment three- and 21-days post-challenge. From each individual, a hepatopancreas sample was taken, followed by RNA isolation and sequencing. c)De novo transcriptome assembly and annotation were conducted for each species. d) Differential gene expression analysis revealed the distinct immune response in the noble crayfish 3 days post-challenge with the Hap B strain of A. astaci and marbled crayfish 3 days post-challenge with the Hap A strain of A. astaci. Immune related DEGs were not present in either species 21 days post-challenge with A. astaci.e) Noble crayfish challenged with the Hap B strain of A. astaci were acutely infected and ultimately moribund, while the A. astaci Hap A challenged marbled crayfish showed high resistance to the pathogen, resulting infected without any mortality.
Dysregulated heparan sulfate proteoglycan metabolism promotes Ewing sarcoma tumor growth
Authors: Vasileva Elena , Warren Mikako , Triche Timothy J. , Amatruda James F. 
Published: May 2021

AbstractThe Ewing sarcoma family of tumors is a group of malignant small round blue cell tumors (SRBCTs) that affects children, adolescents and young adults. The tumors are characterized by reciprocal chromosomal translocations that generate chimeric fusion oncogenes, the most common of which is EWSR1-FLI1. Survival is extremely poor for patients with metastatic or relapsed disease, and no molecularly-targeted therapy for this disease currently exists. The absence of a reliable genetic animal model of Ewing sarcoma has impaired investigation of tumor cell/microenvironmental interactions in vivo. We have developed a new genetic model of Ewing sarcoma based on Cre-inducible expression of human EWSR1-FLI1 in wild type zebrafish, which causes rapid onset of SRBCTs at high penetrance. The tumors express canonical EWSR1-FLI1 target genes and stain for known Ewing sarcoma markers including CD99. Growth of tumors is associated with activation of the MAPK/ERK pathway, which we link to dysregulated extracellular matrix metabolism in general and heparan sulfate catabolism in particular. Targeting heparan sulfate proteoglycans with the specific heparan sulfate antagonist Surfen reduces ERK1/2 signaling and decreases tumorigenicity of Ewing sarcoma cells in vitro and in vivo. These results highlight the important role of the extracellular matrix in Ewing sarcoma tumor growth and the potential of agents targeting proteoglycan metabolism as novel therapies for this disease.
Linking the brain with behaviour: the neural dynamics of success and failure in goal-directed behaviour
Authors: Robinson Amanda K. , Rich Anina N. , Woolgar Alexandra 
Published: May 2021

AbstractThe human brain is extremely flexible and capable of rapidly selecting relevant information in accordance with task goals. Regions of frontoparietal cortex flexibly represent relevant task information such as task rules and stimulus features when participants perform tasks successfully, but less is known about how information processing breaks down when participants make mistakes. This is important for understanding whether and when information coding recorded with neuroimaging is directly meaningful for behaviour. Here, we used magnetoencephalography (MEG) to assess the temporal dynamics of information processing, and linked neural responses with goal-directed behaviour by analysing how they changed on behavioural error. Participants performed a difficult stimulus-response task using two stimulus-response mapping rules. We used time-resolved multivariate pattern analysis to characterise the progression of information coding from perceptual information about the stimulus, cue and rule coding, and finally, motor response. Response-aligned analyses revealed a ramping up of perceptual information prior to a correct response, suggestive of internal evidence accumulation. Strikingly, when participants made a stimulus-related error, and not when they made other types of errors, patterns of activity initially reflected the stimulus presented, but later reversed, and accumulated towards a representation of theincorrectstimulus. This suggests that the patterns recorded at later timepoints reflect an internally generated stimulus representation that was used to make the (incorrect) decision.These results illustrate the orderly and overlapping temporal dynamics of information coding in perceptual decision-making and show a clear link between neural patterns in the late stages of processing and behaviour.
Using linear and natural cubic splines, SITAR, and latent trajectory models to characterise nonlinear longitudinal growth trajectories in cohort studies
Authors: Elhakeem Ahmed , Hughes Rachael A. , Tilling Kate M. , Cousminer Diana L. , Jackowski Stefan A. , Cole Tim J. , Kwong Alex S.F. , Li Zheyuan , Grant Struan F.A. , Baxter-Jones Adam D.G. , Zemel Babette S. , Lawlor Deborah A. 
Published: May 2021

ABSTRACTLongitudinal data analysis can improve our understanding of the influences on health trajectories across the life-course. There are a variety of statistical models which can be used, and their fitting and interpretation can be complex, particularly where there is a nonlinear trajectory. This paper provides a guide to describing nonlinear growth trajectories for repeatedly measured continuous outcomes using linear mixed-effects (LME) models with linear splines and natural cubic splines, nonlinear mixed effects Super Imposition by Translation and Rotation (SITAR) models, and latent trajectory models. The underlying model for each of the four approaches, the similarities and differences between models, and their advantages and disadvantages are described. Their applications and correct interpretation are illustrated by analysing repeated bone mass measures across three cohort studies with 8,500 individuals and 37,000 measurements covering ages 5-40 years. Linear and natural cubic spline LME models and SITAR provided similar descriptions of the mean bone growth trajectory and growth velocity, and the sex differences in growth patterns. Latent trajectory models identified up to four subgroups of individuals with distinct trajectories during adolescence and similar trajectories in childhood and adulthood. Recommendations for choosing a modelling approach are provided along with a discussion and signposting on further modelling extensions for analysing trajectory exposures and outcomes, and multiple cohorts. In summary, we present a resource for characterising nonlinear longitudinal growth trajectories, that could be adapted for other complex traits. Scripts and synthetic datasets are provided so readers can replicate trajectory modelling and visualisation using the open-source R software.
Identification of bipotent progenitors that give rise to myogenic and connective tissues in mouse
Authors: Grimaldi Alexandre , Comai Glenda , Mella Sébastien , Tajbakhsh Shahragim 
Published: May 2021

ABSTRACTHow distinct cell fates are manifested by direct lineage ancestry from bipotent progenitors, or by specification of individual cell types within a field of cells is a key question for understanding the emergence of tissues. The interplay between skeletal muscle progenitors and associated connective tissues cells provides a model for examining how muscle functional units are established. Most craniofacial structures originate from the vertebrate-specific neural crest cells except in the dorsal portion of the head, where they arise from cranial mesoderm. Here, using multiple lineage-traced single cell RNAseq, advanced computational methods and in situ analyses, we identify Myf5+bipotent progenitors that give rise to both muscle and juxtaposed connective tissue. Following this bifurcation, muscle and connective tissue cells retain complementary signalling features and maintain spatial proximity. Interruption of upstream myogenic identity shifts muscle progenitors to a connective tissue fate. Interestingly, Myf5-derived connective tissue cells, which adopt a novel regulatory signature, were not observed in ventral craniofacial structures that are colonised by neural crest cells. Therefore, we propose that an ancestral program gives rise to bifated muscle and connective tissue cells in skeletal muscles that are deprived of neural crest.
A new twist in ABC transporter mediated multidrug resistance – Pdr5 is a drug/proton co-transporter
Authors: Wagner Manuel , Blum Daniel , Raschka Stefanie L. , Nentwig Lea-Marie , Gertzen Christoph G. W. , Chen Minghao , Gatsogiannis Christos , Harris Andrzej , Smits Sander H. J. , Wagner Richard , Schmitt Lutz 
Published: May 2021

AbstractThe two major efflux pump systems are involved in multidrug resistance (MDR): (i) ATP binding cassette (ABC) transporters and (ii) secondary transporters. While the former use binding and hydrolysis of ATP to facilitate export of cytotoxic compounds, the latter utilize electrochemical gradients to expel their substrates. Pdr5 from Saccharomyces cerevisiae is a prominent member of eukaryotic ABC transporters that are involved in MDR and used as a frequently studied model system. Although investigated for decades, the underlying molecular mechanisms of transport and specificity remain elusive. Here, we provide electrophysiological data on reconstituted Pdr5 demonstrating that this MDR efflux pump does not only actively translocate its substrates across the lipid bilayer, but generates a proton motif force in the presence of Mg2+-ATP and substrates by acting as a proton/drug co-transporter. Importantly, a strictly substrate dependent co-transport of protons was also observed in in vitro transport studies using Pdr5-enriched plasma membranes. Similar observations have not yet been reported for any other MDR efflux pump. We conclude from these results that the mechanism of MDR conferred by Pdr5 and likely other transporters is more complex than the sole extrusion of cytotoxic compounds and involves secondary coupled processes suitable to increase the effectiveness.
Construction of redesigned pMAL expression vector for easy and fast purification of active native antimicrobial peptides
Authors: Gardijan Lazar , Miljkovic Marija , Obradovic Mina , Borovic Branka , Vukotic Goran , Jovanovic Goran , Kojic Milan 
Published: May 2021

AbstractMany protein expression and purification systems are commercially available to provide a sufficient amount of pure, soluble and active native protein, such as the pMAL system based onE. colimaltose binding protein tag (MBP). Adding specific amino acid tags to the N- or C-terminus of the protein increases solubility and facilitates affinity purification of proteins. However, many of expressed tagged proteins consequently lose functionality, particularly small peptides such as antimicrobial peptides (AMPs). Objective of this study was to redesign the pMAL expression vector in order to increase the efficacy of MBP tag separation from native peptides. Redesign of the pMAL expression vector included introduction of the His6tag and the enterokinase cleavage site downstream from the original MBP tag and Xa cleavage site enabling purification of native and active peptide (P) following two-step affinity chromatography. In the first step the entire MBP-His6-P fusion protein is purified through binding to Ni-NTA agarose. In the second step, the purification was performed by adding mixture of amylose and Ni-NTA agarose resins following cleavage of the fusion protein with active His6tagged enterokinase. This removes MBP-His6and His6-enterokinase leaving pure native protein in solution. The redesigned pMAL vectors were optimized for cytoplasmic (pMALc5HisEk) and periplasmic (pMALp5HisEk) peptides expression. Two-step purification protocol was successfully applied in purification of active native AMPs, lactococcin A and human β-defensin. Taken together, we established the optimal conditions and pipeline for overexpression and purification of large amount of native peptides, that can be implemented in any laboratory.
ERK1/2 is an ancestral organising signal in spiral cleavage
Authors: Seudre Océane , Carrillo-Baltodano Allan M. , Liang Yan , Martín-Durán José M. 
Published: May 2021

AbstractAnimal development is classified as conditional or autonomous based on whether cell fates are specified through inductive signals or maternal determinants, respectively. Yet how these two major developmental modes evolved remains unclear. During spiral cleavage—a stereotypic embryogenesis ancestral to 15 invertebrate groups, including molluscs and annelids—most lineages specify cell fates conditionally, while some define the primary axial fates autonomously. To identify the mechanisms driving this change, we studiedOwenia fusiformis, an early-branching, conditional annelid. InOwenia, ERK1/2-mediated FGF receptor signalling specifies the endomesodermal progenitor. This cell likely acts as an organiser, inducing mesodermal and posterodorsal fates in neighbouring cells and repressing anteriorising signals. The organising role of ERK1/2 inOweniais shared with molluscs, but not with autonomous annelids. Together, these findings suggest that conditional specification of an ERK1/2+embryonic organiser is ancestral in spiral cleavage and was repeatedly lost in annelid lineages with autonomous development.
Effective prophylaxis of COVID-19 in rhesus macaques using a combination of two parentally-administered SARS-CoV-2 neutralizing antibodies
Authors: Beddingfield Brandon J. , Maness Nicholas J. , Fears Alyssa C. , Rappaport Jay , Aye Pyone Pyone , Russell-Lodrigue Kasi , Doyle-Meyers Lara A. , Blair Robert V. , Carias Ann M. , Madden Patrick J. , Redondo Ramon Lorenzo , Gao HongMei , Montefiori David , Hope Thomas J. , Roy Chad J. 
Published: May 2021

AbstractSARS-CoV-2 is a respiratory borne pathogenic beta coronavirus that is the source of a worldwide pandemic and the cause of multiple pathologies in man. The rhesus macaque model of COVID-19 was utilized to test the added benefit of combinatory parenteral administration of two high-affinity anti-SARS-CoV-2 monoclonal antibodies (mAbs; C144-LS and C135-LS) expressly developed to neutralize the virus and modified to extend their pharmacokinetics. After completion of kinetics study of mAbs in the primate, combination treatment was administered prophylactically to mucosal viral challenge. Results showed near complete virus neutralization evidenced by no measurable titer in mucosal tissue swabs, muting of cytokine/chemokine response, and lack of any discernable pathologic sequalae. Blocking infection was a dose-related effect, cohorts receiving lower doses (6, 2 mg/kg) resulted in low grade viral infection in various mucosal sites compared to that of a fully protective dose (20 mg/kg). A subset of animals within this cohort whose infectious challenge was delayed 75 days later after mAb administration were still protected from disease. Results indicate this combination mAb effectively blocks development of COVID-19 in the rhesus disease model and accelerates the prospect of clinical studies with this effective antibody combination.
TCAB1 prevents nucleolar accumulation of the telomerase RNA to promote telomerase assembly
Authors: Klump Basma M. , Perez Gloria I. , Patrick Eric M. , Adams-Boone Kate , Cohen Scott B. , Han Li , Yu Kefei , Schmidt Jens C. 
Published: May 2021

AbstractLocalization of a wide variety of RNAs to non-membrane bound cellular compartments such as nucleoli, Cajal bodies, and stress-granules is critical for their function and stability. The molecular mechanisms that underly the recruitment and exclusion of specific RNAs from these phase-separated organelles is incompletely understood. Telomerase is a ribonucleoprotein (RNP) that is composed of the reverse transcriptase protein TERT, the telomerase RNA (TR), and several auxiliary proteins that associate with TR, including TCAB1. Here we show that in the absence of TCAB1, TR is tightly bound to the nucleolus, while TERT localizes to the nucleoplasm and is largely excluded from the nucleolus, significantly reducing telomerase assembly. Thus, nuclear compartmentalization by the non-membrane bound nucleolus counteracts telomerase assembly and TCAB1 is required to exclude the telomerase RNA from the nucleolus. Our work provides insight into the mechanism and functional consequences of RNA recruitment to organelles formed by phase separation proposes a new model explaining the critical role of TCAB1 in telomerase function.