Expression of vesiculation-related genes is associated with a tumor-promoting microenvironment: a pan-cancer analysis.

Background: Small extracellular vesicles (sEV) released by tumor cells (tumor-derived sEV; TEX) mediate intercellular communication between tumor and non-malignant cells and were shown to impact disease progression. This study investigates the relationship between the expression levels of the vesiculation-related genes linked to sEV production and the tumor microenvironment (TME).

Methods: Two independent gene sets were analyzed, both previously linked to sEV production in various non-malignant or malignant cells.

Tagless LysoIP for immunoaffinity enrichment of native lysosomes from clinical samples.

Lysosomes are implicated in a wide spectrum of human diseases including monogenic lysosomal storage disorders (LSDs), age-associated neurodegeneration and cancer. Profiling lysosomal content using tag-based lysosomal immunoprecipitation (LysoTagIP) in cell and animal models has substantially moved the field forward, but studying lysosomal dysfunction in human patients remains challenging. Here, we report the development of the 'tagless LysoIP' method, designed to enable the rapid enrichment of lysosomes, via immunoprecipitation, using the endogenous integral lysosomal membrane protein TMEM192, directly from clinical samples and human cell lines (e.

The role of the co-chaperone DNAJB11 in polycystic kidney disease: Molecular mechanisms and cellular origin of cyst formation.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2, encoding polycystin-1 (PC1) and polycystin-2 (PC2), which are required for the regulation of the renal tubular diameter. Loss of polycystin function results in cyst formation. Atypical forms of ADPKD are caused by mutations in genes encoding endoplasmic reticulum (ER)-resident proteins through mechanisms that are not well understood.

Atrial fibrillation and survival on a medical intensive care unit.

Background: Atrial fibrillation (AF) is common among patients in the intensive care unit (ICU) and can be triggered by severe illness or preexisting conditions. It is debated if AF is an independent predictor of poor outcome.

Methods: Data derives from a single center retrospective registry including all patients with a stay on the medical ICU for >24 h.

Safety and efficacy of cerliponase alfa in children with neuronal ceroid lipofuscinosis type 2 (CLN2 disease): an open-label extension study.

Background: Cerliponase alfa is a recombinant human tripeptidyl peptidase 1 (TPP1) enzyme replacement therapy for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2 disease), which is caused by mutations in the TPP1 gene. We aimed to determine the long-term safety and efficacy of intracerebroventricular cerliponase alfa in children with CLN2 disease.

Methods: This analysis includes cumulative data from a primary 48-week, single-arm, open-label, multicentre, dose-escalation study (NCT01907087) and the 240-week open-label extension with 6-month safety follow-up, conducted at five hospitals in Germany, Italy, the UK, and the USA.

HbA1c-dependent projection of long-term renal outcomes.

Background: Diabetes mellitus is a major risk factor for the development of chronic kidney disease (CKD). There is limited data addressing the value of glycated hemoglobin (HbA1c) to predict renal outcomes independent of diabetes status.

Methods: This single-center retrospective observational study presents data of 19,285 subjects, irrespective of initial CKD or diabetes status.

Clinical covariates influencing clinical outcomes in primary membranous nephropathy.

Background: Primary membranous nephropathy (PMN) frequently causes nephrotic syndrome and declining kidney function. Disease progression is likely modulated by patient-specific and therapy-associated factors awaiting characterization. These cofactors may facilitate identification of risk groups and could result in more individualized therapy recommendations.

Experience of pain during mammographic screening by three different compression paddles.

Introduction: Experience of pain during screening mammography is shown to affect further attendance negatively. We aimed to explore the experience of pain during screening mammography using three different breast compression paddles.

Methods: Using a self-report questionnaire, we collected information on pain experienced during mammography from 938 women screened in Bodø at Nordland Hospital County in 2018, as a part of BreastScreen Norway.

Identification of macrocyclic peptides which activate bacterial cylindrical proteases.

The caseinolytic protease complex ClpXP is an important house-keeping enzyme in prokaryotes charged with the removal and degradation of misfolded and aggregated proteins and performing regulatory proteolysis. Dysregulation of its function, particularly by inhibition or allosteric activation of the proteolytic core ClpP, has proven to be a promising strategy to reduce virulence and eradicate persistent bacterial infections. Here, we report a rational drug-design approach to identify macrocyclic peptides which increase proteolysis by ClpP.

Identification of Covariates Modulating B-Cell Repopulation Kinetics in Subjects Receiving Rituximab Treatment.

Objective: B-cell depletion using the anti-CD20 monoclonal antibody rituximab is a cornerstone in the therapeutic concept of multiple autoimmune diseases. B-cell depletion is associated with a higher risk for severe infections, and the time span of B-cell repopulation differs greatly between individuals. Data on factors influencing B-cell repopulation kinetics are limited.

Bacterial catabolism of membrane phospholipids links marine biogeochemical cycles.

In marine systems, the availability of inorganic phosphate can limit primary production leading to bacterial and phytoplankton utilization of the plethora of organic forms available. Among these are phospholipids that form the lipid bilayer of all cells as well as released extracellular vesicles. However, information on phospholipid degradation is almost nonexistent despite their relevance for biogeochemical cycling.

Eculizumab as a treatment for C3 glomerulopathy: a single-center retrospective study.

Background: C3 Glomerulopathy (C3G) is a rare glomerular disease caused by dysregulation of the complement pathway. Based on its pathophysiology, treatment with the monoclonal antibody eculizumab targeting complement C5 may be a therapeutic option. Due to the rarity of the disease, observational data on the clinical response to eculizumab treatment is scarce.

Antibiotic Acyldepsipeptides Stimulate the Clp-ATPase/ClpP Complex for Accelerated Proteolysis.

Clp proteases consist of a proteolytic, tetradecameric ClpP core and AAA+ Clp-ATPases. Streptomycetes, producers of a plethora of secondary metabolites, encode up to five different ClpP homologs, and the composition of their unusually complex Clp protease machinery has remained unsolved. Here, we report on the composition of the housekeeping Clp protease in , consisting of a heterotetradecameric core built of ClpP1, ClpP2, and the cognate Clp-ATPases ClpX, ClpC1, or ClpC2, all interacting with ClpP2 only.

Distinct dissociation rates of murine and human norovirus P-domain dimers suggest a role of dimer stability in virus-host interactions.

Norovirus capsids are icosahedral particles composed of 90 dimers of the major capsid protein VP1. The C-terminus of the VP1 proteins forms a protruding (P)-domain, mediating receptor attachment, and providing a target for neutralizing antibodies. NMR and native mass spectrometry directly detect P-domain monomers in solution for murine (MNV) but not for human norovirus (HuNoV).

Integration of sustained low-efficiency dialysis into extracorporeal membrane oxygenation circuit in critically ill COVID-19 patients: A feasibility study.

Background: Severe COVID-19 can necessitate multiple organ support including veno-venous extracorporeal membrane oxygenation (vvECMO) and renal replacement therapy. The therapy can be complicated by venous thromboembolism due to COVID-19-related hypercoagulability, thus restricting vascular access beyond the vvECMO cannula. Although continuous renal replacement therapy can be performed via a vvECMO circuit, studies addressing sustained low-efficiency dialysis (SLED) integration into vvECMO circuits are scarce.

Assignment of Ala, Ile, Leu, Met, and Val methyl groups of the protruding domain of murine norovirus capsid protein VP1 using methyl-methyl NOEs, site directed mutagenesis, and pseudocontact shifts.

The protruding domain (P-domain) of the murine norovirus (MNV) capsid protein VP1 is essential for infection. It mediates receptor binding and attachment of neutralizing antibodies. Protein NMR studies into interactions of the P-domain with ligands will yield insights not easily available from other biophysical techniques and will extend our understanding of MNV attachment to host cells.

Pathogenic variants in GNPTAB and GNPTG encoding distinct subunits of GlcNAc-1-phosphotransferase differentially impact bone resorption in patients with mucolipidosis type II and III.

Purpose: Pathogenic variants in GNPTAB and GNPTG, encoding different subunits of GlcNAc-1-phosphotransferase, cause mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma. This study aimed to investigate the cellular and molecular bases underlying skeletal abnormalities in patients with MLII and MLIII.

Methods: We analyzed bone biopsies from patients with MLIII alpha/beta or MLIII gamma by undecalcified histology and histomorphometry.

Field Anesthesia of the Maned Wolf (Chrysocyon brachyurus) in Bolivia.

Fifteen maned wolves (Chrysocyon brachyurus) were anesthetized a total of 43 times as part of a long-term ecology and health study in a remote region of northeastern Bolivia. We administered tiletamine-zolazepam (TZ) to wolves in box traps or free-ranging, from blinds or on foot, at a mean dosage of 4.6 mg/kg intramuscularly.

Transgenic inhibition of interleukin-6 trans-signaling does not prevent skeletal pathologies in mucolipidosis type II mice.

Severe skeletal alterations are common symptoms in patients with mucolipidosis type II (MLII), a rare lysosomal storage disorder of childhood. We have previously reported that progressive bone loss in a mouse model for MLII is caused by an increased number of bone-resorbing osteoclasts, which is accompanied by elevated expression of the cytokine interleukin-6 (IL-6) in the bone microenvironment. In the present study we addressed the question, if pharmacological blockade of IL-6 can prevent the low bone mass phenotype of MLII mice.

Current patterns of practice in spinal fusion for chronic low back pain-results from a survey at the German Spine Societies' Annual Congress 2018.

Background: There is debate regarding criteria to select patients for lumbar fusion surgery who have chronic low back pain (CLBP) and corresponding degenerative changes, but without nerve root compression or neurogenic claudication. The aim of this study was to compare patterns in current practice.

Method: A total of 143 printed questionnaires containing 51 questions were distributed at the German Spine Societies' (DWG) annual congress, 6-8 December 2018.

Comparison of different anticoagulation strategies for renal replacement therapy in critically ill patients with COVID-19: a cohort study.

Background: Critically ill coronavirus disease 2019 (COVID-19) patients have a high risk of acute kidney injury (AKI) that requires renal replacement therapy (RRT). A state of hypercoagulability reduces circuit life spans. To maintain circuit patency and therapeutic efficiency, an optimized anticoagulation strategy is needed.

Imbalanced cellular metabolism compromises cartilage homeostasis and joint function in a mouse model of mucolipidosis type III gamma.

Mucolipidosis type III (MLIII) gamma is a rare inherited lysosomal storage disorder caused by mutations in encoding the γ-subunit of GlcNAc-1-phosphotransferase, the key enzyme ensuring proper intracellular location of multiple lysosomal enzymes. Patients with MLIII gamma typically present with osteoarthritis and joint stiffness, suggesting cartilage involvement. Using knockout ( ) mice as a model of the human disease, we showed that missorting of a number of lysosomal enzymes is associated with intracellular accumulation of chondroitin sulfate in chondrocytes and their impaired differentiation, as well as with altered microstructure of the cartilage extracellular matrix (ECM).