E3-Specific Degrader Discovery by Dynamic Tracing of Substrate Receptor Abundance.

Targeted protein degradation (TPD) is a new pharmacology based on small-molecule degraders that induce proximity between a protein of interest (POI) and an E3 ubiquitin ligase. Of the approximately 600 E3s encoded in the human genome, only around 2% can be co-opted with degraders. This underrepresentation is caused by a paucity of discovery approaches to identify degraders for defined E3s.

Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders.

Targeted protein degradation is a novel pharmacology established by drugs that recruit target proteins to E3 ubiquitin ligases. Based on the structure of the degrader and the target, different E3 interfaces are critically involved, thus forming defined 'functional hotspots'. Understanding disruptive mutations in functional hotspots informs on the architecture of the assembly, and highlights residues susceptible to acquire resistance phenotypes.

Towards safety4.0: A novel approach for flexible human-robot-interaction based on safety-related dynamic finite-state machine with multilayer operation modes.

In the era of Industry 4.0 and agile manufacturing, the conventional methodologies for risk assessment, risk reduction, and safety procedures may not fulfill the End-User requirements, especially the SMEs with their product diversity and changeable production lines and processes. This work proposes a novel approach for planning and implementing safe and flexible Human-Robot-Interaction (HRI) workspaces using multilayer HRI operation modes.

Integrated experimental-computational analysis of a HepaRG liver-islet microphysiological system for human-centric diabetes research.

Microphysiological systems (MPS) are powerful tools for emulating human physiology and replicating disease progression in vitro. MPS could be better predictors of human outcome than current animal models, but mechanistic interpretation and in vivo extrapolation of the experimental results remain significant challenges. Here, we address these challenges using an integrated experimental-computational approach.

A rodent thyroid-liver chip to capture thyroid toxicity on organ function level.

Endocrine disruption by environmental chemicals continues to be a concern for human safety. The rat, a widely used model organism in toxicology, is very sensitive to chemical-induced thyroid perturbation, e.g.

A microfluidic thyroid-liver platform to assess chemical safety in humans.

Thyroid hormones (THs) are crucial regulators of human metabolism and early development. During the safety assessment of plant protection products, the human relevance of chemically induced TH perturbations observed in test animals remains uncertain. European regulatory authorities request follow-up in vitro studies to elucidate human-relevant interferences on thyroid gland function or TH catabolism through hepatic enzyme induction.

[Cirrhosis and coagulation : implications for clinical practice].

Coagulation disorders related to abnormalities in hepatic synthesis are well known as prognostic factors in hepatic cirrhosis. The risk of bleeding, mainly linked to portal hypertension, must be weighed against the risk of thrombosis, the most frequent manifestation of which is portal venous thrombosis. Conventional laboratory tests are not a reliable reflection of this delicate balance.

Rational discovery of molecular glue degraders via scalable chemical profiling.

Targeted protein degradation is a new therapeutic modality based on drugs that destabilize proteins by inducing their proximity to E3 ubiquitin ligases. Of particular interest are molecular glues that can degrade otherwise unligandable proteins by orchestrating direct interactions between target and ligase. However, their discovery has so far been serendipitous, thus hampering broad translational efforts.

Plasticity of the Cullin-RING Ligase Repertoire Shapes Sensitivity to Ligand-Induced Protein Degradation.

Inducing protein degradation via small molecules is a transformative therapeutic paradigm. Although structural requirements of target degradation are emerging, mechanisms determining the cellular response to small-molecule degraders remain poorly understood. To systematically delineate effectors required for targeted protein degradation, we applied genome-scale CRISPR/Cas9 screens for five drugs that hijack different substrate receptors (SRs) of cullin RING ligases (CRLs) to induce target proteolysis.

Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML.

The design of selective small molecules is often stymied by similar ligand binding pockets. Here, we report BSJ-03-123, a phthalimide-based degrader that exploits protein-interface determinants to achieve proteome-wide selectivity for the degradation of cyclin-dependent kinase 6 (CDK6). Pharmacologic CDK6 degradation targets a selective dependency of acute myeloid leukemia cells, and transcriptomics and phosphoproteomics profiling of acute degradation of CDK6 enabled dynamic mapping of its immediate role in coordinating signaling and transcription.

Coacervation-Mediated Combinatorial Synthesis of Biomatrices for Stem Cell Culture and Directed Differentiation.

Combinatorial screening represents a promising strategy to discover biomaterials for tailored cell culture applications. Although libraries incorporating different biochemical cues have been investigated, few simultaneously recapitulate relevant biochemical, physical, and dynamic features of the extracellular matrix (ECM). Here, a noncovalent system based on liquid-liquid phase separation (coacervation) and gelation mediated by glycosaminoglycan (GAG)-peptide interactions is reported.

Publisher Correction: Functional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

Translation Termination Factor GSPT1 Is a Phenotypically Relevant Off-Target of Heterobifunctional Phthalimide Degraders.

Protein degradation is an emerging therapeutic strategy with a unique molecular pharmacology that enables the disruption of all functions associated with a target. This is particularly relevant for proteins depending on molecular scaffolding, such as transcription factors or receptor tyrosine kinases (RTKs). To address tractability of multiple RTKs for chemical degradation by the E3 ligase CUL4-RBX1-DDB1-CRBN (CRL4), we synthesized a series of phthalimide degraders based on the promiscuous kinase inhibitors sunitinib and PHA665752.

Field performance of the Determine HBsAg point-of-care test for diagnosis of hepatitis B virus co-infection among HIV patients in Zambia.

Background: We evaluated the field performance of a rapid point-of-care (POC) test for hepatitis B surface antigen (HBsAg) that could support decentralization and scale-up of hepatitis B virus (HBV) diagnosis in Africa.

Objective: To determine the field performance of the Determine HBsAg POC test for diagnosis of HBV co-infection among HIV patients in Zambia.

Study Design: Between 2013-2014, we screened HIV-infected adults for HBsAg at two urban clinics in Zambia.

Functional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model.

Human in vitro physiological models studying disease and drug treatment effects are urgently needed as more relevant tools to identify new drug targets and therapies. We have developed a human microfluidic two-organ-chip model to study pancreatic islet-liver cross-talk based on insulin and glucose regulation. We have established a robust co-culture of human pancreatic islet microtissues and liver spheroids maintaining functional responses up to 15 days in an insulin-free medium.

Awareness and management of elevated blood pressure among human immunodeficiency virus-infected adults receiving antiretroviral therapy in urban Zambia: a call to action.

The prevalence of high blood pressure (HBP) and hypertension (HTN), awareness of the diagnoses, and use of anti-hypertensive drugs were examined among human immunodeficiency virus (HIV)-infected individuals on antiretroviral therapy (ART) in Zambia's capital Lusaka. Within a prospective cohort based at two public sector ART clinics, BP was measured at ART initiation and every 6 months thereafter as a routine clinic procedure. Predictors of HBP (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) during one year on ART were analyzed using logistic regression, and the proportion with HTN (2+ episodes of HBP >3 months apart) described.

Changes of Protein Turnover in Aging .

Protein turnover rates severely decline in aging organisms, including However, limited information is available on turnover dynamics at the individual protein level during aging. We followed changes in protein turnover at one-day resolution using a multiple-pulse N-labeling and accurate mass spectrometry approach. Forty percent of the proteome shows gradual slowdown in turnover with age, whereas only few proteins show increased turnover.

BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment.

Processive elongation of RNA Polymerase II from a proximal promoter paused state is a rate-limiting event in human gene control. A small number of regulatory factors influence transcription elongation on a global scale. Prior research using small-molecule BET bromodomain inhibitors, such as JQ1, linked BRD4 to context-specific elongation at a limited number of genes associated with massive enhancer regions.

Blood cultures in the evaluation of uncomplicated cellulitis.

Purpose: The frequency of bacteremia and the array of microorganisms involved in cellulitis vary greatly among studies. Although current guidelines do not recommend routine blood culture in uncomplicated cellulitis, their implementation in clinical practice remains challenging. We therefore aimed to assess the frequency, determinants and microbiology of bacteremia in hospitalized patients with uncomplicated cellulitis.

Emulating human microcapillaries in a multi-organ-chip platform.

Current microfluidic chip-based tissue culture systems lack a capillary endothelial vessel system, which would enable perfusion with blood. We utilise spatial cell cultures to populate a perfused multi-organ-chip platform-a microfluidic device recently introduced for substance testing. Complete biological vascularization of such culture systems is vital to properly emulate physiological tissue behaviour.

A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents.

Systemic absorption and metabolism of drugs in the small intestine, metabolism by the liver as well as excretion by the kidney are key determinants of efficacy and safety for therapeutic candidates. However, these systemic responses of applied substances lack in most in vitro assays. In this study, a microphysiological system maintaining the functionality of four organs over 28 days in co-culture has been established at a minute but standardized microsystem scale.

Morphological characteristics of osteotomies using different piezosurgical devices. A scanning electron microscopic evaluation.

Purpose: The objective of this study was to compare morphological characteristics of osteotomies performed by 6 Piezosurgical devices.

Materials And Methods: The 6 Piezosurgical units were: (a) Piezotom, (b) SurgySonic, (c) Piezon Master Surgery, (d) VarioSurg, (e) Surgybone, and (f) Piezosurgery 3. Osteotomies on 9 freshly slaughtered cattle ribs (2 cuts by each unit, per rib) from the cortical (first cut at 5 mm) to the cancellous (second cut at 3 mm) bone layer were performed.

Costs of mounting an immune response during pregnancy in a lizard.

Immune defenses are of great benefit to hosts, but reducing the impact of infection by mounting an immune response also entails costs. However, the physiological mechanisms that generate the costs of an immune response remain poorly understood. Moreover, the majority of studies investigating the consequences of an immune challenge in vertebrates have been conducted on mammals and birds.

Influence of sociodemographic factors on Helicobacter pylori prevalence variability among schoolchildren in Leipzig, Germany. A long-term follow-up study.

Background: Until the beginning of this decade the assumption was that the Helicobacter pylori prevalence increases with the age of the population under consideration. More and more epidemiological studies have been suggestive of constancy in Helicobacter pylori prevalence, but to date there has been no long-term follow-up study in a large group of children confirming this hypothesis.

Methods: Following up our study of H.