Endocytosis of Activated Muscarinic m2 Receptor (m2R) in Live Mouse Hippocampal Neurons Occurs via a Clathrin-Dependent Pathway

Our aim was to examine the dynamics of the muscarinic m2 receptor (m2R), a G-protein coupled receptor (GPCR), after agonist activation in living hippocampal neurons, and especially clathrin dependency endocytosis. We have previously shown that the m2R undergoes agonist-induced internalization in vivo. However, the nature of the endocytotic pathway used by m2R after activation is still unknown in living neurons. Using live cell imaging and quantitative analyses, we have monitored the effect of stimulation on the fate of the membrane-bound m2R and on its redistribution in intraneuronal compartments. Shortly (6 min) after activation, m2R is internalized into clathrin immunopositive structures. Furthermore, after clathrin-dependent endocytosis, m2R associates with early and late endosomes and with subcellular organelles involved in degradation. Together, these results provide, for the first time, a description of m2R trafficking in living neurons and prove that m2R undergoes clathrin-dependent endocytosis before being degraded

Spatio-temporal coherent control of thermal excitations in solids

X-ray reflectivity (XRR) measurements of femtosecond laser-induced transient gratings are applied to demonstrate the spatio-temporal coherent control of thermally induced surface deformations on ultrafast timescales. Using gracing incidence X-ray diffraction we unambiguously measure the amplitude of transient surface deformations with sub-\AA{} resolution. Understanding the dynamics of femtosecond TG excitations in terms of superposition of acoustic and thermal gratings makes it possible to develop new ways of coherent control in X-ray diffraction experiments. Being the dominant source of TG signal, the long-living thermal grating with spatial period $\Lambda$ can be canceled by a second, time-delayed TG excitation shifted by $\Lambda/2$. The ultimate speed limits of such an ultrafast X-ray shutter are inferred from the detailed analysis of thermal and acoustic dynamics in TG experiments

Cable Tree Wiring -- Benchmarking Solvers on a Real-World Scheduling Problem with a Variety of Precedence Constraints

Cable trees are used in industrial products to transmit energy and information between different product parts. To this date, they are mostly assembled by humans and only few automated manufacturing solutions exist using complex robotic machines. For these machines, the wiring plan has to be translated into a wiring sequence of cable plugging operations to be followed by the machine. In this paper, we study and formalize the problem of deriving the optimal wiring sequence for a given layout of a cable tree. We summarize our investigations to model this cable tree wiring Problem (CTW) as a traveling salesman problem with atomic, soft atomic, and disjunctive precedence constraints as well as tour-dependent edge costs such that it can be solved by state-of-the-art constraint programming (CP), Optimization Modulo Theories (OMT), and mixed-integer programming (MIP) solvers. It is further shown, how the CTW problem can be viewed as a soft version of the coupled tasks scheduling problem. We discuss various modeling variants for the problem, prove its NP-hardness, and empirically compare CP, OMT, and MIP solvers on a benchmark set of 278 instances. The complete benchmark set with all models and instance data is available on github and is accepted for inclusion in the MiniZinc challenge 2020

What static and dynamic properties should slalom skis possess? Judgments by advanced and expert skiers

Flexural and torsional rigidity are important properties of skis. However, the flexural and torsional rigidity that lead to optimal performance remain to be established. In the present study, four pairs of slalom skis that differed in flexural and torsional rigidity were tested by advanced and expert skiers. Using a 10-item questionnaire, different aspects of the skis’ performance were rated on a 9-point scale. For each pair of skis, physical measurements were compared with the ratings of the two groups of skiers. Correlations (Spearman) were then determined between (i) different mechanical properties of the skis (static and dynamic), (ii) subjective assessments of the participants, and (iii) properties of the skis and the participants’ assessments. The latter showed that expert skiers rate the aspects of the skis more accurately than advanced skiers. Importantly, expert skiers are particularly sensitive to torsion of the skis. These results suggest that such highly rated elements should be addressed in future ski designs

Heart failure in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies conference

The incidence and prevalence of heart failure (HF) and chronic kidney disease (CKD) are increasing, and as such a better understanding of the interface between both conditions is imperative for developing optimal strategies for their detection, prevention, diagnosis, and management. To this end, Kidney Disease: Improving Global Outcomes (KDIGO) convened an international, multidisciplinary Controversies Conference titled Heart Failure in CKD. Breakout group discussions included (i) HF with preserved ejection fraction (HFpEF) and nondialysis CKD, (ii) HF with reduced ejection fraction (HFrEF) and nondialysis CKD, (iii) HFpEF and dialysis-dependent CKD, (iv) HFrEF and dialysis-dependent CKD, and (v) HF in kidney transplant patients. The questions that formed the basis of discussions are available on the KDIGO website http://kdigo.org/conferences/heart-failure-in-ckd/, and the deliberations from the conference are summarized here

Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA)

Intra-abdominal infections (IAI) are an important cause of morbidity and are frequently associated with poor prognosis, particularly in high-risk patients. The cornerstones in the management of complicated IAIs are timely effective source control with appropriate antimicrobial therapy. Empiric antimicrobial therapy is important in the management of intra-abdominal infections and must be broad enough to cover all likely organisms because inappropriate initial antimicrobial therapy is associated with poor patient outcomes and the development of bacterial resistance. The overuse of antimicrobials is widely accepted as a major driver of some emerging infections (such as C. difficile), the selection of resistant pathogens in individual patients, and for the continued development of antimicrobial resistance globally. The growing emergence of multi-drug resistant organisms and the limited development of new agents available to counteract them have caused an impending crisis with alarming implications, especially with regards to Gram-negative bacteria. An international task force from 79 different countries has joined this project by sharing a document on the rational use of antimicrobials for patients with IAIs. The project has been termed AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections). The authors hope that AGORA, involving many of the world's leading experts, can actively raise awareness in health workers and can improve prescribing behavior in treating IAIs

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Controversies in acute kidney injury: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) conference

In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline on the classification and management of acute kidney injury (AKI). The guideline was derived from evidence available through February 2011. Since then, new evidence has emerged that has important implications for clinical practice in diagnosing and managing AKI. In April of 2019, KDIGO held a controversies conference entitled Acute Kidney Injury with the following goals: determine best practices and areas of uncertainty in treating AKI; review key relevant literature published since the 2012 KDIGO AKI guideline; address ongoing controversial issues; identify new topics or issues to be revisited for the next iteration of the KDIGO AKI guideline; and outline research needed to improve AKI management. Here, we present the findings of this conference and describe key areas that future guidelines may address