Vellingstephenson1693

Obesity and its co-morbidities are a growing health epidemic. Interactions between genetic background, the environment and behavior (i.e. diet) greatly influence organismal energy balance. Previously, we described obesogenic mutations in the gene Split ends (Spen) in Drosophila melanogaster, and roles for Spen in fat storage and metabolic state. Lipid catabolism is impaired in Spen-deficient fat storage cells, accompanied by a compensatory increase in glycolytic flux and protein catabolism. Here we investigate gene-diet interactions to determine if diets supplemented with specific macronutrients can rescue metabolic dysfunction in Spen-depleted animals. We show that a high-yeast diet partially rescues adiposity and developmental defects. High sugar partially improves developmental timing as well as longevity of mated females. Gene-diet interactions were heavily influenced by developmental-stage-specific organismal needs extra yeast provides benefits early in development (larval stages) but becomes detrimental in adulthood. High sugar confers benefits to Spen-depleted animals at both larval and adult stages, with the caveat of increased adiposity. A high-fat diet is detrimental according to all tested criteria, regardless of genotype. Whereas Spen depletion influenced phenotypic responses to supplemented diets, diet was the dominant factor in directing the whole-organism steady-state metabolome. Obesity is a complex disease of genetic, environmental, and behavioral inputs. Our results show that diet customization can ameliorate metabolic dysfunction underpinned by a genetic factor. Copyright © 2020, Genetics.The fitness landscapes of genetic sequences are characterized by high dimensionality and "ruggedness" due to sign epistasis. Ascending from low to high fitness on such landscapes can be difficult because adaptive trajectories get stuck at low-fitness local peaks. Compounding matters, recent theoretical arguments have proposed that extremely long, winding adaptive paths may be required to reach even local peaks a "maze-like" landscape topography. The extent to which peaks and mazes shape the mode and tempo of evolution is poorly understood due to empirical limitations and the abstractness of many landscape models. We explore the prevalence, scale and evolutionary consequences of landscape mazes in a biophysically-grounded computational model of protein evolution that captures the frustration between stability and aggregation propensity. Our stability-aggregation landscape exhibits extensive sign epistasis and local peaks galore. Although this frequently obstructs adaptive ascent to high fitness and virtually eliminates reproducibility of evolutionary outcomes, many adaptive paths do successfully complete the ascent from low to high fitness, with hydrophobicity a critical mediator of success. These successful paths exhibit maze-like properties on a global landscape scale, in which taking an indirect path helps to avoid low-fitness local peaks. This delicate balance of "hard but possible" adaptation could occur more broadly in other biological settings where competing interactions and frustration are important. Copyright © 2020, Genetics.In Parkinson's disease (PD), pathologically high levels of beta activity (12-30 Hz) reflect specific symptomatology and normalize with pharmacological or surgical intervention. Although beta characterization in the subthalamic nucleus (STN) of PD patients undergoing deep brain stimulation (DBS) has now been translated into adaptive DBS paradigms, limited number of studies have characterized beta power in the globus pallidus internus (GPi), an equally effective DBS target. Our objective was to compare beta power in the STN and GPi during rest and movement in people with PD undergoing DBS. 37 human male and female participants completed a simple behavioral experiment - consisting of periods of rest and button presses - leading to LFP recordings from 19 (15 participants) STN and 26 (22 participants) GPi nuclei. We examined overall beta power as well as beta time-domain dynamics (i.e., beta bursts). We found higher beta power during rest and movement in the GPi, which also had more beta desynchronization during mWe found that beta dynamics differed across basal ganglia nuclei. Our results show that relative to the STN, beta in the GPi may be readily detected, modulates more with movement, and relates more to clinical impairment. Taken together, this could point to the GPi as a potentially effective target for beta-based adaptive DBS. Copyright © 2020 the authors.BACKGROUND Response criteria developed when cytotoxic chemotherapy was the predominant therapeutic modality to treat patients with cancer, do not capture the full spectrum of tumor response patterns observed with anti-PD-1/PD-L1 antibody treatment. iRECIST was developed to capture both typical and atypical response patterns. METHODS Target, non-target, and new lesion measurements for 7920 patients receiving anti-PD-1/PD-L1 antibody (n=4751) or anti-CTLA-4 antibody (n=613) or undergoing chemotherapy (n=2556) from 14 randomized controlled trials submitted to the U.S. Food and Drug Administration were used to calculate the best overall response, objective response rate and progression-free survival (PFS) per iRECIST (iPFS) and Response Evaluation Criteria in Solid Tumours (RECIST). Associations between either PFS or iPFS and overall survival (OS) were evaluated using the method adopted by Oba et al.1 RESULTS Among 4751 anti-PD-1/PD-L1-antibody treated patients, 31.5% (95% CI 30.2% to 32.9%) and 30.5% (95% CI 29.oying iRECIST will be required to assess whether this response criteria more fully captures the benefit of immune checkpoint inhibitors. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Ubiquitin (UB) transfer cascades consisting of E1, E2, and E3 enzymes constitute a complex network that regulates a myriad of biologic processes by modifying protein substrates. Deubiquitinating enzymes (DUBs) reverse UB modifications or trim UB chains of diverse linkages. Additionally, many cellular proteins carry UB-binding domains (UBDs) that translate the signals encoded in UB chains to target proteins for degradation by proteasomes or in autophagosomes, as well as affect nonproteolytic outcomes such as kinase activation, DNA repair, and transcriptional regulation. Dysregulation of the UB transfer pathways and malfunctions of DUBs and UBDs play causative roles in the development of many diseases. selleckchem A greater understanding of the mechanism of UB chain assembly and the signals encoded in UB chains should aid in our understanding of disease pathogenesis and guide the development of novel therapeutics. The recent flourish of protein-engineering approaches such as unnatural amino acid incorporation, protein semisynthesis by expressed protein ligation, and high throughput selection by phage and yeast cell surface display has generated designer proteins as powerful tools to interrogate cell signaling mediated by protein ubiquitination.