Highly Mutable Linker Regions Regulate HIV-1 Rev Function and Stability.

HIV-1 Rev is an essential viral regulatory protein that facilitates the nuclear export of intron-containing viral mRNAs. It is organized into structured, functionally well-characterized motifs joined by less understood linker regions. Our recent competitive deep mutational scanning study confirmed many known constraints in Rev's established motifs, but also identified positions of mutational plasticity, most notably in surrounding linker regions. Here, we probe the mutational limits of these linkers by testing the activities of multiple truncation and mass substitution mutations. We find that these regions possess previously unknown structural, functional or regulatory roles, not apparent from systematic point mutational approaches. Specifically, the N- and C-termini of Rev contribute to protein stability; mutations in a turn that connects the two main helices of Rev have different effects in different contexts; and a linker region which connects the second helix of Rev to its nuclear export sequence has structural requirements for function. Thus, Rev function extends beyond its characterized motifs, and is tuned by determinants within seemingly plastic portions of its sequence. Additionally, Rev's ability to tolerate many of these massive truncations and substitutions illustrates the overall mutational and functional robustness inherent in this viral protein

Technische Universität Braunschweig - Skripten der Mathematischen Institute

Reflecting ongoing changes in the structure and regulation of modern business practice, Business Organizations: Cases, Problems, and Case Studies, Fourth Edition offers a unique combination of doctrine, problems, and case studies. Recent, high-interest cases are balanced against classic teaching chestnuts. Brief, innovative problems are used in combination with longer case studies. Recent Delaware Supreme Court decisions, updated case studies, and a strong website support a clear and sustained examination of the role and purview of the law in business transactions. New to the Fourth Edition: Recent Delaware Supreme Court and Chancery Court cases, including eBay v. Newmark; DFC Global v. Muirfield Value Partners; In re: Trulia; Kahn v. M&F Worldwide (MFW); Corwin v. KKR; and new parent/subsidiary vicarious liability cases New textual coverage of developing trends such as shareholder activism, exploding deal litigation and judicial efforts to reign it in, hedge fund appraisal arbitrage, and Public Benefit Companies Revised Uniform Partnership Act materials, as updated through 2013 Updated case studies and problems that consistently reinforce topical coveragehttps://digitalcommons.osgoode.yorku.ca/faculty_books/1383/thumbnail.jp

Tribal Relationships in the Gesneriaceae: Evidence from DNA Sequences of the Chloroplast Gene \u3cem\u3endh\u3c/em\u3eF

The tribal relationships of the Gesneriaceae are investigated using ndhF sequences. A full analysis of 70 taxa including 16 species from the Scrophulariaceae, Bigoniaceae, and Acanthaceae as outgroups, resulted in two most-parsimonious trees of 5610 steps each. In all trees the Gesneriaceae were a monophyletic group and Paulownia was the closest single-species outgroup for the analysis. Further analyses eliminated all but the members of the Gesneriaceae and Paulownia in order to better asses relationships within the family. The smaller analysis resulted in a single most-parsimonious tree of 4613 steps. The Klugieae are identified as the sister to the remainder of the family and could potentially be separated as a distinct subfamily. The subfamilies Cyrtandroideae (excluding Klugieae) and Gesnerioideae are monophyletic. The placement of Coronallthereae in Cyrtandroideae does not have support from this analysis, whereas its placement in Gesnerioideae is supported. Alternatively Coronanthereae could be segregated as a seperate subfamily but in order to avoid a paraphyletic Gesnerioideae would either include the Napeantheae and Beslerieae or elevate these two tribes to an additional subfamily. Within Gesnerioideae the genus Sinningia is removed from the tribe Gloxinieae into the Sinningieae, which also contains the recently combined species Sinningia brasiliensis (Lietzia), as well as Paliavana and Vanhouttea. The Episcieae, Gesnerieae, Napeantheae, and Beslerieae are identified as monophyletic groups, as are the remainder of the Gloxineae with Sinningia sensu lato removed. Within Cyrtandroideae, several well-supported, monophyletic lineages within the large, heterogeneous tribe Didymocarpeae are identified, and with the current data the tribe Trichosporeae appears to be polyphyletic. The distribution of chromosome numbers, nodal anatomy, placental structure, and stem modification are examined based on these molecular trees

Biochemical pathways represented by Gene Ontology-Causal Activity Models identify distinct phenotypes resulting from mutations in pathways.

Gene inactivation can affect the process(es) in which that gene acts and causally downstream ones, yielding diverse mutant phenotypes. Identifying the genetic pathways resulting in a given phenotype helps us understand how individual genes interact in a functional network. Computable representations of biological pathways include detailed process descriptions in the Reactome Knowledgebase and causal activity flows between molecular functions in Gene Ontology-Causal Activity Models (GO-CAMs). A computational process has been developed to convert Reactome pathways to GO-CAMs. Laboratory mice are widely used models of normal and pathological human processes. We have converted human Reactome GO-CAMs to orthologous mouse GO-CAMs, as a resource to transfer pathway knowledge between humans and model organisms. These mouse GO-CAMs allowed us to define sets of genes that function in a causally connected way. To demonstrate that individual variant genes from connected pathways result in similar but distinguishable phenotypes, we used the genes in our pathway models to cross-query mouse phenotype annotations in the Mouse Genome Database (MGD). Using GO-CAM representations of 2 related but distinct pathways, gluconeogenesis and glycolysis, we show that individual causal paths in gene networks give rise to discrete phenotypic outcomes resulting from perturbations of glycolytic and gluconeogenic genes. The accurate and detailed descriptions of gene interactions recovered in this analysis of well-studied processes suggest that this strategy can be applied to less well-understood processes in less well-studied model systems to predict phenotypic outcomes of novel gene variants and to identify potential gene targets in altered processes

Feasibility of a “Network of Champions” in Implementing a Program to Address Physician Well-being

Introduction: Healthcare leaders have been challenged to mitigate burnout and foster well-being among physicians. Professional societies are beginning to address this in a systematic manner. Methods: In 2014, the American College of Physicians (ACP) endeavored to improve well-being for its 160,000 members of internists and trainees through a Well-being Champion (WBC) program based in the majority of its 85 national and international chapters. The program was supported by an evidence-based curriculum, chapter volunteers who served as champions, and in-person and virtual trainings. Training included a 1-2 day program in 2018 and 2019, focused on educating champions on causes of burnout, means of systematically collecting well-being data, and methods for using data for system change to reduce burnout and improve well-being. Results: Training included 158 WBCs in 8 countries. After training, over 90% of champions in both years of the program felt able to articulate the evidence for burnout prevention and suggest interventions, access resources, and administer well-being surveys. While 58% of champions noted high interest in wellness, only 26% had a budget allocated for this, and most budgets were small. Ninety-one percent in both years felt able to analyze survey data and 90% in both years felt able to enhance their own well-being. Eighty-eight to 90% felt able to foster a well-being community and importantly, 85% felt comfortable engaging leadership in this topic. Since 2017, 639 activities were recorded, accounting for 87/158 Champions in 69 Chapters. Annual direct costs varied each year but remained Conclusion: This report describes a model for building regional networks to address physician burnout while promoting well-being and professional fulfillment. After training, champions felt capable of performing key aspects of burnout reduction, including survey administration, data analysis and engaging leadership in systems change. To our knowledge, this is the first model to scale burnout prevention throughout an entire professional society. Using the included program descriptions and curricula, this program may be generalizable for other large professional groups wishing to measure and enhance well-being among their membership

Preliminary evidence of neuropathology in nonhuman primates prenatally exposed to maternal immune activation

Maternal infection during pregnancy increases the risk for neurodevelopmental disorders in offspring. Rodent models have played a critical role in establishing maternal immune activation (MIA) as a causal factor for altered brain and behavioral development in offspring. We recently extended these findings to a species more closely related to humans by demonstrating that rhesus monkeys (Macaca mulatta) prenatally exposed to MIA also develop abnormal behaviors. Here, for the first time, we present initial evidence of underlying brain pathology in this novel nonhuman primate MIA model. Pregnant rhesus monkeys were injected with a modified form of the viral mimic polyI:C (poly ICLC) or saline at the end of the first trimester. Brain tissue was collected from the offspring at 3.5 years and blocks of dorsolateral prefrontal cortex (BA46) were used to analyze neuronal dendritic morphology and spine density using the Golgi-Cox impregnation method. For each case, 10 layer III pyramidal cells were traced in their entirety, including all apical, oblique and basal dendrites, and their spines. We further analyzed somal size and apical dendrite trunk morphology in 30 cells per case over a 30 μm section located 100 ± 10 μm from the soma. Compared to controls, apical dendrites of MIA-treated offspring were smaller in diameter and exhibited a greater number of oblique dendrites. These data provide the first evidence that prenatal exposure to MIA alters dendritic morphology in a nonhuman primate MIA model, which may have profound implications for revealing the underlying neuropathology of neurodevelopmental disorders related to maternal infection