Exercise Is a Vital Sign.

Description In this review, we argue that exercise (physical activity) be monitored as a vital sign since no other basic sign or symptom provides as much information about a patient's health status. The influence of regular exercise on patient health is indisputable, with strong evidence to show the power of exercise to mitigate chronic disease and improve overall health. Several simple tools, such as Physical Activity as a Vital Sign and Exercise as a Vital Sign are available to assess patient physical activity. When properly applied, there is evidence to support the efficacy of these tools, but there are barriers that prevent broad inclusion in primary care, among which are time and provider knowledge. In our review, we also discussed the value of physician-led lifestyle discussions with patients and found they view these discussions favorably. There is also evidence that physicians who exercise are more likely to have these lifestyle discussions with their patients, but the proportion of physicians who exercise regularly is fairly low. We believe physicians' awareness of their patients' sedentary lifestyles should prompt a prescription to increase physical activity, but additional in-clinic support and community resources need to be in place for patients to get a regular dose.

Texas field crickets (Gryllus texensis) use visual cues to place learn but perform poorly when intra- and extra-maze cues conflict.

Central place foraging field crickets are an ideal system for studying the adaptive value of learning and memory, but more research is needed on ecologically relevant cognition in these invertebrates. Here, we test the visuospatial place learning of Texas field crickets (Gryllus texensis) in a radial arm maze. Our study expands previous work on G. texensis cognition for accuracy measures and extends our previous findings on females to both sexes. Additionally, our study examines whether crickets use intra- or extra-maze cues to locate a food reward using a maze rotation that puts the cues in conflict. We found that male and female crickets improved performance over trials when measured by accuracy variables but not latency variables. Thigmotaxis negatively impacted performance in both sexes. In a reward-absent trial, both male and female crickets demonstrated place memory. When intra- and extra-maze cues conflicted during a rotation trial, crickets' performance was not better than chance. Our rotation results suggest that crickets may experience reciprocal overshadowing of conflicting cues - a result most often seen in other taxa with conflicting multi-modal cues. We conclude that crickets do not rely solely on: (1) a single-cue association, (2) route-following, or (3) their own scent cues to navigate the maze. Instead, male and female Texas field crickets seem to learn the location of the reward using a combination of proximal and distal cues. The possibility to test large numbers of wild-caught or laboratory-reared individuals opens the door to future investigations on the evolutionary ecology of visuospatial learning in these invertebrates.

Diverse Catalytic Reactions for the Stereoselective Synthesis of Cyclic Dinucleotide MK-1454.

As practitioners of organic chemistry strive to deliver efficient syntheses of the most complex natural products and drug candidates, further innovations in synthetic strategies are required to facilitate their efficient construction. These aspirational breakthroughs often go hand-in-hand with considerable reductions in cost and environmental impact. Enzyme-catalyzed reactions have become an impressive and necessary tool that offers benefits such as increased selectivity and waste limitation. These benefits are amplified when enzymatic processes are conducted in a cascade in combination with novel bond-forming strategies. In this article, we report a highly diastereoselective synthesis of MK-1454, a potent agonist of the stimulator of interferon gene (STING) signaling pathway. The synthesis begins with the asymmetric construction of two fluoride-bearing deoxynucleotides. The routes were designed for maximum convergency and selectivity, relying on the same benign electrophilic fluorinating reagent. From these complex subunits, four enzymes are used to construct the two bridging thiophosphates in a highly selective, high yielding cascade process. Critical to the success of this reaction was a thorough understanding of the role transition metals play in bond formation.

Development of a Robust Manufacturing Route for Molnupiravir, an Antiviral for the Treatment of COVID-19.

Herein is described the development of a large-scale manufacturing process for molnupiravir, an orally dosed antiviral that was recently demonstrated to be efficacious for the treatment of patients with COVID-19. The yield, robustness, and efficiency of each of the five steps were improved, ultimately culminating in a 1.6-fold improvement in overall yield and a dramatic increase in the overall throughput compared to the baseline process.

How general is cognitive ability in non-human animals? A meta-analytical and multi-level reanalysis approach.

General intelligence has been a topic of high interest for over a century. Traditionally, research on general intelligence was based on principal component analyses and other dimensionality reduction approaches. The advent of high-speed computing has provided alternative statistical tools that have been used to test predictions of human general intelligence. In comparison, research on general intelligence in non-human animals is in its infancy and still relies mostly on factor-analytical procedures. Here, we argue that dimensionality reduction, when incorrectly applied, can lead to spurious results and limit our understanding of ecological and evolutionary causes of variation in animal cognition. Using a meta-analytical approach, we show, based on 555 bivariate correlations, that the average correlation among cognitive abilities is low (r = 0.185; 95% CI: 0.087-0.287), suggesting relatively weak support for general intelligence in animals. We then use a case study with relatedness (genetic) data to demonstrate how analysing traits using mixed models, without dimensionality reduction, provides new insights into the structure of phenotypic variance among cognitive traits, and uncovers genetic associations that would be hidden otherwise. We hope this article will stimulate the use of alternative tools in the study of cognition and its evolution in animals.

Genetic decline, restoration and rescue of an isolated ungulate population.

Isolation of small populations is expected to reduce fitness through inbreeding and loss of genetic variation, impeding population growth and compromising population persistence. Species with long generation time are the least likely to be rescued by evolution alone. Management interventions that maintain or restore genetic variation to assure population viability are consequently of significant importance. We investigated, over 27 years, the genetic and demographic consequences of a demographic bottleneck followed by artificial supplementation in an isolated population of bighorn sheep (Ovis canadensis). Based on a long-term pedigree and individual monitoring, we documented the genetic decline, restoration and rescue of the population. Microsatellite analyses revealed that the demographic bottleneck reduced expected heterozygosity and allelic diversity by 6.2% and 11.3%, respectively, over two generations. Following supplementation, first-generation admixed lambs were 6.4% heavier at weaning and had 28.3% higher survival to 1 year compared to lambs of endemic ancestry. Expected heterozygosity and allelic diversity increased by 4.6% and 14.3% after two generations through new alleles contributed by translocated individuals. We found no evidence for outbreeding depression and did not see immediate evidence of swamping of local genes. Rapid intervention following the demographic bottleneck allowed the genetic restoration and rescue of this bighorn sheep population, likely preventing further losses at both the genetic and demographic levels. Our results provide further empirical evidence that translocation can be used to reduce inbreeding depression in nature and has the potential to mitigate the effect of human-driven environmental changes on wild populations.

Development of a stereoselective and scalable process for the preparation of a methylcyclobutanol-pyridyl ether.

The evolution of a scalable process for the preparation of methylcyclobutanol-pyridyl ether 1 is described. Key aspects of this development including careful control of the stereochemistry, elimination of chromatography, and application to kilogram-scale synthesis are addressed.

Discovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity.

Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.

Solution to the C3-Arylation of Indazoles: Development of a Scalable Method.

3-(Hetero)arylindazoles are important motifs in several biologically active compounds. Mild and flexible palladium-mediated Negishi reaction conditions are reported for the introduction of (hetero)aryl moieties at the 3-position of N(2)-SEM-protected indazoles in high yields. The requisite Zn-species are readily obtained via regioselective deprotonation and subsequent transmetalation. The methodology tolerates a variety of functional groups on both coupling partners and has been extended to bis-haloarene and heteroarene coupling partners where the most reactive halogen reacts first, leaving the second halogen for subsequent functionalization.

Development of a novel tricyclic class of potent and selective FIXa inhibitors.

Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.