Breaking the Cycle: How Nevada Can Effectuate Meaningful Criminal Justice Reform

Why does society punish criminals? This paper examines what Nevada is attempting to accomplish through enacting and enforcing its criminal laws. We examine the current state of, as well as the challenges facing, Nevada’s criminal justice system. Additionally, we identify and propose certain solutions to reduce both recidivism and the financial burden that incarceration imposes on the state by looking to best practices in other states, as well as certain mechanisms and provisions that were, for one reason or another, removed from Nevada Assembly Bill 236

Franks (Kenneth) v. State, 135 Nev. Adv. Op. 1 (Jan. 3, 2019)

The Court reviewed whether a district court’s decision to allow the State to introduce prior incidents of uncharged sexual acts as evidence of the defendant’s propensity for committing sexual offenses violated NRS 48.045(3) and concluded such evidence as long as it is first evaluated for relevance and its heightened risk of unfair prejudice

Baiguen v. Harrah’s Las Vegas, LLC, 134 Nev., Adv. Op. 71 (Sept. 13, 2018) (en banc)

The Court determined that (1) an employee’s injuries that originate before entering the workplace but are aggravated due to an employer’s failure to provide timely medical assistance arise out of and in the course of employment; and (2) that employees’ recovery against their employers for such injuries are confined to the exclusive remedies for workers’ compensation under the Nevada Industrial Insurance Act (NIIA)

Star formation triggered by non-head-on cloud-cloud collisions, and clouds with pre-collision sub-structure

In an earlier paper, we used smoothed particle hydrodynamics (SPH) simulations to explore star formation triggered by head-on collisions between uniform-density 500 M clouds, and showed that there is a critical collision velocity, vCRIT. At collision velocities below vCRIT, a hub-and-spoke mode operates and delivers a monolithic cluster with a broad mass function, including massive stars (M 10 M) formed by competitive accretion. At collision velocities above vCRIT, a spider’s-web mode operates and delivers a loose distribution of small sub-clusters with a relatively narrow mass function and no massive stars. Here we show that,if the head-on assumption is relaxed, vCRIT is reduced. However, if the uniform-density assumption is also relaxed, the collision velocity becomes somewhat less critical: a low collision velocity is still needed to produce a global hub-and-spoke system and a monolithic cluster, but, even at high velocities, large cores – capable of supporting competitive accretion and thereby producing massive stars – can be produced. We conclude that cloud–cloud collisions may be a viable mechanism for forming massive stars – and we show that this might even be the major channel for forming massive stars in the Galaxy

Social, Environmental, and Racial/Ethnic Factors in Diabetes Prevalence in the U.S.

PURPOSE: The purpose of this study was to determine the extent to which socioeconomic status, race/ ethnicity, and disparities in neighborhood environmental factors affect diabetes prevalence among U.S. adults. METHODS: County-level data were collected from the 1000 U.S. counties with the highest diabetes incidence and the 1000 U.S. counties with the lowest diabetes incidence using the 2014 USDA Food Environmental Atlas. The dependent measure was diabetes prevalence. Independent measures were median household income, percentage of people with no car, percentage of population that was black, white, or Hispanic, and the number of fitness centers, fast food restaurants, farmer’s markets, and grocery stores. Stepwise multiple linear regression was used to assess the relationship of these independent variables to diabetes incidence. RESULTS: Of the nine independent measures evaluated, seven explained a significant amount of the variance in diabetes prevalence (Table 1). Median household income accounted for the largest proportion of variance (38%) with the non-white population percentages collectively accounting for an additional 19%. The specific indicators of commercial entities accounted for small (≤1%) but significant proportions of variance. CONCLUSION: The results of this study indicate socioeconomic and racial/ethnic factors account for the majority of variance in prevalence of diabetes in the U.S. However, not only availability but access to healthy foods and lifestyle choices also seem to play a role in the magnitude of the incidence of diabetes. There is an apparent need for local and federal programs to focus on these high-risk areas of concentrated poverty and minority populations in order to educate communities, increase social support, and improve access to factors related to developing healthy lifestyles

A Leucine-enriched Diet Enhances Overload-induced Growth and Suppresses Markers of Protein Degradation in Aged Rat Skeletal Muscle

Introduction: The hypertrophic response to overload in fast-twitch skeletal muscle is impaired in aged humans and rats, and upregulation of protein degradation pathways are hypothesized to be a contributing factor. Muscle growth occurs when protein synthesis is greater than protein degradation. Dietary supplementation of the essential amino acid leucine has been shown to reduce protein degradation in both young and aged skeletal muscle. Specifically, leucine acts in part by attenuating 5\u27-AMP-activated protein kinase (AMPK) activation as well as the translocation of the forkhead box transcription factor 3A (FoxO3, known to promote transcription of mRNAs encoding degradation pathway proteins) to the nucleus. Akt (a promoter of muscle growth) prevents translocation of FoxO3 into the nucleus by phosphorylating FoxO3 phosphorylation at Ser318/321. However, AMPK, inhibits Akt\u27s phosphorylation of FoxO3, allowing it to enter the nucleus and increase transcription of protein degradation pathway genes encoding ubiquitin ligase proteins such as muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx, or Atrogin-1). During the aging process, AMPK Thr172 phosphorylation (and thus its activation) is increased, purportedly inhibiting gains in muscle mass and strength. Although dietary leucine supplementation has been shown to enhance strength gians in response to resistance training in young humans, the potential for leucine supplementation to enhance overload-induced muscle hypertrophy in aged humans or animal models has not been examined. Thus, the aim of this study was to determine whether dietary leucine supplementation can attenuate markers of protein degradation and rescue hypertrophy during overload in the fast-twitch skeletal muscles of aged rats to levels comparable to their younger counterparts. It was hypothesized that dietary leucine supplementation during 7 days of fast-twitch plantaris muscle overload would enhance plantaris muscle hypertrophy in aged rats to levels observed in young adult rats not receiving leucine. It was also hypothesized that dietary leucine supplementation during the overload period would alter markers of protein degradation (enhance FoxO3 phosphorylation and reduce the levels of AMPK phosphorylation, Atrogin-1 protein content, and MuRF1 protein content) in the overloaded fast-twitch plantaris muscles of the aged rats to levels observed in young adult rats not receiving leucine. Methods: Young adult (8 mo.) and old (33 mo.) male Fisher 344 x Brown Norway F1 Hybrid (FBN) rats underwent a 1-week unilateral overload of the fast-twitch plantaris muscles via tenotomy of the synergistic gastrocnemius muscle. Within each age group, animals were matched for body weight and separated into either a dietary leucine supplementation group (normal rat chow supplemented by an additional 5% leucine content in place of 5% of the carbohydrate content; n = 7/age group) or placebo group (normal rat chow; n = 6/age group). The leucine groups started the leucine-enriched diet 2 days prior to, and throughout, the overload intervention. All animals had ad libitum access to water and chow during the entire experiment; no differences in daily calorie consumption were observed between the placebo vs. leucine groups within each age group. At the end of the overload period, sham-operated and overloaded plantaris muscles were harvested and analyzed via western blotting for the phosphorylations of AMPK and FoxO3 as well as total levels of Atrogin-1 and MuRF1. A 2x2x2 ANOVA with repeated measures was used for analyses of the effects of age, dietary intervention, and overload (the repeated measure) on muscle hypertrophy. A 2x2 ANOVA was used to measure the percent changes in hypertrophy and western blot analyses. Post-hoc comparisons were accomplished via a Fisher\u27s Least Significant Difference test, with statistical significance being set at p ≤ 0.05. Results: Dietary leucine enrichment significantly (p ≤ 0.05) enhanced overload-induced fast-twitch plantaris muscle hypertrophy in old, but not in young adult, animals. A similar effect was also observed in the slow-twitch soleus muscles, but western blotting analyses are only presented for the fast-twitch plantaris muscles. Sham and overloaded plantaris muscle AMPK phosphorylation was significantly higher in aged animals receiving normal chow compared to young adult animals; however, leucine supplementation in old animals reduced this AMPK phosphorylation to levels similar to young adult animals. Compared to placebo, leucine also non-significantly (p = 0.07) enhanced FoxO3 phosphorylation in the overloaded muscles of both young adult and old animals (thus theoretically reducing FoxO3 translocation to the nucleus). Accordingly, leucine also non-significantly (p = 0.07) reversed the overload-induced increase (from a 22.8% increase to a 17.0% decrease) in Atrogin-1 content in aged muscles and non-significantly (p = 0.14) enhanced the overload-induced decrease in MuRF1 content in the muscles of both age groups. Discussion: These novel findings indicate that a leucine-enriched diet may potentially enhance overload-induced growth of aged fast-twitch muscle, in part by suppressing pathways known to stimulate protein degradation. This is in accord with previous findings of leucine’s suppressive effect on protein degradation in both young adult and aged skeletal muscle under resting conditions. The fact that leucine supplementation enhanced overload-induced hypertrophy only in the old (and not the young) animals may reflect the high growth stimulus of the chronic overload model. That is, the balance of protein synthesis/degradation rates under such a large chronic growth stimulus may not be the limiting factor in young animals, in which muscle growth is not impaired (i.e., synthesis/degradation rates may reach futile levels, and another factor such as sarcomere assembly may be limiting). However, the impaired balance of protein synthesis/degradation rates may be the limiting factor to growth in aged muscle, and leucine may correct this imbalance to restore muscle growth to levels observed in young animals

A Leucine-enriched Diet Enhances Overload-induced Growth and Markers of Protein Synthesis in Aged Rat Skeletal Muscle

Introduction: The hypertrophic response to overload in fast-twitch skeletal muscle is impaired in aged humans and rats, and impaired protein synthesis pathway activation is hypothesized to be a contributing factor. Muscle growth occurs when protein synthesis exceeds protein degradation. Dietary supplementation of the essential amino acid leucine has been shown to enhance protein synthesis in both young and aged skeletal muscle. Leucine acts in part by activating mammalian target of rapamycin (mTOR; a key upstream regulator of protein synthesis pathways) as well as by attenuating the activation of 5\u27-AMP-activated protein kinase (AMPK; a negative regulator of mTOR and protein synthesis). During the aging process, AMPK Thr172 phosphorylation (and thus its activation) is increased, purportedly inhibiting gains in muscle mass and strength. Although dietary leucine supplementation has been shown to enhance strength gains in response to resistance training in young humans, the potential for leucine supplementation to enhance overload-induced muscle hypertrophy in aged humans or animal models has not been examined. Thus, the aim of this study was to determine whether dietary leucine supplementation can enhance markers of protein synthesis and rescue hypertrophy in overloaded fast-twitch skeletal muscles of aged rats to levels comparable to their younger counterparts. It was hypothesized that dietary leucine supplementation during 7 days of fast-twitch plantaris muscle overload would enhance plantaris muscle hypertrophy in aged rats to levels observed in young adult rats not receiving leucine. It was also hypothesized that dietary leucine supplementation during the overload period would suppress AMPK phosphorylation and enhance markers of protein synthesis [70 kDa ribosomal protein S6 kinase (p70S6k), ribosomal protein S6 (rpS6), and eukaryotic elongation factor 2 (eEF2)] in the overloaded fast-twitch plantaris muscles of the aged rats to levels observed in young adult rats not receiving leucine. Methods: Young adult (8 mo.) and old (33 mo.) male Fisher 344 x Brown Norway F1 Hybrid (FBN) rats underwent a 1-week unilateral overload of the fast-twitch plantaris muscles via tenotomy of the synergistic gastrocnemius muscle. Within each age group, animals were matched for body weight and separated into either a dietary leucine supplementation group (normal rat chow supplemented by an additional 5% leucine content in place of 5% of the carbohydrate content; n = 7/age group) or placebo group (normal rat chow; n = 6/age group). The leucine groups started the leucine-enriched diet 2 days prior to, and throughout, the overload intervention. All animals had ad libitum access to water and chow during the entire experiment; no differences in daily calorie consumption were observed between the placebo vs. leucine groups within each age group. At the end of the overload period, sham-operated and overloaded plantaris muscles were harvested and analyzed via western blotting for the phosphorylations of AMPK, p70S6k, rpS6, and eEF2. A 2x2x2 ANOVA with repeated measures was used for analyses of the effects of age, dietary intervention, and overload (the repeated measure) on muscle hypertrophy. A 2x2 ANOVA was used to measure the percent changes in hypertrophy and western blot analyses. Post-hoc comparisons were accomplished via a Fisher\u27s Least Significant Difference test, with statistical significance being set at p ≤ 0.05. Results: Dietary leucine enrichment significantly (p ≤ 0.05) enhanced overload-induced fast-twitch plantaris muscle hypertrophy in old, but not in young adult, animals. A similar effect was also observed in the slow-twitch soleus muscles, but western blotting analyses are only presented for the fast-twitch plantaris muscles. Sham and overloaded plantaris muscle AMPK phosphorylation (Thr172) was significantly higher in aged animals receiving normal chow compared to young adult animals; however, leucine supplementation in old animals reduced this AMPK phosphorylation to levels similar to young adult animals. Phospho-p70S6k (Thr389) and phospho-rpS6 (Ser235/Ser236) were significantly lower in old vs. young overloaded muscles under placebo conditions, but leucine partially restored both p70S6k and rpS6 phosphorylations in old overloaded muscles to that of young adult overloaded muscles. Overload significantly increased total eEF2 content and decreased inhibitory eEF2 phosphorylation (Thr56; normalized to total eEF2) in young adult muscles regardless of leucine supplementation. Total eEF2 content was unaffected by overload in old placebo muscles, but leucine supplementation in old animals non-significantly (p = 0.09) restored the overload-induced increase in total eEF2 content. Muscle eEF2 phosphorylation was unaffected by overload or leucine supplementation in old animals. Discussion: These novel findings indicate that a leucine-enriched diet may potentially enhance overload-induced growth of aged fast-twitch muscle, in part by enhancing pathways known to stimulate protein synthesis. This is in accord with previous findings of leucine’s stimulating effect on protein synthesis in both young adult and aged skeletal muscle under resting conditions. The fact that leucine supplementation enhanced overload-induced hypertrophy only in the old (and not the young) animals may reflect the high growth stimulus of the chronic overload model. That is, the balance of protein synthesis/degradation rates under such a large chronic growth stimulus may not be the limiting factor in young animals, in which muscle growth is not impaired (i.e., synthesis/degradation rates may reach futile levels, and another factor such as sarcomere assembly may be limiting). However, the impaired balance of protein synthesis/degradation rates may be the limiting factor to growth in aged muscle, and leucine may correct this imbalance to restore muscle growth to levels observed in young animals

SPR-measured dissociation kinetics of PROTAC ternary complexes influence target degradation rate

Bifunctional degrader molecules, known as proteolysis-targeting chimeras (PROTACs), function by recruiting a target to an E3 ligase, forming a target/PROTAC/ligase ternary complex. Despite the importance of this key intermediate species, no detailed validation of a method to directly determine binding parameters for ternary complex kinetics has been reported, and it remains to be addressed whether tuning the kinetics of PROTAC ternary complexes may be an effective strategy to improve the efficiency of targeted protein degradation. Here, we develop an SPR-based assay to quantify the stability of PROTAC-induced ternary complexes by measuring for the first time the kinetics of their formation and dissociation <i>in vitro</i> using purified proteins. We benchmark our assay using four PROTACs that target the bromodomains (BDs) of bromodomain and extraterminal domain proteins Brd2, Brd3, and Brd4 to the von Hippel–Lindau E3 ligase (VHL). We reveal marked differences in ternary complex off-rates for different PROTACs that exhibit either positive or negative cooperativity for ternary complex formation relative to binary binding. The positively cooperative degrader MZ1 forms comparatively stable and long-lived ternary complexes with either Brd4^BD2 or Brd2^BD2 and VHL. Equivalent complexes with Brd3^BD2 are destabilized due to a single amino acid difference (Glu/Gly swap) present in the bromodomain. We observe that this difference in ternary complex dissociative half-life correlates to a greater initial rate of intracellular degradation of Brd2 and Brd4 relative to Brd3. These findings establish a novel assay to measure the kinetics of PROTAC ternary complexes and elucidate the important kinetic parameters that drive effective target degradation

Early antenatal prediction of gestational diabetes in obese women: development of prediction tools for targeted intervention

All obese women are categorised as being of equally high risk of gestational diabetes (GDM) whereas the majority do not develop the disorder. Lifestyle and pharmacological interventions in unselected obese pregnant women have been unsuccessful in preventing GDM. Our aim was to develop a prediction tool for early identification of obese women at high risk of GDM to facilitate targeted interventions in those most likely to benefit. Clinical and anthropometric data and non-fasting blood samples were obtained at 15+0–18+6 weeks’ gestation in 1303 obese pregnant women from UPBEAT, a randomised controlled trial of a behavioural intervention. Twenty one candidate biomarkers associated with insulin resistance, and a targeted nuclear magnetic resonance (NMR) metabolome were measured. Prediction models were constructed using stepwise logistic regression. Twenty six percent of women (n = 337) developed GDM (International Association of Diabetes and Pregnancy Study Groups criteria). A model based on clinical and anthropometric variables (age, previous GDM, family history of type 2 diabetes, systolic blood pressure, sum of skinfold thicknesses, waist:height and neck:thigh ratios) provided an area under the curve of 0.71 (95%CI 0.68–0.74). This increased to 0.77 (95%CI 0.73–0.80) with addition of candidate biomarkers (random glucose, haemoglobin A1c (HbA1c), fructosamine, adiponectin, sex hormone binding globulin, triglycerides), but was not improved by addition of NMR metabolites (0.77; 95%CI 0.74–0.81). Clinically translatable models for GDM prediction including readily measurable variables e.g. mid-arm circumference, age, systolic blood pressure, HbA1c and adiponectin are described. Using a ≥35% risk threshold, all models identified a group of high risk obese women of whom approximately 50% (positive predictive value) later developed GDM, with a negative predictive value of 80%. Tools for early pregnancy identification of obese women at risk of GDM are described which could enable targeted interventions for GDM prevention in women who will benefit the most

Is the molecular KS relationship universal down to low metallicities?

Funding: . RJS gratefully acknowledges an STFC Ernest Rutherford fellowship (grant ST/N00485X/1). SCOG, RT, MCS, and RSK acknowledge funding from the European Research Council via the ERC Synergy Grant ‘ECOGAL – Understanding our Galactic ecosystem: From the disc of the Milky Way to the formation sites of stars and planets (project ID 855130).In recent years, it has been speculated that in extreme low-metallicity galactic environments, stars form in regions that lack H2. In this paper, we investigate how changing the metallicity and ultraviolet (UV) field strength of a galaxy affects the star formation within, and the molecular gas Kennicutt–Schmidt (KS) relation. Using extremely high-resolution AREPO simulations of isolated dwarf galaxies, we independently vary the metallicity and UV field to between 1 per cent and 10 per cent solar neighbourhood values. We include a non-equilibrium, time-dependent chemical network to model the molecular composition of the interstellar medium and include the effects of gas shielding from an ambient UV field. Crucially, our simulations directly model the gravitational collapse of gas into star-forming clumps and cores and their subsequent accretion using sink particles. In this first publication, we find that reducing the metallicity and UV field by a factor of 10 has no effect on star formation and minimal effect on the cold, dense star-forming gas. The cold gas depletion times are almost an order of magnitude longer than the molecular gas depletion time due to the presence of star formation in H I dominated cold gas. We study the H2 KS relationship that arises naturally within the simulations and find a near-linear power-law index of N = 1.09 ± 0.014 in our fiducial 10 per cent solar metallicity model. As the metallicity and UV field are reduced, this becomes moderately steeper, with a slope of N = 1.24 ± 0.022 for our 1 per cent solar metallicity and 1 per cent solar UV field model.Peer reviewe