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Background: Despite the limitations the carceral environment may impose on mental wellness, mental healthcare is increasingly becoming a carceral endeavor. Over the course of the last several decades, prisons and jails have become the de facto mental healthcare provider for thousands of incarcerated individuals. Furthermore, practices like mandated mental healthcare for supervised individuals further broaden the population experiencing mental healthcare within the criminal legal system at large. This study examines the perspectives of nine individuals who experienced mental healthcare within the carceral state, whether in prison or on parole or probation, with a special focus on how attributes of the carceral state create ideological and functional barriers to effective mental healthcare., Methods: Data for the parent study of this analysis was collected via in-depth, one-on-one interviews of about one hour's length, conducted at six-month intervals over the course of 2 years. These interviews were analyzed using an iterative process of open-coding, thematic code development, and code application to participant interviews., Results: The results showed a common perception of mental healthcare received within the carceral state as serving goals of the prison system, including control and punishment, rather than therapeutic goals of healing and empowerment. This often had negative implications for the quality of the treatment received, including patterns of diagnostic ambiguity, treatment that was ill-fitting to participants' needs, and treatment that was undermined by the new trauma created by the prison environment. The results also highlighted racial disparities prevalent within the carceral system. Despite the barriers created by the subjection of therapeutic practices to carceral goals, participants demonstrated resourcefulness and creativity in engaging with these treatment modalities to reap benefits where possible., Conclusions: Overall, these results highlight the inappropriateness of combining therapeutic and carceral spaces, the need for greater public attention to how carceral mechanisms disadvantage vulnerable populations, and the need for a cultural reconceptualization of mental illness such that it is met not with criminal punishment but appropriate care., (© 2022. The Author(s).)

Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.

Background: Consumption of almonds or dark chocolate and cocoa has favorable effects on markers of coronary heart disease; however, the combined effects have not been evaluated in a well-controlled feeding study. The aim of this study was to examine the individual and combined effects of consumption of dark chocolate and cocoa and almonds on markers of coronary heart disease risk., Methods and Results: A randomized controlled, 4-period, crossover, feeding trial was conducted in overweight and obese individuals aged 30 to 70 years. Forty-eight participants were randomized, and 31 participants completed the entire study. Each diet period was 4 weeks long, followed by a 2-week compliance break. Participants consumed each of 4 isocaloric, weight maintenance diets: (1) no treatment foods (average American diet), (2) 42.5 g/d of almonds (almond diet [ALD]), (3) 18 g/d of cocoa powder and 43 g/d of dark chocolate (chocolate diet [CHOC]), or (4) all 3 foods (CHOC+ALD). Compared with the average American diet, total cholesterol, non-high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol after the ALD were lower by 4%, 5%, and 7%, respectively ( P <0.05). The CHOC+ALD decreased apolipoprotein B by 5% compared with the average American diet. For low-density lipoprotein subclasses, compared with the average American diet, the ALD showed a greater reduction in large buoyant low-density lipoprotein particles (-5.7±2.3 versus -0.3±2.3 mg/dL; P =0.04), whereas the CHOC+ALD had a greater decrease in small dense low-density lipoprotein particles (-12.0±2.8 versus -5.3±2.8 mg/dL; P =0.04). There were no significant differences between diets for measures of vascular health and oxidative stress., Conclusions: Our results demonstrate that consumption of almonds alone or combined with dark chocolate under controlled-feeding conditions improves lipid profiles. Incorporating almonds, dark chocolate, and cocoa into a typical American diet without exceeding energy needs may reduce the risk of coronary heart disease., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01882881., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Optimization of KDM6B (JMJD3) HTS hit 12 led to the identification of 3-((furan-2-ylmethyl)amino)pyridine-4-carboxylic acid 34 and 3-(((3-methylthiophen-2-yl)methyl)amino)pyridine-4-carboxylic acid 39 that are inhibitors of the KDM4 (JMJD2) family of histone lysine demethylases. Compounds 34 and 39 possess activity, IC50 ≤ 100 nM, in KDM4 family biochemical (RFMS) assays with ≥ 50-fold selectivity against KDM6B and activity in a mechanistic KDM4C cell imaging assay (IC50 = 6-8 μM). Compounds 34 and 39 are also potent inhibitors of KDM5C (JARID1C) (RFMS IC50 = 100-125 nM).

Following the discovery of cell penetrant pyridine-4-carboxylate inhibitors of the KDM4 (JMJD2) and KDM5 (JARID1) families of histone lysine demethylases (e.g., 1), further optimization led to the identification of non-carboxylate inhibitors derived from pyrido[3,4-d]pyrimidin-4(3H)-one. A number of exemplars such as compound 41 possess interesting activity profiles in KDM4C and KDM5C biochemical and target-specific, cellular mechanistic assays.

Background: The present study aimed to explore facilitators and barriers to weight loss (WL) and weight loss maintenance (WLM) in women who participated in a primary, 18-week comparative trial that promoted WL with an energy-restricted diet., Methods: Twenty-three women participated in seven focus groups conducted by a moderator and co-facilitator using open-ended questions and probes. Focus groups were held in a private room and audio tape-recorded. Tapes were transcribed verbatim and thematic analysis was used to evaluate transcripts for common themes., Results: Accountability to others, social support, planning ahead, awareness and mindfulness of food choices, basic nutrition education, portion control, exercise, and self-motivation were perceived as key facilitators for WL and WLM by women. Identified barriers included life transitions, health status changes, internal factors, environmental pressures, lack of accountability and an absence of social support., Conclusions: Future interventions should address these salient facilitators and barriers to promote sustainable changes in women across their WL and WLM journeys., (© 2014 Authors. Journal of Human Nutrition and Dietetics published by John Wiley & Sons Ltd on behalf of British Dietetic Association.)

Background/objectives: The type of sweet snack incorporated into an energy-restricted diet (ERD) may produce differential effects on metabolic improvements associated with body weight (BW) loss. This study compared effects of incorporating either twice daily energy-controlled dark chocolate snacks plus once daily sugar-free cocoa beverage (DC) to non-chocolate snacks plus sugar-free non-cocoa beverage (NC) into an ERD on BW loss and metabolic outcomes., Materials/methods: In an 18-week randomized comparative trial, 60 overweight/obese premenopausal women were assigned to DC (n = 30) or NC group (n = 30). Dietary intake was measured at baseline and week 18, and BW, anthropometrics, blood pressure (BP) and serum glucose, insulin and lipid concentrations were measured at baseline, and weeks 6, 12 and 18. Data were analyzed using repeated measures ANOVA., Results: Using intention-to-treat analysis, women in DC and NC groups reduced energy intake (both P < 0.001) and lost 4.4 ± 0.6 kg and 5.0 ± 0.9 kg (both P < 0.001), respectively. Both groups lowered systolic and diastolic BP [DC = 2.7 (P < 0.05), 2.7 (P < 0.01); NC = 3.4 (P < 0.01), 4.2 (P < 0.01) mmHg, respectively]. Glucose and insulin concentrations decreased by 0.72 mmol/L (P < 0.001) and 13.20 pmol/L (P < 0.01) in DC group and by 0.83 mmol/L (P < 0.001) and 13.20 pmol/L (P < 0.01), respectively, in NC group. Total cholesterol increased in NC group (P < 0.05), with no significant lipid changes in DC group. There were no significant differences in biomarker outcomes between groups., Conclusions: Overweight/obese premenopausal women following an 18-week ERD that included either DC or NC sweet snack and sugar-free beverage lost equivalent amounts of BW and improved BP measurements and glucose and insulin concentrations.

The consumption of cocoa and dark chocolate is associated with a lower risk of CVD, and improvements in endothelial function may mediate this relationship. Less is known about the effects of cocoa/chocolate on the augmentation index (AI), a measure of vascular stiffness and vascular tone in the peripheral arterioles. We enrolled thirty middle-aged, overweight adults in a randomised, placebo-controlled, 4-week, cross-over study. During the active treatment (cocoa) period, the participants consumed 37 g/d of dark chocolate and a sugar-free cocoa beverage (total cocoa = 22 g/d, total flavanols (TF) = 814 mg/d). Colour-matched controls included a low-flavanol chocolate bar and a cocoa-free beverage with no added sugar (TF = 3 mg/d). Treatments were matched for total fat, saturated fat, carbohydrates and protein. The cocoa treatment significantly increased the basal diameter and peak diameter of the brachial artery by 6% (+2 mm) and basal blood flow volume by 22%. Substantial decreases in the AI, a measure of arterial stiffness, were observed in only women. Flow-mediated dilation and the reactive hyperaemia index remained unchanged. The consumption of cocoa had no effect on fasting blood measures, while the control treatment increased fasting insulin concentration and insulin resistance (P= 0·01). Fasting blood pressure (BP) remained unchanged, although the acute consumption of cocoa increased resting BP by 4 mmHg. In summary, the high-flavanol cocoa and dark chocolate treatment was associated with enhanced vasodilation in both conduit and resistance arteries and was accompanied by significant reductions in arterial stiffness in women.

Like caffeine, theobromine crosses the blood-brain barrier and binds to adenosine receptors, suggesting it might share caffeine's beneficial effects on mood and vigilance. Therefore, the purpose of this study was to assess the effect of theobromine doses commonly found in foods on mood and vigilance parameters sensitive to caffeine. Caffeine was tested as a positive control. Twenty-four men (age, 23 [3] years) completed 6 double-blind trials during which they consumed experimental beverages, assessed their mood using standardized self-report questionnaires, and completed a 2-hour visual vigilance task. Three experimental doses (100, 200, and 400 mg theobromine) were delivered in a cocoa-based beverage; 3 matched control treatments (0 mg theobromine, 400 mg theobromine, and 100 mg caffeine) were delivered in a non-cocoa beverage. Mean salivary concentrations of theobromine exhibited significant dose-dependent differences (400 mg trials > 200 mg trial > 100 mg trial > 0 mg trials; P < 0.005). At every dose tested, theobromine failed to consistently affect mood state or vigilance (P > 0.05), but 100-mg caffeine significantly decreased lethargy/fatigue and increased vigor (P = 0.006 and 0.011, respectively). These findings indicate theobromine does not influence mood and vigilance when administered in nutritionally relevant doses, despite sharing many of caffeine's structural characteristics.

An inverse relation exists between intake of flavonoid-rich foods, such as cocoa, and cardiovascular-related mortality. Favorable effects of flavonoids on the endothelium may underlie these associations. We performed a randomized, double-blind, placebo-controlled study to test the hypothesis that acute cocoa ingestion dose dependently increases endothelium-dependent vasodilation, as measured by an increase in brachial artery flow-mediated dilation (FMD), in healthy older adults. Measurements were obtained before (preingestion) and after (1- and 2-h postingestion) ingestion of 0 (placebo), 2, 5, 13, and 26 g of cocoa in 23 adults (63 ± 2 yr old, mean ± SE). Changes in brachial artery FMD 1- and 2-h postingestion compared with preingestion were used to determine the effects of cocoa. FMD was unchanged 1 (Δ-0.3 ± 0.2%)- and 2-h (Δ0.1 ± 0.1%) after placebo (0 g cocoa). In contrast, FMD increased both 1-h postingestion (2 g cocoa Δ0.0 ± 0.2%, 5 g cocoa Δ0.8 ± 0.3%, 13 g cocoa Δ1.0 ± 0.3%, and 26 g cocoa Δ1.6 ± 0.3%: P < 0.05 compared with placebo for 5, 13, and 26 g cocoa) and 2-h postingestion (2 g cocoa Δ0.5 ± 0.3%, 5 g cocoa Δ1.0 ± 0.3%, 13 g cocoa Δ1.4 ± 0.2%, and 26 g cocoa Δ2.5 ± 0.4%: P < 0.05 compared with placebo for 5, 13, and 26 g cocoa) on the other study days. A serum marker of cocoa ingestion (total epicatechin) correlated with increased FMD 1- and 2-h postingestion (r = 0.44-0.48; both P < 0.05). Collectively, these results indicate that acute cocoa ingestion dose dependently increases brachial artery FMD in healthy older humans. These responses may help to explain associations between flavonoid intake and cardiovascular-related mortality in humans.

The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Reduced-calorie diets are difficult to follow because they often require elimination of certain foods, leading to poor compliance and limited success. However, a low-calorie, nutrient-dense diet has the potential to accommodate a daily snack without exceeding energy requirements, even during weight loss. This pilot study evaluated the effects of a reduced-calorie diet including either a daily dark chocolate snack or a non-chocolate snack on anthropometric and body composition measurements. In a randomized clinical trial, 26 overweight and obese (body mass index ≥25 to ≤43) premenopausal women were assigned to a reduced-calorie diet that included either a daily dark chocolate snack or non-chocolate snack (n=13 per group) for 18 weeks. At baseline and end of study, body weight and waist and hip circumferences were measured along with fat mass, lean mass, and body fat percentage by dual-energy x-ray absorptiometry. Energy and macronutrient intakes were estimated from 4-day food records. Within- and between-group changes from baseline were analyzed using paired t tests and independent t tests, respectively. Women in both snack groups reduced estimated daily energy intake (P<0.001). Women in both the dark chocolate snack and non-chocolate snack groups, respectively, experienced decreases (P<0.001) in body weight (-5.1 vs -5.1 kg), hip circumference (-5.8 vs -5.4 cm), waist circumference (-5.7 vs -3.5 cm), fat mass (-3.9 vs -3.6 kg), and body fat percentage (-3.4% vs -3.1%), with no change in lean mass. Improvements in anthropometric and body composition measurements among overweight and obese premenopausal women can be achieved with a reduced-calorie diet including either a daily dark chocolate snack or non-chocolate snack., (Copyright © 2011 American Dietetic Association. Published by Elsevier Inc. All rights reserved.)

Diet plays a seminal role in the prevention and treatment of cardiovascular disease. Consumption of tree nuts has been shown to reduce low-density lipoprotein cholesterol (LDL-C), a primary target for coronary disease prevention, by 3-19%. Almonds have been found to have a consistent LDL-C-lowering effect in healthy individuals, and in individuals with high cholesterol and diabetes, in both controlled and free-living settings. Almonds are low in saturated fatty acids, rich in unsaturated fatty acids, and contain fiber, phytosterols, and plant protein. Other cardioprotective nutrients unique to almonds include α-tocopherol, arginine, magnesium, copper, manganese, calcium, and potassium. Mechanisms responsible for the LDL-C reduction observed with almond consumption are likely associated with the nutrients almonds provide. Biologically active by nature, these nutrients target primary mechanistic routes of LDL-C reduction, including decreased (re)absorption of cholesterol and bile acid, increased bile acid and cholesterol excretion, and increased LDL-C receptor activity. The nutrients present in almonds may regulate enzymes involved in de novo cholesterol synthesis and bile acid production. Research is needed to understand all mechanisms by which almonds reduce cardiovascular disease risk., (© 2011 International Life Sciences Institute.)

Background: Numerous popular media sources have developed lists of "Super Foods" and, more recently, "Super Fruits". Such distinctions often are based on the antioxidant capacity and content of naturally occurring compounds such as polyphenols within those whole fruits or juices of the fruit which may be linked to potential health benefits. Cocoa powder and chocolate are made from an extract of the seeds of the fruit of the Theobroma cacao tree. In this study, we compared cocoa powder and cocoa products to powders and juices derived from fruits commonly considered "Super Fruits"., Results: Various fruit powders and retail fruit products were obtained and analyzed for antioxidant capacity (ORAC (μM TE/g)), total polyphenol content (TP (mg/g)), and total flavanol content (TF (mg/g)). Among the various powders that were tested, cocoa powder was the most concentrated source of ORAC and TF. Similarly, dark chocolate was a significantly more concentrated source of ORAC and TF than the fruit juices., Conclusions: Cocoa powder and dark chocolate had equivalent or significantly greater ORAC, TP, and TF values compared to the other fruit powders and juices tested, respectively. Cacao seeds thus provide nutritive value beyond that derived from their macronutrient composition and appear to meet the popular media's definition of a "Super Fruit".

Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD.

The Boredetella pertussis wlbD gene product is a putative uridine-5-diphosphate N-acetylglucosamine (UDP-GlcNAc) 2'-epimerase involved in Band A lipopolysaccharide biosynthesis. The wlbD gene is homologous to Escherichia coli rffE (32% identical), an established UDP-GlcNAc 2'-epimerase that is involved in enterobacterial common antigen (ECA) formation. The structure of the rffE protein reveals an unexpected role for a bound sodium ion in orientating a substrate-binding alpha-helix in the enzyme active site. Whilst key active-site residues in rffE are present in the wlbD sequence, the sodium-binding residues outside the active site are absent. This raises questions about the modulation of enzyme activity in these two enzymes. The wlbD gene from B. pertussis has been cloned and overexpressed in E. coli and the resulting protein has been purified to homogeneity. In the current study, crystals of the mutant Gln339Arg wlbD enzyme have been obtained by sitting-drop vapour diffusion. Uncomplexed Gln339Arg and UDP-GlcNAc complex data sets have been collected in-house on a rotating-anode generator to 2.1 A. Combined, the data sets identify the space group as P2(1)2(1)2(1), with unit-cell parameters a = 78, b = 91, c = 125 A, alpha = beta = gamma = 90 degrees. The asymmetric unit contains two monomers and 53% solvent.