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OBJECTIVE: The objective of this study is to investigate the prevalence of diabetes in a clinical population of primarily Indigenous women in Guatemala. RESULTS: In a retrospective chart review of a clinical program serving 13,643 primarily Indigenous women in Guatemala, crude diabetes prevalence was 8.3% (95% Confidence Interval [CI]: 7.8 to 8.7) and age-adjusted diabetes prevalence was 7.9% (95% CI: 7.3 to 8.5). Among those with diabetes, 37.9% (95% CI: 35.1 to 40.8) of women were undiagnosed. Diabetes prevalence rose significantly with increasing age and was significantly higher among women with obesity (risk ratio: 1.4 [95% CI: 1.1 to 1.8]) and among women least likely to be in poverty (risk ratio: 2.0 [95% CI: 1.5 to 2.6]). Diabetes prevalence was significantly lower among Indigenous women (risk ratio: 0.7 [95% CI: 0.6 to 0.9]) and among women who spoke Mayan languages rather than Spanish (risk ratio: 0.7 [95% CI: 0.6 to 0.9]). There was no significant difference in diabetes prevalence between women who lived in rural settings and women who lived in urban settings.

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OBJECTIVES: Pole dancing is an extreme form of performance physical activity, combining considerable feats of muscular strength, flexibility, dancing and acrobatics on a vertical metal apparatus. Despite rapid growth in the artform, many pole dancers continue to participate without fulfilling physical requirements to withstand the forces and physicality required. The aim of this systematic review was to determine the incidence, prevalence and characteristics of injuries sustained by pole dancing participants reported in published studies. METHODS: Five databases were comprehensively searched in February 2023. Authors independently screened titles and abstracts, with full copies of eligible studies reviewed using specific inclusion/exclusion criteria. Studies were included if they referenced pole dancing, were in English language and Level I-III-3 in accordance with the Australian National Health and Medical Research Council, with case reports considered if included 10 or more participants. The National Institute of Health quality assessment tool for observational cohort and cross-sectional studies was used to review the quality of reporting of selected studies. RESULTS: Eleven articles were retrieved based on searches, with five studies meeting full inclusion/exclusion criteria, published between 2020-2022. In total 787 study participants were identified, with 623 sustaining a total of 1,803 pole dancing injuries. Data from all studies in injury profiles reported 42.4% of injuries sustained to the upper limb, 44.8% lower limb, 10.5% trunk, 0.02% associated with the head and neck, and several injuries affecting multiple regions. Acute injuries comprised 51.6% of reported injuries compared to 48.4% chronic. Injury characteristics were varied due to inconsistencies in reporting across studies. CONCLUSIONS: This systematic review highlights a paucity of knowledge regarding injuries in pole dancing, perhaps expected with a relatively young sport. Improvement in reporting is required to aid in identification of injuries and opportunities for development of injury risk reduction strategies. PROSPERO Registration no. CRD42023401012.

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There are limited data on diabetes among Indigenous populations in Guatemala. In a retrospective chart review of a clinical program serving more than 13 000 primarily Indigenous women in Guatemala, age-adjusted diabetes prevalence was 7.9% (95% CI: 7.3 to 8.5), and 37.9% (95% CI: 35.1 to 40.8%) of women were undiagnosed.

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The Molecular Education and Research Consortium in Undergraduate Computational Chemistry (MERCURY) has supported a diverse group of faculty and students for over 20 years by providing computational resources as well as networking opportunities and professional support. The consortium comprises 38 faculty (42% women) at 34 different institutions, who have trained nearly 900 undergraduate students, more than two-thirds of whom identify as women and one-quarter identify as students of color. MERCURY provides a model for the support necessary for faculty to achieve professional advancement and career satisfaction. The range of experiences and expertise of the consortium members provides excellent networking opportunities that allow MERCURY faculty to support each other's teaching, research, and service needs, including generating meaningful scientific advancements and outcomes with undergraduate researchers as well as being leaders at the departmental, institutional, and national levels. While all MERCURY faculty benefit from these supports, the disproportionate number of women in the consortium, relative to their representation in computational sciences generally, produces a sizable impact on advancing women in the computational sciences. In this report, the women of MERCURY share how the consortium has benefited their careers and the careers of their students.

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ABSTRACT: Anemia is common, affecting 1 in 3 women in their lifetime. Despite high prevalence rates, awareness is poor. This is relevant for women undertaking sport as anemia can lead to reduced physical performance. There is no current screening program for testing of anemia for exercising women. Therefore, the objective of the present study was to assess a simple screening tool to predict anemia in exercising women.Cross sectional survey study.National fitness festival.Three hundred exercising women.Screening methodology (Female Health Questionnaire and a haemoglobin concentration measurement).The Female Health Questionnaire inquired about; previous iron status, menstrual blood loss, diet, and motherhood. Participants were asked to self-report any symptoms of iron deficiency, including; brain fog, palpitations, shortness of breath, restless legs, hair loss, and pica. Results were compared to fingerprick haemoglobin levels with anemia defined as [Hb] < 120 g/L.Average age was 31.21years (s.d.7.72), average [Hb] was 131.76 g/L (s.d.11.5) and 36 (12%) had anemia. A history of iron deficiency was reported by 127 (43.49%), 127 (43.49%) reported heavy menstrual bleeding (HMB), 75 were vegetarian (18%) or vegan (8%) and 33 were mothers (11%). In total 80 reported taking time off work (total 1612 days). Women with anemia more commonly reported HMB (58.33% vs. 41.57%, P = .04), and those with HMB were more likely to report days off (39.37% vs. 18.18%, P < .001).Anemia was common in exercising women, particularly those with HMB. A simple screening tool for HMB and finger prick haemoglobin testing for anemia is recommended in women undertaking exercise.

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Activation of the CB2 receptor has been shown to have anti-inflammatory and antinociceptive effects without causing psychoactive effects. Previously, we reported that the compound ethyl 2(2-(N-(2,3-dimethylphenyl) phenylsulfonamido)acetamido)benzoate (ABK5) is a CB2 subtype selective agonist with anti-inflammatory and antinociceptive effects. In the present study, we tested four ABK5 derivatives, ABK5-1, ABK5-2, ABK5-5, and ABK5-6, to analyze the structure of ABK5 to obtain CB2-selective agonists with higher affinity and efficacy. Affinity, subtype selectivity, and G-protein coupling were determined by radioligand binding assays. Selected compounds were then subjected to evaluation of anti-inflammatory effects using two different cell lines, Jurkat (ABK5-1 and 5-2) and BV-2 cells (ABK5-1), which are models of T cells and microglia, respectively. ABK5-1, ABK5-2, and ABK5-6 had comparable CB2 binding affinity with ABK5 (and stimulated G-protein coupling), while only ABK5-1 and ABK5-2 maintained CB2-subtype selectivity. ABK5-5 did not bind CB2 in the detectable range. RT-PCR and ELISA analysis showed that the two compounds also inhibit IL-2 and TNF-α production, and they were more efficacious than ABK5 in inhibiting TNF-α production. CXCL-12 mediated chemotaxis was also evaluated by the transwell migration assay, and both ABK5-1 and ABK5-2 inhibited chemotaxis with a stronger effect observed in ABK5-1. In the microglia cell line BV-2, ABK5-1 inhibited IL-1ß and IL-6 production, which suggests this compound has anti-inflammatory effects through targeting multiple immune cells, and may be a candidate for treatment of inflammation.

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The purpose of this article is to share community partner perspectives of impact and lessons learned from a decade long community-academic partnership between the Collaborative Center for Health Equity at the University of Wisconsin-Madison, and the United Community Center/Centro de la Comunidad Unida, a nonprofit community-based organization providing services across the lifespan for Latino communities of Milwaukee. The partnership was established in 2010 to support bidirectional communication, trust building and mutual benefit though community engaged research and collaborative student teaching. Over the years, we have achieved a variety of outcomes on both sides of the partnership. For our community organization, the partnership has evolved to create substantial benefits through opportunities for new collaborations, service program development and grantsmanship. Several factors contributed to our success including sustained stable funding not tied to an individual research project and academic investment in community capacity.

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Although solitary drinking is less common than social drinking, it may be uniquely associated with heavy drinking and alcohol-related problems. There is also evidence that drinking contexts impact both expected and experienced alcohol effects. In particular, solitary drinking may be associated with an increased likelihood of drinking for negative reinforcement (e.g. to relieve stress). The current study examined how drinking context influences tension reduction expectancies and drinking motives, and the extent to which expectancies and motives mediate the link between solitary drinking and alcohol-related problems. We hypothesized that solitary drinking would be associated with greater tension reduction expectancies and coping motives which, in turn, would be associated with more alcohol related problems. Data were from 157 young adult moderate to heavy drinkers (21-30 years of age, 57% male) who completed baseline assessments in an alcohol administration study. A path model in Mplus tested the hypothesized mediated effects. Findings largely supported study hypotheses with significant indirect effects of solitary drinking (but not social drinking) on alcohol problems through stronger tension reduction expectancies and coping motives, though an indirect path through coping motives (but not expectancies) was also identified. Multi-group models by gender and race/ethnicity found that models operated similarly for men and women and for Non-Hispanic Caucasian and Racial/Ethnic Minority participants. The results provide important information about potential mechanisms through which solitary drinking may contribute to alcohol problems. These mechanisms represent potential targets of intervention (e.g. tension reduction expectancies, drinking to cope) for solitary drinkers.

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Cannabinoid CB1 and CB2 receptors are activated by Δ9-tetrahydrocannabinol, a psychoactive component of marijuana. The cannabinoid CB1 receptor is primarily located in the brain and is responsible for the psychoactive side effects, whereas the cannabinoid CB2 receptor is located in immune cells and is an attractive target for immune-related maladies. We identify small molecules that selectively bind to the cannabinoid CB2 receptor and can be further developed into therapeutics. The affinity of three molecules, ABK5, ABK6, and ABK7, to the cannabinoid CB2 receptor was determined with radioligand competition binding. The potency of G-protein coupling was determined with GTPγS binding. The three compounds bound selectively to the cannabinoid CB2 receptor, and no binding to the cannabinoid CB1 receptor was detected up to 10 µM. Immunoblotting studies show that the amount of ERK1/2 and MEK phosphorylation increased in a Gi/o-dependent manner. Furthermore, an immune cell line (Jurkat cells) was treated with ABK5, and as a result, inhibited cell proliferation. These three compounds are novel cannabinoid CB2 receptor agonists and hold promise to be further developed to treat inflammation and the often-associated pain.

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Cannabinoid receptor 1 (CB1) is a G-protein-coupled receptor that is abundant in the central nervous system. It binds several compounds in its orthosteric site, including the endocannabinoids, arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol, and the plant-derived Δ9-tetrahydrocannabinol, one of the main psychoactive components of marijuana. It primarily couples to Gi/o proteins to inhibit adenylate cyclase activity and typically induces downstream signaling that is Gi-dependent. Since this receptor is implicated in several maladies, such as obesity, pain, and neurodegenerative disorders, there is interest in developing therapeutics that selectively target this receptor. Allosteric modulators of CB1 offer one new approach that has tremendous therapeutic potential. Here, we reveal receptor- and cellular-level properties consistent with receptor activation by a series of pyrimidinyl biphenylureas (LDK1285, LDK1288, LDK1305, and PSNCBAM1), including promoting binding of the agonist CP55940 with positive cooperativity and inhibiting binding of the inverse agonist SR141716A with negative cooperativity, demonstrated via radioligand binding studies. Consistent with these findings, the allosteric modulators induced cellular internalization of the receptor and recruitment of ß-arrestin 2 in human embryonic kidney cell line 293 cells monitored with confocal and total internal reflective fluorescence microscopy, respectively. These allosteric modulators, however, caused G-protein-independent but ß-arrestin 1-dependent phosphorylation of the downstream kinases extracellular signal-regulated kinase 1/2, mitogen-activated protein kinase, and Src, shown by immunoblotting studies. These results are consistent with the involvement of ß-arrestin and suggest that these allosteric modulators induce biased signaling.

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Hyperamylinemia is a condition that accompanies obesity and precedes type II diabetes, and it is characterized by above-normal blood levels of amylin, the pancreas-derived peptide. Human amylin oligomerizes easily and can deposit in the pancreas [1], brain [2], and heart [3], where they have been associated with calcium dysregulation. In the heart, accumulating evidence suggests that human amylin oligomers form moderately cation-selective [4,5] channels that embed in the cell sarcolemma (SL). The oligomers increase membrane conductance in a concentration-dependent manner [5], which is correlated with elevated cytosolic Ca2+. These findings motivate our core hypothesis that non-selective inward Ca2+ conduction afforded by human amylin oligomers increase cytosolic and sarcoplasmic reticulum (SR) Ca2+ load, which thereby magnifies intracellular Ca2+ transients. Questions remain however regarding the mechanism of amylin-induced Ca2+ dysregulation, including whether enhanced SL Ca2+ influx is sufficient to elevate cytosolic Ca2+ load [6], and if so, how might amplified Ca2+ transients perturb Ca2+-dependent cardiac pathways. To investigate these questions, we modified a computational model of cardiomyocytes Ca2+ signaling to reflect experimentally-measured changes in SL membrane permeation and decreased sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) function stemming from acute and transgenic human amylin peptide exposure. With this model, we confirmed the hypothesis that increasing SL permeation alone was sufficient to enhance Ca2+ transient amplitudes. Our model indicated that amplified cytosolic transients are driven by increased Ca2+ loading of the SR and that greater fractional release may contribute to the Ca2+-dependent activation of calmodulin, which could prime the activation of myocyte remodeling pathways. Importantly, elevated Ca2+ in the SR and dyadic space collectively drive greater fractional SR Ca2+ release for human amylin expressing rats (HIP) and acute amylin-exposed rats (+Amylin) mice, which contributes to the inotropic rise in cytosolic Ca2+ transients. These findings suggest that increased membrane permeation induced by oligomeratization of amylin peptide in cell sarcolemma contributes to Ca2+ dysregulation in pre-diabetes.

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The endocannabinoid system (ECS) plays a diverse role in human physiology ranging from the regulation of mood and appetite to immune modulation and the response to pain. Drug development that targets the cannabinoid receptors (CB1 and CB2) has been explored; however, success in the clinic has been limited by the psychoactive side effects associated with modulation of the neuronally expressed CB1 that are enriched in the CNS. CB2, however, are expressed in peripheral tissues, primarily in immune cells, and thus development of CB2-selective drugs holds the potential to modulate pain among other indications without eliciting anxiety and other undesirable side effects associated with CB1 activation. As part of a collaborative effort among industry and academic laboratories, we performed a high-throughput screen designed to discover selective agonists or positive allosteric modulators (PAMs) of CB2. Although no CB2 PAMs were identified, 167 CB2 agonists were discovered here, and further characterization of four select compounds revealed two with high selectivity for CB2 versus CB1. These results broaden drug discovery efforts aimed at the ECS and may lead to the development of novel therapies for immune modulation and pain management with improved side effect profiles.

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The cannabinoid CB1 receptor is abundant in the central nervous system and regulates neuronal transmission and other key physiological processes including those leading to pain, inflammation, memory, and feeding behavior. CB1 is activated by the endogenous ligands, arachidonoyl ethanolamine and 2-arachidonoyl glycerol, by various synthetic ligands (e.g., CP55940), and by Δ9-tetrahydrocannabinol, the psychoactive component of Cannabis sativa. These CB1 ligands are orthosteric and transduce downstream signals by binding CB1 and primarily inducing Gi coupling, but Gs and ß-arrestin coupling are also possible. Recently, allosteric modulators for CB1 were discovered that bind to topographically distinct sites and can noncompetitively impact the potency and efficacy of orthosteric compounds. These offer the exciting potential for mechanistic analyses and for developing therapeutics. Yet, it is critical to elucidate whether a compound is a positive allosteric modulator or a negative allosteric modulator of orthosteric ligand-induced CB1 profiles to understand pathway specificity and ameliorate diseases. In this chapter, we present equilibrium and kinetic binding analysis to reveal the impact of allosteric modulators on CB1. Also described are activities consistent with CB1 activation (or inactivation) and include cellular internalization of CB1 and downstream signaling patterns. Since many CB1 allosteric modulators do not enhance G protein coupling, it is critical to distinguish CB1 activation and biased signaling patterns via ß-arrestin from CB1 inactivation. These strategies can illuminate pathway specificity and are valuable for the fine-tuning of CB1 function.

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PURPOSE: Assessing the impact of research requires an approach that is sensitive both to the context of the research and the perspective of the stakeholders trying to understand its benefits. Here, the authors report on a pilot that applied such an approach to research conducted at the Collaborative Center for Health Equity (CCHE) of the University of Wisconsin School of Medicine and Public Health. METHOD: The pilot assessed the academic impact of CCHE's work; the networks between CCHE and community partners; and the reach of CCHE's programs, including an attempt to estimate return on investment (ROI). Data included bibliometrics, findings from a stakeholder survey and in-depth interviews, and financial figures. RESULTS: The pilot illustrated how CCHE programs increase the capacity of community partners to advocate for their communities and engage with researchers to ensure that research benefits the community. The results illustrate the reach of CCHE's programs into the community. The authors produced an estimate of the ROI for one CCHE program targeting childhood obesity, and values ranged from negative to positive. CONCLUSIONS: The authors experienced challenges using novel assessment techniques at a small scale including the lack of comparator groups and the scarcity of cost data for estimating ROI. This pilot demonstrated the value of research from a variety of perspectives-from academic to community. It illustrates how metrics beyond grant income and publications can capture the outputs of an academic health center in a way that may better align with the aims of the center and stakeholders.

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Parvalbumin (PV) is a globular calcium (Ca(2+))-selective protein expressed in a variety of biological tissues. Our computational studies of the rat ß-parvalbumin (ß-PV) isoform seek to elucidate the molecular thermodynamics of Ca(2+) versus magnesium (Mg(2+)) binding at the protein's two EF-hand motifs. Specifically, we have utilized molecular dynamics (MD) simulations and a mean-field electrolyte model (mean spherical approximation (MSA) theory) to delineate how the EF-hand scaffold controls the "local" thermodynamics of Ca(2+) binding selectivity over Mg(2+). Our MD simulations provide the probability density of metal-chelating oxygens within the EF-hand scaffolds for both Ca(2+) and Mg(2+), as well the conformational strain induced by Mg(2+) relative to Ca(2+) binding. MSA theory utilizes the binding domain oxygen and charge distributions to predict the chemical potential of ion binding, as well as their corresponding concentrations within the binding domain. We find that the electrostatic and steric contributions toward ion binding were similar for Mg(2+) and Ca(2+), yet the latter was 5.5 kcal/mol lower in enthalpy when internal strain within the EF hand was considered. We therefore speculate that beyond differences in dehydration energies for the Ca(2+) versus Mg(2+), strain induced in the ß-PV EF hand by cation binding significantly contributes to the nearly 10,000-fold difference in binding affinity reported in the literature. We further complemented our analyses of local factors governing cation binding selectivity with whole-protein (global) contributions, such as interhelical residue-residue contacts and solvent exposure of hydrophobic surface. These contributions were found to be comparable for both Ca(2+)- and Mg(2+)-bound ß-PV, which may implicate local factors, EF-hand strain, and dehydration, in providing the primary means of selectivity. We anticipate these methods could be used to estimate metal binding thermodynamics across a broad range of PV sequence homologues and EF-hand-containing, Ca(2+) binding proteins.

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Cytosolic crowding can influence the thermodynamics and kinetics of in vivo chemical reactions. Most significantly, proteins and nucleic acid crowders reduce the accessible volume fraction, ϕ, available to a diffusing substrate, thereby reducing its effective diffusion rate, Deff, relative to its rate in bulk solution. However, Deff can be further hindered or even enhanced, when long-range crowder/diffuser interactions are significant. To probe these effects, we numerically estimated Deff values for small, charged molecules in representative, cytosolic protein lattices up to 0.1 × 0.1 × 0.1 µm(3) in volume via the homogenized Smoluchowski electro-diffusion equation. We further validated our predictions against Deff estimates from ϕ-dependent analytical relationships, such as the Maxwell-Garnett (MG) bound, as well as explicit solutions of the time-dependent electro-diffusion equation. We find that in typical, moderately crowded cell cytoplasm (ϕ ≈ 0.8), Deff is primarily determined by ϕ; in other words, diverse protein shapes and heterogeneous distributions only modestly impact Deff. However, electrostatic interactions between diffusers and crowders, particularly at low electrolyte ionic strengths, can substantially modulate Deff. These findings help delineate the extent that cytoplasmic crowders influence small molecule diffusion, which ultimately may shape the efficiency and timing of intracellular signaling pathways. More generally, the quantitative agreement between computationally expensive solutions of the time-dependent electro-diffusion equation and its comparatively cheaper homogenized form suggest that the latter is a broadly effective model for diffusion in wide-ranging, crowded biological media.

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OBJECTIVE: Prior studies have demonstrated an association between high-risk sexual behavior and alcohol use, and there is emerging evidence that dating status and sexual behavior are related to risk for subsequent alcohol use. However, relatively little is known regarding the specific attitudinal or behavioral indicators of alcohol-related risk associated with sexual behavior. The present study distinguished between sociosexual attitudes and sociosexual behaviors, two aspects of sexual risk that may contribute to individual differences in drinking behavior. The primary hypothesis was that sociosexual attitudes would indirectly contribute to heavier drinking through greater engagement in sociosexual behaviors. METHOD: Study hypotheses were tested using baseline data from an alcohol challenge study in a sample of young adult heavy drinkers (n = 211, 73.7% male). Participants completed surveys assessing typical drinking behavior and both sociosexual attitudes and sociosexual behaviors. RESULTS: As hypothesized, sociosexual attitudes were indirectly related to heavier alcohol use through greater engagement in sociosexual behavior. However, the relation between sociosexual attitudes and sociosexual behaviors was stronger for men, as were the indirect effects of sociosexual attitudes on drinking behavior. CONCLUSIONS: Engagement in sociosexual behavior appears to be a risk factor for heavy alcohol use. This highlights the potential utility of targeted alcohol interventions in settings associated with sexual risk, including sexually transmitted infection clinics and college campuses. Future research should explore the mechanisms through which sociosexual behaviors contribute to drinking outcomes to further inform targeted alcohol interventions and to bolster protective factors among those who engage in sociosexual behaviors.

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The S100A1 protein mediates a wide variety of physiological processes through its binding of calcium (Ca(2+)) and endogenous target proteins. S100A1 presents two Ca(2+)-binding domains: a high-affinity "canonical" EF (cEF) hand and a low-affinity "pseudo" EF (pEF) hand. Accumulating evidence suggests that both Ca(2+)-binding sites must be saturated to stabilize an open state conducive to peptide recognition, yet the pEF hand's low affinity limits Ca(2+) binding at normal physiological concentrations. To understand the molecular basis of Ca(2+) binding and open-state stabilization, we performed 100 ns molecular dynamics simulations of S100A1 in the apo/holo (Ca(2+)-free/bound) states and a half-saturated state, for which only the cEF sites are Ca(2+)-bound. Our simulations indicate that the pattern of oxygen coordination about Ca(2+) in the cEF relative to the pEF site contributes to the former's higher affinity, whereas Ca(2+) binding strongly reshapes the protein's conformational dynamics by disrupting ß-sheet coupling between EF hands. Moreover, modeling of the half-saturated configuration suggests that the open state is unstable and reverts toward a closed state in the absence of the pEF Ca(2+) ion. These findings indicate that Ca(2+) binding at the cEF site alone is insufficient to stabilize opening; thus, posttranslational modification of the protein may be required for target peptide binding at subsaturating intracellular Ca(2+) levels.

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Human cannabinoid type 1 (CB1) G-protein coupled receptor is a potential therapeutic target for obesity. The previously predicted and experimentally validated ensemble of ligand-free conformations of CB1 [Scott, C. E. et al. Protein Sci. 2013 , 22 , 101 - 113 ; Ahn, K. H. et al. Proteins 2013 , 81 , 1304 - 1317] are used here to predict the binding sites for known CB1-selective inverse agonists including rimonabant and its seven known derivatives. This binding pocket, which differs significantly from previously published models, is used to identify 16 novel compounds expected to be CB1 inverse agonists by exploiting potential new interactions. We show experimentally that two of these compounds exhibit inverse agonist properties including inhibition of basal and agonist-induced G-protein coupling activity, as well as an enhanced level of CB1 cell surface localization. This demonstrates the utility of using the predicted binding sites for an ensemble of CB1 receptor structures for designing new CB1 inverse agonists.

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