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Recidivism after orthopedic trauma results in greater morbidity and costs. Prior studies explored the effects of social and medical factors affecting the frequency of return to the hospital with new, unrelated injury. Identification of mental, social and other risk factors for trauma recidivism may provide opportunities for mitigation. The purposes of this study are to determine the rates of subsequent, unrelated injury noted among orthopedic trauma patients at a large urban trauma center and to evaluate what patient and injury features are associated with greater rates of trauma recidivism. We hypothesize higher rates of new injuries will be related to ballistic trauma and other forms of assault, alcohol and recreational drug use, unemployment, and unmarried status among our trauma patients.A series of 954 skeletally mature patients at a level 1 trauma center over a 5 year period were included in the study. All were treated operatively for thoracolumbar, pelvic ring, acetabulum, and/or proximal or shaft femoral fractures from a high energy mechanism. Retrospective review of demographic, injury, medical, and social factors, and subsequent care was performed. Trauma recidivism was defined as returning to the emergency department for treatment of any new injury. A backward stepwise logistic regression statistical analysis was used to identify independent predictors of recidivism.Mean age of all patients was 41.2 years, and 73.2% were male. 136 patients (14.3%) returned with a new injury within a mean of 21 months. These trauma recidivists were more likely to sustain a GSW (22.1% vs 11.4%, p = 0.001). They had higher rates of substance use, including tobacco (57.4% vs 41.8%, p = 0.001) and recreational drugs (50.7% vs 34.4%, p = 0.001), and were less likely to be married (10% vs 25.9%, p0.001). Mental illness was pervasive, noted in 56.6% of patients with new injury (vs 32.8%, p0.001). Medicaid insurance was most common in the trauma recidivist population (58.1% vs 35.0%, p = 0.001), and 12.5% were uninsured. Completing high school or more education was protective (93% non-recidivist (vs 79%, p = 0.001). Sixty-nine patients (50.7%) were repeat trauma recidivists within the study period. Independent predictors of new injury included recreational drug use (OR 1.64, p = 0.05) and history of assault due to GSW or other means (OR 1.67, p = 0.05). History of pre-existing mental illness represented the greatest risk factor for trauma recidivism (OR 2.55, p0.001).New injuries resulting in emergency department presentation after prior orthopedic trauma occurred in 14.3% and were associated with history of assault, lower education, Medicaid insurance, tobacco smoking and recreational drug use. Mental illness was the greatest risk factor. Over half of patients with these additional injuries were repeat trauma recidivists, returning for another new injury within less than 2 years. Awareness of risk factors may promote focused education and other interventions to mitigate this burden.Level 3 retrospective, prognostic.

The digital alchemy framework is an extended ensemble simulation technique that incorporates particle attributes as thermodynamic variables, enabling the inverse design of colloidal particles for desired behavior.

Purpose: Malignancy after heart transplantation is associated with poor outcomes. At present, no prediction model exists for any malignancy within the first year after transplant. Methods: We studied adults who underwent heart transplantation included in the multicenter, national Scientific Registry of Transplant Recipients from January 2000 through April 2021. Possible predictors of malignancy were identified based on their known association with malignancy. Multiple imputations were conducted for missing values using predictive mean matching. A multivariable logistic regression model for predicting malignancy development within the first year after transplant was developed and internally validated via 500 bootstrapped samples to estimate the optimism-corrected measures of model accuracy and performance. Results: Among the 47 212 recipients comprising 16% females, 76% whites, 7% with prior malignancy, and a median age of 56 years; 865 (2.3% of those with non-missing data) developed malignancy within the first year after transplant. Prior malignancy, older age at heart transplantation, white race, and nonischemic heart failure etiology were the strongest predictors of new malignancy. The optimism-corrected model had modest discrimination (C-statistic: 0.70, 95% CI: 0.69-0.72) and good calibration and performance (calibration slope: 0.96; Cox-Snell R2: 0.063), particularly at lower predicted risk. A nomogram for the practicing clinician was developed. Conclusions: Using selection variables previously linked to cutaneous malignancy, our model was modestly predictive of the development of any malignancy in the first year after heart transplantation. Future research could identify factors that may improve malignancy prediction, including incorporation of time-to-event data.

Missense mutations along the leucine-rich repeat kinase 2 (LRRK2) protein are a major contributor to Parkinson's Disease (PD), the second most commonly occurring neurodegenerative disorder worldwide. We recently reported the development of allosteric constrained peptide inhibitors that target and downregulate LRRK2 activity through disruption of LRRK2 dimerization. In this study, we designed doubly constrained peptides with the objective of inhibiting C-terminal of Roc (COR)-COR mediated dimerization at the LRRK2 dimer interface. We show that the doubly constrained peptides are cell-permeant, bind wild-type and pathogenic LRRK2, inhibit LRRK2 dimerization and kinase activity, and inhibit LRRK2-mediated neuronal apoptosis, and in contrast to ATP-competitive LRRK2 kinase inhibitors, they do not induce the mislocalization of LRRK2 to skein-like structures in cells. This work highlights the significance of COR-mediated dimerization in LRRK2 activity while also highlighting the use of doubly constrained peptides to stabilize discrete secondary structural folds within a peptide sequence.

Almost all ancient plays have three things in common with most modern musicals. First, the basic structure of most ancient plays, like most musicals, involved alternation between song and speech. Second, the songs of ancient plays, like those of musicals, could have a wider cultural relevance, living on beyond their original performance context. Third, in most ancient plays, as in musicals, there is a strong sense that song and dance are as important as, or even more important than, what occurs in spoken dialogue in providing pleasure to the audience and conveying the meaning of plays. Scholarship of the last decade has made clearer the centrality of music to ancient theater and has taken important steps in understanding how that music worked.

Beta-guanidinopropionic acid (GPA) is a creatine analog suggested as a treatment for hypertension, diabetes, and obesity, which manifest primarily in older adults. A notable side effect of GPA is the induction of mitochondrial DNA deletion mutations. We hypothesized that mtDNA deletions contribute to muscle aging and used the mutation promoting effect of GPA to examine the impact of mtDNA deletions on muscles with differential vulnerability to aging. Rats were treated with GPA for up to 4 months starting at 14 or 30 months of age. We examined quadriceps and adductor longus muscles as the quadriceps exhibits profound age-induced deterioration, while adductor longus is maintained. GPA decreased body and muscle mass and mtDNA copy number while increasing mtDNA deletion frequency. The interactions between age and GPA treatment observed in the quadriceps were not observed in the adductor longus. GPA had negative mitochondrial effects in as little as 4 weeks. GPA treatment exacerbated mtDNA deletions and muscle aging phenotypes in the quadriceps, an age-sensitive muscle, while the adductor longus was spared. GPA has been proposed for use in age-associated diseases, yet the pharmacodynamics of GPA differ with age and include the detrimental induction of mtDNA deletions, a mitochondrial genotoxic stress that is pronounced in muscles that are most vulnerable to aging. Further research is needed to determine if the proposed benefits of GPA on hypertension, diabetes, and obesity outweigh the detrimental mitochondrial and myopathic side effects. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-022-00667-4.

Skin's effectiveness as a barrier to permeation of water and other chemicals rests almost entirely in the outermost layer of the epidermis, the stratum corneum (SC), which consists of layers of corneocytes surrounded by highly organized lipid lamellae. As the only continuous path through the SC, transdermal permeation necessarily involves diffusion through these lipid layers. The role of the SC as a protective barrier is supported by its exceptional lipid composition consisting of ceramides (CERs), cholesterol (CHOL), and free fatty acids (FFAs) and the complete absence of phospholipids, which are present in most biological membranes. Molecular simulation, which provides molecular level detail of lipid configurations that can be connected with barrier function, has become a popular tool for studying SC lipid systems. We review this ever-increasing body of literature with the goals of (1) enabling the experimental skin community to understand, interpret and use the information generated from the simulations, (2) providing simulation experts with a solid background in the chemistry of SC lipids including the composition, structure and organization, and barrier function, and (3) presenting a state of the art picture of the field of SC lipid simulations, highlighting the difficulties and best practices for studying these systems, to encourage the generation of robust reproducible studies in the future. This review describes molecular simulation methodology and then critically examines results derived from simulations using atomistic and then coarse-grained models.

Poor maternal nutrition during gestation can result in reduced offspring muscle growth and altered muscle metabolism. We hypothesized that over- or restricted-nutrition during gestation would alter the longissimus dorsi muscle (LM) proteome of offspring. Pregnant ewes were fed 60% (restricted), 100% (control), or 140% (over) of National Research Council requirements for total digestible nutrients from day 30 of gestation until parturition. Fetal (RES, CON, OVER) LM were collected at days 90 and 135 of gestation, or from offspring within 24 h of birth. Sarcoplasmic proteins were isolated, trypsin digested, and subjected to multiplexed, label-based quantitative mass spectrometry analysis integrating tandem mass tag technology. Differential expression of proteins was identified by ANOVA followed by Tukey's HSD post hoc tests, and regularized regression via the elastic net. Significance was set at P0.05. Over-represented pathways containing differentially expressed proteins were identified by Reactome and included metabolism of proteins, immune system, cellular response to stress/external stimuli, developmental biology, and infectious disease. As a result of maternal diet, a total of 312 proteins were differentially expressed (day 90 = 89 proteins; day 135 = 115 proteins; birth = 131 proteins). Expression of eukaryotic initiation factor (EIF) 2S3, EIF3L, and EIF4G2 was lower in OVER fetuses at day 90 of gestation (P0.05). Calcineurin A and mitogen-activated protein kinase 1 were greater in RES fetuses at day 90 (P0.04). At day 135 of gestation, pyruvate kinase and lactate dehydrogenase A expression were greater in OVER fetuses than CON (P0.04). Thioredoxin expression was greater in RES fetuses relative to CON at day 135 (P = 0.05). At birth, proteins of the COP9 signalosome complex were greater in RES offspring relative to OVER (P0.05). Together, these data indicate that protein degradation and synthesis, metabolism, and oxidative stress are altered in a time and diet-specific manner, which may contribute to the phenotypic and metabolic changes observed during fetal development and postnatal growth.Poor maternal diet during gestation results in changes in body composition and metabolism in the offspring. Here, we demonstrate that over- and restricted-feeding during gestation alter global protein expression in the longissimus dorsi muscle of offspring during gestation and just after birth. These protein changes are related to protein synthesis and degradation, stress responses, metabolism, and oxidative stress. Proteins related to the initiation of protein translation were increased in offspring of over-fed dams at mid-gestation, while changes in abundance of enzymes associated with metabolism were altered in late gestation and just after birth. In offspring of restricted-fed ewes, proteins relating to cell signaling were increased at mid-gestation, while again, changes in late gestation and birth were related to metabolism, protein degradation, and stress responses. Together, these may provide a mechanism by which poor maternal diet during gestation alters the poor growth and development that occurs in these offspring.

Molecular dynamics simulations of mixtures of the ceramide N-(tetracosanoyl)-sphingosine (NS), cholesterol, and a free fatty acid are performed to gain a molecular-level understanding of the structure of the lipids found in the stratum corneum layer of skin. A new coarse-grained force field for cholesterol was developed using the multistate iterative Boltzmann inversion method (MS-IBI). The coarse-grained cholesterol force field is compatible with previously developed coarse-grained force fields for ceramide NS, free fatty acids, and water, and validated against atomistic simulations of these lipids using the CHARMM force field. Self-assembly simulations of multilayer structures using these coarse-grained force fields are performed, revealing that a large fraction of the ceramides adopt extended conformations, which cannot occur in the single bilayer in water structures typically studied using molecular simulation. Cholesterol fluidizes the membrane by promoting packing defects and an increase in cholesterol content is found to reduce the bilayer thickness, due to an increase in interdigitation of the C(24) lipid tails, consistent with experimental observations. Using a reverse-mapping procedure, a self-assembled coarse-grained multilayer system is used to construct an equivalent structure with atomistic resolution. Simulations of this atomistic structure are found to closely agree with experimentally derived neutron scattering length density profiles. Significant interlayer hydrogen bonding is observed in the inner layers of the atomistic multilayer structure that are not found in the outer layers in contact with water or in equivalent bilayer structures. This work highlights the importance of simulating multilayer structures, as compared to the more commonly studied bilayer systems, to enable more appropriate comparisons with multilayer experimental membranes. These results also provide validation of the efficacy of the coarse-grained force fields and the framework for multiscale simulation.

More than 45 countries and several local jurisdictions have implemented sugar-sweetened beverage (SSB) taxes to improve nutrition and population health, and evidence on their outcomes to date is essential to inform policy discussions. Responding to this need, the World Health Organization commissioned a systematic literature review on the outcomes of fiscal policies, including SSB taxes.To assess the associations of implemented SSB taxes with prices, sales, consumption, diet, body weight, product changes, unintended consequences, health, and pregnancy outcomes.Searches of 8 bibliographic databases (Business Source Complete, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL, EconLit, PsycINFO, PubMed, and Scopus) were performed from database inception through June 1, 2020, with no language or setting restrictions. Grey literature was assessed using 14 sources and government websites.The review included primary studies of implemented SSB taxes.The review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. For prices, sales and consumption, results were meta-analyzed using a 3-level random-effects model. Study quality was assessed at the outcome level.Tax pass-through rate for prices, percentage reduction in SSB demand, and price elasticity of demand for sales and consumption. Heterogeneity was assessed using τ2 and the I2 statistic.A total of 86 articles were eligible, with 62 studies contributing to the meta-analysis. The overall tax pass-through rate was 82% (95% CI, 66% to 98%; P .001, I2 = 99%), suggesting tax undershifting. The demand for SSBs was highly sensitive to tax-induced price increases, with the price elasticity of demand of -1.59 (95% CI, -2.11 to -1.08; P .001; I2 = 100%) and a mean reduction in SSB sales of 15% (95% CI, -20% to -9%; P .001; I2 = 100%). There was no evidence of substitution to untaxed beverages, and changes in SSB consumption were not significant. The narrative synthesis found reformulation and reduced sugar content of taxed beverages for tiered taxes, cross-border shopping in most studies of local-level taxes, and no negative changes in employment. Data on the heterogeneity of SSB tax outcomes across subpopulations were limited.In this systematic review and meta-analysis of implemented SSB taxes worldwide, SSB taxes were associated with higher prices and lower sales of taxed beverages.

Type 2 Diabetes (T2D) is an emerging public health problem in Asia. Although ethnic specific mtDNA polymorphisms have been shown to contribute to T2D risk, the functional effects of the mtDNA polymorphisms and the therapeutic potential of mitochondrial-derived peptides at the mtDNA polymorphisms are underexplored. Here, we showed an Asian-specific mitochondrial DNA variation m.1382A>C (rs111033358) leads to a K14Q amino acid replacement in MOTS-c, an insulin sensitizing mitochondrial-derived peptide. Meta-analysis of three cohorts (n = 27,527, J-MICC, MEC, and TMM) show that males but not females with the C-allele exhibit a higher prevalence of T2D. In J-MICC, only males with the C-allele in the lowest tertile of physical activity increased their prevalence of T2D, demonstrating a kinesio-genomic interaction. High-fat fed, male mice injected with MOTS-c showed reduced weight and improved glucose tolerance, but not K14Q-MOTS-c treated mice. Like the human data, female mice were unaffected. Mechanistically, K14Q-MOTS-c leads to diminished insulin-sensitization in vitro. Thus, the m.1382A>C polymorphism is associated with susceptibility to T2D in men, possibly interacting with exercise, and contributing to the risk of T2D in sedentary males by reducing the activity of MOTS-c.

Talent of the practitioner is irrelevant if the person receiving support (or the person responsible for delivering support) does not follow through with the plan. This is true in applied behavior analysis (ABA), medicine, and allied health-care services. The cost of nonadherence and related nonoptimized interventions is a major contributor to the overall cost of health care, estimated at $290–528 billion annually in the United States (New England Healthcare Institute, 2009; Watanabe, McInnis, & Hirsch, 2018). Although a topic of research in medicine for over 60 years, no gold standard for the enhancement of adherence has been demonstrated in any single population, disease condition, or therapeutic approach (Nieuwlaat et al., 2014; Rudd, 1979). Given the broad applicability of behavior analysis as a framework for understanding human behavior, and the need to recognize and address the problem of nonadherence in ABA (Allen & Warzak, 2000) we propose a systematic behavioral model for adherence and the development of strategies to enhance follow-through with individualized support plans.

Decrements in metabolic health elevate disease risk, including type 2 diabetes, heart disease, and certain cancers. Thus, treatment strategies to combat metabolic dysfunction are needed. Reduced ESR1 (estrogen receptor, ERα) expression is observed in muscle from women, men, and animals presenting clinical features of the metabolic syndrome. Human studies of natural expression of ESR1 in metabolic tissues show that muscle expression of ESR1 is positively correlated with markers of metabolic health, including insulin sensitivity. Herein, we highlight the important impact of ERα on mitochondrial form and function and present how these actions of the receptor govern metabolic homeostasis. Studies identifying ERα-regulated pathways for disease prevention will lay the foundation for the design of novel therapeutics to improve the health of women while limiting secondary complications that have plagued traditional hormone replacement interventions.

Objective Traumatic spine injuries are a relatively common occurrence and are associated with functional impairment, loss of neurologic function, and spinal deformity. A number of spinal trauma classification systems have been developed with varying degrees of acceptance. This review provides a chronological overview of spinal trauma classification systems, with special consideration towards the benefits and pitfalls related to each. Cervical, thoracolumbar, and sacral trauma classification systems are discussed. Methods A review of the literature was performed. Published articles that reported on bony spinal trauma classification systems were examined. No year exemptions were identified. The reference lists of all selected articles were screened for additional studies. Article inclusion and exclusion criteria were defined a priori. Results A total of 20 classification systems were identified from years 1938-2017. Of these 20 classification systems, 6 were cervical, 11 were thoracolumbar and 3 were sacral. The modernization of bony spinal trauma classification has been characterized by the development of weighted scales that include injury morphology, integrity of associated ligamentous structures and neurologic status. Conclusion For widespread acceptance and adoption in the clinical setting, future spinal trauma scoring classification will need to remain simple, highly reproducible, and impart information with regard to clinical decision-making and prognosis that may be effectively communicated across each medical specialty involved in the care of these patients.

OBJECTIVE To determine the impact of smoking on intensive care unit (ICU) outcomes in patients who underwent operative fixation for spine trauma. DESIGN Retrospective cohort study. SETTING Single academic level I trauma center. PATIENTS One hundred eighty-one consecutive surgical spine trauma patients from January 2010 to December 2014 requiring ICU stay. INTERVENTION Patients with smoking history compared to patients with no previous smoking history. MAIN OUTCOME MEASUREMENTS ICU length of stay, postoperative complications. RESULTS There were 297 spine trauma patients identified, of which 181 had an ICU stay (61%). There were 96 patients in the smoker cohort (53%) and 85 in the nonsmoker cohort (47%). On univariate analysis, the smoking cohort had a significantly longer ICU length of stay (11.0 ± 12.0 days vs. 8.01 ± 7.98 days, P = 0.046). Adjusting for confounders, smoking (beta: 3.99, P = 0.023), age ≥65 years (beta: 7.61, P = 0.001), body mass index ≥30 (beta: 4.47, P = 0.010), and American Spinal Injury Association Impairment Scale (beta: -1.39, P = 0.013) were independently associated with increased ICU length of stay. Smoking was not significantly associated with pneumonia (P = 0.238) or adult respiratory distress syndrome (P = 0.387) on multivariate analysis. CONCLUSIONS A history of smoking, older age, obesity, and increasing American Spinal Injury Association Impairment Scale was independently associated with increased ICU length of stay in patients with surgical spine trauma. This study highlights the health care burden of smoking in the trauma population and may help physicians triage scarce ICU resources. LEVEL OF EVIDENCE Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

PREMISE The functional significance of leaf margins has long been debated. In this study, we explore influences of climate, leaf lobing, woodiness, and shared evolutionary history on two leaf margin traits within the genus Pelargonium. METHODS Leaves from 454 populations of Pelargonium (161 species) were collected in the Greater Cape Floristic Region and scored for tooth presence/absence and degree of lobing. Tooth density (number of teeth per interior perimeter distance) was calculated for a subset of these. We compared five hypotheses to explain tooth presence and density using mixed effect models. RESULTS Tooth presence/absence was best predicted by the interaction of leaf lobing and mean annual temperature (MAT), but often in patterns opposite those previously reported: species were more likely to be toothed with warmer temperatures, particularly for unlobed and highly lobed leaves. In contrast, tooth density was best predicted by the interaction of MAT and the season of most rain; density declines with temperature as consistent with expectations, but only in winter-rain dominated areas. Woody and nonwoody species within Pelargonium have similar associations between tooth presence/absence and MAT, contrary to the expectation that patterns within nonwoody species would be insignificant. CONCLUSIONS We conclude Pelargonium leaf margins show predictable responses to climate, but these responses are complex and can contradict those found for global patterns across plant communities.

The structural properties of two- and three-component gel-phase bilayers were studied using molecular dynamics simulations. The bilayers contain distearoylphosphatidylcholine (DSPC) phospholipids mixed with alcohols and/or fatty acids of varying tail lengths, with carbon chain lengths of 12, 16, and 24 studied. Changes in both headgroup chemistry and tail length are found to affect the balance between steric repulsion and van der Waals attraction within the bilayers, manifesting in different bilayer structural properties. Lipid components are found to be located at different depths within the bilayer depending on both chain length and headgroup chemistry. The highest bilayer ordering and lowest area per tail are found in systems with medium-length tails. While longer tails can enhance van der Waals attractions, the increased tail-length asymmetry is found to induce disorder and reduce tail packing. Bulkier headgroups further increase steric repulsion, as reflected in increased component offsets and reduced tail packing. These findings help explain how bilayer composition affects the structure of gel-phase bilayers.

Selection pressures along climate gradients give rise to predictable variation in plant functional traits of individual species suggestive of local adaptation. Species whose ranges include winter rainfall, Mediterranean climates, or other strongly seasonal climates, may be exposed to divergent selection pressures at different ends of seasonality gradients. Here, we evaluate how rainfall seasonality in conjunction with other key climatic variables impacts patterns of trait variation in Pelargonium scabrum, a woody shrub from the Greater Cape Floristic Region of South Africa. This biodiversity hotspot encompasses a Mediterranean climate (wet winters and hot, dry summers) and displays steep gradients in temperature and water availability. We used Bayesian regression models to evaluate leaf trait–trait and trait–climate relationships among 26 populations. Models included rainfall seasonality and its interaction with other climate variables (mean annual temperature, mean annual precipitation and potential evapotranspiration) as predictors to test for the impact of climate variation on three leaf traits: size, dissection and leaf mass per area (LMA). We evaluated model explanatory power by calculating Bayesian R² values, and predictive power via leave‐one‐out cross‐validation. Trait–trait associations were modulated by rainfall seasonality, including a reversal in the relationship between leaf size and dissection depending on the proportion of rain received in winter. Trait–climate models were improved by including rainfall seasonality as a predictor for both explanatory and predictive power. For leaf dissection and LMA, we detected significant interactions between rainfall seasonality and other environmental variables, leading to reversals in the relationships between these traits and the three environmental variables depending on the proportion of winter rainfall. Differences in the timing of rainfall, coupled with strong differences in the covariation of climate variables, impose divergent selection pressures on P. scabrum populations resulting in divergence of trait values, trait integration and responses to climate gradients. These patterns are consistent with local adaptation of P. scabrum populations mediated by the interactions between temperature and the amount and timing of rainfall. Species arrayed along broad climate gradients represent an excellent opportunity for investigating patterns of trait variation and abundances and distributions of species in relation to future changes in climate. A free Plain Language Summary can be found within the Supporting Information of this article.

/IntroductionProteins secreted from skeletal muscle, termed myokines, allow muscle to impact systemic physiology and disease. Myokines play critical roles in a variety of processes, including metabolic homeostasis, exercise improvements, inflammation, cancer and cognitive functions1–6. Despite the clear relevance of these factors in mediating a multitude of physiological outcomes, the genetic architecture, regulation and functions of myokines, as well as degree of conservation of these communication circuits remains inadequately understood. Given that biologic sex controls critical aspects of nearly every physiologic outcome, it is essential to consider when relating specific mechanisms to complex genetic and metabolic interactions. Specifically, many metabolic traits impacted by myokines show striking sex differences arising from hormonal7–10, genetic7,11 or gene-by-sex interactions12,13. In this study, we performed a genetic survey of myokine gene regulation and cross-tissue signaling in humans where sex as a biological variable was emphasized. While expression levels of a majority of myokines and cell proportions within skeletal muscle showed little differences between males and females, nearly all significant cross-tissue enrichments operated in a sex-specific or hormone-dependent fashion; in particular, with estrogens. These sex- and hormone-specific effects were consistent across key metabolic tissues: liver, pancreas, hypothalamus, intestine, heart, visceral and subcutaneous adipose tissue. Skeletal muscle estrogen receptor enrichments across metabolic tissues appeared stronger than androgen receptor and, surprisingly, ~3-fold higher in males compared to females. To define the causal roles of estrogen signaling on myokine gene expression and functions, we generated male and female mice which lack estrogen receptor α (Esr1) specifically in skeletal muscle and integrated global RNA-Sequencing with human data. These analyses highlighted mechanisms of sex-dependent myokine signaling conserved between species, such as myostatin enriched for divergent substrate utilization pathways between sexes. Several other sex-dependent mechanisms of myokine signaling were uncovered, such as muscle-derived TNFα exerting stronger inflammatory signaling in females compared to males and GPX3 as a male-specific link between glycolytic fiber abundance and hepatic inflammation. Collectively, we provide the first genetic survey of human myokines and highlight sex and estrogen receptor signaling as critical variables when assaying myokine functions and how changes in cell composition impact other metabolic organs.

Shaowei Jiang,1 Jing Ma,2 Shan Ye,3 Connor Meaney,4 Timothy Evan Moore,4 Shuming Pan,1 Chengjin Gao1 1Department of Emergency, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People’s Republic of China; 2Department of Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People’s Republic of China; 3Department of Internal Medicine, Shanghai Songnan Community Health Service Center, Shanghai, 200092, People’s Republic of China; 4Division of Rheumatology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, 84132, USACorrespondence: Chengjin Gao; Shuming Pan Email gaochengjin@xinhuamed.com.cn; panshuming@xinhuamed.com.cnObjectives(s): Toll-like receptors (TLRs) on platelets have been extensively studied. Both TLR2 and TLR4 have been shown to augment platelet activation and alter its function from a hemostatic regulator to an immune sentinel. However, few studies have investigated the relationship between genetic polymorphisms in TLR2, TLR4 and platelets. We investigated whether genetic polymorphisms of TLR2 and TLR4 were related to thrombocytopenia and coagulation failure in Chinese patients with sepsis.Basic Methods: Adult Chinese patients with sepsis in the intensive care unit of a university medical center were monitored for up to 28 days. Thrombocytopenia and disseminated intravascular coagulation (DIC), diagnosed using Japanese Association for Acute Medicine (JAAM) criteria, were observed as the primary outcomes. Single-nucleotide polymorphisms (SNPs) in TLR2 (rs111200466, rs5743708) and TLR4 (rs11536889, rs145801336, rs11536896, rs7869402) in patients with sepsis were detected by polymerase chain reaction. The data were analyzed using chi-square and rank sum tests.Results: The genotype of TLR2 (rs111200466) (Del/Del) was associated with the initial DIC. The genotype of TLR4 (rs11536889) (C/C&C/G) was associated with initial DIC, DIC onset during hospitalization and platelet counts. Furthermore, both DIC and platelet counts were associated with cytokines and chemokines, especially the IL10.Conclusion: Our results demonstrate that in Chinese sepsis patients, the rs111200466 SNP in TLR2 and rs11536889 SNP in TLR4 are associated with thrombocytopenia and DIC, with potential effects on the TLR4 pathways of platelets.Keywords: sepsis, disseminated intravascular coagulation, TLR2/4, genetic polymorphisms

Colloidal and nanoparticle systems display a rich and exciting phase behavior including the self-assembly of highly complex crystal structures. Nucleation and growth pathways toward crystallization have been studied both computationally and experimentally, but the mechanisms for the formation of the precritical nucleus and consequent crystal growth are yet to be fully understood. Recent advances in the application of machine learning algorithms applied to many-particle systems have led to significant breakthroughs in the ability for high-throughput analysis of phase transitions and the identification of crystal structures. We build upon these techniques to identify and analyze pathways for nucleation and growth in supercooled liquids of colloidal systems modeled with isotropic pair potentials. Our study involves the development of unsupervised machine learning models trained on spherical-harmonics-based descriptors. These models allow us to determine clusters of local environments that are present prior to and during crystallization. We analyze these environments to identify prevalent motifs and local order within the supercooled liquid prior to formation of the critical nucleus.

The self-assembly of binary nanoparticle superlattices from colloidal mixtures is a promising method for the fabrication of complex colloidal co-crystal structures. However, binary mixtures often form amorphous or metastable phases instead of the thermodynamically stable phase. Here we show that in binary mixtures of differently sized spherical particles, an excess of the smaller component can promote -- and, in some cases, may be necessary for -- the self-assembly of a binary co-crystal. Using computer simulations, we identify two mechanisms responsible for this phenomenon. First, excess small particles act like plasticizers and enable systems to reach a greater supersaturation before kinetic arrest occurs. Second, they can disfavor competing structures that may interfere with the growth of the target structure. We find the phase behavior of simulated mixtures of hard spheres closely matches published experimental results. We demonstrate the generality of our findings for mixtures of particles of arbitrary shape by presenting a binary mixture of hard shapes that only self-assembles with an excess of the smaller component. mixtures of particles of arbitrary shape by presenting a binary mixture of hard shapes that only self-assembles with an excess of the smaller component.

The metabolic syndrome is a cluster of conditions that increase an individual's risk of developing diseases. Being physically active throughout life is known to reduce the prevalence and onset of some aspects of the metabolic syndrome. Furthermore, previous studies have demonstrated that an individual's gut microbiome composition has a large influence on several aspects of the metabolic syndrome. However, the mechanism(s) by which physical activity may improve metabolic health are not well understood. We sought to determine if endurance exercise is sufficient to prevent or ameliorate the development of the metabolic syndrome and its associated diseases. We also analyzed the impact of physical activity under metabolic syndrome progression upon the gut microbiome composition. Utilizing whole‐body low‐density lipoprotein receptor (LDLR) knockout mice on a “Western Diet,” we show that long‐term exercise acts favorably upon glucose tolerance, adiposity, and liver lipids. Exercise increased mitochondrial abundance in skeletal muscle but did not reduce liver fibrosis, aortic lesion area, or plasma lipids. Lastly, we observed several changes in gut bacteria and their novel associations with metabolic parameters of clinical importance. Altogether, our results indicate that exercise can ameliorate some aspects of the metabolic syndrome progression and alter the gut microbiome composition., In this study, we sought to determine if endurance exercise is sufficient to prevent or ameliorate the development of metabolic syndrome and its associated diseases and the impact of physical activity under metabolic syndrome progression upon the gut microbiome. Utilizing the whole‐body low‐density lipoprotein receptor (LDLR) knockout mice on a “Western Diet,” we show that long‐term exercise acts favorably upon glucose tolerance, adiposity, and liver lipids. Our results indicate that exercise can ameliorate some aspects of the metabolic syndrome progression and alter the gut microbiome.

Background: There is recent evidence to suggest that the use of polyetheretherketone (PEEK) interbodies are inherently associated with a higher rate of pseudarthrosis, in particular, at the C5-6 and C6-7 levels. Herein, we describe our technique utilizing two parallel structural allografts or “kissing” allografts, designed to mitigate the risk of pseudarthrosis and subsidence at these levels. Materials and Methods: We retrospectively reviewed all anterior cervical discectomy and fusion (ACDF) procedures with “kissing” for degenerative spine pathology at a single institution between 2018 and 2019 for the C5-6 and C6-7 levels. One-year postoperative flexion/extension cervical X-rays were evaluated for evidence of radiographic pseudarthrosis and subsidence. Results: A total of 28 patients met the study criteria. Solid fusion was achieved in 93%. There were no infections or wound complications. One patient developed postoperative dysphagia that resolved at 3-months post-op. Two patients were found to have clinically asymptomatic radiographic pseudarthrosis that did not warrant intervention. One patient developed a postoperative hematoma that required surgical evacuation. Conclusions: “Kissing” allograft ACDF is a safe and effective method designed to address the intrinsically higher risk of pseudarthrosis at the C5-6 and C6-7 levels. Further prospective studies are warranted to comparatively evaluate this technique against single allograft and PEEK interbodies.

Molecular dynamics simulations of mixtures of the ceramide N-(tetracosanoyl)-sphingosine (NS), cholesterol, and a free fatty acid are performed to gain a molecular-level understanding of the structure of the lipids found in the stratum corneum layer of skin. A new coarse-grained model for cholesterol, developed using the multistate iterative Boltzmann inversion method, is compatible with previously developed coarse-grained forcefields for ceramide NS, free fatty acid, and water, and validated against atomistic simulations of these lipids using the CHARMM force field. Self-assembly simulations of multilayer structures using these coarse-grained force fields are performed, revealing that a large fraction of the ceramides adopt extended conformations, which cannot occur in the bilayer structures typically studied using simulation. Cholesterol fluidizes the membrane by promoting packing defects and it is observed that an increase in cholesterol content reduces the bilayer height, due to an increase in interdigitation of the C24 lipid tails, consistent with experimental observations. Through the use of a simple reverse-mapping procedure, a self-assembled coarse-grained multilayer system is used to construct an equivalent structure with atomistic resolution. Simulations of this atomistic structure are found to closely agree with experimentally derived neutron scattering length density profiles. Significant interlayer hydrogen bonding is observed in the inner layers of the atomistic multilayer structure that are not found in the outer layers in contact with water or in equivalent bilayer structures. These results identify several significant differences in the structure and hydrogen bonding of multilayer structures as compared to the more commonly studied bilayer systems, and, as such, highlight the importance of simulating multilayer structures for more accurate comparisons with experiment. These results also provide validation of the efficacy of the coarse-grained forcefields and the framework for multiscale simulation.