δ-Bonding and Spin-Orbit Coupling Make SrAg4Sb2 a Topological Insulator.

Bonding interactions and spin-orbit coupling in the topological insulator SrAg4Sb2 are investigated using DFT with orbital projection analysis. Ag-Ag delta bonding is a key ingredient in the topological insulating state because the 4 d x y + 4 d x 2 - y 2 ${4d_{xy} + 4d_{x^2 - y^2 } }$ delta antibonding band forms a band inversion with the 5 s sigma bonding band. Spin-orbit coupling is required to lift d orbital degeneracies and lower the antibonding band enough to create the band inversion. These bonding effects are enabled by a longer-than-covalent Ag-Ag distance in the crystal lattice, which might be a structural characteristic of other transition metal based topological insulators. A simplified model of the topological bands is constructed to capture the essence of the topological insulating state in a way that may be engineered in other materials.

A scoping review of wildfire smoke risk communications: issues, gaps, and recommendations.

BACKGROUND: Wildfire smoke exposure has become a growing public health concern, as megafires and fires at the wildland urban interface increase in incidence and severity. Smoke contains many pollutants that negatively impact health and is linked to a number of health complications and chronic diseases. Communicating effectively with the public, especially at-risk populations, to reduce their exposure to this environmental pollutant has become a public health priority. Although wildfire smoke risk communication research has also increased in the past decade, best practice guidance is limited, and most health communications do not adhere to health literacy principles: readability, accessibility, and actionability. This scoping review identifies peer-reviewed studies about wildfire smoke risk communications to identify gaps in research and evaluation of communications and programs that seek to educate the public. METHODS: Four hundred fifty-one articles were identified from Web of Science and PubMed databases. After screening, 21 articles were included in the final sample for the abstraction process and qualitative thematic analysis. Ten articles were based in the US, with the other half in Australia, Canada, Italy, and other countries. Fifteen articles examined communication materials and messaging recommendations. Eight papers described communication delivery strategies. Eleven articles discussed behavior change. Six articles touched on risk communications for vulnerable populations; findings were limited and called for increasing awareness and prioritizing risk communications for at-risk populations. RESULTS: This scoping review found limited studies describing behavior change to reduce wildfire smoke exposure, characteristics of effective communication materials and messaging, and communication delivery strategies. Literature on risk communications, dissemination, and behavior change for vulnerable populations was even more limited. CONCLUSIONS: Recommendations include providing risk communications that are easy-to-understand and adapted to specific needs of at-risk groups. Communications should provide a limited number of messages that include specific actions for avoiding smoke exposure. Effective communications should use mixed media formats and a wide variety of dissemination strategies. There is a pressing need for more intervention research and effectiveness evaluation of risk communications about wildfire smoke exposure, and more development and dissemination of risk communications for both the general public and vulnerable populations.

Rat Anterior Cingulate Cortex Continuously Signals Decision Variables in a Patch Foraging Task.

In patch foraging tasks, animals must decide whether to remain with a depleting resource or to leave it in search of a potentially better source of reward. In such tasks, animals consistently follow the general predictions of optimal foraging theory (the marginal value theorem; MVT): to leave a patch when the reward rate in the current patch depletes to the average reward rate across patches. Prior studies implicate an important role for the anterior cingulate cortex (ACC) in foraging decisions based on MVT: within single trials, ACC activity increases immediately preceding foraging decisions, and across trials, these dynamics are modulated as the value of staying in the patch depletes to the average reward rate. Here, we test whether these activity patterns reflect dynamic encoding of decision-variables and whether these signals are directly involved in decision-making. We developed a leaky accumulator model based on the MVT that generates estimates of decision variables within and across trials, and tested model predictions against ACC activity recorded from male rats performing a patch foraging task. Model predicted changes in MVT decision variables closely matched rat ACC activity. Next, we pharmacologically inactivated ACC in male rats to test the contribution of these signals to decision-making. ACC inactivation had a profound effect on rats' foraging decisions and response times (RTs) yet rats still followed the MVT decision rule. These findings indicate that the ACC encodes foraging-related variables for reasons unrelated to patch-leaving decisions.SIGNIFICANCE STATEMENT The ability to make adaptive patch-foraging decisions, to remain with a depleting resource or search for better alternatives, is critical to animal well-being. Previous studies have found that anterior cingulate cortex (ACC) activity is modulated at different points in the foraging decision process, raising questions about whether the ACC guides ongoing decisions or serves a more general purpose of regulating cognitive control. To investigate the function of the ACC in foraging, the present study developed a dynamic model of behavior and neural activity, and tested model predictions using recordings and inactivation of ACC. Findings revealed that ACC continuously signals decision variables but that these signals are more likely used to monitor and regulate ongoing processes than to guide foraging decisions.

Mild membrane depolarization in neurons induces immediate early gene transcription and acutely subdues responses to a successive stimulus.

Immediate early genes (IEGs) are transcribed in response to neuronal activity from sensory stimulation during multiple adaptive processes in the brain. The transcriptional profile of IEGs is indicative of the duration of neuronal activity, but its sensitivity to the strength of depolarization remains unknown. Also unknown is whether activity history of graded potential changes influence future neuronal activity. In this work with dissociated rat cortical neurons, we found that mild depolarization-mediated by elevated extracellular potassium (K+)-induces a wide array of rapid IEGs and transiently depresses transcriptional and signaling responses to a successive stimulus. This latter effect was independent of de novo transcription, translation, and signaling via calcineurin or mitogen-activated protein kinase. Furthermore, as measured by multiple electrode arrays and calcium imaging, mild depolarization acutely subdues subsequent spontaneous and bicuculline-evoked activity via calcium- and N-methyl-d-aspartate receptor-dependent mechanisms. Collectively, this work suggests that a recent history of graded potential changes acutely depress neuronal intrinsic properties and subsequent responses. Such effects may have several potential downstream implications, including reducing signal-to-noise ratio during synaptic plasticity processes.

Findings from a Peer-Facilitated, Social Isolation Intervention in the Veterans Health Administration Healthcare System: A Mixed-Methods, Pilot Feasibility Study.

BACKGROUND: Social isolation is a global public health threat. Veterans are particularly at risk for social isolation due to high rates of comorbid physical and mental health problems. Yet, effective interventions are limited. OBJECTIVES: Our primary objective was to assess the feasibility and acceptability of CONNECTED, a novel, transdiagnostic intervention to reduce social isolation that includes individual and group components and is delivered by peers via telehealth. Secondary objectives were to identify appropriate outcome measures and explore preliminary intervention effects. METHODS: This was a two-phase study. In Phase 1, to evaluate study feasibility, we surveyed 200 veterans to assess prevalence of social isolation and their interest in social connectedness interventions. In Phase 2, we employed a mixed-methods, pre-post study design in which we piloted CONNECTED with 19 veterans through 2 successive cohorts to further assess feasibility, to evaluate acceptability, and to explore preliminary effectiveness. Quantitative analyses involved descriptive and bivariate analyses as well as multivariate modeling. Qualitative interviews were analyzed using thematic analysis. RESULTS: For Phase 1, 39% of veterans surveyed were socially isolated. Participants who were ≤ 55 years old, caregivers, and those who experienced unmet social needs were more likely to report social isolation. Over 61% expressed interest in VA programs to reduce social isolation. For Phase 2, the pilot intervention, recruitment rate was 88% and the enrollment rate was 86%. Retention rates for the two cohorts were 80% and 50%, respectively, and satisfaction rates among intervention completers were 100%. Results also showed statistically significant improvements in social isolation (+ 5.91, SD = 4.99; p = .0028), social support (+ 0.74, SD = 1.09; p = .03), anxiety (-3.92, SD = 3.73; p = .003), and depression (-3.83, SD = 3.13; p = .001). Results for the other measures were not statistically significant. CONCLUSION: CONNECTED is a feasible and acceptable intervention and is likely to be an effective tool to intervene on social isolation among veterans.

The New Role of Telehealth in Contemporary Medicine.

PURPOSE OF REVIEW: Understand the current uses for telehealth as well as future directions as it relates to the COVID-19 pandemic and cardiovascular medicine. RECENT FINDINGS: Telehealth interventions in various forms have proven to be efficacious in the management of obesity, hypertension, glycemic control in diabetes, hyperlipidemia, medication adherence, and ICU length of stay and mortality. The use and study of such interventions have been greatly expanded during the pandemic partly due to the expanded coverage by payers. However, heterogenous interventions and a relative lack of cost analyses are barriers to more widespread adoption. Telehealth has proven efficacy for modifying risk factors for cardiovascular disease. To date, this has not been shown to translate to a reduction in hard cardiovascular endpoints such as mortality. With ongoing research and expanded funding, the role of telehealth is likely to evolve as the COVID pandemic continues.

Sex Differences in Demand for Highly Palatable Foods: Role of the Orexin System.

BACKGROUND: The prevalence of eating disorders, including binge eating disorder, is significantly higher in women. These findings are mirrored by preclinical studies, which indicate that female rats have a higher preference for palatable food and show greater binge-like eating compared with male rats. METHODS: Here, we describe a novel within-session behavioral-economic paradigm that allows for the simultaneous measurement of the intake at null cost (Q0) and normalized demand elasticity (α) of 3 types of palatable food (low fat, high fat, and chocolate sucrose pellets) via demand curve analysis. In light of evidence that the orexin (hypocretin) system is critically involved in reward and feeding behaviors, we also examined the role of orexin function in sex differences of economic demand for palatable foods. RESULTS: The novel within-session behavioral-economic approach revealed that female rats have higher intake (demand) than males for all palatable foods at low cost (normalized to body weight) but no difference in intake at higher prices, indicating sex-dependent differences in the hedonic, but not motivational, aspects of palatable food. Immediately following behavioral-economic testing, we observed more orexin-expressing neurons and Fos expression (measure of recent neural activation) in these neurons in female rats compared with male rats. Moreover, the orexin-1 receptor antagonist SB334867 reduced both low- and high-cost intake for palatable food in both male and female rats. CONCLUSIONS: These findings provide evidence of higher demand at low prices for palatable food in females and indicate that these behavioral differences may be associated with sexual dimorphism in orexin system function.

Beyond Strong Enforcement: Understanding the Factors Related to Retailer Compliance With Tobacco 21.

INTRODUCTION: Tobacco 21 (T21), which sets the minimum legal sales age for tobacco to age 21, is now a national law in the United States. Although T21 is expected to help curb youth tobacco use, its impact may be dampened due to poor retailer compliance. Even within environments where enforcement is strong (ie, compliance checks are conducted with tough sanctions for violations), compliance might vary due to other factors. AIMS AND METHODS: Three studies were conducted in Columbus, OH, where T21 became strongly enforced in 2018. These studies examined how retailer compliance related to features of the neighborhood in which a retailer was located (Study 1), features of the retailer (Study 2), and features of the retail cashier (Study 3). RESULTS: Study 1 found that, after controlling for race- and age-based factors, retailers located in high (vs. low)-poverty neighborhoods had a lower likelihood of conducting identification (ID) checks. Study 2 found that ID checks were related to whether retailers displayed signage about T21, as required by the city law. Study 3 found that, among cashiers, T21 awareness (which was high) and perceptions about T21 (which were moderate) were not generally related to their retailer's compliance; having (vs. not having) scanners for ID checks was related to a higher likelihood of compliance. CONCLUSIONS: These studies emphasize the many, multilevel factors influencing T21 outcomes. Findings also indicate the potential for T21 to widen disparities in tobacco use, indicating the need for strategies to equitably improve T21 compliance. IMPLICATIONS: T21, which sets the minimum legal sales age for all tobacco products to age 21, is now a national law in the United States. Despite optimistic projections about what T21 could achieve, the ultimate impact may be dampened when it is applied in real-world settings. Our project revealed the many, multilevel factors influencing T21 compliance. Findings also indicate the potential for T21 to widen disparities in tobacco use if gaps in compliance persist. Strategies for equitably improving T21 compliance are discussed. This article is of relevance to areas interested in implementing or improving their local T21 enforcement.

Association between eye-level greenness and lung function in urban Chinese children.

BACKGROUND: Health effects of greenness perceived by residents at eye level has received increasing attention. However, the associations between eye-level greenness and respiratory health are unknown. The aim of the study was to investigate the associations between exposure to eye-level greenness and lung function in children. METHODS: From 2012 to 2013, a total of 6740 school children in seven cities in northeast China were recruited into this cross-sectional study. Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), peak expiratory flow rate (PEF), and maximum mid expiratory flow rate (MMEF) were measured to evaluate lung function and to define lung impairment. Eye-level greenness was extracted from segmented Tencent Map street view images, and a corresponding green view index (GVI) was calculated. Higher GVIs mean more greenness coverage. Mixed-effects logistic regressions were used to estimate the health effects on lung impairment per interquartile range (IQR) increase in GVI. Linear regressions were used to estimate the associations between GVI and lung function. The health effects of ambient air pollutants were also assessed, including particulate matter with an aerodynamic diameter <1.0 µm (PM1), <2.5 µm (PM2.5), <10 µm (PM10) as well as nitrogen dioxide (NO2). RESULTS: An increase of GVI800m was associated with lung impairment in FEV1, FVC, PEF and MMEF, with ORs ranging from 0.68 (95% CI: 0.59, 0.79) to 0.83 (95% CI: 0.74, 0.93). The associations between an IQR increase of GVI800m and FEV1 (48.15 ml, 95% CI: 30.33-65.97 ml), FVC (50.57 ml, 95% CI: 30.65-70.48 ml), PEF (149.59 ml/s, 95% CI: 109.79-189.38 ml/s), and MMEF (61.18 ml/s, 95% CI: 31.07-91.29 ml/s) were significant, and PM1, PM2.5, and PM10 were found to be mediators of this relationship. CONCLUSION: More eye-level greenness was associated with better lung function and reduced impairment. However, eye-level greenness associations with lung function became non-significant once lower particulate matter air pollution exposures were considered.

Association between maternal outdoor physical exercise and the risk of preterm birth: a case-control study in Wuhan, China.

BACKGROUND: China had the second largest proportion of preterm birth (PTB) internationally. However, only 11% of pregnant women in China meet international guidelines for maternal physical activity, a significantly lower proportion than that in Western countries. This study aims to examine the association between outdoor physical exercise during pregnancy and PTB among Chinese women in Wuhan, China. METHODS: A case-control study was conducted among 6656 pregnant women (2393 cases and 4263 controls) in Wuhan, China from June 2011 to June 2013. Self-reported measures of maternal physical exercise (frequency per week and per day in minutes) were collected. Adjusted odds ratios were estimated using Bayesian hierarchical logistic regression and a generalized additive mixed model (GAMM). RESULTS: Compared to women not involved in any physical activity, those who participated in physical exercise 1-2 times, 3-4 times, and over five times per week had 20% (aOR: 0.80, 95% credible interval [95% CI]: 0.68-0.92), 30% (aOR: 0.70, 95% CI: 0.60-0.82), and 32% (aOR: 0.68, 95% CI: 0.59-0.78) lower odds of PTB, respectively. The Bayesian GAMM showed that increasing physical exercise per day was associated with lower risk of PTB when exercise was less than 150 min per day; however, this direction of association is reversed when physical exercise was more than 150 min per day. CONCLUSION: Maternal physical exercise, at a moderate amount and intensity, is associated with lower PTB risk. More data from pregnant women with high participation in physical exercise are needed to confirm the reported U-shape association between the physical exercise and risk of preterm birth.

Intermittent self-administration of fentanyl induces a multifaceted addiction state associated with persistent changes in the orexin system.

The orexin (hypocretin) system plays a critical role in motivated drug taking. Cocaine self-administration with the intermittent access (IntA) procedure produces a robust addiction-like state that is orexin-dependent. Here, we sought to determine the role of the orexin system in opioid addiction using IntA self-administration of fentanyl. Different groups of male rats were either given continuous access in 1-h period (short access [ShA]), 6-h period (long access [LgA]), or IntA (5 min of access separated by 25 min of no access for 6 h) to fentanyl for 14 days. IntA produced a greater escalation of fentanyl intake, increased motivation for fentanyl on a behavioral economics task, persistent drug seeking during abstinence, and stronger cue-induced reinstatement compared with rats given ShA or LgA. We found that addiction behaviors induced by IntA to fentanyl were reversed by the orexin-1 receptor antagonist SB-334867. IntA to fentanyl was also associated with a persistent increase in the number of orexin neurons. Together, these results indicate that the IntA model is a useful tool in the study of opioid addiction and that the orexin system is critical for the maintenance of addiction behaviors induced by IntA self-administration of fentanyl.

Sources of erroneous sequences and artifact chimeric reads in next generation sequencing of genomic DNA from formalin-fixed paraffin-embedded samples.

Tissues used in pathology laboratories are typically stored in the form of formalin-fixed, paraffin-embedded (FFPE) samples. One important consideration in repurposing FFPE material for next generation sequencing (NGS) analysis is the sequencing artifacts that can arise from the significant damage to nucleic acids due to treatment with formalin, storage at room temperature and extraction. One such class of artifacts consists of chimeric reads that appear to be derived from non-contiguous portions of the genome. Here, we show that a major proportion of such chimeric reads align to both the 'Watson' and 'Crick' strands of the reference genome. We refer to these as strand-split artifact reads (SSARs). This study provides a conceptual framework for the mechanistic basis of the genesis of SSARs and other chimeric artifacts along with supporting experimental evidence, which have led to approaches to reduce the levels of such artifacts. We demonstrate that one of these approaches, involving S1 nuclease-mediated removal of single-stranded fragments and overhangs, also reduces sequence bias, base error rates, and false positive detection of copy number and single nucleotide variants. Finally, we describe an analytical approach for quantifying SSARs from NGS data.

Orexin-1 Receptor Signaling in Ventral Pallidum Regulates Motivation for the Opioid Remifentanil.

Signaling at the orexin-1 receptor (OxR1) is important for motivated drug taking. Using a within-session behavioral economics (BE) procedure, we previously found that pharmacologic blockade of the OxR1 decreased motivation (increased demand elasticity) for the potent and short-acting opioid remifentanil and reduced low-effort remifentanil consumption. However, the mechanism through which orexin regulates remifentanil demand is currently unknown. Previous work implicated OxR1 signaling within ventral pallidum (VP) as a potential target. VP is densely innervated by orexin fibers and is known to regulate opioid reward. Accordingly, this study sought to determine the role of VP OxR1 signaling in remifentanil demand and cue-induced reinstatement of remifentanil seeking in male rats. Intra-VP microinjections of the OxR1 antagonist SB-334867 (SB) decreased motivation (increased demand elasticity; α) for remifentanil without affecting remifentanil consumption at low effort. Baseline α values predicted the degree of cue-induced remifentanil seeking, and microinjection of SB into VP attenuated this behavior without affecting extinction responding. Baseline α values also predicted SB efficacy, such that SB was most effective in attenuating reinstatement behavior in highly motivated rats. Together, these findings support a selective role for VP OxR1 signaling in motivation for the opioid remifentanil. Our findings also highlight the utility of BE in predicting relapse propensity and efficacy of treatment with OxR1 antagonists.SIGNIFICANCE STATEMENT Abuse of opioids has risen rapidly and continues to be a major health crisis. Thus, there is an urgent need to better understand the neurobiological and behavioral mechanisms underlying opioid addiction. Here, we investigate the role of orexin-1 receptor signaling (OxR1) within ventral pallidum (VP) in remifentanil demand and cue-induced reinstatement of remifentanil seeking. Using a within-session behavioral economics procedure, we show that intra-VP microinjections of the OxR1 antagonist SB-334867 decreased motivation (increased demand elasticity) without affecting remifentanil consumption at low effort. We also found that SB microinjected intra-VP attenuated cue-induced reinstatement of remifentanil seeking. Together, our results support a role for VP OxR1 signaling in opioid reward.

A Subgroup of Patients With Hospital-acquired Pneumonia Do Not Require Broad-spectrum Gram-negative Antimicrobial Coverage.

Among 200 patients developing hospital-acquired pneumonia (HAP) outside the intensive care unit, 61% were treated empirically without broad-spectrum Gram-negative coverage, with clinical cure in 69.7%. Lower disease severity markers (systemic inflammatory response syndrome, hypoxia, tachypnoea, neutrophilia) and the absence of diabetes mellitus and prior doxycycline treatment (but not the time to HAP onset) identified patients not requiring broad-spectrum Gram-negative coverage.

Comparison of Clinical and Semiquantitative Cartilage Grading Systems in Predicting Outcomes After Arthroscopic Partial Meniscectomy.

OBJECTIVE. Cartilage loss on preoperative knee MRI is a predictor of poor outcomes after arthroscopic partial meniscectomy. The purpose of this study was to compare the ability to predict outcomes after arthroscopic partial meniscectomy with a clinically used modified Outerbridge system versus a semiquantitative MRI Osteoarthritis Knee Score system for grading cartilage loss. MATERIALS AND METHODS. Patients who underwent preoperative knee MRI within 6 months of arthroscopic partial meniscectomy and who had outcomes available from the time of surgery and 1 year later were eligible for inclusion. Cases were evaluated by two radiologists and one radiology fellow with the use of both grading systems. The accuracy of each system in discriminating between surgical success and failure was estimated using the ROC curve (AUC) with 95% CIs. A Wald test was used to assess noninferiority of the clinical grading system. Interreader agreement regarding the accuracy of the grading systems in predicting outcomes was also compared. RESULTS. A total of 78 patients (38 women and 40 men; mean age, 56.6 years) were included in the study. A prediction model using clinical grading (AUC = 0.695; 95% CI, 0.566-0.824) was noninferior (p = 0.047) to a model using MRI Osteoarthritis Knee Score grading (AUC = 0.683; 95% CI, 0.539-0.827). Both MRI prediction models performed better than a model using demographic characteristics only (AUC = 0.667; 95% CI, 0.522-0.812). Inter-reader agreement with clinical grading (80.8%) was higher than that with MRI Osteoarthritis Knee Score grading (65.0%; p = 0.012). CONCLUSION. A clinically used system to grade cartilage loss on MRI is as effective as a semiquantitative system for predicting outcomes after arthroscopic partial meniscectomy, while also offering improved interreader agreement.

The number of lateral hypothalamus orexin/hypocretin neurons contributes to individual differences in cocaine demand.

Lateral hypothalamus (LH) orexin neuron signaling has been implicated in the motivation to seek and take drugs of abuse. The number of LH orexin neurons has been shown to be upregulated with exposure to drugs of abuse. We sought to determine if the number of LH orexin neurons related to individual differences in motivation (demand) for cocaine in our behavioral economics (BE) paradigm, and whether knockdown of these cells predicted changes in economic demand. We quantified LH orexin cell numbers in animals immediately following our BE paradigm, as well as after a 2-week period of abstinence, to relate the number of LH orexin cells to economic demand for cocaine. We also knocked down LH orexin expression with an orexin morpholino antisense to determine how reduced orexin numbers impacted cocaine demand. We found that animals with greater baseline motivation for cocaine (lower demand elasticity) had more LH orexin neurons. Following a 2-week abstinence from cocaine, the number of LH orexin neurons predicted economic demand for cocaine prior to abstinence, indicating that orexin expression is a persistent marker for demand. Reducing LH orexin cell numbers with antisense decreased motivation for cocaine (increased demand elasticity) without affecting baseline consumption. In addition, the number of spared LH orexin neurons after antisense treatment correlated with individual motivation for cocaine. These studies point to a role for the endogenous number of LH orexin neurons in individual differences in motivation for cocaine.

Human basal cell carcinoma: the induction of anagen hair follicle differentiation.

BACKGROUND: Consistent with cancer stem cell driven pattern of growth, human basal cell carcinomas (BCCs) demonstrate differentiation along hair follicle (HF) lineages. AIM: To define the pattern of differentiation and therapeutic targets that promote BCC differentiation and therefore BCC cancer stem cell exhaustion. METHODS: An alkaline phosphatase substrate kit was used to determine dermal papilla cells within the BCC stroma. Autonomous HF cycle-dependent gene expression was identified by analysis of the human homologues of a murine gene set (total 2289 genes) that is differentially expressed in hair cycle phases. The findings were validated by quantitative real-time PCR and immunofluorescence, as well as in vitro transforming growth factor (TGF)-ß2 stimulation of BCC cancer stem cell colonies. RESULTS: As in the HF, keratin expression in the inner root sheath and matrix in BCC correlated with proliferative index and was tightly regulated, despite the absence of dermal papilla cells. Cross-species microarray analysis comparing human BCC and murine synchronous HF growth cycle datasets revealed 74% concordance with telogen differentiation compared with anagen (23%, P < 0.01) and catagen (49%; P < 0.01). Incomplete anagen differentiation within BCC was characterized by reduced expression of the anagen master regulator DLX3 (-5.5-fold), and increased expression of telogen-associated genes: AEBP1 (2.2-fold), DEFB8 (35.3-fold), MMP3 (106.0-fold) and MMP12 (12.9-fold). Restoration of dermal papilla signals by in vitro addition of TGF-ß2 enhanced anagen differentiation. CONCLUSION: Our findings show that BCC cells differentiate along HF lineages and may be susceptible to exogenous HF cycle modulators.

Hair follicle differentiation-specific keratin expression in human basal cell carcinoma.

BACKGROUND: Identification of human basal cell carcinoma (BCC) cancer stem cells and cellular hierarchy inherently implies the presence of differentiation. By conventional histological analysis, BCC demonstrates tumour nodules that appear relatively homogeneous. AIM: As BCCs arise from hair follicle (HF) keratinocytes, we sought to define the pattern of HF differentiation. METHODS: BCC, squamous cell carcinoma (SCC) and normal skin tissues were analysed using a microarray chip. The expression of individual keratins, regulatory pathways and proliferative states were analysed using reverse transcription-PCR and immunofluorescence microscopy. RESULTS: Microarray analysis of BCC, SCC and normal hair-bearing skin revealed that BCCs express a wide range of HF genes, including HF- specific keratins. BCC demonstrated outer (KRT5, KRT514, KRT516, KRT517 and KRT519) and inner (KRT25, KRT27, KRT28, KRT32, KRT35, KRT71, KRT75 and KRT85) root sheath differentiation, but not hair shaft differentiation. As in the HF, differentiation-specific keratins in BCC keratinocytes correlated with a reduced proliferative index and regulatory pathway activation despite the oncogenic drive towards tumour growth. Our findings show the close correlation between HF and BCC keratinocyte differentiation. CONCLUSION: This work has defined the differentiation pattern within BCCs, enabling development of targeted therapies that promote differentiation and result in BCC cancer stem cell exhaustion.

Demand elasticity predicts addiction endophenotypes and the therapeutic efficacy of an orexin/hypocretin-1 receptor antagonist in rats.

Behavioral economics is a powerful, translational approach for measuring drug demand in both humans and animals. Here, we asked if demand for cocaine in rats with limited drug experience could be used to identify individuals most at risk of expressing an addiction phenotype following either long- or intermittent access self-administration schedules, both of which model the transition to uncontrolled drug-seeking. Because the orexin-1 receptor antagonist SB-334867 (SB) is particularly effective at reducing drug-seeking in highly motivated individuals, we also asked whether demand measured after prolonged drug experience could predict SB efficacy. Demand elasticity (α) measured immediately following acquisition of cocaine self-administration ('baseline α') was positively correlated with α assessed after 2w of long- or intermittent access. Baseline α also predicted the magnitude of compulsive responding for cocaine, drug-seeking in initial abstinence and cued reinstatement following long-, intermittent- or standard short access. When demand was measured after these differential access conditions, α predicted the same addiction endophenotypes predicted by baseline α, as well as primed reinstatement and the emergence of negative emotional mood behavior following abstinence. α also predicted the efficacy of SB, such that high demand rats showed greater reductions in motivation for cocaine following SB compared to low demand rats. Together, these findings indicate that α might serve as a behavioral biomarker to predict individuals most likely to progress from controlled to uncontrolled drug use, and to identify individuals most likely to benefit from orexin-based therapies for the treatment of addiction.

Allometric Grip Strength Norms for American Children.

Kocher, MH, Oba, Y, Kimura, IF, Stickley, CD, Morgan, CF, and Hetzler, RK. Allometric grip strength norms for American children. J Strength Cond Res 33(8): 2251-2261, 2019-To develop normative data from a large cohort of American school children (ages 6-18) for unscaled and allometrically scaled handgrip strength data that are uninfluenced by body size (body mass [BM] and stature [Ht]). Data (age, handgrip strength, BM, and Ht) were collected from the 2011-2012 and 2013-2014 National Health and Nutrition Examination Survey databases, resulting in 4,665 cases (2,384 boys and 2,281 girls). Multiple log-linear regressions were used to determine allometric exponents for BM and Ht separately for each age and sex to satisfy the common exponent and group difference principles described by Vanderburgh. Appropriateness of the allometric model was assessed through regression diagnostics, including normality and homoscedasticity of residuals. Allometrically scaled, ratio-scaled, and unscaled grip strength were then correlated with BM and Ht to examine the effectiveness of the procedure in controlling for body size. The data did not allow for development of a common exponent across age and sex that did not violate the common exponent and group difference principles. Correlations between allometrically scaled handgrip strength with BM and Ht were not significant (p ≤ 0.479) and approached zero, unlike correlations of unscaled handgrip strength with BM and Ht (p < 0.001 for all), indicating that allometric scaling was successful in removing the influence of body size. Allometric scaling handgrip strength by age and sex effectively controls for body size (Ht and BM) and perhaps maturation (Ht). The allometric exponents and normative values developed can be used to compare handgrip strength within age and sex while controlling for body size.