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Abstract Background Social behaviour plays a key role in mental health and wellbeing, and developing greater understanding of mechanisms underlying social interaction—particularly social motivation—holds substantial transdiagnostic impact. Common rodent behavioural assays used to assess social behaviour are limited in their assessment of social motivation, whereas the social operant conditioning model can provide unique and valuable insights into social motivation. Further characterisation of common experimental parameters that may influence social motivation within the social operant model, as well as complementary methodological and analytical approaches, are warranted. Methods This study investigated the effects of biological sex, housing condition, and time-of-day, on social motivation using the social operant model. This involved training rats to lever press (FR1) for 60-s access to a social reward (same-sex conspecific stimulus). Subjects were male and female Wistar rats, housed under individual or paired conditions, and sessions were conducted either in the mid-late light phase (ZT6-10) or early-mid dark phase (ZT13-17). A behavioural economics approach was implemented to measure social demand and the influence of stimulus partner sex (same- vs. opposite-sex stimulus) on social operant responding. Additionally, video tracking analyses were conducted to assess the degree of convergence between social appetitive and consummatory behaviours. Results Biological sex, housing conditions, the interaction between sex and housing, and stimulus partner sex potently influenced social motivation, whereas time-of-day did not. Behavioural economics demonstrated that sex, housing, and their interaction influence both the hedonic set-point and elasticity of social demand. Video analysis of social interaction during social operant sessions revealed that social appetitive and consummatory behaviours are not necessarily convergent, and indicate potential social satiety. Lastly, oestrus phase of female experimental and stimulus rats did not impact social motivation within the model. Conclusions Social isolation-dependent sex differences exist in social motivation for rats, as assessed by social operant conditioning. The social operant model represents an optimal preclinical assay that comprehensively evaluates social motivation and offers a platform for future investigations of neurobiological mechanisms underlying sex differences in social motivation. These findings highlight the importance of continued consideration and inclusion of sex as a biological variable in future social operant conditioning studies. Plain English summary Humans are social creatures—our everyday interactions with others and the support this provides play a key role in our wellbeing. For those experiencing mental health conditions, people’s motivation to engage with others can wane, which can lead them to withdraw from those who support them. Therefore, to develop better treatment strategies for these conditions, we need to gain a deeper understanding of social motivation. Studying social behaviour in animals can facilitate this investigation of social motivation as it allows for a causal understanding of underlying neurobiology that is not possible in human experiments. An optimal way to study social motivation in animals is using the social operant conditioning model, where rats learn to press a lever that opens a door and allows them to interact with another rat for a short time. This study characterised the social operant model by testing whether sex, housing conditions, time-of-day, and the sex of the stimulus partner influence rats’ motivation to seek interaction with another rat. We found that female rats were more socially motivated than males, and that rats living alone were more motivated than those living with another rat; interestingly, this effect of housing affected females more than males. Regardless of sex, rats were more motivated to interact with a rat of the opposite sex. These findings provide insights into sex differences in social motivation in rats and new insights into the social operant model which will help guide future research into social motivation and other mental health conditions.

Lisdexamfetamine (LDX) is the only medication to have gained FDA approval for the treatment of binge eating disorder (BED). LDX treatment is generally effective at reducing binge eating symptoms but is associated with several unwanted side effects. How BED patients perceive the therapeutic efficacy vs. associated side effects of LDX has not been explored. We carried out a thematic analysis of 111 online reviews posted to the website Drugs.com by persons prescribed LDX to treat BED. We also explored how qualitative themes were associated with perceptions of treatment efficacy on a quantitative (1–10 scale) scale. Themes associated with higher efficacy ratings included improved binge eating outcomes, enhanced focus/concentration, as well as weight loss (χ2 tests, p's

Summary: Signal-dependent RNA polymerase II (RNA Pol II) productive elongation is an integral component of gene transcription, including that of immediate early genes (IEGs) induced by neuronal activity. However, it remains unclear how productively elongating RNA Pol II overcomes nucleosomal barriers. Using RNAi, three degraders, and several small-molecule inhibitors, we show that the mammalian switch/sucrose non-fermentable (SWI/SNF) complex of neurons (neuronal BRG1/BRM-associated factor or nBAF) is required for activity-induced transcription of neuronal IEGs, including Arc. The nBAF complex facilitates promoter-proximal RNA Pol II pausing and signal-dependent RNA Pol II recruitment (loading) and, importantly, mediates productive elongation in the gene body via interaction with the elongation complex and elongation-competent RNA Pol II. Mechanistically, RNA Pol II elongation is mediated by activity-induced nBAF assembly (especially ARID1A recruitment) and its ATPase activity. Together, our data demonstrate that the nBAF complex regulates several aspects of RNA Pol II transcription and reveal mechanisms underlying activity-induced RNA Pol II elongation. These findings may offer insights into human maladies etiologically associated with mutational interdiction of BAF functions.

Abstract 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.

The orexin 1 receptor (OX1R) is a G-protein coupled receptor that regulates a variety of physiological processes through interactions with the neuropeptides orexin A and B. Selective OX1R antagonists exhibit therapeutic effects in preclinical models of several behavioral disorders, including drug seeking and overeating. However, currently there are no selective OX1R antagonists approved for clinical use, fueling demand for novel compounds that act at this target. In this study, we meticulously curated a dataset comprising over 1300 OX1R ligands using a stringent filter and criteria cascade. Subsequently, we developed highly predictive quantitative structure-activity relationship (QSAR) models employing the optimized hyper-parameters for the random forest machine learning algorithm and twelve 2D molecular descriptors selected by recursive feature elimination with a 5-fold cross-validation process. The predictive capacity of the QSAR model was further assessed using an external test set and enrichment study, confirming its high predictivity. The practical applicability of our final QSAR model was demonstrated through virtual screening of the DrugBank database. This revealed two FDA-approved drugs (isavuconazole and cabozantinib) as potential OX1R ligands, confirmed by radiolabeled OX1R binding assays. To our best knowledge, this study represents the first report of highly predictive QSAR models on a large comprehensive dataset of diverse OX1R ligands, which should prove useful for the discovery and design of new compounds targeting this receptor.

Abstract The acute phase of the COVID-19 pandemic was associated with significant increases in the prevalence and severity of eating disorders (EDs). Studies also highlighted changes to sleep quality and duration in many individuals throughout this period. Although these two phenomena have been examined separately, here we highlight the need to investigate the potential link between these outcomes. Sleep dysregulation and EDs have previously been hypothesized to interact via a positive feedback loop, wherein poor sleep exacerbates ED symptomatology which, in turn, further worsens sleep. Thus, we speculate that the aggravation of sleep disturbances and EDs during COVID-19 lockdowns may have been somewhat interdependent. We further hypothesize that the worsening of depression and anxiety symptomology during the acute phase of the pandemic may have served as an additional mediating variable. Altogether, in our view, these observations highlight a need for future work to examine the possible causal relationship between sleep and ED pathology, which may ultimately lead to improved clinical management of disordered eating.

Abstract As opioid-related fatalities continue to rise, the need for novel opioid use disorder (OUD) treatments could not be more urgent. Two separate hypothalamic neuropeptide systems have shown promise in preclinical OUD models. The oxytocin system, originating in the paraventricular nucleus (PVN), may protect against OUD severity. By contrast, the orexin system, originating in the lateral hypothalamus (LH), may exacerbate OUD severity. Thus, activating the oxytocin system or inhibiting the orexin system are potential therapeutic strategies. The specific role of these systems with regard to specific OUD outcomes, however, is not fully understood. Here, we probed the therapeutic efficacy of pharmacological interventions targeting the orexin or oxytocin system on two distinct metrics of OUD severity in rats—heroin choice (versus choice for natural reward, i.e., food) and cued reward seeking. Using a preclinical model that generates approximately equal choice between heroin and food reward, we examined the impact of exogenously administered oxytocin, an oxytocin receptor antagonist (L-368,899), and a dual orexin receptor antagonist (DORA-12) on opioid choice. Whereas these agents did not alter heroin choice when rewards (heroin and food) were available, oxytocin and DORA-12 each significantly reduced heroin seeking in the presence of competing reward cues when no rewards were available. In addition, the number of LH orexin neurons and PVN oxytocin neurons correlated with specific behavioral economic variables indicative of heroin versus food motivation. These data identify a novel bidirectional role of the oxytocin and orexin systems in the ability of opioid-related cues to bias reward seeking.

IntroductionAmong all Asian American subgroups, Filipino-Americans have consistently been shown to have the highest rates of hypertension, raising risks of heart attack and stroke. Despite this alarming fact, little has been done to investigate culturally-sensitive interventions to control hypertension rates in this vulnerable population. To address the lack of culturally-relevant lifestyle options for blood pressure management currently available to the Filipino community, this exploratory pilot study used a design thinking approach informed by culinary medicine to develop a culturally-tailored, heart-healthy, and low sodium recipe cookbook for Filipino Americans with hypertension and evaluate its feasibility as a hypertension intervention.MethodsOur team developed a cookbook using participatory methods and design thinking, utilizing input from five Filipino culinary experts and a Registered Dietitian. The cookbook incorporates traditional Filipino recipes, excerpts from community members’ interviews, and nutrient analyses. Twenty Filipinx-identifying individuals* who self-reported physician-diagnosed hypertension were recruited from Filipino community-based organizations, enrolled into this study, provided with the cookbook, and asked to cook at least one recipe. Pre- and post-intervention surveys were conducted and centered around behavior change and features of the cookbook.ResultsThis study provided evidence for the cookbook’s acceptability and feasibility, with participants’ open-ended responses revealing that the recipes, nutrition labels, illustrations, and cultural aspects of the cookbook increased motivation to achieve dietary change, including reducing sodium in their diet to improve their blood pressure. Participant responses also indicated positive behavior change as a result of using the cookbook, with participants reporting increased likelihood of adopting recommended actions to lower their BP after utilizing the cookbook (x¯ = 80.83%), compared to before (x¯ = 63.75%, p < 0.008), according to Hypertension Self-Care Management scaled scores.DiscussionIn conclusion, the results of this pilot study demonstrated acceptability of this unique cookbook and provide preliminary findings consistent with increased motivation in participants to make dietary changes and improve personal health, drawing attention to the importance of considering future culturally-tailored health interventions. Next steps should include a robust, randomized controlled trial design comparing measured blood pressure outcomes of an intervention vs. control group. *Filipinx is an inclusive term representing the gender identities of all participants in our study.

The neural circuits underlying rewarding effects of drugs of abuse and natural rewards are not fully understood. Here the authors investigate the role of the infralimbic cortex to nucleus accumbens shell pathway during heroin or food choice in rats.

Background:. The purpose of the present study was to examine whether Black patients presenting for arthroscopic partial meniscectomy (APM) have worse baseline knee pain, worse knee function, and greater articular cartilage damage than White patients. Methods:. A cohort of 3,086 patients (84% of whom were White; 13%, Black; and 3%, other race, with a median age of 53 years) who underwent APM were enrolled. Patients who underwent concomitant procedures and patients of undisclosed race or self-pay status were excluded. The associations of race with the preoperative Knee injury and Osteoarthritis Outcome Score (KOOS) for pain (KOOS-pain) and the KOOS-Physical Function Short Form (KOOS-function) and the intraoperative assessment of cartilage damage (highest modified Outerbridge grading) were determined by multivariate modeling with adjustment for age, sex, insurance status, years of education, smoking status, body mass index (BMI), meniscal tear location, and Veterans RAND 12-Item Health Survey Mental Component Summary (VR-12 MCS) score. Results:. The 3 factors most strongly associated with worse KOOS-pain and KOOS-function were a lower VR-12 MCS score, increased BMI, and increased age. The 3 factors most strongly associated with higher-grade articular cartilage damage were increased age, increased BMI, and meniscal tear location. All of these factors had an unequal distribution between Black and White patients. After adjusting for confounding variables, the KOOS-pain score for Black patients was a mean of 2.6 points lower than that for White patients regardless of insurance status; the KOOS-function score for Black patients with commercial insurance was a mean of 2.4 points lower than that for White patients with commercial insurance but was not lower than that for Black patients on Medicare. Compared with commercially insured White patients, commercially insured Black patients had 1.4-fold greater odds of having higher-grade articular damage, and no difference in risk was detected among Medicare-insured Black patients. Conclusions:. There are clinically important differences in the distribution of risk factors between Black and White patients presenting for APM regarding several factors associated with worse knee pain, knee function, and greater articular cartilage damage. When controlling for these confounding factors, a significant, but not clinically relevant, racial disparity remained with respect to knee pain, knee function, and cartilage damage. Two of the 3 major risk factors for all 3 included age and BMI. The third factor for knee pain and function was mental health, and the location of a meniscal tear was the third factor for articular cartilage damage. Level of Evidence:. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

The history of cerebral aneurysm treatment has a rich and storied past with multiple notable luminaries contributing insights. The modern era has transitioned from primarily clip ligation to increasing use of endovascular therapy. Even more recently, the use of intrasaccular flow diverters has been introduced for the treatment of wide necked aneurysms. The field is continuing to transform, and bioactive coils and stents have resurfaced as promising adjuvants to promote aneurysm healing. Advanced imaging modalities are being developed that could further advance the endovascular arsenal and allow for porous memory polymer devices to enter the field. This focused review highlights notable historic contributions and advances to the point of futuristic technology that is actively being developed.

Abstract 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.

Heightened novelty seeking is a risk factor for the initiation of drug use and development of substance use disorders. In rats, novelty seeking can be examined by assessing preference for a novel environment. Some evidence indicates that high novelty preferring (HNP) rats have higher drug intake compared to low novelty preferring (LNP) rats, although these data are mixed. Moreover, the extent to which the HNP phenotype can predict other initial drug behaviors, including economic demand for cocaine, has not been tested. Here, we screened a cohort (n=60) of male rats for novelty preference and several subsequent cocaine behaviors, including locomotor reactivity to a cocaine priming injection, acquisition of cocaine self-administration, as well as cocaine demand using a within-session behavioral economics procedure. Novelty preference did not correlate with cocaine behaviors, nor were there any differences between HNP and LNP rats identified using a median split strategy. Moreover, regression analyses indicated that novelty preference did not have predictive utility for any of the cocaine behaviors tested. Thus, the extent to which the novelty preference trait can predict initial cocaine-related behaviors in male rats may be limited. This is in contrast to the novel locomotor reactivity phenotype, which is strongly linked with initial cocaine intake, indicating that these traits are distinct and differentially predict cocaine behaviors in rats.

Background: Management of bone loss in recurrent traumatic anterior shoulder instability remains a topic of debate and controversy in the orthopedic community. The purpose of this study was to survey members of 4 North American orthopedic surgeon associations to assess management trends for bone loss in recurrent anterior shoulder instability. Methods: An online survey was distributed to all members of the American Shoulder and Elbow Surgeons, American Orthopaedic Society for Sports Medicine, and Canadian Orthopaedic Association and to fellow members of the Arthroscopy Association of North America. The survey comprised 3 sections assessing the demographic characteristics of survey respondents, the influence of prognostic factors on surgical decision making, and the operative management of 12 clinical case scenarios of varying bone loss that may be encountered in clinical practice. Results: A total of 150 survey responses were returned. The age of the patient and quantity of bone loss were consistently considered important prognostic criteria. However, little consensus was reached for critical thresholds of bone loss and how this affected the timing (ie, primary or revision surgery) and type of bony augmentation procedure to be performed once a critical threshold was reached, especially in the context of critical humeral and bipolar bone loss. Conclusions: Consistent trends were found for the management of recurrent anterior shoulder instability in cases in which no bone loss existed and when isolated critical glenoid bone loss was present. However, inconsistencies were observed when isolated critical humeral bone loss and bipolar bone loss were present.

Abstract Transcatheter aortic valve replacement (TAVR) is a minimally invasive approach to treat symptomatic severe aortic stenosis. The patient populations that have been shown to benefit from this procedure continue to grow with time. Techniques and technology in TAVR persistently advance with a continued trend toward improved outcomes for patients. In this review, we highlight the advances in vascular access, TAVR valve design, progress in reducing procedural complications, and emerging evidence in the field.

Sarcina Ventriculi is a gram-positive organism, rarely encountered as a human pathogen. It has been described in stomach specimens, often in patients with delayed gastric emptying. The exact role of this organism in human disease is not clear. In this case report, we describe a case of Sarcina organism associated with gastric ulceration. This organism is likely underreported and often overlooked, as it may not be obvious on routine staining. Awareness of this organism and further studies are needed to understand its role in human disease.

Background: There was lack of data on the burdens and trends of upper and lower respiratory infections (URIs and LRIs) over the past three decades in China. Methods: We estimated the incidence, mortality, and disability-adjusted life years (DALYs) due to upper and lower respiratory infections (URIs and LRIs) and attributable risk factors in China by a systematic analysis of the Global Burden of Disease 2019 study. Incidence, mortality, and DALYs were stratified by sex, age, and province. Risk factors for respiratory infections were analyzed from exposure data. Findings: The age-standardized incidence rates of URIs and LRIs were 179,077 and 3926 per 100,000 persons in 2019, with a 7•52% and 35•07% decrease from 1990, respectively. Moreover, 2801 and 185,264 persons died of URIs and LRIs in 2019, respectively. DALYs for URIs and LRIs also decreased from 1,516,727 in 1990 to 928,617 in 2019 and from 38,278,504 in 1990 to 4,020,676 in 2019. The burden of URIs and LRIs were generally similar in males and females, but relatively higher in the new-borns and the elderly. Child malnutrition and low birth weight were the most important cause of age-standardized DALYs of LRIs and URIs, respectively. Interpretation: Future URI and LRI prevention strategies should focus on the maternal and child health, air pollution, and tobacco control, especially in young children and the elderly population. Funding: National Key R&D Program of China (2018YFA0606200); National Natural Science Foundation of China (82041021); Fundamental Research Funds for the Central Universities (20ykpy86) and Guangdong Basic and Applied Basic Research Foundation (2019A1515110003); Bill & Melinda Gates Foundation (No.: INV-006371).

Microbes have the potential to affect multitrophic plant–insect–predator interactions. We examined whether cotton plants treated with potentially beneficial fungi affect interactions between cotton aphids Aphis gossypii and predatory lady beetles Hippodamia convergens. We used Y-tube olfactometer assays to test lady beetle behavioral responses to stimuli emitted by aphid-infested and non-infested cotton plants grown from seeds treated with either Phialemonium inflatum (TAMU490) or Chaetomium globosum (TAMU520) versus untreated control plants. We tested a total of 960 lady beetles (480 males and 480 females) that had been deprived of food for approximately 24 h. In the absence of any fungal treatments, males preferred stimuli from aphid-infested plants, and females spent more time associated with stimuli from aphid-infested versus non-infested plants. When fungal treatments were added, we observed that lady beetles preferred non-aphid-infested P. inflatum plants, and males responded slower to plants treated with P. inflatum in the absence of aphids. We found some evidence to suggest that lady beetle behavioral responses to plants might vary according to the fungal treatment but not strongly impact their use as part of an insect pest management strategy.

Abstract Background Meniscal tears often accompany knee osteoarthritis, a disabling condition affecting 14 million individuals in the United States. While several randomized controlled trials have compared physical therapy to surgery for individuals with knee pain, meniscal tear, and osteoarthritic changes (determined via radiographs or magnetic resonance imaging), no trial has evaluated the efficacy of physical therapy alone in these subjects. Methods The Treatment of Meniscal Tear in Osteoarthritis (TeMPO) Trial is a four-arm multi-center randomized controlled clinical trial designed to establish the comparative efficacy of two in-clinic physical therapy interventions (one focused on strengthening and one containing placebo) and two protocolized home exercise programs. Discussion The goal of this paper is to present the rationale behind TeMPO and describe the study design and implementation strategies, focusing on methodologic and clinical challenges. Trial registration The TeMPO Trial was first registered at clinicaltrials.gov with registration No. NCT03059004. on February 14, 2017.

Noradrenergic pathways have been implicated in eating pathologies. These experiments sought to examine how dietary-induced binge eating influences the neuronal activity of the locus coeruleus (LC)-norepinephrine (NE) system. Young adult female Sprague Dawley rats (7–8 weeks old) were exposed to a repeated intermittent (twice weekly) cycle of 30-min access to a highly palatable sweetened fat (i.e., vegetable shortening with 10% sucrose) with or without intermittent (24 h) calorie restriction (Restrict Binge or Binge groups, respectively). Age- and weight-matched female control rats were exposed to standard chow feeding (Naive group) or intermittent chow feeding (Restrict group). The Binge and Restrict Binge groups demonstrated an escalation in sweet-fat food intake after 2.5 weeks. On week 3, in vivo single-unit LC electrophysiological activity was recorded under isoflurane anesthesia. Restrict Binge (20 cells from six rats) and Binge (27 cells from six rats) had significantly reduced (approximate 20% and 26%, respectively) evoked LC discharge rates compared with naive rats (22 cells, seven rats). Spontaneous and tonic discharge rates were not different among the groups. Signal-to-noise ratio was reduced in the groups with intermittent sweetened fat exposure. In order to investigate the neuropeptide alterations as a consequence of dietary binge eating, relative gene expression of neuropeptide Y (NPY), glucagon-like peptide 1 receptor (GLP-1r), prodynorphin, and related genes were measured in LC and hypothalamic arcuate (Arc) regions. Glp-1r, Npy2r, and Pdyn in LC region were reduced with repeated intermittent restriction. Npy1r was reduced by approximately 27% in ARC of Restrict compared with Naive group. Such data indicate that dietary-induced binge eating alters the neural response of LC neurons to sensory stimuli and dampens the neural stress response.

Melanoma pathogenesis from normal neural crest-derived melanocytes is often fatal due to aggressive cell invasion throughout the body. The identification of signals that reprogram de-differentiated, metastatic melanoma cells to a less aggressive and stable phenotype would provide a novel strategy to limit disease progression. In this study, we identify and test the function of developmental signals within the chick embryonic neural crest microenvironment to reprogram and sustain the transition of human metastatic melanoma to a neural crest cell-like phenotype. Results reveal that co-culture of the highly aggressive and metastatic human melanoma cell line C8161 upregulate a marker of melanosome formation (Mart-1) in the presence of embryonic day 3.5 chick trunk dorsal root ganglia. We identify nerve growth factor (NGF) as the signal within this tissue driving Mart-1 re-expression and show that NGF receptors trkA and p75 cooperate to induce Mart-1 re-expression. Furthermore, Mart-1 expressing C8161 cells acquire a gene signature of poorly aggressive C81-61 cells. These data suggest that targeting NGF signaling may yield a novel strategy to reprogram metastatic melanoma toward a benign cell type.

In this manuscript we examine an accelerated charged particle moving through an optical medium, and explore the emission of accelerated-Cherenkov radiation. The particle’s reaction to acceleration creates a low-frequency spectral cutoff in the Cherenkov emission that has a sharp resonance at the superluminal threshold. Moreover, the effect of recoil on the radiation is incorporated kinematically through the use of an Unruh-DeWitt detector by setting an energy gap, i.e. the change in electron energy, to the recoil energy of the emitted photon. The simultaneous presence of recoil and acceleration conspire to produce a localized resonance peak in the emission. These theoretical considerations could be used to construct high precision tests of radiation reaction using Cherenkov emission under acceleration.

Arthroscopic partial meniscectomy (APM) is extensively used to relieve pain in patients with symptomatic meniscal tear (MT) and knee osteoarthritis (OA). Recent studies have failed to show the superiority of APM compared to other treatments. We aim to examine whether existing evidence is sufficient to reject use of APM as a cost-effective treatment for MT+OA.We built a patient-level microsimulation using Monte Carlo methods and evaluated three strategies: Physical therapy ('PT') alone; PT followed by APM if subjects continued to experience pain ('Delayed APM'); and 'Immediate APM'. Our subject population was US adults with symptomatic MT and knee OA over a 10 year time horizon. We assessed treatment outcomes using societal costs, quality-adjusted life years (QALYs), and calculated incremental cost-effectiveness ratios (ICERs), incorporating productivity costs as a sensitivity analysis. We also conducted a value-of-information analysis using probabilistic sensitivity analyses.Calculated ICERs were estimated to be $12,900/QALY for Delayed APM as compared to PT and $103,200/QALY for Immediate APM as compared to Delayed APM. In sensitivity analyses, inclusion of time costs made Delayed APM cost-saving as compared to PT. Improving efficacy of Delayed APM led to higher incremental costs and lower incremental effectiveness of Immediate APM in comparison to Delayed APM. Probabilistic sensitivity analyses indicated that PT had 3.0% probability of being cost-effective at a willingness-to-pay (WTP) threshold of $50,000/QALY. Delayed APM was cost effective 57.7% of the time at WTP = $50,000/QALY and 50.2% at WTP = $100,000/QALY. The probability of Immediate APM being cost-effective did not exceed 50% unless WTP exceeded $103,000/QALY.We conclude that current cost-effectiveness evidence does not support unqualified rejection of either Immediate or Delayed APM for the treatment of MT+OA. The amount to which society would be willing to pay for additional information on treatment outcomes greatly exceeds the cost of conducting another randomized controlled trial on APM.

IntroductionAmong all Asian American subgroups, Filipino-Americans have consistently been shown to have the highest rates of hypertension, raising risks of heart attack and stroke. Despite this alarming fact, little has been done to investigate culturally-sensitive interventions to control hypertension rates in this vulnerable population. To address the lack of culturally-relevant lifestyle options for blood pressure management currently available to the Filipino community, this exploratory pilot study used a design thinking approach informed by culinary medicine to develop a culturally-tailored, heart-healthy, and low sodium recipe cookbook for Filipino Americans with hypertension and evaluate its feasibility as a hypertension intervention.MethodsOur team developed a cookbook using participatory methods and design thinking, utilizing input from five Filipino culinary experts and a Registered Dietitian. The cookbook incorporates traditional Filipino recipes, excerpts from community members' interviews, and nutrient analyses. Twenty Filipinx-identifying individuals* who self-reported physician-diagnosed hypertension were recruited from Filipino community-based organizations, enrolled into this study, provided with the cookbook, and asked to cook at least one recipe. Pre- and post-intervention surveys were conducted and centered around behavior change and features of the cookbook.ResultsThis study provided evidence for the cookbook's acceptability and feasibility, with participants' open-ended responses revealing that the recipes, nutrition labels, illustrations, and cultural aspects of the cookbook increased motivation to achieve dietary change, including reducing sodium in their diet to improve their blood pressure. Participant responses also indicated positive behavior change as a result of using the cookbook, with participants reporting increased likelihood of adopting recommended actions to lower their BP after utilizing the cookbook ( x¯ = 80.83%), compared to before ( x¯ = 63.75%, p < 0.008), according to Hypertension Self-Care Management scaled scores.DiscussionIn conclusion, the results of this pilot study demonstrated acceptability of this unique cookbook and provide preliminary findings consistent with increased motivation in participants to make dietary changes and improve personal health, drawing attention to the importance of considering future culturally-tailored health interventions. Next steps should include a robust, randomized controlled trial design comparing measured blood pressure outcomes of an intervention vs. control group. *Filipinx is an inclusive term representing the gender identities of all participants in our study.

Recent work has established that the paraventricular thalamus (PVT) is a central node in the brain reward-seeking pathway. This role is likely mediated in part through the dense projections to the PVT from hypothalamic peptide transmitter systems such as orexin, and cocaine- and amphetamine-regulated transcript (CART), both of which play key roles in drug-seeking behaviour. Consistent with this proposition, we previously found that inactivation of the PVT or infusions of CART into the PVT suppressed drug-seeking behaviour in an animal model of contingent cocaine self-administration. Despite this work, very few studies have assessed the basic physiological properties of PVT neurons and how these parameters are altered by exposure to drugs such as cocaine. We set out to address these questions by employing an electrophysiological approach to record from anterior PVT (aPVT) neurons from cocaine-treated and control animals. First, we determined the excitability of aPVT neurons by injecting a series of depolarizing current steps and characterizing the resulting action potential (AP) discharge properties. Second, we investigated the effects of CART on excitatory synaptic inputs to aPVT neurons. We found that the majority of aPVT neurons exhibited tonic firing (TF), and initial bursting (IB) consistent with previous studies. However, we also identified PVT neurons that exhibited delayed firing (DF), single spiking (SS) and reluctant firing (RF). Interestingly, cocaine exposure shifted the proportion of aPVT neurons that exhibited TF. Further, application of CART suppressed excitatory synaptic drive to PVT. This finding is consistent with our previous behavioural data, which showed that CART signaling in the PVT negatively regulates drug-seeking behaviour. Together, these studies support previous anatomical evidence that the PVT can integrate reward-relevant information and provides a putative mechanism through which drugs of abuse can dysregulate this system in addiction.

Early life stress (ELS) is a known antecedent for the development of mood disorders such as depression. Orexin neurons drive arousal and motivated behaviors in response to stress. We tested the hypothesis that ELS alters orexin system function and leads to an altered stress-induced behavioral phenotype in adulthood. We also investigated if voluntary exercise during adolescent development could reverse the ELS-induced changes. Male and female Wistar rats were subjected to maternal separation stress on postnatal days (PND) 2-14. A subset of animals was given access to running wheels in late adolescence (1hr/day, PND40-70). In adulthood, rats were exposed to restraint stress and then tested on the open field (OF) and elevated plus maze (EPM). Brains were processed for Fos-protein and orexin or tyrosine hydroxylase immunohistochemistry. Restraint stress stimulated Fos-protein expression in perifornical area orexin cells, the paraventricular hypothalamic nucleus, and paraventricular thalamic nuclei, but this neuronal response was dampened in male and female rats exposed to ELS. ELS also reduced exploration in the OF, without affecting EPM behavior. These neural and behavioral changes are consistent with a depressive-like phenotype. Adolescent exercise reversed the orexin deficits in ELS males. Exercise was not protective in females, although this may be due to sex differences in running behaviour. Our findings highlight the inherent plasticity of the orexin system—a trait that may lead to a state of pathological rewiring but could also be treated using non-pharmacological approaches. We also highlight a need to better understand the sex-specific changes in orexin circuits and stress-related pathology.

The tight regulation of sleep/wake states is critical for mental and physiological wellbeing. For example, dysregulation of sleep/wake systems predisposes individuals to metabolic disorders such as obesity and psychiatric problems, including depression. Contributing to this understanding, the last decade has seen significant advances in our appreciation of the complex interactions between brain systems that control the transition between sleep and wake states. A pivotal moment in this pathway to discovery was the description of a group of neurons in the lateral hypothalamus (LH) that express the neuropeptides orexin A and B (hypocretin, Hcrt-1 and Hcrt-2). Orexin neurons were quickly placed at centre stage with the demonstration that loss of normal orexin function is associated with the development of narcolepsy – a condition in which sufferers fail to maintain normal levels of daytime wakefulness. Since these initial seminal findings, much progress has been made in our understanding of the physiology and function of the orexin system. For example, the orexin system has been identified as a key modulator of autonomic and neuroendocrine function, arousal and reward and attention. Notably, studies in animals suggest that dysregulation of orexin function is associated with neuropsychiatric states such as addiction and mood disorders including depression and anxiety. This review discusses the progress associated with therapeutic attempts to restore orexin system function and treat neuropsychiatric conditions such as addiction, depression and anxiety. We also highlight potential pitfalls and challenges associated with targeting this system to treat these neuropsychiatric states.

Animal and human studies have demonstrated that early pain experiences can produce alterations in the nociceptive systems later in life including increased sensitivity to mechanical, thermal, and chemical stimuli. However, less is known about the impact of neonatal immune challenge on future responses to noxious stimuli and the reactivity of neural substrates involved in analgesia. Here we demonstrate that rats exposed to Lipopolysaccharide (LPS; 0.05 mg/kg IP, Salmonella enteritidis) during postnatal day (PND) 3 and 5 displayed enhanced formalin-induced flinching but not licking following formalin injection at PND 22. This LPS-induced hyperalgesia was accompanied by distinct recruitment of supra-spinal regions involved in analgesia as indicated by significantly attenuated Fos-protein induction in the rostral dorsal periaqueductal grey (DPAG) as well as rostral and caudal axes of the ventrolateral PAG (VLPAG). Formalin injections were associated with increased Fos-protein labelling in lateral habenula (LHb) as compared to medial habenula (MHb), however the intensity of this labelling did not differ as a result of neonatal immune challenge. These data highlight the importance of neonatal immune priming in programming inflammatory pain sensitivity later in development and highlight the PAG as a possible mediator of this process.

Over 4000 flavonoids have been identified so far and among these, many are known to have antitumor activities. The basis of the relationships between chemical structures, type and position of substituent groups and the effects these compounds exert specifically on cancer cells are not completely elucidated. Here we report the differential cytotoxic effects of two flavone isomers on human cancer cells from breast (MCF7, SK-BR-3), colon (Caco-2, HCT116), pancreas (MIA PaCa, Panc 28), and prostate (PC3, LNCaP) that vary in differentiation status and tumorigenic potential. These flavones are derived from plants of the family Asteraceae, genera Gnaphalium and Achyrocline reputed to have anti-cancer properties. Our studies indicate that 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5,7-dihydroxy-3,6,8-trimethoxy flavone) displays potent activity against more differentiated carcinomas of the colon (Caco-2), and pancreas (Panc28), whereas 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone) cytototoxic action is observed on poorly differentiated carcinomas of the colon (HCT116), pancreas (Mia PaCa), and breast (SK-BR3). Both flavones induced cell death (>50%) as proven by MTT cell viability assay in these cancer cell lines, all of which are regarded as highly tumorigenic. At the concentrations studied (5-80 µM), neither flavone demonstrated activity against the less tumorigenic cell lines, breast cancer MCF-7 cells, androgen-responsive LNCaP human prostate cancer line, and androgen-unresponsive PC3 prostate cancer cells. 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5,7-dihydroxy-3,6,8-trimethoxy flavone) displays activity against more differentiated carcinomas of the colon and pancreas, but minimal cytotoxicity on poorly differentiated carcinomas of these organs. On the contrary, 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone) is highly cytotoxic to poorly differentiated carcinomas of the colon, pancreas, and breast with minimal activity against more differentiated carcinomas of the same organs. These differential effects suggest activation of distinct apoptotic pathways. In conclusion, the specific chemical properties of these two flavone isomers dictate mechanistic properties which may be relevant when evaluating biological responses to flavones.

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.