The Relative Reinforcing Value of Menthol Among Young Adult Cigarette Smokers: Results From a Behavioral Choice Task.

INTRODUCTION: Menthol cigarettes are associated with experimentation and progression to regular use. Although reinforcement processes likely underlie menthol's appeal, the reinforcing value of menthol cigarettes remains unknown. AIMS AND METHODS: This study examined the relative reinforcing value (RRV) of menthol versus nonmenthol cigarettes in young adult menthol (n = 54) and nonmenthol (n = 53) smokers, and differences in menthol's RRV by race, ethnicity, and sexual orientation. Overnight abstinent participants completed a choice task assessing willingness to "work" to click targets on a computer screen to earn menthol or nonmenthol cigarette puffs. A progressive ratio schedule was used where the menthol target had to be clicked progressively more times, over 10 trials, to earn a menthol cigarette puff, while clicks for the nonmenthol target were fixed across trials. RRV for menthol was defined by the breakpoint, or the highest trial (out of to 10) completed for a menthol cigarette puff. Number of clicks for menthol and nonmenthol puffs were also examined. RESULTS: Menthol smokers worked harder for menthol versus nonmenthol cigarette puffs (breakpoint = 9.17; ~1236 clicks vs. 24 clicks). Breakpoint was higher among Hispanic (6.49) versus NH White (4.83) and NH non-White smokers (4.43). In exploratory analyses of interactions of menthol preference with race and ethnicity, nonmenthol Hispanic smokers worked harder for menthol cigarette puffs versus NH non-White and NH White nonmenthol smokers. CONCLUSIONS: Menthol cigarettes are highly reinforcing for young adult menthol and Hispanic smokers. A menthol ban may reduce addiction risk among younger individuals and some minoritized groups of smokers. IMPLICATIONS: This study provides evidence of the greater relative reinforcing value of menthol compared to nonmenthol cigarettes among young adults who had a cigarette flavor preference, suggesting increased addiction risk of menthol cigarettes. Young adult menthol smokers and Hispanic (vs. non-Hispanic) smokers worked harder to earn menthol (vs. nonmenthol) cigarette puffs. Findings add to the evidence base supporting the U.S. Food and Drug Administration's (FDA) intent to ban menthol in cigarettes. Further, prevention messaging campaigns and cessation programs should take into account the reinforcing value of menthol in cigarettes, especially in vulnerable and at-risk populations.

Inhibitors identify an auxiliary role for mTOR signalling in necroptosis execution downstream of MLKL activation.

Necroptosis is a lytic and pro-inflammatory form of programmed cell death executed by the terminal effector, the MLKL (mixed lineage kinase domain-like) pseudokinase. Downstream of death and Toll-like receptor stimulation, MLKL is trafficked to the plasma membrane via the Golgi-, actin- and microtubule-machinery, where activated MLKL accumulates until a critical lytic threshold is exceeded and cell death ensues. Mechanistically, MLKL's lytic function relies on disengagement of the N-terminal membrane-permeabilising four-helix bundle domain from the central autoinhibitory brace helix: a process that can be experimentally mimicked by introducing the R30E MLKL mutation to induce stimulus-independent cell death. Here, we screened a library of 429 kinase inhibitors for their capacity to block R30E MLKL-mediated cell death, to identify co-effectors in the terminal steps of necroptotic signalling. We identified 13 compounds - ABT-578, AR-A014418, AZD1480, AZD5363, Idelalisib, Ipatasertib, LJI308, PHA-793887, Rapamycin, Ridaforolimus, SMI-4a, Temsirolimus and Tideglusib - each of which inhibits mammalian target of rapamycin (mTOR) signalling or regulators thereof, and blocked constitutive cell death executed by R30E MLKL. Our study implicates mTOR signalling as an auxiliary factor in promoting the transport of activated MLKL oligomers to the plasma membrane, where they accumulate into hotspots that permeabilise the lipid bilayer to cause cell death.

Large-scale genomic investigation of pediatric cholestasis reveals a novel hepatorenal ciliopathy caused by PSKH1 mutations.

PURPOSE: Pediatric cholestasis is the phenotypic expression of clinically and genetically heterogeneous disorders of bile acid synthesis and flow. Although a growing number of monogenic causes of pediatric cholestasis have been identified, the majority of cases remain undiagnosed molecularly. METHODS: In a cohort of 299 pediatric participants (279 families) with intrahepatic cholestasis, we performed exome sequencing as a first-tier diagnostic test. RESULTS: A likely causal variant was identified in 135 families (48.56%). These comprise 135 families that harbor variants spanning 37 genes with established or tentative links to cholestasis. In addition, we propose a novel candidate gene (PSKH1) (HGNC:9529) in 4 families. PSKH1 was particularly compelling because of strong linkage in 3 consanguineous families who shared a novel hepatorenal ciliopathy phenotype. Two of the 4 families shared a founder homozygous variant, whereas the third and fourth had different homozygous variants in PSKH1. PSKH1 encodes a putative protein serine kinase of unknown function. Patient fibroblasts displayed abnormal cilia that are long and show abnormal transport. A homozygous Pskh1 mutant mouse faithfully recapitulated the human phenotype and displayed abnormally long cilia. The phenotype could be rationalized by the loss of catalytic activity observed for each recombinant PSKH1 variant using in vitro kinase assays. CONCLUSION: Our results support the use of genomics in the workup of pediatric cholestasis and reveal PSKH1-related hepatorenal ciliopathy as a novel candidate monogenic form.

Behavioral economic analysis of the comorbidity of alcohol problems and posttraumatic stress: Findings from high-risk young adults and general community adults.

A behavioral economic reinforcer pathology model theorizes that alcohol problems are influenced by steep delay discounting, overvaluation of alcohol reinforcement, and low reinforcement from alcohol-free activities. Extending this account to the comorbidity of alcohol problems and posttraumatic stress disorder (PTSD), the present study tested the hypothesis that alcohol problems and PTSD symptom severity would interact and be positively associated with indicators from these three domains. High-risk emerging adults from North America (Study 1, n = 1,311, Mage = 22.13) and general community adults from Canada (Study 2, n = 1,506, Mage = 36.80) completed measures of alcohol problems, PTSD symptoms, delay discounting, alcohol demand, and proportionate alcohol-related reinforcement. Across studies, regression analyses revealed significant main effects of alcohol problems and PTSD symptoms in relation to selected reinforcer pathology indicators, but no significant interactions were present for delay discounting or proportionate alcohol-related reinforcement. Interactions were observed for alcohol consumption at $0 (intensity) and the rate of change in consumption across the demand curve (elasticity; Study 1) and for elasticity and maximum alcohol expenditure (Omax; Study 2), but not in the predicted directions. Higher synergistic severity was associated with lower alcohol reinforcing value in each case. These findings reveal expected relations between reinforcer pathology indicators and both alcohol problems and PTSD symptomatology in general but did not support the hypothesized synergistic relationship. The relation between alcohol problems and PTSD is more complex than predicted by existing extensions of the reinforcer pathology model, warranting further investigation. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Horizontal and vertical distribution of Clarireedia spp., in asymptomatic and symptomatic creeping bentgrass cultivars.

Dollar spot is an important disease of both cool- and warm-season turfgrasses caused by six fungal species in the genus Clarireedia, yet the ecology and epidemiology of these pathogens remains poorly understood. The goal of this study was to determine the distribution of Clarireedia in asymptomatic and symptomatic creeping bentgrass (Agrostis stolonifera) in the field using a previously developed qPCR assay. To determine the horizontal distribution of the pathogen, the abundance of Clarireedia spp. was measured in leaf and crown tissue from 90, 1-cm diameter cores spaced 10-cm apart in May 2019 and 2020 (asymptomatic tissue) and August 2019 and July 2020 (symptomatic tissue). Thirty-seven to 69% of cores sampled from asymptomatic turfgrass and 77 to 95% of cores taken from symptomatic turfgrass yielded positive detections for Clarireedia. Spatial analysis indicated that Clarireedia was randomly distributed in the field in both asymptomatic and symptomatic turfgrass. To assess the vertical distribution of the pathogen, the abundance of Clarireedia was measured in the foliar, crown, and thatch layers of 39, 1-cm dia. x 2.5-cm deep cores of creeping bentgrass maintained at fairway height (9.5 mm) during 2019 and 2020. Clarireedia was most abundant in foliar tissue, followed by crown tissue, and thatch (lowest abundance) throughout the two-year study. Both studies provide evidence that Clarireedia is widely distributed in turfgrass swards prior to symptom development and that it can persist within turfgrass as an endophyte. These findings will improve our understanding of Clarireedia epidemiology and may lead to more sustainable dollar spot management.

First Report of Phialocephala bamuru Causing Root Rot on Hard Fescue (Festuca brevipila) in the United States.

Turfgrasses are susceptible to a wide variety of ectotrophic root-infecting (ERI) fungi that cause root rot (Tredway et al., 2023). Among the root rot diseases, fairway patch, caused by Phialocephala bamuru P.T.W. Wong & C. Dong sp. nov., was recently identified and characterized in Australia infecting bermudagrass (Cynodon dactylon) and kikuyu (Pennisetum clandestinum) grass (Wong et al., 2015). Symptoms begin as small, 5-10 cm diameter patches of yellowed turf that may coalesce into larger areas of diseased grass. A characteristic sign of fairway patch is roots colonized by dark brown to black, ectotrophic mycelium. In June 2020, many tan colored, irregular-shaped patches ranging from 10-30 cm in diameter developed on a hard fescue (Festuca brevipila) cultivar 'Beacon' turfgrass field in North Brunswick, New Jersey, USA. The centers of these patches later died and became sunken or filled in partially by recovering hard fescue. The patches grew into tan irregular-shaped rings with diameters up to 3 m by Aug 2023. Symptoms were indicative of a root disease. Five 'Beacon' hard fescue soil cores at the interface of the symptomatic and non-symptomatic area were sampled in Aug 2023. Root and crown samples were observed under a dissecting microscope and dark ectotrophic hyphae were observed on both. Roots with visible ectotrophic mycelium were removed, rinsed in sterile water three times, cut into 5 mm pieces, and plated onto 10% potato dextrose agar amended with streptomycin and gentamicin at 100 mg/L (PDA+). The plates were incubated at 25°C in the dark for 5 days. The most abundant colonies being characteristic long, septate hyphae that were hyaline at the edge and dark brown to black in the center and resembled the fungus described in Wong et al., 2015. These colonies were subcultured onto PDA+ medium and selected for molecular identification. Other less abundant colonies could be identified using morphology after subcultured and had no record being pathogenic to turfgrass. To confirm the isolate's identity, its internal transcribed spacer (ITS) region was amplified in PCR using the ITS1F/ITS4 primers (Bellemain et al., 2010). The amplicon was then sequenced with both ITS1 and ITS4 primers by Sanger sequencing. Sequences were assembled (GenBank #PP000819). The consensus sequence was then BLASTn analyzed with default settings, and the result showed 99.64% sequence identity with P. bamuru (GenBank #MG195534.1). Koch's postulate was conducted in an environmentally controlled growth chamber. Six healthy 'Beacon' hard fescue plugs were sampled from the field. Three of the six plugs (treatment) were each inoculated with P. bamuru by placing 20 g of P. bamuru colonized millets beneath and around the plug before filling the pots with sand. The other three plugs (control) received the same treatment except the P. bamuru colonized millets were autoclaved. The pots were incubated in the growth chamber with a 16 h light period and 25/20°C day/night temperatures. Symptoms resembling those observed in the field appeared on the treatment pots after 21 days of incubation while the control pots remained healthy. The roots from the treatment pots were examined under the dissecting microscope to confirm the colonization of P. bamuru on the roots, and P. bamuru was reisolated and confirmed using the aforementioned morphological traits and molecular assays (GenBank #PP000820). This is the first report of a turfgrass root rot disease caused by P. bamuru in the United States. Further epidemiological, disease ecological, and pathogen biological studies are required to clarify the importance of this disease in the United States and establish proper disease containment or control measures.

Smoking Cessation Tool Utilization Among Individuals with and Without Cancer Across Smoking Status.

Background: There are many tools to assist with cigarette smoking cessation (e.g., counseling, pharmacotherapy). However, tool use among cancer patients is understudied despite the consequences of continued smoking after a cancer diagnosis.Objectives: Study aims included describing and comparing cessation tool use among individuals with and without cancer who were currently smoking and who quit to determine if there are different preferences among those with cancer.Methods: Participants (N = 203) completed an online survey about demographics, cigarette use, and cessation tool use.Results: Eighty-nine participants reported being diagnosed with cancer (45 quit after diagnosis, 44 currently smoking) and 114 reported not having cancer (57 quit, 57 currently smoking). Individuals with cancer who were smoking used more evidence-based resources than those with cancer who quit (B = 1.86, SE = 0.50, p < 0.0001). Individuals with cancer who were smoking used more total cessation resources than participants without cancer who were smoking (B = 2.00, SE = 0.58, p = 0.001), but there was no difference in use of evidence-based resources between these two groups (p > 0.05). Lastly, individuals with cancer who quit also used more total cessation tools (B = 1.23, SE = 0.41, p = 0.003) and evidence-based tools (B = 1.03, SE = 0.36, p = 0.005) than those without cancer who quit.Conclusions: Individuals with cancer may be using more resources before successfully quitting. Cancer patients may need additional help to quit smoking, and further research is needed to better understand unique barriers that preclude quitting among this vulnerable population.

Death at a funeral: Activation of the dead enzyme, MLKL, to kill cells by necroptosis.

Necroptosis is a lytic form of programmed cell death implicated in inflammatory pathologies, leading to intense interest in the underlying mechanisms and therapeutic prospects. Here, we review our current structural understanding of how the terminal executioner of the pathway, the dead kinase, mixed lineage kinase domain-like (MLKL), is converted from a dormant to killer form by the upstream regulatory kinase, RIPK3. RIPK3-mediated phosphorylation of MLKL's pseudokinase domain toggles a molecular switch that induces dissociation from a cytoplasmic platform, assembly of MLKL oligomers, and trafficking to the plasma membrane, where activated MLKL accumulates and permeabilises the lipid bilayer to induce cell death. We highlight gaps in mechanistic knowledge of MLKL's activation, how mechanisms diverge between species, and the power of modelling in advancing structural insights.

Racial disparities in colorectal cancer outcomes and access to care: a multi-cohort analysis.

Introduction: Non-Hispanic Black (NHB) Americans have a higher incidence of colorectal cancer (CRC) and worse survival than non-Hispanic white (NHW) Americans, but the relative contributions of biological versus access to care remain poorly characterized. This study used two nationwide cohorts in different healthcare contexts to study health system effects on this disparity. Methods: We used data from the Surveillance, Epidemiology, and End Results (SEER) registry as well as the United States Veterans Health Administration (VA) to identify adults diagnosed with colorectal cancer between 2010 and 2020 who identified as non-Hispanic Black (NHB) or non-Hispanic white (NHW). Stratified survival analyses were performed using a primary endpoint of overall survival, and sensitivity analyses were performed using cancer-specific survival. Results: We identified 263,893 CRC patients in the SEER registry (36,662 (14%) NHB; 226,271 (86%) NHW) and 24,375 VA patients (4,860 (20%) NHB; 19,515 (80%) NHW). In the SEER registry, NHB patients had worse OS than NHW patients: median OS of 57 months (95% confidence interval (CI) 55-58) versus 72 months (95% CI 71-73) (hazard ratio (HR) 1.14, 95% CI 1.12-1.15, p = 0.001). In contrast, VA NHB median OS was 65 months (95% CI 62-69) versus NHW 69 months (95% CI 97-71) (HR 1.02, 95% CI 0.98-1.07, p = 0.375). There was significant interaction in the SEER registry between race and Medicare age eligibility (p < 0.001); NHB race had more effect in patients <65 years old (HR 1.44, 95% CI 1.39-1.49, p < 0.001) than in those ≥65 (HR 1.13, 95% CI 1.11-1.15, p < 0.001). In the VA, age stratification was not significant (p = 0.21). Discussion: Racial disparities in CRC survival in the general US population are significantly attenuated in Medicare-aged patients. This pattern is not present in the VA, suggesting that access to care may be an important component of racial disparities in this disease.

The association between PTSD symptom clusters and religion/spirituality with alcohol use among first responders.

Alcohol misuse and posttraumatic stress disorder (PTSD) co-occur at high rates among first responders (e.g., law enforcement, firefighters, paramedics), underscoring the need to better understand these relations to inform intervention efforts. Identifying malleable processes relevant to the association between PTSD and alcohol among first responders could inform tailored interventions. An example of such a malleable process is spirituality. As such, the current study examined the unique relationships between PTSD symptom clusters and alcohol misuse, while also accounting for the role of select demographics and religion/spirituality, in a sample of first responders. A national online sample of first responders (N = 320) completed measures of PTSD symptomology, alcohol misuse, religion/spirituality and demographics. Hierarchical linear regression analyses revealed that PTSD Intrusion (Cluster B) symptom severity was associated with greater alcohol misuse and PTSD Avoidance (Cluster C) was associated with lower alcohol misuse. Additionally, positive and negative spiritual coping were also associated with alcohol misuse. In the context of similar research among military samples, findings suggest potentially unique associations between PTSD symptom clusters and alcohol misuse among first responders. Additionally, findings highlight the potentially protective role of religion/spirituality in this population. Future research should explore nuanced relationships between PTSD symptom clusters and alcohol misuse as well as the salience of spirituality/religion in this unique population.

Associations Between Radiation Oncologist Demographic Factors and Segmentation Similarity Benchmarks: Insights From a Crowd-Sourced Challenge Using Bayesian Estimation.

PURPOSE: The quality of radiotherapy auto-segmentation training data, primarily derived from clinician observers, is of utmost importance. However, the factors influencing the quality of clinician-derived segmentations are poorly understood; our study aims to quantify these factors. METHODS: Organ at risk (OAR) and tumor-related segmentations provided by radiation oncologists from the Contouring Collaborative for Consensus in Radiation Oncology data set were used. Segmentations were derived from five disease sites: breast, sarcoma, head and neck (H&N), gynecologic (GYN), and GI. Segmentation quality was determined on a structure-by-structure basis by comparing the observer segmentations with an expert-derived consensus, which served as a reference standard benchmark. The Dice similarity coefficient (DSC) was primarily used as a metric for the comparisons. DSC was stratified into binary groups on the basis of structure-specific expert-derived interobserver variability (IOV) cutoffs. Generalized linear mixed-effects models using Bayesian estimation were used to investigate the association between demographic variables and the binarized DSC for each disease site. Variables with a highest density interval excluding zero were considered to substantially affect the outcome measure. RESULTS: Five hundred seventy-four, 110, 452, 112, and 48 segmentations were used for the breast, sarcoma, H&N, GYN, and GI cases, respectively. The median percentage of segmentations that crossed the expert DSC IOV cutoff when stratified by structure type was 55% and 31% for OARs and tumors, respectively. Regression analysis revealed that the structure being tumor-related had a substantial negative impact on binarized DSC for the breast, sarcoma, H&N, and GI cases. There were no recurring relationships between segmentation quality and demographic variables across the cases, with most variables demonstrating large standard deviations. CONCLUSION: Our study highlights substantial uncertainty surrounding conventionally presumed factors influencing segmentation quality relative to benchmarks.

Correspondence between the alcohol-P3 event-related potential and alcohol reward phenotypes among young adults.

BACKGROUND: Behavioral economic theory suggests that the value of alcohol depends upon elements of the choice context, such that increasing constraints on alternatives (e.g., price) or increasing the benefits of alcohol (e.g., social context) may result in greater likelihood of heavy drinking. The P3 event-related potential elicited by alcohol-related cues, a proposed marker of incentive salience, may be an electrophysiological parallel for behavioral economic alcohol demand. However, these indices have not been connected in prior research, and studies typically do not disaggregate social influences in the context of alcohol cue reactivity. METHOD: The current study recruited heavy drinking young adults (N = 81) who completed measures of alcohol use and alcohol demand, in addition to a 2 (social/nonsocial) × 2 (alcohol/nonalcohol) visual oddball task to elicit the P3. RESULTS: In multilevel models controlling for demographic characteristics, P3 reactivity was greater to alcohol (p < 0.001) and social (p < 0.001) cues than to nonalcohol and nonsocial cues, but without a significant interaction. Higher alcohol consumption (p = 0.02) and lower elasticity of demand (p = 0.01) were associated with greater P3 response to alcohol than nonalcohol cues. CONCLUSIONS: The results highlight a brain-behavior connection that may be an important marker for alcohol reward across units of analysis and may be sensitive to changes in the economic choice contexts that influence the likelihood of alcohol use.

Efficiently Quantifying Egocentric Social Network Cannabis Use: Initial Psychometric Validation of the Brief Cannabis Social Density Assessment.

OBJECTIVE: Social environment is a key determinant of substance use, but cannabis-related social network analysis is not common, in part due to the assessment burden of comprehensive egocentric social network analysis. METHOD: The current pre-registered secondary analysis assessed the psychometric properties (i.e., convergent, criterion-related, incremental validity) of the Brief Cannabis Social Density Assessment (B-CaSDA) in a cross-sectional sample of adults who use cannabis (N = 310) using a survey-based design. The B-CaSDA assesses the quantity and frequency of cannabis use for the respondent's four closest (non-parent) relationships. RESULTS: Cannabis use severity was elevated for each additional person who used cannabis at all or daily in the individual's social network. B-CaSDA indices (i.e., frequency, quantity, total score) were positively correlated with cannabis consumption, cannabis use severity indicators, and established risk factors for harmful cannabis use. B-CaSDA indices also discriminated between those above and below a clinical cutoff on the Cannabis Use Disorder Identification Test - Revised (CUDIT-R). Finally, in omnibus models that included common risk factors for cannabis use severity, the B-CaSDA quantity index contributed additional variance when predicting CUDIT-R total score, and B-CaSDA frequency contributed additional variance in predicting the CUDIT-R quantity-frequency subscale. CONCLUSIONS: The results suggest that the B-CaSDA has the potential to expand social network research on cannabis use and misuse by increasing its assessment feasibility in diverse designs.

Molecular dissection of the pseudokinase ZED1 expands effector recognition to the tomato immune receptor ZAR1.

The highly conserved angiosperm immune receptor HOPZ-ACTIVATED RESISTANCE 1 (ZAR1) is a bacterial pathogen recognition hub that mediates resistance by guarding host kinases for modification by pathogen effectors. The pseudokinase HOPZ-ETI DEFICIENT 1 (ZED1) is the only known ZAR1-guarded protein that interacts directly with a pathogen effector, HopZ1a, from the bacterial pathogen Pseudomonas syringae, making it a promising system for rational design of effector recognition for plant immunity. Here, we conducted an in-depth molecular analysis of ZED1. We generated a library of 164 random ZED1 mutants and identified 50 mutants that could not recognize the effector HopZ1a when transiently expressed in Nicotiana benthamiana. Based on our random mutants, we generated a library of 27 point mutants and found evidence of minor functional divergence between Arabidopsis (Arabidopsis thaliana) and N. benthamiana ZAR1 orthologs. We leveraged our point mutant library to identify regions in ZED1 critical for ZAR1 and HopZ1a interactions and identified two likely ZED1-HopZ1a binding conformations. We explored ZED1 nucleotide and cation binding activity and showed that ZED1 is a catalytically dead pseudokinase, functioning solely as an allosteric regulator upon effector recognition. We used our library of ZED1 point mutants to identify the ZED1 activation loop regions as the most likely cause of interspecies ZAR1-ZED1 incompatibility. Finally, we identified a mutation that abolished ZAR1-ZED1 interspecies incompatibility while retaining the ability to mediate HopZ1a recognition, which enabled recognition of HopZ1a through tomato (Solanum lycopersicum) ZAR1. This provides an example of expanded effector recognition through a ZAR1 ortholog from a non-model species.

An immunohistochemical atlas of necroptotic pathway expression.

Necroptosis is a lytic form of regulated cell death reported to contribute to inflammatory diseases of the gut, skin and lung, as well as ischemic-reperfusion injuries of the kidney, heart and brain. However, precise identification of the cells and tissues that undergo necroptotic cell death in vivo has proven challenging in the absence of robust protocols for immunohistochemical detection. Here, we provide automated immunohistochemistry protocols to detect core necroptosis regulators - Caspase-8, RIPK1, RIPK3 and MLKL - in formalin-fixed mouse and human tissues. We observed surprising heterogeneity in protein expression within tissues, whereby short-lived immune barrier cells were replete with necroptotic effectors, whereas long-lived cells lacked RIPK3 or MLKL expression. Local changes in the expression of necroptotic effectors occurred in response to insults such as inflammation, dysbiosis or immune challenge, consistent with necroptosis being dysregulated in disease contexts. These methods will facilitate the precise localisation and evaluation of necroptotic signaling in vivo.

Co-clustering of EphB6 and ephrinB1 in trans restrains cancer cell invasion.

EphB6 is an understudied ephrin receptor tyrosine pseudokinase that is downregulated in multiple types of metastatic cancers. Unlike its kinase-active counterparts which autophosphorylate and transmit signals upon intercellular interaction, little is known about how EphB6 functions in the absence of intrinsic kinase activity. Here, we unveil a molecular mechanism of cell-cell interaction driven by EphB6. We identify ephrinB1 as a cognate ligand of EphB6 and show that in trans interaction of EphB6 with ephrinB1 on neighboring cells leads to the formation of large co-clusters at the plasma membrane. These co-clusters exhibit a decreased propensity towards endocytosis, suggesting a unique characteristic for this type of cell-cell interaction. Using lattice light-sheet microscopy, 3D structured illumination microscopy and cryo-electron tomography techniques, we show that co-clustering of EphB6 and ephrinB1 promotes the formation of double-membrane tubular structures between cells. Importantly, we also demonstrate that these intercellular structures stabilize cell-cell adhesion, leading to a reduction in the invasive behavior of cancer cells. Our findings rationalize a role for EphB6 pseudokinase as a tumor suppressor when interacting with its ligands in trans.

Osteo-cutaneous microvascular free-flaps are a viable option for reconstructing the temporomandibular joint.

Background: There are multiple reconstructive options after mandibular resection and disarticulation of the condyle. The purpose of this study was to assess the clinical outcomes and functionality of osteocutaneous free flaps in the reconstruction of mandibular defects that involve the Temporo-Mandibular Joint (TMJ). Methods: Our study is a retrospective cohort study involving subjects who underwent mandibular resection and needed TMJ reconstruction with vascularized bony-free flaps from February 2016 to June 2018. Data gathered included patient demographics, post-operative function, maximum interincisal opening (MIO), occlusion status, deviation on opening, and TMJ symptoms. Data points collected from postoperative CT imaging included the following: position of the flap in relation to the glenoid fossa and articular eminence, and closest point of contact. Results: Eight out of the nine patients who underwent free flap reconstruction of mandibular defects involving the TMJ qualified for the study. The mean age was 39.7 years old. In all 8 cases, virtual surgical planning (VSP) was used. The mean follow-up time was 18.75 months. The flap success rate was 100%. The mean MIO was 37.37 mm. Six patients resumed their premorbid diet, and one patient developed dysphagia and was peg tube dependent. In seven cases the occlusion was intact and reproducible, one case was without sufficient teeth for occlusion. On imaging, the mean distance from the neo-condyle to the glenoid fossa was 14 mm and to the articular eminence 8.68 mm. The point of closest contact in all cases appeared to be the articular eminence. Conclusion: Vascularized Osteocutaneous-flaps such as FFFs and DCIA flaps provide a good option for the reconstruction of mandibular defects that involve the TMJ. Ipsilateral deviation on opening does not negatively affect clinical outcomes or function. Placing patients in Maxillomandibular fixation for 4-6 weeks may help to prevent condylar sag and provide stable post-operative occlusion.

Relationships of State Alcohol Policy Environments With Homicides and Suicides.

INTRODUCTION: Alcohol use is involved in a large proportion of homicides and suicides each year in the U.S., but there is limited evidence on how policies targeting alcohol influence violence in the U.S. CONTEXT: Extant studies generally focus on individual policies in isolation of each other. This study examines the impacts of changes in states' alcohol policy restrictions on overall homicide and suicide rates and firearm-related homicide and suicide rates using a holistic measure of states' alcohol policy environments. METHODS: Using a composite measure of state-level alcohol policies (Alcohol Policy Scale) and data from the National Vital Statistics System from 2002 to 2018, this study applied a Bayesian time series model to estimate the impacts of alcohol policy changes on overall and firearm-involved homicide and suicide rates. The analysis was performed in 2023 and 2024. RESULTS: A 1 SD change in the Alcohol Policy Scale was associated with a 6% decline in homicide rates both overall (incident rate ratio=0.94; 95% credible interval = 0.89, 1.00) and for firearm homicides specifically (incident rate ratio=0.94, 95% CI=0.88, 1.01). There was no clear association of alcohol policy with suicides. The model predicts that a nationwide increase in alcohol restrictions equivalent to a shift from the 25th to 75th percentile of the scale's distribution would result in almost 1,200 fewer homicides annually. CONCLUSIONS: Increases in the restrictiveness of state-level alcohol policies are associated with reductions in homicides. More restrictive alcohol policy environments may offer an opportunity to reduce homicides.

Neural correlates of increased alcohol demand following alcohol cue exposure in adult heavy drinkers.

Alcohol use disorder is associated with overvaluation of alcohol relative to other rewards, in part due to dynamic increases in value in response to alcohol-related cues. In a neuroeconomic framework, alcohol cues increase behavioral economic demand for alcohol, but the neural correlates these cue effects are unknown. This functional magnetic resonance imaging study combined a neuroeconomic alcohol purchase task with an alcohol cue exposure in 72 heavy drinkers with established sensitivity to alcohol cues (51 % female; mean age=33.74). Participants reported how many drinks they would consume from $0-$80/drink following exposure to neutral and alcohol images in a fixed order. Participants purchased significantly more drinks in the alcohol compared to the neutral condition, which was also evident for demand indices (i.e., intensity, breakpoint, Omax, elasticity; ps<0.001; ds=0.46-0.92). Alcohol purchase decisions were associated with activation in rostral middle and medial frontal gyri, anterior insula, posterior parietal cortex, and dorsal striatum, among other regions. Activation was lower across regions in the alcohol relative to neutral cue condition, potentially due to greater automaticity of choices in the presence of alcohol cues or attenuation of responses due to fixed cue order. These results contribute to growing literature using neuroeconomics to understand alcohol misuse and provide a foundation for future research investigating decision-making effects of environmental alcohol triggers.