Resident cardiac macrophages mediate adaptive myocardial remodeling.

Cardiac macrophages represent a heterogeneous cell population with distinct origins, dynamics, and functions. Recent studies have revealed that C-C Chemokine Receptor 2 positive (CCR2+) macrophages derived from infiltrating monocytes regulate myocardial inflammation and heart failure pathogenesis. Comparatively little is known about the functions of tissue resident (CCR2-) macrophages. Herein, we identified an essential role for CCR2- macrophages in the chronically failing heart. Depletion of CCR2- macrophages in mice with dilated cardiomyopathy accelerated mortality and impaired ventricular remodeling and coronary angiogenesis, adaptive changes necessary to maintain cardiac output in the setting of reduced cardiac contractility. Mechanistically, CCR2- macrophages interacted with neighboring cardiomyocytes via focal adhesion complexes and were activated in response to mechanical stretch through a transient receptor potential vanilloid 4 (TRPV4)-dependent pathway that controlled growth factor expression. These findings establish a role for tissue-resident macrophages in adaptive cardiac remodeling and implicate mechanical sensing in cardiac macrophage activation.

Binding of GTP to BifA is required for the production of Pel-dependent biofilms in Pseudomonas aeruginosa.

The Pel exopolysaccharide is one of the most mechanistically conserved and phylogenetically diverse bacterial biofilm matrix determinants. Pel is a major contributor to the structural integrity of Pseudomonas aeruginosa biofilms, and its biosynthesis is regulated by the binding of cyclic-3',5'-dimeric guanosine monophosphate (c-di-GMP) to the PelD receptor. c-di-GMP is synthesized from two molecules of guanosine triphosphate (GTP) by diguanylate cyclases with GGDEF domains and degraded by phosphodiesterases with EAL or HD-GYP domains. As the P. aeruginosa genome encodes 43 c-di-GMP metabolic enzymes, one way signaling specificity can be achieved is through direct interaction between specific enzyme-receptor pairs. Here, we show that the inner membrane hybrid GGDEF-EAL enzyme, BifA, directly interacts with PelD via its cytoplasmic HAMP, GGDEF, and EAL domains. Despite having no catalytic function, the degenerate active site motif of the BifA GGDEF domain (GGDQF) has retained the ability to bind GTP with micromolar affinity. Mutations that abolish GTP binding result in increased biofilm formation but stable global c-di-GMP levels. Our data suggest that BifA forms a dimer in solution and that GTP binding induces conformational changes in dimeric BifA that enhance the BifA-PelD interaction and stimulate its phosphodiesterase activity, thus reducing c-di-GMP levels and downregulating Pel biosynthesis. Structural comparisons between the dimeric AlphaFold2 model of BifA and the structures of other hybrid GGDEF-EAL proteins suggest that the regulation of BifA by GTP may occur through a novel mechanism.IMPORTANCEc-di-GMP is the most common cyclic dinucleotide used by bacteria to regulate phenotypes such as motility, biofilm formation, virulence factor production, cell cycle progression, and cell differentiation. While the identification and initial characterization of c-di-GMP metabolic enzymes are well established, our understanding of how these enzymes are regulated to provide signaling specificity remains understudied. Here we demonstrate that the inactive GGDEF domain of BifA binds GTP and regulates the adjacent phosphodiesterase EAL domain, ultimately downregulating Pel-dependent P. aeruginosa biofilm formation through an interaction with PelD. This discovery adds to the growing body of literature regarding how hybrid GGDEF-EAL enzymes are regulated and provides additional precedence for studying how direct interactions between c-di-GMP metabolic enzymes and effectors result in signaling specificity.

Phosphatidylethanol Detects Occult Heavy Alcohol Use in Patients With Acute and Chronic Pancreatitis.

Given the paucity of interventions to treat pancreatitis, it is imperative to identify and intervene upon modifiable risk factors such as heavy alcohol use. Current trends indicate a concerning increase in alcohol misuse and alcohol-related disease since the onset of the coronavirus disease-2019 pandemic.1 The incidence of pancreatitis associated with alcohol misuse has increased by approximately 3% annually from 1961 to 2016.2 Alcohol recidivism may be the most important risk factor for pancreatitis recurrence and development of chronic pancreatitis in the United States.3 Early identification of alcohol misuse as a modifiable risk factor is paramount to mitigating pancreatitis-related morbidity. However, blood ethanol and urine ethyl glucuronide levels may be low in symptomatic individuals because they clear rapidly and patients may abstain from drinking in the days before their clinical presentation. Patient self-report may underestimate the quantity of alcohol intake and falsely reassure the provider that this is not a contributing factor to the presentation.4.

Induction of Activity-Dependent Plasticity at Auditory Nerve Synapses.

Exposure to nontraumatic noise in vivo drives long-lasting changes in auditory nerve synapses, which may influence hearing, but the induction mechanisms are not known. We mimicked activity in acute slices of the cochlear nucleus from mice of both sexes by treating them with high potassium, after which voltage-clamp recordings from bushy cells indicated that auditory nerve synapses had reduced EPSC amplitude, quantal size, and vesicle release probability (P r). The effects of high potassium were prevented by blockers of nitric oxide (NO) synthase and protein kinase A. Treatment with the NO donor, PAPA-NONOate, also decreased P r, suggesting NO plays a central role in inducing synaptic changes. To identify the source of NO, we activated auditory nerve fibers specifically using optogenetics. Strobing for 2 h led to decreased EPSC amplitude and P r, which was prevented by antagonists against ionotropic glutamate receptors and NO synthase. This suggests that the activation of AMPA and NMDA receptors in postsynaptic targets of auditory nerve fibers drives release of NO, which acts retrogradely to cause long-term changes in synaptic function in auditory nerve synapses. This may provide insight into preventing or treating disorders caused by noise exposure.SIGNIFICANCE STATEMENT Auditory nerve fibers undergo long-lasting changes in synaptic properties in response to noise exposure in vivo, which may contribute to changes in hearing. Here, we investigated the cellular mechanisms underlying induction of synaptic changes using high potassium and optogenetic stimulation in vitro and identified important signaling pathways using pharmacology. Our results suggest that auditory nerve activity drives postsynaptic depolarization through AMPA and NMDA receptors, leading to the release of nitric oxide, which acts retrogradely to regulate presynaptic neurotransmitter release. These experiments revealed that auditory nerve synapses are unexpectedly sensitive to activity and can show dramatic, long-lasting changes in a few hours that could affect hearing.

Time Course of Activity-Dependent Changes in Auditory Nerve Synapses Reveals Multiple Underlying Cellular Mechanisms.

Abnormal levels of acoustic activity can result in hearing problems such as tinnitus and language processing disorders, but the underlying cellular and synaptic changes triggered by abnormal activity are not well understood. To address this issue, we studied the time course of activity-dependent changes that occur at auditory nerve synapses in mice of both sexes after noise exposure and conductive hearing loss. We found that EPSC amplitude and synaptic depression decreased within 2 d of noise exposure through a decrease in the probability of vesicle release (Pr). This was followed by a gradual increase in EPSC amplitude through a larger pool of releasable vesicles (N). Occlusion of the ear canal led to a rapid decrease in EPSC amplitude through a decrease in N, which was followed by an increase in EPSC amplitude and synaptic depression through an increase in Pr After returning to normal sound levels, synaptic depression recovered to control levels within 1-2 d. However, repeated exposure to noise for as little as 8 h/d caused synaptic changes after 7 d, suggesting recovery did not fully offset changes. Thus, there appear to be three activity-dependent mechanisms in auditory nerve synapses-bidirectional changes in Pr in 1-2 d, slower bidirectional changes in N through synaptic growth or retraction, and rapid downregulation of N with low activity. The dynamic changes indicate that multiple mechanisms are present to fine-tune synaptic fidelity across different acoustic conditions in a simple relay.SIGNIFICANCE STATEMENT Hearing impairments can arise from exposure to noise or conductive hearing loss. This appears to result from changes in the brain, but the mechanisms are not well understood. We study this issue by studying the synapses made by auditory nerve fibers called endbulbs of Held. These synapses undergo bidirectional changes in size and release probability of neurotransmitter in response to increased or decreased activity. Here, we made a close examination of how quickly these synaptic characteristics change, which indicates there are at least three cellular mechanisms underlying changes. Furthermore, repeated exposure to brief periods of noise can produce cumulative effects. These changes could significantly affect hearing, especially because they occur at the start of the central auditory pathway.

Magnetic resonance imaging parameters on lacrimal gland in thyroid eye disease: a systematic review and meta-analysis.

BACKGROUND: Thyroid eye disease is an extrathyroidal manifestation of Graves' disease and is associated with dry eye disease. This is the first systematic review and meta-analysis to evaluate the role of magnetic resonance imaging lacrimal gland parameters in thyroid eye disease diagnosis, activity grading, and therapeutic responses prediction. METHODS: Up to 23 August, 2022, 504 studies from PubMed and Cochrane Library were analyzed. After removing duplicates and imposing selection criteria, nine eligible studies were included. Risk of bias assessment was done. Meta-analyses were performed using random-effect model if heterogeneity was significant. Otherwise, fixed-effect model was used. Main outcome measures include seven structural magnetic resonance imaging parameters (lacrimal gland herniation, maximum axial area, maximum coronal area, maximum axial length, maximum coronal length, maximum axial width, maximum coronal width), and three functional magnetic resonance imaging parameters (diffusion tensor imaging-fractional anisotropy, diffusion tensor imaging-apparent diffusion coefficient or mean diffusivity, diffusion-weighted imaging-apparent diffusion coefficient). RESULTS: Thyroid eye disease showed larger maximum axial area, maximum coronal area, maximum axial length, maximum axial width, maximum coronal width, diffusion tensor imaging-apparent diffusion coefficient/ mean diffusivity, and lower diffusion tensor imaging-fractional anisotropy than controls. Active thyroid eye disease showed larger lacrimal gland herniation, maximum coronal area, diffusion-weighted imaging-apparent diffusion coefficient than inactive. Lacrimal gland dimensional (maximum axial area, maximum coronal area, maximum axial length, maximum axial width, maximum coronal width) and functional parameters (diffusion tensor imaging-apparent diffusion coefficient, diffusion tensor imaging-apparent diffusion coefficient) could be used for diagnosing thyroid eye disease; lacrimal gland herniation, maximum coronal area, and diffusion-weighted imaging-apparent diffusion coefficient for differentiating active from inactive thyroid eye disease; diffusion tensor imaging parameters (diffusion tensor imaging-fractional anisotropy, diffusion tensor imaging-mean diffusivity) and lacrimal gland herniation for helping grading and therapeutic responses prediction respectively. CONCLUSIONS: Magnetic resonance imaging lacrimal gland parameters can detect active thyroid eye disease and differentiate thyroid eye disease from controls. Maximum coronal area is the most effective indicator for thyroid eye disease diagnosis and activity grading. There are inconclusive results showing whether structural or functional lacrimal gland parameters have diagnostic superiority. Future studies are warranted to determine the use of magnetic resonance imaging lacrimal gland parameters in thyroid eye disease.

Testing the Effects of a Multicomponent Frailty Management Program for Community-Dwelling Older Adults in Singapore: A Feasibility Study.

Frailty in later life is often associated with functional declines and reduced quality of life. A multicomponent frailty management program (mFMP) is lacking in Singapore. This study aimed to determine the feasibility and effects of an mFMP in reducing frailty and increasing participation among frail community-living older adults. Pre- and postassessments at three time points were conducted to compare the differences in body functions between the mFMP (experimental group [EG]) and a fitness program (control group [CG]). Recruitment, dropouts, and fall data were collected. Weekly field notes and semistructured interviews postintervention were thematically analyzed. Sixteen out of 23 participants (EG: eight; CG: eight) completed the 12-week interventions with reduced frailty immediately postintervention. At 3-month postintervention, 10 participants (EG: five; CG: five) being followed up had a sustained level of frailty (p < .05). The EG and CG reported zero and two falls, respectively. The mFMP demonstrated its feasibility and exhibited a trend to facilitate personal behavioral changes postintervention.

Pediatric Lymphedema: Study of 180 Patients Referred to a Tertiary Lymphedema Clinic.

BACKGROUND: Lymphedema is due to dysfunction of the lymphatic system. It can be primary or secondary. Pediatric lymphedema is more often primary and is a chronic disease with a heavy burden on quality of life. METHODS: Medical records of patients under 18 years of age referred between 1996 and 2021 to the specialized lymphedema clinic at the Sainte-Justine University Hospital Center were reviewed. Demographic data, sex, age at presentation, location of the lymphedema, clinical features, genetic testing, symptoms, complications, investigations, and treatment were collected. RESULTS: Of 180 referred patients, lymphedema was confirmed in 151, and 137 were primary lymphedema. Median age of apparition of primary lymphedema was 7.00 years and was significantly lower in boys than in girls. Primary congenital lymphedema was more frequent in boys (51.0%, 27.3% in girls, P = .007), and onset of primary lymphedema during adolescence was more frequent in girls (53.4%, 25.0% in boys, P = .001). Lower limbs were the most impacted (88.3%). Sixty patients had genetic testing, and 38 (63.3%) of them were discovered to have a pertinent genetic mutation. The most common mutated gene was the FLT4 gene (in 9 patients). Seven patients (5.1%) had associated extensive/central lymphatic malformation and 24 (17.6%) had a polymalformative syndrome/syndromic lymphedema. CONCLUSIONS: Pediatric lymphedema is more frequent in girls, usually involves lower limb, and is most often sporadic, but often associated with a genetic mutation, and genetic testing should be performed.

Behavioral Willingness, Descriptive Normative Perceptions, and Prescription Stimulant Misuse among Young Adults 18-20.

Objective: It is critical to gain further understanding of etiologic factors, such as descriptive normative perceptions and behavioral willingness, that are associated with prescription stimulant misuse (PSM) among young adults. Our primary hypotheses were that descriptive normative perceptions for PSM (i.e., perceptions of how much and how often others engage in PSM) and perceived peer willingness (i.e., perceptions of how open others are to PSM under certain circumstances) would be positively associated with higher willingness to engage in PSM, which in turn would account for significant shared variance with self-reported PSM. Method: Data were collected from a U.S. sample of 18-20-year-olds (N = 1,065; 54.5% females; 70.5% White) recruited for a larger study on alcohol-related risky sexual behavior. Results: Findings indicated higher descriptive normative perceptions and higher perceived peer willingness were associated with higher participants' willingness to engage in PSM. Participants' own willingness was positively associated with PSM. Finally, participants' own willingness to use, descriptive normative perceptions, and perceived peer willingness were associated with higher willingness to engage in PSM, which accounted for significant shared variance with self-reported PSM. Conclusions: Findings suggest the potential utility of personalized feedback interventions for PSM that focus on constructs such as descriptive normative perceptions and behavioral willingness.

Mechanisms and Functional Consequences of Presynaptic Homeostatic Plasticity at Auditory Nerve Synapses.

Multiple forms of homeostasis influence synaptic function under diverse activity conditions. Both presynaptic and postsynaptic forms of homeostasis are important, but their relative impact on fidelity is unknown. To address this issue, we studied auditory nerve synapses onto bushy cells in the cochlear nucleus of mice of both sexes. These synapses undergo bidirectional presynaptic and postsynaptic homeostatic changes with increased and decreased acoustic stimulation. We found that both young and mature synapses exhibit similar activity-dependent changes in short-term depression. Experiments using chelators and imaging both indicated that presynaptic Ca2+ influx decreased after noise exposure, and increased after ligating the ear canal. By contrast, Ca2+ cooperativity was unaffected. Experiments using specific antagonists suggest that occlusion leads to changes in the Ca2+ channel subtypes driving neurotransmitter release. Furthermore, dynamic-clamp experiments revealed that spike fidelity primarily depended on changes in presynaptic depression, with some contribution from changes in postsynaptic intrinsic properties. These experiments indicate that presynaptic Ca2+ influx is homeostatically regulated in vivo to enhance synaptic fidelity.SIGNIFICANCE STATEMENT Homeostatic mechanisms in synapses maintain stable function in the face of different levels of activity. Both juvenile and mature auditory nerve synapses onto bushy cells modify short-term depression in different acoustic environments, which raises the question of what the underlying presynaptic mechanisms are and the relative importance of presynaptic and postsynaptic contributions to the faithful transfer of information. Changes in short-term depression under different acoustic conditions were a result of changes in presynaptic Ca2+ influx. Spike fidelity was affected by both presynaptic and postsynaptic changes after ear occlusion and was only affected by presynaptic changes after noise-rearing. These findings are important for understanding regulation of auditory synapses under normal conditions and also in disorders following noise exposure or conductive hearing loss.

The human posterior cingulate and the stress-response benefits of viewing green urban landscapes.

The mechanistic and neural bases of why green environments drive positive mental health outcomes remain poorly understood. We show that viewing green urban landscapes that vary in terms of green-space density elicits corresponding changes in the activity of the human ventral posterior cingulate cortex that is correlated to behavioural stress-related responses. We further show that cingulate responses are engaged early in the processing cascade, influencing attentional and executive regions in a predominantly feedforward manner. Our data suggest a key role for this region in regulating (nature) dose-dependent changes in stress responses, potentially through its extensive connections to the prefrontal and hippocampal regions which in turn project towards the neuroendocrine system. As the posterior cingulate cortex is implicated in a variety of neurological diseases and disorders, these findings raise a therapeutic potential for natural environmental exposure, highlighting green-cover as a modifiable element that links to changes in limbic responses, and has health consequences for practitioners and city-planners alike.

An International Comparison of a Web-Based Personalized Feedback Intervention for Alcohol use During the Transition out of High School in the United States and Sweden.

Young adult drinkers engage in a range of drinking patterns from abstaining to heavy drinking in both the United States and Sweden. Heavy drinking during young adulthood in both countries is associated with a variety of negative consequences. Personalized feedback interventions have been identified as effective prevention strategies to prevent or reduce heavy drinking in the United States. This study examined transitions in drinking profiles and compared the efficacy of a personalized feedback intervention for 3965 young adults in the United States (1,735) and Sweden (2230) during their transition out of high school. Using goodness-of-fit criteria, results indicated that three drinking profiles exist among young adults transitioning out of high school: very low drinkers/abstainers, moderate to heavy drinkers, and very heavy drinkers. Latent Markov models revealed a moderating effect of country on personalized feedback intervention such that intervention condition participants in the United States were more likely to belong to the light drinker/abstainer or moderate to heavy profile relative to the very heavy drinking profile at 6-month follow-up. There was no significant effect of personalized feedback intervention in Sweden. Future research could investigate the impact of when personalized feedback interventions are administered and could examine if personalized feedback interventions should be more intentionally culturally adapted in order to be more effective.

Patterns, Consequences, and Motives in Simultaneous Use of Prescription Stimulant Medication with Alcohol and Marijuana.

OBJECTIVE: Nonmedical use of prescription stimulants (NPS) continues to be a concern on college campuses. Previous research demonstrates a strong link between NPS and use of other substances, particularly alcohol and marijuana among college students. Simultaneous use of NPS with other substances has become an increasing concern. Given the high rates of NPS and simultaneous NPS with other substances, research examining substance use patterns and motives among students is warranted. Method: This study evaluated group differences in alcohol and marijuana use patterns, consequences, and motives among college students: a) with no NPS history (No NPS); b) engaged in NPS with no simultaneous use (Non-Sim NPS); and c) engaged in simultaneous NPS with alcohol and/or marijuana (Sim NPS). Participants included 1,108 students from three universities who reported past-year marijuana and alcohol use. Results: Overall, 32.8% reported lifetime NPS with 12.5% indicating NPS in the previous 3 months, of which 51.1% reported simultaneous NPS with alcohol and 40.2% with marijuana. Significant group differences for all drinking and marijuana outcomes were found, with heaviest rates among the Sim NPS group, followed by the Non-Sim NPS group, and the No NPS group. The Sim NPS group reported greater motives for using marijuana to alter the effects of other substances. Conclusions: College students engaged in simultaneous NPS with alcohol and marijuana are a high-risk group that should be the focus of prevention and intervention programs in the campus setting.

Nonmedical Use of Prescription Stimulants as a "Red Flag" for Other Substance Use.

BACKGROUND: Nonmedical use of prescription stimulants (NMPS) has increased on college campuses during the past two decades. NMPS is primarily driven by academic enhancement motives, and normative misperceptions exist as well. However, large, nationwide studies have not yet been conducted to generalize findings more broadly and gain a deeper understanding of the relationship between NMPS and other substance use (e.g. alcohol use, marijuana, etc.). The present study was conducted to lay the foundation for prevention efforts related to NMPS by establishing NMPS prevalence, practices surrounding NMPS, and other substance use. METHODS: N = 2,989 students from seven universities around the U.S. completed a web-based survey assessing NMPS practices and related behaviors. Prevalence and factors associated with NMPS were explored. RESULTS: Analyses revealed a 17% past-year prevalence of NMPS with associated widespread misperceptions of peer use. NMPS was significantly related to alcohol use, binge drinking, and marijuana use, as well as skipped classes and affiliation with Greek life. CONCLUSIONS: Although most college students do not report NMPS, those who do also are more likely to report alcohol use, binge drinking, and marijuana use, and NMPS could be a "red flag" for other risk behaviors worth exploring. Implications for prevention and intervention are discussed.

Human Depth Sensitivity Is Affected by Object Plausibility.

Using behavioral and fMRI paradigms, we asked how the physical plausibility of complex 3-D objects, as defined by the object's congruence with 3-D Euclidean geometry, affects behavioral thresholds and neural responses to depth information. Stimuli were disparity-defined geometric objects rendered as random dot stereograms, presented in plausible and implausible variations. In the behavior experiment, observers were asked to complete (1) a noise-based depth task that involved judging the depth position of a target embedded in noise and (2) a fine depth judgment task that involved discriminating the nearer of two consecutively presented targets. Interestingly, results indicated greater behavioral sensitivities of depth judgments for implausible versus plausible objects across both tasks. In the fMRI experiment, we measured fMRI responses concurrently with behavioral depth responses. Although univariate responses for depth judgments were largely similar across cortex regardless of object plausibility, multivariate representations for plausible and implausible objects were notably distinguishable along depth-relevant intermediate regions V3 and V3A, in addition to object-relevant LOC. Our data indicate significant modulations of both behavioral judgments of and neural responses to depth by object context. We conjecture that disparity mechanisms interact dynamically with the object recognition problem in the visual system such that disparity computations are adjusted based on object familiarity.

Using Gas-Phase Air Quality Sensors to Disentangle Potential Sources in a Los Angeles Neighborhood.

In the late summer of 2016, our team deployed a network of low-cost air quality sensing systems in partnership with community-based organizations in a neighborhood in South Los Angeles, California. Residents of this community were concerned about possible emissions from local oil and gas activity, however in addition to these potential emissions, the neighborhood is also subject to a complex mixture of pollutants from other nearby sources including major highways. For this deployment, metal-oxide VOC sensors were quantified to provide methane (CH4) and total non-methane hydrocarbon (TNMHCs) concentration estimates. This data along with other sensor signals, meteorological data, and community member observations was used to examine the composition and possible origins of observed emissions. The sensor network displayed expected environmental trends and highlighted short-term elevations in CH4 and/or TNMHCs, which we were then able to investigate more closely. The results indicated that sources of both combusted and volatilized hydrocarbons were likely affecting air quality throughout the community, including near the site of the local oil and gas activity. This deployment may serve as a model for how multi-sensor systems deployed in networks can be leveraged to better understand sources in complex areas, potentially supporting future community-based air quality research.

Synthetic Biology: Immunotherapy by Design.

Cellular immunotherapy holds great promise for the treatment of human disease. Clinical evidence suggests that T cell immunotherapies have the potential to combat cancers that evade traditional immunotherapy. Despite promising results, adverse effects leading to fatalities have left scientists seeking tighter control over these therapies, which is reflected in the growing body of synthetic biology literature focused on developing tightly controlled, context-independent parts. In addition, researchers are adapting these tools for other uses, such as for the treatment of autoimmune disease, HIV infection, and fungal interactions. We review this body of work and devote special attention to approaches that may lend themselves to the development of an "ideal" therapy: one that is safe, efficient, and easy to manufacture. We conclude with a look toward the future of immunotherapy: how synthetic biology can shift the paradigm from the treatment of disease to a focus on wellness and human health as a whole.

Simultaneous Alcohol and Marijuana Use Among College Students: Patterns, Correlates, Norms, and Consequences.

BACKGROUND: Alcohol and marijuana users often engage in simultaneous alcohol and marijuana (SAM) use (i.e., using the 2 substances together so that their effects overlap), which can result in more negative consequences than using either substance alone. Nevertheless, little is known about SAM use among contemporary college students to aid in the development of preventive interventions. This study examined SAM use patterns, demographic correlates of SAM use, and normative influences on SAM use and related negative consequences among college students. METHODS: Students who had used alcohol and marijuana in the past year were recruited from 3 state universities in states with different laws regarding recreational marijuana use (N = 1,389). They completed an online survey, which assessed their own alcohol, marijuana, and SAM use and related consequences, their perceptions of the proportion of same-gender peers and close friends who engaged in SAM use, marijuana access, and demographic characteristics. RESULTS: About three-fourths of participants reported at least 1 occasion of SAM use in the past year with an average frequency of twice per month among SAM users. There were significant differences in SAM use prevalence and frequency by sociodemographic characteristics controlling for past-year alcohol and marijuana frequency. Students in a state with decriminalized recreational marijuana use reported higher frequency of past-year SAM use than students in states with legalized or criminalized use. There were significant demographic differences in perceived norms regarding SAM use among close friends and same-gender peers. SAM users endorsed significantly higher perceived peer and friend norms than nonusers. Also, higher perceived norms predicted more frequent SAM use and more negative consequences of use. CONCLUSIONS: Results indicate a need for prevention programs on college campuses that address SAM use. Interventions that use personalized normative feedback may be effective.

Clathrin light chains' role in selective endocytosis influences antibody isotype switching.

Clathrin, a cytosolic protein composed of heavy and light chain subunits, assembles into a vesicle coat, controlling receptor-mediated endocytosis. To establish clathrin light chain (CLC) function in vivo, we engineered mice lacking CLCa, the major CLC isoform in B lymphocytes, generating animals with CLC-deficient B cells. In CLCa-null mice, the germinal centers have fewer B cells, and they are enriched for IgA-producing cells. This enhanced switch to IgA production in the absence of CLCa was attributable to increased transforming growth factor ß receptor 2 (TGFßR2) signaling resulting from defective endocytosis. Internalization of C-X-C chemokine receptor 4 (CXCR4), but not CXCR5, was affected in CLCa-null B cells, and CLC depletion from cell lines affected endocytosis of the δ-opioid receptor, but not the ß2-adrenergic receptor, defining a role for CLCs in the uptake of a subset of signaling receptors. This instance of clathrin subunit deletion in vertebrates demonstrates that CLCs contribute to clathrin's role in vivo by influencing cargo selectivity, a function previously assigned exclusively to adaptor molecules.