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I study optimal income taxation when human capital investment is imperfectly observable by employers. In the model, Bayesian inference about worker productivity compresses the wage distribution, lowering the private return to human capital investment. An externality arises: given the same information, employers are more optimistic about each individual if workers are generally more productive. The significance of this externality hinges on the accuracy of employers’ beliefs and the responsiveness of human capital. For the United States, taking it into account lowers optimal marginal tax rates for most workers, reducing them by a maximum of 9–13 percentage points between $50,000 and $100,000. (JEL D83, H21, H24, J24, J31, M51, M52)

While infection and perceived infection risk can influence social and reproductive behavior in several taxa, relatively little is known about how infection specifically affects pair bond behaviors. Some pair bond maintenance behaviors may be costly to maintain during infection, and infection could promote avoidance behaviors within an established pair. Many species exhibiting pair bonds are part of larger social groups, and behavioral shifts in established pairs can result in altered extra-pair contact rates that could also shape disease transmission. Using captive zebra finches (Taeniopygia guttata), we examined how an immune challenge with lipopolysaccharide (LPS) influences activity, social behavior, and pair bond maintenance behaviors in established pairs and their healthy neighbors. We observed shifts in individual and pair maintenance behaviors in both immune-challenged pairs and healthy pairs exposed to a social cue of infection (sick conspecifics). Specifically, LPS-challenged birds decreased activity and social interaction attempts relative to control birds, consistent with LPS-induced sickness behavior. LPS-challenged birds also increased the frequency of clumping (perching together in bodily contact) between individuals within a pair. Healthy birds exposed to immune-challenged conspecifics decreased flight activity and increased self-preening, behaviors which could function to limit infection risk. Exploring how both infection and the perceived risk of infection shape behaviors within and among paired individuals will increase our understanding of the role of social behaviors in shaping disease dynamics.

Myocardial infarction, stroke, and pulmonary embolism are all deadly conditions associated with excessive thrombus formation. Standard treatment for these conditions involves systemic delivery of thrombolytic agents to break up clots and restore blood flow; however, this treatment can impact the hemostatic balance in other parts of the vasculature, which can lead to excessive bleeding. To avoid this potential danger, targeted thrombolytic treatments that can successfully target thrombi and release an effective therapeutic load are necessary. Because activated platelets and fibrin make up a large proportion of clots, these two components provide ample opportunities for targeting. This review will highlight potential thrombus targeting mechanisms as well as recent advances in thrombolytic therapies which utilize blood cells and clotting proteins to effectively target and lyse clots.

To minimize exposure of healthcare workers and clinical laboratory personnel to infectious liquids, we designed biofluid manipulators for on-demand handling of liquid droplets, in-plane or out-of-plane, in a remote and lossless manner.

Personalized feedback interventions are effective in reducing alcohol consumption and related problems. However, little is known about the role of choice in outcomes. The current study sought to (a) characterize individuals who opt in for brief alcohol-related feedback, (b) assess participants' consistency in that choice over two time points, and (c) evaluate changes in peak alcohol consumption among those who did and did not receive feedback.Participants reporting past-12-month alcohol consumption were recruited through Prolific. At the outset of the survey, participants were asked if they would like to receive feedback on their drinking at the end of the survey ("opt in"). Participants at Time 1 (T1;Those reporting higher maximum drinks and more drug use were more likely to opt in to feedback than those with lower use. Further, 85% of participants were consistent in their choice of whether to receive feedback across T1 and T2 (κ = .65). Among heavy drinking participants with T1 and T2 data (Individuals who engage in heavy alcohol use are more likely to opt in to personalized alcohol feedback, and most do so consistently. Among heavy drinkers, feedback at T1 reduced intensity of consumption at T2, but the effect was small and requires future replication in more diverse samples.

The objective was to examine the associations of socioecological connectedness with bullying victimization and depressive symptoms in early adolescence and with non-suicidal self-injury (NSSI) in mid-adolescence, and how these might differ between genders. Diverse adolescents (N = 4115; 49.1% girls) in the 7th grade reported on connections with parents/family, peers, school, and neighborhood, as well as bullying victimization and depressive symptoms, and NSSI in 10th grade (Me = 16.1 years). Structural equation modeling with WSLMV indicated that the lower likelihood of NSSI in 10th grade was associated with higher perceptions of connections between adolescents and their families, both directly as well as indirectly through reduced bully victimization and depressive symptoms three years earlier. Higher school connectedness was indirectly associated with the lower likelihood of NSSI through bullying victimization and depressive symptoms. Paths to NSSI varied for girls and boys. Results advance the understanding of developmental pathways leading to NSSI in adolescent girls and boys.

Background: Implementing ecological momentary assessment (EMA) methodology to evaluate the substance use disorder (SUD) treatment pipeline has clear advantages, including learning about participants’ day-to-day experiences to aid in the improvement of services and accessibility for those seeking treatment. Given that the SUD treatment pipeline spans long periods of time, EMA burst designs (deployment of multiple short EMA periods spread over time) can be advantageous for evaluating the treatment pipeline over time while keeping participant burden low. Objectives: This feasibility study describes (1) the process and study design of implementing EMA burst methodology to evaluate the SUD treatment pipeline experience; (2) study implementation from the perspective of researchers, including discussion of collaboration with community partners; and (3) participant feedback on the experience of engaging with this type of research. Method: EMA metrics, feasibility ratings, and general experience ratings in the study are presented from 22 participants (64% women) who participated in a parent EMA study evaluating the SUD treatment pipeline and 8 who provided feedback in a follow-up survey. Results: Participants found the EMA burst design to be acceptable and not burdensome, although technology issues were present for some participants. Steps to partnering with community treatment programs and implementation of a burst design are outlined. Conclusions: Strategies and recommendations for implementation of an EMA burst study with community partners are provided, including aspects of study design, technology issues, retention, and funding.

Purpose: Examine the reliability of field-based fitness assessments in school-aged children with emotional or behavioral difficulties (EBD). Understanding the impact of fitness on physical activity participation for children with EBD is limited by our ability to reliably measure it. Methods: Fifteen children aged 7–12 years with EBD completed 7 assessments—standing broad jump, overhead throw, grip strength, isometric plank hold, isometric wall squat, unilateral heel raise, and modified 6-minute walk test—in a random order on 2 separate occasions. Intraclass correlation coefficients (ICCs) were computed to evaluate reliability. Results: ICCs ranged from .65 to .99 representing moderate to excellent reliability for all assessments. Shorter assessments requiring less attention and behavior regulation tended to demonstrate higher ICC values while assessments with greater attention or behavioral regulation demands tended to have lower ICC values. Conclusion: Results demonstrate varied reliability for fitness tests in children with EBD. Practitioners can use grip strength and standing broad jump assessments with confidence. Other assessments have good reliability but greater variability indicating they may be a challenge for some children with EBD.

Because individuals with a history of depression who are receiving opioids are at higher risk for adverse events, the authors examined whether antidepressant treatment reduces risk for overdose and self-harm among individuals with a history of depression who receive opioids.Commercial insurance claims of individuals with a history of depression receiving opioids from 2007 to 2017 were used to quantify the association between antidepressant fills and adverse events among individuals after initiation of opioid treatment; the authors accounted for selection into treatment and used discrete-time, proportional hazards survival models.Among 283,374 adults with a history of depression treatment, 8,203 experienced 47,486 adverse events from 2007 to 2017 in the 12 months after initiation of opioid treatment. Approximately half (N=144,052, 50.8%) filled an antidepressant prescription at least once in the 12 months after the opioid episode began. Individuals receiving antidepressants for at least 6 weeks had a reduced risk for any adverse event (adjusted odds ratio [AOR]=0.79, 95% confidence interval [CI]=0.65-0.97) as well as a reduced risk for opioid overdoses (AOR=0.78, 95% CI=0.64-0.96), overdoses from nonopioid controlled substances (AOR=0.76, 95% CI=0.62-0.94), overdoses from other substances (AOR=0.79, 95% CI=0.65-0.97), and other self-harm events (AOR=0.82, 95% CI=0.67-1.00).Individuals with a history of depression who received opioid analgesics had a significantly lower risk for overdose and self-harm after they had been taking antidepressants for at least 6 weeks. Universal screening for mood disorders among individuals receiving opioids, and promptly providing evidence-based depression treatment when appropriate, may reduce adverse events.

An orthogonal, noncovalent approach to direct the assembly of higher-order DNA origami nanostructures is described. By incorporating perfluorinated tags into the edges of DNA origami tiles we control their hierarchical assembly via fluorous-directed recognition. When we combine this approach with Watson-Crick base-pairing we form discrete dimeric constructs in significantly higher yield (8x) than when either molecular recognition method is used in isolation. This integrated "catch-and-latch" approach, which combines the strength and mobility of the fluorous effect with the specificity of base-pairing, provides an additional toolset for DNA nanotechnology, one that enables increased assembly efficiency while requiring significantly fewer DNA sequences. As a result, our integration of fluorous-directed assembly into origami systems represents a cheap, atom-efficient means to produce discrete superstructures.

Co-use of alcohol and cigarettes is common and associated with greater negative consequences compared to use of either substance alone. Furthermore, alcohol and cigarettes are often used at the same time, and these "simultaneous" use events are associated with greater consumption of each substance. Given the prevalence and negative consequences associated with this pattern, we sought to identify proximal predictors and reinforcers of simultaneous use in individuals with a range of emotional and behavioral dysregulation who may be at greater risk of experiencing substance-related problems. Specifically, 41 adults who drank alcohol and smoked cigarettes (28 with borderline personality disorder and 13 community individuals) completed 21 days of ecological momentary assessment (EMA). First, we used multilevel models on cigarette-use moments to examine whether momentary cigarette motive endorsement differed based on whether participants were also drinking alcohol in that moment. Second, we used multilevel models on all EMA moments to examine whether simultaneous use was associated with greater craving and reinforcing effects compared to use of either substance alone. Participants reported greater enhancement and social motives for smoking cigarettes when also drinking alcohol compared to when they were only smoking. Participants also reported greater alcohol craving, greater sedation, attenuated positive affect, and greater fear following simultaneous use compared to use of either substance alone. Our results add to a growing body of research characterizing proximal influences on simultaneous substance use. Findings highlight potential treatment targets for individuals seeking to better understand or cut down on their use of alcohol, cigarettes, or both. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The title compound, C14H10S2, was prepared from dibenzo[c,e]oxepine-5(7H)-one and Lawesson's reagent in refluxing toluene. Pink blocks were grown by slow evaporation from petroleum ether. The resulting crystal structure resides in the orthorhombic space group Pbca with Z = 8 and Z′ = 1. The structure is comprised of a network of C—H...S and C—H...π interactions. No π–π interactions between ring moieties were observed, most likely due to the lack of molecular planarity.

Although limited, extant research suggests that incarcerated women are more likely than men to be placed in restrictive housing (e.g., administrative or disciplinary segregation) for disruptive behaviors that are linked to psychiatric symptomology and interpersonal deficits. Yet, few scholarly works discuss specific interventions or recommendations for treating incarcerated women in or at-risk of segregation. In this paper, we address the extent to which criminogenic and mental health needs of incarcerated women likely apply to women often placed in segregation, offer considerations for treatment planning when working with this subpopulation, and describe the process of piloting a manualized program specifically developed for segregated clients with women in a state prison. Descriptive data on 18 program participants are reported. Among program completers (n = 10), reductions in emotional stability, wellness, and criminal attitudes were endorsed from pre- to post-treatments and all women were rule-violation free at 3-month follow-up. Although preliminary outcomes are promising, controlled treatment outcome research is needed. We conclude with a call to advocate for the humane treatment and management of women who are in or prone to restrictive housing. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Objective Examine whether distribution of tablets to patients with access barriers influences their adoption and use of patient portals. Materials and Methods This retrospective cohort study included Veterans Affairs (VA) patients (n = 28 659) who received a VA-issued tablet between November 1, 2020 and April 30, 2021. Tablets included an app for VA’s My HealtheVet (MHV) portal. Veterans were grouped into 3 MHV baseline user types (non-users, inactive users, and active users) based on MHV registration status and feature use pre-tablet receipt. Three multivariable models were estimated to examine the factors predicting (1) MHV registration among non-users, (2) any MHV feature use among inactive users, and (3) more MHV use among active users post-tablet receipt. Differences in feature use during the 6 months pre-/post-tablet were examined with McNemar chi-squared tests of proportions. Results In the 6 months post-tablet, 1298 (8%) non-users registered for MHV, 525 (24%) inactive users used at least one MHV feature, and 4234 (46%) active users increased feature use. Across veteran characteristics, there were differences in registration and feature use post-tablet, particularly among older adults and those without prior use of video visits (P Conclusion Providing patients who experience barriers to in-person care with a portal-enabled device supports engagement in health information and management tasks. Additional strategies are needed to promote registration and digital inclusion among inactive and non-users of portals.

With the numerous advances and broad applications of mobile health (mHealth), establishing concrete data sharing, privacy, and governance strategies at national (or regional) levels is essential to protect individual privacy and data usage. This article applies the recent Health Data Governance Principles to provide a guiding framework for low- and middle-income countries (LMICs) to create a comprehensive mHealth data governance strategy. We provide three objectives: (1) establish data rights and ownership to promote equitable benefits from health data, (2) protect people through building trust and addressing patients’ concerns, and (3) promote health value by enhancing health systems and services. We also recommend actions for realizing each objective to guide LMICs based on their unique mHealth data ecosystems. These objectives require adopting a regulatory framework for data rights and protection, building trust for data sharing, and enhancing interoperability to use new datasets in advancing healthcare services and innovation.

We investigated the electrophysiological relationships in the cortico-basal ganglia network on a sub-centimeter scale to increase our understanding of neural functional relationships in Parkinson's disease (PD).Data was intraoperatively recorded from 2 sources in the human brain-a microelectrode in the subthalamic nucleus (STN) and a micro-electrocorticography grid on the motor association cortex-during bilateral deep brain stimulation (DBS) electrode placement. STN neurons and local field potential (LFP) were defined as functionally connected when the 99.7% confidence intervals of the action potential (AP)-aligned average LFP and control did not overlap.APs from STN neurons were functionally connected to the STN LFP for 18/46 STN neurons. This functional connection was observed between STN neuron APs and cortical LFP for 25/46 STN neurons. The cortical patterns of electrophysiological functional connectivity differed for each neuron.A subset of single neurons in the STN exhibited functional connectivity with electrophysiological activity in the STN and at a distance with the motor association cortex surveyed on a sub-centimeter spatial scale. These connections show a per neuron differential topography on the cortex.The cortico-basal ganglia circuit is organized on a sub-centimeter scale, and plays an important role in the mechanisms of PD and DBS.

Respiratory diseases are a global burden, with millions of deaths attributed to pulmonary illnesses and dysfunctions. Therapeutics have been developed, but they present major limitations regarding pulmonary bioavailability and product stability. To circumvent such limitations, we developed room-temperature-stable inhalable lung-derived extracellular vesicles or exosomes (Lung-Exos) as mRNA and protein drug carriers. Compared with standard synthetic nanoparticle liposomes (Lipos), Lung-Exos exhibited superior distribution to the bronchioles and parenchyma and are deliverable to the lungs of rodents and nonhuman primates (NHPs) by dry powder inhalation. In a vaccine application, severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein encoding mRNA-loaded Lung-Exos (S-Exos) elicited greater immunoglobulin G (IgG) and secretory IgA (SIgA) responses than its loaded liposome (S-Lipo) counterpart. Importantly, S-Exos remained functional at room-temperature storage for one month. Our results suggest that extracellular vesicles can serve as an inhaled mRNA drug-delivery system that is superior to synthetic liposomes.

Undernutrition-induced growth restriction in the early stages of life increases the risk of chronic disease in adulthood. Although metabolic impairments have been observed, few studies have characterized the gut microbiome and gut-liver metabolome profiles of growth-restricted animals during early-to-mid-life development. To induce growth restriction, mouse offspring were either born to gestational undernutrition (GUN) or suckled from postnatal undernutrition (PUN) dams fed a protein-restricted diet (8% protein) or control diet (CON; 20% protein) until weaning at postnatal age of 21 days (PN21). At PN21, all mice were fed the CON diet until adulthood (PN80). Livers were collected at PN21 and PN80, and fecal samples were collected weekly starting at PN21 (

Although significant progress in recent years has been made in defining key innate immune receptors involved in Alzheimer’s disease (AD), our knowledge of the specific intracellular signaling molecules that coordinate immune responses in AD remains poorly defined. In these studies, we have identified a previously undescribed role for the innate immune signaling molecule CARD9 in an amyloid beta (Ab)-mediated mouse model of AD. We specifically demonstrate that CARD9 deletion in the 5xFAD mouse model of AD leads to impaired control of Ab, worsened cognitive decline, and aberrant microglial activation. We further show that pharmacological activation of CARD9 provides a strategy to boost Ab clearance from the hippocampus. Collectively, these findings uncover a previously uncharacterized molecular signaling molecule used by the innate immune system in Ab-mediated neurological disease, and help to establish CARD9 as a novel molecular player that can be targeted in AD.

In the present study, we tested a visual feedback triggering system based on real-time tracking of response time (RT) in a sustained attention task. In our task, at certain points, brief visual feedback epochs were presented without interrupting the task itself. When these feedback epochs were performance-linked—meaning that they were triggered because participants were responding more quickly than usual—RTs were slowed after the presentation of feedback. However, visual feedback epochs displayed at predetermined times that were independent of participants’ performance did not slow RTs. Results from a second experiment support the idea that this is not simply a return to baseline that would have occurred had the feedback not been presented, but instead suggest that the feedback itself was effective in altering participants’ responses. In a third experiment, we replicated this result across with both written word feedback and visual symbolic feedback, as well as in cases where the participant was explicitly told that the feedback was linked to their performance. All together, these data provide insight into potential mechanisms for detecting and disrupting lapses in sustained attention without interrupting a continuous task.

The 2021/2022 epizootic of high pathogenicity avian influenza (HPAIV) remains one of the largest ever in the UK, being caused by a clade 2.3.4.4b H5N1 HPAIV. This epizootic affected more than 145 poultry premises, most likely through independent incursion from infected wild birds, supported by more than 1700 individual detections of H5N1 from wild bird mortalities. Here an H5N1 HPAIV, representative of this epizootic (H5N1-21), was used to investigate its virulence, pathogenesis and transmission in layer chickens and Pekin ducks, two species of epidemiological importance. We inoculated both avian species with decreasing H5N1-21 doses. The virus was highly infectious in ducks, with high infection levels and accompanying shedding of viral RNA, even in ducks inoculated with the lowest dose, reflecting the strong waterfowl adaptation of the clade 2.3.4.4 HPAIVs. Duck-to-duck transmission was very efficient, coupled with high environmental contamination. H5N1-21 was frequently detected in water sources, serving as likely sources of infection for ducks, but inhalable dust and aerosols represented low transmission risks. In contrast, chickens inoculated with the highest dose exhibited lower rates of infection compared to ducks. There was no evidence for experimental H5N1-21 transmission to any naive chickens, in two stocking density scenarios, coupled with minimal and infrequent contamination being detected in the chicken environment. Systemic viral dissemination to multiple organs reflected the pathogenesis and high mortalities in both species. In summary, the H5N1-21 virus is highly infectious and transmissible in anseriformes, yet comparatively poorly adapted to galliformes, supporting strong host preferences for wild waterfowl. Key environmental matrices were also identified as being important in the epidemiological spread of this virus during the continuing epizootic.

During 2021-22 High Pathogenicity Avian Influenza (HPAI) killed thousands of wild birds across Europe and North America, suggesting a change in infection dynamics and a shift to new hosts, including seabirds. Northern Gannets (Morus bassanus) appeared especially severely impacted, but limited understanding of how the virus spread across the metapopulation, or the demographic consequences of mass mortality limit our understanding of its severity. Accordingly, we collate information on HPAIV outbreaks across most North Atlantic gannet colonies and for the largest colony (Bass Rock, UK), provide impacts on population size, breeding success, adult survival, and preliminary results on serology. Unusually high numbers of dead gannets were first noted in Iceland during April 2022. Outbreaks in May occurred in many Scottish colonies, followed by colonies in Canada, Germany and Norway. By the end of June, outbreaks had occurred in five Canadian colonies and in the Channel Islands. Outbreaks in 12 UK and Ireland colonies appeared to follow a clockwise pattern with the last infected colonies recorded in late August/September. Unusually high mortality was recorded at 40 colonies (75% of global total colonies). Dead birds testing positive for HPAIV H5N1 were associated with 58% of these colonies. At Bass Rock, the number of occupied sites decreased by at least 71%, breeding success declined by ∼66% compared to the long-term UK mean and adult survival between 2021 and 2022 was 42% lower than the preceding 10-year average. Serological investigation detected antibodies specific to H5 in apparently healthy birds indicating that some gannets recover from HPAIV infection. Further, most of these recovered birds had black irises, suggestive of a phenotypic indicator of previous infection. Untangling the impacts of HPAIV infection from other key pressures faced by seabirds is key to establishing effective conservation strategies for threatened seabird populations, HPAIV being a novel and pandemic threat.

Research has linked childhood sexual trauma (CST) with adverse adult outcomes (AAOs) that span physical, psychological, and social domains of functioning. Differences in conceptualizing and measuring CST, however, have inhibited the examination of trauma-related variables hypothesized to impact adult outcomes. We used National Sexual Health Survey (NSHS; 1995–1996) data to examine trauma chronicity (i.e., duration) and AAOs (domains: physical and mental health, close relationships, and achievement). The NSHS (N = 6537, 18–70 years) assessed duration using perpetrator-specific CST reports. Adjusting for background characteristics, we examined CST duration in relation to AAOs and CST-related help-seeking. Approximately 8% of participants reported CST. Chronic (vs. single-exposure) CST survivors were at substantially higher risk of experiencing AAOs [i.e., mean AAOs and specific AAOs (e.g., physical and emotional health problems, divorce/separation, and poverty)]. CST had direct effects on sexual dysfunction and satisfaction, and on relationship stressors which may impact sexual relationship quality. Although 62% of CST survivors did not seek help, those with more chronic CST histories reported a higher prevalence of trauma-related help-seeking. Our work underscores the importance of examining CST chronicity in relation to long-term developmental outcomes. Chronicity assessment may be an important screening tool in the therapeutic context and in broader community screening efforts.

Parental influence is critical in shaping a child's growth and development. This phenomenological study examines the authoritarian mothering experiences of 15 top-performing Senior High School students in the Philippines and their psychosocial and emotional well-being. The data were analyzed thematically following the in-depth interviews. The findings indicate that the majority of informants were dissatisfied with the effectiveness of authoritarian parenting. This is because authoritarian mothering is detrimental to their health. The informants were experiencing psycho-emotional distress due to their exhaustion from their authoritarian mothers' constant pressure and rigid attitude. When it came to social relationships, authoritarian mothers lacked involvement in their children's psycho-emotional lives. The findings of this study could be used to develop effective mothering practices that balance academic success and the health of top-performing students.

UNSTRUCTURED Rapid development and adoption of natural language processing (NLP) techniques has led to a multitude of exciting and innovative societal and healthcare applications. These advancements have also generated concerns around perpetuating historical injustices and tools that lack cultural considerations. While traditional healthcare NLP processes typically include clinical subject matter experts to extract health information or aid in interpretation, few NLP tools involve community stakeholders with lived experiences. In this perspective, we draw upon the field of Community-Based Participatory Research, which gathers input from community members for development of public health interventions, to identify and examine ways to equitably involve communities in developing healthcare NLP tools. To realize the potential of community-based NLP (CBNLP), research and development teams must thoughtfully consider mechanisms and resources needed to effectively collaborate with community members for maximal societal and ethical impact of NLP-based tools.

M6620, a selective ATP-competitive inhibitor of the ATM and RAD3-related (ATR) kinase, is currently under investigation with radiation in patients with non–small cell lung cancer (NSCLC) brain metastases. We evaluated the DNA damage response (DDR) pathway profile of NSCLC and assessed the radiosensitizing effects of M6620 in a preclinical NSCLC brain metastasis model. Mutation analysis and transcriptome profiling of DDR genes and pathways was performed on NSCLC patient samples. NSCLC cell lines were assessed with proliferation, clonogenic survival, apoptosis, cell cycle, and DNA damage signaling and repair assays. NSCLC brain metastasis patient-derived xenograft models were used to assess intracranial response and overall survival. In vivo IHC was performed to confirm in vitro results. A significant portion of NSCLC patient tumors demonstrated enrichment of DDR pathways. DDR pathways correlated with lung squamous cell histology; and mutations in ATR, ATM, BRCA1, BRCA2, CHEK1, and CHEK2 correlated with enrichment of DDR pathways in lung adenocarcinomas. M6620 reduced colony formation after radiotherapy and resulted in inhibition of DNA DSB repair, abrogation of the radiation-induced G2 cell checkpoint, and formation of dysfunctional micronuclei, leading to enhanced radiation-induced mitotic death. The combination of M6620 and radiation resulted in improved overall survival in mice compared with radiation alone. In vivo IHC revealed inhibition of pChk1 in the radiation plus M6620 group. M6620 enhances the effect of radiation in our preclinical NSCLC brain metastasis models, supporting the ongoing clinical trial (NCT02589522) evaluating M6620 in combination with whole brain irradiation in patients with NSCLC brain metastases.

Supplementary Data

Collective cell migration is an adaptive, coordinated interactive process involving cell–cell and cell–extracellular matrix (ECM) microenvironmental interactions. A critical aspect of collective migration is the sensing and establishment of directional movement. It has been proposed that a subgroup of cells known as leader cells localize at the front edge of a collectively migrating cluster and are responsible for directing migration. However, it is unknown how and when leader cells arrive at the front edge and what environmental cues dictate leader cell development and behavior. Here, we addressed these questions by combining a microfluidic device design that mimics multiple tumor microenvironmental cues concurrently with biologically relevant primary, heterogeneous tumor cell organoids. Prior to migration, breast tumor leader cells (K14+) were present throughout a tumor organoid and migrated (polarized) to the leading edge in response to biochemical and biomechanical cues. Impairment of either CXCR4 (biochemical responsive) or the collagen receptor DDR2 (biomechanical responsive) abrogated polarization of leader cells and directed collective migration. This work demonstrates that K14+ leader cells utilize both chemical and mechanical cues from the microenvironment to polarize to the leading edge of collectively migrating tumors.Significance:These findings demonstrate that pre-existing, randomly distributed leader cells within primary tumor organoids use CXCR4 and DDR2 to polarize to the leading edge and direct migration.

Movie demonstrating K14-GFP migration

Movie demonstrating DDR2-/- cells migration

Supplementary Figure from Exploratory Study of NPC-0501 Trial: Optimal Cisplatin Dose of Concurrent and Induction/Adjuvant Chemotherapy for Locoregionally Advanced Nasopharyngeal Carcinoma

Movie demonstrating collective migration

Objective Addressing high-risk alcohol and cannabis use represent major challenges to institutions of higher education. A range of evidence-based treatment approaches are available, but little is known concerning students' receptiveness to such approaches. Prior work identified that students were most open to individual therapy and self-help options for reducing alcohol use, but less open to medication. The current study examines student receptiveness to intervention approaches across a wider range of intervention approaches (e.g., remote/telehealth), and extends to evaluate cannabis intervention receptiveness. Method Undergraduate students reported on alcohol and cannabis use, motives for and reasons against use, and openness to an array of interventions for reducing alcohol and cannabis use. Results Informal options (self-help, talking with family/friends), individual therapy, and appointments with a primary care provider (PCP) were endorsed most frequently. Group therapy and medication were less commonly endorsed, though medication was endorsed at a higher prevalence than in prior studies. Women generally expressed higher receptiveness than men. Lower alcohol consumption was associated with increased receptiveness to some approaches. Students at high risk for alcohol and/or cannabis dependence were less receptive to many treatment options. Conclusions College students were open to a wide variety of approaches for reducing their alcohol and cannabis use. These results can inform selection, implementation, and availability of campus-wide services, especially as low-cost technological-based approaches are expanding. Further attention to existing services (e.g., PCP) for addressing alcohol and cannabis use may be considered, given students' receptiveness to such approaches. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The re-emergence of the high pathogenicity avian influenza virus (HPAIV) subtype H5N1 in the United Kingdom in 2021-2022 has caused unprecedented epizootic events in wild birds and poultry. During the summer of 2022 there was a shift in virus transmission dynamics resulting in increased HPAIV infection in seabirds and consequently a profound impact on seabird populations. To understand the pathological impact of HPAIV in seabirds, we have evaluated the virus distribution and associated pathological changes in the tissues of great skua (Stercorarius skua, n=8), long tailed skua (Stercorarius longicaudus, n=1), European herring gull (Larus argentatus, n=5), and black-headed gull (Chroicocephalus ridibundus, n=4). Grossly there was gizzard ulceration in one great skua and pancreatic necrosis in four herring gulls, which were confirmed for virus infectionin situby immunohistochemistry. Microscopical analysis revealed neuro-, pneumo-, lymphoidand cardiotropism of HPAIV H5N1, with the most common virus-associated pathological changes being pancreatic and splenic necrosis. Examination of the reproductive tract of the great skua revealed HPAIV-associated oophoritis and salpingitis, and virus replication within the oviductal epithelium. Across the birds, epitheliotropism was evident in the intestine, nasal turbinate, and trachea. This was, in contrast, not observed in the 2021 summer mortality event in great skuas and may be significant for the disease epidemiology observed in 2022. The emergence of HPAIV in seabirds, particularly during summer 2022, has challenged the dogma of HPAIV dynamics, posing a significant threat to wild bird life with potential implications to the reproductive performance of seabirds of conservation importance.

This focus article has been prepared by Marco Falchieri, Scott M. Reid, Craig S. Ross, Joe James, Alexander M. P. Byrne, Madalina Zamfir, Ian H. Brown and Ashley C. Banyard of the APHA; Glen Tyler and Emma Philip of NatureScot; and Will Miles of Scottish Oceans Institute, School of Biology, University of St Andrews.

Methadone (MTD) is a commonly prescribed treatment for opioid use disorder in pregnancy, despite limited information on the effects of passive exposure on fetal brain development. Animal studies suggest a link between perinatal MTD exposure and impaired white matter development. In this study, we characterized the effect of perinatal MTD exposure through the evaluation of oligodendrocyte development and glial cell activation in the neonatal rat brain. Six pregnant Sprague Dawley rat dams were randomized to MTD (0.2 mL/L) or untreated drinking water from embryonic day 7. Pups were terminated at postnatal day 7 and tissue sections were harvested from six randomly selected pups (one male and one female per litter) of each experimental group for immunohistochemistry in areas of corpus callosum (CC), lateral CC, external capsule (EC), and cerebellar white matter. In the MTD-exposed rat pups, myelination was significantly decreased in the CC, lateral CC, EC, and arbor vitae compared with the controls. The increased density and percentage of oligodendrocyte precursor cells (OPCs) were observed in the CC and cerebellar white matter. The highly active proliferation of OPCs as well as decreased density and percentage of differentiated oligodendrocytes were found in the cerebellum but no differences in the cerebrum. Apoptotic activities of both differentiated oligodendrocytes and myelinating oligodendrocytes were significantly increased in all regions of the cerebrum and cerebellum after MTD exposure. There was no quantitative difference in astrocyte, however, cell density and/or morphologic difference consistent with activation were observed in microglia throughout MTD-exposed CC and cerebellum. Taken together, perinatal MTD exposure reveals global attenuation of myelination, accelerated apoptosis of both differentiated and myelinating oligodendrocytes, and microglia activation, supporting an association between antenatal MTD exposure and impaired myelination in the developing brain.