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Although obsessive-compulsive disorder (OCD) is associated with clinically significant distress, many OCD patients do not seek treatment. Studies show that Black Americans with OCD are even less likely to obtain treatment due to differences in access. This study explored demographic and symptom outcomes associated with mental health service use for obsessions and compulsions among a nationally representative sample of African American adults (n = 3,570). The analytic sample for this analysis is African Americans who endorsed either obsessions (n = 435) or compulsions (n = 543). Few respondents sought care from their doctor for obsessions (14.25%, n = 62) and even fewer sought care for compulsions (7.55%, n = 36). Respondents were significantly more likely to seek care for obsessions if they had poorer self-rated mental health and perceived impairment due to obsessions-however, they were significantly less likely to seek care for obsessions if they had a high school education or less. Additionally, respondents were more likely to seek care for compulsions if they had poorer self-rated mental health. Our findings suggest that demographic factors, such as level of education, can impact care-seeking behaviors and, therefore, treatment outcomes for African Americans with obsessive-compulsive symptoms. Knowledge of factors associated with OCD care-seeking behavior can help inform potential barriers to treatment and strategies to ensure equity in access to mental health care for this population. Clinical implications and future directions are discussed., (Copyright © 2024 Association for Behavioral and Cognitive Therapies. Published by Elsevier Ltd. All rights reserved.)

Life satisfaction and happiness are related but distinct assessments of life quality with established links to sociodemographic and health factors. Despite a rich literature on quality of life, there remains a paucity of research on this topic among African Americans. This investigation explored (1) the sociodemographic correlates of life satisfaction and happiness and (2) how life satisfaction and happiness are related to health factors and adversity-relevant life circumstances. Ordinary least squares regression was used to identify correlates of life satisfaction and happiness among a nationally representative sample of African American adults (National Survey of American Life). Findings confirmed several sociodemographic and health correlates, as well as unique differences. Regional differences indicated that residents in the Northeast had lower life satisfaction ratings, while those in the West had higher happiness ratings. Education was negatively related to both life satisfaction and happiness. Self-rated physical health and oral health and adversity-relevant life circumstances were associated with both life satisfaction and happiness. In contrast, self-rated childhood health and experiences of everyday racial discrimination were only associated with happiness, while being a parent was only associated with lower life satisfaction. Noted differences suggest that, while related, satisfaction and happiness represent distinct assessments of life quality.

For 50 years, the National Institute on Aging (NIA) has supported and promoted research on religious involvement among older adult populations. NIA funding of research on religious involvement has (i) broadened our understanding of how religious involvement is conceptualized and measured; (ii) explored the important role of social networks and interactions within religious communities in relation to congregants' health; (iii) supported research on national samples of the U.S. population that explore demographic variability in religious practices and beliefs, as well as their social correlates; and (iv) examined health-relevant frameworks and topics in relation to religion's association with physical and mental health and well-being. This article focuses on research on African Americans and Mexican Americans as well as comparative work involving non-Latino Whites. Selected topics in religion and aging include Conceptualization and Measurement of Religious Participation; Religious Participation; Religion and Mental Health; Religion and Physical Health, Church-Based Informal Support, Church Support, and Mental and Physical Health; Religious Coping; and the Use of Clergy for serious problems. NIA's long record of support for scholarship and research has significantly enriched our understanding of why and how religion matters for the health and social well-being of diverse populations of older adults., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Exposure and resulting tissue concentrations of various elements from natural and anthropogenic sources are influenced by multiple factors, such as geographic location, age, diet, and metabolic rate, that can influence wildlife health. Essential and non-essential elements were assessed in lanugo and whole blood collected in 2019 from 102 Steller sea lion (Eumetopias jubatus) pups from two rookeries from the western and central Aleutian Islands: Agattu (WAI, n = 54) and Ulak Islands (CAI, n = 48). Rookery, sex, dorsal standard length, and trophic ecology (ẟ 15 N, ẟ 13 C values) effects on element concentration were evaluated. Significant differences in element concentrations of lanugo were exhibited across rookeries (p < 0.05), except for zinc (Zn). For example, higher mercury (Hg) and selenium (Se) concentrations were observed in WAI than CAI, while other elements were lower in WAI. Whole blood showed higher sulfur (S) and Se concentrations in CAI compared to WAI, while WAI had elevated strontium (Sr) and Hg concentrations relative to CAI. Trophic ecology significantly influenced most element concentrations, possibly due to regional variations in adult female feeding and food web dynamics. Interactions between elements were found in lanugo across both rookeries, with varying strengths. Whole blood displayed less pronounced yet consistent associations, with variable intensities. Essential elements sodium (Na), potassium (K), and calcium (Ca) formed a distinct group whose interaction is crucial for nervous system function and muscle contraction. Another group comprised zinc (Zn), iron (Fe), manganese (Mn), magnesium (Mg), phosphorous (P), S, and Se, which are known for indirectly interacting with enzyme function and metabolic pathways. Hg and Se formed a distinct group probably due to their known chemical interactions and physiological protective interactions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Neurite initiation from newly born neurons is a critical step in neuronal differentiation and migration. Neuronal migration in the developing cortex is accompanied by dynamic extension and retraction of neurites as neurons progress through bipolar and multipolar states. However, there is a relative lack of understanding regarding how the dynamic extension and retraction of neurites is regulated during neuronal migration. In recent work we have shown that CIP4, a member of the F-BAR family of membrane bending proteins, inhibits cortical neurite formation in culture, while family member FBP17 induces premature neurite outgrowth. These results beg the question of how CIP4 and FBP17 function in radial neuron migration and differentiation in vivo , including the timing and manner of neurite extension and retraction. Indeed, the regulation of neurite outgrowth is essential for the transitions between bipolar and multipolar states during radial migration. To examine the effects of modulating expression of CIP4 and FBP17 in vivo , we used in utero electroporation, in combination with our published Double UP technique, to compare knockdown or overexpression cells with control cells within the same mouse tissue of either sex. We show that either knockdown or overexpression of CIP4 and FBP17 results in the marked disruption of radial neuron migration by modulating neuronal morphology and neurite outgrowth, consistent with our findings in culture. Our results demonstrate that the F-BAR proteins CIP4 and FBP17 are essential for proper radial migration in the developing cortex and thus play a key role in cortical development., Competing Interests: CONFLICT OF INTEREST STATEMENT The authors declare no competing financial interests.

Nonvesicular lipid trafficking pathways are an important process in every domain of life. The mechanisms of these processes are poorly understood in part due to the difficulty in kinetic characterization. One important class of glycolipids, lipopolysaccharides (LPS), are the primary lipidic component of the outer membrane of Gram-negative bacteria. LPS are synthesized in the inner membrane and then trafficked to the cell surface by the l ipo p olysaccharide t ransport proteins, Lpt B 2 FGCADE. By characterizing the interaction of a fluorescent probe and LPS, we establish a quantitative assay to monitor the flux of LPS between proteoliposomes on the time scale of seconds. We then incorporate photocaged ATP into this system, which allows for light-based control of the initiation of LPS transport. This control allows us to measure the initial rate of LPS transport (3.0 min -1 per LptDE). We also find that the rate of LPS transport by the Lpt complex is independent of the structure of LPS. In contrast, we find the rate of LPS transport is dependent on the proper function of the LptDE complex. Mutants of the outer membrane Lpt components, LptDE, that cause defective LPS assembly in live cells display attenuated transport rates and slower ATP hydrolysis compared to wild type proteins. Analysis of these mutants reveals that the rates of ATP hydrolysis and LPS transport are correlated such that 1.2 ± 0.2 ATP are hydrolyzed for each LPS transported. This correlation suggests a model where the outer membrane components ensure the coupling of ATP hydrolysis and LPS transport by stabilizing a transport-active state of the Lpt bridge.

Chemical post-translational protein-protein conjugation is an important technique with growing applications in biotechnology and pharmaceutical research. Maleimides represent one of the most widely employed bioconjugation reagents. However, challenges associated with the instability of first- and second-generation maleimide technologies are yet to be fully addressed. We report the development of a novel class of maleimide reagents that can undergo on-demand ring-opening hydrolysis of the resulting thio-succinimide. This strategy enables rapid post-translational assembly of protein-protein conjugates. Thio-succinimide hydrolysis, triggered upon application of chemical, photochemical, or enzymatic stimuli, allowed homobifunctional bis-maleimide reagents to be applied in the production of stable protein-protein conjugates, with complete temporal control. Bivalent and bispecific protein-protein dimers constructed from small binders targeting antigens of oncological importance, PD-L1 and HER2, were generated with high purity, stability, and improved functionality compared to monomeric building blocks. The modularity of the approach was demonstrated through elaboration of the linker moiety through a bioorthogonal propargyl handle to produce protein-protein-fluorophore conjugates. Furthermore, extending the functionality of the homobifunctional reagents by temporarily masking reactive thiols included in the linker allowed the assembly of higher order trimeric and tetrameric single-domain antibody conjugates. The potential for the approach to be extended to proteins of greater biochemical complexity was demonstrated in the production of immunoglobulin single-domain antibody conjugates. On-demand control of thio-succinimide hydrolysis combined with the facile assembly of chemically defined homo- and heterodimers constitutes an important expansion of the chemical methods available for generating stable protein-protein conjugates.

Eosinophilic gastrointestinal diseases (EGIDs) are chronic, immune-mediated disorders, characterized clinically by gastrointestinal (GI) symptoms and histologically by eosinophil-predominant infiltration in ≥1 GI tract segment. 1 A recent, international consensus by 91 experts proposed a new framework for EGID nomenclature to establish updated terms, designations, and conventions. 2 Although this framework offers a standardized starting point for the field, debate is ongoing regarding the appropriate terminology for cases involving multiple areas, such as "non-eosinophilic esophagitis (EoE) EGID and EoE" or "non-EoE EGID with esophageal involvement (EI)." Notably, in a survey of these experts, 61% agreed with the later term "non-EoE EGID with EI," because EoE is isolated to the esophagus by current diagnostic criteria. 3 However, limited molecular and pathogenic data exist to support the distinction. Furthermore, disease burden of symptoms and comorbidities generally is higher in non-EoE EGIDs than EoE. 4 Presently, there is no screen to predict non-EoE EGID concomitance in EoE; therefore, decision-making to further explore other GI segment involvement is clinically challenging. We aimed to answer 2 fundamental questions in the field (Figure 1A): Is there a shared or distinct pathogenesis between patients with isolated EoE and non-EoE EGIDs with EI as assessed by patient characteristics and molecular profiles? Can we predict concomitant non-EoE EGIDs when EoE exists? Herein, we report a similar molecular signature between EoE and EI and a potential predictive model to identify concomitant non-EoE EGIDs in patients with EoE., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Dendritic spines, the mushroom-shaped extensions along dendritic shafts of excitatory neurons, are critical for synaptic function and are one of the first neuronal structures disrupted in neurodevelopmental and neurodegenerative diseases. Microtubule (MT) polymerization into dendritic spines is an activity-dependent process capable of affecting spine shape and function. Studies have shown that MT polymerization into spines occurs specifically in spines undergoing plastic changes. However, discerning the function of MT invasion of dendritic spines requires the specific inhibition of MT polymerization into spines, while leaving MT dynamics in the dendritic shaft, synaptically connected axons and associated glial cells intact. This is not possible with the unrestricted, bath application of pharmacological compounds. To specifically disrupt MT entry into spines we coupled a MT elimination domain (MTED) from the Efa6 protein to the actin filament-binding peptide LifeAct. LifeAct was chosen because actin filaments are highly concentrated in spines and are necessary for MT invasions. Temporally controlled expression of this LifeAct-MTED construct inhibits MT entry into dendritic spines, while preserving typical MT dynamics in the dendrite shaft. Expression of this construct will allow for the determination of the function of MT invasion of spines and more broadly, to discern how MT-actin interactions affect cellular processes.

Eosinophilic gastrointestinal diseases (EGIDs) are a group of diseases characterized by selective eosinophil infiltration of the gastrointestinal (GI) tract in the absence of other causes of eosinophilia. These diseases are generally driven by type 2 inflammation, often in response to food allergen exposure. Among all EGIDs, the clinical presentation often includes a history of atopic disease with a variety of GI symptoms. EGIDs are traditionally separated into eosinophilic esophagitis (EoE) and non-EoE EGIDs. EoE is relatively better understood and now associated with clinical guidelines and 2 US Food and Drug Administration-approved treatments, whereas non-EoE EGIDs are rarer and less well-understood diseases without US Food and Drug Administration-approved treatments. Non-EoE EGIDs are further subclassified by the area of the GI tract that is involved; they comprise eosinophilic gastritis, eosinophilic enteritis (including eosinophilic duodenitis), and eosinophilic colitis. As with other GI disorders, the disease presentations and mechanisms differ depending on the involved segment of the GI tract; however, the differences between EoE and non-EoE EGIDs extend beyond which GI tract segment is involved. The aim of this article is to summarize the commonalities and differences between the clinical presentations and disease mechanisms for EoE and non-EoE EGIDs., Competing Interests: Disclosure statement Supported by the National Institutes of Health (grant K99/R00 AI158660 [to T.S.] and grants R01 AI045898, R01 AI124355, and U19 AI070235 [to M.E.R.]); the Digestive Health Center (Pilot and Feasibility Program; grant P30 DK078392 [to T.S.]); Cincinnati Children's Trustee Award (to T.S.); the Campaign Urging Research for Eosinophilic Disease (CURED) (to M.E.R.); the Sunshine Charitable Foundation and its supporters Denise A. Bunning and David G. Bunning (to M.E.R.); and CEGIR (U54 AI117804 to M.E.R.), which is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS, and is funded through collaboration between NIAID, NIDDK, NCATS. CEGIR is also supported by patient advocacy groups including the Campaign Urging Research for Eosinophilic Diseases (CURED), American Partnership for Eosinophilic Disorders (APFED), and Eosinophilic Family Coalition (EFC). As a member of the RDCRN, CEGIR is also supported by its Data Management and Coordinating Center (DMCC) (U2CTR002818). Funding support for the DMCC is provided by the National Center for Advancing Translational Sciences (NCATS) and the National Institute of Neurological Disorders and Stroke (NINDS). Disclosure of potential conflict of interest: M. E. Rothenberg is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Celldex, Uniquitybio, Santa Ana Bio, EnZen Therapeutics, Bristol Myers Squibb, AstraZeneca, Pfizer, GlaxoSmith Kline, Regeneron/Sanofi, and Guidepoint and has an equity interest in the first 8 listed plus Allakos and royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust), and UpToDate. In addition, T. Shoda and M. E. Rothenberg are inventors of patents owned by Cincinnati Children’s Hospital. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

The commoditization of nuclear power through the factory production of sealed micro-power units within a digitally enabled holistic assurance framework is described. This would revolutionize nuclear power-plant design, construction, operation and decommissioning through a paradigm shift to manufacture-operate-remove-recycle (MORR). The potential impact of recent research on an integrated nuclear digital environment for large bespoke nuclear power plants and the design, build and operation of fusion power plants using such a digital environment is explored. These strands are interwoven to discuss the technical, economic and socio-political implications of MORR in the context of micro-reactors and to consider the potential evolution of safeguarding issues based on a digital assurance framework that leads to type approvals. Commoditization of nuclear power would lower costs in line with offshore wind and the output from a single production line in a factory could replace a third of current fossil fuel-based electricity generation in the UK over a 15-year period, making a significant contribution to achieving zero greenhouse gas emissions. The challenges associated with the changes in culture, both in the nuclear industry and in society, as well as the technology gaps, that need to be addressed in realizing this paradigm shift are identified and discussed., Competing Interests: We declare we have no competing interests., (© 2024 The Authors.)

Purpose: Surgical resection remains the only curative therapy for pancreatic cancer. Unfortunately, many patients have borderline or unresectable disease at diagnosis due to proximity of major abdominal vessels. Neoadjuvant chemotherapy and radiation are used to down-stage, however, there is a risk that there will be a positive/close surgical margin. The CivaSheet is a low-dose-rate (LDR) brachytherapy device placed at the time of surgery to target the area of highest risk of margin positivity. The purpose of this study is to assess the clinical value of brachytherapy in addition to standard-of-care therapy in pancreatic therapy., Methods and Materials: Between 2017 and 2022 patients with borderline and locally advanced pancreatic cancer treated with neoadjuvant chemotherapy and radiation followed by surgical resection were included. There were 2 cohorts of patients: (1) Those who had the LDR brachytherapy device placed at the time of surgery and (2) those who did not. Sixteen of 19 (84%) patients who had brachytherapy were enrolled in a prospective clinical trial (NCT02843945). Patients were matched for comorbidities, cancer staging, and treatment details. The primary outcome was progression-free survival (PFS)., Results: Thirty-five patients were included in this analysis, 19 in the LDR brachytherapy group and 16 in the comparison cohort. The 2-year PFS was 21% vs. 0% (p = 0.11), 2-year OS was 26% vs. 13% (p = 0.43), and the pancreatic cancer cause-specific survival was 84% vs. 56% (p = 0.13) in favor of the brachytherapy patients., Conclusions: Use of LDR brachytherapy at the time of resection shows a trend towards improved progression free and overall survival for patients with borderline or locally advanced pancreatic cancer treated with neoadjuvant chemoradiation., (Copyright © 2024 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Objectives: We sought to describe outcomes for locally advanced cutaneous squamous cell carcinoma (SCC) involving the parotid treated with volumetric modulated arc therapy (VMAT) versus pencil beam scanning proton beam therapy (PBT)., Materials and Methods: Patients were gathered from 2016 to 2022 from 5 sites of a large academic RT department; included patients were treated with RT and had parotid involvement by: direct extension of a cutaneous primary, parotid regional spread from a previously or contemporaneously resected but geographically separate cutaneous primary, or else primary parotid SCC (with a cutaneous primary ostensibly occult). Acute toxicities were provider-reported (CTCAE v5.0) and graded at each on treatment visit. Statistical analyses were conducted., Results: Median follow-up was 12.9 months (1.3 - 72.8); 67 patients were included. Positive margins/extranodal extension were present in 34 cases; gross disease in 17. RT types: 39 (58.2 %) VMAT and 28 (41.8 %) PBT. Concurrent systemic therapy was delivered in 10 (14.9 %) patients. There were 17 treatment failures (25.4 %), median time of 168 days. Pathologically positive neck nodes were associated with locoregional recurrence (p = 0.015). Oral cavity, pharyngeal constrictor, and contralateral parotid doses were all significantly lower for PBT. Median weight change was -3.8 kg (-14.1 - 5.1) for VMAT and -3 kg (-16.8 - 3) for PBT (p = 0.013). Lower rates of ≥ grade 1 xerostomia (p = 0.002) and ≥ grade 1 dysguesia (p < 0.001) were demonstrated with PBT., Conclusions: Cutaneous SCC involving the parotid can be an aggressive clinical entity despite modern multimodal therapy. PBT offers significantly lower dose to organs at risk compared to VMAT, which seemingly yields diminished acute toxicities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cancers harness embryonic programs to evade aging and promote survival. Normally, sequences at chromosome ends called telomeres shorten with cell division, serving as a countdown clock to limit cell replication. Therefore, a crucial aspect of cancerous transformation is avoiding replicative aging by activation of telomere repair programs. Mouse embryonic stem cells (mESCs) activate a transient expression of the gene Zscan4 , which correlates with chromatin de-condensation and telomere extension. Head and neck squamous cell carcinoma (HNSCC) cancers reactivate ZSCAN4, which in turn regulates the phenotype of cancer stem cells (CSCs). Our study reveals a new role for human ZSCAN4 in facilitating functional histone H3 acetylation at telomere chromatin. Next-generation sequencing indicates ZSCAN4 enrichment at telomere chromatin. These changes correlate with ZSCAN4-induced histone H3 acetylation and telomere elongation, while CRISPR/Cas9 knockout of ZSCAN4 leads to reduced H3 acetylation and telomere shortening. Our study elucidates the intricate involvement of ZSCAN4 and its significant contribution to telomere chromatin remodeling. These findings suggest that ZSCAN4 induction serves as a novel link between 'stemness' and telomere maintenance. Targeting ZSCAN4 may offer new therapeutic approaches to effectively limit or enhance the replicative lifespan of stem cells and cancer cells.

Background: Anxiety disorders are among the most prevalent psychiatric conditions worldwide, and the incidence of anxiety disorders among adults in the U.S. have increased over the last decade. Anxiety disorders can have debilitating effects on multiple areas of functioning and quality of life. Recently, social isolation has emerged as an important public health problem associated with worse health and well-being outcomes. Research on the connection between social isolation and mental health has found that multiple dimensions of social isolation may negatively impact mental health, but few inquiries have focused on the association between social isolation and anxiety. This study examined the relationships between multiple dimensions of social isolation and anxiety disorders in a nationally representative sample of adults aged 18 and older., Methods: The sample includes 6082 individuals from the National Survey of American Life. This study examined whether three different dimensions of social isolation-subjective, interpersonal, and structural-were associated with 12-month and lifetime anxiety disorders (any anxiety disorder, posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), panic disorder (PD), social anxiety disorder (SAD), and agoraphobia (AG). Logistic regressions were used to test the associations between the three social isolation variables and the anxiety outcomes., Results: This study found that of the three dimensions of social isolation, subjective isolation was most consistently related to both lifetime and 12-month anxiety disorders. Those who were subjectively isolated had increased odds of meeting criteria for any anxiety disorder, PTSD, GAD, PD, and AG over the past 12 months and throughout their lifetimes. Structural isolation was negatively associated with lifetime and 12-month AG., Conclusions: Public health approaches should include mental health and primary care providers and need to target social isolation, especially subjective isolation, which may be key in preventing anxiety disorders and the worsening of anxiety disorders. Future public health research is needed on how and in what ways the differing dimensions of social isolation impact mental health., (© 2024. The Author(s).)

Dendritic spines, the mushroom-shaped extensions along dendritic shafts of excitatory neurons, are critical for synaptic function and are one of the first neuronal structures disrupted in neurodevelopmental and neurodegenerative diseases. Microtubule (MT) polymerization into dendritic spines is an activity-dependent process capable of affecting spine shape and function. Studies have shown that MT polymerization into spines occurs specifically in spines undergoing plastic changes. However, discerning the function of MT invasion of dendritic spines requires the specific inhibition of MT polymerization into spines, while leaving MT dynamics in the dendritic shaft, synaptically connected axons and associated glial cells intact. This is not possible with the unrestricted, bath application of pharmacological compounds. To specifically disrupt MT entry into spines we coupled a MT elimination domain (MTED) from the Efa6 protein to the actin filament-binding peptide LifeAct. LifeAct was chosen because actin filaments are highly concentrated in spines and are necessary for MT invasions. Temporally controlled expression of this LifeAct-MTED construct inhibits MT entry into dendritic spines, while preserving typical MT dynamics in the dendrite shaft. Expression of this construct will allow for the determination of the function of MT invasion of spines and more broadly, to discern how MT-actin interactions affect cellular processes.

Spirituality is a significant cultural strength and resource for Black emerging adults. Numerous studies show that increasing numbers of emerging adults tend to identify themselves as being spiritual but not religious. However, no studies to date have identified the demographic correlates of spirituality for Black emerging adults from different ethnic groups (i.e., African American vs. Black Caribbean). Data from the National Survey of American Life was used to identify the demographic correlates of 2 indicators of spirituality (e.g., self-rated spirituality and subjective spirituality) for 802 African American and 428 Black Caribbean emerging adults using linear regression. For African Americans, being a woman predicted both greater self-rated spirituality and subjective spirituality. However, among Black Caribbeans men rated spirituality higher in importance than women. African Americans who reported higher educational attainment tended to report higher levels of self-rated spirituality and subjective spirituality. Romantic status for Black Caribbeans, whether they had no romantic involvement or a current romantic partner, was associated with lower self-ratings of spirituality. Unmarried cohabitating individuals in both ethnic groups tended to report lower levels of self-related spirituality. Unemployment for Black Caribbeans was associated with lower subjective spirituality. Findings are of interest to those who serve and work with Black emerging adults.

Social isolation is associated with worse health; however, few studies have examined the health effects of isolation among African Americans. The purpose of this study is to evaluate associations between social isolation and self-rated physical and oral health from the National Survey of American Life, a nationally representative sample of African Americans. Social isolation was operationalized to reflect both objective isolation (lack of contact) and subjective isolation (lack of emotional closeness). Self-rated physical and oral health were regressed on objective and subjective isolation while controlling for marital status, gender, age, family income, education, and health behaviors. Poorer self-rated physical health was associated with objective isolation, while poorer self-rated oral health was associated with subjective isolation. This study contributes to the small literature of the impact of social isolation on health among African Americans; furthermore, it is the first to examine the relationship between isolation and self-rated oral health in this population.

Hexavalent chromium, Cr(VI), is a heavy metal endocrine disruptor used widely in various industries worldwide and is considered a reproductive toxicant. Our previous studies demonstrated that lactational exposure to Cr(VI) caused follicular atresia, disrupted steroid hormone biosynthesis and signaling, and delayed puberty. However, the underlying mechanism was unknown. The current study investigated the effects of Cr(VI) exposure (25 ppm) during postnatal days 1-21 via dam's milk on epigenetic alterations in the ovary of F1 offspring. Data indicated that Cr(VI) disrupted follicle development and caused apoptosis by increasing DNMT3a /3b and histone methyl marks (H3K27me3 and H3K9me3) along with decreasing histone acetylation marks (H3K9ac and H3K27ac). Our study demonstrates that exposure to Cr(VI) causes changes in the epigenetic marks, partially contributing to the transcriptional repression of genes regulating ovarian development, cell proliferation (PCNA), cell survival (BCL-XL and BCL-2), and activation of genes regulating apoptosis (AIF and cleaved caspase-3), resulting in follicular atresia. The current study suggests a role for epigenetics in Cr(VI)-induced ovotoxicity and infertility., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Friends are crucial for companionship, sharing personal thoughts and feelings, and are positively associated with psychological well-being and mental health. This is one of the first studies to provide an in-depth investigation of social support networks of African American friendship. Using a nationally representative sample of African American adults drawn from the National Survey of American Life, this study investigated sociodemographic correlates, as well as expanded information on marital status and life circumstances of friendships. Additionally, we examined the interrelationships among several aspects of friendship. The findings indicate that, apart from income and region, all other correlates (i.e., age, gender, education, marital status, material hardship, military service, incarceration history, parental status, and urbanicity) were significantly associated with involvement in friendship support networks (i.e., subjective friendship closeness, frequency of contact with friends, frequency of receiving support from friends, and frequency of providing support to friends). Moreover, subjective closeness to friends was positively associated with friend contact, and both subjective closeness to and contact with friends were positively associated with supportive exchanges with friends. These findings indicate the importance of understanding the life circumstances and contexts within which friendships occur and the need for much more quantitative and qualitative research on African American friendships., Competing Interests: DISCLOSURE STATEMENT The authors report no potential conflicts of interest.

The management and exploitation of knowledge can contribute to the competitive advantage of an organisation and hence can be a driver of its value. This paper examines knowledge management practices within two engineering organisations with an emphasis on barriers to its effectiveness and the influence of current and anticipated deployment of digital technologies. Two methods were used to gather research data across both organisations by combining a series of semi-structured interviews with a quantitative social network analysis. Examination of the acquired data provided insights into the relationship between the knowledge management culture in both organisations and their adoption of digital tools. Hudson's evolutionary model of safety culture has been modified to describe the culture of knowledge management in an organisation and the acquired data used to locate the two organisations on their knowledge management journey. It is proposed that social networks could be used as an indicator of the stage of evolution of knowledge management in engineering organisations more generally with low network densities and dispersed networks representing higher stages of evolution., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Patterson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Total mercury ([THg]) and selenium ([TSe]) concentrations were determined in California sea lion (Zalophus californianus) lanugo from the Gulf of California in 2021 and 2022. Relationships with sex, morphometrics, and year were evaluated. Following toxicological thresholds of concern for piscivorous mammals, most pups had a [THg] < 10 ppm, one pup (2021) had a [THg] > 20 ppm, no pups had a [THg] > 30 ppm. Females had significantly higher [TSe] than males; sex did not influence [THg]. [THg] and [TSe] in 2022 were significantly higher in the general population and male cohorts compared to 2021. Significant negative correlations were observed between [THg], [TSe], and morphometrics (2021). These results indicate that, compared to other pinniped species, regional California sea lions may have a decreased likelihood of experiencing Hg-related adverse health effects. Year-related changes in element concentrations suggest continued monitoring of this population to assess pinniped, environmental, and potentially, human health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Cardiovascular disease (CVD) and diabetes mellitus are major health issues in Tonga and other Pacific countries, although mortality levels and trends are unclear. We assess the impacts of cause-of-death certification on coding of CVD and diabetes as underlying causes of death (UCoD)., Methods: Tongan records containing cause-of-death data (2001-2018), including medical certificates of cause-of-death (MCCD), had UCoD assigned according to International Classification of Diseases 10th revision (ICD-10) coding rules. Deaths without recorded cause were included to ascertain total mortality. Diabetes and hypertension causes were reallocated from Part 1 of the MCCD (direct cause) to Part 2 (contributory cause) if potentially fatal complications were not recorded, and an alternative UCoD was assigned. Proportional mortality by cause based on the alternative UCoD were applied to total deaths then mortality rates calculated by age and sex using census/intercensal population estimates. CVD and diabetes mortality rates for unaltered and alternative UCoD were compared using Poisson regression., Results: Over 2001-18, in ages 35-59 years, alternative CVD mortality was higher than unaltered CVD mortality in men (p = 0.043) and women (p = 0.15); for 2010-18, alternative versus unaltered measures in men were 3.3/10 3 (95%CI: 3.0-3.7/10 3 ) versus 2.9/10 3 (95%CI: 2.6-3.2/10 3 ), and in women were 1.1/10 3 (95%CI: 0.9-1.3/10 3 ) versus 0.9/10 3 (95%CI: 0.8-1.1/10 3 ). Conversely, alternative diabetes mortality rates were significantly lower than the unaltered rates over 2001-18 in men (p < 0.0001) and women (p = 0.013); for 2010-18, these measures in men were 1.3/10 3 (95%CI: 1.1-1.5/10 3 ) versus 1.9/10 3 (95%CI: 1.6-2.2/10 3 ), and in women were 1.4/10 3 (95%CI: 1.2-1.7/10 3 ) versus 1.7/10 3 (95%CI: 1.5-2.0/10 3 ). Diabetes mortality rates increased significantly over 2001-18 in men (unaltered: p < 0.0001; alternative: p = 0.0007) and increased overall in women (unaltered: p = 0.0015; alternative: p = 0.014)., Conclusions: Diabetes reporting in Part 1 of the MCCD, without potentially fatal diabetes complications, has led to over-estimation of diabetes, and under-estimation of CVD, as UCoD in Tonga. This indicates the importance of controlling various modifiable risks for atherosclerotic CVD (including stroke) including hypertension, tobacco use, and saturated fat intake, besides obesity and diabetes. Accurate certification of diabetes as a direct cause of death (Part 1) or contributory factor (Part 2) is needed to ensure that valid UCoD are assigned. Examination of multiple cause-of-death data can improve understanding of the underlying causes of premature mortality to better inform health planning., (© 2023. The Author(s).)

Environmental mercury (Hg) contamination of the global tropics outpaces our understanding of its consequences for biodiversity. Knowledge gaps of pollution exposure could obscure conservation threats in the Neotropics: a region that supports over half of the world's species, but faces ongoing land-use change and Hg emission via artisanal and small-scale gold mining (ASGM). Due to their global distribution and sensitivity to pollution, birds provide a valuable opportunity as bioindicators to assess how accelerating Hg emissions impact an ecosystem's ability to support biodiversity, and ultimately, global health. We present the largest database on Neotropical bird Hg concentrations (n = 2316) and establish exposure baselines for 322 bird species spanning nine countries across Central America, South America, and the West Indies. Patterns of avian Hg exposure in the Neotropics broadly align with those in temperate regions: consistent bioaccumulation across functional groups and high spatiotemporal variation. Bird species occupying higher trophic positions and aquatic habitats exhibited elevated Hg concentrations that have been previously associated with reductions in reproductive success. Notably, bird Hg concentrations were over four times higher at sites impacted by ASGM activities and differed by season for certain trophic niches. We developed this synthesis via a collaborative research network, the Tropical Research for Avian Conservation and Ecotoxicology (TRACE) Initiative, which exemplifies inclusive, equitable, and international data-sharing. While our findings signal an urgent need to assess sampling biases, mechanisms, and consequences of Hg exposure to tropical avian communities, the TRACE Initiative provides a meaningful framework to achieve such goals. Ultimately, our collective efforts support and inform local, scientific, and government entities, including Parties of the United Nations Minamata Convention on Mercury, as we continue working together to understand how Hg pollution impacts biodiversity conservation, ecosystem function, and public health in the tropics., (© 2023. The Author(s).)

Background: The first-in-class brain-penetrating synthetic hydroxylated lipid idroxioleic acid (2-OHOA; sodium 2-hydroxyoleate), activates sphingomyelin synthase expression and regulates membrane-lipid composition and mitochondrial energy production, inducing cancer cell autophagy. We report the findings of a multicentric first-in-human Phase 1/2A trial (NCT01792310) of 2-OHOA, identifying the maximum tolerated dose (MTD) and assessing safety and preliminary efficacy., Methods: We performed an open-label, non-randomised trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumour activity of daily oral treatment with 2-OHOA monotherapy (BID/TID) in 54 patients with glioma and other advanced solid tumours. A dose-escalation phase using a standard 3 + 3 design was performed to determine safety and tolerability. This was followed by two expansion cohorts at the MTD to determine the recommended Phase-2 dose (RP2D)., Results: In total, 32 recurrent patients were enrolled in the dose-escalation phase (500-16,000 mg/daily). 2-OHOA was rapidly absorbed with dose-proportional exposure. Treatment was well-tolerated overall, with reversible grade 1-2 nausea, vomiting, and diarrhoea as the most common treatment-related adverse events (AEs). Four patients had gastrointestinal dose-limiting toxicities (DLTs) of nausea, vomiting, diarrhoea (three patients at 16,000 mg and one patient at 12,000 mg), establishing an RP2D at 12,000 mg/daily. Potential activity was seen in patients with recurrent high-grade gliomas (HGG). Of the 21 patients with HGG treated across the dose escalation and expansion, 5 (24%) had the clinical benefit (RANO CR, PR and SD >6 cycles) with one exceptional response lasting >2.5 years., Conclusions: 2-OHOA demonstrated a good safety profile and encouraging activity in this difficult-to-treat malignant brain-tumour patient population, placing it as an ideal potential candidate for the treatment of glioma and other solid tumour malignancies., Clinical Trial Registration: EudraCT registration number: 2012-001527-13; Clinicaltrials.gov registration number: NCT01792310., (© 2023. Crown.)

We present an apparatus for detection of cyclotron radiation yielding a frequency-based β^{±} kinetic energy determination in the 5 keV to 2.1 MeV range, characteristic of nuclear β decays. The cyclotron frequency of the radiating β particles in a magnetic field is used to determine the β energy precisely. Our work establishes the foundation to apply the cyclotron radiation emission spectroscopy (CRES) technique, developed by the Project 8 Collaboration, far beyond the 18-keV tritium endpoint region. We report initial measurements of β^{-}'s from ^{6}He and β^{+}'s from ^{19}Ne decays to demonstrate the broadband response of our detection system and assess potential systematic uncertainties for β spectroscopy over the full (MeV) energy range. To our knowledge, this is the first direct observation of cyclotron radiation from individual highly relativistic β's in a waveguide. This work establishes the application of CRES to a variety of nuclei, opening its reach to searches for new physics beyond the TeV scale via precision β-decay measurements.

Background: Studies suggest Black Americans have a lower prevalence of depression than White Americans despite greater exposure to risk factors for depression across the life course. We examined whether this paradox exists among students in higher education, and whether the paradox may be partly explained by racial differences in reports of impairment from depression, which is a required criterion for clinical diagnosis., Methods: We analyzed data from the Healthy Minds Study (2020-2021), restricting the sample to young adults (18-29) who identified as either Black or White. Using modified Poisson regression models to estimate risk ratios, we examined associations between race and depression impairment across five levels of depression severity, adjusting for age and gender., Results: Approximately 23% of Black students reported depression impairment, which is significantly lower than the 28% of White students who reported depression impairment. For all students, greater depression severity was associated with greater probability of impairment; however, the relationship was more modest among Black students. At severe, moderately severe, and moderate depression levels, Black students had lower risk of depression impairment compared with White students., Conclusion: White students may be more likely than Black students to report significant impairment at high levels of depression. These findings open the possibility that racial differences in the impairment criterion of clinical diagnoses may explain some the racial depression paradox.

Background: Minimal data exist on pregnancy following recovery from Ebola in people of child-bearing potential (females aged roughly 18-45 years). The aim of this study was to assess viral persistence or reactivation in pregnancy, the frequency of placental transfer of anti-Ebola IgG antibodies, and pregnancy outcomes in this population., Methods: In this observational cohort study, we studied self-reported pregnancies in two groups: seropositive people who had recovered from Ebola virus disease (seropositive group) and seronegative people who had close contact with people with Ebola (seronegative group). Participants had enrolled in the PREVAIL III longitudinal study and were exposed during the 2014-2016 Liberian Ebola outbreak. The primary outcome was pregnancy result. We assessed rates of livebirths and other pregnancy results in both study groups, and presence of Ebola RNA by PCR in samples of placenta, maternal and cord blood, breastmilk, and vaginal secretions from people who had recovered from Ebola who conceived a median of 14 months after acute Ebola virus disease. Mixed-model logistic regression evaluated associations between first-reported pregnancy outcome, age, and study group. Growth and neurodevelopment in the infants born to people in the seropositive group were assessed at 6-month intervals for 2 years. Data were accrued by PREVAIL III study staff., Findings: 1566 participants were enrolled between June 17, 2015, and Dec 14, 2017, of whom 639 became pregnant (215 seropositive, 424 seronegative) and 589 reported pregnancy outcomes (206 seropositive, 383 seronegative). 105 infants born to 98 mothers in the seropositive group were enrolled in the birth cohort. Ebola RNA was not detected in 205 samples of placenta, cord blood, or maternal blood taken at birth from 54 mothers in the seropositive group, nor in 367 vaginal swabs. Viral RNA was found in two of 354 longitudinal breastmilk samples. All but one of 57 infants born during these 54 births were seropositive for anti-Ebola antibodies. Neonates showed high concentrations of anti-Ebola IgG, which declined after 6 months. Odds of adverse pregnancy outcome among the two groups were indistinguishable (OR 1·13, 95% CI 0·71-1·79). Compared with WHO standards, infants born to those in the seropositive group had lower median weight and length, and larger median head circumference over 2 years. Compared with a cohort from the USA accrual of gross motor developmental milestones was similar, whereas attainment of pincer grasp and early vocalisation were mildly delayed., Interpretation: The risks of Ebola virus reactivation in the peripartum and postpartum period and of adverse birth outcomes are low in those who have recovered from Ebola virus disease and become pregnant approximately 1 year after acute Ebola virus disease. The implication for clinical practice is that care of people who are pregnant and who have recovered from Ebola can be offered without risks to health-care providers or stigmatisation of the mothers and their offspring. The implication for prospective mothers is that safe pregnancies are entirely possible after recovery from Ebola., Funding: National Institute of Allergy and Infectious Diseases and Liberia Ministry of Health., Competing Interests: Declaration of interests SGK reports support from the National Institute of Allergy and Infectious Diseases for travel to Liberia, to serve as site physician between May and June, 2015, and to attend the annual meeting in March, 2016. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Knowledge of protein dynamics is fundamental to the understanding of biological processes, with NMR and 2D-IR spectroscopy being two of the principal methods for studying protein dynamics. Here, we combine these two methods to gain a new understanding of the complex mechanism of a cytokine:receptor interaction. The dynamic nature of many cytokines is now being recognised as a key property in the signalling mechanism. Interleukin-17s (IL-17) are proinflammatory cytokines which, if unregulated, are associated with serious autoimmune diseases such as psoriasis, and although there are several therapeutics on the market for these conditions, small molecule therapeutics remain elusive. Previous studies, exploiting crystallographic methods alone, have been unable to explain the dramatic differences in affinity observed between IL-17 dimers and their receptors, suggesting there are factors that cannot be fully explained by the analysis of static structures alone. Here, we show that the IL-17 family of cytokines have varying degrees of flexibility which directly correlates to their receptor affinities. Small molecule inhibitors of the cytokine:receptor interaction are usually thought to function by either causing steric clashes or structural changes. However, our results, supported by other biophysical methods, provide evidence for an alternate mechanism of inhibition, in which the small molecule rigidifies the protein, causing a reduction in receptor affinity. The results presented here indicate an induced fit model of cytokine:receptor binding, with the more flexible cytokines having a higher affinity. Our approach could be applied to other systems where the inhibition of a protein-protein interaction has proved intractable, for example due to the flat, featureless nature of the interface. Targeting allosteric sites which modulate protein dynamics, opens up new avenues for novel therapeutic development., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Daniel J. Shaw, Monika-Sarah E. D. Schulze, Christine E. Prosser, Alastair D. G. Lawson, Alistair J. Henry and Richard J. Taylor are or have been employees of UCB and may hold UCB shares and/or stock options., (This journal is © The Royal Society of Chemistry.)

James S. Jackson (1944-2020) is remembered as a groundbreaking social psychologist whose career contributions in scholarship, research, and service were fundamental to the field of psychology. This article briefly outlines his career-long work and contributions. A strong believer in interdisciplinary work, his research spanned other related social science disciplines (e.g., sociology, political science), as well as health and social welfare professions (public health, social work, medicine). As the founding director of the Program for Research on Black Americans at the Institute for Social Research, James Jackson initiated and led a long-standing program with a dual focus on research and training and mentoring doctoral students, postdoctoral scholars, and early career scientists. Jackson's efforts in the development of several nationally representative surveys of the Black population in the United States (e.g., National Survey of Black Americans, National Survey of American Life) revolutionized research focusing on the lives of Black Americans. James Jackson's international influence and reputation included numerous prestigious positions within national science organizations and honors and awards for his scientific contributions. Among James S. Jackson's most enduring legacies is the vast network of current scientists, researchers, and academics who were trained under his direction and leadership. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background: To determine if the extent of high-dose gross tumor volume (GTV) to clinical target volume (CTV) expansion is associated with local control in patients with p16-positive oropharynx cancer (p16+ OPC) treated with definitive intensity modulated proton therapy (IMPT)., Methods: We performed a retrospective analysis of patients with p16+ OPC treated with IMPT at a single institution between 2016 and 2021. Patients with a pre-treatment PET-CT and restaging PET-CT within 4 months following completion of IMPT were analyzed., Results: Sixty patients were included for analysis with a median follow-up of 17 months. The median GTV to CTV expansion was 5 mm (IQR: 2 mm). Thirty-three percent of patients (20 of 60) did not have a GTV to CTV expansion. There was one local failure within the expansion group (3%)., Conclusion: Excellent local control was achieved using IMPT for p16+ OPC independent of GTV expansion. IMPT with minimal target expansions represent a potential harm-minimization technique for p16-positive oropharynx cancer., (© 2023 Wiley Periodicals LLC.)

Trotter and Gleser presented two sets of stature estimation equations for the US White males in their 1952 and 1958 studies. Following Trotter's suggestion favouring the 1952 equations simply due to the smaller standard errors, the 1958 equations have been seldom used and have gone without additional systematic validation tests. This study aims to assess the performance of the Trotter and Gleser 1952, Trotter and Gleser 1958, and FORDISC equations for the White males in a quantitative and systematic way, particularly when applied to the WWII and Korean War casualties. In sum, 27 equations (7 from the 1952 study, 10 from the 1958 study, and 10 from FORDISC) were applied to the osteometric data of 240 accounted-for White male casualties of the WWII and Korean War. Then, the bias, accuracy, and Bayes factor for each set of stature estimates were calculated. The results show that, overall, Trotter and Gleser's 1958 equations outperform the 1952 and FORDISC equations in terms of all three measures. Particularly, the equations with higher Bayes factors produced stature estimates where distributions were closer to that of the reported statures than those with lower Bayes factors. When considering Bayes factors, the best performing equation was the "Radius" equation from the 1958 study (BF = 15.34) followed by the "Humerus+Radius" equation from FORDISC (BF = 14.42) and the "Fibula" equation from the 1958 study (BF = 13.82). The results of this study will provide researchers and practitioners applying the Trotter and Gleser stature estimation method with a practical guide for equation selection., Key Points: The performance of three stature estimation methods was compared quantitatively.Trotter and Gleser's (1952, 1958) and FORDISC White male equations were included.Overall, Trotter and Gleser's 1958 method outperformed the other methods.This study provides a practical guide for stature estimation equation selection., (© The Author(s) 2023. Published by OUP on behalf of the Academy of Forensic Science.)

The placenta is an essential organ that regulates and maintains mammalian development in utero. The placenta is responsible for the transfer of nutrients and waste between the mother and fetus and the production and delivery of growth factors and hormones. Placental genetic manipulations in mice are critical for understanding the placenta's specific role in prenatal development. Placental-specific Cre-expressing transgenic mice have varying effectiveness, and other methods for placental gene manipulation can be useful alternatives. This paper describes a technique to directly alter placental gene expression using CRISPR gene manipulation, which can be used to modify the expression of targeted genes. Using a relatively advanced surgical approach, pregnant dams undergo a laparotomy on embryonic day 12.5 (E12.5), and a CRISPR plasmid is delivered by a glass micropipette into the individual placentas. The plasmid is immediately electroporated after each injection. After dam recovery, the placentas and embryos can continue development until assessment at a later time point. The evaluation of the placenta and offspring after the use of this technique can determine the role of time-specific placental function in development. This type of manipulation will allow for a better understanding of how placental genetics and function impact fetal growth and development in multiple disease contexts.

α-synuclein (αS) is an intrinsically disordered protein whose functional ambivalence and protein structural plasticity are iconic. Coordinated protein recruitment ensures proper vesicle dynamics at the synaptic cleft, while deregulated oligomerization on cellular membranes contributes to cell damage and Parkinson's disease (PD). Despite the protein's pathophysiological relevance, structural knowledge is limited. Here, we employ NMR spectroscopy and chemical cross-link mass spectrometry on 14 N/ 15 N-labeled αS mixtures to provide for the first time high-resolution structural information of the membrane-bound oligomeric state of αS and demonstrate that in this state, αS samples a surprisingly small conformational space. Interestingly, the study locates familial Parkinson's disease mutants at the interface between individual αS monomers and reveals different oligomerization processes depending on whether oligomerization occurs on the same membrane surface (cis) or between αS initially attached to different membrane particles (trans). The explanatory power of the obtained high-resolution structural model is used to help determine the mode-of-actionof UCB0599. Here, it is shown that the ligand changes the ensemble of membrane-bound structures, which helps to explain the success this compound, currently being tested in Parkinson's disease patients in a phase 2 trial, has had in animal models of PD.

COPI-coated vesicles mediate transport between Golgi stacks and retrograde transport from the Golgi to the endoplasmic reticulum. The COPI coat exists as a stable heptameric complex in the cytosol termed coatomer and is recruited en bloc to the membrane for vesicle formation. Recruitment of COPI onto membranes is mediated by the Arf family of small GTPases, which, in their GTP-bound state, bind both membrane and coatomer. Arf GTPases also influence cargo selection, vesicle scission and vesicle uncoating. Guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) regulate nucleotide binding by Arf GTPases. To understand the mechanism of COPI-coated vesicle trafficking, it is necessary to characterize the interplay between coatomer and Arf GTPases and their effectors. It is also necessary to understand interactions between coatomer and cargo, cargo adaptors/receptors and tethers facilitating binding to the target membrane. Here, we summarize current knowledge of COPI coat protein structure; we describe how structural and biochemical studies contributed to this knowledge; we review mechanistic insights into COPI vesicle biogenesis and disassembly; and we discuss the potential to answer open questions in the field., (© 2022 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Objectives: To survey academic and community physician preferences regarding the virtual multidisciplinary tumor board (MTB) for further improvement and expansion., Study Design: This anonymous 14-question survey was sent to individuals that participated in the head and neck virtual MTBs. The survey was sent via email beginning August 3, 2021, through October 5, 2021., Setting: The University of Maryland Medical Center and regional practices in the state of Maryland., Methods: Survey responses were recorded and presented as percentages. Subset analysis was performed to obtain frequency distributions by facility and provider type., Results: There were 50 survey responses obtained with a response rate of 56%. Survey participants included 11 surgeons (22%), 19 radiation oncologists (38%), and 8 medical oncologists (16%), amongst others. More than 96% of participants found the virtual MTB to be useful when discussing complex cases and impactful to future patient care. A majority of respondents perceived a reduction in time to adjuvant care (64%). Community and academic physician responses strongly agreed that the virtual MTB improved communication (82% vs 73%), provided patient-specific information for cancer care (82% vs 73%), and improved access to other specialties (66% vs 64%). Academic physicians, more so than community physicians, strongly agreed that the virtual MTB improves access to clinical trial enrollment (64% vs 29%) and can be useful in obtaining CME (64% vs 55%)., Conclusion: Academic and community physicians view the virtual MTB favorably. This platform can be adapted regionally and further expanded to improve communication between physicians and improve multidisciplinary care for patients., Competing Interests: The authors declare that there are no conflicts of interest., (© 2023 The Authors. OTO Open published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Lipopolysaccharide (LPS) is an essential component of the outer membrane (OM) of many Gram-negative bacteria, providing a barrier against the entry of toxic molecules. In Escherichia coli, LPS is exported to the cell surface by seven essential proteins (LptA-G) that form a transenvelope complex. At the inner membrane, the ATP-binding cassette (ABC) transporter LptB 2 FG associates with LptC to power LPS extraction from the membrane and transfer to the periplasmic LptA protein, which is in complex with the OM translocon LptDE. LptC interacts both with LptB 2 FG and LptADE to mediate the formation of the transenvelope bridge and regulates the ATPase activity of LptB 2 FG. A genetic screen has previously identified suppressor mutants at a residue (R212) of LptF that are viable in the absence of LptC. Here, we present in vivo evidence that the LptF R212G mutant assembles a six-protein transenvelope complex in which LptA mediates interactions with LptF and LptD in the absence of LptC. Furthermore, we present in vitro evidence that the mutant LptB 2 FG complexes restore the regulation of ATP hydrolysis as it occurs in the LptB 2 FGC complex to achieve wild-type efficient coupling of ATP hydrolysis and LPS movement. We also show the suppressor mutations restore the wild-type levels of LPS transport both in vivo and in vitro , but remarkably, without restoring the affinity of the inner membrane complex for LptA. Based on the sensitivity of lptF suppressor mutants to selected stress conditions relative to wild-type cells, we show that there are additional regulatory functions of LptF and LptC that had not been identified. IMPORTANCE The presence of an external LPS layer in the outer membrane makes Gram-negative bacteria intrinsically resistant to many antibiotics. Millions of LPS molecules are transported to the cell surface per generation by the Lpt molecular machine made, in E. coli, by seven essential proteins. LptC is the unconventional regulatory subunit of the LptB 2 FGC ABC transporter, involved in coordinating energy production and LPS transport. Surprisingly, despite being essential for bacterial growth, LptC can be deleted, provided that a specific residue in the periplasmic domain of LptF is mutated and LptA is overexpressed. Here, we apply biochemical techniques to investigate the suppression mechanism. The data produced in this work disclose an unknown regulatory function of LptF in the transporter that not only expands the knowledge about the Lpt complex but can also be targeted by novel LPS biogenesis inhibitors.

Purpose: To develop an automated lung tumor segmentation method for radiation therapy planning based on deep learning and dual-modality positron emission tomography (PET) and computed tomography (CT) images., Methods and Materials: A 3-dimensional (3D) convolutional neural network using inputs from diagnostic PETs and simulation CTs was constructed with 2 parallel convolution paths for independent feature extraction at multiple resolution levels and a single deconvolution path. At each resolution level, the extracted features from the convolution arms were concatenated and fed through the skip connections into the deconvolution path that produced the tumor segmentation. Our network was trained/validated/tested by a 3:1:1 split on 290 pairs of PET and CT images from patients with lung cancer treated at our clinic, with manual physician contours as the ground truth. A stratified training strategy based on the magnitude of the gross tumor volume (GTV) was investigated to improve performance, especially for small tumors. Multiple radiation oncologists assessed the clinical acceptability of the network-produced segmentations., Results: The mean Dice similarity coefficient, Hausdorff distance, and bidirectional local distance comparing manual versus automated contours were 0.79 ± 0.10, 5.8 ± 3.2 mm, and 2.8 ± 1.5 mm for the unstratified 3D dual-modality model. Stratification delivered the best results when the model for the large GTVs (>25 mL) was trained with all-size GTVs and the model for the small GTVs (<25 mL) was trained with small GTVs only. The best combined Dice similarity coefficient, Hausdorff distance, and bidirectional local distance from the 2 stratified models on their corresponding test data sets were 0.83 ± 0.07, 5.9 ± 2.5 mm, and 2.8 ± 1.4 mm, respectively. In the multiobserver review, 91.25% manual versus 88.75% automatic contours were accepted or accepted with modifications., Conclusions: By using an expansive clinical PET and CT image database and a dual-modality architecture, the proposed 3D network with a novel GTVbased stratification strategy generated clinically useful lung cancer contours that were highly acceptable on physician review., (Copyright © 2022 Elsevier Inc. All rights reserved.)