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Background Social media plays a pivotal role in adolescents’ lives. Social media encounters, including online risk behaviors, may influence real-world risk behaviors and mental health. This study explored the magnitude and patterns of social media use, risk behaviors, and mental health among boys and girls and examined associations between these factors. Methods A survey was administered to Grade 9 students in New Providence, The Bahamas, in 2023 to assess their social media use, including platforms used, online activities, and experiences of online risk behavior, as well as their risk behavior engagement and mental health. We analyzed data from 1,563 students using generalized linear mixed models. Results Two-thirds of the students spent three hours or more on social media daily. Online risk behaviors, such as cyberbullying and sexting (sending, receiving, or forwarding sexually explicit messages), were also prevalent. Approximately 48% had suicidal ideation during their lifetime. Girls reported higher rates of social media usage, active and passive engagement on social media, cyberbullying experiences, and mental health issues, while boys were more likely to engage in sexting and offline risk behaviors. Factors associated with suicidal ideation included being female, experiencing sexting or cyberbullying, using X, and engaging in risk behaviors such as inappropriate touching and weapon carrying. Conclusions Future studies should clarify the complex interplay among the content consumed by adolescents, their online activities, and gender-specific effects on mental health. This study highlights the need for programs that can both foster a positive and supportive online environment and provide targeted assistance for victims of online harm.

Trogocytosis is a process which involves the transfer of membrane fragments and cell surface proteins between cells. Various types of T cells have been shown to be able to acquire membrane-bound proteins from antigen-presenting cells and their functions can be modulated following trogocytosis. However, it is not known whether induced regulatory T cells （iTregs） can undergo trogocytosis, and if so, what the functional consequences of this process might entail. In this study, we show that iTregs can be generated from CD80-/-CD86-/- double knockout （DKO） mice. Using flow cytometry and confocal fluorescence microscopy, we demonstrate that iTregs generated from DKO mice are able to acquire both CD80 and CD86 from mature dendritic cells （mDCs） and that the acquisition of CD86 occurs to a higher extent than that of CD80. Furthermore, we found that after co-incubation with iTregs, dendritic cells （DCs） downregulate their surface expression of CD80 and CD86. The trogocytosis of both CD80 and CD86 occurs in a cytotoxic T lymphocyte-associated antigen-4 （CTLA-4）, CD28 and programmed death ligand-1 （PDL1）-independent manner. Importantly, we showed that iTregs that acquired CD86 from mDCs expressed higher activation markers and their ability to suppress naive CD4＋ T-cell proliferation was enhanced, compared to iTregs that did not acquire CD86. These data demonstrate, for the first time, that iTregs can acquire CD80 and CD86 from mDCs, and the acquisition of CD86 may enhance their suppressive function. These findings provide novel understanding of the interaction between iTregs and DCs, suggesting that trogocytosis may play a significant role in iTreg-mediated immune suppression.

Histologic variant (HV) subtypes of bladder cancer are clinically aggressive tumors that are more resistant to standard therapy compared to conventional urothelial carcinoma (UC). Little is known about the transcriptional programs that account for their biological differences. Here we show using single cell analysis that HVs harbor a tumor cell state characterized by expression of MUC16 (CA125), MUC4 , and KRT24 . This cell state is enriched in metastases, predicted to be highly resistant to chemotherapy, and linked with poor survival. We also find enriched expression of TM4SF1 , a transmembrane protein, in HV tumor cells. Chimeric antigen receptor (CAR) T cells engineered against TM4SF1 protein demonstrated in vitro and in vivo activity against bladder cancer cell lines in a TM4SF1 expression-dependent manner, highlighting its potential as a therapeutic target. Single cell analysis of histologic variant bladder tumors detects a shared CA125+ tumor cell state associated with aggressive clinical features and reveals enriched expression of TM4SF1, a membrane protein that can be targeted with CAR T cells.

Background Effective mentorship is an important component of medical education with benefits to all stakeholders. In recent years, conceptualization of mentorship has gone beyond the traditional dyadic experienced mentor-novice mentee relationship to include group and peer mentoring. Existing theories of mentorship do not recognize mentoring’s personalized, evolving, goal-driven, and context-specific nature. Evidencing the limitations of traditional cause-and-effect concepts, the purpose of this review was to systematically search the literature to determine if mentoring can be viewed as a complex adaptive system (CAS). Methods A systematic scoping review using Krishna’s Systematic Evidence-Based Approach was employed to study medical student and resident accounts of mentoring and CAS in general internal medicine and related subspecialties in articles published between 1 January 2000 and 31 December 2023 in PubMed, Embase, PsycINFO, ERIC, Google Scholar, and Scopus databases. The included articles underwent thematic and content analysis, with the themes identified and combined to create domains, which framed the discussion. Results Of 5,704 abstracts reviewed, 134 full-text articles were evaluated, and 216 articles were included. The domains described how mentoring relationships and mentoring approaches embody characteristics of CAS and that mentorship often behaves as a community of practice (CoP). Mentoring’s CAS-like features are displayed through CoPs, with distinct boundaries, a spiral mentoring trajectory, and longitudinal mentoring support and assessment processes. Conclusion Recognizing mentorship as a CAS demands the rethinking of the design, support, assessment, and oversight of mentorship and the role of mentors. Further study is required to better assess the mentoring process and to provide optimal training and support to mentors.

Chemoresistance to platinum therapy is a major obstacle that needs to be overcome in the treatment of ovarian cancer patients. The high rates and patterns of therapeutic failure seen in patients are consistent with a steady accumulation of drug-resistant cancer stem cells (CSCs). This study demonstrates that the Notch signaling pathway and Notch3 in particular are critical for the regulation of CSCs and tumor resistance to platinum. We show that Notch3 overexpression in tumor cells results in expansion of CSCs and increased platinum chemoresistance. In contrast, γ-secretase inhibitor (GSI), a Notch pathway inhibitor, depletes CSCs and increases tumor sensitivity to platinum. Similarly, a Notch3 siRNA knockdown increases the response to platinum therapy, further demonstrating that modulation of tumor chemosensitivity by GSI is Notch specific. Most importantly, the cisplatin/GSI combination is the only treatment that effectively eliminates both CSCs and the bulk of tumor cells, indicating that a dual combination targeting both populations is needed for tumor eradication. In addition, we found that the cisplatin/GSI combination therapy has a synergistic cytotoxic effect in Notch-dependent tumor cells by enhancing the DNA-damage response, G ₂/M cell-cycle arrest, and apoptosis. Based on these results, we conclude that targeting the Notch pathway could significantly increase tumor sensitivity to platinum therapy. Our study suggests important clinical applications for targeting Notch as part of novel treatment strategies upon diagnosis of ovarian cancer and at recurrence. Both platinum-resistant and platinum-sensitive relapses may benefit from such an approach as clinical data suggest that all relapses after platinum therapy are increasingly platinum resistant.

The Arctic warms nearly four times faster than the global average, and aerosols play an increasingly important role in Arctic climate change. In the Arctic, sea salt is a major aerosol component in terms of mass concentration during winter and spring. However, the mechanisms of sea salt aerosol production remain unclear. Sea salt aerosols are typically thought to be relatively large in size but low in number concentration, implying that their influence on cloud condensation nuclei population and cloud properties is generally minor. Here we present observational evidence of abundant sea salt aerosol production from blowing snow in the central Arctic. Blowing snow was observed more than 20% of the time from November to April. The sublimation of blowing snow generates high concentrations of fine-mode sea salt aerosol (diameter below 300 nm), enhancing cloud condensation nuclei concentrations up to tenfold above background levels. Using a global chemical transport model, we estimate that from November to April north of 70° N, sea salt aerosol produced from blowing snow accounts for about 27.6% of the total particle number, and the sea salt aerosol increases the longwave emissivity of clouds, leading to a calculated surface warming of +2.30 W m−2 under cloudy sky conditions.Fine sea salt aerosols produced by blowing snow in the Arctic impact cloud properties and warm the surface, according to observations from the MOSAiC expedition.

Sphingosine-1-phosphate (S1P) is a crucial sphingolipid mediator in vasculature and neovascular eye diseases by controlling angiogenesis, inflammation and fibrosis. Five S1P receptors (S1PRs) are key therapeutic targets, with several S1PR-targeted drugs already in clinical use or trials. However, the vascular function of its major metabolic product, the reactive lipid aldehyde 2-hexadecenal (2-HD), remains unexplored. Here, we show that loss of the aldehyde dehydrogenase ALDH3B1 impairs 2-HD detoxification and leads to retinal vascular abnormalities in zebrafish, without affecting the trunk vasculature. Mechanistically, multi-omics analyses reveal that 2-HD accumulation disrupts iron homeostasis and induces ferroptosis by directly interacting with S1PR5. This finding is supported by integrative analyses of single-cell RNA sequencing and RNA sequencing from human neovascular retinal samples, identifying S1PR5 as a clinically relevant target. These findings uncover a previously unrecognized role of S1P derived 2-HD in vasculature and retinal vascular homeostasis, suggesting that targeting S1PR5 could offer a therapeutic strategy for diabetic retinopathy. Sphingolipids mediate inflammation, although the role of lipid aldehyde 2-HD is poorly understood. Here, the authors show ALDH3B1 detoxifies 2-HD to protect retinal vasculature, with 2HD accumulation causing vascular abnormalities.

Isomerization of aspartic acid (Asp) in therapeutic proteins could lead to safety and efficacy concerns. Thus, accurate quantitation of various Asp isomerization along with kinetic understanding of the variant formations is needed to ensure optimal process development and sufficient product quality control. In this study, we first observed Asp-succinimide conversion in complementarity-determining regions (CDRs) Asp-Gly motif of a recombinant mAb through ion exchange chromatography, intact protein analysis by mass spectrometry, and LC-MS/MS. Then, we developed a specific peptide mapping method, with optimized sample digestion conditions, to accurately quantitate Asp-succinimide-isoAsp variants at peptide level without method-induced isomerization. Various kinetics of Asp-succinimide-isoAsp isomerization pathways were elucidated using 18O labeling followed by LC-MS analysis. Molecular modeling and molecular dynamic simulation provide additional insight on the kinetics of Asp-succinimide formation and stability of succinimide intermediate. Findings of this work shed light on the molecular construct and the kinetics of the formation of isoAsp and succinimide in peptides and proteins, which facilitates analytical method development, protein engineering, and late phase development for commercialization of therapeutic proteins.

The Geostationary Lightning Mapper (GLM) on the Geostationary Operational Environmental Satellite 16 (GOES-16) detects total lightning continuously, with a high spatial resolution and detection efficiency. Coincident data from the GLM and the Advanced Baseline Imager (ABI) are used to explore the correlation between the cloud top properties and flash activity across the continental United States (CONUS) sector from May to September 2020. A large number of collocated infrared (IR) brightness temperature (TBB), cloud top height (CTH) and lightning data provides robust statistics. Overall, the likelihood of lightning occurrence and high flash density is higher if the TBB is colder than 225 K. The higher CTH is observed to be correlated with a larger flash rate, a smaller flash size, stronger updraft, and larger optical energy. Furthermore, the cloud top updraft velocity (w) is estimated based on the decreasing rate of TBB, but it is smaller than the updraft velocity of the convective core. As a result, the relationship between CTH and lightning flash rate is investigated independently of w over the continental, oceanic and coastal regimes in the tropics and mid-latitudes. When the CTH is higher than 12 km, the flash rates of oceanic lightning are 38% smaller than those of both coastal and continental lightning. In addition, it should be noted that more studies are necessary to examine why the oceanic lightning with low clouds (CTH < 8 km) has higher flash rates than lightning over land and coast. Finally, the exponents of derived power relationship between CTH and lightning flash rate are smaller than four, which is underestimated due to the GLM detection efficiency and the difference between IR CTH and 20 dBZ CTH. The results from combining the ABI and GLM products suggest that merging multiple satellite datasets could benefit both lightning activity and parameterization studies, although the parallax corrections should be considered.

Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3 months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5 years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9 months after initial neurological presentation. Mutations were detected in PRF1 in 23 patients (61%), RAB27A in 10 (26%), UNC13D in 3 (8%), LYST in 1 (3%), and STXBP2 in 1 (3%) with a mean interval to diagnosis of 28.3 months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 non-transplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome.