THEMIS promotes T cell development and maintenance by rising the signaling threshold of the inhibitory receptor BTLA.

The current paradigm about the function of T cell immune checkpoints is that these receptors switch on inhibitory signals upon cognate ligand interaction. We here revisit this simple switch model and provide evidence that the T cell lineage protein THEMIS enhances the signaling threshold at which the immune checkpoint BTLA (B- and T-lymphocyte attenuator) represses T cell responses. THEMIS is recruited to the cytoplasmic domain of BTLA and blocks its signaling capacity by promoting/stabilizing the oxidation of the catalytic cysteine of the tyrosine phosphatase SHP-1. In contrast, THEMIS has no detectable effect on signaling pathways regulated by PD-1 (Programmed cell death protein 1), which depend mainly on the tyrosine phosphatase SHP-2. BTLA inhibitory signaling is tuned according to the THEMIS expression level, making CD8+ T cells more resistant to BTLA-mediated inhibition than CD4+ T cells. In the absence of THEMIS, the signaling capacity of BTLA is exacerbated, which results in the attenuation of signals driven by the T cell antigen receptor and by receptors for IL-2 and IL-15, consequently hampering thymocyte positive selection and peripheral CD8+ T cell maintenance. By characterizing the pivotal role of THEMIS in restricting the transmission of BTLA signals, our study suggests that immune checkpoint operability is conditioned by intracellular signal attenuators.

Tetrahydroxy stilbene glucoside rejuvenates aging hematopoietic stem cells with predilection for lymphoid differentiation via AMPK and Tet2.

INTRODUCTION: Aging of hematopoietic stem cells (HSCs) has emerged as an important challenge to human health. Recent advances have raised the prospect of rejuvenating aging HSCs via specific medical interventions, including pharmacological treatments. Nonetheless, efforts to develop such drugs are still in infancy until now. OBJECTIVES: We aimed to screen the prospective agents that can rejuvenate aging HSCs and explore the potential mechanisms. METHODS: We screened a set of natural anti-aging compounds through oral administration to sub-lethally irradiated mice, and identified 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) as a potent rejuvenating agent for aging HSCs. Then naturally aged mice were used for the follow-up assessment to determine the HSC rejuvenating potential of TSG. Finally, based on the transcriptome and DNA methylation analysis, we validated the role of the AMP-activated protein kinase (AMPK)-ten-eleven-translocation 2 (Tet2) axis (the AMPK-Tet2 axis) as the underlying mechanisms of TSG for ameliorating HSCs aging. RESULTS: TSG treatment not only significantly increased the absolute number of common lymphoid progenitors (CLPs) along with B lymphocytes, but also boosted the HSCs/CLPs repopulation potential of aging mice. Further elaborated mechanism research demonstrated that TSG supplementation restored the stemness of aging HSCs, as well as promoted an epigenetic reprograming that was associated with an improved regenerative capacity and an increased rate of lymphopoiesis. Such effects were diminished when the mice were co-treated with an AMPK inhibitor, or when it was performed in Tet2 knockout mice as well as senescent cells assay. CONCLUSION: TSG is effective in rejuvenating aging HSCs by modulating the AMPK- Tet2 axis and thus represents a potential candidate for developing effective HSC rejuvenating therapies.

Construction of cyclobutane-fused tetracyclic skeletons via substrate-dependent EnT-enabled dearomative [2+2] cycloaddition of benzofurans (benzothiophenes)/maleimides.

Herein, a novel and facile organic photosensitizer (thioxanthone)-mediated energy-transfer-enabled (EnT-enabled) dearomative [2+2] cycloaddition of aromatic heterocycles/maleimides for green synthesis of cyclobutane-fused polycyclic skeletons is reported. Mechanistic investigations revealed that different EnT pathways by triplet thioxanthone were initiated when different aromatic heterocycles participated in the reaction, giving the corresponding excited intermediates, which underwent the subsequent intermolecular [2+2] cycloaddition to access the desired highly functionalized cyclobutane-fused polycyclic skeletons.

Sub-pixel marking and depth-based correction methods for the elimination of voxel drifting in integral imaging display.

Integral imaging is a kind of true three-dimensional (3D) display technology that uses a lens array to reconstruct vivid 3D images with full parallax and true color. In order to present a high-quality 3D image, it's vital to correct the axial position error caused by the misalignment and deformation of the lens array which makes the reconstructed lights deviate from the correct directions, resulting in severe voxel drifting and image blurring. We proposed a sub-pixel marking method to measure the axial position error of the lenses with great accuracy by addressing the sub-pixels under each lens and forming a homologous sub-pixel pair. The proposed measurement method relies on the geometric center alignment of image points, which is specifically expressed as the overlap between the test 3D voxel and the reference 3D voxel. Hence, measurement accuracy could be higher. Additionally, a depth-based sub-pixel correction method was proposed to eliminate the voxel drifting. The proposed correction method takes the voxel depth into consideration in the correction coefficient, and achieves accurate error correction for 3D images with different depths. The experimental results well confirmed that the proposed measuring and correction methods can greatly suppress the voxel drifting caused by the axial position error of the lenses, and greatly improve the 3D image quality.

Incorporating machine learning and PPI networks to identify mitochondrial fission-related immune markers in abdominal aortic aneurysms.

Purpose: The aim of this study is to investigate abdominal aortic aneurysm (AAA), a disease characterised by inflammation and progressive vasodilatation, for novel gene-targeted therapeutic loci. Methods: To do this, we used weighted co-expression network analysis (WGCNA) and differential gene analysis on samples from the GEO database. Additionally, we carried out enrichment analysis and determined that the blue module was of interest. Additionally, we performed an investigation of immune infiltration and discovered genes linked to immune evasion and mitochondrial fission. In order to screen for feature genes, we used two PPI network gene selection methods and five machine learning methods. This allowed us to identify the most featrue genes (MFGs). The expression of the MFGs in various cell subgroups was then evaluated by analysis of single cell samples from AAA. Additionally, we looked at the expression levels of the MFGs as well as the levels of inflammatory immune-related markers in cellular and animal models of AAA. Finally, we predicted potential drugs that could be targeted for the treatment of AAA. Results: Our research identified 1249 up-regulated differential genes and 3653 down-regulated differential genes. Through WGCNA, we also discovered 44 genes in the blue module. By taking the point where several strategies for gene selection overlap, the MFG (ITGAL and SELL) was produced. We discovered through single cell research that the MFG were specifically expressed in T regulatory cells, NK cells, B lineage, and lymphocytes. In both animal and cellular models of AAA, the MFGs' mRNA levels rose. Conclusion: We searched for the AAA novel targeted gene (ITGAL and SELL), which most likely function through lymphocytes of the B lineage, NK cells, T regulatory cells, and B lineage. This analysis gave AAA a brand-new goal to treat or prevent the disease.

The effects of flow settings during high-flow nasal cannula oxygen therapy for neonates and young children.

BACKGROUND: During neonatal and paediatric high-flow nasal cannula therapy, optimising the flow setting is crucial for favourable physiological and clinical outcomes. However, considerable variability exists in clinical practice regarding initial flows and subsequent adjustments for these patients. Our review aimed to summarise the impact of various flows during high-flow nasal cannula treatment in neonates and children. METHODS: Two investigators independently searched PubMed, Embase, Web of Science, Scopus and Cochrane for in vitro and in vivo studies published in English before 30 April 2023. Studies enrolling adults (≥18 years) or those using a single flow setting were excluded. Data extraction and risk of bias assessments were performed independently by two investigators. The study protocol was prospectively registered with PROSPERO (CRD42022345419). RESULTS: 38 406 studies were identified, with 44 included. In vitro studies explored flow settings' effects on airway pressures, humidity and carbon dioxide clearance; all were flow-dependent. Observational clinical studies consistently reported that higher flows led to increased pharyngeal pressure and potentially increased intrathoracic airway pressure (especially among neonates), improved oxygenation, and reduced respiratory rate and work of breathing up to a certain threshold. Three randomised controlled trials found no significant differences in treatment failure among different flow settings. Flow impacts exhibited significant heterogeneity among different patients. CONCLUSION: Individualising flow settings in neonates and young children requires consideration of the patient's peak inspiratory flow, respiratory rate, heart rate, tolerance, work of breathing and lung aeration for optimal care.

A novel variant in a Chinese boy with lysinuric protein intolerance: A case report and literature review.

We report a case of a 4-year-old boy with lysinuric protein intolerance in China. The patient presented with interstitial lung disease with obvious clubbing of the fingers and toes. During the course of diagnosis and treatment, we found he was averse to a high-protein diet, intolerant to activity, and had a history of diarrhea and fractures. Physical examination revealed hepatosplenomegaly and clubbing of the fingers and toes. Next-generation sequencing revealed compound heterozygous mutations (c.1387delG, c.958T > C) in SLC7A7, which was confirmed as a disease-causing gene for lysinuric protein intolerance. After a literature review, we found that c.958T > C had not been previously reported, and summarized the clinical and genetic characteristics of patients from different continents. His symptoms improved significantly after 3 months of being on a low-protein diet, supplementation with lysine, citrulline, carnitine, and trace elements, and oral corticosteroid treatment for 2 months. The patient is still under follow-up.

Advancing Adolescent and Young Adult HIV Prevention and Care and Treatment Through Use of Multi-level Theories and Frameworks: A Scoping Review and Adapted HIV Ecological Framework.

While multi-level theories and frameworks have become a cornerstone in broader efforts to address HIV inequities, little is known regarding their application in adolescent and young adult (AYA) HIV research. To address this gap, we conducted a scoping review to assess the use and application of multi-level theories and frameworks in AYA HIV prevention and care and treatment empirical research. We systematically searched five databases for articles published between 2010 and May 2020, screened abstracts, and reviewed eligible full-text articles for inclusion. Of the 5890 citations identified, 1706 underwent full-text review and 88 met the inclusion criteria: 70 focused on HIV prevention, with only 14 on care and treatment, 2 on both HIV prevention and care and treatment, and 2 on HIV-affected AYA. Most authors described the theory-based multi-level framework as informing their data analysis, with only 12 describing it as informing/guiding an intervention. More than seventy different multi-level theories were described, with 38% utilizing socio-ecological models or the eco-developmental theory. Findings were used to inform the adaptation of an AYA World Health Organization multi-level framework specifically to guide AYA HIV research.

The enhancement of nonlinear optical properties of azulene-based nanographene by N atoms: a finishing touch.

Nonlinear optical (NLO) materials play an increasingly important role in optoelectronic devices, biomedicine, micro-nano processing, and other fields. The development of organic materials with strong second or (and) third NLO properties and a high stability is still challenging due to the unknown strategies for obtaining enhanced high order NLO properties. In the present work, π-conjugated systems are constructed by doping boron or (and) nitrogen atoms in the azulene moiety of azulene-based nanographenes (formed with an azulene chain with two bridging HCCHs at the two sides of the connecting CC bonds between azulenes, A1A2A3), and the NLO properties are predicted with time-dependent density functional theory based methods and a sum-over-states model. The doping of heteroatoms induces charge redistribution, tunes the frontier molecular orbital energy gap, changes the composition of some frontier molecular orbitals, and affects the NLO properties of those nanographenes. Among the designed nanographenes, the azulene-based nanographene with two nitrogen atoms at the two ends has the largest static first hyperpolarizability (91.30 × 10-30 esu per heavy atom), and the further introduction of two N atoms at the two ends of the central azulene moiety of this nanographene results in a large static second hyperpolarizability while keeping the large static first hyperpolarizability.

Photomediated Hydro(deutero)acylation of Olefins by Decarboxylative Addition of α-Oxocarboxylic Acids.

Acyl radicals have been generated from the decarboxylation of α-oxocarboxylic acids by using a readily accessible organic pyrimidopteridine photoredox catalyst under ultraviolet-A (UV-A) light irradiation. These reactive acyl radicals were smoothly added to olefins such as styrenes and diverse Michael acceptors, with the assistance of H2O/D2O as hydrogen donors, enabling easy access to a diverse range of ketones/ß-deuterio ketones. A wide range of α-oxocarboxylic acids are compatible with this reaction, which shows a reliable, atom-economical, and eco-friendly protocol. Furthermore, postsynthetic diversifications and applications are presented.

Feasibility of a Mobile Health Intervention for Providing a Continuum of HIV Services for MSM: Pilot Study of the WeTest Program in 3 Cities in China.

BACKGROUND: Men who have sex with men (MSM) in China have a high risk for HIV infection but experience suboptimal rates of HIV testing and service engagement due to various social and structural barriers. We developed a mobile health (mHealth) intervention entitled "WeTest-Plus" (WeTest+) as a user-centered "one-stop service" approach for delivering access to comprehensive information about HIV risk, HIV self-testing, behavioral and biomedical prevention, confirmatory testing, treatment, and care. OBJECTIVE: The goal of the current study was to investigate the feasibility of WeTest+ to provide continuous HIV services to high-risk MSM. METHODS: Participants completed a 3-week pilot test of WeTest+ to examine acceptability, feasibility, and recommendations for improvement. Participants completed a structured online questionnaire and qualitative exit interviews facilitated by project staff. "Click-through" rates were assessed to examine engagement with online content. RESULTS: 28 participants were included, and the average age was 27.6 years (standard deviation = 6.8). Almost all participants (96.4%) remained engaged with the WeTest+ program over a 3-week observational period. The majority (92.9%) self-administered the HIV self-test and submitted their test results through the online platform. Overall click-through rates were high (average 67.9%). Participants provided favorable comments about the quality and relevance of the WeTest+ information content, the engaging style of information presentation, and the user-centered features. CONCLUSION: This pilot assessment of WeTest+ supports the promise of this program for promoting HIV self-testing and linkage to in-person services for MSM in China. Findings underscore the utility of a user-centered approach to mHealth program design.

Therapeutic effects of long-term HBOT on Alzheimer's disease neuropathologies and cognitive impairment in APPswe/PS1dE9 mice.

Alzheimer's disease (AD) is the most common neurodegenerative disorder with the pathological hallmarks of amyloid beta (Aß) plaques and neurofibrillary tangles (NFTs) in the brain. Although there is a hope that anti-amyloid monoclonal antibodies may emerge as a new therapy for AD, the high cost and side effect is a big concern. Non-drug therapy is attracting more attention and may provide a better resolution for the treatment of AD. Given the fact that hypoxia contributes to the pathogenesis of AD, hyperbaric oxygen therapy (HBOT) may be an effective intervention that can alleviate hypoxia and improve AD. However, it remains unclear whether long-term HBOT intervention in the early stage of AD can slow AD progression and ultimately prevent cognitive impairment in this disease. In this study we applied consecutive 3-month HBOT interventions on 3-month-old APPswe/PS1dE9 AD mice which represent the early stage of AD. When the APPswe/PS1dE9 mice at 9-month-old which represent the disease stage we measured cognitive function, 24-h blood oxygen saturation, Aß and tau pathologies, vascular structure and function, and neuroinflammation in APPswe/PS1dE9 mice. Our results showed that long-term HBOT can attenuate the impairments in cognitive function observed in 9-month-old APPswe/PS1dE9 mice. Most importantly, HBOT effectively reduced the progression of Aß plaques deposition, hyperphosphorylated tau protein aggregation, and neuronal and synaptic degeneration in the AD mice. Further, long-term HBOT was able to enhance blood oxygen saturation level. Besides, long-term HBOT can improve vascular structure and function, and reduce neuroinflammation in AD mice. This study is the first to demonstrate that long-term HBOT intervention in the early stage of AD can attenuate cognitive impairment and AD-like pathologies. Overall, these findings highlight the potential of long-term HBOT as a disease-modifying approach for AD treatment.

Inter-fractional portability of deep learning models for lung target tracking on cine imaging acquired in MRI-guided radiotherapy.

MRI-guided radiotherapy systems enable beam gating by tracking the target on planar, two-dimensional cine images acquired during treatment. This study aims to evaluate how deep-learning (DL) models for target tracking that are trained on data from one fraction can be translated to subsequent fractions. Cine images were acquired for six patients treated on an MRI-guided radiotherapy platform (MRIdian, Viewray Inc.) with an onboard 0.35 T MRI scanner. Three DL models (U-net, attention U-net and nested U-net) for target tracking were trained using two training strategies: (1) uniform training using data obtained only from the first fraction with testing performed on data from subsequent fractions and (2) adaptive training in which training was updated each fraction by adding 20 samples from the current fraction with testing performed on the remaining images from that fraction. Tracking performance was compared between algorithms, models and training strategies by evaluating the Dice similarity coefficient (DSC) and 95% Hausdorff Distance (HD95) between automatically generated and manually specified contours. The mean DSC for all six patients in comparing manual contours and contours generated by the onboard algorithm (OBT) were 0.68 ± 0.16. Compared to OBT, the DSC values improved 17.0 - 19.3% for the three DL models with uniform training, and 24.7 - 25.7% for the models based on adaptive training. The HD95 values improved 50.6 - 54.5% for the models based on adaptive training. DL-based techniques achieved better tracking performance than the onboard, registration-based tracking approach. DL-based tracking performance improved when implementing an adaptive strategy that augments training data fraction-by-fraction.

Acupuncture-Induced Hemothorax with Hypovolemic Shock: A Case Report.

This report describes a very rare but life-threatening complication that occurred in a 43-year-old woman after an acupuncture (AC) for lumbago. The patient presented to the emergency department displaying symptoms indicative of shock. Physical examination revealed the absence of breath sounds on the right thoracic side, further investigations indicated the presence of a hemothorax. Emergency surgery was performed to evacuate the hemothorax and control bleeding from two intercostal veins. Although AC is often considered a gentle form of medicine, it is important to recognize that it can occasionally result in severe complications, especially when acupoints are used on the thorax.

Racial and Ethnic Disparities in Glycemic Control Among Patients With SARS-CoV-2 in the Baltimore-Washington, District of Columbia Region.

Introduction: Diabetes is a leading risk factor for COVID-19, disproportionally impacting marginalized populations. We analyzed racial/ethnic differences in glycemic control among patients who tested positive for SARS-CoV-2 in the Baltimore-Washington, District of Columbia region. Methods: Glycemic control measured by HbA1c was compared by race and ethnicity among patients with a positive SARS-CoV-2 test at the Johns Hopkins Health System between March 1, 2020, and March 31, 2022. Risk factors associated with poor glycemic control (HbA1c≥8) were identified using logistic regression. Results: Black, Latino, and Asian patients had a higher rate of prediabetes (HbA1c=5.7%-6.49%) and diabetes (HbA1c≥6.5%) than non-Hispanic White patients. Among patients with diabetes, poor glycemic control (HbA1c≥8%) was significantly higher among young adults (aged ≤44 years), Latino patients (AOR=1.5; 95% CI=1.1, 1.9), Black patients (AOR=1.2; 95% CI=1.0, 1.5), uninsured patients (AOR=1.5; 95% CI=1.2, 1.9), and those with limited English proficiency (AOR=1.3; 95% CI=1.0, 1.6) or without a primary care physician (AOR=1.6; 95% CI=1.3, 2.1). Conclusions: Disparities in glycemic control among patients who tested positive for SARS-CoV-2 were associated with underlying structural factors such as access to care, health insurance, and language proficiency. There is a need to implement accessible, culturally and language-appropriate preventive and primary care programs to engage socioeconomically disadvantaged populations in diabetic screening and care.

A Neuro-Influence Experiment to Evaluate the Persuasiveness of Pre-Exposure Prophylaxis Promotion Messages Among Men Who Have Sex With Men: Protocol for a Randomized Controlled Trial.

BACKGROUND: Pre-exposure prophylaxis (PrEP) is recommended by the US Centers for Disease Control and Prevention, but behavioral factors limit uptake, especially among men who have sex with men. A better understanding of how humans cognitively process information may inform health message development to promote PrEP uptake. OBJECTIVE: This paper is informed by the neuroscience of persuasion and influence and describes the protocol of a neuro-influence experiment using functional near-infrared spectroscopy (fNIRS) to evaluate the persuasiveness of PrEP promotion messages among men who have sex with men in Baltimore, Maryland. METHODS: We will conduct a randomized controlled trial using fNIRS to measure brain activation among 60 participants viewing PrEP promotion messages either developed through a crowdsourcing open contest implemented by the study team or developed with a traditional social marketing approach. We will evaluate the effectiveness of PrEP promotion messages by assessing brain activation in the regions associated with persuasion and changes in PrEP willingness, behavioral intention, initiation, and action between the 2 groups. RESULTS: This study is funded by the National Institutes of Health (National Institute of Mental Health: R34MH116725). Participant recruitment and data collection were completed in October 2023. The first results are expected to be submitted for publication in 2024. CONCLUSIONS: In addition to providing insight into the effectiveness of PrEP promotion messages, this study will examine the feasibility, acceptability, and utility of neuroimaging techniques to evaluate PrEP promotion messages for high-risk men who have sex with men. The findings can also demonstrate the utility of fNIRS as a tool for preproduct testing of health campaigns and enable the public health community to deliver more effective messages to improve health outcomes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52546.

Depression and Anxiety Symptoms and Their Associated Factors Among Chinese Residents After the Lifting of the Dynamic Zero-COVID Policy: A Cross-Sectional Study.

Purpose: China lifted its strict zero-Covid approach on December 7, 2022. This study aimed to investigate depression and anxiety symptoms and their associations among Chinese residents after the change in public policy. Methods: A cross-sectional sample of 925 Chinese residents (726 females and 199 males) was recruited using convenience and snowball sampling approach between 16 and 25 December 2022. Participants completed online questionnaires on basic information, depression, anxiety, COVID-19 related perceptions, and protective behaviors change. Results: Mild and moderate-to-severe depression symptoms were reported by 35.6% and 19.1% of participants, respectively. Nearly 40% of participants reported mild anxiety and 18.7% reported moderate-to-severe anxiety. Results from multinomial logistic regression analysis indicated that male gender, younger age, the presence of chronic disease, poorer self-rated mental health status, perceived impact, and worry were risk factors for both depression and anxiety, while higher education and protective behaviors change were protective factors. Besides, living with or caring for children (4-6 years), family members or other housemates currently with influenza-like symptoms, and perceived severity were also risk factors for depression. Conclusion: Our findings provided initial evidence that Chinese residents may face heightened depression and anxiety during the early stage after the policy was released. Furthermore, we identified some vulnerable populations in need of prioritizing mental health assistance and some potentially modifiable factors associated with depression and anxiety, which provides an important guide for developing timely and effective psychological interventions and preparing for future pandemics.

Muscone inhibits angiotensin II-induced cardiac hypertrophy through the STAT3, MAPK and TGF-ß/SMAD signaling pathways.

BACKGROUND: Muscone is a chemical monomer derived from musk. Although many studies have confirmed the cardioprotective effects of muscone, the effects of muscone on cardiac hypertrophy and its potential mechanisms are unclear.The aim of the present study was to investigate the effect of muscone on angiotensin (Ang) II-induced cardiac hypertrophy. METHODS AND RESULTS: In the present study, we found for the first time that muscone exerted inhibitory effects on Ang II-induced cardiac hypertrophy and cardiac injury in mice. Cardiac function was analyzed by echocardiography measurement, and the degree of cardiac fibrosis was determined by the quantitative real-time polymerase chain reaction (qRT-PCR), Masson trichrome staining and western blot assay. Secondly, qRT-PCR experiment showed that muscone attenuated cardiac injury by reducing the secretion of pro-inflammatory cytokines and promoting the secretion of anti-inflammatory cytokines. Moreover, western blot analysis found that muscone exerted cardio-protective effects by inhibiting phosphorylation of key proteins in the STAT3, MAPK and TGF-ß/SMAD pathways. In addition, CCK-8 and determination of serum biochemical indexes showed that no significant toxicity or side effects of muscone on normal cells and organs. CONCLUSIONS: Muscone could attenuate Ang II-induced cardiac hypertrophy, in part, by inhibiting the STAT3, MAPK, and TGF-ß/SMAD signaling pathways.