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.

Incompatible and sterile insect techniques combined eliminate mosquitoes.

The radiation-based sterile insect technique (SIT) has successfully suppressed field populations of several insect pest species, but its effect on mosquito vector control has been limited. The related incompatible insect technique (IIT)-which uses sterilization caused by the maternally inherited endosymbiotic bacteria Wolbachia-is a promising alternative, but can be undermined by accidental release of females infected with the same Wolbachia strain as the released males. Here we show that combining incompatible and sterile insect techniques (IIT-SIT) enables near elimination of field populations of the world's most invasive mosquito species, Aedes albopictus. Millions of factory-reared adult males with an artificial triple-Wolbachia infection were released, with prior pupal irradiation of the released mosquitoes to prevent unintentionally released triply infected females from successfully reproducing in the field. This successful field trial demonstrates the feasibility of area-wide application of combined IIT-SIT for mosquito vector control.

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.

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.

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.

Significant neutralizing escapes of Omicron and its sublineages in SARS-CoV-2-infected individuals vaccinated with inactivated vaccines.

In China, most SARS-CoV-2-infected individuals had been vaccinated with inactivated vaccines. However, little is known about their immune resistances to the previous variants of concerns (VOCs) and the current Omicron sublineages. Here, we collected convalescent serum samples from SARS-CoV-2-infected individuals during the ancestral, Delta, and Omicron BA.1 waves, and evaluated their cross-neutralizing antibodies (nAbs) against the previous VOCs and the current Omicron sublineages using VSV-based pseudoviruses. In the convalescents who had been unvaccinated and vaccinated with two doses of inactivated vaccines, we found infections from either the ancestral or the Delta strain elicited moderate cross-nAbs to previous VOCs, but very few cross-nAbs to the Omicron sublineages, including BA.1, BA.2, BA.3, and BA.4/5. The individuals who had been vaccinated with two doses of inactivated vaccines before Omicron BA.1 infection had moderate nAbs to Omicron BA.1, but weak cross-nAbs to the other Omicron sublineages. While three doses of inactivated vaccines followed Omicron BA.1 infection induced elevated and still weak cross-nAbs to other Omicron sublineages. Our results indicate that the Omicron sublineages show significant immune escape in the previously SARS-CoV-2-infected individuals and thus highlights the importance of vaccine boosters in this population.

Integral imaging three-dimensional display system with anisotropic backlight for the elimination of voxel aliasing and separation.

Compared with conventional scattered backlight systems, integral imaging (InIm) display system with collimated backlight can reduce the voxel size, but apparent voxel separation and severe graininess still exist in reconstructed 3D images. In this paper, an InIm 3D display system with anisotropic backlight control of sub-pixels was proposed to resolve both voxel aliasing and voxel separation simultaneously. It consists of an anisotropic backlight unit (ABU), a transmissive liquid crystal panel (LCP), and a lens array. The ABU with specific horizontal and vertical divergence angles was proposed and designed. Within the depth of field, the light rays emitted from sub-pixels are controlled precisely by the ABU to minimize the voxel size as well as stitch adjacent voxels seamlessly, thus improving the 3D image quality effectively. In the experiment, the prototype of our proposed ABU-type InIm system was developed, and the spatial frequency was nearly two times of conventional scattered backlight InIm system. Additionally, the proposed system eliminated the voxel separation which usually occurs in collimated backlight InIm system. As a result, voxels reconstructed by our proposed system were stitched in space without aliasing and separation, thereby greatly enhancing the 3D resolution and image quality.

Butterfly-Shaped Nanographenes with Excellent Second-Order Nonlinear Optical Properties: The Synergy of B/N and Azulene.

Azulene, a simple polar polycyclic aromatic hydrocarbon with connected electron donor and acceptor (DA), ignites the hope of designing second-order nonlinear optical (NLO) molecular materials from pure nonpolar carbon nanomaterials. In this work, a butterfly-shaped nanographene (π-DA-π) was designed by incorporating azulene between two coronenes. One more electron in a N atom or one electron fewer in a B atom with respect to a C atom can polarize charge distribution in carbon nanomaterials, and further doping of B and N in the designed butterfly-shaped nanographene changes the system from π-DA-π to D-π-A, leading to strong NLO responses. For example, the largest static first hyperpolarizability even reaches 173.89×10-30  esu per heavy atom. The synergetic role of B, N and azulene in the nanographene is scrutinized, and such a doping strategy is found to provide an effective means for the design of carbon-based functional materials. The strong second-order NLO responses of these butterfly-shaped carbon-based nanographenes under external fields, for example, sum frequency generation and difference frequency generation, could inspire future experimental exploration.

Timely Second-Dose Completion of mRNA COVID-19 Vaccination at Community-Based and Mobile Vaccine Clinics in Maryland.

To assess factors associated with timely second-dose completion, we analyzed COVID-19 vaccine data from community-based and mobile vaccine clinics in Maryland. Overall, 85.3% of patients received a timely second dose. Factors associated with a timely second dose included Latino ethnicity (adjusted odds ratio [AOR] = 1.5; 95% confidence interval [CI] = 1.1, 2.0) and receipt of the first dose at community-based vaccine clinics (AOR = 2.1; 95% CI = 1.8, 2.5). Future health initiatives for underserved communities should focus on establishing vaccine clinics in trusted community spaces with culturally sensitive support. (Am J Public Health. 2023;113(9):947-951. https://doi.org/10.2105/AJPH.2023.307338).

A Community-Engaged Social Marketing Campaign to Promote Equitable Access to COVID-19 Services Among Latino Immigrants.

To address disparities in COVID-19 outcomes among Latinos with limited English proficiency in Maryland, our team developed a culturally congruent intervention that coupled a statewide social marketing campaign with community-based COVID-19 services. In the first year, we reached 305 122 people through social media advertisements and had 9607 visitors to the Web site. Social marketing campaigns represent an opportunity to promote COVID-19 testing and vaccine uptake among Latino populations, especially when they are paired with community services that simultaneously address structural barriers to care. (Am J Public Health. 2023;113(3):263-266. https://doi.org/10.2105/10.2105/AJPH.2022.307191).

HIV Stigma, HIV status disclosure, and ART adherence in the context of an integrated opioid use disorder and HIV treatment setting in Dar es Salaam, Tanzania.

Little is known about social factors, including stigma, that affect antiretroviral therapy (ART) adherence among people enrolled in opioid use disorder treatment (OUDT) in the context of integrated OUDT and HIV treatment models. We qualitatively examined the relationship between HIV stigma, HIV status disclosure, and ART adherence among clients living with HIV at an OUDT clinic with integrated HIV services in Tanzania. We conducted in-depth interviews with 25 clients receiving HIV care at an OUDT clinic in Dar es Salaam, Tanzania between January and April 2020. HIV stigma, particularly anticipated stigma, and HIV status disclosure were key factors that affected ART adherence. Participants feared non-voluntary HIV status disclosure to and HIV stigma from their peers enrolled in OUDT. Most participants reported concealing their HIV status from peers at the OUDT clinic and not associating with other clients living with HIV at the clinic. Reducing HIV stigma and enhancing clinic structures and procedures to maintain privacy and confidentiality are essential to mitigating the effects of stigma on ART adherence.

Willingness to use and intention to adhere to pre-exposure prophylaxis (PrEP) among men who have sex with men in Jiangsu Province, China.

ABSTRACTPre-exposure prophylaxis (PrEP) is a biomedical prevention approach that significantly reduces HIV acquisition. Our study aimed to explore factors associated with PrEP willingness and intention to adhere to PrEP among MSM through a cross-sectional survey in Nanjing, Jiangsu province, China. Location sampling (TLS) and online recruitment were used to recruit participants to gauge their PrEP willingness and intention to adhere. Of 309 HIV-negative/unknown serostatus MSM, 75.7% were willing to use PrEP and 55.3% had high intention to take PrEP daily. Willingness to use PrEP was positively associated with having a college degree or higher (AOR = 1.90, 95%CI: 1.11-3.26) and higher anticipated HIV stigma (AOR = 2.74, 95%CI: 1.13-6.61). Facilitators of intention to adhere included higher education levels (AOR = 2.12, 95%CI: 1.33-3.39) and higher anticipated HIV stigma (AOR = 3.65, 95%CI: 1.36-9.80), whereas a primary barrier was community homophobia (AOR = 0.43, 95%CI: 0.20-0.92). This study documented high willingness to use PrEP, yet lower intention to adhere to PrEP in a sample of MSM in China. Public interventions and programs to promote adherence of PrEP for MSM is urgently needed in China. Psychosocial factors should be addressed and taken into consideration for PrEP implementation and adherence programs.

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.

The search for a maximum of the D-π-A paradigm for second order nonlinear optical molecular materials.

Push-pull π-conjugated molecules are one of the paradigms of second order nonlinear optical (NLO) materials and have been extensively explored. However, high-performance second order NLO materials with an optimum electron donor (D), π-bridge (π) and acceptor (A) under this paradigm are still the most sought-after. In the present work, D-π-A molecules with optimal D, π and A combination for strong second order NLO properties are proposed based on molecular orbital theories. The optimal D-π-A push-pull molecule achieves an unprecedentedly strong NLO response under the D-π-A paradigm, i.e., the static first hyperpolarizability reaches -453.92 × 10-30 esu per heavy atom using azulene as part of the π-bridge and acceptor to synergistically reinforce the strength of the acceptor. The protocols of D-π-A NLO molecule design through frontier molecular orbital matching of D, π and A with optimal combination of electron donating and accepting strengths shed light on future molecular NLO materials exploration. The simulated two-dimensional second order spectra provide useful information (e.g., sum frequency generation) on the applications of those D-π-A push-pull molecules in nonlinear optics.

FoRSR1 Is Important for Conidiation, Fusaric Acid Production, and Pathogenicity in Fusarium oxysporum f. sp. ginseng.

The root rot disease caused by Fusarium oxysporum f. sp. ginseng is one of the most destructive diseases of ginseng, an economically important herb. However, little is known about the pathogen's toxin biosynthesis or the molecular mechanisms regulating infection of ginseng. In this study we identified and functionally characterized the FoRSR1 gene that encodes a Ras-related (RSR) small GTPase homologous to yeast Rsr1 in F. oxysporum f. sp. ginseng. Disruption of FoRSR1 resulted in a significant reduction in mycelial dry weight in liquid cultures, although vegetative growth rate was not affected on culture plates. Notably, the Forsr1 mutant exhibited blunted and swollen hyphae with multi-nucleated compartments. It produced fewer and morphologically abnormal conidia and was defective in chlamydospore formation. In infection assays with ginseng roots, the Forsr1 mutant was significantly less virulent and caused only limited necrosis at the wounding sites. Deletion of FoRSR1 also affected pigmentation, autophagy, and production of fusaric acid. Furthermore, the expression of many candidate genes involved in secondary metabolism was significantly downregulated in the mutant, suggesting that FoRSR1 is also important for secondary metabolism. Overall, our results indicated that FoRSR1 plays important roles in conidiation, vacuolar morphology, secondary metabolism, and pathogenesis in F. oxysporum f. sp. ginseng.

Nonlinear connection between remnant cholesterol and stroke risk: evidence from the China health and retirement longitudinal study.

OBJECTIVE: The evidence on the relationship between remnant cholesterol (RC) and stroke remains controversial. Therefore, this study aimed to explore the relationship between RC and stroke risk in a Chinese population of middle-aged and elderly individuals. METHODS: The present study included 10067 Chinese subjects of middle-aged and elderly individuals. The connection between RC and incident stroke was investigated using the multivariate Cox proportional hazards regression model, several sensitivity analyses, generalized additive models, and smoothed curve fitting. RESULTS: A total of 1180 participants with stroke were recorded during the follow-up period. The multivariate Cox proportional hazards regression model identified a positive connection between RC and stroke risk (hazard ratio (HR) = 1.087, 95% confidence interval (CI): 1.001-1.180). In addition, the current study discovered a nonlinear connection between RC and incident stroke, and the point of inflection for RC was 1.78 mmol/L. The risk of stroke increased by 25.1% with each unit increase in RC level when RC was < 1.78 mmol/L (HR:1.251, 95%CI: 1.089-1.437, P = 0.0015). The results were not affected by sensitivity tests. CONCLUSION: The current study showed a positive and nonlinear connection between RC and stroke risk in a middle-aged and elderly Chinese population. These findings provided new information to help researchers better understand the relationship between RC levels and incident stroke.

Personalized checkpoint acupuncture can reduce postoperative pain after abdominal surgery-a STRICTA-conform pilot study.

BACKGROUND: Optimal pain management is one of the core elements of Enhanced Recovery After Surgery (ERAS®) protocols and remains a challenge. Acupuncture (AC) is an effective treatment for various pain conditions. Systematic and personalized allocation of acupoints may be decisive for efficacy. METHODS: Based on the predominant pressure sensitivity of six gastrointestinal (GI) checkpoints (G1-G6), we devised a method to detect personalized patterns of pain and a corresponding set of acupoints. We performed a single AC treatment with semi-permanent needles and assessed the visual analogue scale (VAS) score, pain threshold based on pressure algometry (PA), and temperature changes on abdominal skin areas before and 5 min after AC. RESULTS: Between April and June 2021, thirty-eight patients were prospectively included in this pilot study. The mean reduction in subjective pain sensation as assessed by VAS was 86%, paralleled by an augmentation of the pain threshold as measured by PA by 64%. A small but significant increase in the skin temperature was observed above the abdominal surface. These effects were independent of the type of surgery. CONCLUSION: Checkpoint acupuncture may be a complementary tool for postoperative pain management. Further investigations are needed to explore this analgesic effect.

CD5 signalosome coordinates antagonist TCR signals to control the generation of Treg cells induced by foreign antigens.

CD5 is characterized as an inhibitory coreceptor with an important regulatory role during T cell development. The molecular mechanism by which CD5 operates has been puzzling and its function in mature T cells suggests promoting rather than repressing effects on immune responses. Here, we combined quantitative mass spectrometry and genetic studies to analyze the components and the activity of the CD5 signaling machinery in primary T cells. We found that T cell receptor (TCR) engagement induces the selective phosphorylation of CD5 tyrosine 429, which serves as a docking site for proteins with adaptor functions (c-Cbl, CIN85, CRKL), connecting CD5 to positive (PI3K) and negative (UBASH3A, SHIP1) regulators of TCR signaling. c-CBL acts as a coordinator in this complex enabling CD5 to synchronize positive and negative feedbacks on TCR signaling through the other components. Disruption of CD5 signalosome in mutant mice reveals that it modulates TCR signal outputs to selectively repress the transactivation of Foxp3 and limit the inopportune induction of peripherally induced regulatory T cells during immune responses against foreign antigen. Our findings bring insights into the paradigm of coreceptor signaling, suggesting that, in addition to providing dualistic enhancing or dampening inputs, coreceptors can engage concomitant stimulatory and inhibitory signaling events, which act together to promote specific functional outcomes.

Adjunctive Effect and Safety of Chinese Herbal Medicine in Patients with Coronary Artery Disease Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis.

Objective: The primary objectives of this systematic review and meta-analysis were to assess the impact of Chinese herbal medicine (CHM) as an adjunctive therapy in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) and to evaluate its safety and efficacy. Methods: Studies were obtained from multiple databases, including PubMed, Web of Science, China National Knowledge Infrastructure Database (CNKI), WanFang Data (WanFang), and Chinese Science and Technology Journal Database (VIP). Randomized controlled trials evaluating the effects of CHM intravenously or orally in patients with CAD undergoing PCI were included. The primary outcome was improvements in major adverse cardiovascular events (MACEs), and the secondary outcomes included differences in echocardiography, serum biomarkers, vascular structures and functions, clinical symptoms, and adverse drug reactions. Data synthesis was conducted using relative risk (RR), weighted mean difference (MD), and 95% confidence intervals (CI). Results: Forty-seven trials, including 12,638 participants, were included in the meta-analyses. CHM significantly reduced MACEs compared with the control group(RR = 0.51, 95% CI= 0.45 to 0.58)). CHM also led to improvements in left ventricular ejection fraction((MD=6.93, 95% CI = 4.03 to 8.03), ventricular end-diastolic dimension(MD=-5.01, 95% CI = -7.0 to -3.03), and cardiac troponin-I levels(MD=-0.37, 95% CI = -0.77 to 0.03]). The anti-inflammatory effects of CHM were observed through downregulation of C-reactive protein(MD=-2.13, 95% CI = -3.1 to -1.05) and high-sensitivity CRP (MD=-1.47, 95% CI= -2.47 to -0.48) when compared with the control groups. CHM also showed a protective effect on renal function and augmented platelet inhibition(7.05, 95% CI=5.91 to 8.19, P < .00001). The blood stasis scores of patients treated with Chinese Medicine were lower in the CHM group (MD=-4.30, 95% CI= -6.53 to -2.07). No significant difference in adverse events was found between the CHM and control groups. Conclusion: The addition of CHM to conventional treatment in patients undergoing PCI for CAD improved primary and secondary endpoint events with no significant adverse drug reactions. These findings suggest that CHM has better clinical efficacy and safety. However, more high-quality studies are needed to validate these results and provide further evidence for the clinical application of CHM in CAD patients undergoing PCI.

Cognitive and motor skill competence are different: Results from a prospective randomized trial using virtual reality simulator and educational video in laparoscopic cholecystectomy.

BACKGROUND AND PURPOSE: Cognitive transfer represents an important issue in surgical education. It is essential for the acquisition of competence, such as decision making and error avoidance. This randomized study aims to compare the effectivity of cognitive transfer by observing the surgery versus using modern virtual reality simulators for learning a laparoscopic cholecystectomy. METHOD: This was a prospective, randomized, single centre study. 40 medical students from a university hospital, a tertiary care teaching institution, were enrolled. After a short introduction of laparoscopic cholecystectomy, they were randomized into two groups (video group and simulator group). In the video group, participants watched the step-by-step educational video twice. In the simulator group, participants underwent training using the virtual reality simulator, including tutorial procedural tasks of laparoscopic cholecystectomy as well as a complete cholecystectomy on the simulator. After the training, cognitive competence including decision making and error awareness was assessed using a questionnaire. RESULTS: In the most critical step of laparoscopic cholecystectomy, "Dissection in Calot's triangle", as well as in the aspect of planning next step, the video group was superior significantly (P = 0.038 and P = 0.04). No significant differences concerning the recognition of critical anatomical structures, choosing the necessary instruments as well as error awareness were found. CONCLUSIONS: Learning by watching a high-quality educational video is more effective in acquiring the cognitive competence to combine learned single tasks. Traditional learning means as watching educational videos and modern, sophisticated VRS should be deployed complementarily to establish cognitive and motor competencies separately.