CD300ld on neutrophils is required for tumour-driven immune suppression.

The immune-suppressive tumour microenvironment represents a major obstacle to effective immunotherapy1,2. Pathologically activated neutrophils, also known as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), are a critical component of the tumour microenvironment and have crucial roles in tumour progression and therapy resistance2-4. Identification of the key molecules on PMN-MDSCs is required to selectively target these cells for tumour treatment. Here, we performed an in vivo CRISPR-Cas9 screen in a tumour mouse model and identified CD300ld as a top candidate of tumour-favouring receptors. CD300ld is specifically expressed in normal neutrophils and is upregulated in PMN-MDSCs upon tumour-bearing. CD300ld knockout inhibits the development of multiple tumour types in a PMN-MDSC-dependent manner. CD300ld is required for the recruitment of PMN-MDSCs into tumours and their function to suppress T cell activation. CD300ld acts via the STAT3-S100A8/A9 axis, and knockout of Cd300ld reverses the tumour immune-suppressive microenvironment. CD300ld is upregulated in human cancers and shows an unfavourable correlation with patient survival. Blocking CD300ld activity inhibits tumour development and has synergistic effects with anti-PD1. Our study identifies CD300ld as a critical immune suppressor present on PMN-MDSCs, being required for tumour immune resistance and providing a potential target for cancer immunotherapy.

Efficacy of Voluntary Medical Male Circumcision to Prevent HIV Infection Among Men Who Have Sex With Men : A Randomized Controlled Trial.

BACKGROUND: Observational studies suggest that voluntary medical male circumcision (VMMC) may lower HIV risk among men who have sex with men (MSM). A randomized controlled trial (RCT) is needed to confirm this. OBJECTIVE: To assess the efficacy of VMMC in preventing incident HIV infection among MSM. DESIGN: An RCT with up to 12 months of follow-up. (Chinese Clinical Trial Registry: ChiCTR2000039436). SETTING: 8 cities in China. PARTICIPANTS: Uncircumcised, HIV-seronegative men aged 18 to 49 years who self-reported predominantly practicing insertive anal intercourse and had 2 or more male sex partners in the past 6 months. INTERVENTION: VMMC. MEASUREMENTS: Rapid testing for HIV was done at baseline and at 3, 6, 9, and 12 months. Behavioral questionnaires and other tests for sexually transmitted infections were done at baseline, 6 months, and 12 months. The primary outcome was HIV seroconversion using an intention-to-treat analysis. RESULTS: The study enrolled 124 men in the intervention group and 123 in the control group, who contributed 120.7 and 123.1 person-years of observation, respectively. There were 0 seroconversions in the intervention group (0 infections [95% CI, 0.0 to 3.1 infections] per 100 person-years) and 5 seroconversions in the control group (4.1 infections [CI, 1.3 to 9.5 infections] per 100 person-years). The HIV hazard ratio was 0.09 (CI, 0.00 to 0.81; P = 0.029), and the HIV incidence was lower in the intervention group (log-rank P = 0.025). The incidence rates of syphilis, herpes simplex virus type 2, and penile human papillomavirus were not statistically significantly different between the 2 groups. There was no evidence of HIV risk compensation. LIMITATION: Few HIV seroconversions and limited follow-up period. CONCLUSION: Among MSM who predominantly practice insertive anal intercourse, VMMC is efficacious in preventing incident HIV infection; MSM should be included in VMMC guidelines. PRIMARY FUNDING SOURCE: The National Science and Technology Major Project of China.

Mechanism of ferroptosis in breast cancer and research progress of natural compounds regulating ferroptosis.

Breast cancer is the most prevalent cancer worldwide and its incidence increases with age, posing a significant threat to women's health globally. Due to the clinical heterogeneity of breast cancer, the majority of patients develop drug resistance and metastasis following treatment. Ferroptosis, a form of programmed cell death dependent on iron, is characterized by the accumulation of lipid peroxides, elevated levels of iron ions and lipid peroxidation. The underlying mechanisms and signalling pathways associated with ferroptosis are intricate and interconnected, involving various proteins and enzymes such as the cystine/glutamate antiporter, glutathione peroxidase 4, ferroptosis inhibitor 1 and dihydroorotate dehydrogenase. Consequently, emerging research suggests that ferroptosis may offer a novel target for breast cancer treatment; however, the mechanisms of ferroptosis in breast cancer urgently require resolution. Additionally, certain natural compounds have been reported to induce ferroptosis, thereby interfering with breast cancer. Therefore, this review not only discusses the molecular mechanisms of multiple signalling pathways that mediate ferroptosis in breast cancer (including metastasis, invasion and proliferation) but also elaborates on the mechanisms by which natural compounds induce ferroptosis in breast cancer. Furthermore, this review summarizes potential compound types that may serve as ferroptosis inducers in future tumour cells, providing lead compounds for the development of ferroptosis-inducing agents. Last, this review proposes the potential synergy of combining natural compounds with traditional breast cancer drugs in the treatment of breast cancer, thereby suggesting future directions and offering new insights.

A single-plasmid approach for genome editing coupled with long-term lineage analysis in chick embryos.

An important strategy for establishing mechanisms of gene function during development is through mutation of individual genes and analysis of subsequent effects on cell behavior. Here, we present a single-plasmid approach for genome editing in chick embryos to study experimentally perturbed cells in an otherwise normal embryonic environment. To achieve this, we have engineered a plasmid that encodes Cas9 protein, gene-specific guide RNA (gRNA), and a fluorescent marker within the same construct. Using transfection- and electroporation-based approaches, we show that this construct can be used to perturb gene function in early embryos as well as human cell lines. Importantly, insertion of this cistronic construct into replication-incompetent avian retroviruses allowed us to couple gene knockouts with long-term lineage analysis. We demonstrate the application of our newly engineered constructs and viruses by perturbing ß-catenin in vitro and Sox10, Pax6 and Pax7 in the neural crest, retina, and neural tube and segmental plate in vivo, respectively. Together, this approach enables genes of interest to be knocked out in identifiable cells in living embryos and can be broadly applied to numerous genes in different embryonic tissues.

Efficacy and safety of gut microbiota-based therapies in autoimmune and rheumatic diseases: a systematic review and meta-analysis of 80 randomized controlled trials.

BACKGROUND: Previous randomized controlled trials (RCTs) suggested that gut microbiota-based therapies may be effective in treating autoimmune diseases, but a systematic summary is lacking. METHODS: Pubmed, EMbase, Sinomed, and other databases were searched for RCTs related to the treatment of autoimmune diseases with probiotics from inception to June 2022. RevMan 5.4 software was used for meta-analysis after 2 investigators independently screened literature, extracted data, and assessed the risk of bias of included studies. RESULTS: A total of 80 RCTs and 14 types of autoimmune disease [celiac sprue, SLE, and lupus nephritis (LN), RA, juvenile idiopathic arthritis (JIA), spondyloarthritis, psoriasis, fibromyalgia syndrome, MS, systemic sclerosis, type 1 diabetes mellitus (T1DM), oral lichen planus (OLP), Crohn's disease, ulcerative colitis] were included. The results showed that gut microbiota-based therapies may improve the symptoms and/or inflammatory factor of celiac sprue, SLE and LN, JIA, psoriasis, PSS, MS, systemic sclerosis, Crohn's disease, and ulcerative colitis. However, gut microbiota-based therapies may not improve the symptoms and/or inflammatory factor of spondyloarthritis and RA. Gut microbiota-based therapies may relieve the pain of fibromyalgia syndrome, but the effect on fibromyalgia impact questionnaire score is not significant. Gut microbiota-based therapies may improve HbA1c in T1DM, but its effect on total insulin requirement does not seem to be significant. These RCTs showed that probiotics did not increase the incidence of adverse events. CONCLUSIONS: Gut microbiota-based therapies may improve several autoimmune diseases (celiac sprue, SLE and LN, JIA, psoriasis, fibromyalgia syndrome, PSS, MS, T1DM, Crohn's disease, and ulcerative colitis).

Achieving Low-Dose Rate X-Ray Imaging Based on 2D/3D-Mixed Perovskite Films.

X-ray detection and imaging are widely used in medical diagnosis, product inspection, security monitoring, etc. Large-scale polycrystalline perovskite thick films possess high potential for direct X-ray imaging. However, the notorious problems of baseline drift and high detection limit caused by ions migration are still remained. Here, ion migration is reduced by incorporating 2D perovskite into 3D perovskite, thereby increasing the ion activation energy. This approach hinders ion migration within the perovskite film, consequently suppressing baseline drift and reducing the lowest detection limit(LOD) of the device. As a result, the baseline drifting declines by 20 times and the LOD reduces to 21.1 nGy s-1, while the device maintains a satisfactory sensitivity of 5.6 × 103 µC Gy-1 cm-2. This work provides a new strategy to achieve low ion migration in large-scale X-ray detectors and may provide new thoughts for the application of mixed-dimension perovskite.

Heterologous overexpression of Tawzy1-2 gene encoding an SK3 dehydrin enhances multiple abiotic stress tolerance in Escherichia coli and Nicotiania benthamiana.

MAIN CONCLUSION: The nuclear localized TaWZY1-2 helps plants resist abiotic stress by preserving the cell's ability to remove reactive oxygen species and decrease lipid oxidation under such conditions. In light of the unpredictable environmental conditions in which food crops grow, precise strategies must be developed by crops to effectively cope with abiotic stress and minimize damage over their lifespan. A key component in this endeavor is the group II of late embryogenesis abundant (LEA) proteins, known as dehydrins, which play crucial roles in enhancing the tolerance of plants to abiotic stress. Tawzy1-2 is a dehydrin-encoding gene which is constitutively expressed in various tissues of wheat. However, the biological function of TaWZY1-2 is not yet fully understood. In this study, TaWZY1-2 was isolated and identified in the wheat genome, and its functional role in conferring tolerance to abiotic stresses was detected in both prokaryotic and eukaryotic cells. Results showed that TaWZY1-2 is a nuclear localized hydrophilic protein that accumulates in response to multiple stresses. Escherichia coli cells expressing TaWZY1-2 showed enhanced tolerance to multiple stress conditions. Overexpression of TaWZY1-2 in Nicotiania benthamiana improved growth, germination and survival rate of the transgenic plants exposed to four kinds of abiotic stress conditions. Our results show that Tawzy1-2 transgenic plants exhibit improved capability in clearing reactive oxygen species and reducing lipid degradation, thereby enhancing their resistance to abiotic stress. This demonstrates a significant role of TaWZY1-2 in mitigating abiotic stress-induced damage. Consequently, these findings not only establish a basis for future investigation into the functional mechanism of TaWZY1-2 but also contribute to the expansion of functional diversity within the dehydrin protein family. Moreover, they identify potential candidate genes for crop optimization.

High-resolution anorectal manometry for diagnosing obstructed defecation syndrome associated with moderate rectocele compared to healthy individuals.

BACKGROUND: Few studies have investigated healthy female individuals (HFI) and those with obstructed defecation syndrome associated with moderate rectocele in women (MRW), identified using three-dimensional high-resolution anorectal manometry (3D HRAM) parameters that correlate with age stratification. OBJECTIVE: We aimed to explore the clinical diagnostic values of the MRW and HFI groups using 3D HRAM parameters related to age stratification. METHODS: A prospective non-randomized controlled trial involving 128 cases from the MRW (treatment group, 68 cases) and HFI (control group, 60 cases) groups was conducted using 3D HRAM parameters at Tianjin Union Medical Center between January 2017 and June 2022, and patients were divided into two subgroups based on their ages: the ≥50 and < 50 years subgroups. RESULTS: Multivariate binary logistic regression analysis showed that age (P = 0.024) and rectoanal inhibitory reflex (P = 0.001) were independent factors affecting the disease in the MRW group. Compared to the HFI group, the receiver operating characteristic (ROC) curve demonstrated that the 3D HRAM parameters exhibited a higher diagnostic value for age (Youden index = 0.31), urge to defecate (Youden index = 0.24), and rectoanal pressure differential (Youden index = 0.21) in the MRW group. CONCLUSIONS: Compared to the HFI group, the ROC curve of the 3D HRAM parameters suggests that age, urge to defecate, and rectoanal pressure differential in the MRW group have a significant diagnostic value. Because the Youden index is lower, 3D HRAM cannot be considered the gold standard method for diagnosing MRW.

Demographic and clinical factors correlated with clinical outcomes among people with HIV treated by antiretroviral therapy: a retrospective cohort study.

BACKGROUND: As is known, CD4 cell count is a significant parameter predicting HIV progression, opportunistic infections and death in HIV-infected individuals, as well was an important indicator for initiating antiretroviral therapy (ART). In China's National Free Antiretroviral Treatment Program, people with HIV (PWH) on ART can receive a CD4 count test at least once every six months. Importantly, the baseline CD4 count (before ART initiation) is significantly correlated with ART and even prognosis, but the influence of the peak CD4 cell count on ART and/or clinical outcomes is still unknown. METHODS: A retrospective study was conducted among 7965 PWH who received ART from October 2003 to September 2022 at Yunnan Infectious Disease Hospital. Clinical features and laboratory data were collected and analyzed by Chi-square test, univariate and multivariate Cox regression analysis. After elimination of confounding variables, multivariate Cox regression analysis was performed to identify survival-related factors. RESULTS: Of a total of 7965 PWH in the ART treatment cohort who met the inclusion and exclusion criteria, 7939 were finally included in the subsequent analyses. First, it was found that the proportion of clinical variables, including sex, age distribution, interval from diagnosis to ART initiation, marital status, and others, was significantly different between the living and dead groups (P < 0.05). Impressively, significantly more PWH had the higher level of baseline, peak and recent CD4 cell counts in the living group compared to those in the dead group. Due to multicollinearity effect, after excluding confounders, the following factors were found to be significantly associated with mortality by multivariate Cox regression analysis: (1) male sex (hazard ratio (HR) = 1.268 [1.032, 1.559]; P = 0.024); (2) time from HIV confirmation to ART initiation ≥ 6 months (HR = 1.962 [1.631, 2.360]; P < 0.001); (3) peak CD4 cell count: Peak CD4 < 100cells/µL group (HR = 16.093 [12.041, 21.508]; P < 0.001), 100cells/µL ≤ x < 200cells/µL group (HR = 7.904 [6.148, 10.160]; P < 0.001), 200cells/µL ≤ x < 350cells/µL group (HR = 3.166 [2.519, 3.980]; P < 0.001), 350cells/µL ≤ x < 500cells/µL group (HR = 1.668 [1.291, 2.155]; P < 0.001). CONCLUSION: Interestingly, patients in male, time from HIV confirmation to ART initiation ≥ 6 months, or peak CD4 count < 500 cells/µl had inferior clinical outcomes, in other word, a lower peak CD4 cell count significantly increased the risk of death, and peak CD4 cell was independent in predicting the overall survival of PWH. It is important to promote "early diagnosis and treatment of HIV" and regularly monitor CD4 levels in HIV/AIDS to evaluate the efficacy of ART and immune reconstitution, and optimize the ART regimen in time to further reduce the mortality of PWH.

High-performance liquid chromatography analysis of alkaloids in various parts of lotus extracts with ion mobility spectrometry and mass spectrometry dual detection.

Using high-performance liquid chromatography coupled with electrospray ionization-ion mobility spectrometry and mass spectrometry, we proposed a dual-detection method for the identification and profiling of alkaloids in various lotus parts including leaf, plumule, stem, seed epicarp, and receptacle. The eluent from high-performance liquid chromatography was split and conducted to electrospray ionization-ion mobility spectrometry and time-of-flight mass spectrometry separately to facilitate the compound identification. In total, 23 kinds of alkaloids were identified based on m/z, drift time, and retention time, including alkaloid isomers such as lirinidine, N-nornuciferine, and O-nornuciferine with identical m/z that are difficult to differentiate using mass spectrometry alone. Using this method, we investigated the changing dynamics of alkaloid accumulation in lotus leaves and lotus stems at different harvesting periods. The total alkaloid content showed an increasing trend with the growth and development of leave and stem. Overall, the developed dual detection method has the advantages of high peak capacity and high sensitivity compared with the conventional detection method and facilitates the identification of detected compounds.

TRIM21 suppresses CHK1 activation by preferentially targeting CLASPIN for K63-linked ubiquitination.

Expression of the E3 ligase TRIM21 is increased in a broad spectrum of cancers; however, the functionally relevant molecular pathway targeted by TRIM21 overexpression remains largely unknown. Here, we show that TRIM21 directly interacts with and ubiquitinates CLASPIN, a mediator for ATR-dependent CHK1 activation. TRIM21-mediated K63-linked ubiquitination of CLASPIN counteracts the K6-linked ubiquitination of CLASPIN which is essential for its interaction with TIPIN and subsequent chromatin loading. We further show that overexpression of TRIM21, but not a TRIM21 catalytically inactive mutant, compromises CHK1 activation, leading to replication fork instability and tumorigenesis. Our findings demonstrate that TRIM21 suppresses CHK1 activation by preferentially targeting CLASPIN for K63-linked ubiquitination, providing a potential target for cancer therapy.

Circ_FNDC3B Promotes Cell Proliferation and Metastasis in Esophageal Squamous Cell Carcinoma via Regulating MAPK1 by Binding to miR-136-5p.

A handful of circular RNAs (circRNAs) associated with cancer progression have been indicated in esophageal squamous cell carcinoma (ESCC). The current study aimed to investigate the functional mechanism of circular RNA Fibronectin type III domain containing 3B (circ_FNDC3B) in ESCC. Circ_FNDC3B, FNDC3B, microRNA-136-5p (miR-136-5p) and mitogen-activated protein kinase 1 (MAPK1) were examined via the quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8) and colony formation assays. Transwell assay was performed to measure cell migration and invasion. Protein analysis was implemented by western blot. Cell apoptosis was assessed via flow cytometry. Target interaction was affirmed using dual-luciferase reporter assay. The function analysis of circ_FNDC3B in vivo was explored by xenograft models. The upregulation of circ_FNDC3B was detected in ESCC tissues and cells. Functionally, ESCC cell proliferation and metastasis were repressed but apoptosis was promoted by circ_FNDC3B knockdown. Besides, circ_FNDC3B silence inhibited ESCC progression through MAPK1 downregulation. Further target analysis identified miR-136-5p as a target of circ_FNDC3B and an upstream control of MAPK1. Additionally, the regulation of si-circ_FNDC3B in ESCC was also dependent on targeting miR-136-5p. Moreover, circ_FNDC3B targeted miR-136-5p to affect MAPK1 level. Tumorigenesis in vivo was also suppressed by downregulating circ_FNDC3B to regulate miR-136-5p/MAPK1 axis. Circ_FNDC3B downregulation impeded the development of ESCC via the mediation of miR-136-5p/MAPK1 axis. This report afforded a novel insight into the functional mechanism of circ_FNDC3B in ESCC.

Epigenetic activation of the TUSC3 gene as a potential therapy for XMEN disease.

BACKGROUND: X-linked MAGT1 deficiency with increased susceptibility to Epstein-Barr virus infection and N-linked glycosylation defect (XMEN) disease is a rare combined immunodeficiency caused by loss-of-function mutations in the magnesium transporter 1 (MAGT1) gene. MAGT1 deficiency impairs magnesium transport and the N-linked glycosylation of a panel of proteins, which subsequently abolishes the expression of key immune receptors such as natural killer group 2, member D (aka NKG2D). These effects induce immune system abnormalities, chronic Epstein-Barr virus infection, and neoplasia. Recent research shows that MAGT1 and tumor candidate suppressor 3 (TUSC3) share high sequence and functional similarity. OBJECTIVE: We sought to investigate the feasibility of activating TUSC3 expression to provide a potential therapeutic strategy for XMEN disease. METHODS: The expression profiles of MAGT1 and TUSC3 were analyzed using multiple databases, real-time quantitative PCR, and Western blot. The effects of decitabine and panobinostat on the regulation of TUSC3 expression were explored in both MAGT1 knockout (KO)/patient-derived lymphocytes and MAGT1 KO hepatocytes. RESULTS: Although TUSC3 is widely expressed, it is undetectable specifically in the immune system and liver, consistent with the main diseased tissues in patients with XMEN disease. CRISPR/Cas9-mediated KO of MAGT1 in the NKL cell line successfully mimicked the phenotypes of XMEN patient-derived lymphocytes, and exogenous expression of TUSC3 rescued the deficiencies in KO NKL cells. Using this in vitro model, we identified 2 epigenetic drugs, decitabine and panobinostat, by screening. Combination treatment using these 2 drugs significantly upregulated TUSC3 expression and rescued the immune and liver abnormalities. CONCLUSIONS: Epigenetic activation of TUSC3 expression constitutes an effective therapeutic strategy for XMEN disease.

A feedback loop between NONHSAT024276 and PTBP1 inhibits tumor progression and glycolysis in HCC by increasing the PKM1/PKM2 ratio.

Hepatocellular carcinoma (HCC) is one of the most common malignancies with a hallmark of aberrant metabolism. The mechanism of long noncoding RNAs (lncRNAs) underlying the aggressive behaviors and glycolysis of HCC is poorly understood. In this study, we identified, via microarray, novel lncRNA NONHSAT024276 as a potential tumor suppressor in HCC. The downregulation of NONHSAT024276 closely correlated with larger tumor volume and higher aspartate transaminase levels. Functional experiments were performed to verify the role of NONHSAT024276 in HCC progression, and the negative effects of NONHSAT024276 expression on cell proliferation and migration were identified. Mechanistically, NONHSAT024276 directly bound to polypyrimidine tract-binding protein 1 (PTBP1), downregulating it and forming a feedback loop. Furthermore, NONHSAT024276 increased the ratio of M1 and M2 isoforms of pyruvate kinase (PKM1/PKM2) and also obstructed the PTBP1/PKM-mediated glycolysis. Finally, the rescue assays confirmed that NONHSAT024276 functioned in HCC via downregulating PTBP1 to increase the PKM1/PKM2 ratio. Hence, this study supported a model in which NONHSAT024276 downregulated PTBP1 and formed a feedback loop to increase the PKM1/PKM2 ratio to inhibit glycolysis and progression of HCC, opening new prospects for preventing or treating HCC.

Lactate-Responsive Gene Editing to Synergistically Enhance Macrophage-Mediated Cancer Immunotherapy.

Combination therapies involving metabolic regulation and immune checkpoint blockade are considered an encouraging new strategy for cancer therapy. However, the effective utilization of combination therapies for activating tumor-associated macrophages (TAMs) remains challenging. Herein, a lactate-catalyzed chemodynamic approach to activate the therapeutic genome editing of signal-regulatory protein α (SIRPα) to reprogram TAMs and improve cancer immunotherapy is proposed. This system is constructed by encapsulating lactate oxidase (LOx) and clustered regularly interspaced short palindromic repeat-mediated SIRPα genome-editing plasmids in a metal-organic framework (MOF). The genome-editing system is released and activated by acidic pyruvate, which is produced by the LOx-catalyzed oxidation of lactate. The synergy between lactate exhaustion and SIRPα signal blockade can enhance the phagocytic ability of TAMs and promote the repolarization of TAMs to the antitumorigenic M1 phenotype. Lactate exhaustion-induced CD47-SIRPα blockade efficiently improves macrophage antitumor immune responses and effectively reverses the immunosuppressive tumor microenvironment to inhibit tumor growth, as demonstrated by in vitro and in vivo studies. This study provides a facile strategy for engineering TAMs in situ by combining CRISPR-mediated SIRPα knockout with lactate exhaustion for effective immunotherapy.

Impact of combination preventative interventions on hospitalization and death under the pandemic of SARS-CoV-2 Omicron variant in China.

With a large population most susceptible to Omicron and emerging SARS-CoV-2 variants, China faces uncertain scenarios if reopening its border. Thus, we aimed to predict the impact of combination preventative interventions on hospitalization and death. An age-stratified susceptible-infectious-quarantined-hospitalized-removed-susceptible (SIQHRS) model based on the new guidelines of COVID-19 diagnosis and treatment (the ninth edition) was constructed to simulate the transmission dynamics of Omicron within 365 days. At baseline, we assumed no interventions other than 60% booster vaccination in individuals aged ≤60 years and 80% in individuals aged >60 years, quarantine and hospitalization. Oral antiviral medications for COVID-19 and nonpharmaceutical interventions (NPIs) such as social distancing and antigen self-testing were considered in subsequent scenarios. Sensitivity analyses were conducted to reflect different levels of interventions. A total of 0.73 billion cumulative quarantines (95% CI 0.53-0.83), 33.59 million hospitalizations (22.41-39.31), and 0.62 million deaths (0.40-0.75) are expected in 365 days. The case fatality rate with pneumonia symptoms (moderate, severe and critical illness) is expected to be 1.83% (1.68-1.99%) and the infected fatality rate is 0.38‰ (0.33-0.4‰). The highest existing hospitalization and ICU occupations are 3.11 (0.30-3.85) and 20.33 (2.01-25.20) times of capacity, respectively. Sensitivity analysis showed that interventions can be adjusted to meet certain conditions to reduce the total number of infections and deaths. In conclusion, after sufficient respiratory and ICU beds are prepared and the relaxed NPIs are in place, the SARS-CoV-2 Omicron variant would not seriously impact the health system.

Monkeypox awareness and low vaccination hesitancy among men who have sex with men in China.

Men who have sex with men (MSM) have been recommended for targeted monkeypox vaccination. We aimed to investigate monkeypox awareness and explore the correlates of monkeypox vaccination hesitancy among MSM in China. We conducted a cross-sectional survey from August 10 to September 9, 2022. Awareness related to monkeypox and attitude toward monkeypox vaccination among MSM aged ≥18 years were collected. Multivariable logistic regression was applied to evaluate correlates of vaccination hesitancy. The discrepancy in awareness between subgroups regarding HIV status was assessed. A total of 1090 MSM were included (age: median 30 years, interquartile range [IQR], 25-35; HIV-infected: 53.12%). Only 13.85% of respondents expressed high monkeypox vaccination hesitancy. Hesitancy was associated with no fixed income (adjuster odds ratio [aOR], 2.46, 95% confidence interval [CI], 1.48-4.11), infrequent information following (sometimes, 3.01, 1.55-5.83; seldom or never, 5.66, 2.58-12.45), and lack of worries about monkeypox endemic (1.78, 1.11-2.87). Participants who believed that HIV-infected cases accounted for a smaller proportion (1.62, 1.01-2.60), disagreed that monkeypox virus could be detected in semen (2.21, 1.26-3.88), and considered either replication-competent (1.84, 1.14-2.96) or replication-deficient (4.80, 2.26-10.21) monkeypox vaccine unsuitable for HIV-infected people were generally more hesitant. Compared with HIV-uninfected MSM, HIV-infected MSM supported more for vaccination promotion. MSM in China had low hesitancy toward monkeypox vaccination. Safety and affordability of vaccine and availability of information were essential aspects to reduce hesitancy. Education on vaccination benefits should be encouraged to promote future vaccination plans.

VG161 activates systemic antitumor immunity in pancreatic cancer models as a novel oncolytic herpesvirus expressing multiple immunomodulatory transgenes.

The VG161 represents the first recombinant oncolytic herpes simplex virus type 1 carrying multiple synergistic antitumor immuno-modulating factors. Here, we report its antitumor mechanisms and thus provide firm theoretical foundation for the upcoming clinical application in pancreatic cancer. Generally, the VG161-mediated antitumor outcomes were analyzed by a collaboration of techniques, namely the single-cell sequencing, airflow-assisted desorption electrospray ionization-mass spectrometry imaging (AFADSI-MSI) and nanostring techniques. In vitro, the efficacy of VG161 together with immune checkpoint inhibitors (ICIs) has been successfully shown to grant a long-term antitumor effect by altering tumor immunity and remodeling tumor microenvironment (TME) metabolisms. Cellular functional pathways and cell subtypes detected from patient samples before and after the treatment had undergone distinctive changes including upregulated CD8+ T and natural killer cells. More importantly, significant antitumor signals have emerged since the administration of VG161 injection. In conclusion, VG161 can systematically activate acquired and innate immunity in pancreatic models, as well as improve the tumor immune microenvironment, indicative of strong antitumor potential. The more robusting antitumor outcome for VG161 monotherapy or in combination with other therapies on pancreatic cancer is worth of being explored in further clinical trials.

Self-imaging-based high-power all-fiber coherent combiners: fabrication and preliminary demonstration.

Self-imaging combiners can achieve near-perfect filled-aperture coherent beam combination in an all-fiber format with a high-power operation capability. In this Letter, the fabrication of proposed self-imaging combiners is presented, along with a demonstration of a 2 × 2 configuration that uses commercially available large-mode-area fibers, glass tube and square-core fiber. Two types of self-imaging combiners have been fabricated using polarization-maintaining fibers and non-polarization-maintaining fibers, respectively, and these have been tested in an all-fiber coherent beam combination system. Preliminary results reveal that non-polarization-maintaining fibers can achieve better positioning precision, and a maximal combining efficiency of 52.7% has been achieved. The deviation of the demonstrated combining efficiency from the theoretical prediction is mainly attributed to the distortion of the fiber bundle and square-core output fiber, which can be further improved by refining the fabrication process and employing specially developed square-core fiber with better geometrical precision. To the best of the authors' knowledge, this is the first validation of all-fiber coherent beam combining based on the self-imaging effect.

ARHGAP39 is a prognostic biomarker involved in immune infiltration in breast cancer.

BACKGROUND: Current studies on the role of ARHGAP39 mainly focused on its effect on neurodevelopment. However, there are few studies on the comprehensive analysis of ARHGAP39 in breast cancer. METHODS: ARHGAP39 expression level was analyzed based on the Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression Project (GTEx), and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database and validated by qPCR in various cell lines and tumor tissues. The prognostic value was analyzed using Kaplan-Meier curve analysis. CCK-8 and transwell assays were conducted to identify the biological function of ARHGAP39 in tumorigenesis. Signaling pathways related to ARHGAP39 expression were identified by the GO and KEGG enrichment analysis and gene set enrichment analysis (GSEA). The correlations between ARHGAP39 and cancer immune infiltrates were investigated via TIMER, CIBERSORT, ESTIMATE and tumor-immune system interactions database (TISIDB). RESULTS: ARHGAP39 was overexpressed in breast cancer and associated with poor survival outcomes. In vitro experiments revealed that ARHGAP39 could facilitate the proliferation, migration, and invasion capability of breast cancer cells. GSEA analysis showed that the main enrichment pathways of ARHGAP39 was immunity-related pathways. Considering the immune infiltration level, ARHGAP39 was negatively associated with infiltrating levels of CD8 + T cell and macrophage, and positively associated with CD4 + T cell. Furthermore, ARHGAP39 was significantly negatively correlated with immune score, stromal score, and ESTIMATE score. CONCLUSIONS: Our findings suggested that ARHGAP39 can be used as a potential therapeutic target and prognostic biomarker in breast cancer. ARHGAP39 was indeed a determinant factor of immune infiltration.