Severe fever with thrombocytopenia syndrome virus induces platelet activation and apoptosis via a reactive oxygen species-dependent pathway.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV) and with a high fatality rate. Thrombocytopenia is a major clinical manifestation observed in SFTS patients, but the underlying mechanism remains largely unclear. Here, we explored the effects of SFTSV infection on platelet function in vivo in severely infected SFTSV IFNar-/- mice and on mouse and human platelet function in vitro. Results showed that SFTSV-induced platelet clearance acceleration may be the main reason for thrombocytopenia. SFTSV-potentiated platelet activation and apoptosis were also observed in infected mice. Further investigation showed that SFTSV infection induced platelet reactive oxygen species (ROS) production and mitochondrial dysfunction. In vitro experiments revealed that administration of SFTSV or SFTSV glycoprotein (Gn) increased activation, apoptosis, ROS production, and mitochondrial dysfunction in separated mouse platelets, which could be effectively ameliorated by the application of antioxidants (NAC (N-acetyl-l-cysteine), SKQ1 (10-(6'-plastoquinonyl) decyltriphenylphosphonium) and resveratrol). In vivo experiments showed that the antioxidants partially rescued SFTSV infection-induced thrombocytopenia by improving excessive ROS production and mitochondrial dysfunction and down-regulating platelet apoptosis and activation. Furthermore, while SFTSV and Gn directly potentiated human platelet activation, it was completely abolished by antioxidants. This study revealed that SFTSV and Gn can directly trigger platelet activation and apoptosis in an ROS-MAPK-dependent manner, which may contribute to thrombocytopenia and hemorrhage during infection, but can be abolished by antioxidants.

Genomic Evidence for the Nonpathogenic State in HIV-1-Infected Northern Pig-Tailed Macaques.

HIV-1 is a highly host-specific retrovirus that infects humans but not most nonhuman primates. Thus, the lack of a suitable primate model that can be directly infected with HIV-1 hinders HIV-1/AIDS research. In the previous study, we have found that the northern pig-tailed macaques (NPMs) are susceptible to HIV-1 infection but show a nonpathogenic state. In this study, to understand this macaque-HIV-1 interaction, we assembled a de novo genome and longitudinal transcriptome for this species during the course of HIV-1 infection. Using comparative genomic analysis, a positively selected gene, Toll-like receptor 8, was identified with a weak ability to induce an inflammatory response in this macaque. In addition, an interferon-stimulated gene, interferon alpha inducible protein 27, was upregulated in acute HIV-1 infection and acquired an enhanced ability to inhibit HIV-1 replication compared with its human ortholog. These findings coincide with the observation of persistently downregulated immune activation and low viral replication and can partially explain the AIDS-free state in this macaque following HIV-1 infection. This study identified a number of unexplored host genes that may hamper HIV-1 replication and pathogenicity in NPMs and provided new insights into the host defense mechanisms in cross-species infection of HIV-1. This work will facilitate the adoption of NPM as a feasible animal model for HIV-1/AIDS research.

Longitudinal analysis of immunocyte responses and inflammatory cytokine profiles in SFTSV-infected rhesus macaques.

Severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging bunyavirus, causes severe fever with thrombocytopenia syndrome (SFTS), with a high fatality rate of 20%-30%. At present, however, the pathogenesis of SFTSV remains largely unclear and no specific therapeutics or vaccines against its infection are currently available. Therefore, animal models that can faithfully recapitulate human disease are important to help understand and treat SFTSV infection. Here, we infected seven Chinese rhesus macaques (Macaca mulatta) with SFTSV. Virological and immunological changes were monitored over 28 days post-infection. Results showed that mild symptoms appeared in the macaques, including slight fever, thrombocytopenia, leukocytopenia, increased aspartate aminotransferase (AST) and creatine kinase (CK) in the blood. Viral replication was persistently detectable in lymphoid tissues and bone marrow even after viremia disappeared. Immunocyte detection showed that the number of T cells (mainly CD8+ T cells), B cells, natural killer (NK) cells, and monocytes decreased during infection. In detail, effector memory CD8+ T cells declined but showed increased activation, while both the number and activation of effector memory CD4+ T cells increased significantly. Furthermore, activated memory B cells decreased, while CD80+/CD86+ B cells and resting memory B cells (CD27+CD21+) increased significantly. Intermediate monocytes (CD14+CD16+) increased, while myeloid dendritic cells (mDCs) rather than plasmacytoid dendritic cells (pDCs) markedly declined during early infection. Cytokines, including interleukin-6 (IL-6), interferon-inducible protein-10 (IP-10), and macrophage inflammatory protein 1 (MCP-1), were substantially elevated in blood and were correlated with activated CD4+ T cells, B cells, CD16+CD56+ NK cells, CD14+CD16+ monocytes during infection. Thus, this study demonstrates that Chinese rhesus macaques infected with SFTSV resemble mild clinical symptoms of human SFTS and provides detailed virological and immunological parameters in macaques for understanding the pathogenesis of SFTSV infection.

Treatment of radiation-induced brain injury with bisdemethoxycurcumin.

Radiation therapy is considered the most effective non-surgical treatment for brain tumors. However, there are no available treatments for radiation-induced brain injury. Bisdemethoxycurcumin (BDMC) is a demethoxy derivative of curcumin that has anti-proliferative, anti-inflammatory, and anti-oxidant properties. To determine whether BDMC has the potential to treat radiation-induced brain injury, in this study, we established a rat model of radiation-induced brain injury by administering a single 30-Gy vertical dose of irradiation to the whole brain, followed by intraperitoneal injection of 500 µL of a 100 mg/kg BDMC solution every day for 5 successive weeks. Our results showed that BDMC increased the body weight of rats with radiation-induced brain injury, improved learning and memory, attenuated brain edema, inhibited astrocyte activation, and reduced oxidative stress. These findings suggest that BDMC protects against radiation-induced brain injury.

[Factors Affecting the Surgical Level of Major Amputations in Patients with Severe Diabetic Foot].

Objective: To investigate the main factors affecting the surgical level of major amputations in patients with severe diabetic foot. Methods: A case-control study was conducted to analyze the clinical data of severe diabetic foot patients who had major amputations and were admitted to the Intensive Care Unit (ICU), Air Force Hospital of PLA Eastern Theater Command between July 2020 and July 2022. According to their surgical level of amputation, patients were divided into transtibial amputation (TT) group and transfemoral amputation (TF) group. Correlation analysis was performed with the clinical data of the patients, and multivariate logistic regression was performed to screen for relevant factors affecting the surgical level of major amputation. Results: The data of 48 patients with major amputations were collected, including 15 patients in the TT group and 33 patients in the TF group. The proportion of patients who had cardiovascular and cerebrovascular complications in the TT group was lower than that in the TF group (26.67% [4/15] vs. 57.58% [19/33], P<0.05), the proportion of patients who had lower extremity arterial intervention history was higher in the TT group than that in the TF group (40% [6/15] vs. 9.09% [3/33], P<0.05), and the proportion of patients who had elevated creatinine level was lower in the TT group than that in the TF group (70.31±22.98 vs. 127.98±108.38, P<0.05). Moreover, the history of lower extremity arterial intervention may be an independent protective factor for determining the surgical level of major amputations (odds ratio [ OR]=0.15, 95% confidence interval [ CI]: 0.03-0.72, P=0.018). Conclusion: History of cardiovascular and cerebrovascular diseases, serum creatinine level and history of lower extremity arterial intervention are the main factors affecting the surgical level of major amputations in patients with severe diabetic foot, and the history of lower extremity arterial intervention may be an independent protective factor.

Successful treatment of metastatic vulvar malignant melanoma with toripalimab: A rare case report and review of the literature.

RATIONALE: Vulvar melanoma is a rare and aggressive tumor with a high risk of local recurrence and distant metastasis. The prognosis is poor with a 5-year overall survival rate of only 46.6%. Management of vulvar melanoma remains a clinical challenge. Recent evidences have shown that immune checkpoint inhibitors are effective in the treatment of vulvar melanoma. PATIENT CONCERNS AND DIAGNOSES: A 63-year-old woman with vulvar malignant melanoma suffered inguinal lymph node metastasis after vulvectomy and chemotherapy. She underwent inguinal lymph node dissection and inguinal radiotherapy. The tumor progressed again and she received immunotherapy. INTERVENTIONS: The tumor progressed again, and she was admitted to our hospital and received toripalimab combined with apatinib and abraxane. OUTCOMES: After 6 cycles of immunotherapy, the efficacy achieved partial remission. And with toripalimab as maintenance therapy, the patient achieved durable antitumor efficacy and good safety. LESSONS: In this rare case, the patient with metastatic vulvar malignant melanoma had durable antitumor efficacy and good safety when receiving toripalimab.

Hydrosulfonylation of Alkenes with Sulfonyl Imines via Ir/Cu Dual Photoredox Catalysis.

Sulfonamides exhibit the advantages of wide prevalence, excellent prefunctionalization capability, and broad functional group compatibility. We report here utilizing sulfonyl imines as sulfonyl radical precursors for hydrosulfonylation of activated alkenes via visible-light irradiation. By preinstallation of functional groups into the sulfonamides and subsequent hydrosulfonylation, a variety of complex sulfones were synthesized with good efficiency under Ir/Cu dual photoredox catalysis. Additionally, this protocol expands the research in late-stage N-S bond modification in sulfonamides.

Relationships between Willingness to Participate in the Nursing Clinical Ladder Program and Its Related Factors among Clinical Nurses.

The professional nursing competence ladder system can effectively inspire nurses' work morale, improve quality of life, and avoid the issue of senior staff leaving the clinical setting. The aim of this study was to explore the willingness to participate in the professional nursing competence ladder system and its related factors among nurses. A cross-sectional study design with a structured questionnaire was used. Purposive sampling was employed, and 696 nurses who qualified to be promoted as N2 were recruited from a medical center in southern Taiwan. The results showed most nurses were willing to participate in the nursing ladder system. There were significant differences between willingness to participate in the ladder system and age, education level, as well as promotion experience. This study emphasizes the importance of intensifying internal encouraging factors and strengthening external encouraging factors to improve participation rates. Healthcare institutions could provide instruction on case report writing to increase nurses' willingness to participate in the clinical ladder program.

Visible-Light-Mediated Late-Stage Sulfonylation of Anilines with Sulfonamides.

A visible-light-mediated late-stage sulfonylation of anilines with sulfonamides under simple reaction conditions is presented. Various primary or secondary sulfonamides including several pharmaceuticals were incorporated successfully via N-S bond activation and C-H bond sulfonylation. The synthetic utility of this strategy is highlighted by the construction of complex anilines bearing diverse bioactive groups.

Artificial intelligence for prediction of COVID-19 progression using CT imaging and clinical data.

OBJECTIVES: Early recognition of coronavirus disease 2019 (COVID-19) severity can guide patient management. However, it is challenging to predict when COVID-19 patients will progress to critical illness. This study aimed to develop an artificial intelligence system to predict future deterioration to critical illness in COVID-19 patients. METHODS: An artificial intelligence (AI) system in a time-to-event analysis framework was developed to integrate chest CT and clinical data for risk prediction of future deterioration to critical illness in patients with COVID-19. RESULTS: A multi-institutional international cohort of 1,051 patients with RT-PCR confirmed COVID-19 and chest CT was included in this study. Of them, 282 patients developed critical illness, which was defined as requiring ICU admission and/or mechanical ventilation and/or reaching death during their hospital stay. The AI system achieved a C-index of 0.80 for predicting individual COVID-19 patients' to critical illness. The AI system successfully stratified the patients into high-risk and low-risk groups with distinct progression risks (p < 0.0001). CONCLUSIONS: Using CT imaging and clinical data, the AI system successfully predicted time to critical illness for individual patients and identified patients with high risk. AI has the potential to accurately triage patients and facilitate personalized treatment. KEY POINT: • AI system can predict time to critical illness for patients with COVID-19 by using CT imaging and clinical data.

Associations of Circulating microRNA-221 and 222 With the Severity of Coronary Artery Lesions in Acute Coronary Syndrome Patients.

Circulating levels of microRNA-221 and 222 (miR-221/222) in patients with coronary artery disease (CAD) are elevated, yet the relationship between circulating miR-221/222 and the severity of coronary lesions in patients with acute coronary syndrome (ACS) remains unknown. In this study, the relative expression levels of circulating miR-221/222 in patients with ACS (n = 267) and controls (n = 71) were compared by real-time fluorescence quantitative-polymerase chain reaction (RT-qPCR). The ACS group was further divided into unstable angina pectoris (UA) group (n = 191) and acute myocardial infarction (AMI) group (n = 76). Significant upregulation of circulating miR-221/222 was observed in ACS. A positive linear correlation between circulating miR-221/222 and Gensini scores was demonstrated. The area under the curve (AUC) of circulating miR-221/222 in the diagnosis of coronary artery stenosis ≥50% was 0.605 and 0.643, respectively. The circulating miRNA-221/222 expression levels in ACS patients were elevated and positively associated with the severity of the coronary artery lesions. Circulating miR-221/222 may be novel biomarkers for the diagnosis of coronary artery stenosis ≥50% and the occurrence of ACS.

Overexpression of Twist1 in vascular endothelial cells promotes pathological retinal angiogenesis in mice.

Retinal angiogenesis is a critical process for normal retinal function. However, uncontrolled angiogenesis can lead to pathological neovascularization (NV), which is closely related to most irreversible blindness-causing retinal diseases. Understanding the molecular basis behind pathological NV is important for the treatment of related diseases. Twist-related protein 1 (TWIST1) is a well-known transcription factor and principal inducer of epithelial-mesenchymal transition (EMT) in many human cancers. Our previous study showed that Twist1 expression is elevated in pathological retinal NV. To date, however, the role of TWIST1 in retinal pathological angiogenesis remains to be elucidated. To study the role of TWIST1 in pathological retinal NV and identify specific molecular targets for antagonizing pathological NV, we generated an inducible vascular endothelial cell (EC)-specific Twist1 transgenic mouse model ( Tg-Twist1 iEC+ ). Whole-mount retinas from Tg-Twist1 iEC+ mice showed retarded vascular progression and increased vascular density in the front end of the growing retinal vasculature, as well as aneurysm-like pathological retinal NV. Furthermore, overexpression of Twist1 in the ECs promoted cell proliferation but disturbed cell polarity, thus leading to uncontrolled retinal angiogenesis. TWIST1 promoted pathological NV by activating the Wnt/ß-catenin signaling pathway and inducing the expression of NV formation-related genes, thereby acting as a 'valve' in the regulation of pathological angiogenesis. This study identified the critical role of TWIST1 in retinal pathological NV, thus providing a potential therapeutic target for pathological NV.

Jejunal epithelial barrier disruption triggered by reactive oxygen species in early SIV infected rhesus macaques.

Intestinal epithelial barrier destruction occurs earlier than mucosal immune dysfunction in the acute stage of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections. At present, however, the cause of compromised gastrointestinal integrity in early SIV infection remains unknown. In the current study, we investigated the effects of SIV infection on epithelial barrier integrity and explored oxidative stress-mediated DNA damage and apoptosis in epithelial cells from early acute SIVmac239-infected Chinese rhesus macaques (Macaca mulatta). Results showed that the sensitive molecular marker of small intestinal barrier dysfunction, i.e., intestinal fatty acid-binding protein (IFABP), was significantly increased in plasma at 14 days post-SIV infection. SIV infection induced a profound decrease in the expression of tight junction proteins, including claudin-1, claudin-3, and zonula occludens (ZO)-1, as well as a significant increase in the active form of caspase-3 level in epithelial cells. RNA sequencing (RNA-seq) analysis suggested that differentially expressed genes between pre- and post-SIV-infected jejuna were enriched in pathways involved in cell redox homeostasis, oxidoreductase activity, and mitochondria. Indeed, a SIV-mediated increase in reactive oxygen species (ROS) in the epithelium and macrophages, as well as an increase in hydrogen peroxide (H2O2) and decrease in glutathione (GSH)/glutathione disulfide (GSSG) antioxidant defense, were observed in SIV-infected jejuna. In addition, the accumulation of mitochondrial dysfunction and DNA oxidative damage led to an increase in senescence-associated ß-galactosidase (SA-ß-gal) and early apoptosis in intestinal epithelial cells. Furthermore, HIV-1 Tat protein-induced epithelial monolayer disruption in HT-29 cells was rescued by antioxidant N-acetylcysteine (NAC). These results indicate that mitochondrial dysfunction and oxidative stress in jejunal epithelial cells are primary contributors to gut epithelial barrier disruption in early SIV-infected rhesus macaques.

Pim1 knockout alleviates sarcopenia in aging mice via reducing adipogenic differentiation of PDGFRα+ mesenchymal progenitors.

BACKGROUND: Sarcopenia widely exists in elderly people and triggers numerous age-related events. The essential pathologic change lies in the increased intramuscular adipose tissue after aging with no exception to non-obese objects. Pim1 appears to be associated with adipogenic differentiation in recent studies, inspiring us to explore whether it regulates adipogenesis in aging muscles and affects sarcopenia. METHODS: Wild-type and Pim1 knockout C57/BL6J mice were randomized into young and old groups. Histo-pathological and molecular biological methods were applied to assess the intramuscular adipose tissue content, the atrophy and regeneration, and the expressions of Pim1 and adipogenic transcription factors. PDGFRα+ mesenchymal progenitors were separated and their replicative aging model were established. Different time of adipogenic induction and different amounts of Pim1 inhibitor were applied, after which the adipogenic potency were evaluated. The expressions of Pim1 and adipogenic transcription factors were measured through western blotting. RESULTS: The aging mice demonstrated decreased forelimb grip strength (P = 0.0003), hanging impulse (P < 0.0001), exhaustive running time (P < 0.0001), tetanic force (P = 0.0298), lean mass (P = 0.0008), and percentage of gastrocnemius weight in body weight (P < 0.0001), which were improved by Pim1 knockout (P = 0.0015, P = 0.0222, P < 0.0001, P = 0.0444, P = 0.0004, and P = 0.0003, respectively). To elucidate the mechanisms, analyses showed that Pim1 knockout decreased the fat mass (P = 0.0005) and reduced the intramuscular adipose tissue content (P = 0.0008) by inhibiting the C/EBPδ pathway (P = 0.0067) in aging mice, resulting in increased cross-sectional area of all and fast muscle fibres (P = 0.0017 and 0.0024 respectively), decreased levels of MuRF 1 and atrogin 1 (P = 0.0001 and 0.0329 respectively), and decreased content of Pax7 at the basal state (P = 0.0055). In vitro, senescent PDGFRα+ mesenchymal progenitors showed significantly increased the intracellular adipose tissue content (OD510) compared with young cells after 6 days of adipogenic induction (P < 0.0001). The Pim1 expression was elevated during adipogenic differentiation, and Pim1 inhibition significantly reduced the OD510 in senescent cells (P = 0.0040) by inhibiting the C/EBPδ pathway (P = 0.0047). CONCLUSIONS: Pim1 knockout exerted protective effects in sarcopenia by inhibiting the adipogenic differentiation of PDGFRα+ mesenchymal progenitors induced by C/EBPδ activation and thus reducing the intramuscular adipose tissue content in aging mice. These results provide a potential target for the treatment of sarcopenia.

Catalyst-free arylation of sulfonamides via visible light-mediated deamination.

A novel arylation of sulfonamides with boronic acids to afford numerous diaryl sulfones via a visible light-mediated N-S bond cleavage other than the typical transition-metal-catalyzed C(O)-N bond activation is described. This methodology, which represents the first catalyst-free protocol for the sulfonylation of boronic acids, is characterized by its simple reaction conditions, good functional group tolerance and high efficiency. Several successful examples for the late-stage functionalization of diverse sulfonamides indicate the high potential utility of this method in pharmaceutical science and organic synthesis.

Base-Mediated Borylsilylation/Silylation of Ammonium Salts with Silylborane.

This work describes a base-mediated borylsilylation of benzylic ammonium salts to synthesize geminal silylboronates bearing benzylic proton under mild reaction conditions. Deaminative silylation of aryl ammonium salts was also achieved in the presence of LiOtBu. This strategy which is featured with high efficiency, mild reaction conditions, and good functional group tolerance provides efficient routes for late-stage functionalization of amines.

Severe immune-related hyperthermia followed by immune-related pneumonitis with PD-1 inhibitor (sintilimab) in small cell lung cancer: A case report.

Immune checkpoint inhibitors (ICIs) have achieved prominent efficacy in the treatment of numerous cancers, which is the most significant breakthrough in cancer therapy in recent years. However, ICIs are associated with a series of immune-related adverse events (irAEs). Pneumonitis is an uncommon but potentially fatal irAE. In the case reported here, a patient with advanced small cell lung cancer (SCLC) had rapid progression of disease following chemotherapy and received ICIs. The patient experienced severe immune-related hyperthermia followed by immune-related pneumonitis. Fortunately, a good clinical response was achieved after the patient received corticosteroids and tocilizumab.

Changes in sensorimotor regions of the cerebral cortex in congenital amusia: a case-control study.

Perceiving pitch is a central function of the human auditory system; congenital amusia is a disorder of pitch perception. The underlying neural mechanisms of congenital amusia have been actively discussed. However, little attention has been paid to the changes in the motor rain within congenital amusia. In this case-control study, 17 participants with congenital amusia and 14 healthy controls underwent functional magnetic resonance imaging while resting with their eyes closed. A voxel-based degree centrality method was used to identify abnormal functional network centrality by comparing degree centrality values between the congenital amusia group and the healthy control group. We found decreased degree centrality values in the right primary sensorimotor areas in participants with congenital amusia relative to controls, indicating potentially decreased centrality of the corresponding brain regions in the auditory-sensory motor feedback network. We found a significant positive correlation between the degree centrality values and the Montreal Battery of Evaluation of Amusia scores. In conclusion, our study identified novel, hitherto undiscussed candidate brain regions that may partly contribute to or be modulated by congenital amusia. Our evidence supports the view that sensorimotor coupling plays an important role in memory and musical discrimination. The study was approved by the Ethics Committee of the Second Xiangya Hospital, Central South University, China (No. WDX20180101GZ01) on February 9, 2019.

The microvesicle/CD36 complex triggers a prothrombotic phenotype in patients with non-valvular atrial fibrillation.

The mechanisms responsible for platelet activation, the prothrombotic state, in non-valvular atrial fibrillation (NVAF) are still obscure. Microvesicles (MVs) can transfer various messages to target cells and may be helpful for exploring the detailed mechanisms. We aimed to investigate the possible mechanisms by which proatherogenic factors of NVAF contribute to platelet activation. Two hundred and ten patients with NVAF were stratified as being at 'low to moderate risk' or 'high risk' for stroke according to the CHADS2 score. Levels of platelet-derived MVs (PMVs) and platelet activation were examined. CD36-positive or CD36-deficient human platelets were stimulated by MVs isolated from NVAF patients with or without various inhibitors in vitro. Levels of PMVs and platelet activation markers enhanced significantly in high-risk patients. The MVs isolated from plasma of NVAF patients bound to platelet CD36 and activated platelets by phosphorylating the mitogen-activated protein kinase 4/Jun N-terminal kinase 2 (MKK4/JNK2) pathways. However, CD36 deficiency protected against MV-induced activation of platelets. We reveal a possible mechanism of platelet activation in NVAF and suggest that the platelet CD36 might be an effective target in preventing the prothrombotic state in NVAF.