Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer.

Emotional distress (ED), commonly characterized by symptoms of depression and/or anxiety, is prevalent in patients with cancer. Preclinical studies suggest that ED can impair antitumor immune responses, but few clinical studies have explored its relationship with response to immune checkpoint inhibitors (ICIs). Here we report results from cohort 1 of the prospective observational STRESS-LUNG study, which investigated the association between ED and clinical efficacy of first-line treatment of ICIs in patients with advanced non-small-cell lung cancer. ED was assessed by Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale. The study included 227 patients with 111 (48.9%) exhibiting ED who presented depression (Patient Health Questionnaire-9 score ≥5) and/or anxiety (Generalized Anxiety Disorder 7-item score ≥5) symptoms at baseline. On the primary endpoint analysis, patients with baseline ED exhibited a significantly shorter median progression-free survival compared with those without ED (7.9 months versus 15.5 months, hazard ratio 1.73, 95% confidence interval 1.23 to 2.43, P = 0.002). On the secondary endpoint analysis, ED was associated with lower objective response rate (46.8% versus 62.1%, odds ratio 0.54, P = 0.022), reduced 2-year overall survival rate of 46.5% versus 64.9% (hazard ratio for death 1.82, 95% confidence interval 1.12 to 2.97, P = 0.016) and detriments in quality of life. The exploratory analysis indicated that the ED group showed elevated blood cortisol levels, which was associated with adverse survival outcomes. This study suggests that there is an association between ED and worse clinical outcomes in patients with advanced non-small-cell lung cancer treated with ICIs, highlighting the potential significance of addressing ED in cancer management. ClinicalTrials.gov registration: NCT05477979 .

Transcriptome analysis and functional verification reveal the roles of copper in resistance to potato virus Y infection in tobacco.

Potato virus Y (PVY) is one of the most important pathogens in the genus Potyvirus that seriously harms agricultural production. Copper (Cu), as a micronutrient, is closely related to plant immune response. In this study, we found that foliar application of Cu could inhibit PVY infection to some extent, especially at 7 days post inoculation (dpi). To explore the effect of Cu on PVY infection, transcriptome sequencing analysis was performed on PVY-infected tobacco with or without Cu application. Several key pathways regulated by Cu were identified, including plant-pathogen interaction, inorganic ion transport and metabolism, and photosynthesis. Moreover, the results of virus-induced gene silencing (VIGS) assays revealed that NbMLP423, NbPIP2, NbFd and NbEXPA played positive roles in resistance to PVY infection in Nicotiana benthamiana. In addition, transgenic tobacco plants overexpressing NtEXPA11 showed increased resistance to PVY infection. These results contribute to clarify the role and regulatory mechanism of Cu against PVY infection, and provide candidate genes for disease resistance breeding.

Gender, Sexism, and Police Attitudes Toward Policing Intimate Partner Violence in China.

This study examines the impact of gender and sexism on police officers' attitudes toward policing intimate partner violence (IPV). Data were collected from 826 Chinese police officers through online questionnaires. A hierarchical multiple regression analysis found that male police officers and those with sexist attitudes believe that handling IPV cases is illegitimate; they tend to perceive that the police are not morally bound to regulate such cases. Meanwhile, policewomen are less likely to consider that IPV interventions are difficult and resource-intensive. Findings indicate the need to amend policies and practices concerning gender and sexism among police officers to control IPV.

Accelerated 3D MR neurography of the brachial plexus using deep learning-constrained compressed sensing.

OBJECTIVES: To explore the use of deep learning-constrained compressed sensing (DLCS) in improving image quality and acquisition time for 3D MRI of the brachial plexus. METHODS: Fifty-four participants who underwent contrast-enhanced imaging and forty-one participants who underwent unenhanced imaging were included. Sensitivity encoding with an acceleration of 2 × 2 (SENSE4x), CS with an acceleration of 4 (CS4x), and DLCS with acceleration of 4 (DLCS4x) and 8 (DLCS8x) were used for MRI of the brachial plexus. Apparent signal-to-noise ratios (aSNRs), apparent contrast-to-noise ratios (aCNRs), and qualitative scores on a 4-point scale were evaluated and compared by ANOVA and the Friedman test. Interobserver agreement was evaluated by calculating the intraclass correlation coefficients. RESULTS: DLCS4x achieved higher aSNR and aCNR than SENSE4x, CS4x, and DLCS8x (all p < 0.05). For the root segment of the brachial plexus, no statistically significant differences in the qualitative scores were found among the four sequences. For the trunk segment, DLCS4x had higher scores than SENSE4x (p = 0.04) in the contrast-enhanced group and had higher scores than SENSE4x and DLCS8x in the unenhanced group (all p < 0.05). For the divisions, cords, and branches, DLCS4x had higher scores than SENSE4x, CS4x, and DLCS8x (all p ≤ 0.01). No overt difference was found among SENSE4x, CS4x, and DLCS8x in any segment of the brachial plexus (all p > 0.05). CONCLUSIONS: In three-dimensional MRI for the brachial plexus, DLCS4x can improve image quality compared with SENSE4x and CS4x, and DLCS8x can maintain the image quality compared to SENSE4x and CS4x. CLINICAL RELEVANCE STATEMENT: Deep learning-constrained compressed sensing can improve the image quality or accelerate acquisition of 3D MRI of the brachial plexus, which should be benefit in evaluating the brachial plexus and its branches in clinical practice. KEY POINTS: •Deep learning-constrained compressed sensing showed higher aSNR, aCNR, and qualitative scores for the brachial plexus than SENSE and CS at the same acceleration factor with similar scanning time. •Deep learning-constrained compressed sensing at acceleration factor of 8 had comparable aSNR, aCNR, and qualitative scores to SENSE4x and CS4x with approximately half the examination time. •Deep learning-constrained compressed sensing may be helpful in clinical practice for improving image quality and acquisition time in three-dimensional MRI of the brachial plexus.

Identification and Characterization of Retinitis Pigmentosa in a Novel Mouse Model Caused by PDE6B-T592I.

The cGMP-phosphodiesterase 6 beta subunit (PDE6B) is an essential component in the phototransduction pathway for light responses in photoreceptor cells. PDE6B gene mutations cause the death of rod photoreceptors, named as hereditary retinitis pigmentosa (RP) in humans and retinal degeneration (RD) in rodents. Here, we report a new RD model, identified from a phenotypic screen of N-ethyl-N-nitrosourea (ENU)-induced mutant mice, which displays retinal degeneration caused by a point mutation in the Pde6b gene that results in PDE6B-T592I mutant protein. The homozygous mutant mice show an extensive loss of rod photoreceptors at the age of 3 weeks; unexpectedly, the loss of rod photoreceptors can be partly rescued by dark rearing. Thus, this RD mutant model displays a light-dependent loss of rod photoreceptors. Both western blot and immunostaining results show very low level of mutant PDE6B-T592I protein in the retina. Structure modeling suggests that the T592I mutation probably affects the function and stability of PDE6B protein by changing intramolecular interactions. We further demonstrate that the expression of wild-type PDE6B delivered by subretinally injected adeno-associated virus (rAAV) prevents photoreceptor cell death in this RD model in vivo. The PDE6B-T592I mutant is, therefore, a valuable RD model for evaluating rAAV-mediated treatment and for investigating the molecular mechanism of light-dependent rod photoreceptor cell death that is related to impaired PDE6B function.

Getting Good Sleep with Family Support: The Role of Fear of Crime and Loneliness.

Sleep problems in middle-aged and older people can threaten their physical and mental health. Family support is regarded as a key factor that affects sleep quality, but the influence mechanism remains underexplored. This study analyzes the mediating effects of fear of crime (FOC) and loneliness in the relationship between family support and sleep quality, and explores whether gender plays a moderating role between family support and FOC. A questionnaire survey was conducted among 1043 Chinese middle-aged and older people aged 45-93 years. Using 10,000 bootstrapped samples, the study shows that middle-aged and older people who receive more family support have better sleep quality, and FOC and loneliness play mediating role in this association. Gender moderates the relationship between family support and FOC. Compared with men, family support for females has a greater impact on their FOC condition, and the mediating effect of family support on sleep quality through FOC is also greater among women. Family support can affect sleep quality through the chain mediating effect of FOC and loneliness for women. This study provides an in-depth understanding of the relationship between family support and sleep quality.

Impaired autophagy contributes to the aggravated deterioration of osteoarthritis articular cartilage by peroxisome proliferator-activated receptor α deficiency, associated with decreased ERK and Akt activation.

BACKGROUND: Although the chondroprotection of peroxisome proliferator-activated receptor α (PPARα) activation against osteoarthritis (OA) has been revealed, the regulatory mechanism of PPARα deficiency to aggravate osteoarthritic cartilage deterioration remains unclear. Here, we aimed to investigate whether and how autophagy is involved in OA pathological progression. METHODS: Model of experimental OA was established using destabilization of the medial meniscus in PPARα-KO 129S4/SvJae male mice, followed by histopathological detection of articular cartilage and immunohistochemistry detection of extracellular matrix (ECM) or autophagy-related signal molecules. Meanwhile, human OA chondrocytes obtained from total knee replacement surgery patients with OA were cultured with the pretreatment of IL-1ß, followed with the treatment of PPARα agonist WY14643 and the detection of related signal molecules. RESULTS: PPARα deficiency aggravated cartilage damage with decreased LC3B level in combination with an increase in P62 level, accompanied with reduced p-Akt and p-ERK levels in PPARα-KO mouse model of experimental OA. On the contrary, PPARα activation by WY14643 promoted ECM synthesis in IL-1ß-treated human OA chondrocytes, accompanied with increased LC3B-II/I ratio and Beclin 1 level and decreased P62 and Bcl2 levels. Meanwhile, it was observed that activated ERK and Akt by PPARα activation contributed to the enhancement of autophagy and ECM synthesis in human OA chondrocytes. CONCLUSIONS: Impaired autophagy contributed to the aggravated deterioration of osteoarthritis articular cartilage by PPARα deficiency associated with the suppression of ERK and Akt, with an implication that triggering PPARα activation ought to be a potential promising therapeutic target for OA therapy.

Alienation from medical care policy, medical care avoidance, and the role of sex and risk perception.

BACKGROUND: Medical care avoidance affects individuals' health status. Previous studies on medical care avoidance have mainly focused on medical costs and people's satisfaction with medical services. This study investigates whether an individual's sense of policy alienation toward medical care policy (SPA-M) affects behavioral intention of medical care avoidance, and to what extent an intermediary variable-medical financial risk perception-mediates the relationship between SPA-M and medical care avoidance. METHODS: A cross-sectional survey was conducted involving 434 people aged 35-59 years from Wuhu, a city in China's Anhui province. A moderated mediation model was constructed to investigate the research question and sex (biological: male and female) was used as a moderating variable between SPA-M and medical financial risk perception. RESULTS: We found that SPA-M significantly impacted medical care avoidance, and that medical financial risk perception played a complete mediating role in this relationship, while sex moderated the relationship between SPA-M and medical financial risk perception. CONCLUSION: This study contributes to the literature by enhancing our understanding of the factors that influence behavioral intention regarding medical care avoidance, deepening our understanding of the role of SPA-M in medical care policy, and expanding the role of sex differences in the analysis of the relationship between SPA-M, medical financial risk perception, and medical care avoidance, offering implications for public and community health.

Adaptive Optical Two-Photon Fluorescence Microscopy Probes Cellular Organization of Ocular Lenses In Vivo.

Purpose: The mammalian ocular lens is an avascular multicellular organ that grows continuously throughout life. Traditionally, its cellular organization is investigated using dissected lenses, which eliminates in vivo environmental and structural support. Therefore, in vivo optical imaging methods for studying lenses in their native context in live animals are urgently needed. Methods: Here, we demonstrated that two-photon fluorescence microscopy can visualize lens cells in vivo. To maintain subcellular resolution at depth, we used adaptive optics to correct aberrations owing to ocular and lens tissues, which led to substantial signal and resolution improvements. Results: Imaging lens cells up to 980 µm deep, we observed novel cellular organizations including suture-associated voids, enlarged vacuoles, and large cavities, contrary to the conventional view of a highly ordered organization. We tracked these features longitudinally over weeks and observed the incorporation of new cells during growth. Conclusions: Taken together, noninvasive longitudinal in vivo imaging of lens morphology using adaptive optics two-photon fluorescence microscopy will allow us to observe the development or alterations of lens cellular organization in living animals directly.

Retinal microvascular and neuronal pathologies probed in vivo by adaptive optical two-photon fluorescence microscopy.

The retina, behind the transparent optics of the eye, is the only neural tissue whose physiology and pathology can be non-invasively probed by optical microscopy. The aberrations intrinsic to the mouse eye, however, prevent high-resolution investigation of retinal structure and function in vivo. Optimizing the design of a two-photon fluorescence microscope (2PFM) and sample preparation procedure, we found that adaptive optics (AO), by measuring and correcting ocular aberrations, is essential for resolving putative synaptic structures and achieving three-dimensional cellular resolution in the mouse retina in vivo. Applying AO-2PFM to longitudinal retinal imaging in transgenic models of retinal pathology, we characterized microvascular lesions with sub-capillary details in a proliferative vascular retinopathy model, and found Lidocaine to effectively suppress retinal ganglion cell hyperactivity in a retinal degeneration model. Tracking structural and functional changes at high-resolution longitudinally, AO-2PFM enables microscopic investigations of retinal pathology and pharmacology for disease diagnosis and treatment in vivo.

Does health literacy affect older people's avoidance of medical care? The sense of medical care policy alienation and perceptions of control.

We aimed to clarify whether health literacy (HL)  impacts medical care avoidance through an underexplored mediator: a sense of policy alienation towards medical care policy for residents (SPA-M). A moderated mediation model with control perception as a moderator was used to analyze the inner relationship between HL and SPA-M. A cross-sectional survey of 470 people ≥ 60 years old, revealed a significant negative association between HL and medical care avoidance intention, which bootstrapped moderated mediation analysis confirmed is partially mediated by SPA-M. When older people's control perception was high, HL had a significant negative impact on medical care avoidance intention through SPA-M; for low control perception, the effect was insignificant. This study elucidates HL's impact of HL on medical care avoidance, highlighting control perception's relevance to medical care policymaking for older people.

Crystal Structure of a Classical MHC Class I Molecule in Dogs; Comparison of DLA-88*0 and DLA-88*5 Category Molecules.

DLA-88 is a classical major histocompatibility complex (MHC) class I gene in dogs, and allelic DLA-88 molecules have been divided into two categories named "DLA-88*0" and "DLA-88*5." The defining difference between the two categories concerns an LQW motif in the α2 domain helical region of the DLA-88*5 molecules that includes the insertion of an extra amino acid compared to MHC class I consensus length. We here show that this motif has been exchanged by recombination between different DLA-88 evolutionary lineages. Previously, with pDLA-88*508:01, the structure of a molecule of the DLA-88*5 category was elucidated. The present study is the first to elucidate a structure, using X-ray crystallography, of the DLA-88*0 category, namely DLA-88*001:04 complexed with ß2m and a nonamer peptide derived from canine distemper virus (CDV). The LQW motif that distinguishes DLA-88*5 from DLA-88*0 causes a shallower peptide binding groove (PBG) and a leucine exposed at the top of the α2 domain helix expected to affect T cell selection. Peptide ligand amino acid substitution and pMHC-I complex formation and stability analyses revealed that P2 and P3 are the major anchor residue positions for binding to DLA-88*001:04. We speculate that the distribution pattern of the LQW motif among canine classical MHC class I alleles represents a strategy to enhance allogeneic rejection by T cells of transmissible cancers such as canine transmissible venereal tumor (CTVT).

Adaptive optical two-photon fluorescence microscopy probes cellular organization of ocular lenses in vivo.

The mammalian ocular lens is an avascular multicellular organ that grows continuously throughout life. Traditionally, its cellular organization is investigated using dissected lenses, which eliminates in vivo environmental and structural support. Here, we demonstrated that two-photon fluorescence microscopy (2PFM) can visualize lens cells in vivo. To maintain subcellular resolution at depth, we employed adaptive optics (AO) to correct aberrations due to ocular and lens tissues, which led to substantial signal and resolution improvements. Imaging lens cells up to 980 µm deep, we observed novel cellular organizations including suture-associated voids, enlarged vacuoles, and large cavities, contrary to the conventional view of a highly ordered organization. We tracked these features longitudinally over weeks and observed the incorporation of new cells during growth. Taken together, non-invasive longitudinal in vivo imaging of lens morphology using AO 2PFM will allow us to directly observe the development or alterations of lens cellular organization in living animals.

Conversion Hip Arthroplasty Using Standard and Long Stems after Failed Internal Fixation of Intertrochanteric Fractures.

OBJECTIVE: Failed internal fixation of intertrochanteric fractures (FIF-ITF) is often treated by conversion hip arthroplasty (CHA). This study aimed to evaluate the results and complications of using standard and long femoral stems in this operation. METHODS: This retrospective, multi-center study enrolled 31 total hip arthroplasty (THA) and 23 hemiarthroplasties (HA) cases (30 women, 24 men; mean age 76 years) after FIF-ITF between 2012 and 2019, divided into two groups: standard stem group (n = 20) and long stem group (n = 34). The initial internal fixation includes 38 cases of proximal femoral nail anti-rotation (PFNA), eight cases of the dynamic hip screw (DHS), and eight cases of locking proximal femoral plate (LPFP). The indications for CHA included 38 cases of failure of fixation, seven cases of nonunion, and nine cases of avascular necrosis or posttraumatic osteoarthritis. Perioperative data and complications related to fracture and operation were collected, and preoperative and postoperative clinical and radiological data were analyzed. Clinical outcomes were assessed using Harris hip score (HHS) and 36-item Short Form survey (SF-36: including physical function (PF) score and body pain (BP) score). Statistical analyses were performed using the chi-square or Fisher's exact test, and the 2-sample t-test or Wilcoxon rank sum test. RESULTS: At an average of 5.6 years with a minimum of 2 years follow-up. A significant overall surgeon-related complication rate was detected (27.8% [15/54]), five cases had an intraoperative femur fracture, one case had a late periprosthetic femoral fracture, two cases had a stem penetration, one case had a cement leakage, and two patients had an early postoperative dislocation, one infection and three cases of stem loosening or subsidence. Long stems had an increased risk of complication (13/34) compared to standard stems (2/20) (P = 0.031). The operation time and blood loss in the long stem group were higher than those in the standard stem group (P = 0.002; 0.017). HHS and SF-36 significantly improved in both groups from preoperative to the final follow-up and did not present significant differences at the final follow-up (P > 0.05). CONCLUSION: CHA following FIF-ITF showed a successful mid-term clinical result, long stem arthroplasty should be approached with caution for the risks of higher complication rate, especially intraoperative femoral fractures.

Predicting malignancy in thyroid nodules based on conventional ultrasound and elastography: the value of predictive models in a multi-center study.

BACKGROUND: This study aimed to establish predictive models based on features of Conventional Ultrasound (CUS) and elastography in a multi-center study to determine appropriate preoperative diagnosis of malignancy in thyroid nodules with different risk stratification based on 2017 Thyroid Imaging Reporting and Data System by the American College of Radiology (ACR TI-RADS) guidelines. METHODS: Five hundred forty-eight thyroid nodules from three centers pathologically confirmed by the cytology or histology were retrospectively enrolled in the study, which were examined by CUS and elastography before fine needle aspiration (FNA) and surgery. Characteristics of CUS of thyroid nodules were reviewed according to 2017 ACR TI-RADS. Binary logistic regression analysis was used to develop the prediction models based on the different risk stratification of CUS features and elastography which were statistically significant. Values of predictive models were evaluated regarding the discrimination and calibration. RESULTS: Binary logistic regression showed that patients' age, taller-than-wider, lobulated or irregular boundary, extra-thyroid extension, microcalcification and the elastic parameter of Virtual touch tissue imaging quantification (VTIQ) max were independent predictors for thyroid malignancy (p < 0.05) in the ACR model and showed the area under the curve (AUC) in training (0.912) and validation cohort (internal and external: 0.877 vs 0.935). Predictive models showed predictors in ACR TR4 and TR5 for malignancy and diagnostic performance of AUC in training, internal and external validation cohort respectively: the VTIQ max (p < 0.001) with AUC of 0.809 vs 0.842 vs 0.705 and the age, taller than wide, VTIQ max variables with AUC of 0.859 vs 0.830 vs 0.906 in validation cohort. All predictive models have better calibration capabilities (p > 0.05). CONCLUSIONS: Predictive models combined CUS and elastography features would aid clinicians to make appropriate preoperative diagnosis of thyroid nodules among different risk stratification. The elastography parameter of VTIQ max has the priority in distinguishing thyroid malignancy with moderately suspicious (ACR TR4).

RRBP1 depletion of bone metastatic cancer cells contributes to enhanced expression of the osteoblastic phenotype.

Bone metastatic cancer-secreted extracellular factors are capable of modifying the bone microenvironment through interacting with bone cells, including osteoblasts. Reticulum ribosome-binding protein 1 (RRBP1) is substantially expressed in certain bone metastatic cancer cells. This study was undertaken to determine whether RRBP1 from bone metastatic cancer cells affects the osteoblastic phenotype expression. Breast and prostate cancer cells, MDA-MB-231 and PC3, were cultured, respectively, followed by collecting conditioned mediums (CMs) and identifying the abundance of RRBP1 in CMs using LC-MS/MS. MC3T3-E1 cells were cultured with a mixed medium (including CMs from shRRBP1-transduced two-type cancer cells) with or without endoplasmic reticulum (ER) stress inhibitor 4-PBA, followed by measuring the levels of osteoblastic phenotype expression and biomarkers of ER stress using western blotting, qPCR, and ARS staining, respectively. Similar experiments were performed in shRrbp1-transduced MC3T3-E1 cells cultured with a mixed medium (including CMs from the two-type cancer cells). Bone formation parameters were measured in the tibia of nude mice injected with shRRBP1-transduced two-type cancer cells using micro-CT analysis. These results showed that RRBP1 is the sole shared high-abundance protein in CMs from the two-type cancer cells, involving osteoblast differentiation. CMs from shRRBP1-transduced two-type cells boosted the osteoblastic phenotype expression partially through increasing ER stress. CMs from the two-type cancer cells partially offset the similar alterations induced by shRrbp1 in MC3T3-E1 cells. Injection with shRRBP1-transduced two-type cells ameliorated the bone lesions in nude mice. Therefore, RRBP1 depletion of bone metastatic cancer enhanced the osteoblastic phenotype expression, suggesting a role of RRBP1 in the bone microenvironment.

The Inhibitory Role of Hydrogen Sulfide in UII-Induced Cardiovascular Effects and the Underlying Signaling Pathways.

Urotensin II (UII) could increase blood pressure and heart rate via increased central reactive oxygen species (ROS) levels. We reported previously that hydrogen sulfide (H2S) exerts an antihypertensive effect by suppressing ROS production. The aim of the current study is to further examine the effects of endogenous and exogenous H2S on UII-induced cardiovascular effects by using an integrated physiology approach. We also use cell culture and molecular biological techniques to explore the inhibitory role of H2S on UII-induced cardiovascular effects. In this study, we found that cystathionine-ß-synthase (CBS), the main H2S synthesizing enzyme in CNS, was expressed in neuronal cells of the rostral ventrolateral medulla (RVLM) area. Cellular distribution of CBS and urotensin II receptor (UT) in SH-SY5Y cells that are confirmed as glutamatergic were identified by immunofluorescent and Western blots assay. In Sprague-Dawley rats, administration of UII into the RVLM resulted in an increase in mean arterial pressure (MAP), heart rate (HR), ROS production, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and phosphorylation of p47phox, extracellular signal-regulated protein kinase (ERK)1/2 and p38MAPK, but not stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK). These effects of UII were attenuated by application into the RVLM of endogenous (L-cysteine, SAM) or exogenous (NaHS) H2S. These results were confirmed in SH-SY5Y cells. UII-induced cardiovascular effects were also significantly abolished by pretreatment with microinjection of Tempol, Apocynin, SB203580, or PD98059 into the RVLM. Preincubated SH-SY5Y cells with Apocynin before administration of UII followed by Western blots assay showed that ROS is in the upstream of p38MAPK/ERK1/2. Gao activation assay in SH-SY5Y cells suggested that H2S may exert an inhibitory role on UII-induced cardiovascular effects by inhibiting the activity of Gαo. These results suggest that both endogenous and exogenous H2S attenuate UII-induced cardiovascular effects via Gαo-ROS-p38MAPK/ERK1/2 pathway.

Rictor maintains endothelial integrity under shear stress.

Background: Endothelial injury induced by low shear stress (LSS) is an initiating factor in the pathogenesis of various cardiovascular diseases, including atherosclerosis, hypertension, and thrombotic diseases. Low shear stress activates the mammalian target of rapamycin complex 2 (mTORC2) signaling pathway. Rictor, the main constituent protein of mTORC2, is involved in vascular development. However, the impact of conditional Rictor ablation on endothelial homeostasis, especially on endothelial-specific markers, such as vascular endothelial-cadherin (VE-cadherin) and von Willebrand factor (VWF), under blood flow stimulation is unclear. Objective: We aimed to investigate whether endothelial Rictor is involved in maintaining vascular endothelial integrity and the potential role of Rictor in atheroprone blood flow-mediated endothelial injury. Methods and results: Immunofluorescence staining showed that endothelial Rictor was successfully knocked out in a mouse model. Scanning electron microscopy (EM) detection revealed disruption of the endothelial monolayer in the thoracic aorta of Rictor-deficient mice. Furthermore, scanning electron microscopy and transmission electron microscopy showed that Rictor deletion disrupted endothelial integrity and expanded cell junctions in the left common carotid artery region. In vitro, low shear stress disrupted actin filament polarity and the promoted the translocation of vascular endothelial-cadherin, the key component of adherens junctions (AJs) in human umbilical vein endothelial cells. After Rictor downregulation by small interfering RNA, the translocation of vascular endothelial-cadherin and stress fibers increased. Rictor knockdown inhibited low shear stress-induced von Willebrand factor upregulation, and downregulation of vascular endothelial-cadherin decreased low shear stress-induced von Willebrand factor expression. These results suggest that vascular endothelial-cadherin/von Willebrand factor is a possible mechanism mediated by Rictor in the pathological process of low shear stress-induced endothelial injury. Conclusion: Rictor is a key protein that regulates endothelial integrity under vascular physiological homeostasis, and Rictor mediates low shear stress-induced endothelial injury by regulating adherens junctions and von Willebrand factor.

The Diagnostic Value of Mitochondrial Mass of Peripheral T Lymphocytes in Early Sepsis.

Background: Studies have shown that lymphocyte dysfunction can occur during the early stages of sepsis and that cell dysfunction is associated with mitochondrial dysfunction. Therefore, quantifying the mitochondrial function of lymphocytes in patients with sepsis could be valuable for the early diagnosis of sepsis. Methods: Seventy-nine patients hospitalized from September 2020 to September 2021 with Sepsis-3 were retrospectively analyzed and subsequently compared with those without sepsis. Results: Univariate analysis showed statistical differences between the data of the two groups regarding age, neutrophil/lymphocyte, procalcitonin (PCT), C-reactive protein, total bilirubin, serum creatinine, type B natriuretic peptide, albumin, prothrombin time, activated partial thromboplastin time, lactic acid, single-cell mitochondrial mass (SCMM)-CD3, SCMM-CD4, SCMM-CD8, and Acute Physiology and Chronic Health Evaluation II score (P < 0.05). Multivariate logistic regression analysis performed on the indicators mentioned above demonstrated a statistical difference in PCT, lactic acid, SCMM-CD4, and SCMM-CD8 levels between the two groups (P < 0.05). The receiver operating characteristic curves of five models were subsequently compared [area under the curve: 0.740 (PCT) vs. 0.933 (SCMM-CD4) vs. 0.881 (SCMM-CD8) vs. 0.961 (PCT + SCMM-CD4) vs. 0.915 (PCT+SCMM-CD8), P < 0.001]. Conclusion: SCMM-CD4 was shown to be a better diagnostic biomarker of early sepsis when compared with the traditional biomarker, PCT. Furthermore, the value of the combination of PCT and SCMM-CD4 in the diagnosis of early sepsis was better than that of SCMM-CD4 alone.

Centranthera grandiflore alleviates alcohol-induced oxidative stress and cell apoptosis.

Alcohol liver disease (ALD) has become a global threat to human health. It is associated with a wide range of liver diseases including alcohol fatty liver, steatosis, fibrosis and cirrhosis, and finally leads to liver cancer and even death. Centranthera grandiflora is a traditional Chinese medicinal herb commonly used to treat ALD, but no research about its mechanism is available. This study evaluated the hepatoprotective effect and mechanism of C. grandiflora against alcohol-induced liver injury in mice. We found that the ethanol extracts of C. grandiflora (CgW) alleviated the alcohol-induced liver injury, enhanced the levels of antioxidant enzymes, and reduced the amount of lipid peroxides. CgW also affected cell apoptosis by inhibiting the activity of Bax, cleaved-caspase 3 and cleaved-caspase 9, and increasing the activity of Bcl-2. In conclusion, the results showed that CgW can effectively improve ALD through alleviating oxidative stress and inhibiting cell apoptosis for the first time. This study suggested that C. grandiflora is a promising herbal medicine for ALD treatment.