Piezo1 Knockout Improves Post-Stroke Cognitive Dysfunction by Inhibiting the Interleukin-6 (IL-6)/Glutathione Peroxidase 4 (GPX4) Pathway.

Background: Cerebral infarction often results in post-stroke cognitive impairment, which impairs the quality of life and causes long-term disability. Astrocytes, the most abundant glial cells in the central nervous system, have a crucial role in cerebral ischemia and neuroinflammation. We explored the possible advantages of interleukin-6 (IL-6), a powerful pro-inflammatory cytokine produced by astrocytes, for post-stroke cognitive function. Methods: Mendelian randomization was applied to analyze the GWAS database of stroke patients, obtaining a causal relationship between IL-6 and stroke. Further validation of this relationship and its mechanisms was conducted. Using a mouse model of cerebral infarction, we demonstrated a significant increase in IL-6 expression in astrocytes surrounding the ischemic lesion. This protective effect of Piezo1 knockout was attributed to the downregulation of matrix metalloproteinases and upregulation of tight junction proteins, such as occludin and zonula occludens-1 (ZO-1). Results: Two-step Mendelian randomization revealed that IL-6 exposure is a risk factor for stroke. Moreover, we conducted behavioral assessments and observed that Piezo1 knockout mice that received intranasal administration of astrocyte-derived IL-6 showed notable improvement in cognitive function compared to control mice. This enhancement was associated with reduced neuronal cell death and suppressed astrocyte activation, preserving ZO-1. Conclusion: Our study shows that astrocyte-derived IL-6 causes cognitive decline after stroke by protecting the blood-brain barrier. This suggests that piezo1 knockout may reduce cognitive impairment after brain ischemia. Further research on the mechanisms and IL-6 delivery methods may lead to new therapies for post-stroke cognition.

Development of Biomarkers and Prognosis Model of Mortality Risk in Patients with COVID-19.

Background: As of 30 April 2023, the COVID-19 pandemic has resulted in over 6.9 million deaths worldwide. The virus continues to spread and mutate, leading to continuously evolving pathological and physiological processes. It is imperative to reevaluate predictive factors for identifying the risk of early disease progression. Methods: A retrospective study was conducted on a cohort of 1379 COVID-19 patients who were discharged from Xin Hua Hospital affiliated with Shanghai Jiao Tong University School of Medicine between 15 December 2022 and 15 February 2023. Patient symptoms, comorbidities, demographics, vital signs, and laboratory test results were systematically documented. The dataset was split into testing and training sets, and 15 different machine learning algorithms were employed to construct prediction models. These models were assessed for accuracy and area under the receiver operating characteristic curve (AUROC), and the best-performing model was selected for further analysis. Results: AUROC for models generated by 15 machine learning algorithms all exceeded 90%, and the accuracy of 10 of them also surpassed 90%. Light Gradient Boosting model emerged as the optimal choice, with accuracy of 0.928 ± 0.0006 and an AUROC of 0.976 ± 0.0028. Notably, the factors with the greatest impact on in-hospital mortality were growth stimulation expressed gene 2 (ST2,19.3%), interleukin-8 (IL-8,17.2%), interleukin-6 (IL-6,6.4%), age (6.1%), NT-proBNP (5.1%), interleukin-2 receptor (IL-2R, 5%), troponin I (TNI,4.6%), congestive heart failure (3.3%) in Light Gradient Boosting model. Conclusion: ST-2, IL-8, IL-6, NT-proBNP, IL-2R, TNI, age and congestive heart failure were significant predictors of in-hospital mortality among COVID-19 patients.

Assessment of land use change of ecological green wedge and cooling island effect: A case study of Wuhan, China.

The construction of urban ecological green wedges, which can mitigate the heat island effect through cooling and ventilation effects, is an important way to enhance the adaptation of cities to climate change. Dynamic monitoring and periodic assessment of both the conservation status and cooling effect of ecological green wedges is a key to ensure the heat mitigation benefits. Based on multi-source remote sensing data, we systematically analyzed the land use changes of six ecological green wedges in Wuhan in 2013 and 2020 using the methods of Markov transfer matrix, land use dynamics, and comprehensive index of land use degree, and evaluated the changes in surface temperature of the ecological green wedges and their cooling island effect. Results showed that the ecological green wedges in Wuhan generally had a large amount of construction land encroaching on ecological land from 2013 to 2020, with the water decreased the most. With the continuous deterioration of ecological green wedges, their land surface temperatures showed rising trends, together with significant weakening trends in cooling island effects. Among all the six wedges, the Dadonghu, Tangxun, and Wuhu exhibited relatively better ecological conservation, slighter land use change and lower overall development degree. Qinglinghu and Houguanhu demonstrated average levels of conservation. Fuhe experienced the most severe change under the significant influence of the westward policy of Wuhan City, with the proportion of water decreasing by 7.1%, warming up by 3.00 ℃, and the largest reduction in cooling distance for the cooling island effect, amounting to about 210 m. The results provided scientific evidence for the urban heat island mitigation-oriented planning and management of ecological green wedges for Wuhan City.

The Multiple Functions of HB-EGF in Female Reproduction and Related Cancer: Molecular Mechanisms and Targeting Strategies.

Heparin-binding growth factor (HB-EGF) is a member of the epidermal growth factor (EGF) ligand family which has a crucial role in women's health. However, there is a lack of comprehensive review to summarize the significance of HB-EGF. Therefore, this work first described the expression patterns of HB-EGF in the endometrium and ovary of different species and gestational time. Then, the focus was on exploring how it promotes the successful implantation and regulates the process of decidualization and the function of ovarian granulosa cells as an intermediate molecule. Otherwise, we also focused on the clinical and prognostic significance of HB-EGF in female-related cancers (including ovarian cancer, cervical cancer, and endometrial cancer) and breast cancer. Lastly, the article also summarizes the current drugs targeting HB-EGF in the treatment of ovarian cancer and breast cancer. Overall, these studies found that the expression of HB-EGF in the endometrium is spatiotemporal and species-specific. And it mediates the dialogue between the blastocyst and endometrium, promoting synchronous development of the blastocyst and endometrium as an intermediate molecule. HB-EGF may serve as a potentially valuable prognostic clinical indicator in tumors. And the specific inhibitor of HB-EGF (CRM197) has a certain anti-tumor ability, which can exert synergistic anti-tumor effects with conventional chemotherapy drugs. However, it also suggests that more research is needed in the future to elucidate its specific mechanisms and to accommodate clinical studies with a larger sample size to clarify its clinical value.

Insights on the NF-κB system in polycystic ovary syndrome, attractive therapeutic targets.

The nuclear factor κappa B (NF-κB) signaling plays a well-known function in inflammation and regulates a wide variety of biological processes. Low-grade chronic inflammation is gradually considered to be closely related to the pathogenesis of Polycystic ovary syndrome (PCOS). In this review, we provide an overview on the involvement of NF-κB in the progression of PCOS particularly, such as hyperandrogenemia, insulin resistance, cardiovascular diseases, and endometrial dysfunction. From a clinical perspective, progressive recognition of NF-κB pathway provides opportunities for therapeutic interventions aimed at inhibiting pathway-specific mechanisms. With the accumulation of basic experimental and clinical data, NF-κB signaling pathway was recognized as a therapeutic target. Although there have been no specific small molecule NF-κB inhibitors in PCOS, a plethora of natural and synthetic compound have emerged for the pharmacologic intervention of the pathway. The traditional herbs developed for NF-κB pathway have become increasingly popular in recent years. Abundant evidence elucidated that NF-κB inhibitors can significantly improve the symptoms of PCOS. Herein, we summarized evidence relating to how NF-κB pathway is involved in the development and progression of PCOS. Furthermore, we present an in-depth overview of NF-κB inhibitors for therapy interventions of PCOS. Taken together, the NF-κB signaling may be a futuristic treatment strategy for PCOS.

Pan-cancer analysis of oncogenic role of insulin-like growth factor-binding proteins and validation in ovarian cancer.

BACKGROUND: Numerous studies have shown that the insulin-like growth factor (IGF) pathway is highly associated with tumor initial and progression in several tumors. However, compared with IGF1/1R and IGF2/2R, insufficient studies have focused on IGF-binding proteins (IGFBPs). METHODS: The GDC TCGA and GTEx data of 33 cancers, TCGA pan-cancer immune phenotypes, tumor mutation burdens, and the copy number alterations of IGFBPs were extracted. Next, the prognostic value of IGFBPs was analyzed based on a univariate Cox analysis. Additionally, the ESTIMATE algorithm was used to calculate stromal and immune scores and tumor purity, and the CIBERSORT algorithm was used to estimate tumor-infiltrating immunocyte levels. Ultimately, the correlation between IGFBP expression and cancer hallmark pathways was estimated with a Spearman analysis. RESULTS: The expression of IGFBPs was differentially expressed and correlated with prognosis in specific cancers. IGFBPs may operate as biological markers for carcinogenesis and progression and as prognostic biomarkers. Additionally, IGFBP5 has been proved that promotes the invasion and migration of ovarian cancer. CONCLUSIONS: In general, IGFBPs can serve as predictable biomarkers and potential therapeutic targets for specific tumors. Our results could provide underlying targets for the design of laboratory experiments to elucidate the mechanism of IGFBPs in cancers and identify IGFBP5 as a prognostic factor in ovarian cancers.

USF2 knockdown downregulates THBS1 to inhibit the TGF-ß signaling pathway and reduce pyroptosis in sepsis-induced acute kidney injury.

OBJECTIVE: Acute kidney injury (AKI) is a serious complication of sepsis. This study was performed to explore the mechanism that THBS1 mediated pyroptosis by regulating the TGF-ß signaling pathway in sepsis-induced AKI. METHODS: Gene expression microarray related to sepsis-induced AKI was obtained from the GEO database, and the mechanism in sepsis-induced AKI was predicted by bioinformatics analysis. qRT-PCR and ELISA were performed to detect expressions of THBS1, USF2, TNF-α, IL-1ß, and IL-18 in sepsis-induced AKI patients and healthy volunteers. The mouse model of sepsis-induced AKI was established, with serum creatinine, urea nitrogen, 24-h urine output measured, and renal tissue lesions observed by HE staining. The cell model of sepsis-induced AKI was cultured in vitro, with expressions of TNF-α, IL-1ß, and IL-18, pyroptosis, Caspase-1 and GSDMD-N, and activation of TGF-ß/Smad3 pathway detected. The upstream transcription factor USF2 was knocked down in cells to explore its effect on sepsis-induced AKI. RESULTS: THBS1 and USF2 were highly expressed in patients with sepsis-induced AKI. Silencing THBS1 protected mice against sepsis-induced AKI, and significantly decreased the expressions of NLRP3, Caspase-1, GSDMD-N, IL-1ß, and IL-18, increased cell viability, and decreased LDH activity, thus partially reversing the changes in cell morphology. Mechanistically, USF2 promoted oxidative stress responses by transcriptionally activating THBS1 to activate the TGF-ß/Smad3/NLRP3/Caspase-1 signaling pathway and stimulate pyroptosis, and finally exacerbated sepsis-induced AKI. CONCLUSION: USF2 knockdown downregulates THBS1 to inhibit the TGF-ß/Smad3 signaling pathway and reduce pyroptosis and further ameliorate sepsis-induced AKI.

Change in out-of-hospital 12-lead ECG diagnostic classification following resuscitation from cardiac arrest.

INTRODUCTION: We evaluated the incidence of change in serial 12-lead electrocardiogram (ECG) diagnostic classifications in patients resuscitated from out-of-hospital (OH) cardiac arrest (OHCA) comparing OH to emergency department (ED) ECGs. METHODS: This retrospective case series included: 1) adults (≥ 18 years old), 2) resuscitated from OHCA, 3) ≥ 1 OH and 1 ED ECG/patient, and 4) emergency medical services (EMS) transport to the study hospital. OH and ED ECGs were classified as: 1) STEMI (ST-segment Elevation Myocardial Infarction), 2) Ischemic, and 3) Non-ischemic. Two ED physicians and one cardiologist independently classified all ECGs, then generated a consensus opinion classification for each ECG based on American Heart Association's 2018 Expert Consensus criteria. The most ischemic OH ECG classification was compared with the last ED ECG classification. RESULTS: From 7/27/12 to 7/18/19, 176 patients were entered with a mean age of 61.2 ± 16.6 years; 102/176 (58%) were male. Overall, 504 OH and ED 12-lead ECGs were acquired (2.9 ECGs/patient). ECG classification inter-rater reliability kappa score was 0.63 ± 0.02 (substantial agreement). Overall, 86/176 (49%) changed ECG classification from the OH to ED setting; 69/86 (80%) of these ECGs changed from more to less ischemic classifications. Of 49 OH STEMI ECG classifications, 33/49 (67%) changed to a less ischemic (non-STEMI) ED ECG classification. CONCLUSIONS: Change in 12-lead ECG classification from OH to ED setting in patients resuscitated from OHCA was common (49%). The OH STEMI classification changed to a less ischemic (non-STEMI) ED classification in 67% of cases.

Functional genomic landscape of cancer-intrinsic evasion of killing by T cells.

The genetic circuits that allow cancer cells to evade destruction by the host immune system remain poorly understood1-3. Here, to identify a phenotypically robust core set of genes and pathways that enable cancer cells to evade killing mediated by cytotoxic T lymphocytes (CTLs), we performed genome-wide CRISPR screens across a panel of genetically diverse mouse cancer cell lines that were cultured in the presence of CTLs. We identify a core set of 182 genes across these mouse cancer models, the individual perturbation of which increases either the sensitivity or the resistance of cancer cells to CTL-mediated toxicity. Systematic exploration of our dataset using genetic co-similarity reveals the hierarchical and coordinated manner in which genes and pathways act in cancer cells to orchestrate their evasion of CTLs, and shows that discrete functional modules that control the interferon response and tumour necrosis factor (TNF)-induced cytotoxicity are dominant sub-phenotypes. Our data establish a central role for genes that were previously identified as negative regulators of the type-II interferon response (for example, Ptpn2, Socs1 and Adar1) in mediating CTL evasion, and show that the lipid-droplet-related gene Fitm2 is required for maintaining cell fitness after exposure to interferon-γ (IFNγ). In addition, we identify the autophagy pathway as a conserved mediator of the evasion of CTLs by cancer cells, and show that this pathway is required to resist cytotoxicity induced by the cytokines IFNγ and TNF. Through the mapping of cytokine- and CTL-based genetic interactions, together with in vivo CRISPR screens, we show how the pleiotropic effects of autophagy control cancer-cell-intrinsic evasion of killing by CTLs and we highlight the importance of these effects within the tumour microenvironment. Collectively, these data expand our knowledge of the genetic circuits that are involved in the evasion of the immune system by cancer cells, and highlight genetic interactions that contribute to phenotypes associated with escape from killing by CTLs.

Research on National Disaster Life Support Course in China.

OBJECTIVES: To provide scientific, theoretical support for the improvement of medical disaster training, we systematically analyzed the National Disaster Life Support (NDLS) Course and established a training curriculum with feedback based on the current status of disaster medicine in China. METHODS: The gray prediction model is applied to long-term forecast research on course effect. In line with the hypothesis, the NDLS course with feedback capability is more scientific and standardized. RESULTS: The current training NDLS course system is suitable for Chinese medical disasters. After accepting the course training, audiences' capabilities were enhanced. In the constructed GM (1,1) model prediction, the developing coefficients of the pretest and the posttest are 0.04 and 0.057, respectively. In light of the coefficient, the model is appropriate for the long-term prediction. The predicted results can be used as the basis for constructing training closed-loop optimization feedback. It can indicate that the course system has a good effect as well. CONCLUSIONS: According to the constructed GM model, the NDLS course system is scientific, practical, and operational. The research results can provide reference for relevant departments and be used for the construction of similar training course systems.

Case report: An adult-onset type II citrin deficiency patient in the emergency department.

Mutations in the solute carrier family 25 (SLC25A13) gene may result in neonatal intrahepatic cholestasis caused by citrin deficiency and/or adult-onset type II citrullinemia. These conditions are inherited in an autosomal recessive manner. The current case report describes a 43-year-old man who presented with sudden delirium and upper limb weakness. Upon admission, the patient was fully conscious and alert but later lost consciousness subsequent to a sudden convulsive seizure. Hyperammonemia was detected and analysis of the SLC25A13 gene identified an 851del4 mutation. Thus, the possibility of genetic disease should be considered as a potential cause of the symptoms of patients with altered states of consciousness, such as delirium and loss of consciousness, in cases where the cause of the disturbance is unknown.

Design, synthesis and selection of DNA-encoded small-molecule libraries.

Biochemical combinatorial techniques such as phage display, RNA display and oligonucleotide aptamers have proven to be reliable methods for generation of ligands to protein targets. Adapting these techniques to small synthetic molecules has been a long-sought goal. We report the synthesis and interrogation of an 800-million-member DNA-encoded library in which small molecules are covalently attached to an encoding oligonucleotide. The library was assembled by a combination of chemical and enzymatic synthesis, and interrogated by affinity selection. We describe methods for the selection and deconvolution of the chemical display library, and the discovery of inhibitors for two enzymes: Aurora A kinase and p38 MAP kinase.

[Anatomic study of supratrochlear artery and its application in nasal reconstruction].

OBJECTIVE: To study the anatomy of the cutaneous branch (CB) of supratrochlear artery and its relevance to the design of frontal flap in nasal reconstruction. METHODS: 10 fresh cadavers were dissected to study the position and course of the CB of supratrochlear artery (supraorbital rim and facial midline as landmark). The communication between the CB and supraorbital artery was also studied. 5 cases of ultra-thin frontal flaps and 11 cases of bi-flap( cutaneous flap and muscular flap) were designed on anatomic basis. The survival rate of flap, the stability and aesthetic appearance of the reconstructed nose were followed up. RESULTS: The supratrochlear artery gave off constant CB (1.18 +/- 0.36) cm from upper orbital rim and (1.35 +/- 0.34) cm from the midline of face. The CB passed in a subcutaneous plane and communicated with the bilateral muscular branch, CB of the opposite side and bilateral supraorbital artery. The supratrochlear artery only had CB with no muscular branch in 3 cases. All the flaps survived completely except one with blister on the nose tip which healed spontaneously. The postoperative aesthetic appearance was very satisfactory. CONCLUSIONS: The supratrochlear artery has constant CB. The frontal ultra-thin flap pedicled with the CB can improve the therapeutic effect of nasal reconstruction.

[Strategy study of harvesting total facial flap and donor choice for allograft transplantation in cadaver].

OBJECTIVE: To explore the operational strategy of harvesting total facial allograft by autopsy. METHODS: Twelve fresh human cadavers were dissected. They were divided into two groups randomly. The total facial-scalp flap of the group I was elevated by the bi-pedicle method, the group II was operated with single-pedicle method. Both were dissected at the deep plane of the SMAS. : the time of facial flap harvesting, length of the artery vein and nerve pedicles of the donor were measured and marked, after operation, in each group we transferred one facial allograft to another. Then the free graft of group I was poured through artery by methylthioninium chloride to study vascular territories. RESULTS: Mean harvesting time of the group I (46 +/- 11) minutes, group II (111 +/- 7) minutes, P < 0.01. Perfusion result shows that unilateral superficial temporal artery and the opposite side of the facial artery can supply blood for whole face. The pedicle was long enough for anastomosis. Post-operation appearance: the face looks like neither the donor nor the recipient primarily, It's mainly due to the characteristics of the skeleton and the soft tissues. CONCLUSIONS: The bi-pedicle method of the harvesting total facial allograft is concise, fast, safe can be widely applied in clinical.

[Research of the preservation of the composite facial allograft].

OBJECTIVE: To investigate the effective method of preserving composite facial allograft so as to attenuate ischemic injury. METHODS: The composite facial allografts were harvested from dog, perfused and preserved with 4 degrees C physiological sodium chloride and UW solution respectively. Immediately after the removal of the flap, after 12, 24, 48 h of preservation, MTT assay was used to determine the viability of several kinds of tissue, including skin, mucosa, muscle, bleed vessel, nerve and gland. The results of the two groups were compared in term of viability percentage. The pathology of several tissues were observed after 24 and 48 h of storage. RESULTS: The viability percentage of every tissue conserved in UW solution for 48 hours was more than 75%. There was significant difference between physiological sodium chloride group and UW group (P < 0.05). Some changes, including Porous arrangement of fibers in connective tissue of skin and mucosa, hyalinization of tissue around the hair follicle and edema of cell in hair follicle, enlargement of space between muscle bundles and unclearness of boundary of acinus could be seen in physiological sodium chloride group while no significant change in UW group. CONCLUSIONS: UW solution could be considered as preservation solution for composite facial allograft.

[Establishment of composite facial and scalp allograft transplantation model in canine].

OBJECTIVE: To develop an experimental model of composite facial and scalp allograft in canine in order to investigate technical and immunological aspects and functional recovery of facial muscles of this new approach to facial reconstruction. METHODS: (1) Anatomic study: Four mongrel dogs were used for anatomical dissection of the head and neck region and for harvesting flap experiment. (2) Autologous transplantation (group I): Three types composite facial and scalp autologous transplantation were performed in five mongrel dogs. Type I composite tissue flap (group I a n = 2) included bilateral external ear and orbicularis oculi muscle. Type II (group I b n = 1) included single-lateral external ear, orbicularis oculi muscle, external nose upper and lower lip. Type III (group I c n = 2) included single - lateral external ear and orbicularis oculi muscle. (3) Allograft transplantation (group II): In group II a (n = 2), two allograft transplantation were performed with type III composite facial and scalp . In group II b (n = 4), four allograft transplantation were performed with the modified type III composite facial and scalp which included single - lateral external ear, orbicularis oculi muscle and one third of inferior tarsal plate and palpebral conjunctiva. To prevent allograft rejection, Cyclosporin A (CsA) and Methylprednisolone (MP) or Prednisone (PS ) were combined used as immunosuppressive protocol . Dose of CsA was adjusted depending on its blood drug level. Electromyogram (EMG) of orbicularis oculi muscle was carried out at 4 weeks, 6 weeks, 12 weeks and 6 months postoperation. RESULTS: (1) The facial anatomic characteristic of dog is similar to that of human being, external carotid artery and external jugular vein afford good blood supply to composite facial and scalp. (2) The dogs in group I c were long-term surviving with leakage of salivary juice. (3) In group II a (n = 2), one dog presented rejection reaction at 28th day postoperation, the reversal of rejection was achieved by increasing the dose of CsA and prednisone and with topical clobetasol for 2 weeks, the dog survived indefinitely( > 309 days). In group II b (n = 4), there were three dogs survived indefinitely ( > 159 days, > 129 days, > 108 days) without complication, EMG showed the function of orbicularis oculi muscle was gradually improving. CONCLUSION: The modified type III composite facial and scalp allograft transplantation model is an ideal model for facial allograft transplantation study.