Multifunctional Biomimetic Nanocarriers for Dual-Targeted Immuno-Gene Therapy Against Hepatocellular Carcinoma.

Growing evidences have proved that tumors evade recognition and attack by the immune system through immune escape mechanisms, and PDL1/Pbrm1 genes have a strong correlation with poor response or resistance to immune checkpoint blockade (ICB) therapy. Herein, a multifunctional biomimetic nanocarrier (siRNA-CaP@PD1-NVs) is developed, which can not only enhance the cytotoxic activity of immune cells by blocking PD1/PDL1 axis, but also reduce tumor immune escape via Pbrm1/PDL1 gene silencing, leading to a significant improvement in tumor immunosuppressive microenvironment. Consequently, the nanocarrier promotes DC cell maturation, enhances the infiltration and activity of CD8+ T cells, and forms long-term immune memory, which can effectively inhibit tumor growth or even eliminate tumors, and prevent tumor recurrence and metastasis. Overall, this study presents a powerful strategy for co-delivery of siRNA drugs, immune adjuvant, and immune checkpoint inhibitors, and holds great promise for improving the effectiveness and safety of current immunotherapy regimens.

Amyloid A and lactic acid as a predictor in patients with sepsis in patients with liver cirrhosis.

BACKGROUND: Sepsis is triggered by pathogenic microorganisms, resulting in a systemic inflammatory response. Liver cirrhosis and sepsis create a vicious cycle: cirrhosis weakens immune function, raising infection risk and hindering pathogen clearance. Optimal treatment outcomes depend on understanding liver cirrhosis patients' sepsis risk factors. Thus, preventing sepsis involves addressing these risk factors. Therefore, early identification and understanding of clinical characteristics in liver cirrhosis patients with sepsis are crucial for selecting appropriate antibiotics. A case-control study using logistic regression was conducted to examine the prognostic value of amyloid A/lactate level monitoring in identifying sepsis risk factors in liver cirrhosis patients. METHODS: From March 2020 to March 2022, 136 liver cirrhosis patients treated at our hospital were divided into a sepsis group (n = 35) and a non-sepsis group (n = 101) based on sepsis complications. General clinical data were collected. Univariate analysis screened for liver cirrhosis patients' sepsis risk factors. Multivariate logistic analysis was subsequently employed to evaluate the risk factors. Sepsis patients were followed up for a month. Based on prognosis, patients were categorized into a poor prognosis group (n = 16) and a good prognosis group (n = 19). Serum amyloid A (SAA) and blood lactic acid (BLA) levels were compared between the two groups. The receiver operating characteristic (ROC) curve was used to evaluate the prognostic value of both individual and combined SAA/BLA monitoring. RESULTS: Patient data, including age, diabetes history, liver cancer, hepatic artery embolization, recent antibiotic use, invasive procedures within two weeks, APACHE II Scoring, ALB and SAA and BLA levels, were compared between the sepsis and non-sepsis groups, showing significant differences (P < 0.05). Logistic regression identified factors such as age ≥ 70, recent antibiotic use, recent invasive procedures, history of liver cancer, hepatic artery embolization history, high APACHE II scores, decreased albumin, and elevated SAA and BLA levels as independent sepsis risk factors in liver cirrhosis patients (P < 0.05). Among the 35 sepsis patients, 16 had a poor prognosis, representing an incidence rate of 45.71%. Serum SAA and BLA levels were significantly higher in the poor prognosis group than in the good prognosis group (P < 0.05). The AUC for serum SAA and BLA was 0.831 (95%CI: 0.738-0.924), 0.720 (95%CI: 0.600-0.840), and 0.909 (95%CI: 0.847-0.972), respectively. The combined diagnostic AUC was significantly higher than that of single factor predictions (P < 0.05). The predictive value ranked as follows: joint detection > SAA > BLA. CONCLUSION: In treating liver cirrhosis, prioritize patients with advanced age, a history of hepatic artery embolization, recent invasive operations, history of liver cancer, recent antibiotic exposure, high APACHE II scores and low albumin. Closely monitoring serum SAA and BLA levels in these patients can offer valuable insights for early clinical prevention and treatment.

Identification of key biomarkers of endothelial dysfunction in hypertension with carotid atherosclerosis based on WGCNA and the LASSO algorithm.

Background: Endothelial dysfunction is the early stage of carotid atherosclerosis (CAS) in patients with hypertension. It is worth identifying the potential hub genes of endothelial dysfunction to elucidate pathological mechanism in the progression of the disease. Method: We obtained gene expression profiles of GSE43292 from the Gene Expression Omnibus (GEO) database. Hub genes associated with CAS were identified through weighted gene correlation network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) regression. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore potential biological mechanisms and signaling pathways. Finally, in vitro experiments on human umbilical vein endothelial cells (HUVECs) were conducted to validate these hub genes. Results: The microarray dataset GSE43292 included 32 CAS plaques samples and corresponding macroscopically intact tissues from patients with hypertension. A total of 161 differentially expressed genes were discovered. Through WGCNA analysis, the gray60 module emerged as the most significant module associated with clinical features. The GO and KEGG enrichment analyses of genes in the gray60 module highlighted the substantial involvement of immune response-related signaling pathways. Two key hub genes (CCR1 and NCKAP1L) were pinpointed via LASSO regression. We found a significant increase in the mRNA expression level of the hub genes in oxidized low density lipoprotein (ox-LDL) treated HUVECs. Conclusions: Our study indicated that the hub genes related to immune responses are involved in the development of CAS. Two hub genes (CCR1 and NCKAP1L) of endothelial dysfunction were identified. These genes may provide a valuable therapeutic target of CAS in patients with hypertension.

Heterozygous Variants in KCNJ10 Cause Paroxysmal Kinesigenic Dyskinesia Via Haploinsufficiency.

OBJECTIVE: Most paroxysmal kinesigenic dyskinesia (PKD) cases are hereditary, yet approximately 60% of patients remain genetically undiagnosed. We undertook the present study to uncover the genetic basis for undiagnosed PKD patients. METHODS: Whole-exome sequencing was performed for 106 PRRT2-negative PKD probands. The functional impact of the genetic variants was investigated in HEK293T cells and Drosophila. RESULTS: Heterozygous variants in KCNJ10 were identified in 11 individuals from 8 unrelated families, which accounted for 7.5% (8/106) of the PRRT2-negative probands. Both co-segregation of the identified variants and the significantly higher frequency of rare KCNJ10 variants in PKD cases supported impacts from the detected KCNJ10 heterozygous variants on PKD pathogenesis. Moreover, a KCNJ10 mutation-carrying father from a typical EAST/SeSAME family was identified as a PKD patient. All patients manifested dystonia attacks triggered by sudden movement with a short episodic duration. Patch-clamp recordings in HEK293T cells revealed apparent reductions in K+ currents of the patient-derived variants, indicating a loss-of-function. In Drosophila, milder hyperexcitability phenotypes were observed in heterozygous Irk2 knock-in flies compared to homozygotes, supporting haploinsufficiency as the mechanism for the detected heterozygous variants. Electrophysiological recordings showed that excitatory neurons in Irk2 haploinsufficiency flies exhibited increased excitability, and glia-specific complementation with human Kir4.1 rescued the Irk2 mutant phenotypes. INTERPRETATION: Our study established haploinsufficiency resulting from heterozygous variants in KCNJ10 can be understood as a previously unrecognized genetic cause for PKD and provided evidence of glial involvement in the pathophysiology of PKD. ANN NEUROL 2024.

Oxidative Difunctionalization of N-Aryl Bicyclobutyl Amides with Aldehydes: Divergent Synthesis of Acylated and Alkylated 3-Spirocyclobutyl Oxindoles.

An efficient and operationally simple oxidative radical difunctionalization of N-aryl bicyclobutyl (BCB) amides with aldehydes is described. It was found that acylated 3-spirocyclobutyl oxindoles were generated from the coupling of BCB-amides and aromatic aldehydes, while reactions gave exclusively decarbonylative alkylarylation products using alkyl aldehydes as radical precursors.

Targeting the transmembrane cytokine co-receptor neuropilin-1 in distal tubules improves renal injury and fibrosis.

Neuropilin-1 (NRP1), a co-receptor for various cytokines, including TGF-ß, has been identified as a potential therapeutic target for fibrosis. However, its role and mechanism in renal fibrosis remains elusive. Here, we show that NRP1 is upregulated in distal tubular (DT) cells of patients with transplant renal insufficiency and mice with renal ischemia-reperfusion (I-R) injury. Knockout of Nrp1 reduces multiple endpoints of renal injury and fibrosis. We find that Nrp1 facilitates the binding of TNF-α to its receptor in DT cells after renal injury. This signaling results in a downregulation of lysine crotonylation of the metabolic enzyme Cox4i1, decreases cellular energetics and exacerbation of renal injury. Furthermore, by single-cell RNA-sequencing we find that Nrp1-positive DT cells secrete collagen and communicate with myofibroblasts, exacerbating acute kidney injury (AKI)-induced renal fibrosis by activating Smad3. Dual genetic deletion of Nrp1 and Tgfbr1 in DT cells better improves renal injury and fibrosis than either single knockout. Together, these results reveal that targeting of NRP1 represents a promising strategy for the treatment of AKI and subsequent chronic kidney disease.

Systemic inflammation in midlife is associated with late-life functional limitations.

Systemic inflammation generally coexists with functional limitations that seriously affect quality of life. This study aimed to investigate the association between systemic inflammation in midlife and the risk of functional limitations in late-life. A total of 10,044 participants with an average age of 53.9 ± 5.7 years at baseline were included in a cohort study. At the last follow-up, the prevalence of impaired activities of daily living (ADLs), instrumental activities of daily living (IADLs), and lower extremity function (LEF) was 14.7%, 21.6%, and 50.3%, respectively. The values of four inflammatory biomarkers were used to calculate the inflammation composite score. Compared with the participants in the lowest quartile of the inflammation composite score (Q1), those in the highest quartile (Q4) exhibited an odds ratio (OR) of 1.589 and a 95% confidence interval (CI) of 1.335-1.892 for impaired ADLs, an OR of 1.426 and a 95% CI of 1.228-1.657 for impaired IADLs, and an OR of 1.728 and a 95% CI of 1.526-1.957 for impaired LEF. The association between systemic inflammation and functional limitations was partly mediated by cardiac and brain function. The present study provides evidence that systemic inflammation in midlife is associated with a higher risk of late-life functional limitations. Protecting vital organ functions in midlife may have a positive impact on reducing the risk of future functional limitations.Trial registration: www.clinicaltrials.gov ; Unique identifier: NCT00005131.

Unleashing the Power of Evolution in Xylanase Engineering: Investigating the Role of Distal Mutation Regulation.

The drive to enhance enzyme performance in industrial applications frequently clashes with the practical limitations of exhaustive experimental screening, underscoring the urgency for more refined and strategic methodologies in enzyme engineering. In this study, xylanase Xyl-1 was used as the model, coupling evolutionary insights with energy functions to obtain theoretical potential mutants, which were subsequently validated experimentally. We observed that mutations in the nonloop region primarily aimed at enhancing stability and also encountered selective pressure for activity. Notably, mutations in this region simultaneously boosted the Xyl-1 stability and activity, achieving a 65% success rate. Using a greedy strategy, mutant M4 was developed, achieving a 12 °C higher melting temperature and doubled activity. By integration of spectroscopy, crystallography, and quantum mechanics/molecular mechanics molecular dynamics, the mechanism behind the enhanced thermal stability of M4 was elucidated. It was determined that the activity differences between M4 and the wild type were primarily driven by dynamic factors influenced by distal mutations. In conclusion, the study emphasizes the pivotal role of evolution-based approaches in augmenting the stability and activity of the enzymes. It sheds light on the unique adaptive mechanisms employed by various structural regions of proteins and expands our understanding of the intricate relationship between distant mutations and enzyme dynamics.

A Gaze into the Eyebrow Standards of Asian Versus Caucasian Women.

BACKGROUND: Eyebrow position affects perceived facial expression and youthfulness, and its modification is a key component of facial rejuvenation. OBJECTIVE: This investigation aimed to assess the preferred vertical eyebrow position, apex location, and eyebrow shape in Caucasian and Asian individuals and to analyze gaze patterns during aesthetic judgment using eye-tracking technology. MATERIALS AND METHODS: The study included 76 Asian and Caucasian volunteers with no medical background. Eye movements were captured with a Tobii Pro Nano eye-tracker. Participants viewed AI-generated images of Caucasian and Asian females with varied eyebrow positions (ratios 1:1.3 to 1:2.5), shapes (angles 8° to 20°), and apex positions. Aesthetic preferences were rated on a 5-point Likert scale. Eye-tracking metrics and aesthetic ratings were statistically analyzed using ANOVA and bivariate correlations. RESULTS: Both genders across ethnicities preferred a moderate eyebrow position ratio of 1:1.6. For eyebrow shapes, a 12° angle received the highest ratings, while extremes were less favored, indicating a preference for moderately curved eyebrows. The most appealing apex position was above the lateral canthus for Asians, and halfway between the lateral limbus and lateral canthus for Caucasians. Eye-tracking revealed longer fixations on unattractive features, suggesting more complex cognitive processing, while attractive features were processed more efficiently. CONCLUSION: The study revealed that aesthetic preferences for eyebrow features are influenced by both ethnic background and gender, with a general preference toward moderately curved eyebrows and subtle variations in preferred positions. These findings suggest a need for culturally sensitive approaches in facial aesthetic procedures and highlight the potential of eye-tracking technology to enhance surgical planning. Surgeons are advised to adopt a conservative, patient-centered approach when modifying eyebrow features, considering individual and cultural aesthetics to maximize patient satisfaction. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Eye-Tracking Insights into the Perception of Buttocks.

BACKGROUND: Aesthetic enhancements to the buttock region have grown in demand due to media influence and evolving beauty standards. Using eye-tracking technology, we sought to uncover subconscious visual preferences regarding the buttock aesthetic. The objective of this investigation was to assess visual gaze patterns in assessing female buttocks among Caucasian and Asians through eye-tracking technology. MATERIALS AND METHODS: 67 participants viewed photographs of buttocks from various angles, and eye movements were analyzed using the Tobii Pro Nano eye-tracker. RESULTS: Males fixated on the intergluteal cleft for 0.96 ± 1.1 s and the thigh gap for 0.07 ± 0.2 s; while, females fixated for 0.81 ± 0.9 s and 0.06 ± 0.2 s on the same regions, respectively. Significant gender differences were observed in the intergluteal cleft (p = 0.002) and upper lateral buttock (p < 0.001). CONCLUSION: This study offers new insights into the observation of buttocks. The consistent attention toward the intergluteal cleft across demographics could be of potential significance in the aesthetic perception of buttocks. However, diverse gaze patterns also underscore the multifaceted nature of human attraction. These findings hold implications for plastic surgery, aesthetic medicine, and the sociocultural understanding of beauty. A deeper dive into aesthetic preferences is pivotal for a holistic understanding of human perceptions of attractive buttocks. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to Table of Contents or the online instructions to Authors www.springer.com/00266 .

NADPHnet: a novel strategy to predict compounds for regulation of NADPH metabolism via network-based methods.

Identification of compounds to modulate NADPH metabolism is crucial for understanding complex diseases and developing effective therapies. However, the complex nature of NADPH metabolism poses challenges in achieving this goal. In this study, we proposed a novel strategy named NADPHnet to predict key proteins and drug-target interactions related to NADPH metabolism via network-based methods. Different from traditional approaches only focusing on one single protein, NADPHnet could screen compounds to modulate NADPH metabolism from a comprehensive view. Specifically, NADPHnet identified key proteins involved in regulation of NADPH metabolism using network-based methods, and characterized the impact of natural products on NADPH metabolism using a combined score, NADPH-Score. NADPHnet demonstrated a broader applicability domain and improved accuracy in the external validation set. This approach was further employed along with molecular docking to identify 27 compounds from a natural product library, 6 of which exhibited concentration-dependent changes of cellular NADPH level within 100 µM, with Oxyberberine showing promising effects even at 10 µM. Mechanistic and pathological analyses of Oxyberberine suggest potential novel mechanisms to affect diabetes and cancer. Overall, NADPHnet offers a promising method for prediction of NADPH metabolism modulation and advances drug discovery for complex diseases.

The effect of functional electrical stimulation of the legs on cardiopulmonary function and quality of life in patients with chronic heart failure: A systematic review and meta-analysis.

Introduction: Functional electrical stimulation is important for the rehabilitation of patients with chronic heart failure. This meta-analysis of randomized controlled trials compared the efficacy of functional electrical stimulation versus conventional exercise training or placebo in patients with chronic heart failure. Methods: Studies were searched through PubMed, Embase, and the Cochrane Library databases up to 1 November 2023. The outcomes were cardiopulmonary function index (6-minute walking distance), peak oxygen consumption, and Minnesota Heart Failure Life Questionnaire quality of life scores. A subgroup analysis was conducted according to the ejection fraction. The 95% confidence interval and mean difference represented the outcome of the effect size. Results: Seventeen studies involving 732 participants were included. Compared with the control, functional electrical stimulation significantly improved peak oxygen consumption (MD = 2.84 ml/kg/min, 95% Cl: 1.99-3.68 ml/kg/min), increased 6-minute walking distance (MD = 49.52 m, 95% Cl: 22.61-76.43 m), and improved the life quality scores (MD = -12.86, 95% Cl: -17.48 to -7.88). Compared with functional electrical stimulation, exercise training also improved peak oxygen consumption (MD = -0.94 ml/kg/min-1, 95% Cl: -1.36 to -0.52 ml/kg/min), and the quality of life (QoL, MD = 0.66, 95% Cl: 0.34-0.98, p < 0.05, I 2 = 38%), but the result of 6-minute walking distance (MD = -6.97 m, 95% Cl: -18.32 to -4.38 m) did not show a difference. Further subgroup analysis showed that outcomes including the above, significantly improved under the functional electrical stimulationfor both HF patients with reduced ejection fraction and HF patients with preserved ejection fraction patients, but difference is insignificant of the results between groups of aerobic exercise and functional electrical stimulationacted on patients with HF patients with reduced ejection fraction. Conclusions: Our study demonstrates that compared with placebo, functional electrical stimulation benefits the patients with chronic heart failure on cardiopulmonary function and quality of life. Furthermore, HF patients with reduced ejection fraction patients benefit more from functional electrical stimulation than HF patients with reduced ejection fraction patients. Therefore, functional electrical stimulation is a promising complementary therapy for patients with chronic heart failure.

In-situ forming carboxymethyl chitosan hydrogel containing Paeonia suffruticosa Andr. leaf extract for mixed infectious vaginitis treatment by reshaping the micro-biota.

Mixed infectious vaginitis poses a serious threat to female reproductive health due to complex pathogenic factors, a long course and easy recurrence. Currently, antibiotic-based treatment methods are facing a crisis of drug resistance and secondary dysbiosis. Exploring effective drugs for the treatment of mixed vaginitis from Paeonia suffruticosa Andr., a natural traditional Chinese medicine with a long history of medicinal use, is a feasible treatment strategy. P. suffruticosa Andr. leaf extract (PLE) has significant anti-bacterial effects due to its rich content of polyphenols and flavonoids. The polyphenols in peony leaves have the potential to make carboxymethyl chitosan form in situ gel. In the current study, PLE and carboxymethyl chitosan were combined to develop another type of natural anti-bacterial anti-oxidant hydrogel for the treatment of mixed infectious vaginitis. Through a series of characterisations, CP had a three-dimensional network porous structure with good mechanical properties, high water absorption, long retention and a slow-release drug effect. The mixed infectious vaginitis mouse model induced by a mixture of pathogenic bacteria was used to investigate the therapeutic effects of CP in vivo. The appearance of the vagina, H&E colouring of the tissue and inflammatory factors (TNF-α, IL-6) confirm the good anti-vaginal effect of CP. Therefore, CP was expected to become an ideal effective strategy to improve mixed infection vaginitis due to its excellent hydrogel performance and remarkable ability to regulate flora.

CUX1 attenuates the apoptosis of renal tubular epithelial cells induced by contrast media through activating the PI3K/AKT signaling pathway.

OBJECTIVE: Contrast media (CM) is a commonly applied drug in medical examination and surgery. However, contrast-induced acute kidney injury (CIAKI) poses a severe threat to human life and health. Notably, the CUT-like homeobox 1 (CUX1) gene shows protective effects in a variety of cells. Therefore, the objective of this study was to provide a new target for the treatment of CIAKI through exploring the role and possible molecular mechanism of CUX1 in CIAKI. METHOD: Blood samples were collected from 20 patients with CIAKI and healthy volunteers. Human kidney 2 (HK-2) cells were incubated with 200 mg/mL iohexol for 6 h to establish a contrast-induced injury model of HK-2 cells. Subsequently, qRT-PCR was used to detect the relative mRNA expression of CUX1; CCK-8 and flow cytometry to assess the proliferation and apoptosis of HK-2 cells; the levels of IL(interleukin)-1ß, tumor necrosis factor alpha (TNF-α) and malondialdehyde (MDA) in cells and lactate dehydrogenase (LDH) activity in cell culture supernatant were detect; and western blot to observe the expression levels of CUX1 and the PI3K/AKT signaling pathway related proteins [phosphorylated phosphoinositide 3-kinase (p-PI3K), PI3K, phosphorylated Akt (p-AKT), AKT]. RESULTS: CUX1 expression was significantly downregulated in blood samples of patients with CIAKI and contrast-induced HK-2 cells. Contrast media (CM; iohexol) treatment significantly reduced the proliferation of HK-2 cells, promoted apoptosis, stimulated inflammation and oxidative stress that caused cell damage. CUX1 overexpression alleviated cell damage by significantly improving the proliferation level of HK-2 cells induced by CM, inhibiting cell apoptosis, and reducing the level of LDH in culture supernatant and the expression of IL-1ß, TNF-α and MDA in cells. CM treatment significantly inhibited the activity of PI3K/AKT signaling pathway activity. Nevertheless, up-regulating CUX1 could activate the PI3K/AKT signaling pathway activity in HK-2 cells induced by CM. CONCLUSION: CUX1 promotes cell proliferation, inhibits apoptosis, and reduces inflammation and oxidative stress in CM-induced HK-2 cells to alleviate CM-induced damage. The mechanism of CUX1 may be correlated with activation of the PI3K/AKT signaling pathway.

Precisely Regulating Intermolecular Interactions and Molecular Packing of Nonfused-Ring Electron Acceptors via Halogen Transposition for High-Performance Organic Solar Cells.

The structure of molecular aggregates is crucial for charge transport and photovoltaic performance in organic solar cells (OSCs). Herein, the intermolecular interactions and aggregated structures of nonfused-ring electron acceptors (NFREAs) are precisely regulated through a halogen transposition strategy, resulting in a noteworthy transformation from a 2D-layered structure to a 3D-interconnected packing network. Based on the 3D electron transport pathway, the binary and ternary devices deliver outstanding power conversion efficiencies (PCEs) of 17.46 % and 18.24 %, respectively, marking the highest value for NFREA-based OSCs.

Investigating Facial Muscle Physiology Following Soft Tissue Filler Injections-A Surface-derived Electromyographic and Skin Vector Displacement Analytic Study.

The use of hyaluronic acid-based soft tissue fillers has often been reported to modulate the muscle, that is, to cause myomodulation. To our knowledge, there has been so far no scientific study investigating the potential of hyaluronic acid-based soft tissue fillers to modulate or actually alter the function of facial muscles. To further assess this three-dimensional (3D) surface imaging and electromyography (EMG)-based prospective study investigated the changes of facial muscle contraction after injection of strategically placed hyaluronic acid-based soft tissue fillers to assess the actual validity of the term myomodulation. A total of 13 subjects with a mean age of 37.8 years (12 females, 1 male) were injected according to a predefined injection protocol. Surface EMG and 3D surface imaging were performed prior to the injection and 5 days after the injection. The results showed no significant change in the strength of the muscles (measured in µV) after injection of hyaluronic acid-based soft tissue fillers. However, horizontal and vertical skin displacement upon contraction of the zygomaticus major muscle changed significantly between baseline and follow-up, with a mean horizontal skin displacement increase from 3.2 to 4.1 mm. Upon contraction of the depressor anguli oris muscle, the horizontal skin displacement did not change significantly (2.15 vs. 2.05 mm), while vertical skin displacement increased significantly from 2.9 to 4.3 mm. The modification of the surrounding tissue caused an alteration of the vectorial skin displacement upon contraction of the muscle. A potential explanation could be the increased distance between the origin and insertion of the muscle due to the material deposition in the proximity of the relevant facial muscles, leading to a change of contraction vector.

Associations between modifiable risk factors and frailty progression among individuals with pre-frailty.

BACKGROUND: In the context of the present global aging phenomenon, the senior population and pace of aging in China have emerged as prominent issues on the worldwide stage. Frailty, a complicated condition that is closely linked to the clinical syndrome of advancing age, poses a considerable health risk to older individuals. Frailty status was assessed by the frailty index (FI) ranging from 0 to 1, pre-frailty was defined as >0.10 to <0.25, and frailty was defined as ≥0.25. To look at the connection between modifiable risk factors and frailty progression among individuals in the pre-frailty population. METHODS: Using pre-frailty patients as characterized by the 32-frailty index, the study focused on middle-aged and elderly persons from China and ultimately recruited 5,411 participants for analysis. The relationship between modifiable factors and changes in pre-frailty status throughout follow-up was investigated. Modifiable factors were body mass index (BMI), abdominal obesity, smoking status, alcohol use, and sleep status. We employed logistic regression to examine the relationships between modifiable risk factors and changes in pre-frailty status, as well as the associations between modifiable factors scores and the corresponding pre-frailty progression. Additionally, we generated the modifiable factors scores and examined how these related to modifications in the pre-frailty stage. RESULTS: In this study, after a mean follow-up of 6 years, (OR = 0.59, 95%CI: 0.48-0.71) for BMI ≥ 25 kg/m2 and (OR = 0.74, 95%CI: 0.63-0.89) for concomitant abdominal obesity were significantly associated with lower reversal to a healthy state; (OR = 1.24, 95%CI:1.07-1.44) and (OR = 1.25, 95%CI: 1.10-1.42) for the group that negatively progressed further to frailty were significantly associated with increased frailty progression profile. Subsequently, investigation of modifiable factor scores and changes of pre-frailty status found that as scores increased further, frailty developed (OR = 1.12, 95%CI:1.05-1.18), with scores of 3 and 4 of (OR = 1.38, 95%CI: 1.08-1.77) and (OR = 1.52, 95%CI:1.09-2.14). Finally, we also performed a series of stratified analyses and found that rural unmarried men aged 45 to 60 years with less than a high school degree were more likely to develop a frailty state once they developed abdominal obesity. CONCLUSION: In pre-frailty individuals, maintaining more favorable controllable variables considerably enhances the chance of return to normal and, conversely, increase the risk of progressing to the frailty.

Furin knockdown inhibited EndMT and abnormal proliferation and migration of endothelial cells.

BACKGROUND: In the pathogenesis of atherosclerotic cardiovascular disorders, vascular endothelium is crucial. A critical step in the development of atherosclerosis is endothelial dysfunction. Furin may play a factor in vascular remodeling, inflammatory cell infiltration, regulation of plaque stability, and atherosclerosis by affecting the adhesion and migration of endothelial cells. It is yet unknown, though, how furin contributes to endothelial dysfunction. METHODS: We stimulated endothelial cells with oxidized modified lipoprotein (ox-LDL). Endothelial-to-mesenchymal transition (EndMT) was found using immunofluorescence (IF) and western blot (WB). Furin expression level and Hippo/YAP signal activation were found using reverse transcription-quantitative PCR (RT-qPCR) and WB, respectively. To achieve the goal of furin knockdown, we transfected siRNA using the RNA transmate reagent. Following furin knockdown, cell proliferation, and migration were assessed by the CCK-8, scratch assay, and transwell gold assay, respectively. WB and IF both picked up on EndMT. WB and RT-qPCR, respectively, were used to find furin's expression level. We chose the important micrornas that can regulate furin and we then confirmed them using RT-qPCR. RESULTS: EndMT was created by ox-LDL, evidenced by the up-regulation of mesenchymal cell markers and the down-regulation of endothelial cell markers. Furin expression levels in both protein and mRNA were increased, and the Hippo/YAP signaling pathway was turned on. Furin knockdown dramatically reduced the aberrant migration and proliferation of endothelial cells by ox-LDL stimulation. Furin knockdown can also suppress ox-LDL-induced EndMT, up-regulate indicators of endothelial cells, and down-regulate markers of mesenchymal cells. After ox-LDL stimulation and siRNA transfection, furin's expression level was up-regulated and down-regulated. CONCLUSION: Our study demonstrated that furin knockdown could affect ox-LDL-induced abnormal endothelial cell proliferation, migration, and EndMT. This implies that furin plays an important role in endothelial dysfunction.