Exploring the role of anticipatory postural adjustment duration within APA2 subphase as a potential mediator between clinical disease severity and fall risk in Parkinson's disease.

Introduction: People with Parkinson's Disease (PD) often show reduced anticipatory postural adjustments (APAs) before voluntary steps, impacting their stability. The specific subphase within the APA stage contributing significantly to fall risk remains unclear. Methods: We analyzed center of pressure (CoP) trajectory parameters, including duration, length, and velocity, throughout gait initiation. This examination encompassed both the postural phase, referred to as anticipatory postural adjustment (APA) (APA1, APA2a, APA2b), and the subsequent locomotor phases (LOC). Participants were instructed to initiate a step and then stop (initiating a single step). Furthermore, we conducted assessments of clinical disease severity using the Unified Parkinson's Disease Rating Scale (UPDRS) and evaluated fall risk using Tinetti gait and balance scores during off-medication periods. Results: Freezing of gait (FOG) was observed in 18 out of 110 participants during the measurement of CoP trajectories. The Ramer-Douglas-Peucker algorithm successfully identified CoP displacement trajectories in 105 participants (95.5%), while the remaining 5 cases could not be identified due to FOG. Tinetti balance and gait score showed significant associations with levodopa equivalent daily dose, UPDRS total score, disease duration, duration (s) in APA2a (s) and LOC (s), length in APA1 (cm) and APA2b (cm), mediolateral velocity in APA1 (X) (cm/s), APA2a (X) (cm/s), APA2b (X) (cm/s) and LOC (X) (cm/s), and anterior-posterior velocity in APA2a (Z) (cm/s) and APA2b (Z) (cm/s). Multiple linear regression revealed that only duration (s) in APA2a and UPDRS total score was independently associated with Tinetti gait and balance score. Further mediation analysis showed that the duration (s) in APA2a served as a mediator between UPDRS total score and Tinetti balance and gait score (Sobel test, p = 0.047). Conclusion: APA2 subphase duration mediates the link between disease severity and fall risk in PD, suggesting that longer APA2a duration may indicate reduced control during gait initiation, thereby increasing fall risk.

Cellular and molecular mechanisms of the blood-brain barrier dysfunction in neurodegenerative diseases.

BACKGROUND: Maintaining the structural and functional integrity of the blood-brain barrier (BBB) is vital for neuronal equilibrium and optimal brain function. Disruptions to BBB performance are implicated in the pathology of neurodegenerative diseases. MAIN BODY: Early indicators of multiple neurodegenerative disorders in humans and animal models include impaired BBB stability, regional cerebral blood flow shortfalls, and vascular inflammation associated with BBB dysfunction. Understanding the cellular and molecular mechanisms of BBB dysfunction in brain disorders is crucial for elucidating the sustenance of neural computations under pathological conditions and for developing treatments for these diseases. This paper initially explores the cellular and molecular definition of the BBB, along with the signaling pathways regulating BBB stability, cerebral blood flow, and vascular inflammation. Subsequently, we review current insights into BBB dynamics in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The paper concludes by proposing a unified mechanism whereby BBB dysfunction contributes to neurodegenerative disorders, highlights potential BBB-focused therapeutic strategies and targets, and outlines lessons learned and future research directions. CONCLUSIONS: BBB breakdown significantly impacts the development and progression of neurodegenerative diseases, and unraveling the cellular and molecular mechanisms underlying BBB dysfunction is vital to elucidate how neural computations are sustained under pathological conditions and to devise therapeutic approaches.

Enhancing the Thermal Stability and Enzyme Activity of Ketopantoate Hydroxymethyltransferase through Interface Modification Engineering.

Ketopantoate hydroxymethyltransferase (KPHMT) plays a pivotal role in d-pantothenic acid biosynthesis. Most KPHMTs are homodecamers with low thermal stability, posing challenges for protein engineering and limiting output enhancement. Previously, a high-enzyme activity KPHMT mutant (K25A/E189S) from Corynebacterium glutamicum was screened as mother strain (M0). Building upon this strain, our study focused on interface engineering modifications, employing a multifaceted approach including integrating folding-free energy calculation, B-factor analysis, and conserved site analysis. Preliminary screening led to the selection of five mutants in the interface─E106S, E98T, E98N, S247I, and S247D─showing improved thermal stability, culminating in the double-site mutant M8 (M0-E98N/S247D). M8 exhibited a T1/2 value of 288.79 min at 50 °C, showing a 3.29-fold increase compared to M0. Meanwhile, the Tm value of M8 was elevated from 53.2 to 59.6 °C. Investigations of structural and molecular dynamics simulations revealed alterations in surface electrostatic charge distribution and the formation of increased hydrogen bonds between subunits, contributing to enhanced thermal stability. This investigation corroborates the efficacy of interface engineering modifications in bolstering KPHMT stability while showing its potential for positively impacting industrial d-pantothenic acid synthesis.

Drug Repositioning of Inflammatory Bowel Disease Based on Co-Target Gene Expression Signature of Glucocorticoid Receptor and TET2.

The glucocorticoid receptor (GR) and ten-eleven translocation 2 (TET2), respectively, play a crucial role in regulating immunity and inflammation, and GR interacts with TET2. However, their synergetic roles in inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), remain unclear. This study aimed to investigate the co-target gene signatures of GR and TET2 in IBD and provide potential therapeutic interventions for IBD. By integrating public data, we identified 179 GR- and TET2-targeted differentially expressed genes (DEGs) in CD and 401 in UC. These genes were found to be closely associated with immunometabolism, inflammatory responses, and cell stress pathways. In vitro inflammatory cellular models were constructed using LPS-treated HT29 and HCT116 cells, respectively. Drug repositioning based on the co-target gene signatures of GR and TET2 derived from transcriptomic data of UC, CD, and the in vitro model was performed using the Connectivity Map (CMap). BMS-536924 emerged as a top therapeutic candidate, and its validation experiment within the in vitro inflammatory model confirmed its efficacy in mitigating the LPS-induced inflammatory response. This study sheds light on the pathogenesis of IBD from a new perspective and may accelerate the development of novel therapeutic agents for inflammatory diseases including IBD.

Compliant gait control method based on CVSLIP-FF model for biped robot walking over uneven terrain.

Bipedal walking over uneven terrain remains a challenging task due to the environmental complexity and unavoidable landing impact. To realize the stable and robust walking of biped robots, this paper proposes a compliant gait control method, which focuses on walking compliance and conducts research on two levels. In the gait generation level, a Continuous-Variable Spring-Loaded Inverted Pendulum with Finite-sized Foot (CVSLIP-FF) model is provided with the consideration of the ankle joint and compliant spring-loaded leg. Then, a CVSLIP-FF based gait generation pattern with relevant walking strategies is provided to enhance the mobility of biped robots. In the joint control level, an ankle joint admittance control strategy is applied to achieve compliant robot-environment interaction. Experimental results indicate that compared with the traditional SLIP model, the proposed method performs better adaptability to uneven terrain with a 217.77% improvement, and enables biped robots to cope with slight unknown disturbance.

Prognostic value of proliferation markers Ki-67 and PCNA in esophageal squamous cell carcinoma.

BACKGROUND: Ki-67 and proliferating cell nuclear antigen (PCNA) are markers of proliferation used to assess the growth fraction of the cell population. The present study aimed to explore the prognostic value of these proliferative markers in patients with resected esophageal squamous cell cancer (ESCC) in a large cohort. METHODS: A total of 807 patients with ESCC who underwent radical resection were retrospectively reviewed. Ki-67 and PCNA index were examined as the percentage of positively nuclear-stained cells among total number of cancer cells in three high-power fields by a pathologist who was blinded to the patients' history and outcome. Overall survival (OS) and disease-free survival (DFS) were estimated. The Cox regression model was used to evaluate the independent factor. RESULTS: The cut-off value as 60 and 80% for Ki-67 and PCNA were verified, respectively. Higher Ki-67 expression was associated with low differentiation and more lymph node metastasis. Higher PCNA expression was associated with elevated T stage. However, either expression of Ki-67 or PCNA was not correlated with OS and DFS. While in combination of Ki-67 and PCNA analysis, higher expression of these two proliferative markers predicted worse prognosis (median OS, 47 months versus 54 months, P = 0.04). Whatever the combined proliferative marker, differentiation, lymph node metastasis stage and vascular invasion act as factors in univariate survival analysis, but combined Ki-67 and PCNA is not an independent prognostic variable in multivariate analysis (P = 0.10). CONCLUSION: Our results suggest that proliferative markers of Ki-67 and PCNA may correlate with tumor stage but cannot act as independent predictor of prognosis in ESCC patients.

Clinical Features and Expression Patterns for Burn Patients Developed Marjolin Ulcer.

Marjolin's ulcer is a type of skin cancer that generated from chronic nonhealing trauma. For years, its pathogenesis mechanisms remain unclear. Regarding this situation, the authors retrospectively analyze the patients admitted to their department from 2005 to 2019 to present several representative cases and examine the expression patterns of survivin and its role in this process. Among these patients, the latent period ranges from 2 to 25 years, with 8.43 years in average. There is no notable relationship between the latent period and age (P = .643 > .05). Therefore, Marjolijn's ulcer arises from extremities and joints more often compared with other parts (P < .05). The expression ratio of survivin in Marjolin's ulcer is significantly higher than that in skin ulcer (P < 0.05). And the expression ratio of survivin in patients diagnosed with Marjolin's ulcer is also correlated with lymphatic metastasis (P < .05). Frequent follow-ups and prompt diagnosis and management are necessary as the prognosis is poor for patients with metastasis. Survivin may be a potential target for future development of target therapy in order to maximize the efficacy and improve the quality of life for patients suffering from Marjolin's ulcer.

[Effect of vacuum sealing drainage on expressions of transforming growth factor ß 1 and its receptor in diabetic foot wound].

Objective: To investigate the changes of transforming growth factor ß 1 (TGF- ß 1) and type Ⅱ of TGF-ß-receptor (TßRⅡ) expressions in wound tissue after the treatment of diabetic foot with vaccum sealing drainage (VSD), and to analyze the mechanism of accelerating wound healing. Methods: Between May 2012 and May 2016, 80 patients with diabetic foot were randomly divided into 2 groups, 40 cases in each group. After the same basic treatment, the wounds of VSD group and control group were treated with VSD and external dressing, respectively. There was no significant difference in gender, age, disease duration, body mass, foot ulcer area, and Wagner grade between 2 groups ( P>0.05). The time of foundation preparation and hospitalization stay of 2 groups were recorded. The wound tissue was collected before treatment and at 7 days after treatment, and the positive indexes of TGF-ß 1 and TßRⅡexpressions were measured by immunohistochemical staining. Results: Before skin grafting, the patients in VSD group were treated with VSD for 1 to 3 times (mean, 2 times), and the patients in control group were treated with dressing change for 1 to 6 times (mean, 4 times). The time of foundation preparation and hospitalization stay in VSD group were significantly shorter than those in control group ( t=-13.546, P=0.036; t=-12.831, P=0.041). The skin grafts of both groups survived smoothly and the wound healed well. Before treatment, immunohistochemical staining results showed that the positive indexes of TGF-ß 1 and TßRⅡ expressions in VSD group were 5.3±2.4 and 14.0±2.6, while those in control group were 4.4±2.3 and 14.7±3.1, respectively. There was no significant difference between 2 groups ( t=1.137, P=0.263; t=1.231, P=0.409). At 7 days after treatment, the positive indexes of TGF-ß 1 and TßRⅡ expressions in VSD group were 34.3±2.9 and 41.7±3.7, respectively, and those in control group were 5.8±2.0 and 18.1±2.5. There were significant differences between 2 groups ( t=-35.615, P=0.003; t=23.725, P=0.002). Conclusion: VSD can increase the expressions of TGF-ß 1 and TßRⅡ in diabetic ulcer tissue, promote granulation tissue growth, and accelerate wound healing.

Survivin as a novel target protein for reducing the proliferation of cancer cells.

Survivin, also known as baculoviral inhibitor of apoptosis repeat-containing 5, is a novel member of the inhibitor of apoptosis protein family. Survivin is highly expressed in tumors and embryonic tissues and is associated with tumor cell differentiation, proliferation, invasion and metastasis; however, survivin is expressed at low levels in normal terminally differentiated adult tissues. Meanwhile, the expression level of survivin is also a negative prognostic factor for patients with cancer. These unique characteristics of survivin make it an exciting potential therapeutic target for cancer treatment. This review will discuss the biological characteristics of survivin and its potential use as a treatment target to reduce cancer cell proliferation.

A Case Report of a Complete Penile and Scrotum Skin Degloving Injury.

Male genital injuries are rare and only few of them are total penoscrotal degloving injuries. Though this kind of injury is not life-threatening, it could be psychologically devastating to patients if not treated appropriately. This report presents a case of total male genitalia degloving injury treated by sliding flap and skin graft, assisted by Vacuum Sealing Drainage. Via this therapeutic approach, the injured area was completely healed. Three months after surgery, there were still no scars that affected normal function of male genitalia.This approach, which has never been reported before, yields a satisfactory result for both aesthetic appearance and sexual functions.

CD147 overexpression may serve as a promising diagnostic and prognostic marker for gastric cancer: evidence from original research and literature.

Gastric cancer (GC) is one of the most common malignancies worldwide. The expression of CD147 protein is associated with GC. However, the clinical role of CD147 in GC has not been investigated extensively. Hence, we focused on studying the association between the expression of CD147 and clinicopathological features of GC patients in this study. Firstly, sixteen publications (1752 cases and 391 controls) and one from our own original research (143 cases) were included in the meta-analysis to obtain a more precise estimation of the diagnostic value of CD147. The results showed that expression rate of CD147 in the GC group is higher than that in control group. Moreover, gender, TNM stage, lymph node metastasis, and depth of invasion are all associated with CD147. Further, sections of gastric tissue from 143 cases underwent immunohistochemical staining for evaluation of CD147 protein expression. Our retrospective analysis demonstrated CD147 protein expression was significantly associated with clinical N stage, and tumor stage. Meanwhile, it can also serve as an independent prognosis biomarker. In conclusion, our results support the role of CD147 as a good indicator of diagnosis and prognosis.

Identification of the PAG1 gene as a novel target of inherent radioresistance in human laryngeal carcinoma cells.

Laryngeal carcinoma, as a malignant tumor that occurs in the head and neck region, is widely treated by radiation, but in some cases, the cancer is radioresistant to the radiotherapy. The reason for the radioresistant response needs to be clinically understood. We designed our present study to identify the molecules that may be involved in this radioresistant response. In this study, we initially established the inherent radioresistant (Hep-2max) and radiosensitive (Hep-2min) cell lines from the parental laryngeal cancer cell line Hep-2. Furthermore, using microarray analysis, we identified a novel inherent radioresistance-related gene, phosphoprotein associated with glycosphingolipid-enriched microdomains1 (PAG1). We showed that siRNA directed against PAG1 in a radioresistant (Hep-2max) cell line dramatically enhanced the radiosensitivity and IR-induced cell death. On the contrary, ectopic expression of PAG1 in radiosensitive (Hep-2min) cell lines led to radioresistance and suppressed the IR-induced cell death. Taken together, our results indicate that the PAG1 gene may be a novel, promising radiosensitization target for laryngeal carcinoma.

Prophylactic effects of interleukin-2 receptor antagonists against graft-versus-host disease following unrelated donor peripheral blood stem cell transplantation.

Basiliximab and daclizumab, two interleukin-2 receptor antagonists (IL-2RAs), prevent graft failure in renal transplantation, which also effectively treat steroid-refractory graft-versus-host disease (GVHD). However, only a few studies report that IL-2RAs prevent GVHD. Here we first retrospectively explored the prophylactic effects of basiliximab or daclizumab against GVHD in 82 patients with hematologic malignancies following unrelated donor-peripheral blood stem cell transplantation (URD-PBSCT). All recipients achieved engraftment. The rates of grade II-IV and III-IV acute GVHD (aGVHD) were 35.4% and 15.9%, respectively. Chronic GVHD (cGVHD) developed in 38.7% of evaluable patients. The transplantation-related mortality was 13.4%, while relapse rate was 8.5%. The 2-year overall survival (OS) reached 77.1% and disease-free survival (DFS) accumulated to 72.2%. The side effects of basiliximab and daclizumab were moderate and tolerable. There were no significant differences in aGVHD onset and survival between the daclizumab and basiliximab groups. However, basiliximab presented superior prophylactic effects on cGVHD than daclizumab. In conclusion, basiliximab or daclizumab prevents GVHD efficiently and feasibly following URD-PBSCT, and contributes to favorable outcome. Basiliximab has a similar effect on aGVHD but superior activity against cGVHD. Further prospective and randomized control studies are needed.