Structural insight into the ZFAND1-p97 interaction involved in stress granule clearance.

Arsenite-induced stress granule (SG) formation can be cleared by the ubiquitin-proteasome system aided by the ATP-dependent unfoldase p97. ZFAND1 participates in this pathway by recruiting p97 to trigger SG clearance. ZFAND1 contains two An1-type zinc finger domains (ZF1 and ZF2), followed by a ubiquitin-like domain (UBL); but their structures are not experimentally determined. To shed light on the structural basis of the ZFAND1-p97 interaction, we determined the atomic structures of the individual domains of ZFAND1 by solution-state NMR spectroscopy and X-ray crystallography. We further characterized the interaction between ZFAND1 and p97 by methyl NMR spectroscopy and cryo-EM. 15N spin relaxation dynamics analysis indicated independent domain motions for ZF1, ZF2, and UBL. The crystal structure and NMR structure of UBL showed a conserved ß-grasp fold homologous to ubiquitin and other UBLs. Nevertheless, the UBL of ZFAND1 contains an additional N-terminal helix that adopts different conformations in the crystalline and solution states. ZFAND1 uses the C-terminal UBL to bind to p97, evidenced by the pronounced line-broadening of the UBL domain during the p97 titration monitored by methyl NMR spectroscopy. ZFAND1 binding induces pronounced conformational heterogeneity in the N-terminal domain of p97, leading to a partial loss of the cryo-EM density of the N-terminal domain of p97. In conclusion, this work paved the way for a better understanding of the interplay between p97 and ZFAND1 in the context of SG clearance.

Chemical Micromotors Move Faster at Oil-Water Interfaces.

Many real-world scenarios involve interfaces, particularly liquid-liquid interfaces, that can fundamentally alter the dynamics of colloids. This is poorly understood for chemically active colloids that release chemicals into their environment. We report here the surprising discovery that chemical micromotors─colloids that convert chemical fuels into self-propulsion─move significantly faster at an oil-water interface than on a glass substrate. Typical speed increases ranged from 3 to 6 times up to an order of magnitude and were observed for different types of chemical motors and interfaces made with different oils. Such speed increases are likely caused by faster chemical reactions at an oil-water interface than at a glass-water interface, but the exact mechanism remains unknown. Our results provide valuable insights into the complex interactions between chemical micromotors and their environments, which are important for applications in the human body or in the removal of organic pollutants from water. In addition, this study also suggests that chemical reactions occur faster at an oil-water interface and that micromotors can serve as a probe for such an effect.

Tying a true topological protein knot by cyclization.

Knotted proteins are fascinating to biophysicists because of their robust ability to fold into intricately defined three-dimensional structures with complex and topologically knotted arrangements. Exploring the biophysical properties of the knotted proteins is of significant interest, as they could offer enhanced chemical, thermal, and mechanostabilities. A true mathematical knot requires a closed path; in contrast, knotted protein structures have open N- and C-termini. To address the question of how a truly knotted protein differs from the naturally occurring counterpart, we enzymatically cyclized a 31 knotted YibK protein from Haemophilus influenza (HiYibK) to investigate the impact of path closure on its structure-function relationship and folding stability. Through the use of a multitude of structural and biophysical tools, including X-ray crystallography, NMR spectroscopy, small angle X-ray scattering, differential scanning calorimetry, and isothermal calorimetry, we showed that the path closure minimally perturbs the native structure and ligand binding of HiYibK. Nevertheless, the cyclization did alter the folding stability and mechanism according to chemical and thermal unfolding analysis. These molecular insights contribute to our fundamental understanding of protein folding and knotting that could have implications in the protein design with higher stabilities.

Unraveling the Significance of MET Focal Amplification in Lung Cancer: Integrative NGS, FISH, and IHC Investigation.

MET amplification (METamp) represents a promising therapeutic target in non-small cell lung cancer, but no consensus has been established to identify METamp-dependent tumors that could potentially benefit from MET inhibitors. In this study, an analysis of MET amplification/overexpression status was performed in a retrospectively recruited cohort comprising 231 patients with non-small cell lung cancer from Shanghai Chest Hospital (SCH cohort) using 3 methods: fluorescence in situ hybridization (FISH), hybrid capture-based next-generation sequencing, and immunohistochemistry for c-MET and phospho-MET. The SCH cohort included 130 cases known to be METamp positive by FISH and 101 negative controls. The clinical relevance of these approaches in predicting the efficacy of MET inhibitors was evaluated. Additionally, next-generation sequencing data from another 2 cohorts including 22,010 lung cancer cases were utilized to examine the biological characteristics of different METamp subtypes. Of the 231 cases, 145 showed MET amplification/overexpression using at least 1 method, whereas only half of them could be identified by all 3 methods. METamp can occur as focal amplification or polysomy. Our study revealed that the inconsistency between next-generation sequencing and FISH primarily occurred in the polysomy subtype. Further investigations indicated that compared with polysomy, focal amplification correlated with fewer co-occurring driver mutations, higher protein expressions of c-MET and phospho-MET, and higher incidence in acquired resistance than in de novo setting. Moreover, patients with focal amplification presented a more robust response to MET inhibitors compared with those with polysomy. Notably, a strong correlation was observed between focal amplification and programmed cell death ligand-1 expression, indicating potential therapeutic implications with combined MET inhibitor and immunotherapy for patients with both alterations. Our findings provide insights into the molecular complexity and clinical relevance of METamp in lung cancer, highlighting the role of MET focal amplification as an oncogenic driver and its feasibility as a primary biomarker to further investigate the clinical activity of MET inhibitors in future studies.

Effect of Osteoporosis Treatments on Osteoarthritis Progression in Postmenopausal Women: A Review of the Literature.

PURPOSE OF REVIEW: The purpose of this literature review was to determine if medications used to treat osteoporosis are also effective for treating osteoarthritis (OA). RECENT FINDINGS: A total of 40 relevant articles were identified. Studies were categorized into those (1) discussing estrogen and selective estrogen receptor modulators (SERMs), (2) bisphosphonates, (3) parathyroid hormone (PTH) analogs, and (4) denosumab, and (5) prior review articles. A large amount of evidence suggests that estrogen and SERMs are effective at reducing OA symptoms and disease progression. Evidence suggests that bisphosphonates, the most common medications used to treat osteoporosis, can reduce OA symptoms and disease progression. In vivo studies suggest that PTH analogs may improve the cartilage destruction associated with OA; however, few human trials have examined its use for OA. Denosumab is approved to treat osteoporosis, bone metastases, and certain types of breast cancer, but little study has been done with respect to its effect on OA. The current evidence indicates that medications used to treat osteoporosis are also effective for treating OA. Estrogen, SERMs, and bisphosphonates have the most potential as OA therapies. Less is known regarding the effectiveness of PTH analogs and denosumab in OA, and more research is needed.

Therapeutic advantage of teriparatide in very elderly patients with proximal femoral fractures: a functional and BMD analysis.

BACKGROUND: Teriparatide, a recombinant parathyroid hormone, is pivotal in osteoporosis treatment, particularly in post-surgical recovery for hip fractures. This study investigates its efficacy in functional recovery post-hip fracture surgery in elderly patients, a demographic particularly susceptible to osteoporotic fractures. METHODS: In this retrospective cohort study, 150 elderly patients with proximal femoral fractures undergoing open reduction and internal fixation were enrolled. They were categorized into two groups: receiving 20 µg of daily teriparatide injections for 18 months and receiving standard antiresorptive medications during a 24-month follow-up. Detailed records of patient demographics, Fracture Risk Assessment Tool scores, and comorbidities were kept. Key outcomes, including bone mineral density (BMD) and functional scores (Barthel Index and Visual Analog Scale for hip pain), were evaluated at 3 and 24 months post-surgery. RESULTS: Out of the original cohort, 126 patients (20 men and 106 women with an average age of 85.5 ± 9.3 years) completed the study. The teriparatide group exhibited significant enhancements in both functional scores and BMD when compared to the control group. Notably, functional improvements were less pronounced in male patients compared to female patients. Additionally, the incidence of new fractures was markedly lower in the teriparatide group. CONCLUSION: Administering teriparatide daily for 18 months post-surgery for proximal femoral fractures significantly benefits very elderly patients by improving functionality and bone density, with observed differences in recovery between genders. These results reinforce the efficacy of teriparatide as a potent option for treating osteoporosis-related fractures in the elderly and highlight the importance of considering gender-specific treatment and rehabilitation strategies.

Femoral neck system versus multiple cannulated screws for the fixation of Pauwels classification type II femoral neck fractures in older female patients with low bone mass.

BACKGROUND: Femoral neck fractures in older adult patients are a major concern and often necessitate surgical intervention. This study compared the clinical outcomes of 2 surgical techniques: the femoral neck system (FNS) and cannulated compression screws (CCSs). METHODS: A total of 40 female patients (mean age 73.50 ± 11.55 years) with femoral neck fractures of Pauwels classification type II and receiving surgical fixation between 2020 and 2022 were enrolled. The patients were categorized into an FNS group (n = 12) or a CCS group (n = 28), and surgical duration, intraoperative blood loss, length of hospital stay, and incidence of postoperative adverse events were analyzed. RESULTS: No significant intergroup differences in demographic characteristics were discovered. The mean surgical duration for all patients was 52.88 ± 22.19 min, with no significant difference between the groups. However, the FNS group experienced significantly higher intraoperative blood loss (P = 0.002) and longer hospital stay (P = 0.023) than did the CCS group. The incidence of osteonecrosis was higher in the CCS group, whereas the incidence of nonunion or malunion was higher in the FNS group. The surgical method did not appear to be a significant risk factor. The main risk factor for revision surgery was longer duration until the first adverse event (P = 0.015). CONCLUSION: The FNS does not appear to provide superior surgical outcomes compared with CCSs in older adult women with Pauwels classification type II femoral neck fractures. A longer duration between surgical fixation and the first adverse event before stabilization of the fracture site may be a risk factor for revision surgery.

COVID-19 Infection Was Associated with the Functional Outcomes of Hip Fracture among Older Adults during the COVID-19 Pandemic Apex.

Background and Objectives: Hip fractures are associated with mortality and poor functional outcomes. The COVID-19 pandemic has affected patterns of care and health outcomes among fracture patients. This study aimed to determine the influence of COVID-19 infection on hip fracture recovery. Materials and Methods: We prospectively collected data on patients with hip fractures who presented at Hualien Tzu Chi Hospital between 9 March 2022 and 9 September 2022. The data included demographic information and functional scores taken before, during, and after surgery. The patients were divided into two groups: COVID-19 (+) and COVID-19 (-). Results: This study recruited 85 patients, 12 of whom (14.12%) were COVID-19 (+). No significant differences in preoperative or perioperative parameters between the two groups were observed. The postoperative Barthel index score was significantly impacted by COVID-19 infection (p = 0.001). The incidence of postoperative complications was significantly correlated with general anesthesia (p = 0.026) and the length of stay (p = 0.004) in hospital. Poor postoperative functional scores were associated with lower preoperative Barthel index scores (p < 0.001). Male sex (p = 0.049), old age (p = 0.012), a high American Society of Anesthesiologists grade (p = 0.029), and a high Charlson comorbidity index score (p = 0.028) were associated with mortality. Conclusions: Hip fracture surgeries were not unduly delayed in our hospital during the COVID-19 pandemic, but the patients' postoperative Barthel index scores were significantly influenced by COVID-19 (+). The preoperative Barthel index score may be a good predictive tool for the postoperative functional recovery of these patients.

Effects of miR-9-5p on the migration, invasion and epithelial-mesenchymal transition process in cervical squamous cell carcinoma. / MiR-9-5p对宫颈鳞癌细胞迁移和侵袭能力及上皮间质转化的影响.

OBJECTIVES: Cervical squamous cell carcinoma is the most common cancer in female reproductive system. This study aims to explore the effect of microRNA-9-5p (miR-9-5p) on the migration, invasion, and epithelial-mesenchymal transition (EMT) process of cervical squamous cells. METHODS: Bioinformatics were used to predict the miRNAs that could bind to E-cadherin (E-cad). The Cancer Genome Atlas (TCGA) database was used to analyze and extract significantly differentially expressed miRNAs from part of cervical squamous cell carcinoma tissues and normal cervical tissues, and miR-9-5p was selected as the main research target. The translated regions (UTR) of wild-type E-cad (E-cad-WT 3'-UTR) or the 3'-UTR of mutant E-cad (E-Cad-MUT 3'-UTR) was transfected with miR-9-5p mimic normal control (NC), and miR-9-5p mimic was co-transfected human embryonic kidney cells (293T). The relationship between miR-9-5p and E-cad was detected by double luciferase assay. The expression of miR-9-5p in normal cervical epithelial cell lines (H8) and cervical squamous cell lines (C33A, siha, caski and Me180) were detected by quantitative real-time PCR. Then, the experiments were divided into groups as follows: a block control group, an overexpression control group (mimic-NC group), a miR-95p overexpression group (mimic group), an inhibitory expression control group (inhibitor-NC group), and a miR-9-5p inhibitory expression group (inhibitor group). The changes of migration ability were detected by scratch assay. Transwell invasion assay was used to analyze the changes of invasion ability, and the mRNA and protein changes of E-cad and vimentin were detected by quantitative real-time PCR and Western blotting. RESULTS: MiR-9-5p had a targeting binding relationship with E-cad. Compared with the normal cervical tissue H8 cell line, the miR-9-5p was highly expressed in cervical cancer cell lines (C33A, siha, caski and Me180) (all P<0.05). The luciferase activity of E-cad-MUT was increased compared with that of E-cad-WT in miR-9-5p mimic cells (P<0.05). Compared with the blank control group, the protein and mRNA expressions of E-cad were decreased in the miR-9-5p mimic group (both P<0.05), which were increased in the miR-9-5p inhibitor group (both P<0.05). Compared with H8 cell line, the miR-9-5p was highly expressed in the cervical squamous cell lines (all P<0.05). Compared with the mimic-NC group, the distance of wound healing, the number of caski and Me180 cells invaded below the membrane, and the mRNA and protein expressions of vimentin were all increased in the miR-9-5p mimic group (all P<0.05), while the mRNA and protein of E-cad were decreased (both P<0.05). Compared with the inhibitor-NC group, the distance of wound healing, the number of caski and Me180 cells invading the membrane, and the mRNA and protein expressions of vimentin were decreased in the miR-9-5p inhibitor group (all P<0.05), but the mRNA and protein expressions of E-cad were increased (both P<0.05). CONCLUSIONS: The miR-9-5p is highly expressed in cervical squamous cell carcinoma, which can increase the migration and invasion ability, and promote the EMT process of cancer cells.

HwMR is a novel magnesium-associated protein.

Microbial rhodopsins (MRho) are vital proteins in Haloarchaea for solar light sensing in extreme living environments. Among them, Haloquadratum walsbyi (Hw) is a species known to survive high MgCl2 concentrations, with a total of three MRhos identified, including a high-acid-tolerance light-driven proton outward pump, HwBR, a chloride-insensitive chloride pump, HwHR, and a functionally unknown HwMR. Here, we showed that HwMR is the sole magnesium-sensitive MRho among all tested MRho proteins from Haloarchaea. We identified at least D84 as one of the key residues mediating such magnesium ion association in HwMR. Sequence analysis and molecular modeling suggested HwMR to have an extra H8 helix in the cytosolic region like those in signal-transduction-type MRho of deltarhodopsin-3 (dR-3) and Anabaena sensory rhodopsin (ASR). Further, HwMR showed a distinctly prolonged M-state formation under a high concentration of Mg2+. On the other hand, an H8 helix truncated mutant preserved photocycle kinetics like the wild type, but it led to missing M-state structure. Our findings clearly suggested not only that HwMR is a novel Mg2+-associated protein but that the association with both Mg2+ and the H8 domain stabilizes M-state formation in HwMR. We conclude that Mg2+ association and H8 are crucial in stabilizing HwMR M state, which is a well-known photoreceptor signaling state.

Arthroscopic foveal repair with suture anchors for traumatic tears of the triangular fibrocartilage complex.

BACKGROUND: Foveal tears of the traumatic triangular fibrocartilage complex (TFCC) are the most commonly neglected high-energy injuries of the wrist joint, and the patients with such tears often experience unrecovered ulnar-sided wrist pain and poor wrist function. This study investigated the functional outcomes of patients who underwent arthroscopic repair of foveal TFCC tears with suture anchors and adjuvant platelet-rich plasma (PRP) injections after the surgery. METHODS: From September 2014 to August 2018, 156 men and 45 women with diagnoses of foveal TFCC tears without wrist fractures underwent arthroscopic repair by using the outside-in method with 1.3-mm suture anchors and subsequent PRP injection. After surgery, splinting was applied for 6 weeks, and the patients underwent rehabilitation, re-examination, and follow-up at our clinic. The patients' wrist functional scores and grip strength data were retrospectively collected. RESULTS: The mean follow-up period was 32.6 months, and the mean age was 26.7 years. The mean modified Mayo wrist score improved from 48.5 ± 2.6 to 82.4 ± 2.5, whereas the mean Disabilities of the Arm, Shoulder and Hand (DASH) score decreased from 39.2 ± 6.7 to 10.6 ± 7.5. Overall, the wrist functions of 186 (92.5%) of the patients were satisfactory according to their modified Mayo wrist scores, and the patients with satisfactory scores returned to sports or work activities. These patients retained normal ranges of motion, and their average grip strength in the affected hand was restored to at least 85% of that of the other hand. CONCLUSIONS: According to the postoperative 25-36 months surgical results of our study, arthroscopic repair with adjuvant PRP injections is a satisfactory method of repairing early foveal tears of the TFCC and can enhance wrist function by relieving pain and increasing tolerance for work or sports.

Midterm outcomes of midfoot and hindfoot arthrodesis with strut allograft for Müller-Weiss disease.

BACKGROUND: Müller-Weiss disease (MWD), a rare dysplastic disorder of the foot, is characterized by deformity, sclerosis, and fragmentation of the lateral part of navicular bone. Arthrodesis is the mainstay treatment for MWD. Generally, arthrodesis can be achieved through internal fixation with metallic implants, and morselized chip bone may be packed into the gap for better bone union. However, with this procedure, the original foot size is not maintained and support for the foot arch is not provided. Sequela of short foot, or flatfoot is commonly observed even though these complications of surgery had not been reported with cases of MWD treated by arthrodesis. Herein, we present a retrospective analysis of treating MWD through midfoot and hindfoot arthrodesis combined with strut allograft. METHODS: From August 2006 to June 2019, 20 patients with MWD (mean age, 59.6 years; range, 40-80 years) underwent midfoot and hindfoot arthrodesis with strut bone allograft and were followed for at least 24 months. The patients were able to ambulate and participate in rehabilitation programs 3 months postoperatively. RESULTS: The used four radiographic parameters (Meary's angle in anteroposterior and lateral view, talonavicular coverage angle, calcaneal pitch) demonstrated significant differences (P < .05) preoperatively and postoperatively, but those between the postoperative values and the values at the last follow-up session did not, indicating that strut allograft was able to maintain normal alignment. The mean American Orthopaedic Foot & Ankle Society Ankle-Hindfoot scores at 2 years postoperatively revealed significant improvement from baseline, from 60.2 to 84.2 (P < .05). The 12-item Short Form Health Survey scores also improved significantly (P < .05). All patients reported substantial pain relief and exhibited improved functional outcomes and gait patterns. CONCLUSIONS: For advanced-stage MWD, arthrodesis with a precisely shaped, size-matched strut allograft provided strong support for biomechanical alignment and enhanced functional performance.

Use of an Intramedullary Allogenic Fibular Strut Bone and Lateral Locking Plate for Distal Femoral Fracture with Supracondylar Comminution in Patients over 50 Years of Age.

Background and Objectives: Distal femoral fracture is a severe injury that makes surgery challenging, particularly comminuted fractures in the supracondylar region. This study aimed to evaluate the outcomes of distal femoral fracture treated with the application of an intramedullary fibular allogenic bone strut in open reduction and internal fixation (ORIF) with precontoured locking plates in patients over 50 years of age. Materials and Methods: The study retrospectively enrolled 202 patients over 50 years of age with traumatic comminuted distal femoral fracture (AO/OTA 33-A3, 33-C2 and 33-C3) treated with ORIF with a locking plate from January 2016 to December 2019. The two groups were divided into patients who received an intramedullary allogenic bone strut and those who did not. Patients were followed for at least 1 year, with their function scores and radiographic data recorded. Results: A total of 124 patients were recruited, comprising 60 men and 64 women with an average age of 62.4 ± 8.5 years. The 36 patients who had received an intramedullary allogenic fibular bone strut reported lower postoperative pain scores at 1 month and lower postoperative Knee Society Scores (KSS) at 3 months than the control group. The application of an intramedullary allogenic fibular bone strut appeared to be significantly correlated with better 3-month postoperative KSS. Conclusions: The ORIF of distal femoral comminuted fracture with an intramedullary allogenic fibular bone strut can reduce pain and improve knee function in the early stages of postoperative rehabilitation and may reduce the time to union in patients over 50 years of age.

Direct Visualization of a 26 kDa Protein by Cryo-Electron Microscopy Aided by a Small Scaffold Protein.

Cryo-electron microscopy (cryo-EM)-based structure determination of small proteins is hindered by the technical challenges associated with low signal-to-noise ratios of their particle images in intrinsically noisy micrographs. One solution is to attach the target protein to a large protein scaffold to increase its apparent size and, therefore, image contrast. Here we report a novel scaffold design based on a trimeric helical protein, E. coli ornithine transcarbamylase (OTC), fused to human ubiquitin. As a proof of principle, we demonstrated the ability to resolve a cryo-EM map of a 26 kDa human ubiquitin C-terminal hydrolase (UCHL1) attached to the C-terminus of ubiquitin as part of the trimeric assembly. The results revealed conformational changes in UCHL1 upon binding to ubiquitin, namely, a significant displacement of α-helix 2, which was also observed by X-ray crystallography. Our findings demonstrated the potential of the trimeric OTC scaffold design for studying a large number of ubiquitin interacting proteins by cryo-EM.

The incidence of mental disorder increases after hip fracture in older people: a nationwide cohort study.

BACKGROUND: People living with dementia seem to be more likely to experience delirium following hip fracture. The association between mental disorders (MD) and hip fracture remains controversial. We conducted a nationwide study to examine the prevalence of MD in geriatric patients with hip fractures undergoing surgery and conducted a related risk factor analysis. MATERIAL AND METHODS: This retrospective cohort study used data from Taiwan's National Health Insurance Research Database between 2000 and 2012 and focused on people who were older than 60 years. Patients with hip fracture undergoing surgical intervention and without hip fracture were matched at a ratio of 1:1 for age, sex, comorbidities, and index year. The incidence and hazard ratios of age, sex, and multiple comorbidities related to MD and its subgroups were calculated using Cox proportional hazards regression models. RESULTS: A total of 1408 patients in the hip fracture group and a total of 1408 patients in the control group (no fracture) were included. The overall incidence of MD for the hip fracture and control groups per 100 person-years were 0.8 and 0.5, respectively. Among MD, the incidences of transient MD, depression, and dementia were significantly higher in the hip fracture group than in the control group. CONCLUSIONS: The prevalence of newly developed MD, especially transient MD, depression, and dementia, was higher in the geriatric patients with hip fracture undergoing surgery than that in the control group. Prompt and aggressive prevention protocols and persistent follow-up of MD development is highly necessary in this aged society.

Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models.

Molecules involved in DNA damage response (DDR) are often overexpressed in cancer cells, resulting in poor responses to chemotherapy and radiotherapy. Although treatment efficacy can be improved with the concomitant use of DNA repair inhibitors, the accompanying side effects can compromise the quality of life of patients. Therefore, in this study, we identified a natural compound that could inhibit DDR, using the single-strand annealing yeast-cell analysis system, and explored its mechanisms of action and potential as a chemotherapy adjuvant in hepatocellular carcinoma (HCC) cell lines using comet assay, flow cytometry, Western blotting, immunofluorescence staining, and functional analyses. We developed a mouse model to verify the in vitro findings. We found that hydroxygenkwanin (HGK) inhibited the expression of RAD51 and progression of homologous recombination, thereby suppressing the ability of the HCC cell lines to repair DNA damage and enhancing their sensitivity to doxorubicin. HGK inhibited the phosphorylation of DNA damage checkpoint proteins, leading to apoptosis in the HCC cell lines. In the mouse xenograft model, HGK enhanced the sensitivity of liver cancer cells to doxorubicin without any physiological toxicity. Thus, HGK can inhibit DDR in liver cancer cells and mouse models, making it suitable for use as a chemotherapy adjuvant.

Hepatic encephalopathy increases the risk of hip fracture: a nationwide cohort study.

BACKGROUND: Osteoporotic hip fracture is a common general health problem with a significant impact on human life because it debilitates the patients and largely decreases their quality of life. Early prevention of fractures has become essential in recent decades. This can be achieved by evaluating the related risk factors, as a reference for further intervention. This is especially useful for the vulnerable patient group with comorbidities. Hepatic encephalopathy (HE), a major complication of liver cirrhosis, may increase the rate of falls and weaken the bone. This study evaluated the correlation between hepatic encephalopathy and osteoporotic hip fracture in the aged population using a national database. METHODS: This retrospective cohort study used data from Taiwan's National Health Insurance Research Database between 2000 and 2012. We included people who were older than 50 years with hepatic encephalopathy or other common chronic illnesses. Patients with and without hepatic encephalopathy were matched at a ratio of 1:4 for age, sex, and index year. The incidence and hazard ratios of osteoporotic hip fracture between the both cohorts were calculated using Cox proportional hazard regression models. RESULTS: The mean age of the enrolled patients was 66.5 years. The incidence ratio of osteoporotic hip fracture in the HE group was significantly higher than that in the non-HE group (68/2496 [2.7%] vs 98/9984 [0.98%]). Patients with HE were 2.15-times more likely to develop osteoporotic hip fractures than patients without HE in the whole group. The risk ratio was also significantly higher in female and older individuals. The results were also similar in the comorbidity subgroups of hypertension, diabetes mellitus, hyperlipidemia, senile cataract, gastric ulcer, and depression. Alcohol-related illnesses seemed to not confound the results of this study. CONCLUSIONS: HE is significantly associated with an increased risk of osteoporotic hip fractures, and the significance is not affected by the comorbidities in people aged more than 50 years. The cumulative risk of fracture increases with age.

Anti-Diabetic Effects of Berberis kansuensis Extract on Type 2 Diabetic Rats Revealed by 1 H-NMR-Based Metabolomics and Biochemistry Analysis.

The dried stem bark of Berberis kansuensis C.K.Schneid. (Berberidaceae) was widely used to treat diabetes in traditional Tibetan medicine system. However, its anti-diabetic mechanisms have not been elucidated. In this study, 1 H-NMR-based metabolomics combined with biochemistry assay was applied to investigate the anti-diabetic activities as well as underlying mechanisms of B. kansuensis extract on type 2 diabetic rats. The results showed that after 30 days treatment with B. kansuensis extract, the levels of FBG, GSP, INS, TNF-α, IL-1ß and IL-6 were significantly decreased in B. kansuensis group compared with the model group. Besides, a total of 28 metabolites were identified in rat serum by 1 H-NMR-based metabolomics method, 16 of which were significantly different in the normal group compared with the model group, and eight of them were significantly reversed after B. kansuensis intervention. Further analysis of metabolic pathways indicated that therapeutic effect of B. kansuensis might be predominantly related to their ability to improve glycolysis and gluconeogenesis, citric acid cycle, lipid metabolism, amino acid metabolism and choline metabolism. The results of both metabolomics and biochemical analysis indicated that B. kansuensis extract has a potential anti-diabetic effect on type 2 diabetic rats. Its therapeutic effect may be based on the ability of anti-inflammation, alleviating insulin resistance and restoring several disturbed metabolic pathways.

The Interactions between the Antimicrobial Peptide P-113 and Living Candida albicans Cells Shed Light on Mechanisms of Antifungal Activity and Resistance.

In the absence of proper immunity, such as in the case of acquired immune deficiency syndrome (AIDS) patients, Candida albicans, the most common human fungal pathogen, may cause mucosal and even life-threatening systemic infections. P-113 (AKRHHGYKRKFH), an antimicrobial peptide (AMP) derived from the human salivary protein histatin 5, shows good safety and efficacy profiles in gingivitis and human immunodeficiency virus (HIV) patients with oral candidiasis. However, little is known about how P-113 interacts with Candida albicans or its degradation by Candida-secreted proteases that contribute to the fungi's resistance. Here, we use solution nuclear magnetic resonance (NMR) methods to elucidate the molecular mechanism of interactions between P-113 and living Candida albicans cells. Furthermore, we found that proteolytic cleavage of the C-terminus prevents the entry of P-113 into cells and that increasing the hydrophobicity of the peptide can significantly increase its antifungal activity. These results could help in the design of novel antimicrobial peptides that have enhanced stability in vivo and that can have potential therapeutic applications.

Vasopressin-induced serine 269 phosphorylation reduces Sipa1l1 (signal-induced proliferation-associated 1 like 1)-mediated aquaporin-2 endocytosis.

The abundance of integral membrane proteins in the plasma membrane is determined by a dynamic balance between exocytosis and endocytosis, which can often be regulated by physiological stimuli. Here, we describe a mechanism that accounts for the ability of the peptide hormone vasopressin to regulate water excretion via a phosphorylation-dependent modulation of the PDZ domain-ligand interaction involving the water channel protein aquaporin-2. We discovered that the PDZ domain-containing protein Sipa1l1 (signal-induced proliferation-associated 1 like 1) binds to the cytoplasmic PDZ-ligand motif of aquaporin-2 and accelerates its endocytosis in the absence of vasopressin. Vasopressin-induced aquaporin-2 phosphorylation within the type I PDZ-ligand motif disrupted the interaction, in association with reduced aquaporin-2 endocytosis and prolonged plasma membrane aquaporin-2 retention. This phosphorylation-dependent alteration in the PDZ domain-ligand interaction was explained by 3D structural models, which showed a hormone-regulated mechanism that controls osmotic water transport and systemic water balance in mammals.