FCHSD2 is required for stereocilia maintenance in mouse cochlear hair cells.

Stereocilia are F-actin-based protrusions on the apical surface of inner-ear hair cells and are indispensable for hearing and balance perception. The stereocilia of each hair cell are organized into rows of increasing heights, forming a staircase-like pattern. The development and maintenance of stereocilia are tightly regulated, and deficits in these processes lead to stereocilia disorganization and hearing loss. Previously, we showed that the F-BAR protein FCHSD2 is localized along the stereocilia of cochlear hair cells and cooperates with CDC42 to regulate F-actin polymerization and cell protrusion formation in cultured COS-7 cells. In the present work, Fchsd2 knockout mice were established to investigate the role of FCHSD2 in hearing. Our data show that stereocilia maintenance is severely affected in cochlear hair cells of Fchsd2 knockout mice, which leads to progressive hearing loss. Moreover, Fchsd2 knockout mice show increased acoustic vulnerability. Noise exposure causes robust stereocilia degeneration as well as enhanced hearing threshold elevation in Fchsd2 knockout mice. Lastly, Fchsd2/Cdc42 double knockout mice show more severe stereocilia deficits and hearing loss, suggesting that FCHSD2 and CDC42 cooperatively regulate stereocilia maintenance.

Optimizing human endometrial mesenchymal stem cells for maximal induction of angiogenesis.

Human endometrial mesenchymal stem cells (hEMSCs) have been shown to promote neo-vascularization; however, its angiogenic function lessens with age. To determine the optimal conditions for maximizing hEMSC angiogenic capacity, we examined the effects of serial passaging on hEMSC activity. hEMSCs were cultured from passages (P) 3, 6, 9, and 12, and analyzed for proliferation, migration, differentiation and senescence, as well as their capacity to induce angiogenesis. The results showed that hEMSC proliferation and migration significantly decreased after P12. Furthermore, hEMSC differentiation into adipogenic and osteogenic lineages, as well as their proangiogenic capacity, gradually decreased from P9-12, while senescence only occurred after P12. Evaluation of angiogenic-related protein levels showed that both transforming growth factor ß2 and Tie-2 was significantly reduced in hEMSCs at P12, compared to P3, possibly serving as the basis behind their lowered angiogenic capacity. Furthermore, in vivo angiogenesis evaluation with Matrigel plug assay showed that the optimal hEMSC to HUVEC ratio, for maximizing vessel formation, was 1:4. This study showed that hEMSC passaging was associated with lowered cellular functioning, bringing them closer to a senescent phenotype, especially after P12, thereby defining the optimal time period for cultivating fully functional hEMSCs for therapeutic applications.

Deafness-related protein PDZD7 forms complex with the C-terminal tail of FCHSD2.

In cochlea, deafness-related protein PDZD7 is an indispensable component of the ankle link complex, which is critical for the maturation of inner-ear hair cell for sound perception. Ankle links, connecting the different rows of cochlear stereocilia, are essential for the staircase-like development of stereocilia. However, the molecular mechanism of how PDZD7 governs stereociliary development remains unknown. Here, we reported a novel PDZD7-binding partner, FCHSD2, identified by yeast two-hybrid screening. FCHSD2 was reported to be expressed in hair cell, where it co-operated with CDC42 and N-WASP to regulate the formation of cell protrusion. The association between FCHSD2 and PDZD7 was further confirmed in COS-7 cells. More importantly, we solved the complex structure of FCHSD2 tail with PDZD7 PDZ3 domain at 2.0 Šresolution. The crystal structure shows that PDZD7 PDZ3 adopts a typical PDZ domain topology, comprising five ß strands and two α helixes. The PDZ-binding motif of FCHSD2 tail stretches through the αB/ßB groove of PDZD7 PDZ3. Our study not only uncovers the interaction between FCHSD2 tail and PDZD7 PDZ3 at the atomic level, but also provides clues of connecting the ankle link complex with cytoskeleton dynamics for exploiting the molecular mechanism of stereociliary development.

BAIAP2L2 is required for the maintenance of mechanotransducing stereocilia of cochlear hair cells.

Stereocilia are actin-based cell protrusions of inner ear hair cells that play an essential role in mechano-electrical transduction (MET). Stereocilia are organized into several rows of increasing heights with the MET protein complex localized at the tips of shorter row stereocilia. At the tips of shorter row mechanotransducing stereocilia also resides a so-called "row 2 protein complex" whose dysfunction causes degeneration of the mechanotransducing stereocilia. In the present work, we show that BAIAP2L2 is localized at the tips of shorter row stereocilia in neonatal and adult mouse cochlear hair cells. Baiap2l2 inactivation causes degeneration of the mechanotransducing stereocilia, which eventually leads to profound hearing loss in mice of either sex. Consistently, electrophysiology and FM 1-43FX dye uptake results confirm that MET currents are compromised in Baiap2l2 knockout mice. Moreover, BAIAP2L2 binds to known row 2 complex components EPS8L2, TWF2, and CAPZB2, and the stereociliary tip localization of CAPZB2 is dependent on functional BAIAP2L2. Interestingly, BAIAP2L2 also binds to CIB2, a known MET complex component, and the stereociliary tip localization of BAIAP2L2 is abolished in Cib2 knockout mice. In conclusion, our present data suggest that BAIAP2L2 is a row 2 complex component, and is required for the maintenance of mechanotransducing stereocilia. Meanwhile, specific MET components such as CIB2 might play a direct role in stereocilia maintenance through binding to BAIAP2L2.

Hypoxic preconditioned aged BMSCs accelerates MI injury repair by modulating inflammation, oxidative stress and apoptosis.

The benefits of autologous cell therapy for cardiac repair are diminished in aged individuals due to the limited quality and poor tolerance of aged stem cells in the ischemic micro-environment. The safe and efficient methods to improve the therapeutic effect of aged stem cells are needed to treat the increasing number of aged patients with cardiac diseases. In the present study, we aimed to determine whether hypoxic preconditioning can improve the therapeutic effect of aged stem cells even if the responsiveness of aged MSCs is poor, and to seek the underlying mechanism. Using a murine model of MI, our results showed that hypoxic preconditioning promoted the therapeutic effect of aged BMSCs, which was expressed in improved cardiac function, decreased scar size and alleviated cardiac remodeling in vivo. This in vivo effect of hypoxic preconditioned aged BMSCs was associated with alleviated inflammation, oxidative stress and apoptosis in infarcted heart. In vitro studies confirmed that hypoxic preconditioned aged BMSCs exert cytoprotective impacts on H9C2 cells against lethal hypoxia injury via attenuating oxidative stress and apoptosis. Our data support the promise of hypoxic preconditioning as a potential strategy to improve autologous stem cell therapy for ischemic heart injury in aged individuals.

Effect of neuron-derived neurotrophic factor on rejuvenation of human adipose-derived stem cells for cardiac repair after myocardial infarction.

The decline of cell function caused by ageing directly impacts the therapeutic effects of autologous stem cell transplantation for heart repair. The aim of this study was to investigate whether overexpression of neuron-derived neurotrophic factor (NDNF) can rejuvenate the adipose-derived stem cells in the elderly and such rejuvenated stem cells can be used for cardiac repair. Human adipose-derived stem cells (hADSCs) were obtained from donors age ranged from 17 to 92 years old. The effects of age on the biological characteristics of hADSCs and the expression of ageing-related genes were investigated. The effects of transplantation of NDNF over-expression stem cells on heart repair after myocardial infarction (MI) in adult mice were investigated. The proliferation, migration, adipogenic and osteogenic differentiation of hADSCs inversely correlated with age. The mRNA and protein levels of NDNF were significantly decreased in old (>60 years old) compared to young hADSCs (<40 years old). Overexpression of NDNF in old hADSCs significantly improved their proliferation and migration capacity in vitro. Transplantation of NDNF-overexpressing old hADSCs preserved cardiac function through promoting angiogenesis on MI mice. NDNF rejuvenated the cellular function of aged hADSCs. Implantation of NDNF-rejuvenated hADSCs improved angiogenesis and cardiac function in infarcted mouse hearts.

Decreasing CNPY2 Expression Diminishes Colorectal Tumor Growth and Development through Activation of p53 Pathway.

Neovascularization drives tumor development, and angiogenic factors are important neovascularization initiators. We recently identified the secreted angiogenic factor CNPY2, but its involvement in cancer has not been explored. Herein, we investigate CNPY2's role in human colorectal cancer (CRC) development. Tumor samples were obtained from CRC patients undergoing surgery. Canopy 2 (CNPY2) expression was analyzed in tumor and adjacent normal tissue. Stable lines of human HCT116 cells expressing CNPY2 shRNA or control shRNA were established. To determine CNPY2's effects on tumor xenografts in vivo, human CNPY2 shRNA HCT116 cells and controls were injected into nude mice, separately. Cellular apoptosis, growth, and angiogenesis in the xenografts were evaluated. CNPY2 expression was significantly higher in CRC tissues. CNPY2 knockdown in HCT116 cells inhibited growth and migration and promoted apoptosis. In xenografts, CNPY2 knockdown prevented tumor growth and angiogenesis and promoted apoptosis. Knockdown of CNPY2 in the HCT116 CRC cell line reversibly increased p53 activity. The p53 activation increased cyclin-dependent kinase inhibitor p21 and decreased cyclin-dependent kinase 2, thereby inhibiting tumor cell growth, inducing cell apoptosis, and reducing angiogenesis both in vitro and in vivo. CNPY2 may play a critical role in CRC development by enhancing cell proliferation, migration, and angiogenesis and by inhibiting apoptosis through negative regulation of the p53 pathway. Therefore, CNPY2 may represent a novel CRC therapeutic target and prognostic indicator.

Preparation and biocompatibility of demineralized bone matrix/sodium alginate putty.

Demineralized bone matrix (DBM) powder is widely used for bone regeneration due to its osteoinductivity and osteoconductivity. However, difficulties with handling, tendency to migrate from graft sites and lack of stability after surgery sometimes limit the clinical utility of this material. In this work, the possibility of using sodium alginate (ALG) carrier to deliver DBM powder was assessed. DBM-ALG putty with the DBM:ALG weight ratio of 5:5, 6:4, 7:3, 8:2 were prepared, respectively. The properties of the formed composite, including discrete degree, washout property, pH, equilibrium swelling as well as cytotoxicity in vivo, were adopted to ascertain the optimal ratio of DBM and ALG. The discrete diameter increased from 1.25 cm (5:5) to 2.08 cm (8:2) with the increase of DBM content. There was significant difference between the 8:2 group and the other groups in discrete diameter. The ratio of DBM had a significant effect on the swelling value. The pH of composites showed an increase trend with the DBM ratio's increase, when the ratio reached 7:3, the pH (7.22) was approximately equal to the body fluid. The proliferation of MC3T3-E1 cells was inhibited in the 5:5, 6:4 and 7:3 groups, while a slightly increased in the 8:2 group. The DBM-ALG with the optimal ratio of 7:3 was confirmed based on the results of the above mentioned. The histocompatibility of DBM-ALG (7:3) was examined using a rat model in which the materials were implanted subcutaneously, compared with the polyethylene, ALG and DBM. The study in vivo showed DBM-ALG (7:3) had a lower inflammatory response than DBM, a higher vascularization than ALG. The osteoinduction of DBM-ALG (7:3) was evaluated by co-culturing with MC3T3-E1 in vitro, compared with the DMEM, ALG and DBM. The results indicated calcification area in the DBM-ALG group was similar to that in the DBM group, larger than ALG group and DMEM group. The DBM-ALG (7:3) putty is promising as a directly injectable graft for repair of bone defect.

Involvement of NO and ROS in sulfur dioxide induced guard cells apoptosis in Tagetes erecta.

Both nitric oxide (NO) and reactive oxygen species (ROS) are very important signal molecules, but the roles they play in signal transduction of sulfur dioxide (SO2) induced toxicities on ornamental plants is not clear. In this study, the functions of NO and ROS in SO2-induced death of lower epidermal guard cells in ornamental plant Tagetes erecta were investigated. The results showed that SO2 derivatives (0.4-4.0 mmol L(-1) of final concentrations) could reduce the guard cells' viability and increase their death rates in a dose-dependent manner. Meanwhile, the significant increase of cellular NO, ROS, and Ca(2+) levels (P<0.05) and typical apoptosis features including nucleus condensation, nucleus break and nucleus fragmentation were observed. However, exposure to 2.0 mmol L(-1) of SO2 derivatives combined with either NO antagonists (NO scavenger c-PTIO; nitrate reductase inhibitor NaN3; NO synthase inhibitor L-NAME), ROS scavenger (AsA or CAT) or Ca(2+) antagonists (Ca(2+) scavenger EGTA or plasma membrane Ca(2+) channel blocker LaCl3) can effectively block SO2-induced guard cells death and corresponding increase of NO, ROS and Ca(2+) levels. In addition, addition of L-NAME or AsA in 2.0 mmol L(-1) of SO2 derivatives led to significant decrease in the levels of NO, ROS and Ca(2+), whereas addition of LaCl3 in them just resulted in the decrease of Ca(2+) levels, hardly making effects on NO and ROS levels. It was concluded that NO and ROS were involved in the apoptosis induced by SO2 in T. erecta, which regulated the cell apoptosis at the upstream of Ca(2+).

Preparation of porous PLA/DBM composite biomaterials and experimental research of repair rabbit radius segmental bone defect.

Bone substitutes are used in wide range of orthopaedic application. An ideal bone substitute should exhibit superior osteoinductive and osteoconductive properties. Neither bio-derived materials nor synthetic materials can meet the needs of an ideal bone substitute. Preparation of composite materials is a promising way to improve properties of biomaterial. In this study, the porous poly lactic acid (PLA)/demineralized bone matrix (DBM) composite biomaterials prepared by supercritical CO2 technique were implanted to repair rabbit radius segmental bone defect. By comparing with PLA and bone autograft, the X-ray result and histological analysis showed the repair effect of PLA/DBM porous composite materials is significantly better than that of the PLA group and the blank control group, and is similar to autologous bone. The PLA/DBM can promote the healing of bone defects and can be used as a kind of ideal alternative materials to repair bone defects.

A kidney-targeted chitosan-melanin nanoplatform for alleviating diabetic nephropathy through modulation of blood glucose and oxidative stress.

Diabetic nephropathy (DN) is a serious complication in patients with diabetes, whose expansion process is closely related to oxidative stress caused by hyperglycemia. Herein, we report a chitosan-targeted dagliflozin-loaded melanin nanoparticle (CSMDNPs) that can selectively accumulate in injured kidneys, reduce blood glucose, and alleviate the oxidative stress-induced damage. CSMDNPs possess good dispersion and physiological stability, responsive release at acidic pH, and strong scavenging activities for various reactive oxygen and reactive nitrogen radicals. Moreover, in vitro experiments confirm that CSMDNPs have good biocompatibility, enable targeted uptake in NRK-52E renal tubular cells, and also well alleviate high glucose-induced oxidative stress. In the STZ-induced DN model, CSMDNPs exhibit high targeting distribution and retention in the damaged kidneys of DN mice according to photoacoustic imaging. At the end of CSMDNPs treatment, DN mice show a decrease in fasting blood glucose and a return to near-normal urine and blood indices. H&E, PAS, and masson pathological staining also indicates that CSMDNPs significantly inhibit the expansion of renal interstitium, glycogen, and collagen deposition, showing excellent therapeutic effects. In addition, melanin acts as both drug carrier and antioxidant without exogenous carrier introduction, exhibiting better biosafety and translational prospects.

Priming and Combined Strategies for the Application of Mesenchymal Stem Cells in Ischemic Stroke: A Promising Approach.

Ischemic stroke (IS) is a leading cause of death and disability worldwide. Tissue plasminogen activator (tPA) administration and mechanical thrombectomy are the main treatments but have a narrow time window. Mesenchymal stem cells (MSCs), which are easily scalable in vitro and lack ethical concerns, possess the potential to differentiate into various types of cells and secrete a great number of growth factors for neuroprotection and regeneration. Moreover, MSCs have low immunogenicity and tumorigenic properties, showing safety and preliminary efficacy both in preclinical studies and clinical trials of IS. However, it is unlikely that MSC treatment alone will be sufficient to maximize recovery due to the low survival rate of transplanted cells and various mechanisms of ischemic brain damage in the different stages of IS. Preconditioning was used to facilitate the homing, survival, and secretion ability of the grafted MSCs in the ischemic region, while combination therapies are alternatives that can maximize the treatment effects, focusing on multiple therapeutic targets to promote stroke recovery. In this case, the combination therapy can yield a synergistic effect. In this review, we summarize the type of MSCs, preconditioning methods, and combined strategies as well as their therapeutic mechanism in the treatment of IS to accelerate the transformation from basic research to clinical application.

Case report: Anxiety and depression as initial symptoms in a patient with acute hypoxia and patent foramen ovale.

The prevalence of patent foramen ovale (PFO) is 15-35% among adults. The role of right-to-left shunting through the PFO, anxiety, depression, and hypoxemia in the systemic circulation remains poorly understood. Herein, we present the case of a 52-year-old woman with no heart or lung disease, who was admitted due to anxiety for 5 months and had symptom exacerbation with dizziness for 4 days and presented with cyanosis. She was noted to have acute hypoxemia, with an oxygen saturation of 94.48% on room air, and arterial blood gas showed an oxygen tension of 65.64 mmHg. Agitated saline contrast echocardiography showed right-to-left shunting due to PFO. Arteriovenous fistula, pneumonia, pulmonary embolism, pulmonary hypertension, congestion peripheral cyanosis, ischemic peripheral cyanosis, and methemoglobin were excluded. Additionally, the patient improved by taking Paroxetine, Oxazepam, and Olanzapine. Her oxygen tension returned to 90.42 mmHg, and her symptoms resolved. In the case of severe anxiety and depression, right-to-left shunting through the PFO may cause acute systemic hypoxemia via a flow-driven mechanism, occasionally manifesting as cyanosis. When anxiety improved, hypoxia also improved. Thus, the treatment of anxiety and depression seems effective in improving hypoxemia. Notably, this is a rare report, and we hope to draw the attention of psychosomatic specialists, psychiatrists, and clinicians to seek the relationship between anxiety appearing as acute stress and PFO. This may be a new therapeutic method for treating severe anxiety disorder.

Associations between triglyceride glucose index and depression in middle-aged and elderly adults: A cross-sectional study.

The pathogenesis of depression is unclear, and it responds poorly to treatment. It is thus urgent to identify the pathogenesis of depression and possible therapeutic targets. There may be interactions between insulin resistance (IR) and depression. The purpose of this study was to explore the relationship between depression, triglyceride glucose (TyG) index. The study participants were 198 middle-aged and elderly patients who were admitted to the Hebei General Hospital between January 1, 2021, and August 31, 2022, together with 189 healthy adults as controls. Depression was diagnosed according to ICD-10 diagnostic criteria for depression. IR was assessed by the TyG index. Compared with the control group, patients suffering from depression had higher TyG index (P = .00); There were significant differences in the sex ratio (P = .00), family history (P = .00), body mass index (P = .008), total cholesterol (P = .00), fasting blood glucose (P = .004), high-density lipoprotein (P = .00), and low-density lipoprotein (P = .001) levels between the 2 groups. After excluding other confounding factors, the TyG index was found to be independently associated with depression, with an OR of 2.75. These data support an association of depression with the TyG index. IR thus appears to be a risk factor for depression.

Surviving the shift: College student satisfaction with emergency online learning during COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) epidemic disrupted education systems by forcing systems to shift to emergency online leaning. Online learning satisfaction affects academic achievement. Many factors affect online learning satisfaction. However there is little study focused on personal characteristics, mental status, and coping style when college students participated in emergency online courses. AIM: To assess factors related to satisfaction with emergency online learning among college students in Hebei province during the COVID-19 pandemic. METHODS: We conducted a cross-sectional survey of 1600 college students. The collected information included demographics, psychological aspects of emergent public health events, and coping style. Single factor, correlation, and multiple linear regression analyses were performed to identify factors that affected online learning satisfaction. RESULTS: Descriptive findings indicated that 62.9% (994/1580) of students were satisfied with online learning. Factors that had significant positive effects on online learning satisfaction were online learning at scheduled times, strong exercise intensity, good health, regular schedule, focusing on the epidemic less than one hour a day, and maintaining emotional stability. Positive coping styles were protective factors of online learning satisfaction. Risk factors for poor satisfaction were depression, neurasthenia, and negative coping style. CONCLUSION: College students with different personal characteristics, mental status, and coping style exhibited different degrees of online learning satisfaction. Our findings provide reference for educators, psychologists, and school administrators to conduct health education intervention of college students during emergency online learning.

Temporal and spatial assembly of inner ear hair cell ankle link condensate through phase separation.

Stereocilia are actin-based cell protrusions of inner ear hair cells and are indispensable for mechanotransduction. Ankle links connect the ankle region of developing stereocilia, playing an essential role in stereocilia development. WHRN, PDZD7, ADGRV1 and USH2A have been identified to form the so-called ankle link complex (ALC); however, the detailed mechanism underlying the temporal emergence and degeneration of ankle links remains elusive. Here we show that WHRN and PDZD7 orchestrate ADGRV1 and USH2A to assemble the ALC through liquid-liquid phase separation (LLPS). Disruption of the ALC multivalency for LLPS largely abolishes the distribution of WHRN at the ankle region of stereocilia. Interestingly, high concentration of ADGRV1 inhibits LLPS, providing a potential mechanism for ALC disassembly. Moreover, certain deafness mutations of ALC genes weaken the multivalent interactions of ALC and impair LLPS. In conclusion, our study demonstrates that LLPS mediates ALC formation, providing essential clues for understanding the pathogenesis of deafness.

The characteristic of nonmotor symptoms with different phenotypes and onsets in multiple system atrophy patients.

OBJECTIVES: The characteristic of nonmotor symptoms in patients with multiple system atrophy (MSA) has varied among previous studies. The objective was to investigatethe nonmotor characteristics in MSA patients with different phenotypes, sex and different onset patterns. METHODS: We performed a retrospective review of 1492 MSA patients. All cases were evaluatedby neurologists and assessed with motormanifestations, nonmotor symptoms, auxiliary examinationand brain MRI scans. RESULTS: Multiple system atrophy-cerebellar ataxia (MSA-C) was the predominant phenotype in 998 patients. Average age of onset (56.8 ± 9.2 years) was earlier, the disease duration (2.4 ± 2.2 year) was shorter and brain MRI abnormalities (49.2 %) were more frequently in MSA-C (P < 0.001). Multiple system atrophy-parkinsonism (MSA-P) patients were more likely to have nonmotor symptoms. After adjusted significant parameters, urinary dysfunction (OR 1.441, 95 %CI = 1.067-1.946, P = 0.017), constipation (OR 1.482, 95 %CI = 1.113-1.973, P = 0.007), cognitive impairment (OR 1.509, 95 %CI = 1.074-2.121, P = 0.018) and drooling (OR 2.095, 95 %CI = 1.248-3.518, P = 0.005) were associated with the MSA-P phenotype. Males were more likely to have orthostatic hypotension, urinary dysfunction, sexual dysfunction, drooling and females in constipation and probable RBD. In different onset patterns, constipation (59.2 %) and probable RBD (28.4 %) were more frequently in autonomiconset pattern. CONCLUSIONS: MSA-C is the predominant phenotype in Chinese patients, while many nonmotor symptoms are more common in MSA-P phenotype. Patients with different sex and onset patterns have different nonmotor characteristics. The different clinical features identified could help the physician counseling of MSA patients more easily and more accurately.

FCHSD2 cooperates with CDC42 and N-WASP to regulate cell protrusion formation.

Actin-based, finger-like cell protrusions such as microvilli and filopodia play important roles in epithelial cells. Several proteins have been identified to regulate cell protrusion formation, which helps us to learn about the underlying mechanism of this process. FCH domain and double SH3 domains containing protein 2 (FCHSD2) belongs to the FCH and Bin-Amphiphysin-Rvs (F-BAR) protein family, containing an N-terminal F-BAR domain, two SH3 domains, and a C-terminal PDZ domain-binding interface (PBI). Previously, we found that FCHSD2 interacts with WASP/N-WASP and stimulates ARP2/3-mediated actin polymerization in vitro. In the present work, we show that FCHSD2 promotes the formation of apical and lateral cell protrusions in cultured cells. Our data suggest that FCHSD2 cooperates with CDC42 and N-WASP in regulating apical cell protrusion formation. In line with this, biochemical studies reveal that FCHSD2 and CDC42 simultaneously bind to N-WASP, forming a protein complex. Interestingly, the F-BAR domain of FCHSD2 induces lateral cell protrusion formation independently of N-WASP. Furthermore, we show that the ability of FCHSD2 to induce cell protrusion formation requires its plasma membrane-binding ability. In summary, our present work suggests that FCHSD2 cooperates with CDC42 and N-WASP to regulate cell protrusion formation in a membrane-dependent manner.

Simulating flash flood hydrographs and behavior metrics across China: Implications for flash flood management.

China frequently suffers from considerable and disastrous flash floods with wide areal coverage and high frequency. Obtaining useful information to support flash flood management and decision-making is challenging for massive flash flood events that vary greatly in spatio-temporal characteristics. In this study, hydrological modelling approach (CNFF) and cluster analysis were integrated to assess simulation reliability of entire flash flood processes including both hydrographs and behavior characteristics in a manner of similarity classification, rather than at event scale. A total of 207 hourly events from 13 mountainous catchments with diverse physiographic and meteorological characteristics across China were selected for study. Representative flash flood types were classified using normalized hydrographs with diverse spatio-temporal patterns by k-means clustering algorithm. For individual flash flood types, simulation reliability of CNFF was assessed in capturing corresponding hydrographs, seven behavior metrics measuring flash flood magnitude, intensity, occurrence time, flood timescale, rates of change and variability, and their uncertainties. Results showed that three (fast, intermediate and slow) flash flood types were identified from all the flash flood events with overall average silhouette index of 0.45. Hourly hydrographs of three flash flood types were well reproduced by CNFF, with absolute average relative error of runoff within 15% and Nash-Sutcliffe Efficiency above 0.55. All the behavior metrics were the most accurately reproduced for slow flash flood type with the least average relative root-mean-square error (0.30), followed by intermediate (0.52) and fast (0.58) types. Moreover, the slow flash flood type had the most reliable but greatest uncertainty interval of both hydrograph and behavior metrics, with average relative interval length being 1.24 and 71.96%, and 93.10% and 100% of observations contained in 95% confidence interval, respectively. This study provided efficient and detailed information for flash flood management, and extended application scope of hydrological models to encompass flash flood types and behavior metrics.

The Rho GTPase Cell Division Cycle 42 Regulates Stereocilia Development in Cochlear Hair Cells.

Stereocilia are actin-based cell protrusions on the apical surface of inner ear hair cells, playing a pivotal role in hearing and balancing sensation. The development and maintenance of stereocilia is tightly regulated and deficits in this process usually lead to hearing or balancing disorders. The Rho GTPase cell division cycle 42 (CDC42) is a key regulator of the actin cytoskeleton. It has been reported to localize in the hair cell stereocilia and play important roles in stereocilia maintenance. In the present work, we utilized hair cell-specific Cdc42 knockout mice and CDC42 inhibitor ML141 to explore the role of CDC42 in stereocilia development. Our data show that stereocilia height and width as well as stereocilia resorption are affected in Cdc42-deficient cochlear hair cells when examined at postnatal day 8 (P8). Moreover, ML141 treatment leads to planar cell polarity (PCP) deficits in neonatal hair cells. We also show that overexpression of a constitutively active mutant CDC42 in cochlear hair cells leads to enhanced stereocilia developmental deficits. In conclusion, the present data suggest that CDC42 plays a pivotal role in regulating hair cell stereocilia development.