Usher syndrome type 2 (USH2) is the predominant form of USH, a leading genetic cause of combined deafness and blindness. PDZD7, a paralog of two USH causative genes, USH1C and USH2D (WHRN), was recently reported to be implicated in USH2 and non-syndromic deafness. It encodes a protein with multiple PDZ domains. To understand the biological function of PDZD7 and the pathogenic mechanism caused by PDZD7 mutations, we generated and thoroughly characterized a Pdzd7 knockout mouse model. The Pdzd7 knockout mice exhibit congenital profound deafness, as assessed by auditory brainstem response, distortion product otoacoustic emission and cochlear microphonics tests, and normal vestibular function, as assessed by their behaviors. Lack of PDZD7 leads to the disorganization of stereocilia bundles and a reduction in mechanotransduction currents and sensitivity in cochlear outer hair cells. At the molecular level, PDZD7 determines the localization of the USH2 protein complex, composed of USH2A, GPR98 and WHRN, to ankle links in developing cochlear hair cells, likely through its direct interactions with these three proteins. The localization of PDZD7 to the ankle links of cochlear hair bundles also relies on USH2 proteins. In photoreceptors of Pdzd7 knockout mice, the three USH2 proteins largely remain unchanged at the periciliary membrane complex. The electroretinogram responses of both rod and cone photoreceptors are normal in knockout mice at 1 month of age. Therefore, although the organization of the USH2 complex appears different in photoreceptors, it is clear that PDZD7 plays an essential role in organizing the USH2 complex at ankle links in developing cochlear hair cells. GenBank accession numbers: KF041446, KF041447, KF041448, KF041449, KF041450, KF041451.
) and the NCX inhibitor, SEA0400, were used to study the physiological role of NCX1 in mouse mesenteric arteries. NCX1 protein expression was greatly reduced in arteries from NCX1 SMϪ/Ϫ mice generated with Cre recombinase. Mean blood pressure (BP) was 6 -10 mmHg lower in NCX1 SMϪ/Ϫ mice than in wild-type (WT) controls. Vasoconstriction was studied in isolated, pressurized mesenteric small arteries from WT and NCX1 SMϪ/Ϫ mice and in heterozygotes with a global null mutation (NCX1 Fx/Ϫ ). Reduced NCX1 activity was manifested by a marked attenuation of responses to low extracellular Na ϩ concentration, nanomolar ouabain, and SEA0400. Myogenic tone (MT, 70 mmHg) was reduced by ϳ15% in NCX1 SMϪ/Ϫ arteries and, to a similar extent, by SEA0400 in WT arteries. MT (21, 48). Moreover, the SM-specific overexpression of NCX elevates BP and induces salt-dependent hypertension, and SEA0400 lowers BP in several salt-dependent animal models (21). Indeed, NCX type-1 (NCX1) is upregulated in mesenteric arteries from rats with ouabain-induced hypertension (33) and pulmonary arteries from humans with primary pulmonary hypertension (49). Whether NCX is involved in maintaining normal BP, however, has not been resolved. Here we employ a SM-specific knockout approach to examine the role of NCX in arterial contractility and the maintenance of vascular tone and BP.Three isoforms of NCX have been identified: NCX1 is abundant in the heart and is ubiquitously expressed, whereas NCX2 and NCX3 are both restricted to brain and skeletal muscle (34). NCX1 is the only isoform present in ASMCs, where two splice variants, NCX1.3 and NCX1.7, are expressed (27,35). In cardiac myocytes, NCX1 makes a major contribution to Ca 2ϩ extrusion during diastole (3, 11). Nevertheless, cardiac-specific NCX1 knockout mice thrive: the loss of NCX1 is compensated by a reduced L-type voltage-gated Ca 2ϩ channel (LVGC) current and a shortened action potential because of accelerated Ca 2ϩ -dependent LVGC inactivation and augmented transient outward K ϩ current (18,31,32). Importantly, cardiac NCX1-mediated Ca 2ϩ flux must be inward during depolarization and systole (5). The situation is complicated, however, because exchanger-mediated fluxes depend on the relative activation of the exchanger, governed by cytosolic Na ϩ and Ca 2ϩ (26), as well as on the net driving force, governed by the membrane potential (V m ) and the Na ϩ and Ca 2ϩ electrochemical gradients (5
Aims: Vascular calcification is a risk factor for causing cardiovascular events and has a high prevalence among chronic kidney disease (CKD) patients. However, the molecular mechanism underlying this pathogenic process is still obscure. Methods: Vascular smooth muscle cells (VSMCs) were induced by a concentration of phosphorus (Pi) of 2.5 m
The aim of this study was to analyze the behavior of the porous nano-hydroxyapatite/polyamide 66 (n-HA/PA66) composite grafted for bone defect repair through a series of biological safety experiments, animal experiments, and a more than 5-year long clinical follow-up. The biological safety experiments, carried out in accordance with the Chinese Guo Biao and Tolerancing (GB/T)16886 and GB/T16175, revealed that porous n-HA/PA66 composite had no cytotoxicity, no sensitization effect, no pyrogenic reaction, and that its hemolysis rate was 0.59% (less than 5%). Rabbit models of tibia defects with grafted porous n-HA/PA66 composite were established. After 2 weeks, the experiment showed that osteogenesis was detected in the porous n-HA/PA66 composite; the density of new bone formation was similar to the surrounding host bone at 12 weeks. After 26 weeks, the artificial bone rebuilt to lamellar bone completely. In the clinical study, a retrospective review was carried out for 21 patients who underwent serial radiographic assessment after treatment with porous n-HA/PA66 composite grafts following bone tumor resection. All wounds healed to grade A. No postoperative infections, delayed deep infection, nonspecific inflammation, rejection, or fractures were encountered. At a mean follow-up of 5.3 years, the mean Musculoskeletal Tumor Society’s (MSTS) 93 score was 29.3 points (range: 28–30 points) and mean radiopaque density ratio was 0.77±0.10. The radiologic analysis showed that porous n-HA/PA66 composite had been completely incorporated with the host bone about 1.5 years later. In conclusion, this study indicated that the porous n-HA/PA66 composite had biological safety, and good biocompatibility, osteoinduction, and osseointegration. Thus, the porous n-HA/PA66 composite is an ideal artificial bone substitute and worthy of promotion in the field.
Intracerebral injection of mCMV preferentially causes mCMV-mediated hearing loss relative to IP or TT injections. These results are consistent with the hearing loss reported in human congenital infection and may have implications for understanding the pathophysiology of CMV-mediated labyrinthitis.
Background To compare the clinical efficacy of a femoral neck system (FNS) and cannulated screws (CS) in the treatment of femoral neck fracture in young adults. Methods Data from 69 young adults, who were admitted for femoral neck fracture between March 2018 and June 2020, were retrospectively analyzed. Patients were divided into two groups according to surgical method: FNS and CS. The number of intraoperative fluoroscopies, operative duration, length of hospital stay, fracture healing time, Harris score of hip function, excellent and good rate of hip function, and postoperative complications (infection, cut out the internal fixation, nail withdrawal, and femoral neck shortening) were compared between the two groups. Hip joint function was evaluated using the Harris Hip Scoring system. Results All 69 patients had satisfactory reduction and were followed up for 12–24 months, with a mean follow-up of 16.91 ± 3.01 months. Mean time to fracture healing was13.82 ± 1.59 and 14.03 ± 1.78 weeks in the FNS and CS groups, respectively. There was a statistical difference in the number of intraoperative fluoroscopies between the 2 groups (P = 0.000). There were no significant differences, in operation duration, hospital length of stay, fracture healing time, complications, Harris Hip Score for hip function and excellent and good rate between the two groups (P > 0.05). The incidence of complications was 6.1%(2/33) in the FNS group lower than 25%(9/36) in the CS group, a difference that was statistically significant (P = 0.032). At the last follow-up, the Harris Hip Score of the hip joint in the FNS group was 90.42 ± 4.82and 88.44 ± 5.91 in the CS group. Conclusions Both treatment methods resulted in higher rates of fracture healing and excellent hip function. Compared with CS, the FNS reduced the number of intraoperative fluoroscopies, radiation exposure to medical staff and patients, and short-term complications including femoral neck shortening and bone nonunion.
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