Mutations in PKD1 and TRPP2 account for nearly all cases of autosomal dominant polycystic kidney disease (ADPKD). These 2 proteins form a receptor/ion channel complex on the cell surface. Using a ...combination of biochemistry, crystallography, and a single-molecule method to determine the subunit composition of proteins in the plasma membrane of live cells, we find that this complex contains 3 TRPP2 and 1 PKD1. A newly identified coiled-coil domain in the C terminus of TRPP2 is critical for the formation of this complex. This coiled-coil domain forms a homotrimer, in both solution and crystal structure, and binds to a single coiled-coil domain in the C terminus of PKD1. Mutations that disrupt the TRPP2 coiled-coil domain trimer abolish the assembly of both the full-length TRPP2 trimer and the TRPP2/PKD1 complex and diminish the surface expression of both proteins. These results have significant implications for the assembly, regulation, and function of the TRPP2/PKD1 complex and the pathogenic mechanism of some ADPKD-producing mutations.
Dysferlin is a sarcolemmal protein present in muscle cells. It is responsible for muscle membrane repair. Dysferlin gene (DYSF) mutation, resulting in deficiency in this protein, is termed ...dysferlinopathy. Clinically, it manifests as early adulthood onset of muscle weakness with markedly elevated creatine kinase levels. The main phenotypes are limb-girdle muscular dystrophy type 2B (LGMD2B), affecting proximal muscles, and Miyoshi myopathy (MM), affecting distal muscles. Dysferlin is also present in cardiomyocytes, and case reports have emerged of cardiac abnormalities in dysferlinopathy. While routine methods of cardiac screening, namely, electrocardiography or echocardiography, are convenient and noninvasive, they often exhibit insufficient diagnostic sensitivity for detecting subclinical cardiac remodeling during early stages of cardiomyopathy. Cardiac magnetic resonance imaging though can provide accurate assessment of cardiac chamber sizes and function. With gadolinium administration, it can also detect areas of myocardial scarring and fibrosis. Early diagnosis of neuromuscular disease-related cardiomyopathy is of clinical significance, as appropriate treatment can retard myocardial fibrosis, delaying cardiomyopathy progression. We present a case of a patient with MM incidentally diagnosed with concomitant cardiomyopathy.
Abstract Many drugs used for chronic illnesses can contribute to dry eye syndrome, and elderly patients who have dry eye may concurrently be on systemic medications that worsen the condition. Such ...medications include anticholinergic drugs, eg, antidepressant, antipsychotic, anti-Parkinson's disease, and antihistamine drugs. Other drugs such as anti-acne preparations and antihypertensives can also cause dry eye. In some cases, the adverse effects of the drug on dry eye is dose-related and can be relieved by reducing the dosage. Alternatively, a different drug within the same drug family may alleviate the dry eye problem. Awareness of the drugs that contribute to dry eye will allow ophthalmologists and other physicians to better manage patients who have this common problem.
The aim of this study was to investigate the effects of cold stress on oxidative indexes, immune function, and the expression levels of heat shock protein (Hsp90, Hsp70, Hsp60, Hsp40, and Hsp27) in ...immune organs of chickens. Two hundred forty 15-day-old male chickens were randomly divided into 12 groups and kept under the temperature of (12 ± 1) °C for acute and chronic cold stress. There were one control group and five treatment groups for acute cold stress and three control groups and three treatment groups for chronic cold stress. The results showed that cold stress influence the activities of antioxidant enzymes in the immune organs. The activities of SOD and GSH-Px were first increased then decreased, and activity of total antioxidation capacity (T-AOC) was significantly decreased (P<0.05) at the acute cold stress in chicks; however, T-AOC activities were significantly increased (P<0.05) at the chronic cold stress in these tissues. Cold stress induced higher level of malondialdehyde (MDA) in chicken immune organs. In addition, the cytokine contents were increased in cold stress groups. As one protective factor, the expression levels of Hsps were increased significantly (P<0.05) in both cold stress groups. These results suggested that cold stress induced the oxidative stress in the three tissues and influenced immune function of chicks. Higher expression of Hsps (Hsp90, Hsp70, Hsp60, Hsp40, and Hsp27) may play a role in protecting immune organs against cold stress.
Ultrasound-guided techniques are increasingly prevalent and represent a gold standard of care. Skills such as needle visualisation, optimising the target image and directing the needle require ...deliberate practice. However, training opportunities remain limited by patient case load and safety considerations. Hence, there is a genuine and urgent need for trainees to attain accelerated skill acquisition in a time- and cost-efficient manner that minimises risk to patients. We propose a two-step solution: First, we have created an agar phantom model that simulates human tissue and structures like vessels and nerve bundles. Moreover, we have adopted deep learning techniques to provide trainees with live visualisation of target structures and automate assessment of their user speed and accuracy. Key structures like the needle tip, needle body, target blood vessels, and nerve bundles, are delineated in colour on the processed image, providing an opportunity for real-time guidance of needle positioning and target structure penetration. Quantitative feedback on user speed (time taken for target penetration), accuracy (penetration of correct target), and efficacy in needle positioning (percentage of frames where the full needle is visualised in a longitudinal plane) are also assessable using our model. Our program was able to demonstrate a sensitivity of 99.31%, specificity of 69.23%, accuracy of 91.33%, precision of 89.94%, recall of 99.31%, and F1 score of 0.94 in automated image labelling.
To evaluate the efficacy and safety of latanoprost compared with timolol in the treatment of Asian patients with chronic angle-closure glaucoma (CACG).
Relevant trials were identified through ...systematic searches of Medline, EMBASE, PubMed, Cochrane Library, Google Scholar and several Chinese databases. The main outcome measures included absolute and relative reduction of intraocular pressure (IOP) at mean, peak and trough from baseline, ocular adverse effects and systemic adverse events.
Seven randomized controlled trials with 685 patients were included. In comparison with timolol, latanoprost reduced absolute IOP in CACG patients by more than 2.3 mmHg (95%CI, 1.8∼2.9, P<0.01), 2.4 mmHg (95%CI, 1.9∼2.9, P<0.01) and 2.5 mmHg (95%CI, 1.6∼3.3, P<0.01) at mean, peak and trough, respectively. As for relative IOP, there is 9.0% (95%CI, 6.6∼11.4, P<0.01), 9.7% (95%CI, 7.6∼11.8, P<0.01), and 10.8% (95%CI, 7.4∼14.3, P<0.01) greater reduction among latanoprost users than among timolol users. The differences were statistically significant at all time points (1, 2, 4, 8, 12, and 24 weeks). More ocular adverse effects (OR = 1.49, 95% CI, 1.05∼2.10, P = 0.02) and less systemic adverse events (OR = 0.46, 95% CI, 0.25∼0.84, P = 0.01) were observed in latanoprost group in comparison with timolol group.
Compared with timolol, latanoprost was significantly more effective in lowering IOP of Asian patients with CACG, with higher risk of ocular adverse effects but lower risk of systemic adverse events, and might be a good substitute for CACG patients.
In this paper, improved transponders with multistage automatic gain control (AGC) for radio-over-fiber-based distributed antenna systems are presented. Error vector magnitude performance measurements ...for both uplink and downlink paths are carried out to verify the feasibility of applying this system for IEEE 802.11g signal transmission. The developed conventional radio-over-fiber system shows its capability of supporting the wireless local area network signal transmission for an input dynamic range of approximately 14 dB. The improved radio-over-fiber systems with a single- and two-stage AGC are also demonstrated to have a better input dynamic range of 27 dB and more than 37 dB, respectively. The error vector magnitude for the case with a two-stage AGC is much better than that with a single-stage AGC.
Frank-Ter Haar syndrome (FTHS, MIM #249420) is a rare skeletal dysplasia within the defective collagen remodelling spectrum (DECORS), which is characterised by craniofacial abnormalities, skeletal ...malformations and fibrotic soft tissues changes including dermal fibrosis and joint contractures. FTHS is caused by homozygous or compound heterozygous loss-of-function mutation or deletion of
(Src homology 3 and Phox homology domain-containing protein 2B; MIM #613293).
encodes an adaptor protein with the same name, which is required for full functionality of podosomes, specialised membrane structures involved in extracellular matrix (ECM) remodelling. The pathogenesis of DECORS is still incompletely understood and, as a result, therapeutic options are limited. We previously generated an
knockout zebrafish and demonstrated that it primarily mimics the DECORS-related bone abnormalities. Here, we present a novel
mutant zebrafish,
, which primarily reflects the DECORS-related dermal fibrosis and contractures. In addition to relatively mild skeletal abnormalities,
mutants develop dermal and musculoskeletal fibrosis, contraction of which seems to underlie grotesque deformations that include kyphoscoliosis, abdominal constriction and lateral folding. The discrepancy in phenotypes between
and
mutants suggests that in fish, as opposed to humans, there are differences in spatiotemporal dependence of ECM remodelling on either
or
The
model presented here can be used to further delineate the underlying mechanism of the fibrosis observed in DECORS, as well as screening and subsequent development of novel drugs targeting DECORS-related fibrosis.This paper has an associated First Person interview with the first author of the article.
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