Heterozygous Variants in KCNJ10 Cause Paroxysmal Kinesigenic Dyskinesia Via Haploinsufficiency.

OBJECTIVE: Most paroxysmal kinesigenic dyskinesia (PKD) cases are hereditary, yet approximately 60% of patients remain genetically undiagnosed. We undertook the present study to uncover the genetic basis for undiagnosed PKD patients. METHODS: Whole-exome sequencing was performed for 106 PRRT2-negative PKD probands. The functional impact of the genetic variants was investigated in HEK293T cells and Drosophila. RESULTS: Heterozygous variants in KCNJ10 were identified in 11 individuals from 8 unrelated families, which accounted for 7.5% (8/106) of the PRRT2-negative probands. Both co-segregation of the identified variants and the significantly higher frequency of rare KCNJ10 variants in PKD cases supported impacts from the detected KCNJ10 heterozygous variants on PKD pathogenesis. Moreover, a KCNJ10 mutation-carrying father from a typical EAST/SeSAME family was identified as a PKD patient. All patients manifested dystonia attacks triggered by sudden movement with a short episodic duration. Patch-clamp recordings in HEK293T cells revealed apparent reductions in K+ currents of the patient-derived variants, indicating a loss-of-function. In Drosophila, milder hyperexcitability phenotypes were observed in heterozygous Irk2 knock-in flies compared to homozygotes, supporting haploinsufficiency as the mechanism for the detected heterozygous variants. Electrophysiological recordings showed that excitatory neurons in Irk2 haploinsufficiency flies exhibited increased excitability, and glia-specific complementation with human Kir4.1 rescued the Irk2 mutant phenotypes. INTERPRETATION: Our study established haploinsufficiency resulting from heterozygous variants in KCNJ10 can be understood as a previously unrecognized genetic cause for PKD and provided evidence of glial involvement in the pathophysiology of PKD. ANN NEUROL 2024.

Effects of the nutrient inhibition on the yield of DBPFPs by Microcystis aeruginosa.

The yield of three disinfection byproduct formation potentials (DBPFPs), including trichloromethane, dichloroacetic acid and trichloroacetic acid formation potential (TCMFP, DCAAFP and TCAAFP), by Microcystis aeruginosa under the nitrate and phosphate inhibition conditions was investigated. The results showed that excessive nitrate could inhibit the growth of M. aeruginosa, but the concentration of DBPFPs in the five fractions of algal metabolites, including hydrophilic extracellular organic matter (EOM), hydrophobic EOM, hydrophilic intracellular organic matter, hydrophobic intracellular organic matter and cell debris, only decreased slightly. Accordingly, the productivity of DBPFPs by M. aeruginosa increased by approximately 40% under the nitrate inhibition condition and the increased productivity of DBPFPs mainly came from EOM. The phosphate inhibition also performed a similar pattern with a lesser extent. The nutrient inhibition did not change the proportion of these three DPBFPs, and TCMFP accounted for approximately 87% of the total DBPFPs. The inhibition could promote M. aeruginosa to secrete more metabolites. However, the cyanobacteria tended to secrete more DBPFPs under the nitrate inhibition condition, which resulted in an increased specific DBPFP, while they tended to secrete more non-DBPFPs under the phosphate inhibition condition, which resulted in a decreased specific DBPFP.

Exploration of a nomogram prediction model of 30-day survival in adult ECMO patients.

Objective: To investigate the factors of 30-day survival in ECMO patients, establish a nomogram model, and evaluate the predictive value of the model. Methods: A total of 105 patients with extracorporeal membrane oxygenation (ECMO) were admitted to the Department of Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, from January 2018 to March 2021. Cox regression analysis screened out the risk factors. Based on the results of multivariate analysis, the nomogram model was established by using R software, and the discrimination of the model was verified by bootstrap and calibration. Results: The results showed that sex, acute physiology and chronic health evaluation (APACHE) II score, disseminated intravascular coagulation (DIC) score before ECMO initiation and average daily dose of norepinephrine were independent risk factors for prognosis. Verify that the nomogram model is verified by bootstrap internally, and the corrected C-index is C-index: 0.886, showing a good degree of discrimination. The calibration curve (calibration) showed that the nomogram model had good agreement. The decision curve analysis(DCA) curve shows good clinical validity above the two extreme curves. Kaplan-Meier curves were drawn for patients in the tertile and compared with the first and second groups. The third group predicted the worst 30-day prognosis for ECMO patients. Conclusion: The nomogram prediction model constructed based on the sex, APACHE II and DIC score, average daily dose of norepinephrine can effectively screen out the factors affecting the prognosis and provide a reference for individualized treatment of ECMO patients.

Suppression of SMOC2 alleviates myocardial fibrosis via the ILK/p38 pathway.

Background: Fibrosis of the myocardium is one of the main pathological changes of adverse cardiac remodeling, which is associated with unsatisfactory outcomes in patients with heart disease. Further investigations into the precise molecular mechanisms of cardiac fibrosis are urgently required to seek alternative therapeutic strategies for individuals suffering from heart failure. SMOC2 has been shown to be essential to exert key pathophysiological roles in various physiological processes in vivo, possibly contributing to the pathogenesis of fibrosis. A study investigating the relationship between SMOC2 and myocardial fibrosis has yet to be conducted. Methods: Mice received a continuous ISO injection subcutaneously to induce cardiac fibrosis, and down-regulation of SMOC2 was achieved by adeno-associated virus-9 (AAV9)-mediated shRNA knockdown. Neonatal fibroblasts were separated and cultured in vitro with TGFß to trigger fibrosis and infected with either sh-SMOC2 or sh-RNA as a control. The role and mechanisms of SMOC2 in myocardial fibrosis were further examined and analyzed. Results: SMOC2 knockdown partially reversed cardiac functional impairment and cardiac fibrosis in vivo after 21 consecutive days of ISO injection. We further demonstrated that targeting SMOC2 expression effectively slowed down the trans-differentiation and collagen deposition of cardiac fibroblasts stimulated by TGFß. Mechanistically, targeting SMOC2 expression inhibited the induction of ILK and p38 in vivo and in vitro, and ILK overexpression increased p38 phosphorylation activity and compromised the protective effects of sh-SMOC2-mediated cardiac fibrosis. Conclusion: Therapeutic SMOC2 silencing alleviated cardiac fibrosis through inhibition of the ILK/p38 signaling, providing a preventative and control strategy for cardiac remodeling management in clinical practice.

Identification and expression analysis of the ZRT, IRT-like protein (ZIP) gene family in Camellia sinensis (L.) O. Kuntze.

The ZRT, IRT-like protein (ZIP) family plays an essential role in the homeostasis of zinc and iron in plants. However, studies on this family are mainly limited to model species. Here, 12 CsZIPs were identified and investigated the function in Camellia sinensis, being named CsZIP1-12 and divided into four different groups based on phylogenetic relationships. These CsZIPs contained 2-9 TMDs and other conserved motifs for ZIP proteins. And CsZIPs were located in cell membrane, excepting for CsZIP4 and CsZIP6. The expression of CsZIPs were different in varieties and organs of tea plants. They were involved in the response process of abiotic stresses, such as NaCl, drought, cold and exogenous Me-JA. In addition, 31 types of promoter elements were identified in the CsZIPs, including core promoters, light responsiveness, stress responsive and other elements. The CsZIP1, CsZIP2, CsZIP4, CsZIP5, CsZIP6, CsZIP11 and CsZIP12 could be induced by zinc deficiency and 50 µM Zn treatment, but CsZIP7 and CsZIP8 were up regulated by 300 µM Zn. Heterogeneous complementation analysis showed that CsZIP1, CsZIP2, CsZIP7 and CsZIP8 could complement the Zn sensitivity of △zrc1cot1 yeast double mutant. There was a positive correlation between the expression of CsZIPs and secondary metabolites in tea plant. Together, our analysis of CsZIPs could provide comprehensive insights on the structure and function of this protein family in the regulation of zinc and ion homeostasis in the tea plant.

Performing Precise Biopsy in Naive Patients With Equivocal PI-RADS, Version 2, Score 3, Lesions: An MRI-based Nomogram to Avoid Unnecessary Surgical Intervention.

PURPOSE: The primary objective of the present study was to avoid unnecessary prostate biopsy in biopsy-naive patients with Prostate Imaging Reporting and Data System, version 2 (PI-RADS v2), score 3, lesions. MATERIALS AND METHODS: We reviewed our prospectively maintained database from January 2012 to July 2018. Logistic regression analyses were performed to test different clinical factors as predictors of clinically significant prostate cancer (CSPCa) and build nomograms. Calibration curves were used to assess the concordance between the predictive value and the true risk. Decision curves were created to measure the overall net benefit. RESULTS: The prostate cancer (PCa) and CSPCa detection rates were 37.2% (81 of 218) and 23.9% (52 of 218) in the PI-RADS v2, score 3, cohort. More PCa cases (61.7%; 50 of 81) and CSPCa cases (75%; 39 of 52) were found in the peripheral zone than in the transitional zone. Multivariate analysis showed that age, prostate-specific antigen density, lesion region, and apparent diffusion coefficient (ADC) were predictive factors for CSPCa and PCa. Internally validated calibration curves showed that the predicted risk of CSPCa was closer to the actual probability when the threshold was > 60%. Decision curves showed that a better net benefit was achieved when the model was used to guide clinical practice. CONCLUSIONS: More cases of PCa and CSPCa were seen in the peripheral zone than in the transitional zone among patients with PI-RADS v2, score 3. The positive predictive value for a positive ADC (< 900 µm2/s) for the detection of CSPCa and PCa improved with an increasing prostate-specific antigen density. Biopsy can be avoided if the equivocal lesion has a negative ADC (> 900 µm2/s) and was in the transition zone.

Video-Based Pedestrian Re-Identification by Adaptive Spatio-Temporal Appearance Model.

Pedestrian re-identification is a difficult problem due to the large variations in a person's appearance caused by different poses and viewpoints, illumination changes, and occlusions. Spatial alignment is commonly used to address these issues by treating the appearance of different body parts independently. However, a body part can also appear differently during different phases of an action. In this paper, we consider the temporal alignment problem, in addition to the spatial one, and propose a new approach that takes the video of a walking person as input and builds a spatiotemporal appearance representation for pedestrian re-identification. Particularly, given a video sequence, we exploit the periodicity exhibited by a walking person to generate a spatiotemporal body-action model, which consists of a series of body-action units corresponding to certain action primitives of certain body parts. Fisher vectors are learned and extracted from individual body-action units and concatenated into the final representation of the walking person. Unlike previous spatiotemporal features that only take into account local dynamic appearance information, our representation aligns the spatiotemporal appearance of a pedestrian globally. Extensive experiments on public data sets show the effectiveness of our approach compared with the state of the art.