OTUD1 promotes hypertensive kidney fibrosis and injury by deubiquitinating CDK9 in renal epithelial cells.

Hypertensive renal disease (HRD) contributes to the progression of kidney dysfunction and ultimately leads to end-stage renal disease. Understanding the mechanisms underlying HRD is critical for the development of therapeutic strategies. Deubiquitinating enzymes (DUBs) have been recently highlighted in renal pathophysiology. In this study, we investigated the role of a DUB, OTU Domain-Containing Protein 1 (OTUD1), in HRD models. HRD was induced in wild-type or Otud1 knockout mice by chronic infusion of angiotensin II (Ang II, 1 µg/kg per min) through a micro-osmotic pump for 4 weeks. We found that OTUD1 expression levels were significantly elevated in the kidney tissues of Ang II-treated mice. Otud1 knockout significantly ameliorated Ang II-induced HRD, whereas OTUD1 overexpression exacerbated Ang II-induced kidney damage and fibrosis. Similar results were observed in TCMK-1 cells but not in SV40 MES-13 cells following Ang II (1 µM) treatment. In Ang II-challenged TCMK-1 cells, we demonstrated that OTUD1 bound to CDK9 and induced CDK9 deubiquitination: OTUD1 catalyzed K63 deubiquitination on CDK9 with its Cys320 playing a critical role, promoting CDK9 phosphorylation and activation to induce inflammatory responses and fibrosis in kidney epithelial cells. Administration of a CDK9 inhibitor NVP-2 significantly ameliorated Ang II-induced HRD in mice. This study demonstrates that OTUD1 mediates HRD by targeting CDK9 in kidney epithelial cells, suggesting OTUD1 is a potential target in treating this disease.

[Buyang Huanwu Decoction promotes arteriogenesis after hindlimb ischemia in mice by activating PDGF signaling pathway].

This study aims to investigate the effect of Buyang Huanwu Decoction on blood flow recovery and arteriogenesis after hindlimb ischemia in mice via the platelet-derived growth factor(PDGF) signaling pathway. Forty C57BL/6 mice were randomized into model(clean water, 10 mL·kg~(-1)·d~(-1)), beraprost sodium(positive control, 18 µg·kg~(-1)·d~(-1)), and low-, medium-, and high-dose(10, 20, and 40 g·kg~(-1)·d~(-1), respectively) Buyang Huanwu Decoction groups(n=8). The hindlimb ischemia model was established by femoral artery ligation. The mice were administrated with corresponding agents by gavage daily for 14 days after ligation. For laser Doppler perfusion imaging, the mice were anesthetized and measured under a Periscan PSI imager. The density of capillary and arterio-le in the ischemic gastrocnemius was measured using immunofluorescence staining of the frozen tissue sections. Western blot was employed to determine the expression of PDGF subunit B(PDGFB), phosphorylated mitogen extracellular kinase(p-MEK), MEK, phosphorylated extracellular signal-regulated kinase(p-ERK), and ERK. Real-time PCR was employed to determine the mRNA level of PDGFB. The Buyang Huanwu Decoction-containing serum was used to treat the vascular smooth muscle cells(VSMCs) in hypoxia at doses of 10% and 20%. The proliferation and migration of VSMCs was assessed in vitro. The results showed that compared with the model group, beraprost sodium and Buyang Huanwu Decoction enhanced the blood flow recovery, increased the capillary and arteriole density, and up-regulated the protein levels of PDGFB, p-MEK, p-ERK, and mRNA levels of PDGFB, with the medium-dose Buyang Huanwu Decoction demonstrating the most significant effect. The 10% Buyang Huanwu Decoction-containing serum enhanced the proliferation and migration of VSMCs. Our findings demonstrate that Buyang Huanwu Decoction up-regulates PDGFB transcription and activates PDGF signaling pathway to promote arteriogenesis and blood flow recovery in ischemic gastrocnemius.

The Chinese medaka (Oryzias sinensis) dmrt1 gene converts females to males in medaka (Oryzias latipes).

BACKGROUND: Chinese medaka (Oryzias sinensis) is widely distributed in freshwater rivers in China. Similar to the medaka (Oryzias latipes), Chinese medaka has the characteristics of small size, rapid reproductive cycle, and strong adaptability, which makes it suitable as a model organism for studies in basic biology and environmental toxicology. Chinese medaka exhibits distinct sexual dimorphism. However, due to the lack of complete genomic information, the regulation of sex determination and differentiation-related genes in Chinese medaka remains unclear. METHODS: Chinese medaka dmrt1 (Osdmrt1) was cloned by PCR, and transgenic individuals of medaka [Tg(CMV:Osdmrt1)] overexpressing Osdmrt1 were generated to investigate the role of Osdmrt1 in sex determination. Western blot was used to validate the integration of the Osdmrt1 into the medaka genome. Tissue sectioning and HE staining were used to identify Tg(CMV:Osdmrt1) physiological gender and phenotype. qRT-PCR was used to analyze the expression of gonad-specific genes. RESULTS: Osdmrt1 was cloned and identified, and it shared similar evolutionary relationships with medaka dmrt1. Tg(CMV:Osdmrt1) exhibited partial sex reversal from female to male in the F2 generation, with genetically female individuals developing testes and producing functional sperm. Additionally, the secondary sexual characteristics of the transgenic females also changed to males. CONCLUSION: The Chinese medaka dmrt1 gene could convert females to males in medaka. GENERAL SIGNIFICANCE: These results not only elucidate the function of Chinese medaka dmrt1, but also accumulate knowledge for studying the function of economically important fish genes in model fish by transgenic technology.

The long-term outcomes in drug-resistant epilepsy patients who underwent subtotal hemispherotomy: A single-center retrospective cohort study.

OBJECTIVE: To evaluate the long-term outcomes of subtotal hemispherotomy (SH) in treating drug-resistant epilepsy caused by unilateral hemispheric lesions and try to give the prognostic factors for these outcomes. METHODS: We retrospectively reviewed the clinical data of 19 patients who underwent SH in Sanbo Brain Hospital, Capital Medical University, Beijing, China, from May 2008 to April 2021. All clinical data and factors related to surgical and functional outcomes, including motor, neuropsychiatric, and language function, were collected and analyzed. RESULTS: The surgical outcomes showed 13 (68 %) patients were seizure-free at the last follow-up (2-14 years, mean: 5.6±2.9). No changes were found in motor outcomes in 12 (63 %) patients; seven (37 %) patients had new permanent motor deficits (NPMD). Improvement in the full-scale intelligence quotient (FIQ) (p = 0.009) was observed. Univariate analysis found that patients who did not achieve seizure freedom had a significantly older age at surgery (p = 0.017) and acute post-operative seizures (APOS) (p = 0.046). Kaplan-Meier analysis also identified significant differences in seizure outcomes between the children and adult subgroups (p = 0.0017). Multivariate Cox analysis showed that older age at surgery (HR=1.055, p = 0.034) was associated with shorter time-to-seizure-recurrence. Resection of the central operculum and insula (OR= 80.433, p =0.031) and higher monthly seizure frequency (OR= 1.073, p = 0.040) were also poor prognostic factors for motor function outcomes. CONCLUSION: SH is an effective treatment procedure in treating patients with drug-resistant epilepsy caused by hemispheric lesions with satisfied seizure outcomes, limited impairment of motor function, and preserving neuropsychiatric outcomes.

Development and Validation of a Deep Learning Predictive Model Combining Clinical and Radiomic Features for Short-Term Postoperative Facial Nerve Function in Acoustic Neuroma Patients.

OBJECTIVE: This study aims to construct and validate a predictable deep learning model associated with clinical data and multi-sequence magnetic resonance imaging (MRI) for short-term postoperative facial nerve function in patients with acoustic neuroma. METHODS: A total of 110 patients with acoustic neuroma who underwent surgery through the retrosigmoid sinus approach were included. Clinical data and raw features from four MRI sequences (T1-weighted, T2-weighted, T1-weighted contrast enhancement, and T2-weighted-Flair images) were analyzed. Spearman correlation analysis along with least absolute shrinkage and selection operator regression were used to screen combined clinical and radiomic features. Nomogram, machine learning, and convolutional neural network (CNN) models were constructed to predict the prognosis of facial nerve function on the seventh day after surgery. Receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were used to evaluate model performance. A total of 1050 radiomic parameters were extracted, from which 13 radiomic and 3 clinical features were selected. RESULTS: The CNN model performed best among all prediction models in the test set with an area under the curve (AUC) of 0.89 (95% CI, 0.84-0.91). CONCLUSION: CNN modeling that combines clinical and multi-sequence MRI radiomic features provides excellent performance for predicting short-term facial nerve function after surgery in patients with acoustic neuroma. As such, CNN modeling may serve as a potential decision-making tool for neurosurgery.

Translocation of High Mobility Group Box 1 From the Nucleus to the Cytoplasm in Depressed Patients With Epilepsy.

Depression is a common psychiatric comorbidity in patients with epilepsy, especially those with temporal lobe epilepsy (TLE). The aim of this study was to assess changes in high mobility group box protein 1 (HMGB1) expression in epileptic patients with and without comorbid depression. Sixty patients with drug-resistant TLE who underwent anterior temporal lobectomy were enrolled. Anterior hippocampal samples were collected after surgery and analyzed by immunofluorescence (n = 7/group). We also evaluated the expression of HMGB1 in TLE patients with hippocampal sclerosis and measured the level of plasma HMGB1 by enzyme-linked immunosorbent assay. The results showed that 28.3% of the patients (17/60) had comorbid depression. HMGB1 was ubiquitously expressed in all subregions of the anterior hippocampus. The ratio of HMGB1-immunoreactive neurons and astrocytes was significantly increased in both TLE patients with hippocampal sclerosis and TLE patients with comorbid depression compared to patients with TLE only. The ratio of cytoplasmic to nuclear HMGB1-positive neurons in the hippocampus was higher in depressed patients with TLE than in nondepressed patients, which suggested that more HMGB1 translocated from the nucleus to the cytoplasm in the depressed group. There was no significant difference in the plasma level of HMGB1 among patients with TLE alone, TLE with hippocampal sclerosis, and TLE with comorbid depression. The results of the study revealed that the translocation of HMGB1 from the nucleus to the cytoplasm in hippocampal neurons may play a previously unrecognized role in the initiation and amplification of epilepsy and comorbid depression. The direct targeting of neural HMGB1 is a promising approach for anti-inflammatory therapy.

Analysis of chemical compounds and toxicological evaluation of Forsythia suspensa leaves tea.

To determine the compositions of Forsythia suspensa leaves tea (FSLT) and its safety, the chemical compounds were analysed with some methods, and the toxicity was evaluated in Kunming mice and Wistar rats. The results showed that FSLT contained rich flavonoid, lignans, triperpene acids, amino acids, and mineral elements. In the acute toxicity study, none of the mice died, and no obvious poisoning symptoms were observed after 14 days in mice at the dose of 15 mg/g·body weight (bw) FSLT; in the sub-chronic toxicity, no abnormal or dead rat was found at the dose of 1, 3, and 10 mg/g·bw during 90 days feeding administration; there was no significant difference in bw and food consumption; no significant differences were found in each hematology and serum biochemistry parameter and organ/body weight ratio comparing with the control experimental group. The results revealed that the FSLT has low or no toxicity via oral administration. Therefore, FSLT is very suitable and safe to be used as a new resource food.

Status of glycosylated hemoglobin and prediction of glycemic control among patients with insulin-treated type 2 diabetes in North China: a multicenter observational study.

BACKGROUND: Blood glucose control is closely related to type 2 diabetes mellitus (T2DM) prognosis. This multicenter study aimed to investigate blood glucose control among patients with insulin-treated T2DM in North China and explore the application value of combining an elastic network (EN) with a machine-learning algorithm to predict glycemic control. METHODS: Basic information, biochemical indices, and diabetes-related data were collected via questionnaire from 2787 consecutive participants recruited from 27 centers in six cities between January 2016 and December 2017. An EN regression was used to address variable collinearity. Then, three common machine learning algorithms (random forest [RF], support vector machine [SVM], and back propagation artificial neural network [BP-ANN]) were used to simulate and predict blood glucose status. Additionally, a stepwise logistic regression was performed to compare the machine learning models. RESULTS: The well-controlled blood glucose rate was 45.82% in North China. The multivariable analysis found that hypertension history, atherosclerotic cardiovascular disease history, exercise, and total cholesterol were protective factors in glycosylated hemoglobin (HbA1c) control, while central adiposity, family history, T2DM duration, complications, insulin dose, blood pressure, and hypertension were risk factors for elevated HbA1c. Before the dimensional reduction in the EN, the areas under the curve of RF, SVM, and BP were 0.73, 0.61, and 0.70, respectively, while these figures increased to 0.75, 0.72, and 0.72, respectively, after dimensional reduction. Moreover, the EN and machine learning models had higher sensitivity and accuracy than the logistic regression models (the sensitivity and accuracy of logistic were 0.52 and 0.56; RF: 0.79, 0.70; SVM: 0.84, 0.73; BP-ANN: 0.78, 0.73, respectively). CONCLUSIONS: More than half of T2DM patients in North China had poor glycemic control and were at a higher risk of developing diabetic complications. The EN and machine learning algorithms are alternative choices, in addition to the traditional logistic model, for building predictive models of blood glucose control in patients with T2DM.

Reliability and validity of a Chinese version of the Impact of Pediatric Epilepsy Scale.

The Impact of Pediatric Epilepsy Scale (IPES) is an accurate, acceptable, and quick tool that assesses the impact of epilepsy on the child with epilepsy and his or her family. The aim of this study was to investigate its applicability in China. After multistage translation and cultural adaptation, the final Chinese version was administered to 110 parents of children with epilepsy to evaluate its validity, reliability, and sensitivity. All items contributed significantly to the summary measure. With respect to validity, all items were substantially correlated with the criterion questionnaire subscales, and principal component analysis indicated that three factors accounted for 72% of the variance of the scale. The internal consistency coefficients of the first and second tests for the total were 0.916 and 0.930, respectively, and test-retest reliability ranged from 0.891 to 0.992. Additionally, the IPES can detect differences in health-related quality of life (HRQOL) between subjects according to epilepsy severity. In conclusion, this study indicates that the Chinese IPES has good validity, reliability, and sensitivity, and is an epilepsy-specific HRQOL questionnaire that is a brief, accurate, and valid assessment of the influence of epilepsy on the child and family.

Chest physiotherapy for the prevention of ventilator-associated pneumonia: A meta-analysis.

BACKGROUND: Ventilator-associated pneumonia (VAP) remains a frequent and severe complication in mechanically ventilated patients. We undertook a meta-analysis to evaluate the efficacy of chest physiotherapy (CPT) for the prevention of VAP. METHODS: A systematic literature search of PubMed and Embase databases were searched up until November 25, 2018 for published studies of mechanically ventilated patients comparing CPT with controls and reporting on the occurrence of VAP. Two authors independently selected studies and abstracted data on study quality and outcomes. We pooled data using random-effects models. RESULTS: A total of 6 randomized (n = 704) controlled trials were identified. CPT did not significantly reduce the incidence of VAP (risk ratio = 1.02; 95% confidence interval, 0.82-1.26; P = .87), but reduced hospital mortality (risk ratio = 0.68; 95% confidence interval, 0.48-0.95; P = .02). No significant differences were observed regarding intensive care unit mortality, length of intensive care unit stay, and duration of mechanical ventilation. CONCLUSIONS: CPT may not significantly reduce the incidence of VAP and alter other important clinical outcomes in adult patients receiving mechanical ventilation. However, the results should be interpreted cautiously owing to the heterogeneity and the limited trials. Further large-scale, well-designed randomized controlled trials are needed.

[Linkage location and mutation analysis of generalized epilepsy with febrile seizures plus].

OBJECTIVE: To study the etiologic genes of generalized epilepsy with febrile seizure plus (GEFS+). METHODS: Peripheral blood samples were collected from 25 persons of 2 families, including 2 probands. DNA was extracted from the peripheral blood leukocytes using phenol-chloroform method. Ten microsatellite markers spanning the critical regions of SCN1B, SCN1A, SCN2A, and GABRG2 genes were genotyped for linkage analysis by the software LINKAGE v5.1. The two-point linkage relation was determined by LOD score defining the approximate position of etiologic genes of the 2 GEFS+ families. Mutation analysis of the candidate etiologic genes in all members of these 2 families was performed. Results No sharing allele was discovered among the several microsatellite markers flanking SCN1A, SCN2A, and SCN1B genes, and the involvement of these genes in these 2 families could be excluded. In the family named Tian, sharing alleles were discovered among the markers D5S820, D5S422, and D5S1403 flanking GABRG2 gene. The two-point LOD scores at theta = 0 were 0.67, 1.0, and 0.79 for the marker D5S820, D5S422, and D5S1403, thus indicating possible linkage. In the family named Di, sharing allele was discovered only in the marker D5S1403 flanking the GABRG2 gene. Sequence analysis was performed for nine exons of the GABRG2 gene in these 2 families. Three single nucleotide variations were discovered on the exon 5 (c.588 C > T), exon 3 (c.604 C > T), and noncoding region of the exon 7. No mutation change of the GABRG2 gene was observed in these 2 families. CONCLUSION: No evidence supports the causal relation between the SCN1B, SCN1A, SCN2A, and GABRG2 mutation and the etiologic genes in the two families with GEFS+. It is still not clear what is the common etiologic genes of GEFS+.

Classification and Protection of Peritumoral Draining Veins of Parasagittal and Falcine Meningiomas.

OBJECTIVE: To investigate the importance and types of peritumoral draining veins in parasagittal and falcine meningiomas and administer corresponding protective strategies during surgery according to these different types to improve tumor resection rate and maximize the protection of neurologic functions. METHODS: The clinical information of 156 patients with parasagittal and falcine meningiomas who were admitted at the Neurosurgery Department of our hospital was collected and retrospectively analyzed. All patients underwent pathologic classification, magnetic resonance imaging scanning and enhancement, and magnetic resonance venography examinations. RESULTS: Among these patients, 113 (72.4%) had Simpson grade I and II resection, whereas 43 patients (27.6%) had Simpson grade III and IV resection and underwent postoperative adjuvant gamma knife surgery. Karnofsky Performance Status evaluation was carried out at 1 week after surgery. In total, 69 patients (44.3%) improved, 66 patients (42.3%) had no changes, and 21 patients (13.4%) had worsened conditions (7 patients had hemiplegia, 5 patients had aphasia, 4 patients had decreased vision, and 5 patients had ataxia). There were no deaths. According to the 2016 World Health Organization pathologic grading, 131 patients (84%) were grade I, 22 patients (14%) were grade II, and 3 patients were grade III (2%). Furthermore, 105 patients were followed up for 1-4 years. There were 11 cases of recurrence. CONCLUSIONS: The classification and evaluation of peritumoral draining veins through preoperative-combined magnetic resonance venography can be used as a guide in determining the corresponding protective strategy during surgery. This can significantly improve the tumor resection rate and decrease the postoperative disability rate.

Identification of the epileptogenic zone of temporal lobe epilepsy from stereo-electroencephalography signals: A phase transfer entropy and graph theory approach.

The aim of this research is to apply an approach based on phase transfer entropy (PTE) and graph theory to study the interactions between the stereo-electroencephalography (SEEG) activities recorded in multilobar origin, in order to evaluate their ability to detect the epileptogenic zone (EZ) of temporal lobe epilepsies (TLE). Forty-three patients were included in this retrospective study. Five to sixteen (median = 12) multilead electrodes were implanted per patient, and, for each patient, a sub-set of between 10 and 32 (median = 22) bipolar derivations was selected for analysis. The leads were classified into the onset leads (OLs), the early propagation leads (EPLs), and the rest of the leads (RLs). The results showed that a significantly different dynamic trend of the out/in ratio (more obvious in the gamma band) distinguishes the OLs from RLs in the 23 patients who were seizure-free not only during the ictal event (significant elevation), but also during the inter-,pre-, late-ictal periods, and especially in the post-ictal (sharp decline) state. However, in the 20 patients who were not-seizure-free, the differences between the OLs and RLs during the post-ictal period were not found in any frequency band. The dynamic trend was used to predict surgical outcome, and the results showed that the sensitivity was 91% and the specificity was 70%. In brief, this study indicates that our approach may add new and valuable information, providing efficient quantitative measures useful for localizing the EZ.

A novel mutation of the nicotinic acetylcholine receptor gene CHRNA4 in a Chinese patient with non-familial nocturnal frontal lobe epilepsy.

So far, only two mutations in the CHRNA4 gene (in three studies) and one mutation in the CHRNB2 gene had been identified in the patients with sporadic nocturnal frontal lobe epilepsy (NFLE). The absence of mutations in the candidate genes in the majority of sporadic NFLE patients suggest that they are rare loci for the disease, but the necessity of performing genetic testing for sporadic cases should not be neglected. We designed mutation screening of exon 5 of CHRNA4, exon 5 of CHRNB2, and exon 6 of CHRNA2 in a group of 56 Chinese sporadic NFLE cases. A de novo missense mutation in the transmembrane domain M2 segment of the α4 subunit of the neuronal nicotinic acetylcholine receptor, c.823A>T, was found in a 15 year-old right-handed male, but was not observed in his parents and 400 control chromosomes. The mutation decreased the surrounding hydrophobicity and slightly altered secondary structure of the protein. No mutations were found in CHRNB2 and CHRNA2.