Effective suppression of Ih and INa caused by capsazepine, known to be a blocker of TRPV1 receptor.

A synthetic inhibitor of capsaicin-induced TRPV1 channel activation is called capsazepine (CPZ). In this study, we aimed to explore the effects of CPZ on hyperpolarization-activated cationic current (Ih) and voltage-gated Na + current (INa) in pituitary tumor (GH3) cells. Through patch-clamp recordings, we found that CPZ concentration-dependently inhibited Ih amplitude and slowed its activation time course. The IC50 and KD values were 3.1 and 3.16 µM, respectively. CPZ also shifted the steady-state activation curve of Ih towards a more hyperpolarized potential. However, there was no change in the gating charge of the curve. A modified Markovian model predicted the CPZ-induced decrease in the voltage-dependent hysteresis of Ih. CPZ suppressed INa in GH3 cells, without altering its activation or inactivation time course. Additionally, exposure to CPZ reduced spontaneous firing. These findings suggest that CPZ's inhibitory effects on Ih and INa are direct and not dependent on vanilloid receptor binding. This could provide light on an unidentified ionic mechanism influencing the membrane excitability of neurons and endocrine or neuroendocrine cells in vivo.

Response of species dominance and niche of plant community to wetland degradation along alpine lake riparian.

Alpine wetland degradation threatens riparian biodiversity and ecological balance. Our study, conducted in July 2020 along the northern and eastern shores of Qinghai Lake, seeks to unravel the impacts of such degradation on plant species dominance and ecological niches, using advanced network analysis methods to explore the dynamics and survival strategies of plant species. We applied a space-to-time method to delineate three wetland degradation stage: a healthy swamp wetland, a slightly degraded wet meadow, and a degraded dry meadow. Six representative sampling points were chosen. At each point, three sample lines were randomly established, radiating outward from the center of the lake wetland, with each stage of degradation meticulously examined through three replicates to assess the plant communities in terms of species composition, plant height, coverage, and abundance. The results indicated: Species such as Kobresia tibetica and Leymus secalinus exhibit remarkable abundance across various stages of wetland degradation, indicating a robust tolerance to these conditions. This observation, coupled with the complexity of plant community structures in degrading wetlands, suggests that such intricacy cannot be solely attributed to the dominance of particular species. Instead, it is the result of a diverse array of species adapting to fluctuating water levels, which promotes increased species richness. Despite the prominence of species that exhibit rapid growth and reproduction, the ecological significance of less abundant species in contributing to the community's complexity is also notable. Changes in habitat conditions due to wetland degradation facilitate both competitive and cooperative interactions among species, highlighting the dynamic nature of these ecosystems. Our analysis shows no significant linear relationship between the ecological niche overlap values and niche widths of plant species. However, the strategies employed by dominant species for competition and resource acquisition, as observed in the ecological niche overlap networks, underscore the adaptive capacity of plant communities. These insights underscore the need for tailored restoration strategies to conserve the biodiversity of alpine lake riparian ecosystems. This research not only sheds light on the resilience and adaptability of ecosystems in the Qinghai-Tibetan Plateau but also offers valuable lessons for the conservation of similar habitats worldwide. Our findings underscore the need for tailored restoration strategies to conserve the biodiversity of alpine lake riparian ecosystems. This research not only sheds light on the resilience and adaptability of ecosystems in the Qinghai-Tibetan Plateau but also offers valuable lessons for the conservation of similar habitats worldwide.

Clinical characteristics and identification of novel CNOT1 variants in three unrelated Chinese families with Vissers-Bodmer Syndrome.

Vissers-Bodmer Syndrome, an autosomal dominant disease, is a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, hypotonia and autistic features with a highly variable phenotype. It is caused by variants in the CCR4-NOT transcription complex, subunit 1 gene (CNOT1). However, the pathophysiologic mechanism of the Vissers-Bodmer Syndrome remains unclear. Notably, this syndrome has not been previously reported in the Chinese. In this study, we utilized whole exome sequencing to identify three novel variants in the CNOT1 gene, encompassing one frameshift variant and two missense variants, in three Chinese patients mainly presenting with developmental delay, intellectual disability and/or autism. Interestingly, three patients exhibited novel manifestations including spina bifida occulta, horse-shoe kidney and café-au-lait spot. The frameshift variant, p.Gly172Alafs*5, occurring de novo, leading to a premature stop codon in the protein, was classified into pathogenic. Two missense variants c.3451A > G (p.Asn1151Asp) and c.557C > T (p.Ser186Phe) were predicted to be deleterious by multiple prediction algorithms with high conservation among a variety of species. Additionally, three-dimensional structure modeling and predicting indicated the substitution of the mutated amino acids would decrease the stability of CNOT1 protein. Given that CNOT1 is a relatively novel disease gene, we evaluated the gene-disease validity following ClinGen Standard Operating Procedure. The existing evidence substantiates a "Definitive" level of gene-disease relationship. The genetic findings provide a reliable basis for the genetic counseling of the family reproduction. Moreover, our results expand the genetic and phenotypic spectrum of CNOT1-related Vissers-Bodmer Syndrome.

[Clinical features and genetic analysis of three children with ß-ketothiolase deficiency].

OBJECTIVE: To explore the clinical features and genetic variants in three children suspected for ß-ketothiolase deficiency (BKTD). METHODS: Clinical manifestations, laboratory examination and genetic testing of three children suspected for BKTD at Henan Children's Hospital between January 2018 and October 2022 were collected, and their clinical and genetic variants were retrospectively analyzed. RESULTS: The children were all males with a age from 7 to 11 months. Their clinical manifestations have included poor spirit, shortness of breath, vomiting, convulsions after traumatic stress and/or infection. All of them had severe metabolic acidosis, elevated ketone bodies in blood and urine, hypoglycemia, with increased isoprenyl-carnitine and 3-hydroxyisovalyl-carnitine in the blood, and 2-methyl-3-hydroxybutyrate and methylprotaroyl glycine in the urine. All of them were found to harbor compound heterozygous variants of the ACAT1 gene, including c.1183G>T and a large fragment deletion (11q22.3-11q23.1) in child 1, c.121-3C>G and c.826+5_826+9delGTGTT in child 2, and c.928G>C and c.1142T>C in child 3. The variants harbored by children 2 and 3 were known to be pathogenic or likely pathogenic. The heterozygous c.1183G>T variant in child 1 was unreported previously and rated as a variant of unknown significance (PM2_Supporting+PP3+PP4) based on guidelines from the American College of Medical Genetics and Genomics. The large segment deletion in 11q22.3-11q23.1 has not been included in the DGV Database and was rated as a pathogenic copy number variation. CONCLUSION: The variants of the ACAT1 gene probably underlay the pathogenesis of BKTD in these three children.

Ultrasound-based radiomics-clinical nomogram for noninvasive prediction of residual cancer burden grading in breast cancer.

PURPOSE: To assess the predictive value of an ultrasound-based radiomics-clinical nomogram for grading residual cancer burden (RCB) in breast cancer patients. METHODS: This retrospective study of breast cancer patients who underwent neoadjuvant therapy (NAC) and ultrasound scanning between November 2020 and July 2023. First, a radiomics model was established based on ultrasound images. Subsequently, multivariate LR (logistic regression) analysis incorporating both radiomic scores and clinical factors was performed to construct a nomogram. Finally, Receiver operating characteristics (ROC) curve analysis and decision curve analysis (DCA) were employed to evaluate and validate the diagnostic accuracy and effectiveness of the nomogram. RESULTS: A total of 1122 patients were included in this study. Among them, 427 patients exhibited a favorable response to NAC chemotherapy, while 695 patients demonstrated a poor response to NAC therapy. The radiomics model achieved an AUC value of 0.84 in the training cohort and 0.83 in the validation cohort. The ultrasound-based radiomics-clinical nomogram achieved an AUC value of 0.90 in the training cohort and 0.91 in the validation cohort. CONCLUSIONS: Ultrasound-based radiomics-clinical nomogram can accurately predict the effectiveness of NAC therapy by predicting RCB grading in breast cancer patients.

Investigating the influence of XAV-939, a tankyrase inhibitor, on the density and gating of erg-mediated K+ currents in mouse MA-10 Leydig tumor cells.

XAV-939(XAV) is a chemical compound that inhibits the activity of tankyrase. However, the precise way in which XAV alters membrane ionic currents is not well understood. In this study,our goal was to examine the impact of XAV on the ionic currents in mouse MA-10 Leydig cells, specifically focusing on the magnitude, gating properties,and voltage-dependent hysteresis of erg-mediated K+currents(IK(erg)). In our whole-cell current recordings we observed that the addition of XAV inhibited the density of IK(erg) in a concentration-dependent manner with an IC50 of 3.1 µM. Furthermore we found that continued exposure to XAV, further addition of neither liraglutide nor insulin-like growth factor-1 counteracted XAV-mediated inhibition of IK(erg). Additionally the presence of XAV suppressed the mean current versus voltage relationship of IK(erg) across the entire voltage-clamp step analyzed. This compound shifted the steady-state activation curve of IK(erg) to a less negative potential by approximately 12 mV. The presence of XAV increased the time constant of deactivating IK(erg) in MA-10 cells. The voltage-dependent clockwise hysteresis of IK(erg) responding to prolonged upright isosceles-triangular ramp voltage became diminished by adding XAV; moreover subsequent addition of NS3623 effectively reversed XAV-induced decrease of hysteretic area of IK(erg). XAV also inhibited the proliferation of this cell line and the IC50 value of XAV-induced inhibition of cell proliferation was 2.8M. Overall the suppression of IK(erg) by XAV may serve as a significant ionic mechanism that contribute to the functional properties of MA-10 cells. However, it is important to note that this effect cannot be attributed solely to the inhibition of tankyrase.

[Clinical and genetic analysis of two children with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency].

OBJECTIVE: To explore the clinical characteristics and genetic variants of two children with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD). METHODS: Two children with HMGCLD diagnosed at Henan Provincial Children's Hospital respectively in December 2019 and June 2022 were selected as the study subjects. Clinical data and results of laboratory testing were analyzed retrospectively. RESULTS: Both children had manifested with repeated convulsions, severe hypoglycemia, metabolic acidosis and liver dysfunction. Blood amino acids and acylcarnitine analysis showed increased 3-hydroxy-isovalyl carnitine (C5OH) and 3-hydroxy-isovalyl carnitine/capryloyl carnitine ratio (C5OH/C8), and urinary organic acid analysis showed increased 3-hydroxyl-3-methyl glutaric acid, 3-methyl glutaric acid, 3-methyl glutaconic acid, 3-hydroxyisoglycine and 3-methylprotarylglycine. Child 1 was found to harbor homozygous c.722C>T variants of the HMGCL gene, which was rated as uncertain significance (PM2_Supporting+PP3). Child 2 was found to harbor homozygous c.121C>T variants of the HMGCL gene, which was rated as pathogenic variant (PVS1+PM2_Supporting+PP4). CONCLUSION: Acute episode of HMGCLD is usually characterized by metabolic disorders such as hypoglycemia and metabolic acidosis, and elevated organic acids in urine may facilitate the differential diagnosis, though definite diagnosis will rely on genetic testing.

Safinamide, an inhibitor of monoamine oxidase, modulates the magnitude, gating, and hysteresis of sodium ion current.

BACKGROUND: Safinamide (SAF), an α-aminoamide derivative and a selective, reversible monoamine oxidase (MAO)-B inhibitor, has both dopaminergic and nondopaminergic (glutamatergic) properties. Several studies have explored the potential of SAF against various neurological disorders; however, to what extent SAF modulates the magnitude, gating, and voltage-dependent hysteresis [Hys(V)] of ionic currents remains unknown. METHODS: With the aid of patch-clamp technology, we investigated the effects of SAF on voltage-gated sodium ion (NaV) channels in pituitary GH3 cells. RESULTS: SAF concentration-dependently stimulated the transient (peak) and late (sustained) components of voltage-gated sodium ion current (INa) in pituitary GH3 cells. The conductance-voltage relationship of transient INa [INa(T)] was shifted to more negative potentials with the SAF presence; however, the steady-state inactivation curve of INa(T) was shifted in a rightward direction in its existence. SAF increased the decaying time constant of INa(T) induced by a train of depolarizing stimuli. Notably, subsequent addition of ranolazine or mirogabalin reversed the SAF-induced increase in the decaying time constant. SAF also increased the magnitude of window INa induced by an ascending ramp voltage Vramp. Furthermore, SAF enhanced the Hys(V) behavior of persistent INa induced by an upright isosceles-triangular Vramp. Single-channel cell-attached recordings indicated SAF effectively increased the open-state probability of NaV channels. Molecular docking revealed SAF interacts with both MAO and NaV channels. CONCLUSION: SAF may interact directly with NaV channels in pituitary neuroendocrine cells, modulating membrane excitability.

Clinical and genetic characterization of 47 Chinese pediatric patients with Pitt-Hopkins syndrome: a retrospective study.

BACKGROUND: Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder that remains underdiagnosed and its clinical presentations and mutation profiles in a diverse population are yet to be evaluated. This retrospective study aims to investigate the clinical and genetic characteristics of Chinese patients with PTHS. METHODS: The clinical, biochemical, genetic, therapeutic, and follow-up data of 47 pediatric patients diagnosed with PTHS between 2018 and 2021 were retrospectively analyzed. RESULTS: The Chinese PTHS patients presented with specific facial features and exhibited global developmental delay of wide severity range. The locus heterogeneity of the TCF4 gene in the patients was highlighted, emphasizing the significance of genetic studies for accurate diagnosis, albeit no significant correlations between genotype and phenotype were observed in this cohort. The study also reports the outcomes of patients who underwent therapeutic interventions, such as ketogenic diets and biomedical interventions. CONCLUSIONS: The findings of this retrospective analysis expand the phenotypic and molecular spectra of PTHS patients. The study underscores the need for a long-term prospective follow-up study to assess potential therapeutic interventions.

Exploring the Impact of BKCa Channel Function in Cellular Membranes on Cardiac Electrical Activity.

This review paper delves into the current body of evidence, offering a thorough analysis of the impact of large-conductance Ca2+-activated K+ (BKCa or BK) channels on the electrical dynamics of the heart. Alterations in the activity of BKCa channels, responsible for the generation of the overall magnitude of Ca2+-activated K+ current at the whole-cell level, occur through allosteric mechanisms. The collaborative interplay between membrane depolarization and heightened intracellular Ca2+ ion concentrations collectively contribute to the activation of BKCa channels. Although fully developed mammalian cardiac cells do not exhibit functional expression of these ion channels, evidence suggests their presence in cardiac fibroblasts that surround and potentially establish close connections with neighboring cardiac cells. When cardiac cells form close associations with fibroblasts, the high single-ion conductance of these channels, approximately ranging from 150 to 250 pS, can result in the random depolarization of the adjacent cardiac cell membranes. While cardiac fibroblasts are typically electrically non-excitable, their prevalence within heart tissue increases, particularly in the context of aging myocardial infarction or atrial fibrillation. This augmented presence of BKCa channels' conductance holds the potential to amplify the excitability of cardiac cell membranes through effective electrical coupling between fibroblasts and cardiomyocytes. In this scenario, this heightened excitability may contribute to the onset of cardiac arrhythmias. Moreover, it is worth noting that the substances influencing the activity of these BKCa channels might influence cardiac electrical activity as well. Taken together, the BKCa channel activity residing in cardiac fibroblasts may contribute to cardiac electrical function occurring in vivo.

Non-invasive modulation of meningeal lymphatics ameliorates ageing and Alzheimer's disease-associated pathology and cognition in mice.

Meningeal lymphatic vessels (mLVs) have been shown to be involved in amyloid beta (Aß) clearance, which is considered as a potential therapeutic target for Alzheimer's disease (AD). In this study, based on the superficial spatial distribution of mLVs, a near-infrared light is employed to modulate lymphatic drainage, significantly improving cognition of both aged and AD (5xFAD and APP/PS1) mice, and alleviating AD-associated pathology by reducing Aß deposition, neuroinflammation and neuronal damage. Furthermore, transmission electron microscopy imaging and RNA sequencing data indicate amelioration of mitochondrial metabolism and cellular junction of meningeal lymphatic endothelial cells (mLECs) by light modulation. These studies collectively suggest that near-infrared light treatment can improve cognitive function by strengthening scavenging ability of mLVs through restoring mLEC function. In conclusion, lymphatic drainage potentiation by light promotes pathological remission and cognitive enhancement in aging and AD mouse models, which offers a potential amelioration strategy for neurodegenerative diseases.

Application of multimedia technology to innovative vocational education on learning satisfaction in China.

Multimedia technology holds paramount importance in driving innovation within vocational education, significantly influencing learning satisfaction. Its integration facilitates dynamic and interactive learning environments, catering to diverse learning styles and preferences. Moreover, multimedia technology enables educators to simulate real-world scenarios, providing practical and hands-on training opportunities. This aspect is particularly valuable in vocational education, where practical skills and application are required. The paper investigates the impact of multimedia technology in enhancing learning satisfaction within innovative vocational education. It delves into the utilization of multimedia tools and their correlation with learner satisfaction, exploring how these technologies augment engagement and comprehension in vocational training. The primary data from 515 students of vocational colleges of China has been collected and regression analysis is applied for empirical analysis. The findings of the study highlight that multimedia technology has positive relationship with innovative vocational education and learning outcome. The findings contribute valuable insights for policymakers regarding significant role multimedia plays in fostering enhanced learning experiences and overall satisfaction among vocational learners.

The prognostic evaluation of ALBI score in endoscopic treatment of esophagogastric varices hemorrhage in liver cirrhosis.

To analyze the independent risk factors for recurrent bleeding and death within 1 year after endoscopic treatment of esophagogastric varices hemorrhage (EGVB) in patients with liver cirrhosis, and to validate the predictive value of ALBI score for recurrent bleeding and death within 1 year after endoscopic treatment of EGVB in patients with liver cirrhosis. A total of 338 patients with EGVB who received endoscopic treatment for the first time in the Department of Gastroenterology, First Affiliated Hospital of Nanchang University from January 1, 2016 to March 1, 2020 were selected. A database was established to analyze the patients' demographic data, surgical variables and postoperative outcomes. All patients were contacted and followed up to verify the predictive value of ALBI score for recurrent bleeding and mortality. 130 patients had rebleeding within 1 year after surgery (38.5%). 66 patients died within 1 year after surgery (19.5%). Patients with ALBI grade 3 had significantly higher rebleeding and mortality rates than those with grades 1 and 2. The AUC was used to compare the predictive value of the four scores for rebleeding and mortality within one year after endoscopic surgery. Both ALBI scores had the largest AUC. The ALBI score has certain predictive value for rebleeding and mortality within 1 year after endoscopic therapy in patients with cirrhotic EGVB.

The structure of TRAF7 coiled-coil trimer provides insight into its function in zebrafish embryonic development.

TRAF7 serves as a crucial intracellular adaptor and E3 ubiquitin ligase involved in signal transduction pathways, contributing to immune responses, tumor progression, and embryonic development. Somatic mutations within the coiled-coil (CC) domain and WD40 repeat domain of TRAF7 could cause brain tumors, while germline pathogenic mutations contribute to severe developmental abnormalities. However, the precise molecular mechanism underlying TRAF7 involvement in embryonic development remains unclear. In this study, we employed zebrafish as an in-vivo model system. TRAF7 knockdown caused defects in zebrafish embryonic development. We determined the crystal structure of TRAF7 CC domain at 3.3 Å resolution and found that the CC region trimerization was essential for TRAF7 functionality during zebrafish embryonic development. Additionally, disease-causing mutations in TRAF7 CC region could impair the trimer formation, consequently impacting early embryonic development of zebrafish. Therefore, our study sheds light on the molecular mechanism of TRAF7 CC trimer formation and its pivotal role in embryonic development.

The Value of Transanal Normal Saline Infusion-Assisted Multipath Ultrasonography in the Diagnosis of T1/T2 Rectal Cancer.

ABSTRACT: This study aims to assess the application value of transanal normal saline infusion-assisted multipath ultrasonography (TNSI-MU) in the diagnosis of T1/T2 rectal cancer (RC). All patients first received single-path 360-degree transrectal ultrasonography and then received 360-degree transrectal ultrasonography, transabdominal ultrasonography, or transvaginal ultrasonography after TNSI to determine the T stage. With surgical pathology as the criterion standard, the detection rates of T1/T2 RC lesions and the T-staging results of single-path 360-degree transrectal ultrasonography, TNSI-MU, and contrast-enhanced magnetic resonance imaging (MRI) were compared and analyzed. T1/T2 RC was surgically and pathologically confirmed in 52 patients. Single-path 360-degree transrectal ultrasonography had a lesion detection rate of 57.69% (30/52) and a T-staging accuracy of 80.0% (24/30), the sensitivity was 57.69%, and the specificity was 88.46%. Transanal normal saline infusion-assisted multipath ultrasonography had a lesion detection rate of 100%, and its T-staging accuracy was 84.62% (44/52), the sensitivity was 100%, and the specificity was 88.61%. Transanal normal saline infusion-assisted multipath ultrasonography had a significantly higher detection rate of T1/T2 RC lesions than single-path 360-degree transrectal ultrasonography ( P < 0.001), but the 2 methods had similar T-staging accuracy for T1/T2 RC (χ 2 = 0.286, P = 0.593). Contrast-enhanced MRI had a lesion detection rate of 100% and a T-staging accuracy of 40.38% (21/52), the sensitivity was 98.07%, and the specificity was 61.54%. Transanal normal saline infusion-assisted multipath ultrasonography had significantly higher diagnostic accuracy than contrast-enhanced MRI for T staging of T1/T2 RC ( P < 0.001), and the diagnostic results of the 2 methods were not consistent (κ = 0.151). Transanal normal saline infusion-assisted multipath ultrasonography outperformed single-path 360-degree transrectal ultrasonography in the detection rate of T1/T2 RC lesions and contrast-enhanced MRI in the staging accuracy for T1/T2 RC.

Variable phenotypes and outcomes associated with the MMACHC c.482G > A mutation: follow-up in a large CblC disease cohort.

BACKGROUND: The aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene (MMACHC) c.482G > A mutation in 195 Chinese cases with CblC disease. METHODS: We carried out a national, retrospective multicenter study of 195 Chinese patients with CblC disease attributable to the MMACHC c.482G > A variant either in a homozygous or compound heterozygous state. The control group consisted of 200 patients diagnosed with CblC disease who did not possess the c.482G > A mutation. Clinical features, including disease onset, symptoms, biochemical metabolites, gene mutation, and follow-up outcomes were reviewed and analyzed in detail. The median follow-up period spanned 3 years and 8 months, with a range of 1 year and 2 months to 12 years and 10 months. RESULTS: Among 195 patients carrying the c.482G > A variant, 125 (64.1%) cases were diagnosed by newborn screening (NBS), 60 (30.8%) cases were detected due to disease onset, and 10 (5.1%) cases were identified from sibling diagnoses. One hundred and seventeen (93.6%) individuals who were diagnosed by NBS, and nine patients who came from sibling diagnoses remained asymptomatic in this study. From 69 symptomatic patients of the c.482G > A group, more patients presented with later onset, and the top six common clinical symptoms at disease onset were developmental delay (59.4%), lower limb weakness and poor exercise tolerance (50.7%), cognitive decline (37.7%), gait instability and abnormal posture (36.2%), seizures (26.1%), and psychiatric and behavioral disturbances (24.6%). In the 159 symptomatic patients lacking c.482G > A variants, the most frequently observed clinical manifestations at disease onset included developmental delay (81.8%), lethargy and feeding difficulty (62.9%), lower limb weakness and poor exercise tolerance (54.7%), prolonged neonatal jaundice (51.6%), vomiting (47.2%), and seizures (32.7%). Before treatment, the levels of blood propionylcarnitine, propionylcarnitine/acetylcarnitine ratio, and homocysteine in the c.482G > A group were significantly lower (P < 0.05) than those in the non-c.482G > A group, while the concentration of urinary methylmalonic acid was slightly lower (P > 0.05). The degree of decline in the above metabolites after treatment in different groups significantly differed in both plasma total homocysteine values and urinary methylmalonic acid levels (P < 0.05). In patients carrying the c.482G > A variant compared with the non-c.428G > A group, there were markedly lower rates of mortality (0.5% vs. 2.0%) and developmental delay (20.5% vs. 65.5%). When compared with individuals diagnosed due to disease onset, those identified through NBS in either group exhibited a reduced proportion of disease onset (6.7% vs. 100% in the c.482G > A group, 54.4% vs. 100% in the non-c.482G > A group), lower mortality (0.0% vs. 1.7% in the c.482G > A group, 0.0% vs. 3.6% in the non-c.482G > A group), and had a higher percentage of patients exhibiting normal psychomotor and language development (99.3% vs. 33.3% in the c.482G > A group, 58.9% vs. 10.9% in the non-c.482G > A group). CONCLUSIONS: The c.482G > A variant in MMACHC is associated with late-onset and milder phenotypes of CblC disease. Patients with this mutation tend to have a relatively better response to hydroxocobalamin, better metabolic control, and more favorable neurological outcomes. NBS and other appropriate pre-symptomatic treatments seem to be helpful in early diagnosis, resulting in favorable clinical outcomes. Video Abstract (MP4 136794 kb).

Effects of Vitamin A on Growth Performance, Antioxidants, Gut Inflammation, and Microbes in Weaned Piglets.

Piglet weaning is an important stage in production where changes in the environment and diet can cause problems such as intestinal inflammation and diarrhea. Vitamin A is an essential nutrient for human and animal growth and has immunomodulatory and inflammatory effects. A large body of literature has previously reported on the use of vitamin A in piglet production, so our experiment added different concentrations of vitamin A (0, 1100, 2200, 4400, 8800, and 17,600 IU/kg) to weaned piglet diets to study the effects of different doses on growth performance, intestinal barrier, inflammation, and flora in weaned piglets. We selected 4400 IU/kg as the optimum concentration of vitamin A in relation to average daily weight gain, feed intake, feed-to-weight ratio, and diarrhea rate, and subsequently tested the inflammatory factors, immunoglobulin content, antioxidant levels, and intestinal flora of weaned piglets. Results: We observed that the diarrhea rate of weaned piglets was significantly lower after the addition of 4400 IU/kg of vitamin A to the diet (p < 0.05). A control group and a 4400 IU/kg VA group were selected for subsequent experiments. We found that after the addition of vitamin A, the serum CAT level of weaned piglets increased significantly, the expression of Claudin-1 in the jejunum and ileum increased significantly, the expression of Occludin gene in the jejunum increased significantly, the expression of IL-5 and IL-10 in the ileum increased significantly (p < 0.05), and the expression of IL-4, IL-5, and IL-10 in the ileum increased significantly (p < 0.05). Meanwhile, in the colonic flora of vitamin A-added weaned piglets, the relative abundance of Actinobacteria and Erysipelotrichales decreased significantly, while the relative abundance of Bacteroidales increased significantly (p < 0.05). The results of this study indicated that vitamin A at 4400 IU/kg reduces diarrhea in weaned piglets by increasing antioxidant levels, increasing intestinal tight junction protein gene expression, and regulating colonic gut microbiota.

Potential short-term effects of earthquake on the plant-soil interface in alpine grassland of the Qinghai-Tibetan Plateau.

Earthquakes are environmental disturbances affecting ecosystem functioning, health, and biodiversity, but their potential impacts on plant-soil interface are still poorly understood. In this study, grassland habitats in areas near and away from the seismo-fault in Madou, a region typical of alpine conditions on the Qinghai-Tibetan Plateau, were randomly selected. The impacts of earthquake on soil properties and plant nutrient content in the short term were emphasized, and their potential relationships with community diversity and productivity were examined. According to the findings of the study, the Maduo earthquake led to a decrease in soil nutrient content in alpine grassland ecosystems, especially soil TC, TN, TP, TCa, AP, AK, NH4 +-N, and SOC, and inhibited the absorption of N, Ca, and Mg nutrients by plants. In addition, the diversity and productivity of communities were affected by both direct and indirect earthquake pathways. The negative impacts of seismic fracture on soil structure had the most significant direct impact on plant community diversity. Earthquakes also indirectly reduced community productivity by reducing the soil N content and inhibiting the absorption of plant nutrients. Our findings suggested that earthquakes could potentially decrease the stability of the alpine grassland ecosystem on the QTP by affecting nutrient availability at the plant-soil interface.

Cannabidiol Modulates M-Type K+ and Hyperpolarization-Activated Cation Currents.

Cannabidiol (CBD) is a naturally occurring compound found in the Cannabis plant that is known for its potential therapeutic effects. However, its impact on membrane ionic currents remains a topic of debate. This study aimed to investigate how CBD modifies various types of ionic currents in pituitary GH3 cells. Results showed that exposure to CBD led to a concentration-dependent decrease in M-type K+ currents (IK(M)), with an IC50 of 3.6 µM, and caused the quasi-steady-state activation curve of the current to shift to a more depolarized potential with no changes in the curve's steepness. The CBD-mediated block of IK(M) was not reversed by naloxone, suggesting that it was not mediated by opioid receptors. The IK(M) elicited by pulse-train stimulation was also decreased upon exposure to CBD. The magnitude of erg-mediated K+ currents was slightly reduced by adding CBD (10 µM), while the density of voltage-gated Na+ currents elicited by a short depolarizing pulse was not affected by it. Additionally, CBD decreased the magnitude of hyperpolarization-activated cation currents (Ih) with an IC50 of 3.3 µM, and the decrease was reversed by oxaliplatin. The quasi-steady-state activation curve of Ih was shifted in the leftward direction with no changes in the slope factor of the curve. CBD also diminished the strength of voltage-dependent hysteresis on Ih elicited by upright isosceles-triangular ramp voltage. Collectively, these findings suggest that CBD's modification of ionic currents presented herein is independent of cannabinoid or opioid receptors and may exert a significant impact on the functional activities of excitable cells occurring in vitro or in vivo.