Endothelial TRPV4 channel mediates the vasodilation induced by Tanshinone IIA.

Tanshinone IIA (TSA), the main lipo-soluble component from the dried rhizome of Salvia miltiorrhiza, has been shown to induce vasodilation. However, the underlying mechanisms remains unclear. This study aimed to investigate the effect of TSA on the vasodilation of small resistant arteries ex vivo. Vascular myography revealed that endothelial denudation reduced significantly the vasodilatory effect of TSA. Blocking transient receptor potential vanilloid 4 (TRPV4) channels prevented TSA-induced vasodilation. Whole-cell patch-clamp analysis revealed that the current passing through TRPV4 channels increased after TSA treatment in endothelial cells (ECs). This was attributed to reduced TRPV4 protein degradation along with its increased expression. The TRPV4 inhibitor HC-067047 lowed nitric oxide (NO) production and TSA-induced expression of endothelial nitric oxide synthase (eNOS). Moreover, it increased the production of cyclic guanosine monophosphate (cGMP) and protein kinase G (PKG). The present results indicate that TSA induces endothelium-dependent vasodilation, which is mediated by the TRPV4-NO-PKG signaling pathway. These findings highlight the potential of TSA, a compound known in traditional Chinese medicine as Danshen (Salvia miltiorrhiza), for future cardiovascular therapeutic strategies.

Intra-fractional corrections and clinical outcomes in frameless image-guided radiosurgery for trigeminal neuralgia.

Purpose: Precision targeting is crucial to successful stereotactic radiosurgery for trigeminal neuralgia (TGN). We investigated the impact of intra-fractional 6-dimensional corrections during frameless image-guided radiosurgery (IGRS) for pain outcome in TGN patients. Materials and methods: A total of 41 sets of intra-fractional corrections from 35 patients with TGN treated by frameless IGRS from 2009 to 2013 were retrospectively studied. For each IGRS, the intra-fractional 6-dimensional shifts were conducted at 6 couch angles. Clinical pain outcome was recorded according the Barrow Neurological Institute (BNI) 5-points score. The relationship in 6-dimensional corrections and absolute translational distances between patients with pain relief score points <2 versus ≥2 were analyzed. Results: The absolute mean lateral, longitudinal, and vertical translational shifts were 0.46 ± 0.15 mm, 0.36 ± 0.16 mm and 0.21 ± 0.08 mm, respectively, with 97% of translational shifts being within 0.7 mm. The absolute mean lateral (pitch), longitudinal (roll), and vertical (yaw) rotational corrections are 0.33 ± 0.24°, 0.18 ± 0.09°, and 0.27 ± 0.15°, respectively, with 97% of rotational corrections being within 0.6°. The median follow-up duration for pain outcome was 26 months after IGRS. The average calculated absolute shift for patients with pain relief <2 and ≥2 BNI points, were 0.228 ± 0.008 mm and 0.259 ± 0.007 mm, respectively. There was no statistically significant difference in the translational shifts, rotational corrections or absolute distances between these two patient groups. Conclusions: Our data demonstrate high spatial targeting accuracy of frameless IGRS for TGN with only nominal intra-fraction 6-dimensional corrections.

A comparative assessment of age-related nicotinamide adenine dinucleotide phosphate-diaphorase positivity in the spinal cord and medulla oblongata of pigeons, rats, and mice.

Nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase (N-d) positive neurons have been extensively studied across various animals, and N-d neurodegenerative neurites have been detected in some aged animal models. However, detailed knowledge on N-d positivity and aging-related alterations in the spinal cord and medulla oblongata of pigeons is limited. In this study, we investigated N-d positivity and age-related changes in the pigeon's spinal cord and medulla oblongata and compared them to those in rats and mice. Pigeons, had more N-d neurons in the dorsal horn, around the central canal, and in the column of Terni in the thoracic and lumbar segments, with scattered neurons found in the ventral horn of the spinal segments. N-d neurons were also present in the white matter of the spinal cord. Morphometric analysis revealed that the size of N-d soma in the lumbosacral, cervical, and thoracic regions was substantially altered in aged pigeons compared to young birds. Furthermore, the lumbar to sacral segments underwent significant morphological alterations. The main findings of this study were the presence of age-related N-d positive bodies (ANB) in aged pigeons, predominantly in the external cuneate nucleus (CuE) and occasionally in the gracilis and CuEs. ANBs were also identified in the gracile nuclei and spinal cord in the aged rats and mice, whereas in aged rats, ANBs were detected in the CuE spinal nucleus. Immunohistochemistry showed that the age-related alterations occurred in the cell types and neuropeptides in old animals. The results suggest weak inflammatory response and neuronal dysfunction in the spinal cord in aged pigeons. Our results suggested that the ANB could be a potential aging marker for the central nervous system.

Magnetic chitosan/ZrO2 composites for vanadium(V) adsorption while concurrently being transformed to a dual functional catalyst.

Spent adsorbents for recycling as catalysts have drawn considerable attention due to their environmentally benign chemistry properties. However, traditional thermocatalytic strategies limit their applications. Here, we developed an enhanced photocatalytic strategy to expand the range of their applications. A magnetic chitosan/ZrO2 composites (MZT) for V(V) adsorption, which were prepared using chitosan, ZrO2 and Fe3O4 by one-pot synthesis. The spent MZT as a catalyst was used to synthesize 2-phenylbenzimidazole, yielding up to 89.7%. It also was implemented to photocatalysis reactions for recycle. The discolored rates of rhodamine B (RhB) were 72.3% and 97.4% by new and spent MZT, respectively. The new and spent MZT showed the forbidden bands were 251 nm and 561 nm, respectively. The result displayed spent MZT red shifted to the cyan light region. The mechanism of catalysis also has been studied in detail.

Clinical and hematological characteristics of children infected with the omicron variant of SARS-CoV-2: role of the combination of the neutrophil: lymphocyte ratio and eosinophil count in distinguishing severe COVID-19.

Purpose: Investigate the clinical/hematological characteristics of children infected with the Omicron variant of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and identify an effective indicator to distinguish coronavirus disease 2019 (COVID-19) severity in children. Methods: A retrospective study was conducted through electronic medical records from pediatric patients. The demographic, clinical, and routine blood test (RBT) features of children diagnosed by real-time PCR for SARS-CoV-2 were collected. Results: Data of 261 patients were analyzed. The most common abnormality shown by RBTs was increased monocyte count (68%). Children had "mild-moderate" or "severe" forms of COVID-19. Prevalence of abnormal neutrophil count (p = 0.048), eosinophil count (p = 0.006), mean corpuscular volume (p = 0.033), mean platelet volume (p = 0.006), platelet-large cell ratio (p = 0.043), and red blood cell distribution width-standard deviation (p = 0.031) were significantly different in the two types. A combination of the neutrophil: lymphocyte ratio (NLR) and eosinophil count for diagnosing severe COVID-19 presented the largest AUC (0.688, 95% CI = 0.599-0.777; p < 0.001), and the AUC increased with a decrease in age. Conclusions: Combination of the NLR and eosinophil count might be a promising indicator for identifying severe COVID-19 in children at infection onset.

Highly selective urea electrooxidation coupled with efficient hydrogen evolution.

Electrochemical urea oxidation offers a sustainable avenue for H2 production and wastewater denitrification within the water-energy nexus; however, its wide application is limited by detrimental cyanate or nitrite production instead of innocuous N2. Herein we demonstrate that atomically isolated asymmetric Ni-O-Ti sites on Ti foam anode achieve a N2 selectivity of 99%, surpassing the connected symmetric Ni-O-Ni counterparts in documented Ni-based electrocatalysts with N2 selectivity below 55%, and also deliver a H2 evolution rate of 22.0 mL h-1 when coupled to a Pt counter cathode under 213 mA cm-2 at 1.40 VRHE. These asymmetric sites, featuring oxygenophilic Ti adjacent to Ni, favor interaction with the carbonyl over amino groups in urea, thus preventing premature resonant C⎓N bond breakage before intramolecular N-N coupling towards N2 evolution. A prototype device powered by a commercial Si photovoltaic cell is further developed for solar-powered on-site urine processing and decentralized H2 production.

Incidence of acute Deep Vein Thrombosis in pediatric and adolescent orthopedic trauma hospitalized patients and effect of rivaroxaban treatment.

OBJECTIVE: Deep vein thrombosis (DVT) provoked by orthopedic trauma is increasing in pediatric hospitalized patients. The purpose of our study is to identify the prevalence of acute DVT in pediatric and adolescent orthopedic trauma hospitalized patients and focus on evaluating the anticoagulation strategies and the clinical outcomes after a confirmed acute DVT. METHODS: Patients (age ≤18 years) with a confirmed acute DVT admitted for orthopedic trauma between September 2017 and December 2023 were included. Patients were classified into the non-anticoagulation (NA), the in-hospital anticoagulation (IHA), and the in-and-out-of-hospital anticoagulation (IOHA) groups based on their anticoagulation regimen. Efficacy outcomes were the venous thromboembolism (VTE) recurrence within 3 months and change in thrombus burden by repeat imaging at 2 weeks after discharge compared with baseline. Safety outcomes were major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) within 3 months. RESULTS: Of the 11,206 pediatric and adolescent orthopedic trauma inpatients, 94(median age,16 [15, 18] years) were diagnosed with acute DVT, with an incidence of 0.84 %, of which 8(8.5 %) received NA, 41(43.6 %) received IHA, and 45(47.9 %) received IOHA. After the diagnosis of DVT, of patients who received anticoagulation, 97.9 % were treated with rivaroxaban as an oral anticoagulant, and 71.7 % received an LMWH course of ≥5 days before starting rivaroxaban therapy. With a median anticoagulation course of 22(8, 37.3) days, the duration in the IOHA was significantly longer than the IHA (37 days vs. 8 days, p = 0.000). No patients experienced recurrent VTE and MB at 3 months, and 1 received IOHA had a CRNMB event (0 % vs. 0 % vs. 2.2 %, p = 1.000). Thrombus resolution was significantly higher in patients who received anticoagulation therapy (IOHA 91.1 % vs. IHA 80.5 % vs. NA 37.5 %, P = 0.002), and thrombus-no relevant change was significantly lower in patients who received the IOHA strategy compared with the other groups (4.4 % vs. 19.5 % vs. 62.5 %, P = 0.000). CONCLUSIONS: A rivaroxaban-predominant IOHA strategy significantly reduced the thrombotic burden without increasing the risk of bleeding for the treatment of DVT in adolescents with orthopedic trauma. Duration of anticoagulation therapy <6 weeks appears appropriate for adolescent orthopedic trauma-related DVT.

The Flynn effect and cognitive decline among americans aged 65 years and older.

To contribute to our understanding of cohort differences and the Flynn effect in the cognitive decline among older Americans, this study aims to compare rates of cognitive decline between two birth cohorts within a study of older Americans and to examine the importance of medical and demographic confounders. Analyses used data from the National Health and Aging Trends Study (2011-2019), which recruited older Americans in 2011 and again in 2015 who were then followed for 5 years. We employed mixed-effect models to examine the linear and quadratic main and interaction effects of year of birth while adjusting for covariates such as annual round, sex/gender, education, race/ethnicity, heart disease, hypertension, diabetes, test unfamiliarity, and survey design. We analyzed data from 11,167 participants: 7,325 from 2011 to 2015 and 3,842 from 2015 to 2019. The cohort recruited in 2015 was born, on average, 5.33 years later than that recruited in 2011 and had higher functioning than the one recruited in 2011 across all observed cognitive domains that persisted after adjusting for covariates. In multivariable-adjusted analyses, a 1-year increase in year of birth was associated with increased episodic memory (ß = 0.045, SE = 0.001, p < .001), orientation (ß = 0.034, SE = 0.001, p < .001), and executive function (ß = 0.036, SE = 0.001, p < .001). Participants born 1 year later had slower rates of decline in episodic memory (ß = 0.004, SE = 0.000, p < .001), orientation (ß = 0.003, SE = 0.000, p < .001), and executive function (ß = 0.001, SE = 0.000, p = .002). Additionally, sex/gender modified this relationship for episodic memory (-0.007, SE = 0.002, p < .001), orientation (-0.005, SE = 0.002, p = .008), and executive function (-0.008, SE = 0.002, p < .001). These results demonstrate the persistence of the Flynn effect in old age across cognitive domains and identified a deceleration in the rate of cognitive decline across cognitive domains. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

MRPL35 Induces Proliferation, Invasion, and Glutamine Metabolism in NSCLC Cells by Upregulating SLC7A5 Expression.

BACKGROUND: Mitochondrial ribosomal protein L35 (MRPL35) has been reported to contribute to the growth of non-small cell lung cancer (NSCLC) cells. However, the functions and mechanisms of MRPL35 on glutamine metabolism in NSCLC remain unclear. METHODS: The detection of mRNA and protein of MRPL35, ubiquitin-specific protease 39 (USP39), and solute carrier family 7 member 5 (SLC7A5) was conducted using qRT-PCR and western blotting. Cell proliferation, apoptosis, and invasion were evaluated using the MTT assay, EdU assay, flow cytometry, and transwell assay, respectively. Glutamine metabolism was analyzed by detecting glutamine consumption, α-ketoglutarate level, and glutamate production. Cellular ubiquitination analyzed the deubiquitination effect of USP39 on MRPL35. An animal experiment was conducted for in vivo analysis. RESULTS: MRPL35 was highly expressed in NSCLC tissues and cell lines, and high MRPL35 expression predicted poor outcome in NSCLC patients. In vitro analyses suggested that MRPL35 knockdown suppressed NSCLC cell proliferation, invasion, and glutamine metabolism. Moreover, MRPL35 silencing hindered tumor growth in vivo. Mechanistically, USP39 stabilized MRPL35 expression by deubiquitination and then promoted NSCLC cell proliferation, invasion, and glutamine metabolism. In addition, MRPL35 positively affected SLC7A5 expression in NSCLC cells in vitro and in vivo. Moreover, the anticancer effects of MRPL35 silencing could be rescued by SLC7A5 overexpression in NSCLC cells. CONCLUSION: MRPL35 expression was stabilized by USP39-induced deubiquitination in NSCLC cells, and knockdown of MRPL35 suppressed NSCLC cell proliferation, invasion, and glutamine metabolism in vitro and impeded tumor growth in vivo by upregulating SLC7A5, providing a promising therapeutic target for NSCLC.

Incidence, characteristics, and risk factors of new liver disorders 3.5 years post COVID-19 pandemic in the Montefiore Health System in Bronx.

PURPOSE: To determine the incidence of newly diagnosed liver disorders (LD) up to 3.5-year post-acute COVID-19, and risk factors associated with new LD. METHODS: We analyzed 54,699 COVID-19 patients and 1,409,547 non-COVID-19 controls from March-11-2020 to Jan-03-2023. New liver disorders included abnormal liver function tests, advanced liver failure, alcohol and non-alcohol related liver disorders, and cirrhosis. Comparisons were made with ambulatory non-COVID-19 patients and patients hospitalized for other lower respiratory tract infections (LRTI). Demographics, comorbidities, laboratory data, incomes, insurance status, and unmet social needs were tabulated. The primary outcome was new LD at least two weeks following COVID-19 positive test. RESULTS: Incidence of new LD was not significantly different between COVID-19 and non-COVID-19 cohorts (incidence:1.99% vs 1.90% p>0.05, OR = 1.04[95%CI: 0.92,1.17], p = 0.53). COVID-19 patients with new LD were older, more likely to be Hispanic and had higher prevalence of diabetes, hypertension, chronic kidney disease, and obesity compared to patients without new LD. Hospitalized COVID-19 patients had no elevated risk of LD compared to hospitalized LRTI patients (2.90% vs 2.07%, p>0.05, OR = 1.29[0.98,1.69], p = 0.06). Among COVID-19 patients, those who developed LD had fewer patients with higher incomes (14.18% vs 18.35%, p<0.05) and more with lower incomes (21.72% vs 17.23%, p<0.01), more Medicare and less Medicaid insurance, and more patients with >3 unmet social needs (6.49% vs 2.98%, p<0.001) and fewer with no unmet social needs (76.19% vs 80.42%, p<0.001). CONCLUSIONS: Older age, Hispanic ethnicity, and obesity, but not COVID-19 status, posed increased risk for developing new LD. Lower socioeconomic status was associated with higher incidence of new LD.

Interaction between catechol-O-methyltransferase Val/Met polymorphism and cognitive reserve for negative symptoms in schizophrenia.

BACKGROUND: Cognitive reserve (CR) and the catechol-O-methyltransferase (COMT) Val/Met polymorphism are reportedly linked to negative symptoms in schizophrenia. However, the regulatory effect of the COMT genotype on the relationship between CR and negative symptoms is still unexamined. AIM: To investigate whether the relationship between CR and negative symptoms could be regulated by the COMT Val/Met polymorphism. METHODS: In a cross-sectional study, 54 clinically stable patients with schizophrenia underwent assessments for the COMT genotype, CR, and negative symptoms. CR was estimated using scores in the information and similarities subtests of a short form of the Chinese version of the Wechsler Adult Intelligence Scale. RESULTS: COMT Met-carriers exhibited fewer negative symptoms than Val homozygotes. In the total sample, significant negative correlations were found between negative symptoms and information, similarities. Associations between information, similarities and negative symptoms were observed in Val homozygotes only, with information and similarities showing interaction effects with the COMT genotype in relation to negative symptoms (information, ß = -0.282, 95%CI: -0.552 to -0.011, P = 0.042; similarities, ß = -0.250, 95%CI: -0.495 to -0.004, P = 0.046). CONCLUSION: This study provides initial evidence that the association between negative symptoms and CR is under the regulation of the COMT genotype in schizophrenia.

Multi-scale feature fusion and class weight loss for skin lesion classification.

Skin cancer is one of the common types of cancer. It spreads quickly and is not easy to detect in the early stages, posing a major threat to human health. In recent years, deep learning methods have attracted widespread attention for skin cancer detection in dermoscopic images. However, training a practical classifier becomes highly challenging due to inter-class similarity and intra-class variation in skin lesion images. To address these problems, we propose a multi-scale fusion structure that combines shallow and deep features for more accurate classification. Simultaneously, we implement three approaches to the problem of class imbalance: class weighting, label smoothing, and resampling. In addition, the HAM10000_RE dataset strips out hair features to demonstrate the role of hair features in the classification process. We demonstrate that the region of interest is the most critical classification feature for the HAM10000_SE dataset, which segments lesion regions. We evaluated the effectiveness of our model using the HAM10000 and ISIC2019 dataset. The results showed that this method performed well in dermoscopic classification tasks, with ACC and AUC of 94.0% and 99.3%, on the HAM10000 dataset and ACC of 89.8% for the ISIC2019 dataset. The overall performance of our model is excellent in comparison to state-of-the-art models.

Co-assembly of cisplatin and dasatinib in hyaluronan nanogel to combat triple negative breast cancer with reduced side effects.

Treatment for triple negative breast cancer (TNBC) remains a huge challenge due to the lack of targeted therapeutics and tumor heterogenicity. Cisplatin (Cis) have demonstrated favorable therapeutic response in TNBC and thus is used together with various kinase inhibitors to fight the heterogenicity of TNBC. The combination of Cis with SRC inhibitor dasatinib (DAS) has shown encouraging anti-TNBC efficacy although the additive toxicity was commonly observed. To overcome the severe side effects of this Cis involved therapy, here we co-encapsulated Cis and DAS into a self-assembled hyaluronan (HA) nanogel (designated as HA/Cis/DAS (HCD) nanogel) to afford the TNBC targeted delivery by using the 4T1 mouse model. The acquired HCD nanogel was around 181 nm in aqueous solution, demonstrating the pharmacological activities of both Cis and DAS. Taking advantages of HA's targeting capability towards CD44 that is overexpressed on many TNBC cells, the HCD could well maintain the anticancer efficacy of the Cis and DAS combination, significantly increase the maximum tolerated dose and relieve the renal toxicity in vivo. The current HCD nanogel provides a potent strategy to improve the therapeutic outcome of Cis and DAS combination and thus representing a new targeted treatment option for TNBC.

Discovery and genetic characterization of novel paramyxoviruses from small mammals in Hubei Province, Central China.

Paramyxoviruses are a group of single-stranded, negative-sense RNA viruses, some of which are responsible for acute human disease, including parainfluenza virus, measles virus, Nipah virus and Hendra virus. In recent years, a large number of novel paramyxoviruses, particularly members of the genus Jeilongvirus, have been discovered in wild mammals, suggesting that the diversity of paramyxoviruses may be underestimated. Here we used hemi-nested reverse transcription PCR to obtain 190 paramyxovirus sequences from 969 small mammals in Hubei Province, Central China. These newly identified paramyxoviruses were classified into four clades: genera Jeilongvirus, Morbillivirus, Henipavirus and Narmovirus, with most of them belonging to the genus Jeilongvirus. Using Illumina sequencing and Sanger sequencing, we successfully recovered six near-full-length genomes with different genomic organizations, revealing the more complex genome content of paramyxoviruses. Co-divergence analysis of jeilongviruses and their known hosts indicates that host-switching occurred more frequently in the evolutionary histories of the genus Jeilongvirus. Together, our findings demonstrate the high prevalence of paramyxoviruses in small mammals, especially jeilongviruses, and highlight the diversity of paramyxoviruses and their genome content, as well as the evolution of jeilongviruses.

Effectiveness and Safety of Early Versus Routine Switching from Low-Molecular-Weight Heparin to Maintenance Therapy of Rivaroxaban for Acute Iliofemoral Vein Thrombosis: A Retrospective Cohort Study.

BACKGROUND: The anticoagulation strategy of switching to rivaroxaban after 1 week of initial low-molecular-weight heparin (LMWH) therapy is recommended by a guideline for the treatment of acute iliofemoral deep vein thrombosis (DVT). However, the initial rivaroxaban dose in the switching strategy, as well as the effectiveness and safety of the early switching (less than 1 week) to rivaroxaban, remain inadequately substantiated. We aimed to evaluate the effectiveness and safety of early switching from LMWH to maintenance therapy of rivaroxaban (20 mg once daily) for acute iliofemoral DVT. METHODS: A retrospective cohort study was conducted using data from patients with acute iliofemoral DVT who received initial LMWH anticoagulation followed by rivaroxaban maintenance therapy. The clinical outcomes were compared between early (LMWH course ≤7 days) and routine (LMWH course >7 days) switching strategies within 3 months of initiating anticoagulation. RESULTS: 217 patients were included, 59 (27.2%) receiving early switching and 158 (72.8%) receiving routine switching. Compared with routine switching, patients with early switching had a significantly shorter hospital stay (7 days vs. 14 days, P < 0.001). The length of hospital stay was significantly positively correlated with the duration of LMWH (r = 0.762, P < 0.001). The incidences of recurrent venous thromboembolism (5.1% vs. 2.5%, P = 0.606), major bleeding (0% vs. 1.9%, P = 0.564), clinically relevant nonmajor bleeding (1.7% vs. 2.5%, P = 1.000) and all-cause mortality (6.8% vs. 2.5%, P = 0.283) were not statistically different between the 2 groups. CONCLUSIONS: Direct early switching from LMWH to maintenance therapy of rivaroxaban is effective and safe for acute iliofemoral DVT.

Conditional reprogrammed human limbal epithelial cell model for anti-SARS-CoV-2 drug screening.

To minimize the global pandemic COVID-19 spread, understanding the possible transmission routes of SARS-CoV-2 and discovery of novel antiviral drugs are necessary. We describe here that the virus can infect ocular surface limbal epithelial, but not other regions. Limbal supports wild type and mutant SARS-CoV-2 entry and replication depending on ACE2, TMPRSS2 and possibly other receptors, resulting in slight CPE and arising IL-6 secretion, which symbolizes conjunctivitis in clinical symptoms. With this limbal model, we have screened two natural product libraries and discovered several unreported drugs. Our data reveal important commonalities between COVID-19 and ocular infection with SARS-CoV-2, and establish an ideal cell model for drug screening and mechanism research.

F-actin/DRP1 axis-mediated mitochondrial fission promotes mitophagy in diabetic submandibular glands.

BACKGROUND: Diabetes is accompanied by a high prevalence of hyposalivation, causing severe damage to oral and systemic health. Mitochondrial dynamics play important roles in the pathogenesis of various diabetic complications; however, little is known about their roles in diabetic hyposalivation. MATERIALS AND METHODS: A diabetic mouse model and a high glucose (HG)-induced diabetic submandibular gland (SMG) cell model were employed. RESULTS: More mitochondria surrounded by autophagosomes and higher expression of mitophagy-related proteins were detected in the SMGs of diabetic mice and HG-treated SMG cells. In diabetic SMGs, dynamin-related protein 1 (DRP1) was upregulated, whereas mitofusin-2 was downregulated both in vivo and in vitro. Shortened mitochondria and impaired mitochondrial functions were observed in the HG group. A DRP1-specific inhibitor, mdivi-1, suppressed mitochondrial fission and mitophagy, as well as restored mitochondrial functions in the HG condition. Moreover, the interaction of F-actin and DRP1 was enhanced in the diabetic group. Inhibiting F-actin with cytochalasin D repaired the injured effects of HG on mitochondrial dynamics and functions. Conversely, the F-actin-polymerization-inducer jasplakinolide aggravated mitochondrial fission and dysfunction. CONCLUSIONS: F-actin contributes to HG-evoked mitochondrial fission by interacting with DRP1, which induces mitophagy and impairs mitochondrial function in SMG cells, ultimately damaging the SMG.

Phenomic landscape and pharmacogenomic implications for HLA region in a Taiwan Han Chinese population.

BACKGROUND: The human leukocyte antigen (HLA) genes, exhibiting significant genetic diversity, are associated with susceptibility to various clinical diseases and diverse in drug responses. High costs of HLA sequencing and the population-specific architecture of this genetic region necessitate the establishment of a population-specific HLA imputation reference panel. Moreover, there is a lack of understanding about the genetic and phenotypic landscape of HLA variations within the Taiwanese population. METHODS: We created models for a Taiwanese-specific HLA imputation reference panel. These models were trained with the array genotype data and HLA sequencing data from 845 Taiwanese subjects. HLA imputation was applied for 59,448 Taiwanese subjects to characterize the HLA allele and haplotype frequencies. Additionally, a phenome-wide association study (PheWAS) was conducted to identify the phenotypes associated with HLA variations. The association of the biallelic HLA variants with the binary and quantitative traits were evaluated with additive logistic and linear regression models, respectively. Furthermore, an omnibus test with likelihood-ratio test was applied for each HLA amino acid position in the multiallelic HLA amino acid polymorphisms to compare the difference between a fitted model and a null model following a χ2 distribution of n-1 degree of freedom at a position with n residues. Finally, we estimated the prevalence of adverse drug reactions (ADR)-related HLA alleles in the Taiwanese population. RESULTS: In this study, the reference panel models displayed remarkable accuracy, with averages of 99.3%, 98.9%, and 99.1% for 2-, 4-, 6-digit alleles of the eight classical HLA genes, respectively. For PheWAS, a total of 18,136 significant associations with HLA variants across 26 phenotypes are identified (p < 5×10-8), highlighting the pleiotropy feature of the HLA region. Among the independent signals, 15 are novel, including the association of HLA-B pos 138 variation with ankylosing spondylitis (AS), and rs9266290 and rs9266292 with allergy. Through an analysis spanning the entire HLA region, we identified clusters of phenotype correlations. Finally, the carriers of pharmacogenomic related HLA alleles, including HLA-C*01:02 (35.86%), HLA-B*58:01 (20.9%), and HLA-B*15:02 (8.38%), were characterized in the Taiwanese general population. CONCLUSIONS: We successfully delivered the HLA imputation for 59,448 Taiwanese subjects and characterized the genetic and phenotypic landscapes of the HLA variations. In addition, we quantified the estimated prevalence of the ADR-related HLA alleles in the Taiwanese population. The developed HLA imputation reference panel could be used for estimation of population HLA allele frequencies, which can facilitate further studies in the role of HLA variants in a wider range of phenotypes in the population.

Monodispersed and Organic Amine Modified La(OH)3 Nanocrystals for Superior Advanced Phosphate Removal.

Advanced phosphate removal is critical for alleviating the serious and widespread aquatic eutrophication, strongly depending on the development of superior adsorption materials to overcome low chemical affinity and sluggish mass transfer at low phosphate concentrations. Herein, the first synthesis of monodispersed and organic amine modified lanthanum hydroxide nanocrystals (OA-La(OH)3) for advanced phosphate removal by modulating inner Helmholtz plane (IHP), is reported. These OA-La(OH)3 nanocrystals with positively charged surfaces and abundant exposed La sites exhibit specific affinity toward phosphate, delivering a maximum adsorption capacity of 168 mg P g⁻1 and a wide pH adaptability from 3.0 to 11.0, as well as a robust anti-interference performance, far surpassing those of documented phosphate removal materials. The superior phosphate removal performance of OA-La(OH)3 is attributed to its protonated organic amine in IHP, which enhances the electrostatic attraction around the adsorbent-solution interface. Impressively, OA-La(OH)3 can treat ≈5 000 and ≈3 200 bed volumes of simulated and real phosphate-containing wastewater to below extremely strict standard (0.1 mg L⁻1) in a fixed-bed adsorption mode, exhibiting great potential for advanced phosphate removal. This study offers a facile modification strategy to improve phosphate removal performance of nanoscale adsorbents, and sheds light on the structure-reactivity relationship of La-based materials.

Echinococcus granulosus ubiquitin-conjugating enzymes (E2D2 and E2N) promote the formation of liver fibrosis in TGFß1-induced LX-2 cells.

BACKGROUND: Cystic echinococcosis (CE) is a widespread zoonosis caused by the infection with Echinococcus granulosus sensu lato (E. granulosus s.l.). CE cysts mainly develop in the liver of intermediate hosts, characterized by the fibrotic tissue that separates host organ from parasite. However, precise mechanism underlying the formation of fibrotic tissue in CE remains unclear. METHODS: To investigate the potential impact of ubiquitin-conjugating enzymes on liver fibrosis formation in CE, two members of ubiquitin-conjugating (UBC) enzyme of Echinococcus granulosus (EgE2D2 and EgE2N) were recombinantly expressed in Escherichia coli and analyzed for bioinformatics, immunogenicity, localization, and enzyme activity. In addition, the secretory pathway and their effects on the formation of liver fibrosis were also explored. RESULTS: Both rEgE2D2 and rEgE2N possess intact UBC domains and active sites, exhibiting classical ubiquitin binding activity and strong immunoreactivity. Additionally, EgE2D2 and EgE2N were widely distributed in protoscoleces and germinal layer, with differences observed in their distribution in 25-day strobilated worms. Further, these two enzymes were secreted to the hydatid fluid and CE-infected sheep liver tissues via a non-classical secretory pathway. Notably, TGFß1-induced LX-2 cells exposed to rEgE2D2 and rEgE2N resulted in increasing expression of fibrosis-related genes, enhancing cell proliferation, and facilitating cell migration. CONCLUSIONS: Our findings suggest that EgE2D2 and EgE2N could secrete into the liver and may interact with hepatic stellate cells, thereby promoting the formation of liver fibrosis.