A New Orthonairovirus Associated with Human Febrile Illness.

BACKGROUND: In June 2019, a patient presented with persistent fever and multiple organ dysfunction after a tick bite at a wetland park in Inner Mongolia. Next-generation sequencing in this patient revealed an infection with a previously unknown orthonairovirus, which we designated Wetland virus (WELV). METHODS: We conducted active hospital-based surveillance to determine the prevalence of WELV infection among febrile patients with a history of tick bites. Epidemiologic investigation was performed. The virus was isolated, and its infectivity and pathogenicity were investigated in animal models. RESULTS: WELV is a member of the orthonairovirus genus in the Nairoviridae family and is most closely related to the tickborne Hazara orthonairovirus genogroup. Acute WELV infection was identified in 17 patients from Inner Mongolia, Heilongjiang, Jilin, and Liaoning, China, by means of reverse-transcriptase-polymerase-chain-reaction assay. These patients presented with nonspecific symptoms, including fever, dizziness, headache, malaise, myalgia, arthritis, and back pain and less frequently with petechiae and localized lymphadenopathy. One patient had neurologic symptoms. Common laboratory findings were leukopenia, thrombocytopenia, and elevated d-dimer and lactate dehydrogenase levels. Serologic assessment of convalescent-stage samples obtained from 8 patients showed WELV-specific antibody titers that were 4 times as high as those in acute-phase samples. WELV RNA was detected in five tick species and in sheep, horses, pigs, and Transbaikal zokors (Myospalax psilurus) sampled in northeastern China. The virus that was isolated from the index patient and ticks showed cytopathic effects in human umbilical-vein endothelial cells. Intraperitoneal injection of the virus resulted in lethal infections in BALB/c, C57BL/6, and Kunming mice. The Haemaphysalis concinna tick is a possible vector that can transovarially transmit WELV. CONCLUSIONS: A newly discovered orthonairovirus was identified and shown to be associated with human febrile illnesses in northeastern China. (Funded by the National Natural Science Foundation of China and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences.).

Mild cognitive impairment prediction based on multi-stream convolutional neural networks.

BACKGROUND: Mild cognitive impairment (MCI) is the transition stage between the cognitive decline expected in normal aging and more severe cognitive decline such as dementia. The early diagnosis of MCI plays an important role in human healthcare. Current methods of MCI detection include cognitive tests to screen for executive function impairments, possibly followed by neuroimaging tests. However, these methods are expensive and time-consuming. Several studies have demonstrated that MCI and dementia can be detected by machine learning technologies from different modality data. This study proposes a multi-stream convolutional neural network (MCNN) model to predict MCI from face videos. RESULTS: The total effective data are 48 facial videos from 45 participants, including 35 videos from normal cognitive participants and 13 videos from MCI participants. The videos are divided into several segments. Then, the MCNN captures the latent facial spatial features and facial dynamic features of each segment and classifies the segment as MCI or normal. Finally, the aggregation stage produces the final detection results of the input video. We evaluate 27 MCNN model combinations including three ResNet architectures, three optimizers, and three activation functions. The experimental results showed that the ResNet-50 backbone with Swish activation function and Ranger optimizer produces the best results with an F1-score of 89% at the segment level. However, the ResNet-18 backbone with Swish and Ranger achieves the F1-score of 100% at the participant level. CONCLUSIONS: This study presents an efficient new method for predicting MCI from facial videos. Studies have shown that MCI can be detected from facial videos, and facial data can be used as a biomarker for MCI. This approach is very promising for developing accurate models for screening MCI through facial data. It demonstrates that automated, non-invasive, and inexpensive MCI screening methods are feasible and do not require highly subjective paper-and-pencil questionnaires. Evaluation of 27 model combinations also found that ResNet-50 with Swish is more stable for different optimizers. Such results provide directions for hyperparameter tuning to further improve MCI predictions.

Global risk dynamics of Borrelia miyamotoi in the context of climate change.

The impact of Borrelia miyamotoi on human health, facilitated by the expanding geographical distribution and increasing population of Ixodes ticks, remains obscure in the context of global climate change. We employed multiple models to evaluate the effect of global climate change on the risk of B. miyamotoi worldwide across various scenarios. The habitat suitability index of four primary vector tick species for B. miyamotoi, including Ixodes persulcatus, Ixodes ricinus, Ixodes pacificus and Ixodes scapularis, was projected using a boosted regression tree model, considering multiple shared socio-economic pathway scenarios over various time periods. The modelling analysis reveals that, apart from I. scapularis, future global warming will result in a northward shift in the other three vector tick species and a gradual reduction in suitable habitats. Random forest models indicate consistent changes in B. miyamotoi and its primary tick species, with potential risk areas shrinking and shifting northward, particularly in the eastern USA, northeastern and northern Europe and northeast Asia. These findings highlight the urgent need for enhanced active surveillance of B. miyamotoi infection in primary vector tick species across projected potential risk areas. The effect of climate change on B. miyamotoi distribution might have significant implications for public health decision-making regarding tick-borne pathogens.

Virulence plasmid with IroBCDN deletion promoted cross-regional transmission of ST11-KL64 carbapenem-resistant hypervirulent Klebsiella pneumoniae in central China.

BACKGROUND: Carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CR-hvKP) caused infections of high mortality and brought a serious impact on public health. This study aims to evaluate the epidemiology, resistance and virulence characteristics of CR-hvKP and to identify potential drivers of cross-regional transmission in different regions of China, in order to provide a basis for developing targeted prevention measures. METHODS: Clinical K. pneumoniae strains were collected from Jiujiang and Nanchang in Jiangxi province between November 2021 to June 2022. Clinical data of patients (age, sex, source of infection, and diagnosis) were also gathered. We characterized these strains for their genetic relatedness using PFGE, antimicrobial and virulence plasmid structures using whole-genome sequencing, and toxicity using Galleria mellonella infection model. RESULTS: Among 609 strains, 45 (7.4%) CR-hvKP were identified, while the strains. isolated from Nanchang and Jiujiang accounted for 10.05% (36/358) and 3.59% (9/251). We observed that ST11-KL64 CR-hvKP had an overwhelming epidemic dominance in these two regions. Significant genetic diversity was identified among all ST11-KL64 CR-hvKP cross-regional transmission between Nanchang and Jiujiang and this diversity served as the primary driver of the dissemination of clonal groups. Virulence genes profile revealed that ST11-KL64 CR-hvKP might harbour incomplete pLVPK-like plasmids and primarily evolved from CRKP by acquiring the hypervirulence plasmid. We found the predominance of truncated-IncFIB/IncHI1B type virulence plasmids with a 25 kb fragment deletion that encoded iroBCDN clusters. CONCLUSION: ST11-KL64 is the most cross-regional prevalent type CR-hvKPs in Jiangxi province, which mainly evolved from CRKPs by acquiring a truncated-IncHI1B/IncFIB virulence plasmid with the deletion of iroBCDN. Stricter surveillance and control measures are urgently needed to prevent the epidemic transmission of ST11-KL64 CR-hvKP.

Cost and outcomes of Hospital-based Usual cAre versus Tele-monitor self-directed Rehabilitation (HUATR) in patients with total knee arthroplasty: A randomized, controlled, non-inferiority trial.

OBJECTIVE: To evaluate the clinical efficacy and cost-effectiveness of telemonitored self-directed rehabilitation (TR) compared with hospital-based rehabilitation (HBR) for patients with total knee arthroplasty (TKA). DESIGN: In this randomized, non-inferiority clinical trial, 114 patients with primary TKA who were able to walk independently preoperatively were randomized to receive HBR (n = 58) or TR (n = 56). HBR comprised at least five physical therapy sessions over 10 weeks. TR comprised a therapist-led onboarding session, followed by a 10-week unsupervised home-based exercise program, with asynchronous monitoring of rehabilitation outcomes using a telemonitoring system. The primary outcome was fast-paced gait speed at 12 weeks, with a non-inferiority margin of 0.10 m/s. For economic analysis, quality-adjusted-life-years (QALY) was the primary economic outcome (non-inferiority margin, 0.027 points). RESULTS: In Bayesian analyses, TR had >95% posterior probability of being non-inferior to HBR in gait speed (week-12 adjusted TR-HBR difference, 0.02 m/s; 95%CrI, -0.05 to 0.10 m/s; week-24 difference, 0.01 m/s; 95%CrI, -0.07 to 0.10 m/s) and QALY (0.006 points; 95%CrI, -0.006 to 0.018 points). When evaluated from a societal perspective, TR was associated with lower mean intervention cost (adjusted TR-HBR difference, -S$227; 95%CrI, -112 to -330) after 24 weeks, with 82% probability of being cost-effective compared with HBR at a willingness to pay of S$0/unit of effect for the QALYs. CONCLUSIONS: In patients with uncomplicated TKAs and relatively good preoperative physical function, home-based, self-directed TR was non-inferior to and more cost-effective than HBR over a 24-week follow-up period. TR should be considered for this patient subgroup.

Prognostic factors and clinical outcomes in Fournier's Gangrene: a retrospective study of 35 patients.

BACKGROUND: Fournier's gangrene is a severe form of infectious necrotizing fasciitis affecting the perineum, perianal, and genital areas; it is associated with substantial morbidity and mortality. Hence, it is important to identify prognostic factors that can predict clinical outcomes and guide treatment strategies. Thus, our study aimed to analyze patient characteristics and determine prognostic factors affecting clinical outcomes in Fournier's gangrene. METHODS: This retrospective study involved examining medical records spanning 18 years for patients with Fournier's gangrene at our institution. Considering the exclusion criteria, data from 35 patients were included in this study. RESULTS: A total of 35 patients were included in the analysis. The mean age of the patients showed no statistically significant difference between the survivor and non-survivor groups. The Charlson Comorbidity Index, American Society of Anesthesiologists score, and Acute Physiology and Chronic Health Evaluation II score were not significantly different between the two groups. Notably, the initial Sequential Organ Failure Assessment score was significantly higher in the non-survivor group than that in the survivor group. The overall in-hospital mortality rate was 17.1%. Moreover, the prevalence of multidrug resistant bacterial infection was markedly higher in the non-survivor group than that in the survivor group. Coagulation dysfunction was significantly more prevalent in the non-survivor group than that in the survivor group, and had the most significant impact on in-hospital mortality. A multivariable logistic regression analysis identified multidrug resistant bacterial infection to be independently associated with high in-hospital mortality. CONCLUSIONS: Coagulation dysfunction and multidrug resistant bacterial infection were identified as independent negative prognostic factors, highlighting the need for prompt monitoring and proactive strategies against Fournier's gangrene.

Investigation of Far Infrared Emission and UV Protection Properties of Polypropylene Composites Embedded with Candlenut-Derived Biochar for Health Textiles.

Far infrared radiation (FIR) within the wavelength range of 4-14 µm can offer human health benefits, such as improving blood flow. Therefore, additives that emit far infrared radiation have the potential to be incorporated into polymer/fabric matrices to develop textiles that could promote health. In this study, biochar derived from candlenuts and pyrolyzed with activated carbon (AC) was incorporated into polypropylene (PP) films and investigated for its potential as a health-promoting textile additive. The properties of biochar were compared with other far infrared (FIR) emitting additives such as hematite, Indian red ochre, and graphene. The addition of biochar increased FIR emissivity to 0.90, which is 9% higher than that of pristine PP. Additionally, biochar enhanced UV and near-infrared (NIR) blocking capabilities, achieving an ultra-protection factor (UPF) of 91.41 and NIR shielding of 95.85%. Incorporating 2 wt% biochar resulted in a 3.3-fold higher temperature increase compared to pristine PP after 30 s of exposure to an FIR source, demonstrating improved heat retention. Furthermore, the ability to achieve the lowest thermal effusivity among other additives supports the potential use of biochar-incorporated fabric as a warming material in cold climates. The tensile properties of PP films with biochar were superior to those with other additives, potentially contributing to a longer product lifespan. Additionally, samples with red ochre exhibited the highest FIR emissivity, while samples with hematite showed the highest capacity for UV shielding.

Global profiling of protein lysine lactylation and potential target modified protein analysis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, often metastasizes to the lungs. The implications of lysine lactylation (Kla), a recently identified histone post-translational modification (PTM), in the pathology of HCC remain unclear. Here, we report the first proteomic survey of this specific modification in HCC (with no metastasis during 3 years of follow-up), normal liver tissues, and lung metastasis samples of HCC. Of the 2045 modification sites detected on 960 proteins, 1438 sites on 772 proteins contained quantitative information. Subsequently, we analyzed the differentially modified proteins among the different groups. Differentially lactylated proteins were found to be involved in several biological processes, including-but not limited to-amino acid metabolism, ribosomal protein synthesis, and fatty acid metabolism. In addition, we identified numerous highly valuable lactate-modified proteins from the literature. Among them, we verified the lactate modification levels of the following two tumor-related proteins and obtained similar results: USP14 and ABCF1. These two modified proteins will be further investigated in our future studies. This paper is the first report on the lactylome of HCC and it provides a reliable foundation for further research on Kla in HCC.

Projecting spatiotemporal dynamics of severe fever with thrombocytopenia syndrome in the mainland of China.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with increasing incidence and geographic extent. The extent to which global climate change affects the incidence of SFTS disease remains obscure. We use an integrated multi-model, multi-scenario framework to assess the impact of global climate change on SFTS disease in China. The spatial distribution of habitat suitability for the tick Haemaphysalis longicornis was predicted by applying a boosted regression tree model under four alternative climate change scenarios (RCP2.6, RCP4.5, RCP6.0, and RCP8.5) for the periods 2030-2039, 2050-2059, and 2080-2089. We incorporate the SFTS cases in the mainland of China from 2010 to 2019 with environmental variables and the projected distribution of H. longicornis into a generalized additive model to explore the current and future spatiotemporal dynamics of SFTS. Our results demonstrate an expanded geographic distribution of H. longicornis toward Northern and Northwestern China, showing a more pronounced change under the RCP8.5 scenario. In contrast, the environmental suitability of H. longicornis is predicted to be reduced in Central and Eastern China. The SFTS incidence in three time periods (2030-2039, 2050-2059, and 2080-2089) is predicted to be increased as compared to the 2010s in the context of various RCPs. A heterogeneous trend across provinces, however, was observed, when an increased incidence in Liaoning and Shandong provinces, while decreased incidence in Henan province is predicted. Notably, we predict possible outbreaks in Xinjiang and Yunnan in the future, where only sporadic cases have been reported previously. These findings highlight the need for tick control and population awareness of SFTS in endemic regions, and enhanced monitoring in potential risk areas.

Recent advances in structure-based enzyme engineering for functional reconstruction.

Structural information can help engineer enzymes. Usually, specific amino acids in particular regions are targeted for functional reconstruction to enhance the catalytic performance, including activity, stereoselectivity, and thermostability. Appropriate selection of target sites is the key to structure-based design, which requires elucidation of the structure-function relationships. Here, we summarize the mutations of residues in different specific regions, including active center, access tunnels, and flexible loops, on fine-tuning the catalytic performance of enzymes, and discuss the effects of altering the local structural environment on the functions. In addition, we keep up with the recent progress of structure-based approaches for enzyme engineering, aiming to provide some guidance on how to take advantage of the structural information.

Coevolving stability and activity of LsCR by a single point mutation and constructing neat substrate bioreaction system.

Carbonyl reductase (CR)-catalyzed bioreduction in the organic phase and the neat substrate reaction system is a lasting challenge, placing higher requirements on the performance of enzymes. Protein engineering is an effective method to enhance the properties of enzymes for industrial applications. In the present work, a single point mutation E145A on our previously constructed CR mutant LsCRM3 , coevolved thermostability, and activity. Compared with LsCRM3 , the catalytic efficiency kcat /KM of LsCRM3 -E145A (LsCRM4 ) was increased from 6.6 to 21.9 s-1 mM-1 . Moreover, E145A prolonged the half-life t1/2 at 40°C from 4.1 to 117 h, T m ${T}_{m}$ was increased by 5°C, T 50 30 ${T}_{50}^{30}$ was increased by 14.6°C, and Topt was increased by 15°C. Only 1 g/L of lyophilized Escherichia coli cells expressing LsCRM4 completely reduced up to 600 g/L 2-chloro-1-(3,4-difluorophenyl)ethanone (CFPO) within 13 h at 45°C, yielding the corresponding (1S)-2-chloro-1-(3,4-difluorophenyl)ethanol ((S)-CFPL) in 99.5% eeP , with a space-time yield of 1.0 kg/L d, the substrate to catalyst ratios (S/C) of 600 g/g. Compared with LsCRM3 , the substrate loading was increased by 50%, with the S/C increased by 14 times. Compared with LsCRWT , the substrate loading was increased by 6.5 times. In contrast, LsCRM4 completely converted 600 g/L CFPO within 12 h in the neat substrate bioreaction system.

Deciphering gp120 sequence variation and structural dynamics in HIV neutralization phenotype by molecular dynamics simulations and graph machine learning.

Human immunodeficiency virus (HIV) exploits the sequence variation and structural dynamics of the envelope glycoprotein gp120 to evade the immune attack of neutralization antibodies, contributing to various HIV neutralization phenotypes. Although the HIV neutralization phenotype has been experimentally characterized, the roles of rapid sequence variability and significant structural dynamics of gp120 are not well understood. Here, 45 prefusion gp120 from different HIV strains belong to three tiers of sensitive, moderate, and resistant neutralization phenotype are structurally modeled by homology modeling and then investigated by molecular dynamics (MD) simulations and graph machine learning (ML). Our results show that the structural deviations, population distribution, and conformational flexibility of gp120 are related to the HIV neutralization phenotype. Per-residue dynamics indicate the local regions especially in the second structural elements with high-flexibility, may be responsible for the HIV neutralization phenotype. Moreover, a graph ML model with the attention mechanism was trained to explore inherent representation related to the classification of the HIV neutralization phenotype, further distinguishing the strong related gp120 sequence variation together with structural dynamics in the HIV neutralization phenotype. Our study not only deciphers gp120 sequence variation and structural dynamics in the HIV neutralization phenotype but also explores complex relationships between the sequence, structure, and dynamics of protein by combining MD simulations and ML.

Long-term renal safety between patients with chronic hepatitis B receiving tenofovir vs. entecavir therapy: A multicenter study.

Renal safety is a critical issue in chronic hepatitis B (CHB) patients receiving long-term entecavir (ETV) or tenofovir disofuroxil fumarate (TDF) therapy. We investigated their effects on estimated glomerular filtration rate (eGFR). Treatment-naive CHB patients receiving ETV or TDF for ≥1 year were recruited. The eGFR was assessed using the Chronic Kidney Disease Epidemiology Collaboration equation. We calculated average annual percent change (AAPC) in eGFR using Joinpoint regression. At the beginning of the observation, the ETV group had more unfavorable conditions than the TDF group: lower eGFR and higher FIB-4 and APRI than the TDF group (all p < .001). After 6 years of antiviral therapy, the mean eGFR in the ETV group (n = 1793) was maintained (96.0 at first year to 95.6 ml/min/1.73 m2 at sixth year; AAPC -0.09%; p = .322), whereas that in the TDF group (n = 1240) significantly decreased annually (101.9 at first year to 96.9 ml/min/1.73 m2 at sixth year; AAPC -0.88%; p < .001). Notably, in the TDF group, even patients without diabetes (AAPC -0.80%; p = 0.001) or hypertension (AAPC -0.87%; p = .001) experienced significant decrease in eGFR. Expectably, accompanying diabetes (AAPC -1.59%; p = .011) or hypertension (AAPC -1.00%; p = .002) tended to accelerate eGFR decrease. TDF treatment (odds ratio 1.66, p < .001), along with eGFR<60 ml/min/1.73 m2 , serum albumin<3.5 mg/dl, and hypertension, were independently associated with ongoing renal dysfunction, defined as a negative slope of the mean eGFR change. In conclusion, compared with ETV, long-term TDF treatment induced slow, but progressive renal dysfunction. Although the annual eGFR change by TDF was small, careful monitoring is necessary, especially in patients requiring life-long therapy.

Coinfections in hospitalized patients with severe fever with thrombocytopenia syndrome: A retrospective study.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease with a high case fatality rate. Few studies have been performed on bacterial or fungal coinfections or the effect of antibiotic therapy. A retrospective, observational study was performed to assess the prevalence of bacterial and fungal coinfections in patients hospitalized for SFTSV infection. The most commonly involved microorganisms and the effect of antimicrobial therapy were determined by the site and source of infection. A total of 1201 patients hospitalized with SFTSV infection were included; 359 (29.9%) had microbiologically confirmed infections, comprised of 292 with community-acquired infections (CAIs) and 67 with healthcare-associated infections (HAIs). Death was independently associated with HAIs, with a more significant effect than that observed for CAIs. For bacterial infections, only those acquired in hospitals were associated with fatal outcomes, while fungal infection, whether acquired in hospital or community, was related to an increased risk of fatal outcomes. The infections in the respiratory tract and bloodstream were associated with a higher risk of death than that in the urinary tract. Both antibiotic and antifungal treatments were associated with improved survival for CAIs, while for HAIs, only antibiotic therapy was related to improved survival, and no effect from antifungal therapy was observed. Early administration of glucocorticoids was associated with an increased risk of HAIs. The study provided novel clinical and epidemiological data and revealed risk factors, such as bacterial coinfections, fungal coinfections, infection sources, and treatment strategies associated with SFTS deaths/survival. This report might be helpful in curing SFTS and reducing fatal SFTS.

Effects of textured food masticatory performance in older people with different dental conditions.

BACKGROUND: Physiological deterioration (aging, poor dental status, and reduced tongue pressure) makes chewing difficult. This study aimed to investigate the chewing patterns of older people with or without dentures, evaluate the textural and masticatory properties of texture-modified radish Kimchi, and investigate the correlation between dental status and tongue pressure. Additionally, differences in the subjective-objective concordance of texture-modified Kimchi were investigated using the preference test. METHODS: This study included 32 Korean women aged between 65 and 85 years. Masticatory behavior was recorded by electromyography, and tongue pressure was measured using the Iowa Oral Performance Instrument. A preference test, with hardness as the relevant textural property, determined the participants' preferences among the test samples (food with a homogeneous structure-radish Kimchi). To assess preference differences, a questionnaire suitable for older people was designed. The preference for cooked radish Kimchi with various blanching times based on overall acceptability and self-reporting of preference was investigated to develop elderly-friendly food. The subjective scores indicated whether the sample (radish Kimchi) was hard or soft based on the chewing ability of the participants. Dental status, muscle activities, and tongue pressure were considered for the food design with optimized texture. The relationship between subject score and mastication properties were examined using multiple regression analysis. RESULTS: The number of chews and chewing time increased with hardness, significantly activating the masseter and temporalis muscles. The evaluation of masseter muscle activity, particularly for level-6 radish Kimchi, showed that older people with complete dentures chewed less actively than those with natural teeth (p < 0.05). The older people with natural teeth (18.94 ± 10.27 kPa) exhibited higher tongue pressure than those with complete dentures (10.81 ± 62.93 kPa), and the difference was statistically significant (p < 0.01). Older people preferred food with familiar tastes and textures. An association was found between the subjective hardness score and the objective hardness level. The perceived hardness intensity was linked to the chewing ability of the participant. Denture wearers exhibited a lower chewing ability, and at level 6, they perceived greater hardness of food than those with natural teeth. CONCLUSIONS: Developing food with a modified texture can bridge the gap between physiological and psychological aspects of food texture; texture-modified radish Kimchi, with limited blanching time, may be favorable for older people.

IκB kinase promotes Nrf2 ubiquitination and degradation by phosphorylating cylindromatosis, aggravating oxidative stress injury in obesity-related nephropathy.

BACKGROUND: Obesity-related nephropathy (ORN) has become one of the leading causes of end-stage renal disease and has tripled over the past decade. Previous studies have demonstrated that decreased reactive oxygen species production may contribute to improving ORN by ameliorating oxidative stress injury. Here, IκB kinase (IKK) was hypothesized to inactivate the deubiquitination activity of cylindromatosis (CYLD) by activating the phosphorylation of CYLD, thus promoting the ubiquitination of NF-E2-related factor 2 (Nrf2) and further aggravating oxidative stress injury of the kidney in ORN. This study was aimed to confirm this hypothesis. METHODS: Haematoxylin and eosin (HE), periodic acid-Schiff (PAS) and Oil Red O staining were performed to assess histopathology. Dihydroethidium (DHE) staining and MDA, SOD, CAT, and GSH-PX assessments were performed to measure reactive oxygen species (ROS) production. Immunohistochemical (IHC) staining, qRT-PCR and/or western blotting were performed to assess the expression of related genes. JC-1 assays were used to measure the mitochondrial membrane potential (ΔΨm) of treated HK-2 cells. Co-immunoprecipitation experiments (Co-IP) were used to analyse the interaction between CYLD and Nrf2 in ORN. RESULTS: ORN in vivo and in vitro models were successfully constructed, and oxidative stress injury was detected in the model tissues and cells. Compared with the control groups, the phosphorylation level of CYLD increased while Nrf2 levels decreased in ORN model cells. An IKK inhibitor reduced lipid deposition, ROS production, CYLD phosphorylation levels and ΔΨm in vitro, which were reversed by knockdown of CYLD. Nrf2 directly bound to CYLD and was ubiquitinated in ORN cells. The proteasome inhibitor MG132 activated the Nrf2/ARE signalling pathway, thereby reversing the promoting effect of CYLD knockdown on oxidative stress. CONCLUSION: IKK inactivates the deubiquitination activity of CYLD by activating the phosphorylation of CYLD, thus promoting the ubiquitination of Nrf2 and further aggravating oxidative stress injury of the kidney in ORN. This observation provided a feasible basis for the treatment of kidney damage caused by ORN.

Treatable Rapid Progressive Dementia: A First Case Report of Anti-dipeptidyl-peptidase-like Protein 6 Encephalitis in Taiwan.

PURPOSE: Anti-dipeptidyl-peptidase-like protein 6 (DPPX) encephalitis is a rare but treatable autoimmune disorder, characterized by gastrointestinal symptoms, cognitive dysfunction, and central nervous system hyperexcitability. CASE REPORT: Herein, we report a case of an 80-year-old male patient who presented with unexplained diarrhea, weight loss, rapidly progressive dementia, tremors, and myoclonus. His serum tested positive for anti-DPPX antibodies. He was treated with plasma exchange, oral prednisolone, and azathioprine. All his symptoms improved substantially after treatment. CONCLUSION: Early recognition of anti-DPPX encephalitis is important because it can be treated with immunotherapy. To the best of our knowledge, this is the first reported case of anti-DPPX encephalitis in Taiwan.

A CpxR-Regulated zapD Gene Involved in Biofilm Formation of Uropathogenic Proteus mirabilis.

Proteus mirabilis, a frequent uropathogen, forms extensive biofilms on catheters that are infamously difficult to treat. To explore the mechanisms of biofilm formation by P. mirabilis, we performed in vivo transposon mutagenesis. A mutant with impaired biofilm formation was isolated. The mutant was found to have Tn5 inserted in the zapD gene, encoding an outer membrane protein of the putative type 1 secretion system ZapBCD. zapBCD and its upstream zapA gene, encoding a protease, constitute an operon under the control of CpxR, a two-component regulator. The cpxR mutant and zapA mutant strains also had a biofilm-forming defect. CpxR positively regulates the promoter activities of zapABCD, cpxP, and cpxR An electrophoretic mobility shift assay revealed that CpxR binds zapA promoter DNA. The loss of zapD reduced CpxR-regulated gene expression of cpxR, zapA, cpxP, and mrpA, the mannose-resistant Proteus-like (MR/P) fimbrial major subunit gene. The restoration of biofilm formation in the zapD mutant with a CpxR-expressing plasmid reinforces the idea that CpxR-mediated gene expression contributes to zapD-involved biofilm formation. In trans expression of zapBCD from a zapBCD-expressing plasmid also reestablished the biofilm formation ability of the cpxR mutant to a certain level. The zapD and cpxR mutants had significantly lower protease activity, adhesion, and autoaggregation ability and production of exopolysaccharides and extracellular DNA (eDNA) than did the wild type. Finally, we identified copper as a signal for CpxR to increase biofilm formation. The loss of cpxR or zapD abolished the copper-mediated biofilm upshift. CpxR was required for copper-induced expression of zapA and cpxR Taken together, these data highlight the important role of CpxR-regulated zapD in biofilm formation and the underlying mechanisms in P. mirabilis.

LncRNA ST8SIA6-AS1 promotes hepatocellular carcinoma cell proliferation and resistance to apoptosis by targeting miR-4656/HDAC11 axis.

BACKGROUND: Dysregulation of long non-coding RNAs (lncRNAs) results in development of human diseases including hepatocellular carcinoma (HCC). Although several HCC related lncRNAs have been reported, the biological functions of many lncRNAs during the development of HCC remains unknown. METHODS: The expression of ST8SIA6-AS1 was studied by realtime PCR (RT-qPCR) and bioinformatic analysis. The biological functions of ST8SIA6-AS1 was examined by CCK-8 assay and flow cytometry analysis. The target of ST8SIA6-AS1 was analyzed by bioinformatic analysis and validated by dual luciferase reporter assay, western blotting and RT-qPCR. RESULTS: In this study we demonstrated that ST8SIA6-AS1 was an upregulated lncRNA in hepatocellular carcinoma. SiRNA-mediated knockdown of ST8SIA6-AS1 repressed cell proliferation and induced cell apoptosis in HCC cells. Bioinformatic analysis and RT-qPCR further showed that ST8SIA6-AS1 mainly located in cytoplasm. Dual luciferase reporter assay further revealed that ST8SIA6-AS1 interacted with miR-4656 in HCC cells. In addition, HDAC11 was identified as a target gene in HCC cells and ST8SIA6-AS1 could upregulate HDAC11 via sponging miR-4656. Transfection of recombinant HDAC11 partially rescued the inhibition of cell proliferation and increase of cell apoptosis inducing by knockdown of ST8SIA6-AS1. CONCLUSION: In conclusion, our findings suggested that ST8SIA6-AS1 was a novel upregulated lncRNA in HCC and could facilitate cell proliferation and resistance to cell apoptosis via sponging miR-4656 and elevation of HDAC11, which might be a promising biomarker for patients with HCC.

The effect of levetiracetam and oxcarbazepine monotherapy on thyroid hormones and bone metabolism in children with epilepsy: A prospective study.

BACKGROUND: Long-term treatment with certain antiepileptic drugs may lead to thyroid function disturbances or alterations in bone metabolism; the data on the effects of new antiepileptic drugs on this are limited and conflicting, especially in children with epilepsy. Therefore, the aim of this study was to investigate the effects of levetiracetam and oxcarbazepine on thyroid hormone levels and bone metabolism in children with epilepsy. METHODS: A total of 51 children with new-onset partial epilepsy were selected. They were randomly treated with either levetiracetam (n = 25), or oxcarbazepine (n = 26) monotherapy. Eight of the 51 patients were excluded for failing to take the drug continuously or failing to undergo a regular review. Thus, 43 patients were finally included (levetiracetam: 23 patients, oxcarbazepine: 20 patients). A control group consisting of age- and sex-matched healthy subjects (n = 20) was included for comparison. Serum triiodothyronine, tetraiodothyronine, free triiodothyronine, free thyroxine, thyroid-stimulating hormone, calcium, phosphorus, alkaline phosphatase, osteocalcin, parathyroid hormone, and 25-hydroxyvitamin D levels and bone mineral density values were measured before and at 6 and 12 months after therapy in all groups. RESULTS: At baseline, thyroid hormone levels, bone metabolism index, and bone mineral density values did not differ between the control group and the drug-treated groups. Levetiracetam-treated patients showed no significant changes in thyroid hormone levels, bone metabolism, and bone mineral density during the 12-month follow-up period compared with baseline values. In the oxcarbazepine group, compared to baseline values, serum free thyroxine levels decreased after 12 months of treatment (Z = -3.115, p = 0.002), and after 6 and 12 months of treatment, calcium levels decreased (Z = -3.705, p < 0.001 and Z = -3.884, p < 0.001, respectively) and parathyroid hormone levels increased (Z = -3.698, p < 0.001 and Z = -3.921, p < 0.001, respectively); however, all other parameters did not differ from baseline values. CONCLUSION: Our data show that levetiracetam treatment has no significant effect on thyroid function and bone metabolism in children with epilepsy. Long-term use of oxcarbazepine may reduce serum free thyroxine levels, resulting in impaired thyroid function, and may reduce serum calcium and increase parathyroid hormone levels, leading to bone metabolism disorders.