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Background: Few randomized controlled trials (RCTs) investigated the effects of mindfulness intervention on affective and cognitive symptoms in older adults with mild cognitive impairment (MCI). Furthermore, no RCTs on mindfulness followed participants beyond two years. Objective: To examine the longitudinal effects of a mindful awareness practice (MAP) intervention on depressive, anxiety, and cognitive symptoms in MCI. Methods: In this parallel-arm and assessor-blinded RCT, 55 community-dwelling older adults with MCI were randomized into the MAP or active control, i.e., health education program (HEP). Intervention sessions were conducted weekly for three months and monthly for the subsequent six months. Assessments and follow-up were conducted at baseline, 3-month, 9-month, and 5-year time points. Depressive, anxiety, and cognitive symptoms were measured using the Geriatric Depression Scale-15 (GDS-15), Geriatric Anxiety Inventory-20 (GAI-20), and Mini-Mental State Examination (MMSE), respectively. Linear-mixed models, following the intention-to-treat principle, were used for data analyses. Results: A total of 55 participants aged 60 to 86 (Mean age: 71.3±6 years old) was recruited, with n = 28 allocated to the MAP arm and n = 27 allocated to the HEP arm. Compared to HEP, GDS-15, GAI-20, and MMSE scores did not differ significantly in MAP during follow-ups. Conclusion: Compared to HEP, MAP did not improve affective symptoms nor delay deteriorations in general cognition in community-dwelling older adults with MCI. Compared to our previous findings showing domain-specific improvements in MAP over HEP in attention and memory up to 9 months, this study highlights the importance of examining domain-specificity using detailed cognitive measures in non-pharmacological intervention with MCI.

Myeloid-derived suppressor cells (MDSC) are a group of heterogeneous immature myeloid cells and display immunosuppressive function. In this study, MDSC populations were evaluated in acquired aplastic anemia (AA) (n=65) in which aberrant immune mechanisms contributed to bone marrow destruction. Our data demonstrate that both the proportion and immunosuppressive function of MDSC are impaired in AA patients. Decreased percentage of MDSC, especially monocytic MDSC, in the blood of AA patients (n=15) is positively correlated with the frequency of T-regulatory cells, bone marrow level of WT1 and decreased plasma level of arginase-1. RNA sequencing analyses reveal that multiple pathways including DNA damage, interleukin 4, apoptosis, and Jak kinase singnal transducer and activator of transcription are upregulated, whereas transcription, IL-6, IL-18, glycolysis, transforming growth factor and reactive oxygen species are downregulated in MDSC of AA (n=4), compared with that of healthy donors (n=3). These data suggest that AA MDSC are defective. Administration of rapamycin significantly increases the absolute number of MDSC and levels of intracellular enzymes, including arginase-1 and inducible nitric-oxide synthase. Moreover, rapamycin inhibits MDSC from differentiating into mature myeloid cells. These findings reveal that impaired MDSC are involved in the immunopathogenesis of AA. Pharmacologically targeting of MDSC by rapamycin might provide a promising therapeutic strategy for AA.

Recent studies revealed that long non-coding RNAs (lncRNAs) have significant roles in regulating the pathogenesis of ischemia stroke, and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced cell apoptosis. Aberrant expression of NEAT1 was found after the injury of ischemia-reperfusion, but the mechanism was not fully understood.The expression of NEAT1 and Mfn2 were detected in BV-2 and N2a cell with or without OGD/R-induced by qRT-PCR. Inflammatory cytokines secretion was detected by enzyme-linked immunosorbent assay (ELISA). The oxidative stress was evaluated by the examination of ROS, MDA and SOD levels. Flow cytometry and apoptosis marker detection by western blot were performed to examined apoptosis.The expression of NEAT1 and Mfn2 were decreased in OGD/R-induced cell model. Overexpression of NEAT1 or Mfn2 reduced oxidative stress and apoptosis by OGD/R-induced in neuronal cells, while knockdown of Sirt3 reversed the protective effect of NEAT1 and Mfn2. NEAT1 stabilized Mfn2 mRNA via recruiting Nova. NEAT1 alleviates the oxidative stress and apoptosis by OGD/R-induced via activating Sirt3.LncRNA NEAT1 stabilizes Mfn2 mRNA via recruiting Nova, therefore increase the expression of Mfn2 and alleviates ischemia-reperfusion induced oxidative stress and apoptosis via Mfn2/Sirt3 pathway.

Circ-Memo1 has been proved to be upregulated in ischemia-reperfusion induced acute injury of kidney tissues. However, the potential role of circ-Memo1 in cerebral hypoxia/reoxygenation (H/R) injury is still unclear.Blood samples were collected from 25 ischemic stroke patients and 25 healthy controls. To construct the H/R model, human brain microvascular endothelial cells (HBMVECs) were cultured under the hypoxic condition, followed by reoxygenation. Cell viability was analyzed by MTT assay. Flow cytometry was carried out to examine cell apoptosis. The level of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were measured by MDA and SOD assay kits, respectively. The levels of TNF-α, IL-1β, and IL-6 were determined by enzyme-linked immunosorbent assay (ELISA). Dual-luciferase reporter gene detection was employed to verify the binding relationships between circ-Memo1, miR-17-5p, and SOS1.Circ-Memo1 and SOS1 expressions were increased, and miR-17-5p expression was reduced in ischemic stroke patients. Circ-Memo1 silencing promoted cell viability, inhibited the activation of ERK/NF-κB signaling pathway, reduced oxidative stress and inflammatory response, and inhibited cell apoptosis. Moreover, miR-17-5p functioned as the sponge of circ-Memo1, and SOS1 was identified as the target of miR-17-5p. The protective effect of circ-Memo1 knockdown on cell injury after H/R treatment was weakened by miR-17-5p inhibition.Knockdown of circ-Memo1 alleviated H/R injury of HBMVEC cells by regulating the miR-17-5p/SOS1 axis, indicating that circ-Memo1 might be a potential treatment target for cerebral H/R injury.

Identification of novel anti-tumor target is crucial for cancer diagnosis, prognosis, and therapeutic strategy. The study aimed to explore the roles and interaction of DEAD-box helicase 21 (DDX21) and cell division cycle 5-like (CDC5L) in colorectal cancer (CRC) progression. Levels of DDX21 and CDC5L were detected in colorectal cancer cell lines by RT-qPCR and Western blot assay. The role of DDX21 and CDC5L on the cell proliferation, cell cycle and tumor growth were evaluated both in vitro and in vivo. The interaction of DDX21 and CDC5L was predicted by The STRING publicly available data and verified by immunoprecipitation. The results showed that DDX21 was dramatically upregulated in colorectal cancer cells. In vivo and in vitro experiments revealed that downregulation of DDX21 suppressed colorectal cancer cell proliferation, colony formation, cell cycle development, and tumor growth, while overexpression of CDC5L reversed the suppressive effects of DDX21 silencing. Furthermore, DDX21 interacted with CDC5L to exert the tumor-promoting effects in CRC. In summary, the data indicate a novel role for DDX21/CDC5L in the development of CRC, which enrich the therapeutic strategy for CRC.

Spinal muscular atrophy (SMA), a degenerative motor neuron disease and a leading cause of infant mortality, is caused by loss of functional survival motor neuron (SMN) protein due to SMN1 gene mutation. Here, using mouse and cell models for behavioral and histological studies, we found that SENP2 (SUMO/sentrin-specific protease 2)-deficient mice developed a notable SMA-like pathology phenotype with significantly decreased muscle fibers and motor neurons. At the molecular level, SENP2 deficiency in mice did not affect transcription but decreased SMN protein levels by promoting the SUMOylation of SMN. SMN was modified by SUMO2 with the E3 PIAS2α and deconjugated by SENP2. SUMOylation of SMN accelerated its degradation by the ubiquitin-proteasome degradation pathway with the ubiquitin E1 UBA1 (ubiquitin-like modifier activating enzyme 1) and E3 ITCH. SUMOylation of SMN increased its acetylation to inhibit the formation of Cajal bodies (CBs). These results showed that SENP2 deficiency induced hyper-SUMOylation of the SMN protein, which further affected the stability and functions of the SMN protein, eventually leading to the SMA-like phenotype. Thus, we uncovered the important roles for hyper-SUMOylation of SMN induced by SENP2 deficiency in motor neurons and provided a novel targeted therapeutic strategy for SMA. KEY MESSAGES: SENP2 deficiency enhanced the hyper-SUMOylation of SMN and promoted the degradation of SMN by the ubiquitin-proteasome pathway. SUMOylation increased the acetylation of SMN to inhibit CB formation. SENP2 deficiency caused hyper-SUMOylation of SMN protein, which further affected the stability and functions of SMN protein and eventually led to the occurrence of SMA-like pathology.

We estimated the symptomatic, PCR-confirmed secondary attack rate (SAR) for 2,382 close contacts of 476 symptomatic persons with coronavirus disease in Yichang, Hubei Province, China, identified during January 23–February 25, 2020. The SAR among all close contacts was 6.5%; among close contacts who lived with an index case-patient, the SAR was 10.8%; among close-contact spouses of index case-patients, the SAR was 15.9%. The SAR varied by close contact age, from 3.0% for those 60 years of age. Multilevel logistic regression showed that factors significantly associated with increased SAR were living together, being a spouse, and being >60 years of age. Multilevel regression did not support SAR differing significantly by whether the most recent contact occurred before or after the index case-patient’s onset of illness (p = 0.66). The relatively high SAR for coronavirus disease suggests relatively high virus transmissibility.

Mutations in TUB-like protein 1 (TULP1) are associated with severe early-onset retinal degeneration in humans. However, the pathogenesis remains largely unknown. There are two homologous genes of TULP1 in zebrafish, namely tulp1a and tulp1b. Here, we generated the single knockout (tulp1a−/− and tulp1b−/−) and double knockout (tulp1-dKO) models in zebrafish. Knockout of tulp1a resulted in the mislocalization of UV cone opsins and the degeneration of UV cones specifically, while knockout of tulp1b resulted in mislocalization of rod opsins and rod-cone degeneration. In the tulp1-dKO zebrafish, mislocalization of opsins was present in all types of photoreceptors, and severe degeneration was observed at a very early age, mimicking the clinical manifestations of TULP1 patients. Photoreceptor cilium length was significantly reduced in the tulp1-dKO retinas. RNA-seq analysis showed that the expression of tektin2 (tekt2), a ciliary and flagellar microtubule structural component, was downregulated in the tulp1-dKO zebrafish. Dual-luciferase reporter assay suggested that Tulp1a and Tulp1b transcriptionally activate the promoter of tekt2. In addition, ferroptosis might be activated in the tulp1-dKO zebrafish, as suggested by the up-regulation of genes related to the ferroptosis pathway, the shrinkage of mitochondria, reduction or disappearance of mitochondria cristae, and the iron and lipid droplet deposition in the retina of tulp1-dKO zebrafish. In conclusion, our study establishes an appropriate zebrafish model for TULP1-associated retinal degeneration and proposes that loss of TULP1 causes defects in cilia structure and opsin trafficking through the downregulation of tekt2, which further increases the death of photoreceptors via ferroptosis. These findings offer insight into the pathogenesis and clinical treatment of early-onset retinal degeneration.

ObjectivesTo investigate the incidence, predisposing factors, diagnosis and management of subcapsular renal haematoma (SRH) after ureteroscopic lithotripsy (URSL).DesignRetrospective observational study.SettingShandong Provincial Hospital, a 4500-bed tertiary hospital in China.ParticipantsThe data from 1535 consecutive patients treated with URSL (including rigid URSL and flexible URSL) between January 2015 and October 2020 were retrospectively analysed.Main outcome measuresSRH after URSL confirmed via CT. The characteristics, operative data and outcomes of these patients were documented and compared.ResultsSix patients were confirmed to have an SRH after URSL on CT. The total incidence of SRH after URSL was 0.39%. The incidences of SRH after rigid URSL and flexible URSL were 0.38% and 0.41%, respectively. Unendurable ipsilateral flank pain and a significant decrease in haemoglobin after surgery were the typical clinical manifestations of SRH after URSL. There were no significant differences in age, sex, history of diabetes mellitus, preoperative hypertension, body mass index, stone laterality or perfusion pressure (p>0.05). However, SRH was significantly associated with the stone size, stone location, degree of hydronephrosis and operative duration (pConclusionsSRH is a rare but potentially serious complication of URSL. Severe hydronephrosis and a thin renal cortex preoperatively and prolonged operative duration are strong predisposing factors for SRH. Laparoscopic ureterolithotomy should be considered as an alternative surgery for patients with severe ureteral tortuosity. SRH is treated based on patients’ clinical manifestations. Most patients can be managed with conservative treatment or percutaneous drainage alone.

Background Cellular experiments revealed that a decreased histone H3 lysine 9 trimethylation (H3K9me3) level was associated with the upregulation of oncogenes in breast cancer cells. Moreover, the role of H3K9me3 in breast cancer was closely associated with estrogen receptor (ER) status. Therefore, we aimed to examine the prognostic value of H3K9me3 on breast cancer by ER status. The level of H3K9me3 in tumors were evaluated with tissue microarrays by immunohistochemistry for 917 women diagnosed with primary invasive breast cancer. Hazard ratios (HRs) and their 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) were estimated using Cox regression models. Interaction between H3K9me3 and ER on the prognosis was assessed on multiplicative scale. Results The level of H3K9me3 in tumor tissues was lower than that in adjacent tissues. The high level of H3K9me3 was associated with a better OS (HR = 0.43, 95% CI: 0.21–0.86) and PFS (HR = 0.49, 95% CI: 0.29–0.81) among only ER-positive but not ER-negative tumors. Moreover, the interaction between the level of H3K9me3 and ER status (negative and positive) on the prognosis was significant (Pinteraction = 0.011 for OS; Pinteraction = 0.022 for PFS). Furthermore, the ER-positive tumors were stratified by ER-low and ER-high positive tumors, and the prognostic role of H3K9me3 was significant among only ER-high positive patients (HR = 0.34, 95% CI: 0.13–0.85 for OS; HR = 0.47, 95% CI: 0.26–0.86 for PFS). Conclusions Our study showed that the prognostic value of H3K9me3 on breast cancer was related to ER status and expression level, and the high level of H3K9me3 was associated with a better prognosis among ER-positive tumors, particularly ER-high positive tumors.

Objectives The ACSM recommends drinking to avoid loss of body mass >2% during exercise to avert compromised performance. Our study aimed to assess the level of dehydration in elite runners following a city marathon in a tropical environment. Design Prospective cohort design. Methods Twelve elite runners (6 males, 6 females; age 24–41 y) had body mass measured to the nearest 0.01 kg in their race attire immediately before and after the 2017 Standard Chartered Singapore Marathon 2017. Body mass change was corrected for respiratory water loss, gas exchange, and sweat retained in clothing, and expressed as % of pre-race mass (i.e. % dehydration). Results Data are expressed as means ± SD (range). Dry bulb temperature and humidity were 27.9 ± 0.1 °C (27.4–28.3 °C) and 79 ± 2% (73–82%). Finish time was 155 ± 10 min (143−172 min). Male runners finishing positions ranged from 2–12 out of 7627 finishers, whilst female runners placed 1–8 out of 1754 finishers. Body mass change (loss) and % dehydration for all runners were 2.5 ± 0.5 kg (1.8–3.5 kg) and 4.6 ± 0.9% (3.6–6.8%). Male runners experienced body mass loss of 2.8 ± 0.5 kg and 4.9 ± 1.2% while females experienced body mass loss of 2.1 ± 0.2 kg and 4.3 ± 0.6%. Conclusions Despite experiencing dehydration (4.6% body mass loss) two-fold higher than current fluid replacement guidelines recommend (≤2%), elite male and female runners performed successfully and without medical complication in a hot weather marathon.

A novel microfluidic photoelectrochemical (PEC) analytical device based on AgBiS

Background Combining immune checkpoint inhibitors with chemotherapy can synergistically improve antitumor activity and are generally well tolerated. Recently, the efficacy and safety of combination therapy has been demonstrated for many cancers, including urothelial carcinomas. The aim of this retrospective pilot study was to evaluate the efficacy and safety of tislelizumab plus chemotherapy as first-line adjuvant treatment for locally advanced or metastatic bladder cancer. Methods We conducted a retrospective analysis of 31 patients with locally advanced or metastatic bladder cancer from December 2020 to January 2022 with an Eastern Cooperative Oncology Group performance status of 0/1. Of the 31 patients, 14 patients received tislelizumab (200 mg i.v. every 3 weeks, Q3W) plus 21 days cycles of chemotherapy (gemcitabine, 1000 mg/m2 i.v. on days 1 and 8 of each cycle + cisplatin, 70 mg/m2 i.v. on day 2 of each cycle) (TGC) treatment and 17 patients received gemcitabine plus cisplatin chemotherapy (GC) treatment. All patients treated with bladder cytoreductive surgery and were treated for four 21 days cycles until disease progression or intolerable treatment-related adverse events (TRAEs). The objective progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR) and TRAEs were recorded and reviewed. Results As of the cut-off date (March 25, 2022), PFS, OS, ORR, DCR, CBR and TRAEs were evaluated in 14 patients receiving combination therapy and 17 patients in the chemotherapy alone group. The median PFS was 36.0 [95% confidence interval (CI) 33.1–38.9] weeks in the TGC group and 29.0 (95% CI 25.4–32.6) weeks in the GC group [hazard ratio (HR) 0.15 (95% CI 0.04–0.55)]. In the GC group, the median OS was 48.0 (95% CI 39.7–56.3) weeks; the median OS was not yet mature for the TGC group [HR 0.26 (95% CI 0.07–0.94)]. Treatment with TGC resulted in improved DCR (TGC 71.4%; GC 65.0%) and CBR (TGC 64.3%; GC 52.9%) compared with GC. However, although higher incidences of grade ≥ 3 TRAEs were observed with TGC compared with GC (35.7% vs 23.5%), the difference was not statistically significant (p = 0.47). Conclusion This study suggested that TGC provided survivors of locally advanced or metastatic bladder cancer with encouraging antitumor activity and was generally well tolerated.

Nanoarrays (NAs) with stable signal output have become the most promising photoelectrochemical (PEC) biosensing substrate. However, a general issue is that interfacial charge-carrier recombination in a single-component semiconductor cannot be easily prevented, resulting in a low photocurrent density. Herein, a biosensor utilizing a Ag-embedded TiO

Background To quantitatively assess the impact of the onset-to-diagnosis interval (ODI) on severity and death for coronavirus disease 2019 (COVID-19) patients. Methods This retrospective study was conducted based on the data on COVID-19 cases of China over the age of 40 years reported through China’s National Notifiable Infectious Disease Surveillance System from February 5, 2020 to October 8, 2020. The impacts of ODI on severe rate (SR) and case fatality rate (CFR) were evaluated at individual and population levels, which was further disaggregated by sex, age and geographic origin. Results As the rapid decline of ODI from around 40 days in early January to Conclusion The ODI was significantly associated with the severity of COVID-19, highlighting the importance of timely diagnosis, especially for patients who were confirmed to gain increased benefit from early diagnosis to some extent.

Idiopathic ventricular tachycardia (VT) occurs in structurally normal hearts and accounts for a significant number of all types of VT. The genome-wide association study is the most effective strategy for identifying novel genetic variants for common diseases. However, no genome-wide association study has been reported for idiopathic VT.We conducted the first genome-wide association study for idiopathic VT in the Chinese Han population using a discovery population with 246 cases and 648 controls and a replication population with 222 cases and4072 controls. Candidate VT genes were functionally characterized in zebrafish. Real-time RT-PCR analysis was used to determine the effects of candidate genes on expression of ion channels and regulators. Patch-clamping was used to record L-type calcium current from neonatal rat cardiomyocytes with overexpression of candidate genes.We identified 4 significant loci represented by rs78960694 (minor allele frequency [MAF]=5.02% in cases and 1.84% in controls;The first genome-wide association study identifies 4 novel loci and 2 risk genes (

Diabetic retinopathy (DR) is a kind of severe retinal neurodegeneration. The advanced glycation end products (AGEs) affect autophagy, and mitochondrial function is involved in DR. Adenosine-activated protein kinase (AMPK) is an important metabolic sensor that can regulate energy homeostasis in cells. However, the effect of AMPK in DR is still not fully understood. In this study, we investigated the effect of AMPK on diabetes-induced photoreceptor cell degeneration. In vivo, a diabetic mouse model was established by streptozotocin (STZ) injection. Haematoxylin-eosin (HE) staining was used to observe retinal morphology and measure the thicknesses of different layers in the retina. Electroretinogram (ERG) was used to evaluate retinal function. In vitro, 661w cells were treated with AGEs with/without an AMPK agonist (metformin) or AMPK inhibitor (compound C). Flow cytometry and CCK-8 assays were used to analyse apoptosis. Mitochondrial membrane potential was analysed by JC-1. Western blotting and qRT-PCR were used to examine the expression of related proteins and genes, respectively. The wave amplitude and the thickness of the outer nuclear layer were decreased in diabetic mice. The expression of rhodopsin and opsin was also decreased in diabetic mice. In vitro, the percentage of apoptotic cells was increased, the expression of the apoptosis-related protein Bax was increased, and Bcl-2 was decreased after AGE treatment in 661w cells. The expression of the autophagy-related protein LC3 was decreased, and p62 was increased. The mitochondrial-related gene expression and membrane potential were decreased, and mitochondrial morphology was abnormal, as observed by TEM. However, AMPK stimulation ameliorated this effect. These results indicate that AMPK stimulation can delay diabetes-induced photoreceptor degeneration by regulating autophagy and mitochondrial function.

An intriguing self-powered cathodic photoelectrochemical (PEC) microfluidic aptasensor with enhanced cathodic photocurrent response is proposed for sensitive detection of prostate-specific antigen (PSA). The self-powered system is constructed by a cadmium sulfide-sensitized zinc oxide nanorod array (CdS/ZnO NA) as a photoanode with an iodide-doped bismuth oxychloride flower-array (I0.2:BiOCI0.8) as a photocathode, which can generate the electrical output under visible light irradiation with no external power supply. In addition, the p-type semiconductor I0.2:BiOCI0.8 with a special internal electric field between the iodide ion layer and the [Bi2O2]2+ layer could increase the cathodic photocurrent response by facilitating the separation of electron/hole pairs under visible light excitation. It is worth noting that dissolved oxygen as an electron acceptor can be reduced by the photogenerated electron to form a superoxide radical (•O2-) in the self-powered cathodic PEC system. The further enhanced cathodic photocurrent response can be achieved by eliminating •O2- that reacts with the luminol anion radical (L•-) to produce chemiluminescence emission, which serves as an inner excitation light source. What is more exciting is that the integration of the photoanode and the photocathode into a microfluidic chip could realize automatic sample injection and detection. On this basis, the proposed aptasensor presents excellent reproducibility and high sensitivity for detecting PSA and exhibits a good linearity range (50 fg·mL-1 to 50 ng·mL-1) with a low detection limit (25.8 fg·mL-1), which opens up a new horizon of potential for sensitively detecting other kinds of disease markers.

Six-axis motion is essential for the evaluation of the wear failure modes of dental prostheses with complete teeth morphologies, and a high occlusal force capacity is vital for static clenching and dynamic bruxism. Additionally, the saliva environment influences abrasive particles and crack growth. The present research was aimed at the development of a six-axis masticatory and saliva simulator with these capacities. The masticatory simulator was designed based on a six-axis parallel mechanism, and the saliva simulator consisted of a saliva circuit and a temperature control loop. A control system of the masticatory and saliva simulators was constructed. The operating interface includes a centric occlusal position search, a static test, a dynamic test, a saliva supply, and data reporting. The motion and force performances of the masticatory simulator were evaluated. The flow rate and temperature change of the saliva simulator were calculated. For the occlusal position-searching, the driving amplitude is linear with the moving variables during minor one-axis motion. For the static tests, the force capacity of the driving chain is 3540 N, while for the dynamic tests, the force capacity is 1390 N. The flow rate of the saliva is 0.18–51.84 mL/min, and the saliva can effectively wet the prosthesis without the risk of overflow. Moreover, the saliva temperature can increase from room temperature (23°C) to body temperature (37°C) in about 6 min. The proposed DUT-2 simulator with six-axis motion, high force, and a salvia environment provides an in vitro testing approach to validate numerical simulation results and explain the clinical failure modes of prostheses. The centric occlusal position-searching, static tests, and dynamic tests could therefore be executed using a single testing machine. Moreover, the proposed device is more compact than previously reported six-axis masticatory simulators, including the Bristol simulator and DUT-1 simulator.

Micro RNAs (miRNAs) have shown great potential as rapid and discriminating biomarkers for acute myocardial infarction (AMI) diagnosis. We have developed a multiplexed ion-exchange membrane-based miRNA (MIX.miR) preconcentration/sensing amplification-free platform for quantifying in parallel a panel of miRNAs, including miR-1, miR-208b, and miR-499, from the same plasma samples from: 1) reference subjects with no evident coronary artery disease (NCAD); 2) subjects with stable coronary artery disease (CAD); and 3) subjects experiencing ST-elevation myocardial infarction (STEMI) prior to (STEMI-pre) and following (STEMI-PCI) percutaneous coronary intervention. The picomolar limit of detection from raw plasma and 3-decade dynamic range of MIX.miR permits detection of the miRNA panel in untreated samples from disease patients and its precise standard curve, provided by large 0.1 to 1 V signals and eliminates individual sensor calibration. The use of molecular concentration feature reduces the assay time to less than 30 minutes and increases the detection sensitivity by bringing all targets close to the sensors. miR-1 was low for NCAD patients but more than one order of magnitude above the normal value for all samples from three categories (CAD, STEMI-pre, and STEMI-PCI) of patients with CAD. In fact, miR-1 expression levels of stable CAD, STEMI-pre and STEMI-PCI are each more than 10-fold higher than the previous class, in that order, well above the 95% confidence level of MIX.miR. Its overexpression estimate is significantly higher than the PCR benchmark. This suggests that, in contrast to protein biomarkers of myocardial injury, miR-1 appears to differentiate ischemia from reperfusion injury and both from non-AMI CAD patients. The battery-operated MIX.miR can be a portable and low-cost AMI diagnostic device, particularly useful in settings where cardiac catheterization is not readily available to determine the status of coronary reperfusion.

3D-grid-based chemistry-transport models, such as the Community Multiscale Air Quality (CMAQ) modeling system, have been widely used for predicting concentrations of ambient air pollutants. However, typical horizontal resolutions of nationwide CMAQ simulations (12×12 km(2)) cannot capture local scale gradients for accurately assessing human exposures and environmental justice disparities. In this study, a Bayesian Ensemble Machine Learning (BEML) framework, that integrates thirteen learning algorithms, was developed for downscaling CMAQ estimates of ozone daily maximum 8-hr averages to census tract level, across the contiguous US and is demonstrated for 2011. Three-stage hyperparameter tuning and targeted validations were designed to ensure the ensemble model’s ability to interpolate, extrapolate, and capture concentration peaks. The Shapley value metric from coalitional game theory was applied to interpret the drivers of subgrid gradients. The flexibility (transferability) of the 2011-trained BEML model was further tested by evaluating its ability to estimate fine-scale concentrations for other years (2012–2017) without re-training. To demonstrate the feasibility of using the BEML approach to strictly “data-limited” situations, the model was applied to downscale CMAQ outputs for a future year scenario-based simulation that considers effects of variations in meteorology associated with climate change.

Background The growing epidemics of severe fever with thrombocytopenia syndrome (SFTS), an emerging tick-borne disease in East Asia, and its high case fatality rate have raised serious public health concerns. Methods Surveillance data on laboratory-confirmed SFTS cases in China were collected. The spatiotemporal dynamics and epidemiological features were explored. The socioeconomic and environmental drivers were identified for SFTS diffusion using survival analysis and for SFTS persistence using a two-stage generalized boosted regression tree model. Results During 2010‒2018, a total of 7721 laboratory-confirmed SFTS cases were reported in China, with an overall case fatality rate (CFR) of 10.5%. The average annual incidence increased >20 times and endemic areas expanded from 27 to 1574 townships, whereas the CFR declined from 19% to 10% during this period. Four geographical clusters—the Changbai Mountain area, the Jiaodong Peninsula, the Taishan Mountain area, and the Huaiyangshan Mountain area—were identified. Diffusion and persistence of the disease were both driven by elevation, high coverages of woods, crops, and shrubs, and the vicinity of habitats of migratory birds but had different meteorological drivers. Residents ≥60 years old in rural areas with crop fields and tea farms were at increased risk to SFTS. Conclusions Surveillance of SFTS and intervention programs need to be targeted at areas ecologically suitability for vector ticks and in the vicinity of migratory birds to curb the growing epidemic., This retrospective study determined the spatiotemporal patterns of severe fever with thrombocytopenia syndrome (SFTS) and socioeconomic and environmental risk drivers for its diffusion and persistence, which bridges the knowledge gap in the epidemiology and ecology of the disease. The ecological model can be used to assess risks of STFS in countries where the disease or vector ticks are emerging to guide the planning of surveillance and controls.

This work outlines an electrochemiluminescence (ECL) platform with versatile and high-performance, which using the complex luminescent molecules [Ru(Ⅱ) complex] formed by carbohydrazide (...

Background Between mid‐January and early February, provinces of mainland China outside the epicentre in Hubei province were on high alert for importations and transmission of COVID‐19. Many properties of COVID‐19 infection and transmission were still not yet established. Methods We collated and analysed data on 449 of the earliest COVID‐19 cases detected outside Hubei province to make inferences about transmission dynamics and severity of infection. We analysed 64 clusters to make inferences on serial interval and potential role of pre‐symptomatic transmission. Results We estimated an epidemic doubling time of 5.3 days (95% confidence interval (CI): 4.3, 6.7) and a median incubation period of 4.6 days (95% CI: 4.0, 5.2). We estimated a serial interval distribution with mean 5.7 days (95% CI: 4.7, 6.8) and standard deviation 3.5 days, and effective reproductive number was 1.98 (95% CI: 1.68, 2.35). We estimated that 32/80 (40%) of transmission events were likely to have occurred prior to symptoms onset in primary cases. Secondary cases in clusters had less severe illness on average than cluster primary cases. Conclusions The majority of transmissions are occurring around illness onset in an infected person, and pre‐symptomatic transmission does play a role. Detection of milder infections among the secondary cases may be more reflective of true disease severity.

An intramolecular photoelectrochemical (PEC) system is designed from the novel electron donor YYYHWRGWV (Y3-H) peptide ligand for the first time. The bifunctional nonapeptide cannot only rely on the HWRGWV sequence as a site-oriented immobilizer to recognize the crystallizable fragment (Fc) domains of the antibody but also acts as electron donors for PEC generation via three tyrosine (Y) of the N-terminal. The Bi2WO6/AgInS2 heterojunction with a significant visible-light absorption is utilized as a photoelectric generator, and the motivation is ascribed to a proven proposition, namely, that short-wavelength illuminant radiates proteins, causing a decline in bioactivity of immune protein. An innovative biosensor is fabricated using the above strategies for the detection of CYFRA21-1, a biomarker of squamous cell lung carcinoma. This sort of PEC-based sensing platform shows convincing experimental data and could be an effective candidate for clinical application in the future due to their extremely skillful conception.

Background/Aim: Pancreatic adenocarcinoma is a highly malignant tumor. Synergistic combinations of anticancer agents for the effective treatment of pancreatic cancer patients are urgently needed. Here, we investigated the combined effect of celecoxib (CEL) and salirasib (SAL) on pancreatic cancer cells. Methods: Cell viability and apoptosis were measured by the trypan blue assay, three-dimensional cultures, propidium iodide staining, and caspase-3 assay. NF-κB activation and the protein levels of Akt, pAkt, and Bcl-2 were determined by the luciferase reporter assay and western blot. Results: Co-treatment with CEL and SAL had stronger effects on decreasing cell viability and inducing apoptosis in Panc-1 cells as compared with each agent individually. This combination strongly inhibited NF-κB activity and reduced pAkt and Bcl-2 levels in Panc-1 cells. Conclusion: SAL in combination with CEL may represent a new approach for effective inhibition of pancreatic cancer.

The mechanisms behind cancer initiation and progression are not clear. Therefore, development of clinically relevant models to study cancer biology and drug response in tumors is essential. In vivo models are very valuable tools for studying cancer biology and for testing drugs; however, they often suffer from not accurately representing the clinical scenario because they lack either human cells or a functional immune system. On the other hand, two-dimensional (2D) in vitro models lack the three-dimensional (3D) network of cells and extracellular matrix (ECM) and thus do not represent the tumor microenvironment (TME). As an alternative approach, 3D models have started to gain more attention, as such models offer a platform with the ability to study cell-cell and cell-material interactions parametrically, and possibly include all the components present in the TME. Here, we first give an overview of the breast cancer TME, and then discuss the current state of the pre-clinical breast cancer models, with a focus on the engineered 3D tissue models. We also highlight two engineering approaches that we think are promising in constructing models representative of human tumors: 3D printing and microfluidics. In addition to giving basic information about the TME in the breast tissue, this review article presents the state-of-the-art tissue engineered breast cancer models. STATEMENT OF SIGNIFICANCE: Involvement of biomaterials and tissue engineering fields in cancer research enables realistic mimicry of the cell-cell and cell-extracellular matrix (ECM) interactions in the tumor microenvironment (TME), and thus creation of better models that reflect the tumor response against drugs. Engineering the 3D in vitro models also requires a good understanding of the TME. Here, an overview of the breast cancer TME is given, and the current state of the pre-clinical breast cancer models, with a focus on the engineered 3D tissue models is discussed. This review article is useful not only for biomaterials scientists aiming to engineer 3D in vitro TME models, but also for cancer researchers willing to use these models for studying cancer biology and drug testing.

The full-contact model has been widely used in tooth preparation and prosthesis fabrication. However, it is rarely used in denture tests. The purpose of the present study was to design a suitable full-contact dental model for denture tests.A standard dental model with the complete tooth morphology was raster scanned and 3D reconstructed. Then, the positioning and fixing surfaces of the dental model were reshaped. The dental model was digitally trimmed into two parts: a fundamental part and a replaceable part. The modular design was presented according to dentition defects around the first molar. The prepared tooth replicas were designed through preparation/scanning/registration/separation sequences. The dental model was fabricated by stereolithography (SLA) 3D-printing rapid prototype technology. The static fracture force of the dental model was predicted using the finite element method. The effects of the four design methods on the suitability of the five testing operations (abutment fabrication, prosthesis fabrication, assembling, loading, and observation) were quantitatively analyzed. The static tests of three fixed partial dentures (FPDs), including tooth-supported, implant-supported, and tooth-tooth-supported prostheses, were conducted to investigate the fracture feature. The dynamic test of a removable partial denture (RPD) was undertaken to study the wear characteristic.The dental model could bear the maximum fracture strength of 4268.3 N. Seven positive and two negative effects of the design methods were produced. The maximum fracture strength of the FPDs were 1331.2 N, 1356.7 N, and 1987.7 N. The wear facets of the RPD in the dynamic denture test were distributed in three regions.The force capacity of the full-contact dental model allows the application of static denture tests. The dental model provides improvements in fixture design, removable design, and replica design for the testing operations. The dental model is recommended more in the dynamic test than in the static test.

Few therapies can reverse the proangiogenic activity of senescent mesenchymal stromal/stem cells (MSCs). In this study, we investigated the effects of rapamycin on the proangiogenic ability of senescent human umbilical cord MSCs (UCMSCs). An in vitro replicative senescent cell model was established in cultured UCMSCs. We found that late passage (P25 or later) UCMSCs (LP-UCMSCs) exhibited impaired proangiogenic abilities. Treatment of P25 UCMSCs with rapamycin (900 nM) reversed the senescent phenotype and notably enhanced the proangiogenic activity of senescent UCMSCs. In a nude mouse model of hindlimb ischemia, intramuscular injection of rapamycin-treated P25 UCMSCs into the ischemic limb significantly promoted neovascularization and ischemic limb salvage. We further analyzed the changes in the expression of angiogenesis-associated genes in rapamycin-primed MSCs and found higher expression of several genes related to angiogenesis, such as VEGFR2 and CTGF/CCN2, in primed cells than in unprimed MSCs. Taken together, our data demonstrate that rapamycin is a potential drug to restore the proangiogenic activity of senescent MSCs, which is of importance in treating ischemic diseases and tissue engineering.

Autophagy and exosome secretion in photoreceptor and RPE cells play an important role during diabetic retinopathy (DR). Thioredoxin (Trx) upregulation delays diabetes-induced photoreceptor cell degeneration, which the effect of autophagy and exosome secretion on it is unclear. Therefore, we investigated the effect of them on Trx upregulation to delay diabetes-induced photoreceptor cell degeneration and to identify the potential therapy for DR in the future.Trx-transgenic mice and 661w cell were as models. Retinal function and morphology were evaluated by electroretinography and HE staining. TUNEL staining was used to evaluate apoptosis. The protein expression was detected by Western blotting. TEM and mRFP-GFP-LC3 method were used to analyze autophagy.In vitro and in vivo, Trx upregulation can delay diabetes-induced photoreceptor cell degeneration. Moreover, the expression of LC3 and p62 was decreasing and the expression of Alix and CD63 was increasing after Trx overexpression. However, it was inhibited after AMPK inhibitor treatment. Additionally, secreted exosomes from photoreceptor were phagocytosed by RPE cells to regulate its physiological function.Trx upregulation can delay diabetes-induced photoreceptor cell degeneration via AMPK-mediated autophagy and exosome secretion. Secreted exosomes from photoreceptor cells could be phagocytosed and degraded by RPE cells in DR.

Purpose: To investigate the clinical outcomes and complications associated with the flanged intrascleral haptic fixation with double-needle technique (a.k.a. the Yamane technique/FIHFT) in patients with Marfan syndrome (MFS) with subluxated or dislocated lenses. Methods: Eighteen eyes of 11 patients with MFS with subluxated or dislocated lenses who had undergone intraocular lens implantation using the FIHFT from March 2019 to October 2020 were evaluated. All patient data were retrospectively collected from medical records, including a complete ophthalmologic examination at baseline and follow-up examinations of uncorrected visual acuity (UCVA, logMAR), best-corrected visual acuity (BCVA, logMAR), intraocular pressure (IOP), and slit-lamp examination. Results: The median follow-up period was 6 ± 3 (range, 3–12) months. The average patient age at the time of surgery was 13 ± 9 (range, 4–34) years. The mean preoperative BCVA was 0.49 ± 0.20 logMAR (Snellen equivalent visual acuity, 20/60), while the mean postoperative BCVA at the end of follow-up was 0.21 ± 0.14 logMAR (20/30), indicating an improvement of 0.28 ± 0.20 logMAR (20/40) postoperatively ( p Conclusions: To our knowledge, the present study is the first to report outcomes of the FIHFT in patients with MFS. Our findings suggested that scleral lens fixation is safe and effective for improving visual acuity in patients with MFS who have subluxated or dislocated lenses.

This study is to obtain precise data on iron physiological requirements in Chinese children using single stable isotope tracer technique.Thirty boys (10.6 ± 0.2 years) and 27 girls (10.4 ± 0.2 years) were received oral 6 mgThe iron physiological requirement was significantly lower in boys than those values in girls (16.88 ± 7.12This study indicate that iron physiological requirement could require more daily iron intake in girls as compare with the values in boys having the same body weight. These findings would be facilitate to the new revised dietary reference intakes.

Nationwide prospective surveillance of all-age patients with acute respiratory infections was conducted in China between 2009‒2019. Here we report the etiological and epidemiological features of the 231,107 eligible patients enrolled in this analysis. Children, China operates a national surveillance program for acute respiratory infections and sampled over 200,000 patients between 2009–2019. Here, the authors present results from this program and describe patterns by age, pathogen type, presence of pneumonia, and season.

Background Short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3, OMIM: 613091) is an autosomal recessive disorder. SRTD3 presents clinically with a narrow thorax, short ribs, shortened tubular bones, and acetabular roof abnormalities. Clinical signs of SRTD3 vary among individuals. Pathogenic variants of DYNC2H1 (OMIM: 603297) have been reported to cause SRTD3. Methods We performed a detailed clinical prenatal sonographic characterization of a foetus with SRTD3. Trio whole-exome sequencing was used to identify causative variants in the family. The identified variants in the families were validated by Sanger sequencing and mass spectrometry. Multiple computational tools were used to predict the harmfulness of the two variants. A minigene splicing assay was carried out to evaluate the impact of the splice-site variant. Results We evaluated prenatal sonographic images of the foetus with SRTD3, including abnormal rib curvature, narrow thorax, bilateral hypoplastic lungs, bilateral polydactyly, syndactyly, and foetal visceral situs inversus with mirror-image dextrocardia. We revealed novel compound variants of DYNC2H1 (NM_001377.3:c.11483T > G (p.Ile3828Arg) and c.2106 + 3A > T). Various statistical methods predicted that the variants would cause harmful effects on genes or gene products. The minigene assay findings suggested that c.2106 + 3A > T caused the skipping over exon 14, producing an exon 14 loss in the protein. Conclusion This study identified a foetus with SRTD3 with situs inversus totalis with mirror-image dextrocardia in a Chinese family, revealing two novel compound heterozygous dynein cytoplasmic 2 heavy chain 1 (DYNC2H1) variants, expanding the phenotypic spectrum of SRTD3. The minigene study of c.2106 + 3A > T was predicted to cause an inframe exclusion of exon 14, which was predicted to have important molecular functions. Our findings strongly supported the use of WES in prenatal diagnosis and helped to understand the correlation of genotype and phenotypes of DYNC2H1. The specific sonographic findings and the molecular diagnosis helped add experience to further our expertise in prenatal counselling for SRTD3.

Mitochondrial complex I deficiency (MCID) is the most common biochemical defect identified in childhood with mitochondrial diseases, mainly including Leigh syndrome, encephalopathy, macrocephaly with progressive leukodystrophy, hypertrophic cardiomyopathy and myopathy.To identify genetic cause in a patient with early onset autosomal recessive MCID.Trio whole-exome sequencing was performed and phenotype-related data analyses were conducted. All candidate mutations were confirmed by Sanger sequencing.Here we report a child of Leigh syndrome presented with global developmental delay, progressive muscular hypotonia and myocardial damage. A missense mutation c.118C T (p.Arg40Trp) and a previously reported mutation c.1157G A (p.Arg386His) in NDUFV1 have been identified as compound heterozygous in the patient. The mutation p.Arg386His is closely associated with the impairment of 4Fe-4S domain and this mutation has been reported pathogenic. The c.118C T mutation has not been reported in ClinVar and HGMD database. In silico protein analyses showed that p.Arg40 is highly conserved in a wide range of species, and the amino acid substitution p.Trp40 largely decreases the stability of NDUFV1. In addition, the mutation has not been detected in the Asian populations and it was predicted to be deleterious by numerous prediction tools.This research expands the mutation spectrum of NDUFV1 and substantially provides an early and accurate diagnosis basis of MCID, which would benefit subsequently effective genetic counseling and prenatal diagnosis for future reproduction of the family.

Herein, a split-type immunoassay strategy instigated by cation exchange (CE) and changing the capacity of an electron donor in an electrolyte solution is optimized, namely, for differentiating the biological-specific binding assay and photoelectrochemical (PEC) analysis. MoSe

The levels of acetone and other ketones in exhaled human breath can be associated with various metabolic conditions, e.g. ketosis, lung cancer, dietary fat loss and diabetes. In this study, ketones in breath samples were charged through the reaction with water radical cations to form [M + H2O]˙+ ions, which were detected by mass spectrometry. Our experimental data indicate that under the optimized experimental conditions, the limit of detection for acetone using our approach is 0.14 ng L−1 (∼0.06 ppb). The linear dynamic range of detection spans four orders of magnitude. The developed approach was applied to real-time semi-quantitative analysis of acetone in the exhaled breath of human volunteers, revealing significantly higher levels of acetone in the breath of smokers compared to non-smokers. The developed approach features the obviation of sample collection, easy operation, high speed of analysis (10 s per run), high sensitivity, and spectral interpretation, which indicates the potential of ambient corona discharge ionization mass spectrometry as a selective, sensitive and noninvasive technique for the determination of exhaled ketones in clinical diagnosis including lung cancer, diabetes, etc.

This research put forward a novel split-type electrochemical (EC) immunosensor which integrated the controlled-release strategy with EC detection for application in the field of biosensing. Concretely, ascorbic acid (AA) was packaged in a cadmium sulfide (CdS)-capped spherical mesoporous bioactive glass (SBG) nanocarrier (SBGCdS) on account of encapsulation technology. To reduce the complexity of the bioanalysis, the detection antibody-labeled SBGCdS-AA bioconjugate was applied in a 96-well microplate for the immunoreaction process, which is independent of the EC determination procedure. Thus, the immune interference and steric hindrance caused by the accumulation of nanomaterials on the electrode could be minimized. Subsequently, AA was released efficiently via the destruction effect of dithiothreitol on the disulfide bond. In addition, for the as-prepared FcAI/l-Cys/gold nanoparticles (GNPs)/porous BiVO4 (p-BVO)/ITO EC sensing platform in the detection solution, the synergetic catalysis of Fc and GNPs/p-BVO toward the oxidation of the released AA could be realized, which triggered AA-mediated significant signal magnification throughout this study. In particular, p-BVO with an ordered nanoarray structure could accelerate the electron transfer to assist in sensitivity improvement of this system. This novel biosensor was capable of assaying the neuron-specific enolase (NSE) biomarker sensitively, from which a linear range of 0.001-100 ng/mL was derived along with a low detection limit of 1.08 pg/mL. An innovative way could be paved in the bioanalysis of NSE and other biomarkers.

Background: The purpose of this study is to determine the mutation frequencies of key driver genes in uveal melanoma (UM) in Chinese patients and to detect associations between metastasis and the mutation of these genes. Method: A total of 85 patients with UM were enrolled in this study, including 18 patients with metastasis and 67 without metastasis. Sanger sequencing covering the mutational hotspot regions of the G protein subunit alpha Q (GNAQ), GNA11, splicing factor 3B subunit 1 (SF3B1), X-linked eukaryotic translation initiation factor 1A (EIF1AX), phospholipase C beta 4 (PLCB4) and cysteinyl leukotriene receptor 2 (CYSLTR2) genes was used to analyse the mutations in Chinese patients. Results: The frequencies of GNAQ and GNA11 mutations in UM were 45% (38/85) and 35% (30/85) respectively. The frequencies of SF3B1 and EIF1AX mutations were 37% (31/85) and 9% (8/85) respectively. Only 2 mutations were detected in exon 4 of GNAQ, and no mutations were detected in exon 4 of GNA11. A novel mutation, c.627G>T (Q209H) in GNA11 was found. The detected mutations affecting SF3B1 were c.1873C>T (R625C), c.1874G>A (R625H) and c.1874G>T (R625L). The association between the mutations in SF3B1 and low risk of metastasis was statistically significant (OR 0.17, 95% CI 0.035–0.819). The mutations affecting EIF1AX were –23G>A (5′-UTR), c.5C>G (P2R), c.23G>A (G8Q), c.25G>C (G9A) and c.38_39GC>CT (R13P). No mutations were found in the PLCB4 and CYSLTR2 genes. Unfortunately, information on BRCA1-associated protein 1 could not be obtained. Conclusions: These data indicate that mutations in the PLCB4 and CYSLTR2 genes are rare in Chinese UM patients. The mutations in GNAQ, GNA11 and EIF1AX were not associated with metastasis, whereas SF3B1 mutations were correlated with low risk of metastasis and demonstrated a protective effect in UM patients in China.

Surface-enhanced Raman spectroscopy (SERS) has emerged as an ultrasensitive molecular-fingerprint-based technique for label-free biochemical analysis of biological systems. However, for conventional SERS substrates, SERS enhancement factors (EFs) strongly depend on background refractive index (RI), which prevents reliable spatiotemporal SERS analysis of living cells consisting of different extra-/intracellular organelles with a heterogeneous distribution of local RI values between 1.30 and 1.60. Here, we demonstrate that nanolaminated SERS substrates can support uniform arrays of vertically oriented nanogap hot spots with large SERS EFs (>107) insensitive to background RI variations. Experimental and numerical studies reveal that the observed RI-insensitive SERS response is due to the broadband multiresonant optical properties of nanolaminated plasmonic nanostructures. As a proof-of-concept demonstration, we use RI-insensitive nanolaminated SERS substrates to achieve label-free Raman profiling and classification of living cancer cells with a high prediction accuracy of 96%. We envision that RI-insensitive high-performance nanolaminated SERS substrates can potentially enable label-free spatiotemporal biochemical analysis of living biological systems.

Metastasis is the main cause of death in colorectal cancer (CRC) patients. Aberrant fucosylation, catalyzed by the specific fucosyltransferases (FUTs), is associated with malignant behaviors. Non-conding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), emerge as key molecules in cancer malignancy. The aim of this study was to investigate HOTAIR/miR-326/FUT6 axis modified fucosylation on sLeX-CD44 (HCELL), which served as E-selectin ligand during CRC progression. Higher levels of HOTAIR and FUT6 were verified in CRC tissues and cell lines, with a positive correlation. HOTAIR was associated with poor clinical prognosis of CRC. Altered HOTAIR levels influenced proliferation, aggressiveness, apoptosis and tumorigenesis of CRC cells. HOTAIR directly harbored miR-326 binding sites and regulated FUT6 expression. Further results corroborated that HOTAIR/miR-326/FUT6 axis modified α1, 3-fucosylation of CD44, which mediated CRC malignancy. Co-modulation of HOTAIR, miR-326 and FUT6 impacted α1, 3-fucosylated CD44, which further triggered PI3K/AKT/mTOR pathway. HOTAIR also mediated CRC tumorigenesis and liver metastasis in vivo. Thus, our findings indicated that HOTAIR/miR-326/FUT6 axis mediated CRC procession through α1, 3-fucosylated CD44 via PI3K/AKT/mTOR pathway. This work rendered new therapeutic targets for CRC.

Atrial fibrillation (AF) affects 33.5 million individuals worldwide. It accounts for 15% of strokes and increases risk of heart failure and sudden death. The voltage-gated cardiac sodium channel complex is responsible for the generation and conduction of the cardiac action potential, and composed of the main pore-forming α-subunit Na(v)1.5 (encoded by the SCN5A gene) and one or more auxiliary β-subunits, including Na(v)β1 to Na(v)β4 encoded by SCN1B to SCN4B, respectively. We and others identified loss-of-function mutations in SCN1B and SCN2B and dominant-negative mutations in SCN3B in patients with AF. Three missense variants in SCN4B were identified in sporadic AF patients and small nuclear families; however, the association between SCN4B variants and AF remains to be further defined. In this study, we performed mutational analysis in SCN4B using a panel of 477 AF patients, and identified one nonsynonymous genomic variant p.Gly8Ser in four patients. To assess the association between the p.Gly8Ser variant and AF, we carried out case-control association studies with two independent populations (944 AF patients vs. 9,81 non-AF controls in the first discovery population and 732 cases and 1,291 controls in the second replication population). Significant association was identified in the two independent populations and in the combined population (p = 4.16 × 10(−4), odds ratio [OR] = 3.14) between p.Gly8Ser and common AF as well as lone AF (p = 0.018, OR = 2.85). These data suggest that rare variant p.Gly8Ser of SCN4B confers a significant risk of AF, and SCN4B is a candidate susceptibility gene for AF.

The long noncoding RNA (lncRNA) H19 has been described to participate in the metastasis of various tumors. Nevertheless, whether H19 promotes or impedes tongue squamous cell carcinoma (TSCC) cell migration and invasion remains controversial. Here we found that the expression of H19 was elevated in TSCC tissues compared with adjacent normal tissues. Moreover, we demonstrated that the expression of H19 was higher in metastasized tumors compared with unmetastasized tumors. Consistently, TSCC cells express higher levels of H19 than human squamous cells. Subsequently, depletion of H19 impaired the migration and invasion abilities of TSCC cells. Mechanistically, we demonstrated that H19 functions as a competing endogenous RNA (ceRNA) to sponge miRNA let-7a, leading to an increase in a let-7a target, the key regulator of tumor metastasis HMGA2, which is enriched in TSCC tissues and cell lines. Intriguingly, inhibition of let-7a significantly rescued the short hairpin H19 (shH19)-induced decrease in TSCC migration and invasion. These findings revealed that the H19/let-7a/HMGA2/EMT axis plays a critical role in the regulation of TSCC migration and invasion, which may provide a new therapeutic target for TSCC.

In this work, the heterostructures of Au nanoparticles loaded on 3D flower-like α-Fe2O3 (Au NPs/α-Fe2O3) as a platform and core-shell CdSe@CdS quantum dots sensitized graphene oxide (GO/CdSe@CdS QDs) as a signal amplification label were established in an ultrasensitive sandwich-type photoelectrochemical (PEC) immunosensor based on the "signal-on" type amplification method for detection of amyloid β-protein (Aβ). Specifically, the ultrahigh sensitivity of the proposed immunosensor came from two main properties. First, Au NPs/α-Fe2O3 could partially absorb visible-light, which dramatically promotes electron transfer because of the excellent conductivity of Au NPs, and effectively inhibits the electron-hole recombination, thanks to the effect of heterostructures. Second, the signal-on type is based on the signal amplification label of GO/CdSe@CdS QDs which on adequate absorption of visible-light can improve generation of photogenerated electron-hole pairs effectively. Under optimal conditions, the well-prepared PEC immunosensor exhibited a low detection limit of 0.02 pg mL-1 and a wide linear range from 0.06 pg mL-1 to 350 ng mL-1 for Aβ detection. Meanwhile, it also presented good reproducibility, specificity, and stability and might open a new promising pathway for detection of other important biomarkers.

Current biomarkers for myocardial infarction (MI) diagnosis are typically late markers released upon cell death, incapable of distinguishing between ischemic and reperfusion injury and can be symptoms of other pathologies. Circulating microRNAs (miRNAs) have recently been proposed as alternative biomarkers for MI diagnosis; however, detecting the changes in the human cardiac miRNA profile during MI is extremely difficult. Here, to study the changes in miRNA levels during acute MI, a heart-on-chip model with a cardiac channel, containing human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes in human heart decellularized matrix and collagen, and a vascular channel, containing hiPSC-derived endothelial cells, is developed. This model is exposed to anoxia followed by normoxia to mimic ischemia and reperfusion, respectively. Using a highly sensitive miRNA biosensor that the authors developed, the exact same increase in miR-1, miR-208b, and miR-499 levels in the MI-on-chip and the time-matched human blood plasma samples collected before and after ischemia and reperfusion, is shown. That the surface marker profile of exosomes in the engineered model changes in response to ischemic and reperfusion injury, which can be used as biomarkers to detect MI, is also shown. Hence, the MI-on-chip model developed here can be used in biomarker discovery.

National-based prospective surveillance of all-age patients with acute diarrhea was conducted in China between 2009‒2018. Here we report the etiological, epidemiological, and clinical features of the 152,792 eligible patients enrolled in this analysis. Rotavirus A and norovirus are the two leading viral pathogens detected in the patients, followed by adenovirus and astrovirus. Diarrheagenic Escherichia coli and nontyphoidal Salmonella are the two leading bacterial pathogens, followed by Shigella and Vibrio parahaemolyticus. Patients aged, Diarrhoea is a major cause of morbidity and mortality in China. Here, the authors present results from a large sentinel surveillance scheme from 217 hospitals in all 31 provinces in mainland China, including ~150,000 patients with acute diarrhoea and covering years 2009-2018.

A photoelectrochemical (PEC) biosensor capable of detecting cytokeratin 19 fragment 21-1 (CYFRA21-1) was optimized by taking advantage of the powerful conjugate repeats of horseradish peroxidase and tyramine (HRP-tyramine)-triggered enzymatic biocatalytic precipitation (BCP) on high-performance BiVO

Mutations in cardiac sodium channel NaThe purpose of this study was to identify structural elements involved in MOG1-NaSystematic analyses of large deletions, microdeletions, and point mutations, and glutathione S-transferases pull-down, co-immunoprecipitation, cell surface protein quantification, and patch-clamping of ILarge deletion analysis defined the MOG1-NaOur findings define the MOG1-Na