Host traits shape virome composition and virus transmission in wild small mammals.

Bats, rodents, and shrews are the most important animal sources of human infectious diseases. However, the evolution and transmission of viruses among them remain largely unexplored. Through the meta-transcriptomic sequencing of internal organ and fecal samples from 2,443 wild bats, rodents, and shrews sampled from four Chinese habitats, we identified 669 viruses, including 534 novel viruses, thereby greatly expanding the mammalian virome. Our analysis revealed high levels of phylogenetic diversity, identified cross-species virus transmission events, elucidated virus origins, and identified cases of invertebrate viruses in mammalian hosts. Host order and sample size were the most important factors impacting virome composition and patterns of virus spillover. Shrews harbored a high richness of viruses, including many invertebrate-associated viruses with multi-organ distributions, whereas rodents carried viruses with a greater capacity for host jumping. These data highlight the remarkable diversity of mammalian viruses in local habitats and their ability to emerge in new hosts.

Author Correction: A new coronavirus associated with human respiratory disease in China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A new coronavirus associated with human respiratory disease in China.

Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health1-3. Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. Epidemiological investigations have suggested that the outbreak was associated with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing4 of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here 'WH-Human 1' coronavirus (and has also been referred to as '2019-nCoV'). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China5. This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.

Prognostic factors in patients with secondary hemophagocytic lymphohistioc ytosis in a Chinese cohort.

Hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome with high mortality mediated by an unbridled and persistent activation of cytotoxic T lymphocytes and natural killer cells. However, the influence factors of early death in adult sHLH patients are still not fully elucidated, which need further investigating. We have conducted an observational study of adult HLH patients between January 2016 and December 2022. All patients are enrolled according to HLH-2004 criteria. Clinical manifestations, laboratory data, treatments, and outcomes have been recorded. Influence factors associated with prognosis are calculated by using logistic regression models. Overall, 220 patients enrolled in this study. The etiologies of HLH were divided into five groups including autoimmune-associated hemophagocytic syndrome (AAHS) (n = 90, 40.9%), malignancies (n = 73, 33.2%), EBV-HLH (n = 18, 8.2%), infection excluded EBV (n = 24, 10.9%), and other triggers (n = 15, 6.8%). Among them, EBV-HLH had the highest mortality (77.8%), and AAHS had the lowest mortality (14.4%). Multivariate analysis indicated that age (≥ 38 years old), cytopenia ≥ 2 lines, platelets (≤ 50 × 109/L), aspartate aminotransferase (≥ 135U/L), prothrombin time (≥ 14.9 s) and activated partial thromboplastin time (≥ 38.5s), EBV, and fungal infection are independent risk factors for poor prognosis of HLH. Adult HLH patients with elder age, cytopenia ≥ 2 lines, levels of decreased platelets, increased AST, prolonged PT and APTT, EBV, and fungal infection tend to have a poor prognosis.

Deep Learning Bridged Bioactivity, Structure, and GC-HRMS-Readable Evidence to Decipher Nontarget Toxicants in Sediments.

Identifying causative toxicants in mixtures is critical, but this task is challenging when mixtures contain multiple chemical classes. Effect-based methods are used to complement chemical analyses to identify toxicants, yet conventional bioassays typically rely on an apical and/or single endpoint, providing limited diagnostic potential to guide chemical prioritization. We proposed an event-driven taxonomy framework for mixture risk assessment that relied on high-throughput screening bioassays and toxicant identification integrated by deep learning. In this work, the framework was evaluated using chemical mixtures in sediments eliciting aryl-hydrocarbon receptor activation and oxidative stress response. Mixture prediction using target analysis explained <10% of observed sediment bioactivity. To identify additional contaminants, two deep learning models were developed to predict fingerprints of a pool of bioactive substances (event driver fingerprint, EDFP) and convert these candidates to MS-readable information (event driver ion, EDION) for nontarget analysis. Two libraries with 121 and 118 fingerprints were established, and 247 bioactive compounds were identified at confidence level 2 or 3 in sediment extract using GC-qToF-MS. Among them, 12 toxicants were analytically confirmed using reference standards. Collectively, we present a "bioactivity-signature-toxicant" strategy to deconvolute mixtures and to connect patchy data sets and guide nontarget analysis for diverse chemicals that elicit the same bioactivity.

Analysis of Prenatal Serological Screening of 116 Pregnant Women with Trisomy 21 Syndrome Fetus.

BACKGROUND: Prenatal serological screening is commonly used to screen for trisomy 21 syndrome (T21); however, it carries a risk of missed detection. In this study, we explored how to reduce missed diagnosis of T21 in serological screening. METHODS: A total of 116 pregnant women with T21 fetuses confirmed by prenatal diagnosis were evaluated. Serological screening and non-invasive prenatal test (NIPT) findings were analyzed. RESULTS: Twenty-nine T21 fetuses were missed in serological screening; the missed diagnosis rate was 25%, 67.65% of the missed cases were of moderate risk, and 79.31% of the missed pregnant women were under 35 years of age. Nuchal translucency (NT) and the free beta subunit of human chorionic gonadotropin (free-HCGß) were higher in the detected T21 cases than in the missed T21 cases, while alpha-fetoprotein (AFP) levels were decreased. Forty-eight pregnant women who underwent NIPT in the second trimester were at high-risk for T21. CONCLUSIONS: Prenatal screening should not be ignored in young pregnant women. For serological screening, moderate risk and abnormal single serum markers should also receive greater attention. NIPT can be extended to first-tier screening.

Prenatal diagnosis, ultrasound findings, and pregnancy outcome of 17q12 deletion and duplication syndromes: a retrospective case series.

OBJECTIVE: Analyze the ultrasound findings, single-nucleotide polymorphism array (SNP-array) results, and pregnancy outcomes of fetuses with 17q12 deletions and duplications in the second and third trimesters. Explore the prenatal ultrasound characteristics and pregnancy outcomes of these fetuses. METHODS: Retrospective data were collected for 16 fetuses diagnosed with 17q12 deletion and seven fetuses with 17q12 duplication through SNP-array during prenatal diagnosis at a single Chinese tertiary medical center from January 2017 to December 2023. Maternal demographics, ultrasound findings of the fetuses, SNP-array results, pregnancy outcomes, and follow-up information were reviewed and analyzed. Peripheral blood from the parents was extracted to determine whether the CNVs in the fetuses were inherited or de novo. RESULTS: The copy-number variation (CNV) sizes ranged from 1.39 to 1.94 Mb in cases of 17q12 deletion and from 1.42 to 1.91 Mb in cases of 17q12 duplication. These CNVs included 15 OMIM genes, such as HNF1B, LHX1, and ACACA. In fetuses with a 17q12 deletion, the primary manifestation was renal abnormalities (93.8%, 15/16). Of these, 13 cases (81.3%, 13/16) exhibited bilateral or unilateral hyperechogenic kidneys, and 12 cases (75%, 12/16) had multicystic hyperechogenic kidneys. Two cases (12.5%, 2/16) showed multiple organ structural abnormalities. In fetuses with a 17q12 duplication, four cases (57.1%, 4/7) revealed cardiovascular system abnormalities, including tetralogy of fallot, pulmonary artery stenosis, ventricular septal defect, and tricuspid regurgitation. Two cases (28.6%, 2/7) presented with upper gastrointestinal obstruction. Additionally, one case was particularly unique, characterized by multiple structural malformations, such as ventricular septal defect, microcephaly, cleft lip, and palate. Nine cases opted for pregnancy termination, and 14 chose to continue the pregnancy. Two cases underwent surgical treatment after birth for upper gastrointestinal obstruction, and the prognosis was good. Among the 10 cases of 17q12 deletion, six cases showed consistent prenatal ultrasound findings and postnatal clinical features. Four cases were found to have discrepancies with prenatal ultrasound findings; while the renal ultrasound phenotype appeared normal during the last follow-up, two of these cases were subsequently diagnosed with neuropsychiatric phenotypes. CONCLUSION: Our study expanded the clinical phenotype spectrum of fetuses with 17q12 deletion and duplication, and conducted a preliminary evaluation of prenatal ultrasound findings and postnatal clinical phenotypes in follow-up cases. We further demonstrated a high correlation between fetuses with 17q12 deletion and hyperechogenic, multicystic kidneys. The primary manifestations in fetuses with 17q12 duplication are likely cardiovascular system malformations, which also exhibit a broad spectrum of phenotypic features.

Combining deep learning and intelligent biometry to extract ultrasound standard planes and assess early gestational weeks.

OBJECTIVES: To develop and validate a fully automated AI system to extract standard planes, assess early gestational weeks, and compare the performance of the developed system to sonographers. METHODS: In this three-center retrospective study, 214 consecutive pregnant women that underwent transvaginal ultrasounds between January and December 2018 were selected. Their ultrasound videos were automatically split into 38,941 frames using a particular program. First, an optimal deep-learning classifier was selected to extract the standard planes with key anatomical structures from the ultrasound frames. Second, an optimal segmentation model was selected to outline gestational sacs. Third, novel biometry was used to measure, select the largest gestational sac in the same video, and assess gestational weeks automatically. Finally, an independent test set was used to compare the performance of the system with that of sonographers. The outcomes were analyzed using the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and mean similarity between two samples (mDice). RESULTS: The standard planes were extracted with an AUC of 0.975, a sensitivity of 0.961, and a specificity of 0.979. The gestational sacs' contours were segmented with a mDice of 0.974 (error less than 2 pixels). The comparison showed that the relative error of the tool in assessing gestational weeks was 12.44% and 6.92% lower and faster (min, 0.17 vs. 16.6 and 12.63) than that of the intermediate and senior sonographers, respectively. CONCLUSIONS: This proposed end-to-end tool allows automatic assessment of gestational weeks in early pregnancy and may reduce manual analysis time and measurement errors. CLINICAL RELEVANCE STATEMENT: The fully automated tool achieved high accuracy showing its potential to optimize the increasingly scarce resources of sonographers. Explainable predictions can assist in their confidence in assessing gestational weeks and provide a reliable basis for managing early pregnancy cases. KEY POINTS: • The end-to-end pipeline enabled automatic identification of the standard plane containing the gestational sac in an ultrasound video, as well as segmentation of the sac contour, automatic multi-angle measurements, and the selection of the sac with the largest mean internal diameter to calculate the early gestational week. • This fully automated tool combining deep learning and intelligent biometry may assist the sonographer in assessing the early gestational week, increasing accuracy and reducing the analyzing time, thereby reducing observer dependence.

Design, synthesis, and biological activity evaluation of novel tubulin polymerization inhibitors based on pyrimidine ring skeletons.

A library of new pyrimidine analogs was designed and synthesized of these, compound K10 bearing a 1,4­benzodioxane moiety and 3,4,5­trimethoxyphenyl group, exhibiting the most potent activity, with IC50 values of 0.07-0.80 µM against four cancer cell lines. Cellular-based mechanism studies elucidated that K10 inhibited microtubule polymerization, blocked the cell cycle at the G2/M phase, and eventually induced apoptosis of HepG2 cells. Additionally, K10 inhibited the migration and invasion of HepG2 cells in a dose-dependent manner. Overall, our work indicates that the tubulin polymerization inhibitor incorporating pyrimidine and the 3,4,5­trimethoxyphenyl ring may deserve consideration for cancer therapy.

α-Klotho: An Early Risk-Predictive Biomarker for Acute Kidney Injury in Patients with Acute Myocardial Infarction.

Background: Acute kidney injury (AKI) was a common and serious complication in patients with acute myocardial infarction (AMI). Novel biomarkers and therapies were deficient and imperative for AKI's early diagnosis and therapy after AMI. α-Klotho was considered as an early biomarker and potential therapy for AKI recently. Previous studies reported that the expression of α-Klotho was decreased in AKI rodents, and supplement of α-Klotho alleviated kidney injury. Nevertheless, its effect has not been studied in patients presenting with AMI. Methods: A total of 155 consecutive diagnosed with AMI at emergency department whose eGFR >60 ml/min ∗ 1.73 m2 were enrolled in this prospective observational cohort study which conducted between May 2016 and April 2019 in Peking University People's Hospital. AKI was defined according to the KDIGO criteria in 2012. At admission, the clinical data of patients were collected and serum α-Klotho was tested by ELISA. The relationship between α-Klotho, serum creatinine, eGFR, systolic pressure, BNP, LVEF, and Hgb of AKI were analyzed and their discrimination performances were compared. The association variables were calculated (adjusted odds ratio) with a confidence interval (CI) of 95% by binary logistic regression. And, we followed up the incidence of CKD and rehospitalization after patients' discharge in one year. Our study was approved by the ethics committee (no. 2016PHB042-01). Results: AKI incidence was 17.4% (27/155) during hospitalization. Compared to patients without AKI, the AKI group had obviously higher mortality and was more female and had higher incidence of chronic kidney disease, worse cardiac function, more cardiac complications, larger doses of diuretics, and less use of angiotensin-converting enzyme inhibitors/angiotensin receptor blocker. By contrary to previous animal experiments, we found serum α-Klotho levels were increased significantly in AKI patients (740.2 ± 306.8 vs. 419.0 ± 272.6 pg/mL, p < 0.001). And, the areas under the receiver operating curves indicated serum α-Klotho levels had a superior discriminative power for predicting AKI after AMI compared with other risk factors (0.792, 95% CI, 0.706-0.878, p < 0.001). Meanwhile, logistic regression model indicates extensive anterior myocardial infarction, Killip classification ≥2 grade, α-Klotho ≥516.9 pg/mL, eGFR (decrease per 10 ml/min ∗ 1.73 m2), Hgb, and nonuse of ACEI/ARB were the risk factors of AKI after AMI. Moreover, one-year follow-up presented AMI patients developed CKD had higher α-Klotho levels (739.7 ± 315.2 vs. 443.8 ± 292.5 pg/mL, p = 0.001), but no significant difference in rehospitalization. And, patients with α-Klotho ≥516.9 pg/ml was 6.699 times more likely to develop CKD than those with α-Klotho <516.9 pg/ml (relative risk 6.699, 95% CI 1.631-27.519, p = 0.007). Conclusion: Compared with traditional cardiac and renal biomarkers, serum α-Klotho could be a more appropriate predict biomarker for AKI after AMI in patients' eGFR >60 ml/min ∗ 1.73 m2. Higher α-Klotho levels are related to the development of AKI during hospitalization and suggest a higher prevalence of CKD after discharge. By contrary to animal experiments, whether the increased expression of α-Klotho could be a protective factor secreted by AKI after AMI, is remained to be further studied.

ACBD3 is up-regulated in gastric cancer and promotes cell cycle G1-to-S transition in an AKT-dependent manner.

It has been reported that ACBD3 is closely related to the malignant process of cells, but its role in gastric cancer has not been elucidated. This study aims to investigate the expression and function of ACBD3 in human gastric cancer. The Cancer Genome Atlas (TCGA) database were selected to analyze mRNA levels of ACBD3 in gastric cancer tissues and normal gastric epithelial tissues. qPCR and Western blot were conducted to detect the expression of ACBD3 in two normal gastric epithelial cell lines and five gastric cancer cell lines which were cultured in our laboratory. To exclude differences in individual background between different patients, we further detected the expression of ACBD3 in 8 pairs of malignant/non-malignant clinical gastric tissues. Through the establishment of stable cells, in vitro cell experiments and in vivo xenotransplantation models in mice, the role of ACBD3 in the proliferation of gastric cancer cells has been further explored. AKT inhibitors were used to deeply explore the molecular regulation mechanism of ACBD3. The results showed that the elevated ACBD3 in gastric cancer tissue were positively correlated with the clinical grade and prognosis of gastric cancer. In terms of molecular function, we found that ACBD3 can enhance the production and growth of gastric cancer cells. At the same time, the activation of AKT kinase played an important role in ACBD3's promotion of G1-to-S transition. The experiments generally indicate that ACBD3 is expected to become a potential diagnostic molecule or therapeutic target for gastric cancer.

miRTarBase 2020: updates to the experimentally validated microRNA-target interaction database.

MicroRNAs (miRNAs) are small non-coding RNAs (typically consisting of 18-25 nucleotides) that negatively control expression of target genes at the post-transcriptional level. Owing to the biological significance of miRNAs, miRTarBase was developed to provide comprehensive information on experimentally validated miRNA-target interactions (MTIs). To date, the database has accumulated >13,404 validated MTIs from 11,021 articles from manual curations. In this update, a text-mining system was incorporated to enhance the recognition of MTI-related articles by adopting a scoring system. In addition, a variety of biological databases were integrated to provide information on the regulatory network of miRNAs and its expression in blood. Not only targets of miRNAs but also regulators of miRNAs are provided to users for investigating the up- and downstream regulations of miRNAs. Moreover, the number of MTIs with high-throughput experimental evidence increased remarkably (validated by CLIP-seq technology). In conclusion, these improvements promote the miRTarBase as one of the most comprehensively annotated and experimentally validated miRNA-target interaction databases. The updated version of miRTarBase is now available at http://miRTarBase.cuhk.edu.cn/.

[Clinical characteristics and prenatal diagnosis of fetuses with sex chromosomal aneuploidies detected by non-invasive prenatal testing during early and midterm pregnancies].

OBJECTIVE: To analyze the indication, karyotyping result, ultrasound finding, pregnancy decision and follow-up of fetuses with sex chromosome aneuploidies (SCA) detected by non-invasive prenatal testing (NIPT) during early and midterm pregnancies. METHODS: The results of 225 singleton pregnancies with fetal SCA detected by NIPT were reviewed and analyzed. RESULTS: The 225 cases included 45,X (n=37), 47,XXY (n=74), 47,XXX (n=50), 47,XYY (n=56) and mosaicisms (n=8), among which 121 (53.8%) have opted to terminate the pregnancy, including 45,X (n=31), 47,XXY (n=61), 47,XXX (n=14), 47,XYY (n=12) and 3 mosaicisms. The remainder 104 (46.2%) have elected to continue with the pregnancy, among which three have opted to terminate due to abnormalities detected by ultrasonography, and two had spontaneous abortions. CONCLUSION: NIPT as a first-tier screening method can effectively detect fetal trisomies 21, 13 and 18 as well as SCA. The types of fetal SCA and presence of ultrasound abnormalities are critical factors for the termination of pregnancy.

Retraction Note to: MicroRNA-322 Cluster Promotes Tau Phosphorylation via Targeting Brain-Derived Neurotrophic Factor.

The Editors have retracted this article [1] following an investigation conducted by the journal. After publication concerns were raised regarding interpretation of the data presented in Fig. 4. The Editors requested additional data and clarification to confirm interpretation of data results. After further review, the Editors found that the additional data were not adequate to support the conclusion of the article and that P-values for the additional data were based on improper statistical analyses. With more appropriate statistical analysis, the reported effects for miR-322 and BDNF were not statistically significant. Dr. Chichu Xie agrees to this retraction. None of the other authors have responded to any correspondence from the publisher about this retraction.

Up-regulated ADP-Ribosylation factor 3 promotes breast cancer cell proliferation through the participation of FOXO1.

ADP-ribosylation factor 3 (ARF3) is a member of the KRAS proto-oncogene, GTPase(Ras) super-family of guanine nucleotide-binding proteins that mediates Golgi-related mitosis, but its role in malignant cells is unclear. In the present study, we found that mRNA and protein expression of ARF3 is up-regulated in breast cancer cells. Immunohistochemical analysis of 167 paraffin-embedded archived breast cancer tissues showed that ARF3 expression was localized primarily in the cytoplasm and was significantly up-regulated in malignant specimens compared to benign specimens. There were strong associations between ARF3 expression and clinicopathological characteristics in breast cancer. We also found that overexpressing ARF3 promoted, while silencing endogenous ARF3 inhibited, the proliferation of breast cancer cells by regulating cell cycle G1-S transition. Moreover, the pro-proliferative effect of ARF3 on breast cancer cells was associated with inactivation of the forkhead box O1 (FOXO1) transcription factor. ARF3 promotes breast cancer cell proliferation through the participation of FOXO1 and represents as a novel prognostic marker and therapeutic target for breast cancer.

Metformin and Docosahexaenoic Acid Hybrid Micelles for Premetastatic Niche Modulation and Tumor Metastasis Suppression.

Metastasis is the major cause of high mortality in cancer patients; thus, blocking the metastatic process is of critical importance for cancer treatments. The premetastatic niche, a specialized microenvironment with aberrant changes related to inflammation, allows the colonization of circulating tumor cells (CTCs) and serves as a potential target for metastasis prevention. However, little effort has been dedicated to developing nanomedicine to amend the premetastatic niche. Here this study reports a premetastatic niche-targeting micelle for the modulation of premetastatic microenvironments and suppression of tumor metastasis. The micelles are self-assembled with the oleate carbon chain derivative of metformin and docosahexaenoic acid, two anti-inflammatory agents with low toxicity, and coated with fucoidan for premetastatic niche-targeting. The obtained functionalized micelles (FucOMDs) exhibit an excellent blood circulation profile and premetastatic site-targeting efficiency, inhibit CTC adhesion to activated endothelial cells, alleviate lung vascular permeability, and reverse the aberrant expression of key marker proteins in premetastatic niches. As a result, FucOMDs prevent metastasis formation and efficiently suppress both primary-tumor growth and metastasis formation when combined with targeted chemotherapy. Collectively, the findings here provide proof of concept that the modulation of the premetastatic niche with targeted anti-inflammatory agents provides a potent platform and a safe and clinical translational option for the suppression of tumor metastasis.

Sequential Targeting TGF-ß Signaling and KRAS Mutation Increases Therapeutic Efficacy in Pancreatic Cancer.

Pancreatic cancer is a highly aggressive malignancy that strongly resists extant treatments. The failure of existing therapies is majorly attributed to the tough tumor microenvironment (TME) limiting drug access and the undruggable targets of tumor cells. The formation of suppressive TME is regulated by transforming growth factor beta (TGF-ß) signaling, while the poor response and short survival of almost 90% of pancreatic cancer patients results from the oncogenic KRAS mutation. Hence, simultaneously targeting both the TGF-ß and KRAS pathways might dismantle the obstacles of pancreatic cancer therapy. Here, a novel sequential-targeting strategy is developed, in which antifibrotic fraxinellone-loaded CGKRK-modified nanoparticles (Frax-NP-CGKRK) are constructed to regulate TGF-ß signaling and siRNA-loaded lipid-coated calcium phosphate (LCP) biomimetic nanoparticles (siKras-LCP-ApoE3) are applied to interfere with the oncogenic KRAS. Frax-NP-CGKRK successfully targets the tumor sites through the recognition of overexpressed heparan sulfate proteoglycan, reverses the activated cancer-associated fibroblasts (CAFs), attenuates the dense stroma barrier, and enhances tumor blood perfusion. Afterward, siKras-LCP-ApoE3 is efficiently internalized by the tumor cells through macropinocytosis and specifically silencing KRAS mutation. Compared with gemcitabine, this sequential-targeting strategy significantly elongates the lifespans of pancreatic tumor-bearing animals, hence providing a promising approach for pancreatic cancer therapy.

Cytoglobin ameliorates the stemness of hepatocellular carcinoma via coupling oxidative-nitrosative stress signals.

Cancer stem cells (CSCs) account for tumor self-renewal and heterogeneity. Oxidative-nitrosative stress (ONS) is an independent etiologic factor throughout tumorigenesis. Emerging evidences indicated that the interaction of ONS with CSCs contributes to tumor progression and resistance to chemoradiotherapy. Cytoglobin (Cygb) is a member of human hexacoordinate hemoglobin family and acts as a dynamic mediator of redox homeostasis. We observed that Cygb is significantly deregulated in human hepatocellular carcinoma (HCC) tissue and its decrease aggravates the growth of liver cancer stem cells (LCSCs) and increases the subpopulation of CD133(+) LCSCs. Cygb restoration inhibits HCC proliferation and LCSC growth, and decreases the subpopulation of CD133 (+) LCSCs in vitro. We found that Cygb absence promotes LCSC phenotypes and PI3 K/AKT activation, whereas Cygb restoration inhibits LCSC phenotypes and PI3 K/AKT activation. Furthermore, exogenous antioxidants can eliminate the inhibitory effect of Cygb to LCSC growth and phenotypes, as well as PI3 K/AKT activation. Collectively, this study demonstrated that cytoglobin functions as a tumor suppressor and targets CSCs at an ONS-dependent manner. Thus, Cygb restoration could be a novel and promising therapeutic strategy against HCC with aberrant ROS/RNS accumulation.

Overexpressed ACBD3 has prognostic value in human breast cancer and promotes the self-renewal potential of breast cancer cells by activating the Wnt/beta-catenin signaling pathway.

Acyl-CoA binding domain containing 3 (ACBD3) is involved in the maintenance of Golgi structure and function through its interaction with the integral membrane protein. However, the clinical significance and biological role of ACBD3 in breast cancer remain unclear. Herein, we found that the mRNA and protein levels of ACBD3 were markedly up-regulated in breast cancer cells and tissues. Immunohistochemical analysis of breast cancer tissues demonstrated that ACBD3 overexpression was significantly associated with advanced clinicopathological features. Univariate and multivariate analysis indicated that ACBD3 overexpression correlates with poor prognosis in breast cancer. Furthermore, overexpressing ACBD3 promoted, while silencing ACBD3 inhibited, self-renewal and tumorigenesis in breast cancer cells in vitro and in vivo respectively. Importantly, upregulating ACBD3 promoted the self-renewal and tumorigenesis of breast cancer cells via activating the Wnt/beta-catenin signaling, and the pro-self-renewal effect of ACBD3 in breast cancer was antagonized by the Wnt signaling inhibitor TCF4-siRNA and Lef1-siRNA.These findings indicate that ACBD3 may represent candidate therapeutic targets to enable the elimination of breast cancer stem cells, providing the preclinical proof-of-concept for the prevention and treatment of breast cancer.

MicroRNA-322 Cluster Promotes Tau Phosphorylation via Targeting Brain-Derived Neurotrophic Factor.

Brain-derived neurotrophic factor (BDNF) is a crucial regulator to support synaptic plasticity and neuronal survival, its significant decrease is a pathophysiological hallmark in Alzheimer's disease (AD) brains and accounts for poor prognosis. MicroRNAs (miRNAs) interfere with the translation of target mRNAs and control a variety of physiological and pathological processes. MiR-322 is the rodent homologue of human miR-424, it is involved in the modulation of cell differentiation, proliferation, apoptosis and metabolic activities in diverse tissues and organs. However, the roles and potential mechanisms of miR-322 remain elusive in AD pathogenesis. Here we observed miR-322 is significantly increased along with BDNF decrease in AD mouse brain. Bioinformatics prediction implicated that BDNF 3'-untranslated region (3'-UTR) possesses the putative target sequence of miR-322. Luciferase reporter assay identified that miR-322 can directly conjugate to BDNF 3'-UTR. The functional research showed that MiR-322 input deregulates BDNF expression at either mRNA or protein levels, whereas miR-322 silence restores BDNF expression in vitro. Furthermore, we found miR-322 promotes Tau phosphorylation via negatively controlling BDNF-TrkB receptor activation, otherwise MiR-322 silence restores TrkB activation and attenuates tau phosphorylation. Collectively, this study demonstrated a novel miRNA-dependent manner of BDNF degradation in AD pathogenesis, it may drive a miRNAs- or BDNF based therapeutic strategies against Alzheimer's disease.