SPRDA: a link prediction approach based on the structural perturbation to infer disease-associated Piwi-interacting RNAs.

piRNA and PIWI proteins have been confirmed for disease diagnosis and treatment as novel biomarkers due to its abnormal expression in various cancers. However, the current research is not strong enough to further clarify the functions of piRNA in cancer and its underlying mechanism. Therefore, how to provide large-scale and serious piRNA candidates for biological research has grown up to be a pressing issue. In this study, a novel computational model based on the structural perturbation method is proposed to predict potential disease-associated piRNAs, called SPRDA. Notably, SPRDA belongs to positive-unlabeled learning, which is unaffected by negative examples in contrast to previous approaches. In the 5-fold cross-validation, SPRDA shows high performance on the benchmark dataset piRDisease, with an AUC of 0.9529. Furthermore, the predictive performance of SPRDA for 10 diseases shows the robustness of the proposed method. Overall, the proposed approach can provide unique insights into the pathogenesis of the disease and will advance the field of oncology diagnosis and treatment.

A NAC transcription factor represses a module associated with xyloglucan content and regulates aluminum tolerance.

The transcriptional regulation of aluminum (Al) tolerance in plants is largely unknown, although Al toxicity restricts agricultural yields in acidic soils.. Here, we identified a NAM, ATAF1/2, and cup-shaped cotyledon 2 (NAC) transcription factor that participates in Al tolerance in Arabidopsis (Arabidopsis thaliana). Al substantially induced the transcript and protein levels of ANAC070, and loss-of-function anan070 mutants showed remarkably increased Al sensitivity, implying a beneficial role of ANAC070 in plant tolerance to Al toxicity. Further investigation revealed that more Al accumulated in the roots of anac070 mutants, especially in root cell walls, accompanied by a higher hemicellulose and xyloglucan level, implying a possible interaction between ANAC070 and genes that encode proteins responsible for the modification of xyloglucan, including xyloglucan endo-transglycosylases/hydrolase (XTH) or ANAC017. Yeast one hybrid analysis revealed a potential interaction between ANAC070 and ANAC017, but not for other XTHs. Furthermore, dual-luciferase reporter assay, RT-qPCR, and GUS analysis revealed that ANAC070 could directly repress the transcript levels of ANAC017, and knockout of ANAC017 in the anac070 mutant partially restored its Al sensitivity phenotype, indicating that ANAC070 contributes to Al tolerance mechanisms other than suppression of ANAC017 expression. Further analysis revealed that the core transcription factor SENSITIVE TO PROTON RHIZOTOXICITY1 (STOP1) and its target genes, which control Al tolerance in Arabidopsis, may also be involved in ANAC070-regulated Al tolerance. In summary, we identified a transcription factor, ANAC070, that represses the ANAC017-XTH31 module to regulate Al tolerance in Arabidopsis.

Unveiling the role of YARS1 in bladder cancer: A prognostic biomarker and therapeutic target.

YARS is responsible for catalysing the binding of tyrosine to its cognate tRNA and plays a crucial role in basic biosynthesis. However, its biological functions in bladder cancer remains to be proven. We analysed variations in YARS1 expression and survival in bladder cancer using multiple data sets, including TCGA-BLCA, GSE13507 and bladder cancer-specific tissue microarrays. Furthermore, we explored the biological functions of YARS1 using transcriptome data. Our findings revealed a noteworthy correlation between YARS1 and immune infiltration in bladder cancer, as determined using the XCELL algorithm and single-cell analysis. In addition, we employed the TIDE algorithm to evaluate the responsiveness of different cohorts to immune checkpoint therapy. We investigated the regulatory associations between YARS1 and various aspects of bladder cancer, including senescence, ferroptosis and stemness. Finally, we established a ceRNA network that is directly linked to the overall prognosis, YARS1 can serve as a prognostic biomarker for bladder cancer; its interaction with MYC has implications for bladder cancer cell senescence, ferroptosis and stemness. Moreover, the identified ceRNA network has potential as a therapeutic target in bladder cancer.

Malignant triton tumor of uterus: A case report and literature review.

Malignant triton tumor (MTT) is a highly aggressive malignant neoplasm, classified as a variant of malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation. There are few reports that MTT occurred in urogenital system. In the present study, we report the first MTT occurring in the uterus. A 57-year-old woman came to the emergency department due to persistent vaginal bleeding for 2 months. The gynecological palpation found that a club-shaped excrescence existed in the vagina about 7 cm × 3 cm × 3 cm. The mass located in the lower segment of the uterus and the cervix was confirmed by gynecological vaginal ultrasound and magnetic resonance imaging, which was preliminarily diagnosed as cervical carcinoma. After neoplasm punch biopsy, the pathological diagnosis was malignant triton tumor. The patient finally lost follow-up. This is the first report about MTT in the uterus and suggests that pathological biopsy combined with imaging examination is necessary for the diagnosis of rarely MTT.

Guidelines for the clinical application of the Xihuang pill for the prevention and treatment of breast hyperplasia diseases.

CONTEXT: The Xihuang pill (XHP) is a traditional Chinese medicine formulation that has been historically used in the prevention and treatment of proliferative breast diseases. However, there is a lack of guidelines that offer recommendations for its clinical use. OBJECTIVE: The task force from the Chinese Guangdong Pharmaceutical Association aims to develop evidence-based guidelines for XHP to prevent and treat proliferative breast diseases. METHODS: We searched six Chinese and English electronic databases, including the China National Knowledge Infrastructure, the Chinese Scientific Journal Database, the Wanfang Medical Database, PubMed, and Embase, up to November 1, 2022. Publications (case reports, clinical observation, clinical trials, reviews) on using XHP to treat proliferative breast diseases were manually searched. The search terms were Xihuang pill, hyperplasia of the mammary gland, breast lump, and mastalgia. The writing team developed recommendations based on the best available evidence. RESULTS: Treatment should be customized based on syndrome identification. We recommend using XHP for the prevention and treatment of breast hyperplasia disease when a patient presents the following syndromes: concurrent blood stasis syndrome, concurrent phlegm-stasis syndrome, and concurrent liver fire syndrome. Safety indicators, including blood analysis and liver and kidney function monitoring, should be performed regularly during treatment. CONCLUSIONS: Current clinical evidence suggests that XHP can be used as a standalone treatment or in conjunction with other medications to prevent and manage breast hyperplasia diseases. More randomized controlled studies are warranted to establish high-quality evidence of its use.

Heat shock protein family A member 8 is a prognostic marker for bladder cancer: Evidences based on experiments and machine learning.

Heat shock protein member 8 (HSPA8) is one of the most abundant chaperones in eukaryotic cells, but its biological roles in bladder cancer (BC) are largely unclear. First, we observed that HSPA8 was abundant in both cell lines and tissues of BC, and the HSPA8-high group had poorer T stages and overall survival (OS) than the HSPA8-low group in the TCGA patients. Next, when we knocked down HSPA8 in BC cells, the growth and migration abilities were significantly decreased, the apoptosis rates were significantly increased, and the Ki67 fluorescence intensity was decreased in BC cells. Moreover, caspase 3 was significantly decreased with overexpression of HSPA8 in BC cells. After that, a machine learning prognostic model was created based on the expression of HSPA8 by applying LASSO Cox regression in TCGA and GEO patients. The model indicated that the low-risk (LR) group with BC had better tumour stages, lymphovascular invasion, and OS than the high-risk (HR) group. Additionally, the risk score was demonstrated to be an independent risk factor for the prognosis of BC by univariate and multivariate Cox analyses. Moreover, the HR group showed a greater rate of TP53 mutations and was mostly enriched in the ECM-receptor interaction pathway than the LR group. Importantly, lower CD8+ T-cell and NK cell infiltration, higher immune exclusion scores, higher expression of PD-L1 and CTLA4 and poorer immune checkpoint therapy effects were found in the HR group. These findings demonstrated how crucial HSPA8 plays a role in determining the prognosis of bladder cancer.

Nitrogen Deposition Effects on Invasive and Native Plant Competition: Implications for Future Invasions.

Nitrogen (N) deposition has increased dramatically in recent decades, which is significantly affecting the invasion and growth of exotic plants. Whether N deposition leads to invasive alien species becoming competitively superior to native species remains to be investigated. In the present study, an invasive species (Oenothera biennis L.) and three co-occurring native species (Artemisia argyi Lévl. et Vant., Inula japonica Thunb., and Chenopodium album L.) were grown in a monoculture (two seedlings of the same species) or mixed culture (one seedling of O. biennis and one seedling of a native species) under three levels of N deposition (0, 6, and 12 g∙m-2∙year-1). Nitrogen deposition had no effect on soil N and P content. Nitrogen deposition enhanced the crown area, total biomass, leaf chlorophyll content, and leaf N to phosphorus ratio in both invasive and native plants. Oenothera biennis dominated competition with C. album and I. japonica due to its high resource acquisition and absorption capacity (greater height, canopy, leaf chlorophyll a to chlorophyll b ratio, leaf chlorophyll content, leaf N content, leaf mass fraction, and lower root-to-shoot ratio). However, the native species A. argyi exhibited competitive ability similar to O. biennis. Thus, invasive species are not always superior competitors of native species; this depends on the identities of the native species. High N deposition enhanced the competitive dominance of O. biennis over I. japonica by 15.45% but did not alter the competitive dominance of O. biennis over C. album. Furthermore, N deposition did not affect the dominance of O. biennis or A. argyi. Therefore, the species composition of the native community must be considered when preparing to resist future biological invasions. Our study contributes to a better understanding of the invasion mechanisms of alien species under N-loading conditions.

The complete chloroplast genome sequence of Vincetoxicum mongolicum (Apocynaceae), a perennial medicinal herb.

Vincetoxicum mongolicum Maxim. (1876), is a perennial medicinal herb, widely distributed in the Loess Plateau of China. Here, we sequenced, assembled, and annotated the complete chloroplast (cp) genome of V. mongolicum, and compared the highly variable gene regions and phylogenetic positions between V. mongolicum and other related species. Results showed that the complete cp genome of V. mongolicum was 160,157 bp in length, containing a large single copy (LSC) region of 91,263 bp, a pair of inverted repeats (IR) region of 23,892 bp, and a small single copy (SSC) region of 21,110 bp. The GC content accounts for 37.8%, and we annotated 131 single genes, which include 86 protein-coding genes, 8 rRNA genes, and 37 tRNA genes. By comparing and analyzing the variable region of the cp gene of V. mongolicum and other Vincetoxicum, we found that the variable sequences of rpoC1-rpoB, ycf4-cemA, ndhF, ndhF-rpl32, and rpl32-ccsA fragments were highly significant, which could be targeted as the DNA barcodes for evidence of V. mongolicum and its relatives in Apocynaceae. Maximum-likelihood (ML) phylogenetic tree analysis elucidated that V. mongolicum was sister to V. pycnostelma with strong support. Our results provide useful information for future phylogenetic studies and plastid super-barcodes of the family Apocynaceae.

Systematic profiling and identification of the peptide-mediated interactions between human Yes-associated protein and its partners in esophageal cancer.

Human Yes-associated protein (YAP) is involved in the Hippo signaling pathway and serves as a coactivator to modulate gene expression, which contains a transactivation domain (TD) responsible for binding to the downstream TEA domain family (TEAD) of transcription factors and two WW1/2 domains that recognize the proline-rich motifs (PRMs) present in a variety of upstream protein partners through peptide-mediated interactions (PMIs). The downstream YAP TD-TEAD interactions are closely associated with gastric cancer, and a number of therapeutic agents have been developed to target the interactions. In contrast, the upstream YAP WW1/2-partner interactions are thought to be involved in esophageal cancer but still remain largely unexplored. Here, we attempted to elucidate the complicated PMIs between the YAP WW1/2 domains and various PRMs of YAP-interacting proteins. A total of 106 peptide segments carrying the class I WW-binding motif [P/L]Px[Y/P] were extracted from 22 partner candidates, which are potential recognition sites of YAP WW1/2 domains. Structural and energetic analyses of the intermolecular interactions between the domains and peptides created a systematic domain-peptide binding profile, from which a number of biologically functional PMIs were identified and then substantiated in vitro using fluorescence spectroscopy assays. It is revealed that: (a) The sequence requirement for the partner recognition site binding to YAP WW1/2 domains is a decapeptide segment that contains a core PRM motif as well as two three-residue extensions from each side of the motif; the core motif and extended sections are responsible for the binding stability and recognition specificity of domain-peptide interaction, respectively. (b) There is an exquisite difference in the recognition specificity of the two domains; the LPxP and PPxP appear to more prefer WW1 than WW2, whereas the WW2 can bind more effectively to LPxY and PPxY than WW1. (c) WW2 generally exhibits a higher affinity to the panel of recognition site candidates than WW1. In addition, a number of partner peptides were found as promising recognition sites of the two domains and/or to have a good selectivity between the two domains. For example, the DVL1 peptide was determined to have moderate affinity to WW2 and strong selectivity for WW2 over WW1. Hydrogen bonds play a central role in selectivity.

Synthesis and biological evaluation of 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine covalent inhibitors as potential agents for the treatment of acute myeloid leukemia.

Fms-like tyrosine kinase 3 (FLT3) mutation has been strongly associated with increased risk of relapse, and the irreversible covalent FLT3 inhibitors had the potential to overcome the drug-resistance. In this study, a series of simplified 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine derivatives containing two types of Michael acceptors (vinyl sulfonamide, acrylamide) were conveniently synthesized to target FLT3 and its internal tandem duplications (ITD) mutants irreversibly. The kinase inhibitory activities showed that compound C14 displayed potent inhibition activities against FLT3 (IC50 = 256 nM) and FLT3-ITD by 73 % and 25.34 % respectively, at the concentration of 1 µM. The antitumor activities indicated that C14 had strong inhibitory activity against the human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 507 nM) harboring FLT3-ITD mutant, as well as MV4-11 (IC50 = 325 nM) bearing FLT3-ITD mutation. The biochemical analyses showed that these effects were related to the ability of C14 to inhibit FLT3 signal pathways, and C14 could induce apoptosis in MV4-11 cell as demonstrated by flow cytometry. Fortunately, C14 showed very weak potency against FLT3-independent human cervical cancer cell line HL-60 (IC50 > 10 µM), indicating that it might have no off-target toxic effects. In light of these data, compound C14 represents a novel covalent FLT3 kinase inhibitor for targeted therapy of AML.

Synthesis and Biological Evaluation of Novel Synthetic Indolone Derivatives as Anti-Tumor Agents Targeting p53-MDM2 and p53-MDMX.

A series of novel indolone derivatives were synthesized and evaluated for their binding affinities toward MDM2 and MDMX. Some compounds showed potent MDM2 and moderate MDMX activities. Among them, compound A13 exhibited the most potent affinity toward MDM2 and MDMX, with a Ki of 0.031 and 7.24 µM, respectively. A13 was also the most potent agent against HCT116, MCF7, and A549, with IC50 values of 6.17, 11.21, and 12.49 µM, respectively. Western blot analysis confirmed that A13 upregulated the expression of MDM2, MDMX, and p53 by Western blot analysis. These results indicate that A13 is a potent dual p53-MDM2 and p53-MDMX inhibitor and deserves further investigation.

Absence of TRIM32 Leads to Reduced GABAergic Interneuron Generation and Autism-like Behaviors in Mice via Suppressing mTOR Signaling.

Mammalian target of rapamycin (mTOR) signaling plays essential roles in brain development. Hyperactive mTOR is an essential pathological mechanism in autism spectrum disorder (ASD). Here, we show that tripartite motif protein 32 (TRIM32), as a maintainer of mTOR activity through promoting the proteasomal degradation of G protein signaling protein 10 (RGS10), regulates the proliferation of medial/lateral ganglionic eminence (M/LGE) progenitors. Deficiency of TRIM32 results in an impaired generation of GABAergic interneurons and autism-like behaviors in mice, concomitant with an elevated autophagy, which can be rescued by treatment embryonically with 3BDO, an mTOR activator. Transplantation of M/LGE progenitors or treatment postnatally with clonazepam, an agonist of the GABAA receptor, rescues the hyperexcitability and the autistic behaviors of TRIM32-/- mice, indicating a causal contribution of GABAergic disinhibition. Thus, the present study suggests a novel mechanism for ASD etiology in that TRIM32 deficiency-caused hypoactive mTOR, which is linked to an elevated autophagy, leads to autism-like behaviors via impairing generation of GABAergic interneurons. TRIM32-/- mouse is a novel autism model mouse.

Changes of [18F]FDG-PET/CT quantitative parameters in tumor lesions by the Bayesian penalized-likelihood PET reconstruction algorithm and its influencing factors.

BACKGROUND: To compare the changes in quantitative parameters and the size and degree of 18F-fluorodeoxyglucose ([18F]FDG) uptake of malignant tumor lesions between Bayesian penalized-likelihood (BPL) and non-BPL reconstruction algorithms. METHODS: Positron emission tomography/computed tomography images of 86 malignant tumor lesions were reconstructed using the algorithms of ordered subset expectation maximization (OSEM), OSEM + time of flight (TOF), OSEM + TOF + point spread function (PSF), and BPL. [18F]FDG parameters of maximum standardized uptake value (SUVmax), SUVmean, metabolic tumor volume (MTV), total lesion glycolysis (TLG), and signal-to-background ratio (SBR) of these lesions were measured. Quantitative parameters between the different reconstruction algorithms were compared, and correlations between parameter variation and lesion size or the degree of [18F]FDG uptake were analyzed. RESULTS: After BPL reconstruction, SUVmax, SUVmean, and SBR were significantly increased, MTV was significantly decreased. The difference values of %ΔSUVmax, %ΔSUVmean, %ΔSBR, and the absolute value of %ΔMTV between BPL and OSEM + TOF were 40.00%, 38.50%, 33.60%, and 33.20%, respectively, which were significantly higher than those between BPL and OSEM + TOF + PSF. Similar results were observed in the comparison of OSEM and OSEM + TOF + PSF with BPL. The %ΔSUVmax, %ΔSUVmean, and %ΔSBR were all significantly negatively correlated with the size and degree of [18F]FDG uptake in the lesions, whereas significant positive correlations were observed for %ΔMTV and %ΔTLG. CONCLUSION: The BPL reconstruction algorithm significantly increased SUVmax, SUVmean, and SBR and decreased MTV of tumor lesions, especially in small or relatively hypometabolic lesions.

New Helvolic Acid Derivatives with Antibacterial Activities from Sarocladium oryzae DX-THL3, an Endophytic Fungus from Dongxiang Wild Rice (Oryza rufipogon Griff.).

Three new helvolic acid derivatives (named sarocladilactone A (1), sarocladilactone B (2) and sarocladic acid A (3a)), together with five known compounds (6,16-diacetoxy-25-hy- droxy-3,7-dioxy-29-nordammara-1,17(20)-dien-21-oic acid (3b), helvolic acid (4), helvolinic acid (5), 6-desacetoxy-helvolic acid (6) and 1,2-dihydrohelvolic acid (7)), were isolated from the endophytic fungus DX-THL3, obtained from the leaf of Dongxiang wild rice (Oryza rufipogon Griff.). The structures of the new compounds were elucidated via HR-MS, extensive 1D and 2D NMR analysis and comparison with reported data. Compounds 1, 2, 4, 5, 6 and 7 exhibited potent antibacterial activities. In particular, sarocladilactone B (2), helvolinic acid (5) and 6-desacetoxy-helvolic acid (6) exhibited strongly Staphylococcus aureus inhibitory activity with minimum inhibitory concentration (MIC) values of 4, 1 and 4 µg/mL, respectively. The structure-activity relationship (SAR) of these compounds was primarily summarized.

NEMPD: a network embedding-based method for predicting miRNA-disease associations by preserving behavior and attribute information.

BACKGROUND: As an important non-coding RNA, microRNA (miRNA) plays a significant role in a series of life processes and is closely associated with a variety of Human diseases. Hence, identification of potential miRNA-disease associations can make great contributions to the research and treatment of Human diseases. However, to our knowledge, many existing computational methods only utilize the single type of known association information between miRNAs and diseases to predict their potential associations, without focusing on their interactions or associations with other types of molecules. RESULTS: In this paper, we propose a network embedding-based method for predicting miRNA-disease associations by preserving behavior and attribute information. Firstly, a heterogeneous network is constructed by integrating known associations among miRNA, protein and disease, and the network representation method Learning Graph Representations with Global Structural Information (GraRep) is implemented to learn the behavior information of miRNAs and diseases in the network. Then, the behavior information of miRNAs and diseases is combined with the attribute information of them to represent miRNA-disease association pairs. Finally, the prediction model is established based on the Random Forest algorithm. Under the five-fold cross validation, the proposed NEMPD model obtained average 85.41% prediction accuracy with 80.96% sensitivity at the AUC of 91.58%. Furthermore, the performance of NEMPD is also validated by the case studies. Among the top 50 predicted disease-related miRNAs, 48 (breast neoplasms), 47 (colon neoplasms), 47 (lung neoplasms) were confirmed by two other databases. CONCLUSIONS: The proposed NEMPD model has a good performance in predicting the potential associations between miRNAs and diseases, and has great potency in the field of miRNA-disease association prediction in the future.

Prediction of drug-target interactions from multi-molecular network based on LINE network representation method.

BACKGROUND: The prediction of potential drug-target interactions (DTIs) not only provides a better comprehension of biological processes but also is critical for identifying new drugs. However, due to the disadvantages of expensive and high time-consuming traditional experiments, only a small section of interactions between drugs and targets in the database were verified experimentally. Therefore, it is meaningful and important to develop new computational methods with good performance for DTIs prediction. At present, many existing computational methods only utilize the single type of interactions between drugs and proteins without paying attention to the associations and influences with other types of molecules. METHODS: In this work, we developed a novel network embedding-based heterogeneous information integration model to predict potential drug-target interactions. Firstly, a heterogeneous multi-molecuar information network is built by combining the known associations among protein, drug, lncRNA, disease, and miRNA. Secondly, the Large-scale Information Network Embedding (LINE) model is used to learn behavior information (associations with other nodes) of drugs and proteins in the network. Hence, the known drug-protein interaction pairs can be represented as a combination of attribute information (e.g. protein sequences information and drug molecular fingerprints) and behavior information of themselves. Thirdly, the Random Forest classifier is used for training and prediction. RESULTS: In the results, under the five-fold cross validation, our method obtained 85.83% prediction accuracy with 80.47% sensitivity at the AUC of 92.33%. Moreover, in the case studies of three common drugs, the top 10 candidate targets have 8 (Caffeine), 7 (Clozapine) and 6 (Pioglitazone) are respectively verified to be associated with corresponding drugs. CONCLUSIONS: In short, these results indicate that our method can be a powerful tool for predicting potential drug-target interactions and finding unknown targets for certain drugs or unknown drugs for certain targets.

Placenta specific 8 gene induces epithelial-mesenchymal transition of nasopharyngeal carcinoma cells via the TGF-ß/Smad pathway.

The present study aimed to investigate the effects and mechanisms of PLAC8 on the epithelial-mesenchymal transition (EMT) of Nasopharyngeal carcinoma (NPC). The expression of PLAC8 in NPC and nasopharyngitis (NPG) tissues from 150 patients was determined using immunohistochemistry. The levels of PLAC8 in five NPC cell lines and nasopharyngeal permanent epithelial cell line were measured using western blotting. We then knocked out or overexpressed PLAC8 in CNE2 cells. Cell proliferation, wound healing, migration, and invasion assays were used to analyze the effects of PLAC8 on the proliferation, migration, and invasion in vivo and vitro. The results showed that the expression of PLAC8 was much higher in NPC tissues than in NPG tissues. The expression of PLAC8 was higher in all the cell lines than in the nasopharyngeal permanent epithelial cells. PLAC8 knockout resulted in significant decreases in cell proliferation, migration, and invasion; associated with lower protein levels of N-cadherin; and increased levels of E-cadherin. Overexpression of PLAC8 had the opposite effect. Furthermore, knockout of PLAC8 inactivated TGF-ß/SMAD signaling pathway and suppressed the growth of NPC xenografts. PLAC8 may promote the carcinogenesis and EMT of NPC via the TGF-ß/Smad pathway, which suggests that PLAC8 may be a potential biomarker for NPC.

Epistatic interaction between the lipase-encoding genes Pnpla2 and Lipe causes liposarcoma in mice.

Liposarcoma is an often fatal cancer of fat cells. Mechanisms of liposarcoma development are incompletely understood. The cleavage of fatty acids from acylglycerols (lipolysis) has been implicated in cancer. We generated mice with adipose tissue deficiency of two major enzymes of lipolysis, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), encoded respectively by Pnpla2 and Lipe. Adipocytes from double adipose knockout (DAKO) mice, deficient in both ATGL and HSL, showed near-complete deficiency of lipolysis. All DAKO mice developed liposarcoma between 11 and 14 months of age. No tumors occurred in single knockout or control mice. The transcriptome of DAKO adipose tissue showed marked differences from single knockout and normal controls as early as 3 months. Gpnmb and G0s2 were among the most highly dysregulated genes in premalignant and malignant DAKO adipose tissue, suggesting a potential utility as early markers of the disease. Similar changes of GPNMB and G0S2 expression were present in a human liposarcoma database. These results show that a previously-unknown, fully penetrant epistatic interaction between Pnpla2 and Lipe can cause liposarcoma in mice. DAKO mice provide a promising model for studying early premalignant changes that lead to late-onset malignant disease.

[Magnetic resonance-ultrasound fusion guided transperineal prostate biopsy for the diagnosis of prostate cancer].

OBJECTIVE: To investigate the application value of magnetic resonance-ultrasound fusion (MR-USF) guided transperineal prostate biopsy (TPPB) in the diagnosis of prostate cancer. METHODS: Relevant data were collected retrospectively from 77 patients undergoing MR-USF guided TPPB (n = 22) or 12-core systematic prostate biopsy (SPB) (n = 55) in Binhai People's Hospital from May to July 2019 and statistically analyzed using the software Graphad Prism 7.0 and SPSS 22.0. RESULTS: The patients were aged 51－91 (70.5 ± 9.7) years, with a mean PSA level of (35.1 ± 115.4) µg/L (1.02－959 µg/L) and an average prostate volume of (48.81 ± 38.4) cm3 (7.54－307.61 cm3). There were no statistically significant differences in age, PSA, and BMI between the two groups of patients (P > 0.05). Prostate cancer was confirmed in 31 of the cases, with a positive rate of 40.26% (31/77), significantly higher in the TPPB (45.45% ï¼»10/22ï¼½ than in the SPB group (38.18% ï¼»21/55ï¼½, P < 0.01). Based on the PI-RADS scores, the Gleason grade was also higher in the former than in the latter group. CONCLUSIONS: MR-USF guided TPPB can improve the biopsy performance. Whether it should be used is based on the patient's PSA level and PI-RADS scores.

BMAL1 Disrupted Intrinsic Diurnal Oscillation in Rat Cerebrovascular Contractility of Simulated Microgravity Rats by Altering Circadian Regulation of miR-103/CaV1.2 Signal Pathway.

The functional and structural adaptations in cerebral arteries could be one of the fundamental causes in the occurrence of orthostatic intolerance after space flight. In addition, emerging studies have found that many cardiovascular functions exhibit circadian rhythm. Several lines of evidence suggest that space flight might increase an astronaut's cardiovascular risks by disrupting circadian rhythm. However, it remains unknown whether microgravity disrupts the diurnal variation in vascular contractility and whether microgravity impacts on circadian clock system. Sprague-Dawley rats were subjected to 28-day hindlimb-unweighting to simulate the effects of microgravity on vasculature. Cerebrovascular contractility was estimated by investigating vasoconstrictor responsiveness and myogenic tone. The circadian regulation of CaV1.2 channel was determined by recording whole-cell currents, evaluating protein and mRNA expressions. Then the candidate miRNA in relation with Ca2+ signal was screened. Lastly, the underlying pathway involved in circadian regulation of cerebrovascular contractility was determined. The major findings of this study are: (1) The clock gene BMAL1 could induce the expression of miR-103, and in turn modulate the circadian regulation of CaV1.2 channel in rat cerebral arteries at post-transcriptional level; and (2) simulated microgravity disrupted intrinsic diurnal oscillation in rat cerebrovascular contractility by altering circadian regulation of BMAL1/miR-103/CaV1.2 signal pathway.