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Abstract Background Only limited data are available regarding postural stability between anterior cruciate ligament (ACL)-injured patients with medial meniscus (MM) tear and those with lateral meniscus (LM) tear. The purpose of this study was to compare preoperative postural stability for both involved and uninvolved knees in ACL rupture combined with MM and LM tears. It was hypothesized that there would be a significant difference in postural stability between these two groups. Methods Ninety-three ACL-injured patients (53 combined with MM tears vs. 40 combined with LM tears) were included. Static and dynamic postural stability were evaluated with the overall stability index (OSI), anterior–posterior stability index (APSI), and medial–lateral stability index (MLSI) using stabilometry. Knee muscle strength was evaluated using an isokinetic testing device. Results In the static postural stability test, none of the stability indices showed significant differences between the two groups for both knees (p > 0.05). In the dynamic postural stability test for involved side knees, the OSI and APSI were significantly higher in the LM tear group compared to the MM tear group (OSI: 2.0 ± 0.8 vs. 1.6 ± 0.5, p = 0.001; APSI: 1.5 ± 0.6 vs. 1.3 ± 0.5, p = 0.023), but not the MLSI (p > 0.05). In the static and dynamic postural stability tests in each group, there were no significant differences between the involved and uninvolved side knees (p > 0.05). There was no significant difference in the knee muscle strength between the two groups (p > 0.05). All postural stability showed no significant correlation with knee muscle strength (p > 0.05). Conclusion Dynamic postural stability was poorer in patients with ACL rupture combined with LM tear than in those with MM tear. Therefore, close monitoring for postural stability would be necessary during preoperative and postoperative rehabilitation, especially for patients with ACL rupture combined with LM tear. Level of evidence: Level III

This study presents the most comprehensive machine-learning analysis for the predictors of blood transfusion, all-cause mortality, and hospitalization period in COVID-19 patients. Data came from Korea National Health Insurance claims data with 7943 COVID-19 patients diagnosed during November 2019–May 2020. The dependent variables were all-cause mortality and the hospitalization period, and their 28 independent variables were considered. Random forest variable importance (GINI) was introduced for identifying the main factors of the dependent variables and evaluating their associations with these predictors, including blood transfusion. Based on the results of this study, blood transfusion had a positive association with all-cause mortality. The proportions of red blood cell, platelet, fresh frozen plasma, and cryoprecipitate transfusions were significantly higher in those with death than in those without death (p-values < 0.01). Likewise, the top ten factors of all-cause mortality based on random forest variable importance were the Charlson Comorbidity Index (53.54), age (45.68), socioeconomic status (45.65), red blood cell transfusion (27.08), dementia (19.27), antiplatelet (16.81), gender (14.60), diabetes mellitus (13.00), liver disease (11.19) and platelet transfusion (10.11). The top ten predictors of the hospitalization period were the Charlson Comorbidity Index, socioeconomic status, dementia, age, gender, hemiplegia, antiplatelet, diabetes mellitus, liver disease, and cardiovascular disease. In conclusion, comorbidity, red blood cell transfusion, and platelet transfusion were the major factors of all-cause mortality based on machine learning analysis. The effective management of these predictors is needed in COVID-19 patients.

Drug repositioning, which involves the identification of new therapeutic indications for approved drugs, considerably reduces the time and cost of developing new drugs. Recent computational drug repositioning methods use heterogeneous networks to identify drug–disease associations. This review reveals existing network-based approaches for predicting drug–disease associations in three major categories: graph mining, matrix factorization or completion, and deep learning. We selected eleven methods from the three categories to compare their predictive performances. The experiment was conducted using two uniform datasets on the drug and disease sides, separately. We constructed heterogeneous networks using drug–drug similarities based on chemical structures and ATC codes, ontology-based disease–disease similarities, and drug–disease associations. An improved evaluation metric was used to reflect data imbalance as positive associations are typically sparse. The prediction results demonstrated that methods in the graph mining and matrix factorization or completion categories performed well in the overall assessment. Furthermore, prediction on the drug side had higher accuracy than on the disease side. Selecting and integrating informative drug features in drug–drug similarity measurement are crucial for improving disease-side prediction.

The gene encoding Thermus caldophilus GK24 (Tca) DNA polymerase was cloned into Escherichia coli using the structural gene coding for Thermus aquaticus YT-l (Taq) DNA polymerase as a hybridization probe. The nucleotide sequence of the cloned DNA was determined. The primary structure of the Tca DNA polymerase was deduced from the nucleotide sequence. The Tca DNA polymerase comprised 834 amino acid residues and its molecular mass was determined to be 93,810. On alignment of the whole amino acid sequence, Tca DNA polymerase showed a high sequence homology with the E. coli DNA polymerase I-like DNA polymerases, and 86% identity with Taq DNA polymerase, 38% with E. coli and Streptococcus pneumoniae (Spn) DNA polymerase I. An extremely high sequence identity was observed in the region containing the polymerase activity. The codon usage in the Tca DNA polymerase gene was in fact similar to the characteristic usages in the genes for proteins from bacteria of genus Thermus: the G+ C content in the third position of the codons was as high as 93 %. The Tca DNA polymerase gene was expressed under the control of tac promoter on a high copy plasmid, pTCA in E. coli. [ABSTRACT FROM AUTHOR]

Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, primarily caused by germline mutation of PKD1 or PKD2, leading to end-stage renal disease. The Hippo signaling pathway regulates organ growth and cell proliferation. Herein, we demonstrate the regulatory mechanism of cystogenesis in ADPKD by transcriptional coactivator with PDZbinding motif (TAZ), a Hippo signaling effector. TAZ was highly expressed around the renal cyst-lining epithelial cells of Pkd1- deficient mice. Loss of Taz in Pkd1-deficient mice reduced cyst formation. In wild type, TAZ interacted with PKD1, which inactivated β-catenin. In contrast, in PKD1-deficient cells, TAZ interacted with AXIN1, thus increasing β-catenin activity. Interaction of TAZ with AXIN1 in PKD1-deficient cells resulted in nuclear accumulation of TAZ together with β-catenin, which up-regulated c-MYC expression. Our findings suggest that the PKD1-TAZ-Wnt-β-catenin- c-MYC signaling axis plays a critical role in cystogenesis and might be a potential therapeutic target against ADPKD. [ABSTRACT FROM AUTHOR]

Cells sense mechanical force and their physical environment to change their fate and behavior through mechanotransduction. The mechanotransduction is, by translating mechanical forces and deformations into biochemical intracellular signaling, changing gene expressions and adjusting cellular and extracellular structure. Given that mechanosensitive signaling modulates cellular functions as diverse as proliferation and differentiation, such signaling is crucial for normal tissue development and homeostasis. Here we review current evidence for the mechanical regulation of cell differentiation, specifically in musculoskeletal tissues, such as skeletal muscle, fat, bone, and cartilage.

Tamoxifen resistance is often observed in the majority of estrogen receptor-positive breast cancers and it remains as a serious clinical problem in breast cancer management. Increased aerobic glycolysis has been proposed as one of the mechanisms for acquired resistance to chemotherapeutic agents in breast cancer cells such as adriamycin. Herein, we report that the glycolysis rates in LCC2 and LCC9--tamoxifen-resistant human breast cancer cell lines derived from MCF7--are higher than those in MCF7S, which is the parent MCF7 subline. Inhibition of key glycolytic enzyme such as hexokinase-2 resulted in cell growth retardation at higher degree in LCC2 and LCC9 than that in MCF7S. This implies that increased aerobic glycolysis even under O2-rich conditions, a phenomenon known as the Warburg effect, is closely associated with tamoxifen resistance. We found that HIF-1α is activated via an Akt/mTOR signaling pathway in LCC2 and LCC9 cells without hypoxic condition. Importantly, specific inhibition of hexokinase-2 suppressed the activity of Akt/mTOR/HIF-1α axis in LCC2 and LCC9 cells. In addition, the phosphorylated AMPK which is a negative regulator of mTOR was decreased in LCC2 and LCC9 cells compared to MCF7S. Interestingly, either the inhibition of mTOR activity or increase in AMPK activity induced a reduction in lactate accumulation and cell survival in the LCC2 and LCC9 cells. Taken together, our data provide evidence that development of tamoxifen resistance may be driven by HIF-1α hyperactivation via modulation of Akt/mTOR and/or AMPK signaling pathways. Therefore, we suggest that the HIF-1α hyperactivation is a critical marker of increased aerobic glycolysis in accordance with tamoxifen resistance and thus restoration of aerobic glycolysis may be novel therapeutic target for treatment of tamoxifen-resistant breast cancer.

Human breast cancers include cancer stem cell populations as well as nontumorigenic cancer cells. Breast cancer stem cells have self-renewal capability and are resistant to conventional chemotherapy. miRNAs regulate the expression of many target genes; therefore, dysregulation of miRNAs has been associated with the pathogenesis of human diseases, including cancer. However, a role for miRNA dysregulation in stemness and drug resistance has yet to be identified. Members of the miR34 family are reportedly tumor-suppressor miRNAs and are associated with various human cancers. Our results confirm that miR34a expression was downregulated in MCF7/ADR cells compared with MCF7 cells. We hypothesized that this reduction was due to the p53 (TP53) mutation in MCF7/ ADRcells. In this study, we found that primary andmature miR34a were suppressed by treatment with p53 RNAi or the dominant-negative p53 mutant in MCF7 cells. Ectopic miR34a expression reduced cancer stemcell properties and increased sensitivity to doxorubicin treatment by directly targetingNOTCH1. Furthermore, tumors from nude mice treated with miR34a were significantly smaller compared with those of mice treated with control lentivirus. Our research suggests that the ectopic expression of miR34a represents a novel therapeutic approach in chemoresistant breast cancer treatment. [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder. Although a myriad of research groups have attempted to identify a new therapeutic target for AD PKD, no drug has worked well in clinical trials. Our research group has focused on the receptor for advanced glycation end products (RAGE) gene as a novel target for ADPKD. This gene is involved in inflammation and cell proliferation. We have already confirmed that blocking RAGE function attenuates cyst growth in vitro. Based on this previous investigation, our group examined the effect of RAGE on cyst enlargement in vivo. PC2R mice, a severe ADPKD mouse model that we generated, were utilized. An adenovirus containing anti-RAGE shRNA was injected intravenously into this model. We observed that RAGE gene knockdown resulted in loss of kidney weight and volume. Additionally, the cystic area that originated from different nephron segments decreased in size because of down-regulation of the RAGE gene. Blood urea nitrogen and creatinine values tended to be lower after inhibiting RAGE. Based on these results, we confirmed that the RAGE gene could be an effective target for ADPKD treatment. [ABSTRACT FROM AUTHOR]

Mutations in the SO42-/Cl- /OH- exchanger Slc26a2 cause the disease diastrophic dysplasia (DTD), resulting in aberrant bone development and, therefore, skeletal deformities. DTD is commonly attributed to a lack of chondrocyte SO42- uptake and proteoglycan sulfation. However, the skeletal phenotype of patients with DTD is typified by reduction in cartilage and osteoporosis of the long bones. Chondrocytes of patients with DTD are irregular in size and have a reduced capacity for proliferation and terminal differentiation. This raises the possibility of additional roles for Slc26a2 in chondrocyte function. Here, we examined the roles of Slc26a2 in chondrocyte biology using two distinct systems: mouse progenitor mesenchymal cells differentiated to chondrocytes and freshly isolated mouse articular chondrocytes differentiated into hypertrophic chondrocytes. Slc26a2 expression was manipulated acutely by delivery of Slc26a2 or shSlc26a2 with lentiviral vectors. We demonstrate that slc26a2 is essential for chondrocyte proliferation and differentiation and for proteoglycan synthesis. Slc26a2 also regulates the terminal stage of chondrocyte cell size expansion. These findings reveal multiple roles for Slc26a2 in chondrocyte biology and emphasize the importance of Slc26a2-mediated protein sulfation in cell signaling, which may account for the complex phenotype of DTD. [ABSTRACT FROM AUTHOR]

Cilia in ciliated cells consist of protruding structures that sense mechanical and chemical signals from the extracellular environment. Cilia are assembled with variety molecules via a process known as intraflagellar transport (IFT). What controls the length of cilia in ciliated cells is critical to understand ciliary disease such as autosomal dominant polycystic kidney disease, which involves abnormally short cilia. But this control mechanism is not well understood. Previously, multiple tubular cysts have been observed in the kidneys of max-interacting protein 1 (Mxi1)-deficient mice aged 6 months or more. Here, we clarified the relationship between Mxi1 inactivation and cilia disassembly. Cilia phenotypes were observed in kidneys of Mxi1-deficient mice using scanning electron microscopy to elucidate the effect of Mxi1 on renal cilia phenotype, and cilia disassembly was observed in Mxi1-deficient kidney. In addition, genes related to cilia were validated in vitro and in vivo using quantitative PCR, and Ift20 was selected as a candidate gene in this study. The length of cilium decreased, and p-ERK level induced by a cilia defect increased in kidneys of Mxi1-deficient mice. Ciliogenesis of Mxi1-deficient mouse embryonic fibroblasts (MEFs) decreased, and this abnormality was restored by Mxi1 transfection in Mxi1-deficient MEFs.We confirmed that ciliogenesis and Ift20 expression were regulated by Mxi1 in vitro. Wealso determined that Mxi1 regulates Ift20 promoter activity via Ets-1 binding to the Ift20 promoter. These results indicate that inactivating Mxi1 induces ciliary defects in polycystic kidney. [ABSTRACT FROM AUTHOR]

The pathogenic mechanisms of human autosomal dominant polycystic kidney disease (ADPKD) have been well known to include the mutational inactivation of PKD2. Although haploinsufficiency and loss of heterozygosity at the Pkd2 locus can cause cyst formation in mice, polycystin-2 is frequently expressed in the renal cyst of human ADPKD, raising the possibility that deregulated activation of PKD2 may be associated with the cystogenesis of human ADPKD. To deter- mine whether increased PKD2 expression is physiologically pathogenic, we generated PKD2-overexpressing transgenic mice. These mice developed typical renal cysts and an increase of proliferation and apoptosis, which are reflective of the human ADPKD phenotype. These manifestations were first observed at six months, and progressed with age. In addition, we found that ERK activation was induced by PKD2 overexpression via B-Raf signaling, providing a possible molecular mechanism of cystogenesis. In PKD2 transgenic mice, B-Raf/MEK/ERK sequential signaling was up-regulated. Additionally, the transgenic human polycystin-2 partially rescues the lethality of Pkd2 knock-out mice and therefore demonstrates that the transgene generated a functional product. Functional strengthening or deregulated activation of PKD2 may be a direct cause of ADPKD. The present study provides evidence for an in vivo role of overexpressed PKD2 in cyst formation. This transgenic mouse model should pro- vide new insights into the pathogenic mechanism of human ADPKD. [ABSTRACT FROM AUTHOR]

Cdt1, a protein essential in G1 for licensing of origins for DNA replication, is inhibited in S-phase, both by binding to geminin and degradation by proteasomes. Cdt1 is also degraded after DNA damage to stop licensing of new origins until after DNA repair. Phosphorylation of Cdt1 by cyclin-dependent kinases promotes its binding to SCF-Skp2 E3 ubiquitin ligase, but the Cdk2/Skp2-mediated pathway is not essential for the degradation of Cdt1. Here we show that the N terminus of Cdt1 contains a second degradation signal that is active after DNA damage and in S-phase and is dependent on the interaction of Cdt1 with proliferating cell nuclear antigen (PCNA) through a PCNA binding motif. The degradation involves N-terminal ubiquitination and requires Cul4 and Ddb1 proteins, components of an E3 ubiquitin ligase implicated in protein degradation after DNA damage. Therefore PCNA, the matchmaker for many proteins involved in DNA and chromatin metabolism, also serves to promote the targeted degradation of associated proteins in S-phase or after DNA damage. [ABSTRACT FROM AUTHOR]

A novel method for the synthesis of cyclic peptide analogues has been developed. The general approach relies on the use of SET-promoted photocyclization reactions of peptides that contain N-terminal phthalimides as light absorbing electron acceptor moieties and C-terminal α-amidosilane or α-amidocarboxylate centers. Prototypical substrates are prepared by coupling preformed peptides with the acid chloride of N-phthalimidoglycine. Irradiation of these substrates results in the generation of cyclic peptide analogues in modest to good yields. The chemical efficiencies of these processes are not significantly affected by (1) the lengths of the peptide chains separating the phthalimide and α-amidosilane or α-amidocarboxylate centers and (2) the nature of the penultimate cation radical α-heterolytic fragmentation process (i.e., desilylation vs decarboxylation). An evaluation of the effects of N-alkyl substitution on the amide residues in the peptide chain showed that N-alkyl substitution does not have a major impact on the efficiencies of the photocyclization reactions but that it profoundly increases the stability of the cyclic peptide. [ABSTRACT FROM AUTHOR]

Presents information stating that autosomal dominant polycystic kidney disease is caused by germline mutations in PKD2. Information on the analysis of the WS25 Pkd2 mutant allele; Details on kidney cysts in WS25 Pkd mutant mice; Indepth look at the loss of polycystin-2 expression which leads to cyst formation; More information on germline mutation in PKD2 which relates to kidney disease.