Ameliorating effect of Erxian decoction combined with Fructus Schisandrae chinensis (Wu Wei Zi) on menopausal sweating and serum hormone profiles in a rat model

Additional file 3. The animal studies were performed following the ARRIVE guideline

Fine Mapping of the NRG1 Hirschsprung's Disease Locus

The primary pathology of Hirschsprung's disease (HSCR, colon aganglionosis) is the absence of ganglia in variable lengths of the hindgut, resulting in functional obstruction. HSCR is attributed to a failure of migration of the enteric ganglion precursors along the developing gut. RET is a key regulator of the development of the enteric nervous system (ENS) and the major HSCR-causing gene. Yet the reduced penetrance of RET DNA HSCR-associated variants together with the phenotypic variability suggest the involvement of additional genes in the disease. Through a genome-wide association study, we uncovered a ∼350 kb HSCR-associated region encompassing part of the neuregulin-1 gene (NRG1). To identify the causal NRG1 variants contributing to HSCR, we genotyped 243 SNPs variants on 343 ethnic Chinese HSCR patients and 359 controls. Genotype analysis coupled with imputation narrowed down the HSCR-associated region to 21 kb, with four of the most associated SNPs (rs10088313, rs10094655, rs4624987, and rs3884552) mapping to the NRG1 promoter. We investigated whether there was correlation between the genotype at the rs10088313 locus and the amount of NRG1 expressed in human gut tissues (40 patients and 21 controls) and found differences in expression as a function of genotype. We also found significant differences in NRG1 expression levels between diseased and control individuals bearing the same rs10088313 risk genotype. This indicates that the effects of NRG1 common variants are likely to depend on other alleles or epigenetic factors present in the patients and would account for the variability in the genetic predisposition to HSCR

Sleep management on multiple machines for energy and flow time

In large data centers, determining the right number of operating servers is often non-trivial, especially when the workload is unpredictable. Using too many machines would waste energy, while using too few would affect the performance. This paper extends the traditional study of online flow-time scheduling on multiple machines to take sleep management and energy into consideration. Specifically, we study online algorithms that can determine dynamically when to wake up (or turn off) some of the machines and how to dispatch and schedule the jobs. The objective is to minimize the sum of flow time and energy. This paper presents two O(1)competitive algorithms, one for the model where machines running at a fixed speed, and the other allows dynamic speed scaling in each machine to further optimize energy usage. Like the previous work on the tradeoff between flow time and energy, the analysis of our algorithms is based on potential functions. What is new here is that the online and offline algorithms would use different subsets of machines at different times, and we need a more general potential analysis that can consider different match-ups of machines

The Dysregulation of MicroRNAs in the Development of Cervical Pre-Cancer—An Update

Globally in 2020, an estimated ~600,000 women were diagnosed with and 340,000 women died from cervical cancer. Compared to 2012, the number of cases increased by 7.5% and the number of deaths increased by 17%. MiRNAs are involved in multiple processes in the pathogenesis of cervical cancer. Dysregulation of miRNAs in the pre-stage of cervical cancer is the focus of this review. Here we summarize the dysregulated miRNAs in clinical samples from cervical pre-cancer patients and relate them to the early transformation process owing to human papillomavirus (HPV) infection in the cervical cells. When HPV infects the normal cervical cells, the DNA damage response is initiated with the involvement of HPV’s E1 and E2 proteins. Later, cell proliferation and cell death are affected by the E6 and E7 proteins. We find that the expressions of miRNAs in cervical pre-cancerous tissue revealed by different studies seldom agreed with each other. The discrepancy in sample types, samples’ HPV status, expression measurement, and methods for analysis contributed to the non-aligned results across studies. However, several miRNAs (miR-34a, miR-9, miR-21, miR-145, and miR-375) were found to be dysregulated across multiple studies. In addition, there are hints that the DNA damage response and cell growth response induced by HPV during the early transformation of the cervical cells are related to these miRNAs. Currently, no review articles analyse the relationship between the dysregulated miRNAs in cervical pre-cancerous tissue and their possible roles in the early processes involving HPV’s protein encoded by the early genes and DNA damage response during normal cell transformation. Our review provides insight on spotting miRNAs involved in the early pathogenic processes and pointing out their potential as biomarker targets of cervical pre-cancer

Analysis of Herbal Formulation in TCM: Infertility as a case study

Herbal prescription in Traditional Chinese Medicine (TCM) relies on the experience of the prescribing doctor after appropriate diagnosis. The combination of herbs chosen, though based on the various Classics, can vary between patients with the same diagnosis. Furthermore, the underlying principles for the choice of herbs are not well defined, and the actual formations can also vary from doctor to doctor. We believe that the prescriptions are the embodiment of the wisdom of the successful doctors, in the process of diagnosis and treatment. Thus it is important to extract the wisdom and discover the knowledge important to the understanding of TCM. The data mining technique employed for analysis here is the Qualitative Comparative Analysis (QCA). This particular analytical method is adopted from social science study, where it is a small-N analysis, meaning that case number is small relative the number of causal factors. The results of this study in the form of configurations indicate not only the herbs (present herbs) necessary for a positive outcome, but the choice of some other herbs (absent herbs) may impact negatively on the outcome

Effect of CKBM on prostate cancer cell growth in vitro and in vivo

Prostate carcinoma and metastasis are common among male subjects worldwide. CKBM is a drug product targeting prostate cancer in multiple ways. Prostate cancer cell lines PC3 and DU145 were treated with CKBM. The effect of CKBM on the cell's viability, cell cycle, adhesive and invasive properties and its growth in an animal model were assessed. Results indicated that CKBM inhibited PC3 and DU145 cell growth in vitro at IC50 values 3.923 and 4.697\% respectively, and it brought about cell cycle arrest at G2/M phase. CKBM also attenuated DU145 cells to invade and adhere to extracellular matrices including Matrigel, laminin, fibronectin and collagen IV. Moreover, PC3 tumor xenograft growth was inhibited by over 60\% after 28-day of 0.2, 0.4 or 0.8 ml/day CKBM treatment. The present study indicates that CKBM is effective against prostate cancer cell growth in vitro and in vivo. Further studies are required to elucidate its mechanism of action

Characterization of miR-200 family members as blood biomarkers for human and laying hen ovarian cancer

MicroRNA-200 (miR-200) family is highly expressed in ovarian cancer. We evaluated the levels of family members relative to the internal control miR-103a in ovarian cancer and control blood specimens collected from American and Hong Kong Chinese institutions, as well as from a laying hen spontaneous ovarian cancer model. The levels of miR-200a, miR-200b and miR-200c were significantly elevated in all human cancer versus all control blood samples. Further analyses showed significantly higher miR-200 levels in Chinese control (except miR-429) and cancer (except miR-200a and miR141) samples than their respective American counterparts. Subtype-specific analysis showed that miR-200b had an overall elevated level in serous cancer compared with controls, whereas miR-429 was significantly elevated in clear cell and endometrioid cancer versus controls. MiR-429 was also significantly elevated in cancer versus control in laying hen plasma samples, consistent with the fact that endometrioid tumor is the prevalent type in this species. A neural network model consisting of miR-200a/200b/429/141 showed an area under the curve (AUC) value of 0.904 for American ovarian cancer prediction, whereas a model consisting of miR-200b/200c/429/141 showed an AUC value of 0.901 for Chinese women. Hence, miR-200 is informative as blood biomarkers for both human and laying hen ovarian cancer

Vitamin D3 and carbamazepine protect against Clostridioides difficile infection in mice by restoring macrophage lysosome acidification

Clostridioides difficile infection (CDI) is a common cause of nosocomial diarrhea. TcdB is a major C. difficile exotoxin that activates macrophages to promote inflammation and epithelial damage. Lysosome impairment is a known trigger for inflammation. Herein, we hypothesize that TcdB could impair macrophage lysosomal function to mediate inflammation during CDI. Effects of TcdB on lysosomal function and the downstream pro-inflammatory SQSTM1/p62-NFKB (nuclear factor kappa B) signaling were assessed in cultured macrophages and in a murine CDI model. Protective effects of two lysosome activators (i.e., vitamin D3 and carbamazepine) were assessed. Results showed that TcdB inhibited CTNNB1/β-catenin activity to downregulate MITF (melanocyte inducing transcription factor) and its direct target genes encoding components of lysosomal membrane vacuolar-type ATPase, thereby suppressing lysosome acidification in macrophages. The resulting lysosomal dysfunction then impaired autophagic flux and activated SQSTM1-NFKB signaling to drive the expression of IL1B/IL-1β (interleukin 1 beta), IL8 and CXCL2 (chemokine (C-X-C motif) ligand 2). Restoring MITF function by enforced MITF expression or restoring lysosome acidification with 1α,25-dihydroxyvitamin D3 or carbamazepine suppressed pro-inflammatory cytokine expression in vitro. In mice, gavage with TcdB-hyperproducing C. difficile or injection of TcdB into ligated colon segments caused prominent MITF downregulation in macrophages. Vitamin D3 and carbamazepine lessened TcdB-induced lysosomal dysfunction, inflammation and histological damage. In conclusion, TcdB inhibits the CTNNB1-MITF axis to suppress lysosome acidification and activates the downstream SQSTM1-NFKB signaling in macrophages during CDI. Vitamin D3 and carbamazepine protect against CDI by restoring MITF expression and lysosomal function in mice. Abbreviations: ATP6V0B: ATPase H+ transporting V0 subunit b; ATP6V0C: ATPase H+ transporting V0 subunit c; ATP6V0E1: ATPase H+ transporting V0 subunit e1; ATP6V1H: ATPase H+ transporting V1 subunit H; CBZ: carbamazepine; CDI: C. difficile infection; CXCL: chemokine C-X-X motif ligand; IL: interleukin; LAMP1: lysosomal-associated membrane protein 1; LC3: microtubule-associated protein 1 light chain 3; LEF: lymphoid enhancer binding factor 1; MITF: melanocyte inducing transcription factor; NFKB: nuclear factor kappa B; PMA: phorbol 12-myristate 13-acetate; TcdA: Clostridial toxin A; TcdB: Clostridial toxin B; TFE3: transcription factor E3; TFEB: transcription factor EB.Published versionThis work was supported by the National Natural Science Foundation of China [82070576] and the Hong Kong Food and Health Bureau (FHB) Commissioned Health and Medical Research Fund [CID-CUHK-C]