TOPOLOGY, ANALYSIS, AND CMOS IMPLEMENTATION OF SWITCHED-CAPACITOR DC-DC CONVERTERS

This review highlights various design and realization aspects of three commonly used charge pump topologies, namely, the linear, exponential, and the Fibonacci type of charge pumps. We shall outline the new methods developed recently for analyzing the steady and dynamic performances of these circuits. Some practical issues for the CMOS implementation of these charge pump structures will be critically discussed. Finally, some conventional voltage regulation methods for maintaining a stable output under a large range of loading current and supply voltage fluctuations will be proposed

Hugus 哈格斯

Hugus is a pair of fluffy dolls designed for two parties who need to spend extended time periods separated by distance. Each of the parties owns one of the dolls. To connect the Hugus, all the parties have to do is to link up their smartphones with the Hugus App via Bluetooth, and set up a reunion date with a pairing code... 哈格斯是一對兩隻的毛毛玩偶，專為長期分隔異地的人而設計。二人雙方各擁一隻哈格斯玩偶，以智能手機透過藍芽接入哈格斯應用程式，再以配對碼設定相聚的日期，就能連結彼此的哈格斯... Award: Merit奬項: 優異

Trends in gender of authors of original research in oncology among major medical journals: a retrospective bibliometric study

MALF was supported by the Spanish National Health Institute Carlos III (Instituto de Salud Carlos III -ISCIII), Miguel Servet--I Investigator Grant/Award Number CP17/00206--EU--FEDER.Objective We evaluated the temporal trend in gender ratios of first and last authors in the field of oncological research published in major general medical and oncology journals and examined the gender pattern in coauthorship. Design We conducted a retrospective study in PubMed using the R package RISmed. We retrieved original research articles published in four general medical journals and six oncology specialty journals. These journals were selected based on their impact factors and popularity among oncologists. We identified the names of first and last authors from 1 January 2002 to 31 December 2019. The gender of the authors was identified and validated using the Gender API database (https:// gender-​api. com/). Primary and secondary outcome measures The percentages of first and last authors by gender and the gender ratios (male to female) and temporal trends in gender ratios of first and last authors were determined. Results We identified 34 624 research articles, in which 32 452 had the gender of both first and last authors identified. Among these 11 650 (33.6%) had women as the first author and 7908 (22.8%) as the last author, respectively. The proportion of female first and last authors increased from 26.6% and 16.2% in 2002, to 32.9% and 27.5% in 2019, respectively. However, the gender ratio (male to female) of first and last authors decreased by 1.5% and 2.6% per year, respectively, which were statistically significant (first author: incidence rate ratio (IRR) 0.98, 95% CI 0.97 to 1.00; last author: IRR 0.97, 95% CI 0.96 to 0.99). Male first and last authorship was the most common combination. Male–female and female– female pairs increased by 2.0% and 5.0%, respectively (IRR 1.02, 95% CI 1.01 to 1.03 and IRR 1.05, 95% CI 1.04 to 1.06, respectively). Conclusions The continued under-representation of women means that more efforts to address parity for advancement of women in academic oncology are needed.Spanish National Health Institute Carlos III (Instituto de Salud Carlos III -ISCIII) CP17/00206--EU--FEDE

ITGAM is associated with disease susceptibility and renal nephritis of systemic lupus erythematosus in Hong Kong Chinese and Thai

ITGAM was recently found to be associated with systemic lupus erythematosus (SLE) in populations of not only European ancestry, but also in Hispanic- and African-Americans, Mexicans and Colombians. The risk alleles in the gene, however, were found to be monomorphic in two Asian populations examined: Japanese and Korean. In this study, using a collection of 910 SLE patients and 2360 controls from Chinese living in Hong Kong, analyzed by both genome-wide association and direct sequencing, we confirmed the association of the same risk alleles in ITGAM with the disease. These findings were further replicated in the Thai population with 278 patients and 383 ethnicity- and geography-matched controls. Subphenotype stratification analyses showed significantly more involvement of the gene in patients with renal nephritis and neurological disorders. Although our results support a pivotal role by rs1143679 (R77H) in disease association, our data also suggests an additional contribution from rs1143683, another non-synonymous polymorphism in this gene (A858V). Therefore, despite the low-allele frequencies of the risk alleles of the gene in our two Asian populations, ITGAM was confirmed to be a risk factor related to disease susceptibility and probably severe manifestations of SLE

The effects of a mindfulness-based family psychoeducation intervention for the caregivers of young adults with first-episode psychosis: A randomized controlled trial

Objective: In this study, we investigated the effects of a mindfulness-based family psychoeducation (MBFPE) program on the mental-health outcomes of both caregivers and young adults with first-episode psychosis with an onset in the past three years through a multi-site randomized controlled trial. We also studied the outcomes of three potential mediating effects of interpersonal mindfulness, expressed emotions, and non-attachment on the program. Method: We randomly assigned 65 caregivers of young adults with psychosis to MBFPE (n = 33) or an ordinary family psychoeducation (FPE) program (n = 32); among them, 18 young adults in recovery also participated in the evaluation of outcomes. Results: Intent-to-treat analyses were conducted. No significant time × group interaction effects of MBFPE and FPE programs were found in any of the caregivers’ outcomes. However, the young adults with psychosis reported higher levels of recovery after the MBFPE program than after the ordinary FPE program (F = 8.268, p = 0.012, d = 1.484). They also reported a larger reduction in over-involvement of their caregivers (F = 4.846, p = 0.044, d = 1.136), showing that MBFPE had a superior effect to FPE in promoting recovery and reducing over-involvement. Conclusions: A brief psychoeducation program may not reduce the burden on or improve the mental-health outcome of caregivers of individuals with recent-onset psychosis. However, integrating mindfulness into a conventional family psychoeducation program may reduce the expressed emotions of caregivers, especially over-involvement. Further studies should explore how psychoeducation programs can reduce the impact of psychosis on family through sustainable effects in terms of reducing their burden and expressed emotions, using a rigorous study and adequate sample size

Transcriptional Repressive H3K9 and H3K27 Methylations Contribute to DNMT1-Mediated DNA Methylation Recovery

DNA methylation and histone modifications are two major epigenetic events regulating gene expression and chromatin structure, and their alterations are linked to human carcinogenesis. DNA methylation plays an important role in tumor suppressor gene inactivation, and can be revised by DNA methylation inhibitors. The reversible nature of DNA methylation forms the basis of epigenetic cancer therapy. However, it has been reported that DNA re-methylation and gene re-silencing could occur after removal of demethylation treatment and this may significantly hamper the therapeutic value of DNA methylation inhibitors. In this study we have provided detailed evidence demonstrating that mammalian cells possess a bona fide DNA methylation recovery system. We have also shown that DNA methylation recovery was mediated by the major human DNA methyltransferase, DNMT1. In addition, we found that H3K9-tri-methylation and H3K27-tri-methylation were closely associated with this DNA methylation recovery. These persistent transcriptional repressive histone modifications may have a crucial role in regulating DNMT1-mediated DNA methylation recovery. Our findings may have important implications towards a better understanding of epigenetic regulation and future development of epigenetic therapeutic intervention

Nuclear-Targeted Deleted in Liver Cancer 1 (DLC1) Is Less Efficient in Exerting Its Tumor Suppressive Activity Both In Vitro and In Vivo

BACKGROUND: Deleted in liver cancer 1 (DLC1) serves as an important RhoGTPase activating protein (RhoGAP) protein that terminates active RhoA signaling in human cancers. Increasing evidence has demonstrated that the tumor suppressive activity of DLC1 depends not only on RhoGAP activity, but also relies on proper focal adhesion localization through its interaction with tensin family proteins. Recently, there are reports showing that DLC1 can also be found in the nucleus; however, the existence and the relative tumor suppressive activity of nuclear DLC1 have never been clearly addressed. METHODOLOGY AND PRINCIPAL FINDINGS: We herein provide new evidence that DLC1 protein, which predominantly associated with focal adhesions and localized in cytosol, dynamically shuttled between cytoplasm and nucleus. Treatment of cells with nuclear export blocker, Leptomycin B (LMB), retained DLC1 in the nucleus. To understand the nuclear entry of DLC1, we identified amino acids 600-700 of DLC1 as a novel region that is important for its nuclear localization. The tumor suppressive activity of nuclear DLC1 was directly assessed by employing a nuclear localization signal (NLS) fusion variant of DLC1 (NLS-DLC1) with preferential nuclear localization. In SMMC-7721 HCC cells, expression of NLS-DLC1 failed to suppress colony formation and actin stress fiber formation in vitro. The abrogated tumor suppressive activity of nuclear DLC1 was demonstrated for the first time in vivo by subcutaneously injecting p53(-/-) RasV12 hepatoblasts with stable NLS-DLC1 expression in nude mice. The injected hepatoblasts with NLS-DLC1 expression effectively formed tumors when compared with the non-nuclear targeted DLC1. CONCLUSIONS/SIGNIFICANCE: Our study identified a novel region responsible for the nuclear entry of DLC1 and demonstrated the functional difference of DLC1 in different cellular compartments both in vitro and in vivo

Upregulation of the Wnt Co-Receptor LRP6 Promotes Hepatocarcinogenesis and Enhances Cell Invasion

Background: Activation of the Wnt/b-catenin signaling pathway plays a crucial role in hepatocellular carcinoma (HCC). Lowdensity lipoprotein (LDL) receptor-related protein-6 (LRP6) is one of the co-receptors of the Wnt/b-catenin pathway and forms a signaling complex with Wnt ligand and Frizzled receptor to activate downstream signaling. However, the role of LRP6 in hepatocarcinogenesis is unclear. In this study, we examined its expression and roles in human HCC. Methodology/Principal Findings: Using real-time quantitative RT-PCR, we found that LRP6 was frequently (45%) overexpressed in human HCCs (P = 0.003). In vitro studies showed that ectopic expression of LRP6 increased the protein level of b-catenin. Moreover, overexpression of the full-length and constitutively active LRP6, respectively, activated the WNT/b-catenin signaling pathway, as shown by the TCF/b-catenin reporter assay. With regard to the effects of LRP6 overexpression in HCC cells, stable overexpression of the constitutively active LRP6 in BEL-7402 HCC cells enhanced cell proliferation, cell migration, and invasion in vitro as well as tumorigenicity in nude mice. Conclusions/Significance: Our findings indicate that overexpression of LRP6 contributes to the hyperactivation of the Wnt

Genome-Wide Association Study in Asian Populations Identifies Variants in ETS1 and WDFY4 Associated with Systemic Lupus Erythematosus

Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33×10−11, OR = 1.29; WDFY4: rs7097397, P = 8.15×10−12, OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3′-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved

Deleted in Liver Cancer 1 (DLC1) Negatively Regulates Rho/ROCK/MLC Pathway in Hepatocellular Carcinoma

Aims: Deleted in liver cancer 1 (DLC1), a member of RhoGTPase activating protein (GAP) family, is known to have suppressive activities in tumorigenicity and cancer metastasis. However, the underlying molecular mechanisms of how DLC1 suppresses cell motility have not been fully elucidated. Rho-kinase (ROCK) is an immediate down-stream effector of RhoA in mediating cellular cytoskeletal events and cell motility. In the present study, we aimed to investigate the effects of DLC1 on Rho/ROCK signaling pathway in hepatocellular carcinoma (HCC). Methodology/Principal Findings: We demonstrated that DLC1 negatively regulated ROCK-dependent actomyosin contractility. From immumofluorescence study, we found that ectopic expression of DLC1 abrogated Rho/ROCK-mediated cytoskeletal reorganization including formation of stress fibers and focal adhesions. It also downregulated cortical phosphorylation of myosin light chain 2 (MLC2). These inhibitory events by DLC1 were RhoGAP-dependent, as RhoGAP-deficient mutant of DLC1 (DLC1 K714E) abolished these inhibitory events. In addition, from western study, DLC1 inhibited ROCK-related myosin light chain phosphatase targeting unit 1 (MYPT1) phosphorylation at Threonine 853. By examining cell morphology under microscope, we found that ectopic expression of dominant-active ROCK released cells from DLC1-induced cytoskeletal collapse and cell shrinkage. Conclusion: Our data suggest that DLC1 negatively regulates Rho/ROCK/ MLC2. This implicates a ROCK-mediated pathway of DLC1 in suppressing metastasis of HCC cells and enriches our understanding in the molecular mechanisms involved in the progression of hepatocellular carcinoma. © 2008 Wong et al.published_or_final_versio