Role of Duplicate Genes in Robustness against Deleterious Human Mutations

It is now widely recognized that robustness is an inherent property of biological systems [1],[2],[3]. The contribution of close sequence homologs to genetic robustness against null mutations has been previously demonstrated in simple organisms [4],[5]. In this paper we investigate in detail the contribution of gene duplicates to back-up against deleterious human mutations. Our analysis demonstrates that the functional compensation by close homologs may play an important role in human genetic disease. Genes with a 90% sequence identity homolog are about 3 times less likely to harbor known disease mutations compared to genes with remote homologs. Moreover, close duplicates affect the phenotypic consequences of deleterious mutations by making a decrease in life expectancy significantly less likely. We also demonstrate that similarity of expression profiles across tissues significantly increases the likelihood of functional compensation by homologs

Effects of Acute Exercise Duration on the Inhibition Aspect of Executive Function in Late Middle-Aged Adults

Objective: This study investigated whether acute exercise duration affects inhibition in late middle-aged adults. Methods: Over four separate days, 40 late middle-aged adults completed, in a counterbalanced order, three exercise sessions consisting of single bouts of moderateto-vigorous intensity cycling, with the main acute exercise durations being 10, 20, and 45 min, and a control session consisting of 30 min of reading. Their inhibition performance was then evaluated by administration of the Stroop test following each session. Results: The participants had shorter mean response times for both the congruent and neutral conditions of the Stroop following the acute exercise lasting 20 min than they did after the control session. The acute exercise lasting 20 min also resulted in shorter response times for both conditions of the Stroop than the acute exercise lasting only 10 min. Meanwhile, the acute exercise lasting 45 min resulted in a shorter mean response time for the neutral Stroop condition than did the control session. Finally, the acute exercise lasting 20 min resulted in the shortest mean response time of all four sessions for the Stroop incongruent condition. Conclusion: The above findings suggest that the moderate-to-vigorous intensity acute exerciselasting20minfacilitatedmultiplecognitivefunctiondomainsingeneral,whereas the exercise sessions of shorter and longer duration had negligible effects on executive function in the late middle-aged adults. These results highlight the need to consider the duration of any moderate-to-vigorous intensity exercise when developing acute exercise programs to facilitate executive function in aged population

Basement membrane components are key players in specialized extracellular matrices

More than three decades ago, basement membranes (BMs) were described as membrane-like structures capable of isolating a cell from and connecting a cell to its environment. Since this time, it has been revealed that BMs are specialized extracellular matrices (sECMs) with unique components that support important functions including differentiation, proliferation, migration, and chemotaxis of cells during development. The composition of these sECM is as unique as the tissues to which they are localized, opening the possibility that such matrices can fulfill distinct functions. Changes in BM composition play significant roles in facilitating the development of various diseases. Furthermore, tissues have to provide sECM for their stem cells during development and for their adult life. Here, we briefly review the latest research on these unique sECM and their components with a special emphasis on embryonic and adult stem cells and their niches

[[alternative]]A comparison of psychological and background factors of career

[[abstract]]本研究的主要的目的在於比較影響傳統與非傳統職業婦女職業選擇相關因 素，藉由比較差異，試圖了解相關因素的影響。為達上述目的，首先經由 文獻探討，研析與婦女職業選擇之相關理論與實證研究，作為本研究之理 論架構；而在研究方法上，採用問卷調查法，研究對象分為醫生、律師、 工程師、建築師等為非傳統職業婦女；中小學教師、護士、圖書館員等為 傳統職業婦女。前者之有效問卷為390 份；後者之有效問卷419 份。研究 工具包括1.基本資料；2.「工作與家庭取向量表」，用以測量研究對象之 成就動機；3.女性角色態度量表，用以了解研究對象對女性當今在家庭上 、工作上所扮演角色的態度。調查所得之資料，則以信度分析、因素分析 、卡方考驗、t 考驗、Pearson 積差相關、逐步多元迴歸分析、區別分析 等加以處理，獲得以下研究發現：一、本研究中發現父親教育程度及職業 水準、母親教育程度及職業水準、個人教育程度、婚姻狀況、配偶教育程 度及職業水準等八個變項與婦女選擇非傳統職業有顯著關連，而母親是否 工作、出生排行、子女數等三個變項並未發現與職業選擇有顯著的關連。 二、在成就動機的差異上，本研究發現非傳統職業婦女比傳統職業婦女有 較高的成就動機、較低的害怕成功。三、在女性角色態度上，研究發現非 傳統職業婦女之女性角色態度較傳統 職業婦女來得開明、平等。四、 傳統與非傳統職業婦女的部份背景變項，可以預測其成就動機。五、非傳 統職業婦女以個人教育程度最能預測其女性角色態度；而傳統職業婦女之 女性角色態度則以婚姻狀況為重要的預測變項。六、個人教育程度與父親 職業水準可以有效區別傳統與非傳統職業婦女。針對上述研究發現，本研 究提出以下的建議： 1.生涯諮商輔導需配合各生涯發展階段與發展任務 提供適合的輔導課程。 2.輔導員不可有性別角色刻板印象，而造成就業 輔導上的偏差。 3.提供成就動機訓練課程。 4.培養開明的性別角色態度 ，提供「二性平權」、「二性關係」的課程。 5.對二度就業或欲轉業的 職業婦女，除了傳統職業訓練課程之外，也不要忽略了非傳統職業訓練課 程。 6.提供兩性平等待遇的學習環境並對女性從事非傳統職業予以支持 。

STIM1 Knockout Enhances PDGF-Mediated Ca2+ Signaling through Upregulation of the PDGFR–PLCγ–STIM2 Cascade

Platelet-derived growth factor (PDGF) has mitogenic and chemotactic effects on fibroblasts. An increase in intracellular Ca2+ is one of the first events that occurs following the stimulation of PDGF receptors (PDGFRs). PDGF activates Ca2+ elevation by activating the phospholipase C gamma (PLCγ)-signaling pathway, resulting in ER Ca2+ release. Store-operated Ca2+ entry (SOCE) is the major form of extracellular Ca2+ influx following depletion of ER Ca2+ stores and stromal interaction molecule 1 (STIM1) is a key molecule in the regulation of SOCE. In this study, wild-type and STIM1 knockout mouse embryonic fibroblasts (MEF) cells were used to investigate the role of STIM1 in PDGF-induced Ca2+ oscillation and its functions in MEF cells. The unexpected findings suggest that STIM1 knockout enhances PDGFR–PLCγ–STIM2 signaling, which in turn increases PDGF-BB-induced Ca2+ elevation. Enhanced expressions of PDGFRs and PLCγ in STIM1 knockout cells induce Ca2+ release from the ER store through PLCγ–IP3 signaling. Moreover, STIM2 replaces STIM1 to act as the major ER Ca2+ sensor in activating SOCE. However, activation of PDGFRs also activate Akt, ERK, and JNK to regulate cellular functions, such as cell migration. These results suggest that alternative switchable pathways can be observed in cells, which act downstream of the growth factors that regulate Ca2+ signaling

Daunorubicin-containing CLL1-targeting nanomicelles have anti-leukemia stem cell activity in acute myeloid leukemia.

Patients with acute myeloid leukemia have a very poor prognosis related to a high rate of relapse and drug-related toxicity. The ability of leukemia stem cells (LSCs) to survive chemotherapy is primarily responsible for relapse, and eliminating LSCs is ultimately essential for cure. We developed novel disulfide-crosslinked CLL1-targeting micelles (DC-CTM), which can deliver high concentrations of daunorubicin (DNR) into both bulk leukemia cells and LSCs. Compared to free DNR, DC-CTM-DNR had a longer half-life, increased DNR area under the curve concentration by 11-fold, and exhibited a superior toxicity profile. In patient-derived AML xenograft models, DC-CTM-DNR treatment led to significant decreases in AML engraftment and impairment of secondary transplantation compared to control groups. Collectively, we demonstrate superior anti-LSC/AML efficacy, and preferable pharmacokinetic and toxicity profiles of DC-CTM-DNR compared to free DNR. DC-CTM-DNR has the potential to significantly improve treatment outcomes and reduce therapy-related morbidity and mortality for patients with AML

Image-guided photo-therapeutic nanoporphyrin synergized HSP90 inhibitor in patient-derived xenograft bladder cancer model.

Photodynamic therapy is a promising and effective non-invasive therapeutic approach for the treatment of bladder cancers. Therapies targeting HSP90 have the advantage of tumor cell selectivity and have shown great preclinical efficacy. In this study, we evaluated a novel multifunctional nanoporphyrin platform loaded with an HSP90 inhibitor 17AAG (NP-AAG) for use as a multi-modality therapy against bladder cancer. NP-AAG was efficiently accumulated and retained at bladder cancer patient-derived xenograft (PDX) over 7 days. PDX tumors could be synergistically eradicated with a single intravenous injection of NP-AAG followed by multiple light treatments within 7 days. NP-AAG mediated treatment could not only specifically deliver 17AAG and produce heat and reactive oxygen species, but also more effectively inhibit essential bladder cancer essential signaling molecules like Akt, Src, and Erk, as well as HIF-1α induced by photo-therapy. This multifunctional nanoplatform has high clinical relevance and could dramatically improve management for bladder cancers with minimal toxicity. Nanomedicine 2018 Apr; 14(3):789-799