On the Moral Acceptability of Physician‐Assisted Dying for Non‐Autonomous Psychiatric Patients

Several authors have recently suggested that the suffering caused by mental illness could provide moral grounds for physician‐assisted dying. Yet they typically require that psychiatric‐assisted dying could come to question in the cases of autonomous, or rational, psychiatric patients only. Given that also non‐autonomous psychiatric patients can sometimes suffer unbearably, this limitation appears questionable. In this article, I maintain that restricting psychiatric‐assisted dying to autonomous, or rational, psychiatric patients would not be compatible with endorsing certain end‐of‐life practices commonly accepted in current medical ethics and law, practices often referred to as ‘passive euthanasia’.     

SHP‐2 Phosphatase Prevents Colonic Inflammation by Controlling Secretory Cell Differentiation and Maintaining Host‐Microbiota Homeostasis

Polymorphisms in the PTPN11 gene encoding for the tyrosine phosphatase SHP‐2 were described in patients with ulcerative colitis. We have recently demonstrated that mice with an intestinal epithelial cell‐specific deletion of SHP‐2 (SHP‐2^IEC‐KO) develop severe colitis 1 month after birth. However, the mechanisms by which SHP‐2 deletion induces colonic inflammation remain to be elucidated. We generated SHP‐2^IEC‐KO mice lacking Myd88 exclusively in the intestinal epithelium. The colonic phenotype was histologically analyzed and cell differentiation was determined by electron microscopy and lysozyme or Alcian blue staining. Microbiota composition was analyzed by 16S sequencing. Results show that innate defense genes including those specific to Paneth cells were strongly up‐regulated in SHP‐2‐deficient colons. Expansion of intermediate cells (common progenitors of the Goblet and Paneth cell lineages) was found in the colon of SHP‐2^IEC‐KO mice whereas Goblet cell number was clearly diminished. These alterations in Goblet/intermediate cell ratio were noticed 2 weeks after birth, before the onset of inflammation and were associated with significant alterations in microbiota composition. Indeed, an increase in Enterobacteriaceae and a decrease in Firmicutes were observed in the colon of these mice, indicating that dysbiosis also occurred prior to inflammation. Importantly, loss of epithelial Myd88 expression inhibited colitis development in SHP‐2^IEC‐KO mice, rescued Goblet/intermediate cell ratio, and prevented NFκB hyperactivation and inflammation. These data indicate that SHP‐2 is functionally important for the maintenance of appropriate barrier function and host‐microbiota homeostasis in the large intestine. J. Cell. Physiol. 231: 2529–2540, 2016. © 2016 The Authors. Journal of Cellular Physiology published by Wiley Periodicals, Inc.     

The Effect of TIGAR Knockdown on Apoptotic and Epithelial‐Mesenchymal Markers Expression in Doxorubicin‐Resistant Non‐Small Cell Lung Cancer A549 Cell Lines

Resistance to chemotherapeutic drugs is a critical problem in cancer therapy, but the underlying mechanism has not been fully elucidated. TP53‐induced glycolysis regulatory phosphatase (TIGAR), an important glycolysis and apoptosis regulator, plays a crucial role in cancer cell survival by protecting cells against oxidative stress‐induced apoptosis. In the present study, we investigated whether TIGAR is involved in epithelial‐mesenchymal transition (EMT) in doxorubicin (DOX)‐resistant human non‐small cell lung cancer (NSCLC), A549/DOX cells. We found that the expression of TIGAR was significantly higher in A549/DOX cells than in the parent A549 cell lines. siRNA‐mediated TIGAR knockdown reduced migration, viability and colony survival of doxorubicin‐resistant lung cancer cells. Also, TIGAR knockdown decreased pro‐survival protein Bcl‐2 and increased pro‐apoptotic Bax and cleaved poly (ADP‐ribose) polymerase (PARP). Moreover, TIGAR depletion significantly up‐regulated both caspase‐3 and caspase‐9 expression. Furthermore, TIGAR depletion up‐regulated the expression of E‐cadherin and down‐regulated the expression of vimentin. These results indicate that TIGAR knockdown may inhibit EMT in doxorubicin (DOX)‐resistant human NSCLC and may represent a therapeutic target for a non‐small lung cancer cells chemoresistance.     

外源NF-IL6(C/EBPβ)对肝癌细胞系BEL-7404的肿瘤抑制效应

目的:探讨核转录因子NFIL6对肝癌细胞系BEL7404恶性度的影响。方法:用磷酸钙介导转染技术,将NFIL6表达载体(pCN)和空载体质粒(pCN空)分别导入肝癌细胞系BEL7404,并借助细胞生长曲线,软琼脂集落形成试验,裸鼠成瘤试验对转染细胞的恶性度进行了检测。结果:与原细胞系BEL7404和空载体转染的该细胞系相比较,转染了NFIL6基因的BEL7404的各细胞克隆生长速度减慢,在软琼脂中集落形成率恶性度下降,裸鼠成瘤试验显示成瘤性明显降低。结论:表明外源转染的NFIL6对肝癌细胞系BEL7404具有明显的肿瘤抑制作用 。     

Eating Disorder or Disordered Eating? Non‐normative Eating Patterns in Obese Individuals

Binge eating disorder (BED) and night eating syndrome (NES) are putative eating disorders frequently seen in obese individuals. Data suggest that BED fulfills criteria for a mental disorder. Criteria for NES are evolving but at present do not require distress or functional impairment. It remains unclear whether BED and NES, as they are currently defined, are optimally useful for characterizing distinct patient subgroups. We propose that a distinction be made between “eating disorders” and “non‐normative” eating patterns without associated distress or impairment. Although non‐normative eating patterns may not be considered mental disorders, they may be very important in terms of their impact on body weight and health. More precise behavioral and metabolic characterization of subgroups with eating disorders and non‐normative eating behaviors has important implications for understanding the etiology, pathophysiology, and treatment of obesity. Ultimately, better understanding of the many pathways to increased energy intake may lead to targeted strategies for prevention of overweight and obesity in at‐risk individuals and populations.     

Trichocysts—Paramecium's Projectile‐like Secretory Organelles

This review summarizes biogenesis, composition, intracellular transport, and possible functions of trichocysts. Trichocyst release by Paramecium is the fastest dense core‐secretory vesicle exocytosis known. This is enabled by the crystalline nature of the trichocyst “body” whose matrix proteins (tmp), upon contact with extracellular Ca²⁺, undergo explosive recrystallization that propagates cooperatively throughout the organelle. Membrane fusion during stimulated trichocyst exocytosis involves Ca²⁺ mobilization from alveolar sacs and tightly coupled store‐operated Ca²⁺‐influx, initiated by activation of ryanodine receptor‐like Ca²⁺‐release channels. Particularly, aminoethyldextran perfectly mimics a physiological function of trichocysts, i.e. defense against predators, by vigorous, local trichocyst discharge. The tmp's contained in the main “body” of a trichocyst are arranged in a defined pattern, resulting in crossstriation, whose period expands upon expulsion. The second part of a trichocyst, the “tip”, contains secretory lectins which diffuse upon discharge. Repulsion from predators may not be the only function of trichocysts. We consider ciliary reversal accompanying stimulated trichocyst exocytosis (also in mutants devoid of depolarization‐activated Ca²⁺ channels) a second, automatically superimposed defense mechanism. A third defensive mechanism may be effectuated by the secretory lectins of the trichocyst tip; they may inhibit toxicyst exocytosis in Dileptus by crosslinking surface proteins (an effect mimicked in Paramecium by antibodies against cell surface components). Some of the proteins, body and tip, are glycosylated as visualized by binding of exogenous lectins. This reflects the biogenetic pathway, from the endoplasmic reticulum via the Golgi apparatus, which is also supported by details from molecular biology. There are fragile links connecting the matrix of a trichocyst with its membrane; these may signal the filling state, full or empty, before and after tmp release upon exocytosis, respectively. This is supported by experimentally produced “frustrated exocytosis”, i.e. membrane fusion without contents release, followed by membrane resealing and entry in a new cycle of reattachment for stimulated exocytosis. There are some more puzzles to be solved: Considering the absence of any detectable Ca²⁺ and of acidity in the organelle, what causes the striking effects of silencing the genes of some specific Ca²⁺‐release channels and of subunits of the H⁺‐ATPase? What determines the inherent polarity of a trichocyst? What precisely causes the inability of trichocyst mutants to dock at the cell membrane? Many details now call for further experimental work to unravel more secrets about these fascinating organelles.     

干细胞、肿瘤干细胞与肿瘤

干细胞是一种具有自我更新、无限增殖和多向分化能力的细胞.而多数肿瘤是由不同增殖潜能的不均一性细胞构成.随着对干细胞的研究不断深入,使人们对肿瘤的发生机制重新进行了审视,并在造血系统、脑、肺、乳腺等部位肿瘤中发现极少量的具有与干细胞非常类似生物学特性的细胞,称之为肿瘤干细胞,它们很可能是肿瘤细胞的起源.肿瘤干细胞的提出.使得靶向性杀伤肿瘤干细胞从而使根治肿瘤和防止肿瘤复发和转移成为可能.所以研究肿瘤干细胞的起源及其与肿瘤的发生关系,成为当前研究和治疗肿瘤领域的新热点.本文就肿瘤干细胞的存在证据、干细胞与肿瘤干细胞的异同点及它们与肿瘤发生之间的关系作简要的综述.     

Contribution of Soft Substrates to Malignancy and Tumor Suppression during Colon Cancer Cell Division

In colon cancer, a highly aggressive disease, progression through the malignant sequence is accompanied by increasingly numerous chromosomal rearrangements. To colonize target organs, invasive cells cross several tissues of various elastic moduli. Whether soft tissue increases malignancy or in contrast limits invasive colon cell spreading remains an open question. Using polyelectrolyte multilayer films mimicking microenvironments of various elastic moduli, we revealed that human SW480 colon cancer cells displayed increasing frequency in chromosomal segregation abnormalities when cultured on substrates with decreasing stiffness. Our results show that, although decreasing stiffness correlates with increased cell lethality, a significant proportion of SW480 cancer cells did escape from the very soft substrates, even when bearing abnormal chromosome segregation, achieve mitosis and undergo a new cycle of replication in contrast to human colonic HCoEpiC cells which died on soft substrates. This observation opens the possibility that the ability of cancer cells to overcome defects in chromosome segregation on very soft substrates could contribute to increasing chromosomal rearrangements and tumor cell aggressiveness.     

Comparative Study of Effects of Terminal Non‐Alkyl Aromatic and Alkyl Groups on Small‐Molecule Solar Cell Performance

Small‐molecule donors for solar cells are usually end‐capped with π‐systems or aliphatic chains extending the π‐conjugation of the molecules's backbone. Compared with alkyl terminals, π‐systems can form π?π arrangements, for example, with an aligning spherical fullerene π‐system. To study the effects of two kinds of terminals on the solar cell performance, the non‐alkyl, branched aromatic and electron‐donating diphenylamine (DPA) and the aliphatic n‐butyl (n‐Bu) unit are selected as end‐capping groups on a diketopyrrolo­pyrrole‐based linear backbone, affording two new solution‐processable small‐molecule donors. Photovoltaic data indicate that by changing the end‐function from n‐Bu to DPA, the photocurrent significantly increases from 8.35 to 15.64 mA cm^?2 and the efficiency from 3.2 to 5.8%. Characterization of absorption, morphology, recombination, and carrier transportation clearly demonstrates that the higher photocurrent can be attributed to a higher density of the mobile carriers (i.e., free holes, in this case). The DPA end‐functions enhance the light‐harvesting capacity, improve the charge dissociation, and reduce the recombination loss, all of which lead to more carriers being collected by the electrode. This work demonstrates that the choice of end‐function along the molecular backbone is as important to improve the cell performance as the light‐harvesting backbone and the side‐chains.     

RB基因与肿瘤抑制

RB基因位于13q14,全长150kb,编码一个由928个氨基酸组成的分子量为110 000蛋白(pp110RB).它能特异性与SV40大T,E1A和E7结合.在视网膜细胞中,RB呈衡定组成性表达,其缺陷除引起RB外,在骨肉瘤、乳腺癌、小细胞肺癌、软组织肉瘤及造血系统增生性疾病也有RB基因的突变.把RB基因导入到基因缺陷的恶性肿瘤细胞能全部或部分抑制其恶性表现.