Sirt1: Def-eating senescence?

Sirt1, the closest mammalian homolog of the Sir2 yeast longevity protein, has been extensively investigated in the last few years as an avenue to understand the connection linking nutrients and energy metabolism with aging and related diseases. From this research effort the picture has emerged of an enzyme at the hub of a complex array of molecular interactions whereby nutrient-triggered signals are translated into several levels of adaptive cell responses, the failure of which underlies diseases as diverse as diabetes, neurodegeneration and cancer. Sirt1 thus connects moderate calorie intake to “healthspan,” and a decline of Sirt-centered protective circuits over time may explain the “catastrophic” nature of aging.     

Sirt1: Def-eating senescence?

Sirt1, the closest mammalian homolog of the Sir2 yeast longevity protein, has been extensively investigated in the last few years as an avenue to understand the connection linking nutrients and energy metabolism with aging and related diseases. From this research effort the picture has emerged of an enzyme at the hub of a complex array of molecular interactions whereby nutrient-triggered signals are translated into several levels of adaptive cell responses, the failure of which underlies diseases as diverse as diabetes, neurodegeneration and cancer. Sirt1 thus connects moderate calorie intake to “healthspan,” and a decline of Sirt-centered protective circuits over time may explain the “catastrophic” nature of aging.     

SIRT1/PGC-1: a neuroprotective axis?

Neurodegenerative diseases are more and more prevalent in our aging societies. A rapid overview of the etiology of many neurodegenerative diseases like Alzheimer, Parkinson, Huntington disease and amyotrophic lateral sclerosis suggests a tight link with mitochondrial dysfunction. Since it has been recently demonstrated that activation of the SIRT1/PGC-1 pathway, in a metabolic context promotes mitochondrial function, we performed a detailed literature review on the implication of this pathway in neurodegeneration. Interestingly, transgenic mice with impaired PGC-1 expression have neurodegenerative lesions and show behavioural abnormalities. As evidenced from independent investigations, enhanced SIRT1 activity has been demonstrated to protect against axonal degeneration and to decrease the accumulation of amyloid beta peptides, the hallmark of Alzheimer disease, in cultured murine embryonic neurons. In addition, several studies suggest that resveratrol, a specific activator of SIRT1, could have protective effects in animal models of neurodegenerative diseases. Taken together, these results strongly suggest that the modulation of the SIRT1/PGC-1 pathway, which has not been well documented in the central nervous system, could become the cornerstone for new therapeutical approaches to combat neurodegeneration.     

GABARAPL1 (GEC1): Original or copycat?

The GABARAPL1 (GABARAP-LIKE 1) gene was first described as an early estrogen-regulated gene that shares a high sequence homology with GABARAP and is thus a part of the GABARAP family. GABARAPL1, like GABARAP, interacts with the GABA_A receptor and tubulin and promotes tubulin polymerization. The GABARAP family members (GABARAP, GABARAPL1 and GABARAPL2) and their close homologs (LC3 and Atg8) are not only involved in the transport of proteins or vesicles but are also implicated in various mechanisms such as autophagy, cell death, cell proliferation and tumor progression. However, despite these similarities, GABARAPL1 displays a complex regulation that is different from that of other GABARAP family members. Moreover, it presents a regulated tissue expression and is the most highly expressed gene among the family in the central nervous system. In this review article, we will outline the specific functions of this protein and also hypothesize about the roles that GABARAPL1 might have in several important biological processes such as cancer or neurodegenerative diseases.     

α-cycloPNA: 1-Aminocylopentane-1-carboxylic Acid-Derived Peptide Nucleic Acid

Abstract

All four diastereoisomers of 3-thymine-1-(^tbutoxycarbonyl)aminocyclopentane- 1-carboxylic acid have been synthesised from (S)-dimethyl malate and thymine monomer 12 has been incorporated into an α-cycloPNA oligomer.     

NPC1L1:固醇脂质吸收的关键蛋白质

NPC1L1是最近发现的一种与NPC1同源的蛋白质。在体内的分布有物种差异性,其亚细胞定位存在很大争议。近些年发现NPC1L1在固醇类脂质代谢途径中起着重要作用,是肠道吸收固醇类脂质尤其是胆固醇的关键蛋白质,这项新发现使得人们对固醇类脂质的吸收机制有了了解。高胆固醇血症是心血管系统疾病的一个高危因子,因此,对NPC1L1的研究具有重大的实际意义,正逐渐成为研究的热点。     

GABARAPL1 (GEC1): original or copycat?

The GABARAPL1 (GABARAP-LIKE 1) gene was first described as an early estrogen-regulated gene that shares a high sequence homology with GABARAP and is thus a part of the GABARAP family. GABARAPL1, like GABARAP, interacts with the GABAA receptor and tubulin and promotes tubulin polymerization. The GABARAP family members (GABARAP, GABARAPL1 and GABARAPL2) and their close homologs (LC3 and Atg8) are not only involved in the transport of proteins or vesicles but are also implicated in various mechanisms such as autophagy, cell death, cell proliferation and tumor progression. However, despite these similarities, GABARAPL1 displays a complex regulation that is different from that of other GABARAP family members. Moreover, it presents a regulated tissue expression and is the most highly expressed gene among the family in the central nervous system. In this review article, we will outline the specific functions of this protein and also hypothesize about the roles that GABARAPL1 might have in several important biological processes such as cancer or neurodegenerative diseases.     

YCF1: A Green TIC?

A pivotal step in the transformation of an endosymbiotic cyanobacterium to a plastid some 1.5 billion years ago was the evolution of a protein import apparatus, the TOC/TIC machinery, in the common ancestor of Archaeplastida. Recently, a putative new TIC member was identified in Arabidopsis thaliana: TIC214. This finding is remarkable for a number of reasons: (1) TIC214 is encoded by ycf1, so it would be the first plastid-encoded protein of this apparatus; (2) ycf1 is unique to the green lineage (Chloroplastida) but entirely lacking in glaucophytes (Glaucophyta) and the red lineage (Rhodophyta) of the Archaeplastida; (3) ycf1 has been shown to be one of the few indispensable plastid genes (aside from the ribosomal machinery), yet it is missing in the grasses; and (4) 30 years of previous TOC/TIC research missed it. These observations prompted us to survey the evolution of ycf1. We found that ycf1 is not only lacking in grasses and some parasitic plants, but also for instance in cranberry (Ericaceae). The encoded YCF proteins are highly variable, both in sequence length and in the predicted number of N-terminal transmembrane domains. The evolution of the TOC/TIC machinery in the green lineage experienced specific modifications, but our analysis does not support YCF1 to be a general green TIC. It remains to be explained how the apparent complete loss of YCF1 can be tolerated by some embryophytes and whether what is observed for YCF1 function in a member of the Brassicaceae is also true for, e.g., algal and noncanonical YCF1 homologs.Some of the best evidence we have for the monophyly of plastids is how they import proteins (McFadden and van Dooren, 2004; Zimorski et al., 2014). Establishing a machinery that translocates proteins across the two membranes separating the organelle’s stroma from the cytosol was crucial for the transition of the endosymbiotic diazotrophic-like cyanobacterium to a plastid in the heterotrophic host (Cavalier-Smith, 2000; McFadden and van Dooren, 2004; Dagan et al., 2013). It was also a prerequisite for the successful transfer of genetic material from the endosymbiont to the host nucleus through endosymbiotic gene transfer (EGT; Martin et al., 1993). Most of the EGT that stripped the plastid genome of its coding capacity occurred in the common ancestor from which the three archaeplastidal lineages—Glaucophyta, Rhodophyta (red lineage), and Chloroplastida (green lineage)—evolved (Martin et al., 1998; Zimorski et al., 2014).Two main protein complexes mediate plastid protein import: the translocon on the outer envelope of chloroplasts (TOC) and the translocon on the inner envelope of chloroplasts (TIC). In accordance with the majority of EGT events, the main TOC/TIC components evolved in the common ancestor of Archaeplastida (Timmis et al., 2004; Kalanon and McFadden, 2008). Most proteins of the TIC complex are of cyanobacterial origin. However, all previously identified TOC and TIC components are encoded on nuclear DNA (Gould et al., 2008; Kalanon and McFadden, 2008; Shi and Theg, 2013), and, thus far, only TIC40 is unique to the Chloroplastida.Recently, Kikuchi et al. (2013) found the plastid-encoded YCF1 to be part of a 1-MD membrane protein complex that included TIC20. This complex contained neither TIC40 nor TIC110 components that were previously identified (Kessler and Blobel, 1996; Chou et al., 2003), but three novel ones, including YCF1 (Kikuchi et al., 2013). YCF1 was the first plastid-encoded protein identified whose presence was shown to be essential for the survival of Chlamydomonas reinhardtii and tobacco (Nicotiana tabacum), but whose function remained elusive (Boudreau et al., 1997; Drescher et al., 2000). YCF1—or in accordance with its newly proposed function, TIC214—would represent the first plastid-encoded protein of the TIC complex. It would also add to the set of TIC components (including TIC40 and a full-length TIC62) that is unique to the green lineage. In the course of evolution, organelles have lost or transferred 1000s of genes to the host nucleus, but they hardly ever gained any. That alone is remarkable and the apparent lack of ycf1 in Glaucophytes and Rhodophytes (whose import apparatus evolved from the same ancestral TOC/TIC as that of Chloroplastida) prompted us to inspect the distribution and sequence diversity of ycf1 in more detail.     

Effect of a fixed-ratio (1:1:1) transfusion protocol versus laboratory-results–guided transfusion in patients with severe trauma: a randomized feasibility trial

Background:

Hemorrhage coupled with coagulopathy remains the leading cause of preventable in-hospital deaths among trauma patients. Use of a transfusion protocol with a predefined ratio of 1:1:1 (1 each of red blood cells [RBC], frozen plasma [FP] and platelets) has been associated with improved survival in retrospective studies in military and civilian settings, but such a protocol has its challenges and may increase the risk of respiratory complications. We conducted a randomized controlled trial to assess the feasibility of a 1:1:1 transfusion protocol and its effect on mortality and complications among patients with severe trauma.

Methods:

We included 78 patients seen in a tertiary trauma centre between July 2009 and October 2011 who had hypotension and bleeding and were expected to need massive transfusion (≥ 10 RBC units in 24 h). We randomly assigned them to either the fixed-ratio (1:1:1) transfusion protocol (n = 40) or to a laboratory-results–guided transfusion protocol (control; n = 38). The primary outcome, feasibility, was assessed in terms of blood product ratios and plasma wastage. Safety was measured based on 28-day mortality and survival free of acute respiratory distress syndrome.

Results:

Overall, a transfusion ratio of 1:1:1 was achieved in 57% (21/37) of patients in the fixed-ratio group, as compared with 6% (2/32) in the control group. A ratio of 1:1 (RBC:FP) was achieved in 73% (27/37) in the fixed-ratio group and 22% (7/32) in the control group. Plasma wastage was higher with the intervention protocol (22% [86/390] of FP units v. 10% [30/289] in the control group). The 28-day mortality and number of days free of acute respiratory distress syndrome were statistically similar between the groups.

Interpretation:

The fixed-ratio transfusion protocol was feasible in our study, but it was associated with increased plasma wastage. Larger randomized trials are needed to evaluate the efficacy of such a protocol in trauma care. Trial registration: ClinicalTrials.gov, no. {"type":"clinical-trial","attrs":{"text":"NCT00945542","term_id":"NCT00945542"}}NCT00945542A fixed-ratio (1:1:1) transfusion strategy is a resuscitation strategy for trauma patients that promotes the transfusion of red blood cells (RBC), plasma and platelets (PLT) at a 1:1:1 ratio while minimizing crystalloid infusion.¹ This balanced transfusion strategy aims to correct both the early coagulopathy of trauma and the volume status of patients in hemorrhagic shock, thus targeting preventable hemorrhage-related deaths.^2,3 Retrospective studies of the 1:1:1 transfusion protocol reported marked reductions in mortality based on retrospectively calculated ratios of plasma:PLT:RBC.^4–6 Methodologic limitations, particularly survivorship bias (where higher mortality was associated with low ratios of plasma and PLT to RBC in unsalvageable patients who died before 1:1:1 transfusion could be achieved), preclude any definitive conclusion on the potential benefit of a 1:1:1 transfusion strategy in terms of efficacy and safety.^7–10The 1:1:1 transfusion strategy has been widely adopted by trauma centres worldwide^11,12 and is being increasingly used in prehospital care and in the care of patients without traumatic injuries.^13–15 Widespread adoption of the strategy has significant resource and safety implications. Its full implementation requires access to thawed type AB plasma, which is chronically in short supply.¹⁶ In addition, because of the difficulty in predicting the need for massive transfusion (commonly defined as ≥ 10 RBC units in 24 h), the 1:1:1 transfusion protocol may lead to unnecessary exposure to blood components and an increased risk of acute respiratory distress syndrome, sepsis and multiple organ dysfunction.¹⁷We conducted a pilot randomized controlled trial comparing a 1:1:1 transfusion strategy with the standard of care at our institution (laboratory-results–guided transfusion; laboratory results are available for transfusion decisions throughout resuscitation) in trauma patients predicted to need massive transfusion. Our primary objective was to assess the feasibility and safety of the fixed-ratio protocol in patients with severe trauma.     

STIM1 and Orai1: novel targets for vascular diseases?

The past five years have witnessed the discovery of the endoplasmic reticulum calcium (Ca²⁺) sensor STIM1 and the plasma membrane Ca²⁺ channel Orai1 as the bona fide molecular components of the store-operated Ca²⁺ entry (SOCE) and the Ca²⁺ release-activated Ca²⁺ current (I _CRAC). It has been known for two decades that SOCE and I _CRAC are required for lymphocyte activation as evidenced by severe immunodeficient phenotypes in patients lacking I _CRAC. In recent years however, studies have uncovered expression of STIM1 and Orai1 proteins in various tissues and described additional roles for these proteins in physiological functions and pathophysiological conditions. Here, we will summarize novel findings pertaining to the role of STIM1 and Orai1 in the vascular system and discuss their potential use as targets in the therapy of vascular disease.     

Cytokine-like factor 1 (CLF1): Life after development?

Cytokine-like factor 1 (CLF1) is a secreted receptor belonging to the interleukin-6 family of cytokines. CLF1 and its physiologic partner, cardiotrophin-like cytokine (CLC) are secreted as a heterodimer and engage the tripartite signaling complex of ciliary neurotrophic factor receptor (CNTFR), leukemia inhibitory factor (LIFR) and gp130. Ligation of this receptor complex leads to activation of the STAT3 and MAPK pathways and mediates survival pathways in neurons. Mutations in CLF1, CLC, or CNTFR in mice lead to the birth of mice that die on post-natal day 1 because of an inability to nurse. These animals exhibit significant decreases in the number of motor neurons in the facial nucleus and the spinal cord. CLF1 or CLC deficiency is associated with the development of the human cold-induced sweating syndromes. A growing body of research suggests that CLF1 expression may be associated with several post-natal disease processes. In this review, we summarize the current understanding of CLF1 expression and suggest future studies to understand the potentially important role of CLF1 in postnatal life and disease.     

Emi1 and Erp1: who can stop these eggs?

Vertebrate eggs prevent parthenogenetic development by producing cytostatic factor (CSF), which blocks exit from metaphase of meiosis II until fertilization. CSF was never purified but recently suspected to inhibit the anaphase-promoting complex (APC), an ubiquitin ligase required for entry into anaphase. In a recent paper in Genes & Development, Schmidt et al. describe the Xenopus APC inhibitor Erp1, which seems to be the best candidate yet for the downstream effector of CSF activity.     

Mutators in SACCHAROMYCES CEREVISIAE: MUT1–1, MUT1–2 and MUT2–1

The purpose of this study was to characterize two mutator stocks of yeast which were induced and selected on the basis of high spontaneous reversion rates of the suppressible "ochre" nonsense allele lys1-1. In the mutator stock VA-3, a single mutation, designated mut1-1, is responsible for the increase in the reversion rate of the ochre alleles lys1-1 and arg4-17. In stock VA-105, there are two separate mutator mutations. Tetrad analysis data showed these two loci are loosely linked. Based on complementation data, one of these mutations is at the same locus as mut1-1 and designated mut1-2. The second mutator of stock VA-105 was designated mut2-1. All three mutators are recessive. Both mut1-1 and mut1-2 give a high mutation rate for ochre nonsense suppressor (SUP) loci, but not for the ochre nonsense alleles. On the contrary, the mutation rates of the ochre alleles are greatly reduced. With the mutant mut2-1 there were mutations at both the lys1-1 site and its suppressors; mut2-1 is as effective as mut1-2 but not as effective as mut1-1 in inducing reversions of a missense mutant, his1-7. Neither mut1-1, mut1-2 nor mut2-1 were effective in inducing reversions of a putative frameshift mutation, hom3-10, or in inducing forward mutations to canavanine resistance.     

HIV-1的隐身术:变异与进化

HIV-1以其庞大的基因多样性及快速的变异能力,不断地逃逸人类免疫系统的监控,至今为止,尚未研发出有效的疫苗和治愈方法。研究HIV-1的进化模式及其与人类免疫系统之间的"博弈",有助于鉴定新的抗病毒治疗靶点、探寻可诱导广谱免疫应答的免疫表位和设计新型有效的艾滋病疫苗。现从HIV-1进化的角度,简述了HIV-1的起源、分类、流行;讨论了HIV-1基因多样性产生的原因及其快速的进化模式;分析了HIV-1变异与中和抗体产生以及特异CTL作用之间的关联;总结了HIV-1在抗病毒药物治疗下的进化;最后也概括了HIV-1适应宿主限制性因子的作用,以期为艾滋病治愈策略及有效疫苗研发提供借鉴。