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61.
62.
Sergey Nepomnyachiy Nir Ben-Tal Rachel Kolodny 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(32):11691-11696
To explore protein space from a global perspective, we consider 9,710 SCOP (Structural Classification of Proteins) domains with up to 70% sequence identity and present all similarities among them as networks: In the “domain network,” nodes represent domains, and edges connect domains that share “motifs,” i.e., significantly sized segments of similar sequence and structure. We explore the dependence of the network on the thresholds that define the evolutionary relatedness of the domains. At excessively strict thresholds the network falls apart completely; for very lax thresholds, there are network paths between virtually all domains. Interestingly, at intermediate thresholds the network constitutes two regions that can be described as “continuous” versus “discrete.” The continuous region comprises a large connected component, dominated by domains with alternating alpha and beta elements, and the discrete region includes the rest of the domains in isolated islands, each generally corresponding to a fold. We also construct the “motif network,” in which nodes represent recurring motifs, and edges connect motifs that appear in the same domain. This network also features a large and highly connected component of motifs that originate from domains with alternating alpha/beta elements (and some all-alpha domains), and smaller isolated islands. Indeed, the motif network suggests that nature reuses such motifs extensively. The networks suggest evolutionary paths between domains and give hints about protein evolution and the underlying biophysics. They provide natural means of organizing protein space, and could be useful for the development of strategies for protein search and design.How are proteins related to each other? Which physicochemical considerations affect protein evolution and how? A global view of the protein universe may shed light on these fundamental questions. It could also suggest new strategies for protein search and design (1–3). However, forming a global picture of the protein universe is difficult because we have to piece it together from the many local glimpses that our empirical data and computational tools provide. In other words, a global picture needs to portray the relationships among all proteins, yet we only have evidence of such relationships among several proteins, based on the similarity between their sequences, structures, and functions. The considerable size of the Protein Data Bank (4) also complicates this task.In particular, an intensely debated question is whether protein space is “discrete” or “continuous” (2, 3, 5–10). These terms are loosely defined. Discrete implies that the global picture consists of separate, island-like, structural entities. In the hierarchical protein domains Structural Classification of Proteins (SCOP) (11) these entities are termed “folds,” and in the CATH database (12) they are called “topologies.” Alternatively, “continuous” implies that the space between these entities is generally populated by cross-fold similarities (e.g., refs. 2, 5, 6, 9, 13–15). If such similarities are abundant, then one must account for them when organizing and searching proteins (5, 8, 16). In support of the abundance of such similarities is the remarkable success of structure prediction methods that piece together predictions of protein fragments or larger protein segments (e.g., ref. 17).There are different approaches to forming a global view of the protein universe (18). The most significant efforts are the ones embodied in the hierarchical classifications CATH and SCOP. However, a hierarchy implicitly assumes that there are isolated regions in protein space. An alternative approach is to study the protein universe via maps––where domains are represented by points in two or three dimensions, placed so that the distances between them depend on the dissimilarity between their corresponding domains (e.g., refs. 19–21). By coloring the points according to domain characteristics, one can visually identify global properties of the protein universe (19, 20). However, a map representation in low-dimensional Euclidean space implicitly suggests that similarity among domains is transitive (i.e., that similarity within the pairs AB and BC implies that AC is similar too); we know that this is often not the case (6). Finally, a third approach to study protein space is via similarity and cooccurrence networks. In similarity networks, nodes typically represent protein domains and edges connect similar domains. Several successful studies of protein space capitalize on such networks (22, 23). Cooccurrence networks of protein domains, in which nodes represent domains and edges connect cooccurring domains, were also studied to better understand protein evolution (24–26).Here, we study the global nature of the protein universe using domain and motif networks (Fig. 1). To construct these networks, we identify evolutionary relationships among a representative set of SCOP domains; we relate two domains if they share a significantly sized part (denoted motif) with similar structure and sequence. Our analysis reveals that protein space is both discrete and continuous: SCOP domains of the all-alpha, all-beta, and alpha + beta classes, in which alpha and beta elements do not mix, mostly populate the discrete parts, whereas alpha/beta domains, with alternating alpha and beta segments, mostly populate the continuous ones. We also find that recurring motifs are very abundant; the motifs from the all-alpha and alpha/beta domains are the more abundant, and the more gregarious ones.Open in a separate windowFig. 1.Constructing the domain and motif networks. (A) The aligned protein segments, marked in colors, are the motifs. (B) In the domain network, edges connect domains that share similar motifs (e.g., domain d1wjga_ and d1vlua_ that share the cyan motif). (C) In the motif network, edges connect cooccurring motifs (e.g., the orange and cyan motifs cooccur in the d1vlua_ domain). 相似文献
63.
64.
65.
Gregor K Wenning Felix Geser Florian Krismer Klaus Seppi Susanne Duerr Sylvia Boesch Martin Köllensperger Georg Goebel Karl P Pfeiffer Paolo Barone Maria Teresa Pellecchia Niall P Quinn Vasiliki Koukouni Clare J Fowler Anette Schrag Christopher J Mathias Nir Giladi Tanya Gurevich Werner Poewe 《Lancet neurology》2013,12(3):264-274
66.
Victoria C. Wing Mera S. Barr Caroline E. Wass Nir Lipsman Andres M. Lozano Zafiris J. Daskalakis Tony P. George 《Brain stimulation》2013,6(3):221-230
BackgroundTobacco smoking is the leading cause of preventable deaths worldwide, but many smokers are simply unable to quit. Psychosocial and pharmaceutical treatments have shown modest results on smoking cessation rates, but there is an urgent need to develop treatments with greater efficacy. Brain stimulation methods are gaining increasing interest as possible addiction therapeutics.ObjectivesThe purpose of this paper is to review the studies that have evaluated brain stimulation techniques on tobacco addiction, and discuss future directions for research in this novel area of addiction interventions.MethodsElectronic and manual literature searches identified fifteen studies that administered repetitive transcranial magnetic stimulation (rTMS), cranial electrostimulation (CES), transcranial direct current stimulation (tDCS) or deep brain stimulation (DBS).ResultsrTMS was found to be the most well studied method with respect to tobacco addiction. Results indicate that rTMS and tDCS targeted to the dorsolateral prefrontal cortex (DLPFC) were the most efficacious in reducing tobacco cravings, an effect that may be mediated through the brain reward system involved in tobacco addiction. While rTMS was shown to reduce consumption of cigarettes, as yet no brain stimulation technique has been shown to significantly increase abstinence rates. It is possible that the therapeutic effects of rTMS and tDCS may be improved by optimization of stimulation parameters and increasing the duration of treatment.ConclusionAlthough further studies are needed to confirm the ability of brain stimulation methods to treat tobacco addiction, this review indicates that rTMS and tDCS both represent potentially novel treatment modalities. 相似文献
67.
Amson M Lamoureux E Hilzenrat N Tischkowitz M 《Journal canadien de gastroenterologie》2012,26(6):330-332
The authors describe two siblings, each with a different, rare genetic condition that affects liver function. The index case, the 18-year-old asymptomatic brother of a young man recently diagnosed with Wilson disease, presented for Wilson disease screening and was also found to have abnormal liver function suggestive of cholestasis. However, ceruloplasmin level, 24 h urine copper concentration and liver synthetic function were normal. Further hepatic investigations and genetic mutation analysis were performed, ultimately leading to a diagnosis of Alagille syndrome. He was treated with ursodiol, which resulted in normalization of his liver function tests. Subsequently, he was found to be a carrier for a mutation in the Wilson disease gene, ATP7B. In the present report, the potential implications of being a heterozygote for Wilson disease in the context of Alagille syndrome are discussed. Also stressed is that care must be exercised by the clinician when diagnosing family members who may present with two different disorders closely mimicking one another. 相似文献
68.
Colombo PC Ganda A Lin J Onat D Harxhi A Iyasere JE Uriel N Cotter G 《Heart failure reviews》2012,17(2):177-190
Although inflammation is a physiologic response designed to protect us from infection, when unchecked and ongoing it may cause
substantial harm. Both chronic heart failure (CHF) and chronic kidney disease (CKD) are known to cause elaboration of several
pro-inflammatory mediators that can be detected at high concentrations in the tissues and blood stream. The biologic sources
driving this chronic inflammatory state in CHF and CKD are not fully established. Traditional sources of inflammation include
the heart and the kidneys which produce a wide range of pro-inflammatory cytokines in response to neurohormones and sympathetic
activation. However, growing evidence suggests that non-traditional biomechanical mechanisms such as venous and tissue congestion
due to volume overload are also important as they stimulate endotoxin absorption from the bowel and peripheral synthesis and
release of pro-inflammatory mediators. Both during the chronic phase and, more rapidly, during acute exacerbations of CHF
and CKD, inflammation and congestion appear to amplify each other resulting in a downward spiral of worsening cardiac, vascular,
and renal functions that may negatively impact patients’ outcome. Anti-inflammatory treatment strategies aimed at attenuating
end organ damage and improving clinical prognosis in the cardiorenal syndrome have been disappointing to date. A new therapeutic
paradigm may be needed, which involves different anti-inflammatory strategies for individual etiologies and stages of CHF
and CKD. It may also include specific (short-term) anti-inflammatory treatments that counteract inflammation during the unsettled
phases of clinical decompensation. Finally, it will require greater focus on volume overload as an increasingly significant
source of systemic inflammation in the cardiorenal syndrome. 相似文献
69.
Nir Lubezky Yaacov Goykhman Richard Nakache Ada Kessler Roni Baruch Paulina Katz Itzhak Kori Joseph M. Klausner Menahem Ben-Haim 《World journal of surgery》2013,37(6):1430-1437
Background
Graft pseudoaneurysm (PSA) following pancreatic transplantation (PT) is a rarely reported complication that has significant morbidity and mortality. Few case reports and small series of this complication exist.Methods
Retrospective review of files of 106 patients who underwent PT at the Tel-Aviv Sourasky Medical center between 1995 and 2010. Accessible asymptomatic patients (n = 35) were referred for graft PSA screening using ultrasound-Doppler.Results
Eight patients developed graft PSA (8 %). All had early posttransplant sepsis. PSA incidence among patients who had perioperative sepsis is 13 %. Three patients developed early postoperative PSA, presenting as massive abdominal bleeding requiring urgent laparotomy and graft resection. Five patients were diagnosed with late-onset graft PSA between 3 months and 11 years posttransplant: clinical presentations were massive gastrointestinal bleeding (n = 2), acute renal failure (n = 1), and asymptomatic finding on screening ultrasound-Doppler (n = 2, 6 % of screened patients).Conclusions
PSA following PT occurs in 8 % of patients. Perioperative infection is a risk factor. Early PSAs present as massive intra-abdominal bleeding. PSA may develop years posttransplant, may be asymptomatic, but late rupture is possible and presents as gastrointestinal bleeding. We recommend screening of patients at risk with ultrasound Doppler for early detection and treatment of asymptomatic PSAs. 相似文献70.
Ziv Asa Ron Greenberg Ronen Ghinea Roy Inbar Nir Wasserberg Shmuel Avital 《Surgical endoscopy》2013,27(10):3748-3753