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31.
Xingcheng Lin Nathanial R. Eddy Jeffrey K. Noel Paul C. Whitford Qinghua Wang Jianpeng Ma José N. Onuchic 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(33):12049-12054
Influenza hemagglutinin (HA), a homotrimeric glycoprotein crucial for membrane fusion, undergoes a large-scale structural rearrangement during viral invasion. X-ray crystallography has shown that the pre- and postfusion configurations of HA2, the membrane-fusion subunit of HA, have disparate secondary, tertiary, and quaternary structures, where some regions are displaced by more than 100 Å. To explore structural dynamics during the conformational transition, we studied simulations of a minimally frustrated model based on energy landscape theory. The model combines structural information from both the pre- and postfusion crystallographic configurations of HA2. Rather than a downhill drive toward formation of the central coiled-coil, we discovered an order-disorder transition early in the conformational change as the mechanism for the release of the fusion peptides from their burial sites in the prefusion crystal structure. This disorder quickly leads to a metastable intermediate with a broken threefold symmetry. Finally, kinetic competition between the formation of the extended coiled-coil and C-terminal melting results in two routes from this intermediate to the postfusion structure. Our study reiterates the roles that cracking and disorder can play in functional molecular motions, in contrast to the downhill mechanical interpretations of the “spring-loaded” model proposed for the HA2 conformational transition.Hemagglutinin (HA) is a viral receptor-binding and membrane-fusion glycoprotein involved in the invasion of influenza virions into host cells (1). Structural rearrangements of HA during membrane fusion are crucial for the delivery of the viral genome. The postfusion conformation of HA shows considerable similarity to other viral fusion proteins and eukaryotic membrane receptors involved in intracellular vesicle trafficking (2), suggesting there may be common mechanisms in the function of these proteins. Therefore, HA may serve as a model system, allowing characterization of the molecular and energetic details that underlie its conformational transition to provide insights into general principles of membrane fusion (3).HA is a homotrimer consisting of two domains connected by disulfide bonds (4): a globular receptor binding domain (HA1), and a coiled-coil membrane-fusion domain anchored to the viral membrane (HA2). Recognized by the sialic acid receptor of a host cell, the intact virus enters the cell via endocytosis. Low pH in a late endosome then induces the dissociation of HA1 from HA2 (1) and an irreversible conformational transition of HA2. Experimentally, this conformational change can be triggered by either low pH, high temperature, or urea denaturation (5).Structures of HA in pre- and postfusion pH conformations have been solved by X-ray crystallography. The structure of the prefusion ectodomain contains both HA1 and HA2, and was purified from influenza virions (4). A postfusion conformation of HA1 and HA2 were obtained from prefusion viral HA that was sequentially treated with low pH and trypsin (6, 7). Comparison of these two structures shows no structural changes in HA1, but a major rearrangement in HA2, including secondary, tertiary, and quaternary structural changes. The N-terminal domain of HA2, initially adjacent to the transmembrane region in the prefusion configuration, undergoes a large movement (over 100 Å) during the transition. The C-terminal domain of HA2 changes from a globular structure to three extended loops packed against the central coiled-coil.Although experiments have probed the fusion mechanism through mutation (8) and provided measures of fusion kinetics (9), there is a lack of structural information about how HA2 transitions from the prefusion to postfusion conformations. Theoretical models have been suggested to describe the fusion mechanism based on the available experimental kinetic data (10–12). However, because of the large scale of the HA2 rearrangement, only limited computational techniques, such as targeted molecular dynamics (13), have been applied to study the molecular details of the transition.In this study we applied the principles of the energy landscape theory as developed in the context of protein folding (14–16) to examine structural details of the HA2 conformational transition. We used a structure-based model (SBM) (17, 18) built with a dual-funneled landscape (19, 20) that has both the pre- and postfusion structures as explicit minima. The HA2 landscape has at least two competing basins of attraction, corresponding to the pre- and postfusion structures of HA2, respectively. HA1 dissociation sterically enables HA2 to explore beyond the prefusion local free-energy minimum and to diffuse toward the postfusion configuration. The long-length scale and extensive shuffling of secondary and tertiary structures is reminiscent of protein folding, but distinct in that both ends of the HA2 transition can be described by ensembles of structurally similar configurations. Just as in protein folding, there may be free-energy barriers and structural intermediates along the HA2 transition caused by the imperfect cancellation of energy and entropy. These intermediate ensembles may be interesting candidates for drug design to inhibit HA function.Previously, a “spring-loaded” model has been applied to describe the mechanism for the HA2 transition (21). This model suggested a downhill mechanical transition of the N-terminal region of HA2 into an ordered helical structure that orients the fusion peptides away from the virus and toward the host membrane. Our simulations expand this view by showing that the conformational change of the N-terminal domains is associated with an entropic barrier and the unfolding of the C-terminal region is associated with the major energetic barrier during the HA2 conformational transition. Kinetic competition between these two events creates a long-lived metastable intermediate that allows for two dominant routes. The first route (the “sequential route”) resembles the spring-loaded model, and the second route (the “cooperative route”) involves cooperative interactions between the N-terminal and C-terminal domains in forming the central coiled-coil. The presence of these distinct routes suggests multiple mechanisms for HA2 rearrangement and membrane fusion. 相似文献
32.
Z Katsarava A Dzagnidze M Kukava E Mirvelashvili M Djibuti M Janelidze R Jensen LJ Stovner & TJ Steiner 《Cephalalgia : an international journal of headache》2009,29(9):949-952
We present a study of the general-population prevalence of cluster headache in the Republic of Georgia and discuss the advantages and challenges of different methodological approaches. In a community-based survey, specially trained medical residents visited 500 adjacent households in the capital city, Tbilisi, and 300 households in the eastern rural area of Kakheti. They interviewed all ( n = 1145) biologically unrelated adult occupants using a previously validated questionnaire. The household responses rates were 92% in Tbilisi and 100% in Kakheti. The survey identified 32 persons with possible cluster headache, who were then personally interviewed by one of two headache-experienced neurologists. Cluster headache was confirmed in one subject. The prevalence of cluster headache was therefore estimated to be 87/100 000 (95% confidence interval < 258/100 000). We used a conservative approach, which has an obvious advantage of high-quality data collection, but is very demanding of manpower and time. 相似文献
33.
Wai-Sun Chan David L Whitford Ronan Conroy David Gibney Brid Hollywood 《BMC health services research》2011,11(1):15
Background
Psychosocial problems in socioeconomically deprived communities are not always amenable to traditional medical approaches. Mothers living in these areas are a particularly vulnerable group. The objective of this study was to evaluate the effectiveness of a lengthened multi-disciplinary team consultation in primary care in reducing anxiety and depression in mothers. 相似文献34.
Gillian Paul Susan M Smith David Whitford Fergus O'Kelly Tom O'Dowd 《BMC health services research》2007,7(1):136
Background
Diabetes is a chronic illness which requires the individual to assume responsibility for their own care with the aim of maintaining glucose and blood pressure levels as close to normal as possible. Traditionally self management training for diabetes has been delivered in a didactic setting. In recent times alternatives to the traditional delivery of diabetes care have been investigated, for example, the concept of peer support which emphasises patient rather than professional domination. The aim of this paper is to describe the development of a complex intervention of peer support in type 2 diabetes for a randomised control trial in a primary care setting. 相似文献35.
Background
Whole body vibration (WBV) exposure at work is common and studies found evidence that this exposure might cause low back pain (LBP). A recent review concluded there is a lack of evidence of effective strategies to reduce WBV exposure. Most research in this field is focussed on the technical implications, although changing behaviour towards WBV exposure might be promising as well. Therefore, we developed an intervention programme to reduce WBV exposure in a population of drivers with the emphasis on a change in behaviour of driver and employer. The hypothesis is that an effective reduction in WBV exposure, in time, will lead to a reduction in LBP as WBV exposure is a proxy for an increased risk of LBP. 相似文献36.
MP Richardson TJ Williamson SW Lenton MJ Tarlow PT Rudd 《Archives of disease in childhood》1995,72(4):294-297
Transient evoked otoacoustic emissions (TEOAEs) are low amplitude sound waves produced by the healthy cochlea. They can be recorded with a microphone in the external ear. TEOAEs are abolished by hearing losses of 30 dB or more. The feasibility of using TEOAEs as a screening test for hearing loss in children was studied. TEOAE recordings were attempted in 56 children attending an audiology clinic. Recordings were possible from both ears in 52 children; of these 104 ears, 32 had hearing deficits of 30 dB or more. Hearing status was compared with the results of six TEOAE screening criteria. All criteria had a sensitivity of 1.00. Four standard TEOAE criteria yielded specificities of 0.46-0.58. Two new criteria derived from analysis of limited frequencies from the TEOAE waveform gave specificities of 0.76 and 0.82. It can be concluded that, when appropriate pass/fail criteria are employed, TEOAEs are a feasible screening test in children. 相似文献
37.
IJ Griffin TJ Cole KA Duncan AS Hollman MDC Donaldson 《Acta paediatrica (Oslo, Norway : 1992)》1995,84(5):544-549
Recently produced reference curves for various ultrasound dimensions were used to retrospectively assess 67 pelvic ultrasound scans carried out at the initial presentation in girls with sexual precocity. At presentation the group with precocious puberty had significantly increased uterine lengths and ovarian volumes compared with the normal population, and a significantly increased fundal–cervical ratio. Ovarian volume was also significantly increased in thelarche and thelarche variant. The fundal–cervical ratio was significantly increased in thelarche variant. There was considerable overlap between individuals with sexual precocity and normal subjects. The ultrasound findings that best discriminated early or precocious puberty from other forms of sexual precocity were the presence of a midline endometrial echo, and a uterine length above the 97th centile for age. An entirely normal pelvic ultrasound at presentation did not rule out the possibility of precocious puberty. 相似文献
38.
Background
The Licensing Act 2003 (The Act) was implemented on the 24th November 2005 across England and Wales. The Act allowed more flexible and longer opening hours for licensed premises. We investigated the effect of The Act on alcohol related attendances to an inner city emergency department in Birmingham, UK. 相似文献39.
Wang WS; Fan FS; Hsieh RK; Chiou TJ; Lin JK; Lin TC; Yen CC; Liu JH; Hsu H; Chen PM 《Japanese journal of clinical oncology》1997,27(3):174-179
5-Fluorouracil in combination with leucovorin has been shown to be active
in therapeutic trials of metastatic colorectal carcinoma. In this study, we
administered these drugs to 72 patients with metastatic colorectal
carcinoma. Thirty-six of them without previous exposure to 5-fluorouracil
were treated with weekly bolus injections of 5-fluorouracil (425 mg/m2) and
leucovorin (25 mg/m2) supplemented with oral levamisole. Another 36
patients with or without prior 5-fluorouracil treatment received
5-fluorouracil 3,000 mg/m2 and leucovorin 300 mg/m2 in a 48-hour continuous
infusion every two weeks. Clinical efficacy and toxicity were assessed by
WHO criteria. Variables were tested for relations to response and survival
by univariate and multivariate analysis. The response rate was 19.4% in
weekly bolus arm and 13.9% in biweekly high-dose infusion arm (P = 0.527).
Median survivals in the two arms were 18.4 months (weekly) and 21 months
(biweekly) respectively (P = 0.708). Gastrointestinal side effects
including nausea, vomiting, diarrhea and mucositia were the major
toxicities of these regimens. By multivariate analysis, the only factor to
influence response rate was the site of metastases (P = 0.009). The only
factor to affect survival was performance status of the patient (P =
0.0001). We concluded that the two 5-fluorouracil based regimens are
well-tolerated and shown to have a response rate comparable with previous
reports of similar regimens in patients with metastatic colorectal cancer.
Only liver metastases seemed to have a better response to therapy.
Performance status is the most important prognostic factor in patients with
metastatic colorectal cancer.
相似文献
40.
Wang WS; Liu JH; Chiou TJ; Hsieh RK; Yen CC; Chen PM 《Japanese journal of clinical oncology》1997,27(3):180-184
A 28-year-old woman was admitted to our Hospital with a chief complaint of
progressive gingival swelling and loosening of teeth over about a year.
According to past history, she had received total thyroidectomy 2 years
previously due to thyromegaly. The thyroidectomy specimen was at first
interpreted as 'poorly differentiated carcinoma of the thyroid'. One year
ago, she began to be aware of gingival swelling and loosening of teeth. A
gum biopsy was taken and the pathologic features were similar to her
'thyroid carcinoma'. Subsequent investigations, including
immunohistochemical stain, showed the gum was heavily infiltrated with
histiocyte-like Langerhans' cells which were positive for S-100 protein.
Ultrastructural examination of the cells under electron microscope revealed
many typical intra-cytoplasmic Birbeck granules. Langerhans' cell
histiocytosis was diagnosed. Langerhans' cell histiocytosis with thyroid
involvement is extremely rare and may run a relatively indolent course.
Even on a retrospective examination, it may easily be confused with poorly
differentiated carcinoma of the thyroid. We suspect that this error may
have been made on other occasions and that the occurrence of this condition
may be underreported.
相似文献