Enhanced roughness of lipid membranes caused by external electric fields

The behavior of lipid membranes in the presence of an external electric field is studied and used to examine the influence of such fields on membrane parameters such as roughness and show that for a micro sized membrane, roughness grows as the field increases. The dependence of bending rigidity on the electric field is also studied and an estimation of thickness of the accumulated charges around lipid membranes in a free-salt solution is presented.Comment: 9 pages, 6 figures, to appear in Computational Materials Scienc

Pragmatic methods for reviewing exceptionally large bodies of evidence: systematic mapping review and overview of systematic reviews using lung cancer survival as an exemplar.

INTRODUCTION:Lung cancer (LC) is the most common cause of cancer death in the world and associated with significant economic burden. We conducted a review of published literature to identify prognostic factors associated with LC survival and determine which may be modifiable and could be targeted to improve outcomes. METHODS:The exceptionally large volume of LC prognostic research required a new staged approach to reviewing the literature. This comprised an initial mapping review of existing reviews or meta-analyses, based on titles and abstracts, followed by an overview of systematic reviews evaluating factors that independently contribute to lung cancer survival. The overview of reviews was based on full text papers and incorporated a more in-depth assessment of reviews evaluating modifiable factors. RESULTS:A large volume of published systematic reviews and meta-analyses were identified, but very few focused on modifiable factors for LC survival. Several modifiable factors were identified, which are potential candidates for targeted interventions aiming to improve cancer outcomes. The mapping review included 398 reviews, of which 207 investigated the independent effect of prognostic factors on lung cancer survival. The most frequently evaluated factors were novel biomarkers (86 biomarkers in 138 reviews). Only 15 modifiable factors were investigated in 20 reviews. Those associated with significant survival improvement included normal BMI/less weight loss, good performance status, not smoking/quitting after diagnosis, good pre-treatment quality of life, small gross volume tumour, early-stage tumour, lung resection undertaken by a thoracic/cardiothoracic surgeon, care being discussed by a multidisciplinary team, and timeliness of care. CONCLUSIONS:The study utilised a novel approach for reviewing an extensive and complicated body of research evidence. It enabled us to address a broad research question and focus on a specific area of priority. The staged approach ensured the review remained relevant to the stakeholders throughout, whilst maintaining the use of objective and transparent methods. It also provided important information on the needs of future research. However, it required extensive planning, management, and ongoing reviewer training

Gene discovery in the hamster: a comparative genomics approach for gene annotation by sequencing of hamster testis cDNAs

BACKGROUND: Complete genome annotation will likely be achieved through a combination of computer-based analysis of available genome sequences combined with direct experimental characterization of expressed regions of individual genomes. We have utilized a comparative genomics approach involving the sequencing of randomly selected hamster testis cDNAs to begin to identify genes not previously annotated on the human, mouse, rat and Fugu (pufferfish) genomes. RESULTS: 735 distinct sequences were analyzed for their relatedness to known sequences in public databases. Eight of these sequences were derived from previously unidentified genes and expression of these genes in testis was confirmed by Northern blotting. The genomic locations of each sequence were mapped in human, mouse, rat and pufferfish, where applicable, and the structure of their cognate genes was derived using computer-based predictions, genomic comparisons and analysis of uncharacterized cDNA sequences from human and macaque. CONCLUSION: The use of a comparative genomics approach resulted in the identification of eight cDNAs that correspond to previously uncharacterized genes in the human genome. The proteins encoded by these genes included a new member of the kinesin superfamily, a SET/MYND-domain protein, and six proteins for which no specific function could be predicted. Each gene was expressed primarily in testis, suggesting that they may play roles in the development and/or function of testicular cells

Fractionated 131I anti-CEA radioimmunotherapy: effects on xenograft tumour growth and haematological toxicity in mice

Dose fractionation has been proposed as a method to improve the therapeutic ratio of radioimmunotherapy (RIT). This study compared a single administration of 7.4 MBq 131I-anti-CEA antibody given on day 1 with the same total activity given as fractionated treatment: 3.7 MBq (days 1 and 3), 2.4 MBq (days 1, 3, and 5) or 1.8 MBq (days 1, 3, 5, and 8). Studies in nude mice, bearing the human colorectal xenograft LS174T, showed that increasing the fractionation significantly reduced the efficacy of therapy. Fractionation was associated with a decrease in systemic toxicity as assessed by weight, but did not lead to any significant decrease in acute haematological toxicity. Similarly, no significant decrease in marrow toxicity, as assessed by colony-forming unit assays for granulocytes and macrophages (CFUgm), was seen. However, there was a significant depression of CFUgm counts when all treated animals were compared with untreated controls, suggesting that treatment did suppress marrow function. In conclusion, in this tumour model system, fractionated RIT causes less systemic toxicity, but is also less effective at treating tumours

Is Mn-Bound Substrate Water Protonated in the S2 State of Photosystem II?

In spite of great progress in resolving the geometric structure of the water-splitting Mn4OxCa cluster in photosystem II, the binding sites and modes of the two substrate water molecules are still insufficiently characterized. While time-resolved membrane-inlet mass spectrometry measurements indicate that both substrate water molecules are bound to the oxygen-evolving complex (OEC) in the S2 and S3 states (Hendry and Wydrzynski in Biochemistry 41:13328–13334, 2002), it is not known (1) if they are both Mn-bound, (2) if they are terminal or bridging ligands, and (3) in what protonation state they are bound in the different oxidation states Si (i = 0, 1, 2, 3, 4) of the OEC. By employing 17O hyperfine sublevel correlation (HYSCORE) spectroscopy we recently demonstrated that in the S2 state there is only one (type of) Mn-bound oxygen that is water exchangeable. We therefore tentatively identified this oxygen as one substrate ‘water’ molecule, and on the basis of the finding that it has a hyperfine interaction of about 10 MHz with the electron spin of the Mn4OxCa cluster, we suggest that it is bound as a Mn–O–Mn bridge within a bis-μ2 oxo-bridged unit (Su et al. in J Am Chem Soc 130:786–787, 2008). Employing pulse electron paramagnetic resonance, 1H/2H Mims electron-nuclear double resonance and 2H-HYSCORE spectroscopies together with 1H/2H-exchange here, we test this hypothesis by probing the protonation state of this exchangeable oxygen. We conclude that this oxygen is fully deprotonated. This result is discussed in the light of earlier reports in the literature

A Lipopeptide Facilitate Induction of Mycobacterium leprae Killing in Host Cells

Little is known of the direct microbicidal activity of T cells in leprosy, so a lipopeptide consisting of the N-terminal 13 amino acids lipopeptide (LipoK) of a 33-kD lipoprotein of Mycobacterium leprae, was synthesized. LipoK activated M. leprae infected human dendritic cells (DCs) to induce the production of IL-12. These activated DCs stimulated autologous CD4+ or CD8+ T cells towards type 1 immune response by inducing interferon-gamma secretion. T cell proliferation was also evident from the CFSE labeling of target CD4+ or CD8+ T cells. The direct microbicidal activity of T cells in the control of M. leprae multiplication is not well understood. The present study showed significant production of granulysin, granzyme B and perforin from these activated CD4+ and CD8+ T cells when stimulated with LipoK activated, M. leprae infected DCs. Assessment of the viability of M. leprae in DCs indicated LipoK mediated T cell-dependent killing of M. leprae. Remarkably, granulysin as well as granzyme B could directly kill M. leprae in vitro. Our results provide evidence that LipoK could facilitate M. leprae killing through the production of effector molecules granulysin and granzyme B in T cells

Relaxation of Adaptive Evolution during the HIV-1 Infection Owing to Reduction of CD4+ T Cell Counts

Background: the first stages of HIV-1 infection are essential to establish the diversity of virus population within host. It has been suggested that adaptation to host cells and antibody evasion are the leading forces driving HIV evolution at the initial stages of AIDS infection. in order to gain more insights on adaptive HIV-1 evolution, the genetic diversity was evaluated during the infection time in individuals contaminated by the same viral source in an epidemic cluster. Multiple sequences of V3 loop region of the HIV-1 were serially sampled from four individuals: comprising a single blood donor, two blood recipients, and another sexually infected by one of the blood recipients. the diversity of the viral population within each host was analyzed independently in distinct time points during HIV-1 infection.Results: Phylogenetic analysis identified multiple HIV-1 variants transmitted through blood transfusion but the establishing of new infections was initiated by a limited number of viruses. Positive selection (d(N)/d(S)>1) was detected in the viruses within each host in all time points. in the intra-host viruses of the blood donor and of one blood recipient, X4 variants appeared respectively in 1993 and 1989. in both patients X4 variants never reached high frequencies during infection time. the recipient, who X4 variants appeared, developed AIDS but kept narrow and constant immune response against HIV-1 during the infection time.Conclusion: Slowing rates of adaptive evolution and increasing diversity in HIV-1 are consequences of the CD4+ T cells depletion. the dynamic of R5 to X4 shift is not associated with the initial amplitude of humoral immune response or intensity of positive selection.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fed Univ Para, Inst Biotechnol, BR-66059 Belem, Para, BrazilUniv São Paulo, Inst Trop Med, São Paulo, SP, BrazilCDC, Ctr Dis Control & Prevent, Branch Lab, Atlanta, GA 30333 USAUniv Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USABlood Syst Res Inst, San Francisco, CA USABlood Syst Inc, San Francisco, CA USAUniversidade Federal de São Paulo, São Paulo, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilFAPESP: 07/52841-8Web of Scienc

The attitudes, beliefs and behaviours of GPs regarding exercise for chronic knee pain: a systematic review

<p>Abstract</p> <p>Background</p> <p>Joint pain, specifically chronic knee pain (CKP), is a frequent cause of chronic pain and limitation of function and mobility among older adults. Multiple evidence-based guidelines recommend exercise as a first-line treatment for all patients with CKP or knee osteoarthritis (KOA), yet healthcare practitioners' attitudes and beliefs may limit their implementation. This systematic review aims to identify the attitudes, beliefs and behaviours of General Practitioners (GPs) regarding the use of exercise for CKP/KOA.</p> <p>Methods</p> <p>We searched four electronic databases between inception and January 2008, using subject headings to identify studies examining the attitudes, beliefs or behaviours of GPs regarding the use of exercise for the treatment of CKP/KOA in adults aged over 45 years in primary care. Studies referring to patellofemoral pain syndrome or CKP secondary to other causes or that occurring in a prosthetic joint were excluded. Once inclusion and exclusion criteria were applied, study data were extracted and summarised. Study quality was independently reviewed using two assessment tools.</p> <p>Results</p> <p>From 2135 potentially relevant articles, 20 were suitable for inclusion. A variety of study methodologies and approaches to measuring attitudes beliefs and behaviours were used among the studies. Quality assessment revealed good reporting of study objective, type, outcome factors and, generally, the sampling frame. However, criticisms included use of small sample sizes, low response rates and under-reporting of non-responder factors. Although 99% of GPs agreed that exercise should be used for CKP/KOA and reported ever providing advice or referring to a physiotherapist, up to 29% believed that rest was the optimum management approach. The frequency of actual provision of exercise advice or physiotherapy referral was lower. Estimates of provision of exercise advice and physiotherapy referral were generally higher for vignette-based studies (exercise advice 9%-89%; physiotherapy referral 44%-77%) than reviews of actual practice (exercise advice 5%-52%; physiotherapy referral 13-63%). <it>A</it><it>dvice to exercise </it>and exercise <it>prescription </it>were not clearly differentiated.</p> <p>Conclusions</p> <p>Attitudes and beliefs of GPs towards exercise for CKP/KOA vary widely and exercise appears to be underused in the management of CKP/KOA. Limitations of the evidence base include the paucity of studies directly examining attitudes of GPs, poor methodological quality, limited generalisability of results and ambiguity concerning GPs' expected roles. Further investigation is required of the roles of GPs in using exercise as first-line management of CKP/KOA.</p

Phenotypic Plasticity in Response to the Social Environment: Effects of Density and Sex Ratio on Mating Behaviour Following Ecotype Divergence

The ability to express phenotypically plastic responses to environmental cues might be adaptive in changing environments. We studied phenotypic plasticity in mating behaviour as a response to population density and adult sex ratio in a freshwater isopod (Asellus aquaticus). A. aquaticus has recently diverged into two distinct ecotypes, inhabiting different lake habitats (reed Phragmites australis and stonewort Chara tomentosa, respectively). In field surveys, we found that these habitats differ markedly in isopod population densities and adult sex ratios. These spatially and temporally demographic differences are likely to affect mating behaviour. We performed behavioural experiments using animals from both the ancestral ecotype (“reed” isopods) and from the novel ecotype (“stonewort” isopods) population. We found that neither ecotype adjusted their behaviour in response to population density. However, the reed ecotype had a higher intrinsic mating propensity across densities. In contrast to the effects of density, we found ecotype differences in plasticity in response to sex ratio. The stonewort ecotype show pronounced phenotypic plasticity in mating propensity to adult sex ratio, whereas the reed ecotype showed a more canalised behaviour with respect to this demographic factor. We suggest that the lower overall mating propensity and the phenotypic plasticity in response to sex ratio have evolved in the novel stonewort ecotype following invasion of the novel habitat. Plasticity in mating behaviour may in turn have effects on the direction and intensity of sexual selection in the stonewort habitat, which may fuel further ecotype divergence