Molecular Changes in Dengue Envelope Protein Domain III upon Interaction with Glycosaminoglycans.

Dengue fever is a rapidly emerging vector-borne viral disease with a growing global burden of approximately 390 million new infections per annum. The Dengue virus (DENV) is a flavivirus spread by female mosquitos of the aedes genus, but the mechanism of viral endocytosis is poorly understood at a molecular level, preventing the development of effective transmission blocking vaccines (TBVs). Recently, glycosaminoglycans (GAGs) have been identified as playing a role during initial viral attachment through interaction with the third domain of the viral envelope protein (EDIII). Here, we report a systematic study investigating the effect of a range of biologically relevant GAGs on the structure and oligomeric state of recombinantly generated EDIII. We provide novel in situ biophysical evidence that heparin and chondroitin sulphate C induce conformational changes in EDIII at the secondary structure level. Furthermore, we report the ability of chondroitin sulphate C to bind EDIII and induce higher-order dynamic molecular changes at the tertiary and quaternary structure levels which are dependent on pH, GAG species, and the GAG sulphation state. Lastly, we conducted ab initio modelling of Small Angle Neutron Scattering (SANS) data to visualise the induced oligomeric state of EDIII caused by interaction with chondroitin sulphate C, which may aid in TBV development

Genetic specification of left-right asymmetry in the diaphragm muscles and their motor innervation.

The diaphragm muscle is essential for breathing in mammals. Its asymmetric elevation during contraction correlates with morphological features suggestive of inherent left-right (L/R) asymmetry. Whether this asymmetry is due to L versus R differences in the muscle or in the phrenic nerve activity is unknown. Here, we have combined the analysis of genetically modified mouse models with transcriptomic analysis to show that both the diaphragm muscle and phrenic nerves have asymmetries, which can be established independently of each other during early embryogenesis in pathway instructed by Nodal, a morphogen that also conveys asymmetry in other organs. We further found that phrenic motoneurons receive an early L/R genetic imprint, with L versus R differences both in Slit/Robo signaling and MMP2 activity and in the contribution of both pathways to establish phrenic nerve asymmetry. Our study therefore demonstrates L-R imprinting of spinal motoneurons and describes how L/R modulation of axon guidance signaling helps to match neural circuit formation to organ asymmetry

BOW SHOCK FRAGMENTATION DRIVEN BY A THERMAL INSTABILITY IN LABORATORY ASTROPHYSICS EXPERIMENTS

The role of radiative cooling during the evolution of a bow shock was studied in laboratory-astrophysics experiments that are scalable to bow shocks present in jets from young stellar objects. The laboratory bow shock is formed during the collision of two counter-streaming, supersonic plasma jets produced by an opposing pair of radial foil Z-pinches driven by the current pulse from the MAGPIE pulsed-power generator. The jets have different flow velocities in the laboratory frame and the experiments are driven over many times the characteristic cooling time-scale. The initially smooth bow shock rapidly develops small-scale non-uniformities over temporal and spatial scales that are consistent with a thermal instability triggered by strong radiative cooling in the shock. The growth of these perturbations eventually results in a global fragmentation of the bow shock front. The formation of a thermal instability is supported by analysis of the plasma cooling function calculated for the experimental conditions with the radiative packages ABAKO/RAPCAL.Comment: 9 pages, 5 figures, Accepted for publication in The Astrophysical Journal on 5th November 201

Comparing urine samples and cervical swabs for Chlamydia testing in a female population by means of Strand Displacement Assay (SDA)

<p>Abstract</p> <p>Background</p> <p>There has been an increasing number of diagnosed cases of <it>Chlamydia trachomatis </it>in many countries, in particular among young people. The present study was based on a growing request to examine urine as a supplementary or primary specimen in screening for <it>Chlamydia trachomatis </it>in women, with the Becton Dickinson ProbeTec (BDPT) Strand Displacement Assay (SDA). Urine samples may be particularly important in screening young people who are asymptomatic.</p> <p>Methods</p> <p>A total of 603 women aged 15 and older were enrolled from the Sexually Transmitted Infection (STI) clinic at Haukeland University Hospital, Norway, in 2007. Only 31 women were older than 35 years. Cervical swabs and urine samples were tested with BDPT for all participants. In cases of discrepant test results from a given patient, both samples were retested by Cobas TaqManCT and a Polymerase Chain Reaction (PCR)-method (in-house). Prevalence of <it>C. trachomatis</it>, sensitivity, and specificity were estimated by latent class analysis using all test results available. Bootstrap BC confidence intervals (10 000 computations) were estimated for sensitivity and specificity, and their differences in cervix vs. urine tests.</p> <p>Results</p> <p>A total of 1809 specimens were collected from 603 patients. 80 women (13.4%) were positive for <it>C. trachomatis</it>. Among these, BDPT identified 72 and 73 as positive in cervix and urine samples, respectively. Of the 523 <it>C. trachomatis </it>negative women, BDPT identified 519 as negative based on cervical swabs, and 514 based on urine samples. Sensitivity for cervical swabs and urine samples with the BDPT were 89.0% (95% CI 78.8, 98.6) and 90.2% (95% CI 78.1, 95.5), respectively. The corresponding values for specificity were 99.2% (95% CI 98.3, 100) and 98.3% (95% CI 96.4, 100).</p> <p>Conclusions</p> <p>This study indicates that urine specimens are adequate for screening high-risk groups for <it>C. trachomatis </it>by the SDA method (BDPT). Such an approach may facilitate early detection and treatment of the target groups for screening, and be cost-effective for patients and the health services.</p

Study of Bc+B_c^+ decays to the K+K−π+K^+K^-\pi^+ final state and evidence for the decay Bc+→χc0π+B_c^+\to\chi_{c0}\pi^+

A study of $B_c^+\to K^+K^-\pi^+$ decays is performed for the first time using data corresponding to an integrated luminosity of 3.0 $\mathrm{fb}^{-1}$ collected by the LHCb experiment in $pp$ collisions at centre-of-mass energies of $7$ and $8$ TeV. Evidence for the decay $B_c^+\to\chi_{c0}(\to K^+K^-)\pi^+$ is reported with a significance of 4.0 standard deviations, resulting in the measurement of $\frac{\sigma(B_c^+)}{\sigma(B^+)}\times\mathcal{B}(B_c^+\to\chi_{c0}\pi^+)$ to be $(9.8^{+3.4}_{-3.0}(\mathrm{stat})\pm 0.8(\mathrm{syst}))\times 10^{-6}$. Here $\mathcal{B}$ denotes a branching fraction while $\sigma(B_c^+)$ and $\sigma(B^+)$ are the production cross-sections for $B_c^+$ and $B^+$ mesons. An indication of $\bar b c$ weak annihilation is found for the region $m(K^-\pi^+)<1.834\mathrm{\,Ge\kern -0.1em V\!/}c^2$, with a significance of 2.4 standard deviations.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-022.html, link to supplemental material inserted in the reference

Increased Expression of PITX2 Transcription Factor Contributes to Ovarian Cancer Progression

BACKGROUND: Paired-like homeodomain 2 (PITX2) is a bicoid homeodomain transcription factor which plays an essential role in maintaining embryonic left-right asymmetry during vertebrate embryogenesis. However, emerging evidence suggests that the aberrant upregulation of PITX2 may be associated with tumor progression, yet the functional role that PITX2 plays in tumorigenesis remains unknown. PRINCIPAL FINDINGS: Using real-time quantitative RT-PCR (Q-PCR), Western blot and immunohistochemical (IHC) analyses, we demonstrated that PITX2 was frequently overexpressed in ovarian cancer samples and cell lines. Clinicopathological correlation showed that the upregulated PITX2 was significantly associated with high-grade (P = 0.023) and clear cell subtype (P = 0.011) using Q-PCR and high-grade (P<0.001) ovarian cancer by IHC analysis. Functionally, enforced expression of PITX2 could promote ovarian cancer cell proliferation, anchorage-independent growth ability, migration/invasion and tumor growth in xenograft model mice. Moreover, enforced expression of PITX2 elevated the cell cycle regulatory proteins such as Cyclin-D1 and C-myc. Conversely, RNAi mediated knockdown of PITX2 in PITX2-high expressing ovarian cancer cells had the opposite effect. CONCLUSION: Our findings suggest that the increased expression PITX2 is involved in ovarian cancer progression through promoting cell growth and cell migration/invasion. Thus, targeting PITX2 may serve as a potential therapeutic modality in the management of high-grade ovarian tumor.published_or_final_versio

Windbreaks in North American Agricultural Systems

Windbreaks are a major component of successful agricultural systems throughout the world. The focus of this chapter is on temperate-zone, commercial, agricultural systems in North America, where windbreaks contribute to both producer profitability and environmental quality by increasing crop production while simultaneously reducing the level of off-farm inputs. They help control erosion and blowing snow, improve animal health and survival under winter conditions, reduce energy consumption of the farmstead unit, and enhance habitat diversity, providing refuges for predatory birds and insects. On a larger landscape scale windbreaks provide habitat for various types of wildlife and have the potential to contribute significant benefits to the carbon balance equation, easing the economic burdens associated with climate change. For a windbreak to function properly, it must be designed with the needs of the landowner in mind. The ability of a windbreak to meet a specific need is determined by its structure: both external structure, width, height, shape, and orientation as well as the internal structure; the amount and arrangement of the branches, leaves, and stems of the trees or shrubs in the windbreak. In response to windbreak structure, wind flow in the vicinity of a windbreak is altered and the microclimate in sheltered areas is changed; temperatures tend to be slightly higher and evaporation is reduced. These types of changes in microclimate can be utilized to enhance agricultural sustainability and profitability. While specific mechanisms of the shelter response remain unclear and are topics for further research, the two biggest challenges we face are: developing a better understanding of why producers are reluctant to adopt windbreak technology and defining the role of woody plants in the agricultural landscape

Mutation in the Gene Encoding Ubiquitin Ligase LRSAM1 in Patients with Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease (CMT) represents a family of related sensorimotor neuropathies. We studied a large family from a rural eastern Canadian community, with multiple individuals suffering from a condition clinically most similar to autosomal recessive axonal CMT, or AR-CMT2. Homozygosity mapping with high-density SNP genotyping of six affected individuals from the family excluded 23 known genes for various subtypes of CMT and instead identified a single homozygous region on chromosome 9, at 122,423,730–129,841,977 Mbp, shared identical by state in all six affected individuals. A homozygous pathogenic variant was identified in the gene encoding leucine rich repeat and sterile alpha motif 1 (LRSAM1) by direct DNA sequencing of genes within the region in affected DNA samples. The single nucleotide change mutates an intronic consensus acceptor splicing site from AG to AA. Direct analysis of RNA from patient blood demonstrated aberrant splicing of the affected exon, causing an obligatory frameshift and premature truncation of the protein. Western blotting of immortalized cells from a homozygous patient showed complete absence of detectable protein, consistent with the splice site defect. LRSAM1 plays a role in membrane vesicle fusion during viral maturation and for proper adhesion of neuronal cells in culture. Other ubiquitin ligases play documented roles in neurodegenerative diseases. LRSAM1 is a strong candidate for the causal gene for the genetic disorder in our kindred

Depression and Sexual Orientation During Young Adulthood: Diversity Among Sexual Minority Subgroups and the Role of Gender Nonconformity.

Sexual minority individuals are at an elevated risk for depression compared to their heterosexual counterparts, yet less is known about how depression status varies across sexual minority subgroups (i.e., mostly heterosexuals, bisexuals, and lesbians and gay men). Moreover, studies on the role of young adult gender nonconformity in the relation between sexual orientation and depression are scarce and have yielded mixed findings. The current study examined the disparities between sexual minorities and heterosexuals during young adulthood in concurrent depression near the beginning of young adulthood and prospective depression 6 years later, paying attention to the diversity within sexual minority subgroups and the role of gender nonconformity. Drawn from the National Longitudinal Study of Adolescent Health (N = 9421), we found that after accounting for demographics, sampling weight, and sampling design, self-identified mostly heterosexual and bisexual young adults, but not lesbians and gay men, reported significantly higher concurrent depression compared to heterosexuals; moreover, only mostly heterosexual young adults were more depressed than heterosexuals 6 years later. Furthermore, while young adult gender nonconforming behavior was associated with more concurrent depression regardless of sexual orientation, its negative impact on mental health decreased over time. Surprisingly, previous gender nonconformity predicted decreased prospective depression among lesbians and gay men whereas, among heterosexual individuals, increased gender nonconformity was not associated with prospective depression. Together, the results suggested the importance of investigating diversity and the influence of young adult gender nonconformity in future research on the mental health of sexual minorities.The authors acknowledge support for this research: the University of Arizona Norton School of Family and Consumer Sciences Fitch Nesbitt Endowment and a University of Arizona Graduate Access Fellowship to the second author. This research uses data from Add Health, a program project directed by Kathleen Mullan Harris and designed by J. Richard Udry, Peter S. Bearman, and Kathleen Mullan Harris at the University of North Carolina at Chapel Hill, and funded by grant P01-HD31921 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with cooperative funding from 23 other federal agencies and foundations. Special acknowledgment is due Ronald R. Rindfuss and Barbara Entwisle for assistance in the original design. Information on how to obtain the Add Health data files is available on the Add Health website (http://​www.​cpc.​unc.​edu/​addhealth). No direct support was received from grant P01-HD31921 for this analysis. The authors thank Noel Card and Susan Stryker for comments on the previous versions of this article and Richard Lippa and Katerina Sinclair for methodological and statistical consult. The authors also thank the anonymous reviewers and the Editor for their helpful comments.This is the accepted manuscript of a paper published in Archives of Sexual Behavior (Li G, Pollitt AM, Russell ST, Archives of Sexual Behavior 2015, doi:10.1007/s10508-015-0515-3). The final version is available at http://dx.doi.org/10.1007/s10508-015-0515-3

Global Distribution of Polaromonas Phylotypes - Evidence for a Highly Successful Dispersal Capacity

Bacteria from the genus Polaromonas are dominant phylotypes in clone libraries and culture collections from polar and high-elevation environments. Although Polaromonas has been found on six continents, we do not know if the same phylotypes exist in all locations or if they exhibit genetic isolation by distance patterns. To examine their biogeographic distribution, we analyzed all available, long-read 16S rRNA gene sequences of Polaromonas phylotypes from glacial and periglacial environments across the globe. Using genetic isolation by geographic distance analyses, including Mantel tests and Mantel correlograms, we found that Polaromonas phylotypes are globally distributed showing weak isolation by distance patterns at global scales. More focused analyses using discrete, equally sampled distances classes, revealed that only two distance classes (out of 12 total) showed significant spatial structuring. Overall, our analyses show that most Polaromonas phylotypes are truly globally distributed, but that some, as yet unknown, environmental variable may be selecting for unique phylotypes at a minority of our global sites. Analyses of aerobiological and genomic data suggest that Polaromonas phylotypes are globally distributed as dormant cells through high-elevation air currents; Polaromonas phylotypes are common in air and snow samples from high altitudes, and a glacial-ice metagenome and the two sequenced Polaromonas genomes contain the gene hipA, suggesting that Polaromonas can form dormant cells