Mutations in the E2 glycoprotein and the 3\u27 untranslated region enhance chikungunya virus virulence in mice

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes debilitating musculoskeletal pain and inflammation and can persist for months to years after acute infection. Although studies of humans and experimentally infected animals suggest that CHIKV infection persists in musculoskeletal tissues, the mechanisms for this remain poorly understood. To evaluate this further, we isolated CHIKV from the serum of persistently infected Rag1 -/- mice at day 28. When inoculated into naive wild-type (WT) mice, this persistently circulating CHIKV strain displayed a capacity for earlier dissemination and greater pathogenicity than the parental virus. Sequence analysis revealed a nonsynonymous mutation in the E2 glycoprotein (E2 K200R) and a deletion within the 3' untranslated region (3'-UTR). The introduction of these changes into the parental virus conferred enhanced virulence in mice, although primary tropism for musculoskeletal tissues was maintained. The E2 K200R mutation was largely responsible for enhanced viral dissemination and pathogenicity, although these effects were augmented by the 3'- UTR deletion. Finally, studies with Irf3/Irf7 -/- and Ifnar1 -/- mice suggest that the E2 K200R mutation enhances viral dissemination from the site of inoculation independently of interferon regulatory factor 3 (IRF3)-, IRF7-, and IFNAR1-mediated responses. As our findings reveal viral determinants of CHIKV dissemination and pathogenicity, their further study should help to elucidate host-virus interactions that determine acute and chronic CHIKV infection

Insect visual sensitivity to long wavelengths enhances colour contrast of insects against vegetation

The sensitivity of animal photoreceptors to different wavelengths of light strongly influence the perceived visual contrast of objects in the environment. Outside of the human visual wavelength range, ultraviolet sensitivity in many species provides important and behaviourally relevant visual contrast between objects. However, at the opposite end of the spectrum, the potential advantage of red sensitivity remains unclear. We investigated the potential benefit of long wavelength sensitivity by modelling the visual contrast of a wide range of jewel beetle colours against flowers and leaves of their host plants to hypothetical insect visual systems. We find that the presence of a long wavelength sensitive photoreceptor increases estimated colour contrast, particularly of beetles against leaves. Moreover, under our model parameters, a trichromatic visual system with ultraviolet (λ(max) = 355 nm), short (λ(max) = 445 nm) and long (λ(max) = 600 nm) wavelength photoreceptors performed as well as a tetrachromatic visual system, which had an additional medium wavelength photoreceptor (λ(max) = 530 nm). When we varied λ(max) for the long wavelength sensitive receptor in a tetrachromatic system, contrast values between beetles, flowers and leaves were all enhanced with increasing λ(max) from 580 nm to at least 640 nm. These results suggest a potential advantage of red sensitivity in visual discrimination of insect colours against vegetation and highlight the potential adaptive value of long wavelength sensitivity in insects

Palliative care and Parkinson's disease : meeting summary and recommendations for clinical research

Introduction: Palliative care is an approach to caring for patients and families affected by serious illnesses that focuses on the relief of suffering through the management of medical symptoms, psychosocial issues, advance care planning and spiritual wellbeing. Over the past decade there has been an emerging clinical and research interest in the application of palliative care approaches to Parkinson’s disease (PD) and outpatient palliative care services are now offered by several movement disorders centers. Methods: An International Working Group Meeting on PD and Palliative Care supported by the Parkinson’s Disease Foundation was held in October 2015 to review the current state of the evidence and to make recommendations for clinical research and practice. Results: Topics included: 1) Defining palliative care for PD; 2) Lessons from palliative care for heart failure and other chronic illnesses; 3) Patient and caregiver Needs; 4) Needs assessment tools; 5) Intervention strategies; 6) Predicting prognosis and hospice referrals; 7) Choice of appropriate outcome measures; 8) Implementation, dissemination and education research; and 9) Need for research collaborations. We provide an overview of these discussions, summarize current evidence and practices, highlight gaps in our knowledge and make recommendations for future research. Conclusions: Palliative Care for PD is a rapidly growing area which holds great promise for improving outcomes for PD patients and their caregivers. While clinical research in this area can build from lessons learned in other diseases, there is a need for observational, methodological and interventional research to address the unique needs of PD patients and caregivers

Comparisons of Two Proteomic Analyses of Non-Mucoid and Mucoid Pseudomonas aeruginosa Clinical Isolates from a Cystic Fibrosis Patient

Pseudomonas aeruginosa chronically infects the lungs of cystic fibrosis (CF) patients. The conditions in the CF lung appear to select for P. aeruginosa with advantageous phenotypes for chronic infection. However, the mechanisms that allow the establishment of this chronic infection have not been fully characterized. We have previously reported the transcriptional analysis of two CF isolates strains 383 and 2192. Strain 2192 is a mucoid, alginate overproducing strain whereas strain 383 is non-mucoid. Mucoid strains are associated with chronic infection of the CF lung and non-mucoid strains are the typical initially infecting isolates. To elucidate novel differences between these two strains, we employed two methods of shotgun proteomics: isobaric tags for relative and absolute quantitation (iTRAQ) and two-dimensional gel electrophoresis (2-DE). iTRAQ compares the amount of protein between samples and relies on protein abundance, while 2-DE gel electrophoresis depends on selection of separated protein spots. For both these methods, mass spectrometry was then used to identify proteins differentially expressed between the two strains. The compilation of these two proteomic methods along with Western blot analysis revealed proteins of the HSI-I operon of the type 6 secretion system, showed increased expression in 383 compared to 2192, confirming the our previous transcriptional analysis. Proteomic analysis of other proteins did not fully correlate with the transcriptome but other differentially expressed proteins are discussed. Also, differences were noted between the results obtained for the two proteomic techniques. These shotgun proteomic analyses identified proteins that had been predicted only through gene identification; we now refer to these as “proteins of unknown functions” since their existence has now been established however their functional characterization remains to be elucidated

Matrix Rigidity Regulates Cancer Cell Growth by Modulating Cellular Metabolism and Protein Synthesis

Background: Tumor cells in vivo encounter diverse types of microenvironments both at the site of the primary tumor and at sites of distant metastases. Understanding how the various mechanical properties of these microenvironments affect the biology of tumor cells during disease progression is critical in identifying molecular targets for cancer therapy. Methodology/Principal Findings: This study uses flexible polyacrylamide gels as substrates for cell growth in conjunction with a novel proteomic approach to identify the properties of rigidity-dependent cancer cell lines that contribute to their differential growth on soft and rigid substrates. Compared to cells growing on more rigid/stiff substrates (>10,000 Pa), cells on soft substrates (150–300 Pa) exhibited a longer cell cycle, due predominantly to an extension of the G1 phase of the cell cycle, and were metabolically less active, showing decreased levels of intracellular ATP and a marked reduction in protein synthesis. Using stable isotope labeling of amino acids in culture (SILAC) and mass spectrometry, we measured the rates of protein synthesis of over 1200 cellular proteins under growth conditions on soft and rigid/stiff substrates. We identified cellular proteins whose syntheses were either preferentially inhibited or preserved on soft matrices. The former category included proteins that regulate cytoskeletal structures (e.g., tubulins) and glycolysis (e.g., phosphofructokinase-1), whereas the latter category included proteins that regulate key metabolic pathways required for survival, e.g., nicotinamide phosphoribosyltransferase, a regulator of the NAD salvage pathway. Conclusions/Significance: The cellular properties of rigidity-dependent cancer cells growing on soft matrices are reminiscent of the properties of dormant cancer cells, e.g., slow growth rate and reduced metabolism. We suggest that the use of relatively soft gels as cell culture substrates would allow molecular pathways to be studied under conditions that reflect the different mechanical environments encountered by cancer cells upon metastasis to distant sites

Systematic inference of the long-range dependence and heavy-tail distribution parameters of ARFIMA models

Long-Range Dependence (LRD) and heavy-tailed distributions are ubiquitous in natural and socio-economic data. Such data can be self-similar whereby both LRD and heavy-tailed distributions contribute to the self-similarity as measured by the Hurst exponent. Some methods widely used in the physical sciences separately estimate these two parameters, which can lead to estimation bias. Those which do simultaneous estimation are based on frequentist methods such as Whittle’s approximate maximum likelihood estimator. Here we present a new and systematic Bayesian framework for the simultaneous inference of the LRD and heavy-tailed distribution parameters of a parametric ARFIMA model with non-Gaussian innovations. As innovations we use the α-stable and t-distributions which have power law tails. Our algorithm also provides parameter uncertainty estimates. We test our algorithm using synthetic data, and also data from the Geostationary Operational Environmental Satellite system (GOES) solar X-ray time series. These tests show that our algorithm is able to accurately and robustly estimate the LRD and heavy-tailed distribution parameters

An Early and Comprehensive Millimetre and Centimetre Wave and X-ray Study of SN 2011dh: a Non-Equipartition Blast Wave Expanding into a Massive Stellar Wind

Only a handful of supernovae (SNe) have been studied in multiwavelengths from the radio to X-rays, starting a few days after the explosion. The early detection and classification of the nearby Type IIb SN 2011dh/PTF 11eon in M51 provides a unique opportunity to conduct such observations. We present detailed data obtained at one of the youngest phase ever of a core-collapse SN (days 3–12 after the explosion) in the radio, millimetre and X-rays; when combined with optical data, this allows us to explore the early evolution of the SN blast wave and its surroundings. Our analysis shows that the expanding SN shock wave does not exhibit equipartition (ϵe/ϵB ∼ 1000), and is expanding into circumstellar material that is consistent with a density profile falling like R−2. Within modelling uncertainties we find an average velocity of the fast parts of the ejecta of 15 000 ± 1800 km s−1, contrary to previous analysis. This velocity places SN 2011dh in an intermediate blast wave regime between the previously defined compact and extended SN Type IIb subtypes. Our results highlight the importance of early (∼1 d) high-frequency observations of future events. Moreover, we show the importance of combined radio/X-ray observations for determining the microphysics ratio ϵe/ϵB

Real-Time Detection and Rapid Multiwavelength Follow-up Observations of a Highly Subluminous Type II-P Supernova from the Palomar Transient Factory Survey

The Palomar Transient Factory (PTF) is an optical wide-field variability survey carried out using a camera with a 7.8 square degree field of view mounted on the 48-in Oschin Schmidt telescope at Palomar Observatory. One of the key goals of this survey is to conduct high-cadence monitoring of the sky in order to detect optical transient sources shortly after they occur. Here, we describe the real-time capabilities of the PTF and our related rapid multiwavelength follow-up programs, extending from the radio to the gamma-ray bands. We present as a case study observations of the optical transient PTF10vdl (SN 2010id), revealed to be a very young core-collapse (Type II-P) supernova having a remarkably low luminosity. Our results demonstrate that the PTF now provides for optical transients the real-time discovery and rapid-response follow-up capabilities previously reserved only for high-energy transients like gamma-ray bursts.Comment: ApJ, in press; all spectroscopic data available from the Weizmann Institute of Science Experimental Astrophysics Spectroscopy System (WISEASS; http://www.weizmann.ac.il/astrophysics/wiseass/

Cerebrospinal fluid soluble TREM2 levels in frontotemporal dementia differ by genetic and pathological subgroup.

BACKGROUND: Reliable biomarkers of frontotemporal dementia (FTD) are currently lacking. FTD may be associated with chronic immune dysfunction, microglial activation and raised inflammatory markers, particularly in progranulin (GRN) mutation carriers. Levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) are elevated in Alzheimer's disease (AD), but they have not been fully explored in FTD. METHODS: We investigated whether cerebrospinal fluid (CSF) sTREM2 levels differ between FTD and controls, across different clinical and genetic subtypes of FTD, or between individuals with FTD due to AD versus non-AD pathology (based on CSF neurodegenerative biomarkers). We also assessed relationships between CSF sTREM2 and other CSF biomarkers (total tau [T-tau], tau phosphorylated at position threonine-181 [P-tau] and β-amyloid 1-42 [Aβ42]) and age and disease duration. Biomarker levels were measured using immunoassays in 17 healthy controls and 64 patients with FTD (behavioural variant FTD, n = 20; primary progressive aphasia, n = 44). Ten of 64 had familial FTD, with mutations in GRN (n = 3), MAPT (n = 4), or C9orf72 (n = 3). Fifteen of 64 had neurodegenerative biomarkers consistent with AD pathology (11 of whom had logopenic variant PPA). Levels were compared using multivariable linear regressions. RESULTS: CSF sTREM2 levels did not differ between FTD and controls or between clinical subgroups. However, GRN mutation carriers had higher levels than controls (mean ([SD] = 9.7 [2.9] vs. 6.8 [1.6] ng/ml; P = 0.028) and MAPT (3.9 [1.5] ng/ml; P = 0.003] or C9orf72 [4.6 [1.8] ng/ml; P = 0.006) mutation carriers. Individuals with AD-like CSF had higher sTREM2 levels than those with non-AD-like CSF (9.0 [3.6] vs. 6.9 [3.0] ng/ml; P = 0.029). CSF sTREM2 levels were associated with T-tau levels in control and FTD groups and also with P-tau in those with FTD and AD-like CSF. CSF sTREM2 levels were influenced by both age and disease duration in FTD. CONCLUSIONS: Although CSF sTREM2 levels are not raised in FTD overall or in a particular clinical subtype of FTD, levels are raised in familial FTD associated with GRN mutations and in FTD syndromes due to AD pathology. Because CSF sTREM2 levels correlate with a marker of neuronal injury (T-tau), sTREM2 should be explored as a biomarker of disease intensity in future longitudinal studies of FTD

An Early & Comprehensive Millimeter and Centimeter Wave and X-ray Study of Supernova 2011dh: A Non-Equipartition Blastwave Expanding into A Massive Stellar Wind

Only a handful of supernovae (SNe) have been studied in multi-wavelength from radio to X-rays, starting a few days after explosion. The early detection and classification of the nearby type IIb SN2011dh/PTF11eon in M51 provides a unique opportunity to conduct such observations. We present detailed data obtained at the youngest phase ever of a core-collapse supernova (days 3 to 12 after explosion) in the radio, millimeter and X-rays; when combined with optical data, this allows us to explore the early evolution of the SN blast wave and its surroundings. Our analysis shows that the expanding supernova shockwave does not exhibit equipartition (e_e/e_B ~ 1000), and is expanding into circumstellar material that is consistent with a density profile falling like R^-2. Within modeling uncertainties we find an average velocity of the fast parts of the ejecta of 15,000 +/- 1800 km/s, contrary to previous analysis. This velocity places SN 2011dh in an intermediate blast-wave regime between the previously defined compact and extended SN IIb subtypes. Our results highlight the importance of early (~ 1 day) high-frequency observations of future events. Moreover, we show the importance of combined radio/X-ray observations for determining the microphysics ratio e_e/e_B.Comment: 9 pages, 5 figures, submitted to Ap