Identification of plant-derived alkaloids with therapeutic potential for myotonic dystrophy type I

Myotonic dystrophy type I (DM1) is a disabling neuromuscular disease with no causal treatment available. This disease is caused by expanded CTG trinucleotide repeats in the 3 UTR of the dystrophia myotonica protein kinase gene. On the RNA level, expanded (CUG)n repeats form hairpin structures that sequester splicing factors such as muscleblind-like 1 (MBNL1). Lack of availableMBNL1leads to misregulated alternative splicing of many target pre-mRNAs, leading to the multisystemic symptoms in DM1. Many studies aiming to identify small molecules that target the (CUG)n-MBNL1 complex focused on synthetic molecules. In an effort to identify new small molecules that liberate sequesteredMBNL1from (CUG)n RNA, we focused specifically on small molecules of natural origin. Natural products remain an important source for drugs and play a significant role in providing novel leads and pharmacophores for medicinal chemistry. In a new DM1 mechanism-based biochemical assay, we screened a collection of isolated natural compounds and a library of over 2100 extracts from plants and fungal strains. HPLC-based activity profiling in combination with spectroscopic methods were used to identify the active principles in the extracts. The bioactivity of the identified compounds was investigated in a human cell model and in a mouse model of DM1.We identified several alkaloids, including the -carboline harmine and the isoquinoline berberine, that ameliorated certain aspects of theDM1pathology in these models. Alkaloids as a compound class may have potential for drug discovery in other RNA-mediated diseases

The CLIVAR C20C Project: Which components of the Asian-Australian monsoon circulation variations are forced and reproducible?

A multi-model set of atmospheric simulations forced by historical sea surface temperature (SST) or SSTs plus Greenhouse gases and aerosol forcing agents for the period of 1950–1999 is studied to identify and understand which components of the Asian–Australian monsoon (A–AM) variability are forced and reproducible. The analysis focuses on the summertime monsoon circulations, comparing model results against the observations. The priority of different components of the A–AM circulations in terms of reproducibility is evaluated. Among the subsystems of the wide A–AM, the South Asian monsoon and the Australian monsoon circulations are better reproduced than the others, indicating they are forced and well modeled. The primary driving mechanism comes from the tropical Pacific. The western North Pacific monsoon circulation is also forced and well modeled except with a slightly lower reproducibility due to its delayed response to the eastern tropical Pacific forcing. The simultaneous driving comes from the western Pacific surrounding the maritime continent region. The Indian monsoon circulation has a moderate reproducibility, partly due to its weakened connection to June–July–August SSTs in the equatorial eastern Pacific in recent decades. Among the A–AM subsystems, the East Asian summer monsoon has the lowest reproducibility and is poorly modeled. This is mainly due to the failure of specifying historical SST in capturing the zonal land-sea thermal contrast change across the East Asia. The prescribed tropical Indian Ocean SST changes partly reproduce the meridional wind change over East Asia in several models. For all the A–AM subsystem circulation indices, generally the MME is always the best except for the Indian monsoon and East Asian monsoon circulation indices

Regulatory T Cells Expanded from Hiv-1-Infected Individuals Maintain Phenotype, Tcr Repertoire and Suppressive Capacity

While modulation of regulatory T cell (Treg) function and adoptive Treg transfer are being explored as therapeutic modalities in the context of autoimmune diseases, transplantation and cancer, their role in HIV-1 pathogenesis remains less well defined. Controversy persists regarding their beneficial or detrimental effects in HIV-1 disease, which warrants further detailed exploration. Our objectives were to investigate if functional CD4+ Tregs can be isolated and expanded from HIV-1-infected individuals for experimental or potential future therapeutic use and to determine phenotype and suppressive capacity of expanded Tregs from HIV-1 positive blood and tissue. Tregs and conventional T cell controls were isolated from blood and gut-associated lymphoid tissue of individuals with HIV-1 infection and healthy donors using flow-based cell-sorting. The phenotype of expanded Tregs was assessed by flow-cytometry and quantitative PCR. T-cell receptor ß-chain (TCR-β) repertoire diversity was investigated by deep sequencing. Flow-based T-cell proliferation and chromium release cytotoxicity assays were used to determine Treg suppressive function. Tregs from HIV-1 positive individuals, including infants, were successfully expanded from PBMC and GALT. Expanded Tregs expressed high levels of FOXP3, CTLA4, CD39 and HELIOS and exhibited a highly demethylated TSDR (Treg-specific demethylated region), characteristic of Treg lineage. The TCRß repertoire was maintained following Treg expansion and expanded Tregs remained highly suppressive in vitro. Our data demonstrate that Tregs can be expanded from blood and tissue compartments of HIV-1+ donors with preservation of Treg phenotype, function and TCR repertoire. These results are highly relevant for the investigation of potential future therapeutic use, as currently investigated for other disease states and hold great promise for detailed studies on the role of Tregs in HIV-1 infection.Elizabeth Glaser Pediatric AIDS Foundation (Pediatric HIV Vaccine Program Award MV-00-9-900-1429-0-00)Massachusetts General Hospital. Executive Committee on Research (MGH/ECOR Physician Scientist Development Award)National Institutes of Health (U.S.) (NIH NIAID (KO8 AI074405))National Institutes of Health (U.S.) (NIH NIAID AI074405-03S1)Massachusetts General Hospital (William F. Milton Fund)Harvard University. Center for AIDS Research (CFAR Scholar Award)Massachusetts General Hospital. Center for the Study Inflammatory Bowel Disease (P30DK043351)Harvard University. Center for AIDS Research (NIH funded program (5P30AI060354-09

Future changes in the Western North Pacific tropical cyclone activity projected by a multidecadal simulation with a 16-km global atmospheric GCM

How tropical cyclone (TC) activity in the northwestern Pacific might change in a future climate is assessed using multidecadal Atmospheric Model Intercomparison Project (AMIP)-style and time-slice simulations with the ECMWF Integrated Forecast System (IFS) at 16-km and 125-km global resolution. Both models reproduce many aspects of the present-day TC climatology and variability well, although the 16-km IFS is far more skillful in simulating the full intensity distribution and genesis locations, including their changes in response to El Niño–Southern Oscillation. Both IFS models project a small change in TC frequency at the end of the twenty-first century related to distinct shifts in genesis locations. In the 16-km IFS, this shift is southward and is likely driven by the southeastward penetration of the monsoon trough/subtropical high circulation system and the southward shift in activity of the synoptic-scale tropical disturbances in response to the strengthening of deep convective activity over the central equatorial Pacific in a future climate. The 16-km IFS also projects about a 50% increase in the power dissipation index, mainly due to significant increases in the frequency of the more intense storms, which is comparable to the natural variability in the model. Based on composite analysis of large samples of supertyphoons, both the development rate and the peak intensities of these storms increase in a future climate, which is consistent with their tendency to develop more to the south, within an environment that is thermodynamically more favorable for faster development and higher intensities. Coherent changes in the vertical structure of supertyphoon composites show system-scale amplification of the primary and secondary circulations with signs of contraction, a deeper warm core, and an upward shift in the outflow layer and the frequency of the most intense updrafts. Considering the large differences in the projections of TC intensity change between the 16-km and 125-km IFS, this study further emphasizes the need for high-resolution modeling in assessing potential changes in TC activity

HABITAT USE BY GREATER SANDHILL CRANES IN WYOMING

Wyoming suppors approximately 20% of the Rocky Mountain population (RMP) of greater sandhill cranes (Grus canadensis tabida), as well as a number of whooping cranes (Grus americana) from the Grays Lake, Idaho flock. Cranes begin arriving on post-migration staging areas in Wyoming in mid-March and disperse to summer habitat in April or May, depending on snow cover. Fall pre-migration, staging peaks around mid-September; most cranes leave the state by 1 October. Wet meadows and gram fIelds were the major habitat types used by cranes in Wyoming 1985-1987. Use in these types ranged from 69- 100% of total observations in any given 2-week period. Important grains included barley, wheat and oats. Wet meadows were typically either seasonally flooded wetlands or flood-irrigated haylands. Alfalfa fields and cattailbulrush (Typha sp./Scirpus sp.) marshes were also important habitats for cranes

The North American Multi-Model Ensemble (NMME): Phase-1 Seasonal to Interannual Prediction, Phase-2 Toward Developing Intra-Seasonal Prediction

The recent US National Academies report "Assessment of Intraseasonal to Interannual Climate Prediction and Predictability" was unequivocal in recommending the need for the development of a North American Multi-Model Ensemble (NMME) operational predictive capability. Indeed, this effort is required to meet the specific tailored regional prediction and decision support needs of a large community of climate information users. The multi-model ensemble approach has proven extremely effective at quantifying prediction uncertainty due to uncertainty in model formulation, and has proven to produce better prediction quality (on average) then any single model ensemble. This multi-model approach is the basis for several international collaborative prediction research efforts, an operational European system and there are numerous examples of how this multi-model ensemble approach yields superior forecasts compared to any single model. Based on two NOAA Climate Test Bed (CTB) NMME workshops (February 18, and April 8, 2011) a collaborative and coordinated implementation strategy for a NMME prediction system has been developed and is currently delivering real-time seasonal-to-interannual predictions on the NOAA Climate Prediction Center (CPC) operational schedule. The hindcast and real-time prediction data is readily available (e.g., http://iridl.ldeo.columbia.edu/SOURCES/.Models/.NMME/) and in graphical format from CPC (http://origin.cpc.ncep.noaa.gov/products/people/wd51yf/NMME/index.html). Moreover, the NMME forecast are already currently being used as guidance for operational forecasters. This paper describes the new NMME effort, presents an overview of the multi-model forecast quality, and the complementary skill associated with individual models

Toxoplasmosis-associated IRIS involving the CNS: a case report with longitudinal analysis of T cell subsets

Background: HIV-infected patients may present an unforeseen clinical worsening after initiating antiretroviral therapy known as immune reconstitution inflammatory syndrome (IRIS). This syndrome is characterized by a heightened inflammatory response toward infectious or non-infectious triggers, and it may affect different organs. Diagnosis of IRIS involving the central nervous system (CNS-IRIS) is challenging due to heterogeneous manifestations, absence of biomarkers to identify this condition, risk of long-term sequelae and high mortality. Hence, a deeper knowledge of CNS-IRIS pathogenesis is needed. Case presentation: A 37-year-old man was diagnosed with AIDS and cerebral toxoplasmosis. Anti-toxoplasma treatment was initiated immediately, followed by active antiretroviral therapy (HAART) 1 month later. At 2 months of HAART, he presented with progressive hyposensitivity of the right lower limb associated with brain and dorsal spinal cord lesions, compatible with paradoxical toxoplasmosis-associated CNS-IRIS, a condition with very few reported cases. A stereotactic biopsy was planned but was postponed based on its inherent risks. Patient showed clinical improvement with no requirement of corticosteroid therapy. Routine laboratorial analysis was complemented with longitudinal evaluation of blood T cell subsets at 0, 1, 2, 3 and 6 months upon HAART initiation. A control group composed by 9 HIV-infected patients from the same hospital but with no IRIS was analysed for comparison. The CNS-IRIS patient showed lower percentage of memory CD4(+) T cells and higher percentage of activated CD4(+) T cells at HAART initiation. The percentage of memory CD4(+) T cells drastically increased at 1 month after HAART initiation and became higher in comparison to the control group until clinical recovery onset; the percentage of memory CD8(+) T cells was consistently lower throughout follow-up. Interestingly, the percentage of regulatory T cells (Treg) on the CNS-IRIS patient reached a minimum around 1 month before symptoms onset. Conclusion: Although both stereotactic biopsies and steroid therapy might be of use in CNS-IRIS cases and should be considered for these patients, they might be unnecessary to achieve clinical improvement as shown in this case. Immunological characterization of more CNS-IRIS cases is essential to shed some light on the pathogenesis of this condition.Portuguese Foundation for Science and Technology (FCT; PIC/IC/83313/2007) and co-financed by the Portuguese North Regional Operational Program (ON.2 - O Novo Norte) under the National Strategic Reference Framework (QREN) through the European Regional Development Fund (FEDER). A FCT fellowship was attributed to RRS (PD/BD/106047/2015; Inter-University Doctoral Program in Ageing and Chronic Disease) and to CN [SFRH/BPD/65380/2009; Programa Operacional Potencial Humano (POPH) through the Fundo Social Europeu (FSE)]info:eu-repo/semantics/publishedVersio

The Safe Zone--It\u27s not segregation

Let\u27s talk about the Safe Zone. Let\u27s talk about the creation of a ten room, single occupancy wing which is open to heterosexuals, allies, gays, lesbians, bisexual, transgendered, as well as thos who haven\u27t quite self-identified as… Let\u27s be realistic, the Safe Zone, as proposed, will not come close to housing every gay and lesbian on the University of Maine campus, nor is that its attempt