Mutagenesis of a cAMP Response Element within the Latency-Associated Transcript Promoter of HSV-1 Reduces Adrenergic Reactivation

AbstractMutagenesis of a cyclic AMP response element (CRE) within the LAT promoter of HSV-1 reduces the ability of LAT expression to be induced in transient assays, but has only a minimal impact on reactivation of the virus inin vitrosystems. Here we show that a CRE mutation results in a significant reduction of adrenergically induced reactivationin vivoin the rabbit eye model. Spontaneous reactivation frequencies were also reduced. In addition, we demonstrate that this mutation has no effect on the amount of LAT expressed during latency when compared with the parent, 17syn+, and the rescuant. These results indicate a greater effect of CRE on induced reactivationin vivothan inin vitrosystems, but also suggest that the CRE in the LAT promoter is not autonomous in conducting the reactivation signal

ASCR/HEP Exascale Requirements Review Report

This draft report summarizes and details the findings, results, and recommendations derived from the ASCR/HEP Exascale Requirements Review meeting held in June, 2015. The main conclusions are as follows. 1) Larger, more capable computing and data facilities are needed to support HEP science goals in all three frontiers: Energy, Intensity, and Cosmic. The expected scale of the demand at the 2025 timescale is at least two orders of magnitude -- and in some cases greater -- than that available currently. 2) The growth rate of data produced by simulations is overwhelming the current ability, of both facilities and researchers, to store and analyze it. Additional resources and new techniques for data analysis are urgently needed. 3) Data rates and volumes from HEP experimental facilities are also straining the ability to store and analyze large and complex data volumes. Appropriately configured leadership-class facilities can play a transformational role in enabling scientific discovery from these datasets. 4) A close integration of HPC simulation and data analysis will aid greatly in interpreting results from HEP experiments. Such an integration will minimize data movement and facilitate interdependent workflows. 5) Long-range planning between HEP and ASCR will be required to meet HEP's research needs. To best use ASCR HPC resources the experimental HEP program needs a) an established long-term plan for access to ASCR computational and data resources, b) an ability to map workflows onto HPC resources, c) the ability for ASCR facilities to accommodate workflows run by collaborations that can have thousands of individual members, d) to transition codes to the next-generation HPC platforms that will be available at ASCR facilities, e) to build up and train a workforce capable of developing and using simulations and analysis to support HEP scientific research on next-generation systems.Comment: 77 pages, 13 Figures; draft report, subject to further revisio

Outcome after extended follow-up in a prospective study of operable breast cancer: key factors and a prognostic index

In 1990, 215 patients with operable breast cancer were entered into a prospective study of the prognostic significance of five biochemical markers and 15 other factors (pathological/chronological/patient). After a median follow-up of 6.6 years, there were 77 recurrences and 77 deaths (59 breast cancer-related). By univariate analysis, patient outcome related significantly to 13 factors. By multivariate analysis, the most important of nine independent factors were: number of nodes involved, steroid receptors (for oestrogen or progestogen), age, clinical or pathological tumour size and grade. Receptors and grade exerted their influence only in the first 3 years. Progestogen receptors (immunohistochemical) and oestrogen receptors (biochemical) were of similar prognostic significance. The two receptors were correlated (r=+0.50, P=0.001) and displaced each other from the analytical model but some evidence for the additivity of their prognostic values was seen when their levels were discordant

The orphaning experience: descriptions from Ugandan youth who have lost parents to HIV/AIDS

The HIV/AIDS epidemic has continued to pose significant challenges to countries in Sub-Saharan Africa. Millions of African children and youth have lost parents to HIV/AIDS leaving a generation of orphans to be cared for within extended family systems and communities. The experiences of youth who have lost parents to the HIV/AIDS epidemic provide an important ingress into this complex, evolving, multi-dimensional phenomenon. A fundamental qualitative descriptive study was conducted to develop a culturally relevant and comprehensive description of the experiences of orphanhood from the perspectives of Ugandan youth. A purposeful sample of 13 youth who had lost one or both parents to HIV/AIDS and who were affiliated with a non-governmental organization providing support to orphans were interviewed. Youth orphaned by HIV/AIDS described the experience of orphanhood beginning with parental illness, not death. Several losses were associated with the death of a parent including lost social capitol, educational opportunities and monetary assets. Unique findings revealed that youth experienced culturally specific stigma and conflict which was distinctly related to their HIV/AIDS orphan status. Exploitation within extended cultural family systems was also reported. Results from this study suggest that there is a pressing need to identify and provide culturally appropriate services for these Ugandan youth prior to and after the loss of a parent(s)

HST/STIS observations of GRB000301C: CCD imaging and NUV MAMA spectroscopy

We present HST/STIS observations of the optical counterpart (OT) of the gamma-ray burster GRB 000301C obtained on 2000 March 6, five days after the burst. CCD clear aperture imaging reveals a R ~ 21.50+/-0.15 source with no apparent host galaxy. An 8000 s, 1150 < lambda/A < 3300 NUV-MAMA prism spectrum shows a relatively flat continuum (in f_lambda) between 2800 and 3300 A, with a mean flux 8.7 (+0.8,-1.6)+/- 2.6 10^(-18) ergs/s/cm^2/A, and a sharp break centered at 2797+/-25 A. We interpret it as HI Lyman break at z = 2.067+/-0.025 indicating the presence of a cloud with a HI column density log(HI) > 18 on the line-of-sight to the OT. This value is conservatively a lower limit to the GRB redshift. However, the facts that large N(HI) system are usually considered as progenitors of present day galaxies and that other OTs are found associated with star forming galaxies strongly suggest that it is the GRB redshift. In any case, this represents the largest direct redshift determination of a gamma-ray burster to date. Our data are compatible with an OT spectrum represented by a power-law with an intrinsic index \alpha = 1.2((f_nu \propto nu^-alpha) and no extinction in the host galaxy or with alpha = 0.5 and extinction by a SMC-like dust in the OT rest-frame with A_V = 0.15. The large N(HI) and the lack of detected host is similar to the situation for damped Ly-alpha absorbers at z > 2.Comment: Replaced by final version. 10 p., 2 fig. Scheduled to appear in ApJ 555 n2 Jul 10, 2001. Minor changes, both redshift and mean near UV flux are revised with slightly larger values, due to a wrong offset sign in the wavelength calibratio

Macrophage-Specific Chemokines Induced via Innate Immunity by Amino Acid Copolymers and Their Role in EAE

The random amino acid copolymer poly(Y,E,A,K)n (Copaxone®) is widely used in multiple sclerosis treatment and a second generation copolymer poly(Y,F,A,K)n with enhanced efficacy in experimental autoimmune encephalomyelitis in mice has been described. A major mechanism through which copolymers function to ameliorate disease is the generation of immunosuppressive IL-10-secreting regulatory T cells entering the CNS. In addition, the antigen presenting cell to which these copolymers bind through MHC Class II proteins may have an important role. Here, both CCL22 (a Th2 cell chemoattractant) in large amounts and CXCL13 in much smaller amounts are shown to be secreted after administration of YFAK to mice and to a smaller extent by YEAK parallel to their serum concentrations. Moreover, bone marrow-derived macrophages secrete CCL22 in vitro in response to YFAK and to higher concentrations of YEAK. Strikingly, these chemokines are also secreted into serum of MHC Class II −/− mice, indicating that an innate immune receptor on these cells also has an important role. Thus, both the innate and the adaptive immune systems are involved in the mechanism of EAE amelioration by YFAK. The enhanced ability of YFAK to stimulate the innate immune system may account for its enhanced efficacy in EAE treatment

Neuropathologic Correlates of Hippocampal Atrophy in the Elderly: A Clinical, Pathologic, Postmortem MRI Study

The volume of the hippocampus measured with structural magnetic resonance imaging (MRI) is increasingly used as a biomarker for Alzheimer's disease (AD). However, the neuropathologic basis of structural MRI changes in the hippocampus in the elderly has not been directly assessed. Postmortem MRI of the aging human brain, combined with histopathology, could be an important tool to address this issue. Therefore, this study combined postmortem MRI and histopathology in 100 elderly subjects from the Rush Memory and Aging Project and the Religious Orders Study. First, to validate the information contained in postmortem MRI data, we tested the hypothesis that postmortem hippocampal volume is smaller in subjects with clinically diagnosed Alzheimer's disease compared to subjects with mild or no cognitive impairment, as observed in antemortem imaging studies. Subsequently, the relations of postmortem hippocampal volume to AD pathology, Lewy bodies, amyloid angiopathy, gross infarcts, microscopic infarcts, and hippocampal sclerosis were examined. It was demonstrated that hippocampal volume was smaller in persons with a clinical diagnosis of AD compared to those with no cognitive impairment (P = 2.6×10−7) or mild cognitive impairment (P = 9.6×10−7). Additionally, hippocampal volume was related to multiple cognitive abilities assessed proximate to death, with its strongest association with episodic memory. Among all pathologies investigated, the most significant factors related to lower hippocampal volume were shown to be AD pathology (P = 0.0018) and hippocampal sclerosis (P = 4.2×10−7). Shape analysis allowed for visualization of the hippocampal regions most associated with volume loss for each of these two pathologies. Overall, this investigation confirmed the relation of hippocampal volume measured postmortem to clinical diagnosis of AD and measures of cognition, and concluded that both AD pathology and hippocampal sclerosis affect hippocampal volume in old age, though the impacts of each pathology on the shape of the hippocampus may differ

Attrition among families of divorce: Patterns in an outpatient psychiatric population

The accelerated divorce rate has greatly increased the number of children of divorce. In addition, the children and families of divorce are proportionately overrepresented in populations seeking child guidance and psychiatric services. However, the patterns in the use of such services by these families has been unexamined. In our study we find no differences in the use of outpatient psychiatric services between families where both biological parents are present and families of divorce. A closer look at the divorced families reveals that recently divorced mother-headed families more frequently interrupt both the evaluation and treatment phases of clinic contact. Several clinical patterns are described which help explain the finding and it is suggested that the traditional child guidance model may not be the most suitable intervention modality in working with these families.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44293/1/10591_2004_Article_BF00927093.pd

Three New Eclipsing White-dwarf - M-dwarf Binaries Discovered in a Search for Transiting Planets Around M-dwarfs

We present three new eclipsing white-dwarf / M-dwarf binary systems discovered during a search for transiting planets around M-dwarfs. Unlike most known eclipsing systems of this type, the optical and infrared emission is dominated by the M-dwarf components, and the systems have optical colors and discovery light curves consistent with being Jupiter-radius transiting planets around early M-dwarfs. We detail the PTF/M-dwarf transiting planet survey, part of the Palomar Transient Factory (PTF). We present a Graphics Processing Unit (GPU)-based box-least-squares search for transits that runs approximately 8X faster than similar algorithms implemented on general purpose systems. For the discovered systems, we decompose low-resolution spectra of the systems into white-dwarf and M-dwarf components, and use radial velocity measurements and cooling models to estimate masses and radii for the white dwarfs. The systems are compact, with periods between 0.35 and 0.45 days and semimajor axes of approximately 2 solar radii (0.01 AU). We use the Robo-AO laser guide star adaptive optics system to tentatively identify one of the objects as a triple system. We also use high-cadence photometry to put an upper limit on the white dwarf radius of 0.025 solar radii (95% confidence) in one of the systems. We estimate that 0.08% (90% confidence) of M-dwarfs are in these short-period, post-common-envelope white-dwarf / M-dwarf binaries where the optical light is dominated by the M-dwarf. Similar eclipsing binary systems can have arbitrarily small eclipse depths in red bands and generate plausible small-planet-transit light curves. As such, these systems are a source of false positives for M-dwarf transiting planet searches. We present several ways to rapidly distinguish these binaries from transiting planet systems.Comment: 14 pages, 14 figures, submitted to Ap