The X-Ray Position and Infrared Counterpart of the Eclipsing X-Ray Pulsar OAO 1657-415

We have measured the precise position of the 38-s eclipsing X-ray pulsar OAO 1657-415 with the Chandra X-Ray Observatory: RA = 17h00m48.90s, Dec = -41d39m21.6s, equninox J2000, error radius = 0.5 arcsec. Based on the previously measured pulsar mass function and X-ray eclipse duration, this 10.4-d high-mass X-ray binary is believed to contain a B supergiant companion. Deep optical imaging of the field did not detect any stars at the Chandra source position, setting a limit of V>23. However, near-IR imaging revealed a relatively bright star (J=14.1, H=11.9, K_s=10.7) coincident with the Chandra position, and we identify this star as the IR counterpart of OAO 1657-415. The IR colors and magnitudes and the optical non-detections for this star are all consistent with a highly reddened B supergiant (A_V= 20.4 +/- 1.3) at a distance of 6.4 +/- 1.5 kpc. This implies an X-ray luminosity of 3e36 erg/s (2-10 keV). IR spectroscopy can verify the spectral type of the companion and measure its radial velocity curve, yielding a neutron star mass measurement.Comment: 4 pages. ApJ in press (Vol. 573, July 10 issue

Targeting Protein Quality Control Pathways in Spinal and Bulbar Muscular Atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a progressive neurodegenerative disease caused by a CAG/glutamine (polyQ) expansion in the androgen receptor (AR). Like many other age-dependent neurodegenerative diseases, SBMA is characterized by the buildup of misfolded proteins into nuclear aggregates and neurodegeneration. The mutant protein disrupts several cellular pathways, and decreasing levels of disease causing protein may circumvent several of the downstream pathological processes. Here we investigate the effects of manipulating protein quality control pathways in cell and animal models of SBMA, identifying novel therapeutic targets and advancing our understanding of molecular chaperones and their role in protein triage. Cells degrade proteins through two main pathways, autophagy and the ubiquitin proteasome pathway. Autophagy degrades cytosolic proteins in bulk, and increased autophagy has been shown to be beneficial in some models of protein aggregation diseases. Our results however, show that activating autophagy increases muscle wasting, while inhibiting autophagy significantly increases the lifespan and size of muscle fibers in a mouse model of SBMA. Our findings are surprising, and suggest that activation of autophagy in SBMA may exacerbate disease progression. The Hsp90/Hsp70-based chaperone machinery regulates the stabilization and degradation of Hsp90 clients through the proteasome, and presents an alternative therapeutic target to modulate proteostasis. Little is known however, about how this machinery functions to triage misfolded proteins, and few modulators of Hsp70 exist. Here we advance our understanding of chaperone machinery function, and present novel strategies to target Hsp70’s substrate affinity. We demonstrate that inhibiting Hsp70 function leads to accumulation of toxic AR, while increasing Hsp70 substrate affinity through overexpression of the co-chaperone Hip, or through treatment with a newly identified small molecule allosteric activator, promotes client protein ubiquitination and polyQ AR clearance. Both genetic and pharmacologic approaches to increase Hsp70 activity rescue disease phenotype in a Drosophila model of SBMA. Our results reveal a new therapeutic strategy of targeting Hsp70 to treat SBMA and perhaps other neurodegenerative diseases, while providing insights into the role of the chaperone machinery in protein quality control.Ph.D.NeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/91413/1/amwang_1.pd

Temperature Effect on Interactions of Oil Droplet with Water-wetted Shale Kerogen at Reservoir Temperatures: Linear Relationships between Temperature, Free Energy, and Contact Angle

Detailed knowledge about the interfacial interactions between oil and kerogen at nanoscales is imperative for unlocking adsorbed hydrocarbon in tight reservoirs, especially in unconventional shale that retain abundant hydrocarbon in kerogen nanopores. In this study, the temperature effect on interactions of light oil with a type II kerogen in water was investigated using molecular dynamics simulation. Non-polar and polar light oil droplets were modeled by clusters of 30 octane molecules and 30 octanethiol molecules, respectively. The free energy calculations were performed with umbrella sampling at constant temperatures in the range 300-500 $K$, that are comparable to the reservoir conditions of common shale plays. Our result shows that the adsorption/desorption energy of an oil droplet is a linear function of temperature ($T$), which can be described by $f(T) = c_1\times T + c_2$ where $c_1$ and $c_2$ are constant. Comparative simulations show that a single oil molecule cannot qualitatively describe oil droplet. In addition, the most stable contact angles of oil droplets, which are associated with the global energy minimum, were identified by computing free energy across a wide range of distance between the oil droplet and the kerogen surface. The cosine of the contact angle can be linearly correlated with the free energy of oil adsorption/desorption. This study provides a thermodynamic insight at the molecular level on how temperature affects the oil interactions with kerogen, providing valuable implications to improve unconventional oil recovery.Comment: 30 pages, 10 figures, 6 table

Isolation site influences virulence phenotype of serotype 14 Streptococcus pneumoniae strains belonging to multilocus sequence type 15

Streptococcus pneumoniae is a diverse species causing invasive as well as localized infections that result in massive global morbidity and mortality. Strains vary markedly in pathogenic potential, but the molecular basis is obscured by the diversity and plasticity of the pneumococcal genome. We have previously reported that S. pneumoniae serotype 3 isolates belonging to the same multilocus sequence type (MLST) differed markedly in in vitro and in vivo phenotypes, in accordance with the clinical site of isolation, suggesting stable niche adaptation within a clonal lineage. In the present study, we have extended our analysis to serotype 14 clinical isolates from cases of sepsis or otitis media that belong to the same MLST (ST15). In a murine intranasal challenge model, five ST15 isolates (three from blood and two from ears) colonized the nasopharynx to similar extents. However, blood and ear isolates exhibited significant differences in bacterial loads in other host niches (lungs, ear, and brain) at both 24 and 72 h postchallenge. In spite of these differences, blood and ear isolates were present in the lungs at similar levels at 6 h postchallenge, suggesting that early immune responses may underpin the distinct virulence phenotypes. Transcriptional analysis of lung tissue from mice infected for 6 h with blood isolates versus ear isolates revealed 8 differentially expressed genes. Two of these were exclusively expressed in response to infection with the ear isolate. These results suggest a link between the differential capacities to elicit early innate immune responses and the distinct virulence phenotypes of clonally related S. pneumoniae strains

Pre- and post-diagnosis diabetes as a risk factor for all-cause and cancer-specific mortality in breast, prostate, and colorectal cancer survivors: a prospective cohort study

Objective: The relationship between diabetes and all- and cause-specific mortality in individuals with common cancers (breast, colorectal, and prostate) remains both under-researched and poorly understood. Methods: Cancer survivors (N = 37,993) from the National Health Interview Survey with linked data retrieved from the National Death Index served as our study participants. Cox proportional-hazards models were used to assess associations between pre- and post-diabetes and all-cause and cause-specific mortality. Results: Over a median follow-up period of 13 years, 2,350 all-cause, 698 cancer, and 506 CVD deaths occurred. Among all cancer survivors, patients with diabetes had greater risk of: all-cause mortality [hazard ratio (HR) 1.35, 95% CI = 1.27–1.43], cancer-specific mortality (HR: 1.14, 95% CI = 1.03–1.27), CVD mortality (HR: 1.36, 95% CI = 1.18–1.55), diabetes related mortality (HR: 17.18, 95% CI = 11.51–25.64), and kidney disease mortality (HR: 2.51, 95% CI = 1.65–3.82), compared with individuals without diabetes. The risk of all-cause mortality was also higher amongst those with diabetes and specific types of cancer: breast cancer (HR: 1.28, 95% CI = 1.12–1.48), prostate cancer (HR: 1.20, 95% CI = 1.03–1.39), and colorectal cancer (HR: 1.29, 95% CI = 1.10–1.50). Diabetes increased the risk of cancer-specific mortality among colorectal cancer survivors (HR: 1.36, 95% CI = 1.04–1.78) compared to those without diabetes. Diabetes was associated with higher risk of diabetes-related mortality when compared to non-diabetic breast (HR: 9.20, 95% CI = 3.60–23.53), prostate (HR: 18.36, 95% CI = 6.01–56.11), and colorectal cancer survivors (HR: 12.18, 95% CI = 4.17–35.58). Both pre- and post-diagnosis diabetes increased the risk of all-cause mortality among all cancer survivors. Cancer survivors with diabetes had similar risk of all-cause and CVD mortality during the second 5 years of diabetes and above 10 years of diabetes as compared to non-diabetic patients. Conclusions: Diabetes increased the risk of all-cause mortality among breast, prostate, and colorectal cancer survivors, not for pre- or post-diagnosis diabetes. Greater attention on diabetes management is warranted in cancer survivors with diabetes

A New Family of Potent AB5 Cytotoxins Produced by Shiga Toxigenic Escherichia coli

The Shiga toxigenic Escherichia coli (STEC) O113:H21 strain 98NK2, which was responsible for an outbreak of hemolytic uremic syndrome, secretes a highly potent and lethal subtilase cytotoxin that is unrelated to any bacterial toxin described to date. It is the prototype of a new family of AB5 toxins, comprising a single 35-kilodalton (kD) A subunit and a pentamer of 13-kD B subunits. The A subunit is a subtilase-like serine protease distantly related to the BA_2875 gene product of Bacillus anthracis. The B subunit is related to a putative exported protein from Yersinia pestis, and binds to a mimic of the ganglioside GM2. Subtilase cytotoxin is encoded by two closely linked, cotranscribed genes (subA and subB), which, in strain 98NK2, are located on a large, conjugative virulence plasmid. Homologues of the genes are present in 32 out of 68 other STEC strains tested. Intraperitoneal injection of purified subtilase cytotoxin was fatal for mice and resulted in extensive microvascular thrombosis, as well as necrosis in the brain, kidneys, and liver. Oral challenge of mice with E. coli K-12–expressing cloned subA and subB resulted in dramatic weight loss. These findings suggest that the toxin may contribute to the pathogenesis of human disease

Dual effect of CTCF loss on neuroprogenitor differentiation and survival

An increasing number of proteins involved in genome organization have been implicated in neurodevelopmental disorders, highlighting the importance of chromatin architecture in the developing CNS. The CCCTC-binding factor (CTCF) is a zinc finger DNA binding protein involved in higher-order chromatin organization, and mutations in the human CTCF gene cause an intellectual disability syndrome associated with microcephaly. However, information on CTCF function in vivo in the developing brain is lacking. To address this gap, we conditionally inactivated the Ctcf gene at early stages of mouse brain development. Cre-mediated Ctcf deletion in the telencephalon and anterior retina at embryonic day 8.5 triggered upregulation of the p53 effector PUMA (p53 upregulated modulator of apoptosis), resulting in massive apoptosis and profound ablation of telencephalic structures. Inactivation of Ctcf several days later at E11 also resulted in PUMA upregulation and increased apoptotic cell death, and the Ctcf-null forebrain was hypocellular and disorganized at birth. Although deletion of both Ctcf and Puma in the embryonic brain efficiently rescued Ctcf-null progenitor cell apoptosis, it failed to improve neonatal hypocellularity due to decreased proliferative capacity of rescued apical and outer radial glia progenitor cells. This was exacerbated by an independent effect of CTCF loss that resulted in depletion of the progenitor pool due to premature neurogenesis earlier in development. Our findings demonstrate that CTCF activities are required for two distinct events in early cortex formation: first, to correctly regulate the balance between neuroprogenitor cell proliferation and differentiation, and second, for the survival of neuroprogenitor cells, providing new clues regarding the contributions of CTCF in microcephaly/intellectual disability syndrome pathologies. © 2014 the authors

A systematic review and meta-analysis of the effectiveness of hypertension interventions in faith-based organisation settings

From Crossref journal articles via Jisc Publications RouterHistory: epub 2023-10-13, issued 2023-10-13Publication status: PublishedDaniel Reidpath - ORCID: 0000-0002-8796-0420 https://orcid.org/0000-0002-8796-0420Abstract Background Hypertension is the global, leading cause of mortality and is the main risk factor for cardiovascular disease. Community-based partnerships can provide cost-saving ways of delivering effective blood pressure (BP) interventions to people in resource-poor settings. Faith-based organisations (FBOs) prove important potential health partners, given their reach and community standing. This potential is especially strong in hard-to-reach, socio-economically marginalised communities. This systematic review explores the state of the evidence of FBO-based interventions on BP management, with a focus on randomised controlled trials (RCTs) and cluster RCTs (C-RCTs). Methods Seven academic databases (English = 5, Chinese = 2) and grey literature were searched for C-/RCTs of community-based interventions in FBO settings. Only studies with pre- and post-intervention BP measures were kept for analysis. Random effects models were developed using restricted maximum likelihood estimation (REML) to estimate the population average mean change and 95% confidence interval (CI) of both systolic and diastolic blood pressure (SBP and DBP). The overall heterogeneity was assessed by successively adding studies and recording changes in heterogeneity. Prediction intervals were generated to capture the spread of the pooled effect across study settings. Results Of the 19 055 titles identified, only 11 studies of fair to good quality were kept for meta-analysis. Non-significant, average mean differences between baseline and follow-up for the intervention and control groups were found for both SBP (0.78 mm of mercury (mmHg) (95% CI = 2.11-0.55)) and DBP (-0.20 mm Hg (95% CI = -1.16 to 0.75)). Subgroup analysis revealed a significant reduction in SBP of -6.23 mm Hg (95% CI = -11.21 to -1.25) for populations with mean baseline SBP of ≥140 mm Hg. Conclusions The results support the potential of FBO-based interventions in lowering SBP in clinically hypertensive populations. However, the limited evidence was concentrated primarily in Christian communities in the US More research is needed to understand the implications of such interventions in producing clinically meaningful long-term effects in a variety of settings. Further research can illuminate factors that affect success and potential expansion to sites outside the US as well as non-Christian FBOs. Current evidence is inadequate to evaluate the potential of FBO-based interventions in preventing hypertension in non-hypertensive populations. Intervention effects in non-hypertensive population might be better reflected through intermediate outcomes.pubpu