Proteasome-mediated proteolysis of the polyglutamine-expanded androgen receptor is a late event in spinal and bulbar muscular atrophy (SBMA) pathogenesis.

Proteolysis of polyglutamine-expanded proteins is thought to be a required step in the pathogenesis of several neurodegenerative diseases. The accepted view for many polyglutamine proteins is that proteolysis of the mutant protein produces a toxic fragment that induces neuronal dysfunction and death in a soluble form; toxicity of the fragment is buffered by its incorporation into amyloid-like inclusions. In contrast to this view, we show that, in the polyglutamine disease spinal and bulbar muscular atrophy, proteolysis of the mutant androgen receptor (AR) is a late event. Immunocytochemical and biochemical analyses revealed that the mutant AR aggregates as a full-length protein, becoming proteolyzed to a smaller fragment through a process requiring the proteasome after it is incorporated into intranuclear inclusions. Moreover, the toxicity-predicting conformational antibody 3B5H10 bound to soluble full-length AR species but not to fragment-containing nuclear inclusions. These data suggest that the AR is toxic as a full-length protein, challenging the notion of polyglutamine protein fragment-associated toxicity by redefining the role of AR proteolysis in spinal and bulbar muscular atrophy pathogenesis

Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA mice.

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease with substantial mitochondrial and metabolic dysfunctions. SBMA is caused by polyglutamine (polyQ) expansion in the androgen receptor (AR). Activating or increasing the NAD+-dependent deacetylase, SIRT3, reduced oxidative stress and death of cells modeling SBMA. However, increasing diminished SIRT3 in AR100Q mice failed to reduce acetylation of the SIRT3 target/antioxidant, SOD2, and had no effect on increased total acetylated peptides in quadriceps. Yet, overexpressing SIRT3 resulted in a trend of motor recovery, and corrected TCA cycle activity by decreasing acetylation of SIRT3 target proteins. We sought to boost blunted SIRT3 activity by replenishing diminished NAD+ with PARP inhibition. Although NAD+ was not affected, overexpressing SIRT3 with PARP inhibition fully restored hexokinase activity, correcting the glycolytic pathway in AR100Q quadriceps, and rescued motor endurance of SBMA mice. These data demonstrate that targeting metabolic anomalies can restore motor function downstream of polyQ-expanded AR

A small satellite version of a soft x-ray polarimeter

We describe a new implementation of a broad-band soft X-ray polarimeter, substantially based on a previous design. This implementation, the Pioneer Soft X-ray Polarimeter (PiSoX) is a SmallSat, designed for NASA’s call for Astrophysics Pioneers, small missions that could be CubeSats, balloon experiments, or SmallSats. As in REDSoX, the grating arrangement is designed optimally for the purpose of polarimetry with broad-band focussing optics by matching the dispersion of the spectrometer channels to laterally graded multilayers (LGMLs). The system can achieve polarization modulation factors over 90%. For PiSoX, the optics are lightweight Si mirrors in a one-bounce parabolic configuration. High efficiency, blazed gratings from opposite sectors are oriented to disperse to a LGML forming a channel covering the wavelength range from 35 Å to 75 Å (165 - 350 eV). Upon satellite rotation, the intensities of the dispersed spectra, after reflection and polarizing by the LGMLs, give the three Stokes parameters needed to determine a source’s linear polarization fraction and orientation. The design can be extended to higher energies as LGMLs are developed further. We describe examples of the potential scientific return from instruments based on this design

Increased SIRT3 Combined With PARP Inhibition Rescues Motor Function of SBMA Mice

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease with substantial mitochondrial and metabolic dysfunctions. SBMA is caused by polyglutamine (polyQ) expansion in the androgen receptor (AR). Activating or increasing the NAD+-dependent deacetylase, SIRT3, reduced oxidative stress and death of cells modeling SBMA. However, increasing diminished SIRT3 in AR100Q mice failed to reduce acetylation of the SIRT3 target/antioxidant, SOD2, and had no effect on increased total acetylated peptides in quadriceps. Yet, overexpressing SIRT3 resulted in a trend of motor recovery, and corrected TCA cycle activity by decreasing acetylation of SIRT3 target proteins. We sought to boost blunted SIRT3 activity by replenishing diminished NAD+ with PARP inhibition. Although NAD+ was not affected, overexpressing SIRT3 with PARP inhibition fully restored hexokinase activity, correcting the glycolytic pathway in AR100Q quadriceps, and rescued motor endurance of SBMA mice. These data demonstrate that targeting metabolic anomalies can restore motor function downstream of polyQ-expanded AR

Association of anthropometry and weight change with risk of dementia and its major subtypes : A meta-analysis consisting 2.8 million adults with 57 294 cases of dementia

Uncertainty exists regarding the relation of body size and weight change with dementia risk. As populations continue to age and the global obesity epidemic shows no sign of waning, reliable quantification of such associations is important. We examined the relationship of body mass index, waist circumference, and annual percent weight change with risk of dementia and its subtypes by pooling data from 19 prospective cohort studies and four clinical trials using meta-analysis. Compared with body mass index-defined lower-normal weight (18.5-22.4 kg/m(2)), the risk of all-cause dementia was higher among underweight individuals but lower among those with upper-normal (22.5-24.9 kg/m(2)) levels. Obesity was associated with higher risk in vascular dementia. Similarly, relative to the lowest fifth of waist circumference, those in the highest fifth had nonsignificant higher vascular dementia risk. Weight loss was associated with higher all-cause dementia risk relative to weight maintenance. Weight gain was weakly associated with higher vascular dementia risk. The relationship between body size, weight change, and dementia is complex and exhibits non-linear associations depending on dementia subtype under scrutiny. Weight loss was associated with an elevated risk most likely due to reverse causality and/or pathophysiological changes in the brain, although the latter remains speculative.Peer reviewe

The role and timing of aberrant polyglutamine-expanded androgen receptor proteolysis in cell models of spinal and bulbar muscular atrophy

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease resulting from a CAG repeat expansion, encoding a polyglutamine tract in the amino-terminus of the androgen receptor (AR). A histopathological hallmark is the presence of intranuclear inclusions containing amino-terminal portions of the polyglutamine-expanded AR. The aberrant protein cleavage frequently seen in polyglutamine repeat diseases has long been thought a critical step to pathogenesis, but the precise role of proteolysis and whether the resulting fragment is itself toxic or an indicator of disease in SBMA remains unknown. A canonical model describes proteolysis of the mutant protein producing a soluble toxic fragment inducing neuronal dysfunction and death; toxicity of the fragment is buffered by incorporation into inclusions. In contrast, we show, using cell models and biochemical techniques, that in SBMA, proteolysis of the mutant AR to a toxic fragment does not occur. Instead, the mutant AR aggregates as a full-length protein, becoming proteolyzed to an amino-terminal fragment through a proteasome dependent process after its incorporation into intranuclear inclusions. Moreover, the toxicity-predicting antibody 3B5H10 binds to soluble full-length AR species but not to fragment-containing nuclear inclusions. We also identify a specific region of aberrant cleavage in a PC12 cell model of SBMA using mass spectrometry to identify carboxyl-terminal residues, and address the necessity of this cleavage for toxicity and inclusion formation. We show that AR fragments from purified inclusions terminate at residue L163 and/or D146. Mutation of these sites does not prevent inclusion formation or AR cleavage, but does prevent DHT-dependent toxicity in a cell model of SBMA, suggesting a critical role for these residues in the toxicity of polyglutamine-expanded AR. In addition, we show that inclusion formation is dependent on the protease activity of the proteasome, suggesting its involvement in aberrant cleavage and inclusion formation. Taken together, these data fundamentally alter the order of events involving the AR in SBMA, placing cleavage downstream of both toxicity and aggregation. This redefines the role of AR proteolysis in SBMA pathogenesis and describes a critical role for the proteasome in these processes, redirecting attention to full-length AR as the toxic species in SBMA

Automated Percentage of Breast Density Measurements for Full-field Digital Mammography Applications

Centro de perfeccionamiento y velocida

Mammographic Variation Measures, Breast Density, and Breast Cancer Risk.

OBJECTIVE. Our previous work showed that variation measures, which represent breast architecture derived from mammograms, were significantly associated with breast cancer. For replication purposes, we examined the association of three variation measures (variation [V], which is measured in the image domain, and P1 and p1 [a normalized version of P1], which are derived from restricted regions in the Fourier domain) with breast cancer risk in an independent population. We also compared these measures to volumetric density measures (volumetric percent density [VPD] and dense volume [DV]) from a commercial product. MATERIALS AND METHODS. We examined 514 patients with breast cancer and 1377 control patients from a screening practice who were matched for age, date of examination, mammography unit, facility, and state of residence. Spearman rank-order correlation was used to evaluate the monotonic association between measures. Breast cancer associations were estimated using conditional logistic regression, after adjustment for age and body mass index. Odds ratios were calculated per SD increment in mammographic measure. RESULTS. These variation measures were strongly correlated with VPD (correlation, 0.68-0.80) but not with DV (correlation, 0.31-0.48). Similar to previous findings, all variation measures were significantly associated with breast cancer (odds ratio per SD: 1.30 [95% CI, 1.16-1.46] for V, 1.55 [95% CI, 1.35-1.77] for P1, and 1.51 [95% CI, 1.33-1.72] for p1). Associations of volumetric density measures with breast cancer were similar (odds ratio per SD: 1.54 [95% CI, 1.33-1.78] for VPD and 1.34 [95% CI, 1.20-1.50] for DV). When DV was included with each variation measure in the same model, all measures retained significance. CONCLUSION. Variation measures were significantly associated with breast cancer risk (comparable to the volumetric density measures) but were independent of the DV