Compromising the 19S proteasome complex protects cells from reduced flux through the proteasome

Proteasomes are central regulators of protein homeostasis in eukaryotes. Proteasome function is vulnerable to environmental insults, cellular protein imbalance and targeted pharmaceuticals. Yet, mechanisms that cells deploy to counteract inhibition of this central regulator are little understood. To find such mechanisms, we reduced flux through the proteasome to the point of toxicity with specific inhibitors and performed genome-wide screens for mutations that allowed cells to survive. Counter to expectation, reducing expression of individual subunits of the proteasome's 19S regulatory complex increased survival. Strong 19S reduction was cytotoxic but modest reduction protected cells from inhibitors. Protection was accompanied by an increased ratio of 20S to 26S proteasomes, preservation of protein degradation capacity and reduced proteotoxic stress. While compromise of 19S function can have a fitness cost under basal conditions, it provided a powerful survival advantage when proteasome function was impaired. This means of rebalancing proteostasis is conserved from yeast to humans

Angiomatous meningiomas have a distinct genetic profile with multiple chromosomal polysomies including polysomy of chromosome 5

Meningiomas are a diverse group of tumors with a broad spectrum of histologic features. There are over 12 variants of meningioma, whose genetic features are just beginning to be described. Angiomatous meningioma is a World Health Organization (WHO) meningioma variant with a predominance of blood vessels. They are uncommon and confirming the histopathologic classification can be challenging. Given a lack of biomarkers that define the angiomatous subtype and limited understanding of the genetic changes underlying its tumorigenesis, we compared the genomic characteristics of angiomatous meningioma to more common meningioma subtypes. While typical grade I meningiomas demonstrate monosomy of chromosome 22 or lack copy number aberrations, 13 of 14 cases of angiomatous meningioma demonstrated a distinct copy number profile – polysomies of at least one chromosome, but often of many, especially in chromosomes 5, 13, and 20. WHO grade II atypical meningiomas with angiomatous features have both polysomies and genetic aberrations characteristic of other atypical meningiomas. Sequencing of over 560 cancer-relevant genes in 16 cases of angiomatous meningioma showed that these tumors lack common mutations found in other variants of meningioma. Our study demonstrates that angiomatous meningiomas have distinct genomic features that may be clinically useful for their diagnosis

Prevention and early detection of prostate cancer

This Review was sponsored and funded by the International Society of Cancer Prevention (ISCaP), the European Association of Urology (EAU), the National Cancer Institute, USA (NCI) (grant number 1R13CA171707-01), Prostate Cancer UK, Cancer Research UK (CRUK) (grant number C569/A16477), and the Association for International Cancer Research (AICR

Characterizing kernels of operators related to thin-plate magnetizations via generalizations of Hodge decompositions

Recently developed scanning magnetic microscopes measure the magnetic field in a plane above a thin-plate magnetization distribution. These instruments have broad applications in geoscience and materials science, but are limited by the requirement that the sample magnetization must be retrieved from measured field data, which is a generically nonunique inverse problem. This problem leads to an analysis of the kernel of the related magnetization operators, which also has relevance to the 'equivalent source problem' in the case of measurements taken from just one side of the magnetization. We characterize the kernel of the operator relating planar magnetization distributions to planar magnetic field maps in various function and distribution spaces (e.g., sums of derivatives of Lp (Lebesgue spaces) or bounded mean oscillation (BMO) functions). For this purpose, we present a generalization of the Hodge decomposition in terms of Riesz transforms and utilize it to characterize sources that do not produce a magnetic field either above or below the sample, or that are magnetically silent (i.e. no magnetic field anywhere outside the sample). For example, we show that a thin-plate magnetization is silent (i.e. in the kernel) when its normal component is zero and its tangential component is divergence free. In addition, we show that compactly supported magnetizations (i.e. magnetizations that are zero outside of a bounded set in the source plane) that do not produce magnetic fields either above or below the sample are necessarily silent. In particular, neither a nontrivial planar magnetization with fixed direction (unidimensional) compact support nor a bidimensional planar magnetization (i.e. a sum of two unidimensional magnetizations) that is nontangential can be silent. We prove that any planar magnetization distribution is equivalent to a unidimensional one. We also discuss the advantages of mapping the field on both sides of a magnetization, whenever experimentally feasible. Examples of source recovery are given along with a brief discussion of the Fourier-based inversion techniques that are utilized

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Vitamin D supplementation for the prevention of depression and poor physical function in older persons: the D-Vitaal study, a randomized clinical trial

Background: Depressive symptoms and impaired physical functioning are prevalent among older adults. Supplementation with vitamin D might improve both conditions, particularly in persons with low vitamin D status. Objective: The D-Vitaal study primarily aimed to investigate the effect of vitamin D supplementation on depressive symptoms, functional limitations and physical performance in a high-risk older population with low vitamin D status. Secondary aims included examining the effect of vitamin D supplementation on anxiety symptoms, cognitive functioning, mobility, hand grip strength and health-related quality of life. Design: This study was a randomized placebo-controlled trial with 155 participants aged 60-80 years who had clinically relevant depressive symptoms, ≥1 functional limitation and serum 25-hydroxyvitamin D (25(OH)D) concentrations of 15-50/70 nmol/L (depending on season). Participants received 1200 IU/day vitamin D3 (n=76) or placebo tablets (n=77) for 12 months. Serum 25(OH)D was measured at baseline and 6 months; outcomes were assessed at baseline, 6 and 12 months. Linear mixed models analyses were conducted according to the intention-to-treat principle to assess the effect of the intervention. Results: The supplementation increased serum 25(OH)D concentrations in the intervention group to a mean of 85 nmol/L (SD: 16) against 43 nmol/L (SD: 18) in the placebo group after 6 months (P<0.001). No relevant differences between the treatment groups were observed regarding depressive symptoms, functional limitations, physical performance, or any of the secondary outcomes. Conclusions: Supplementation with 1200 IU/day vitamin D for 12 months had no effect on depressive symptoms and physical functioning in older persons with relatively low vitamin D status, clinically relevant depressive symptoms and poor physical functioning. KEYWORDS Vitamin D, 25(OH)D, Depressive symptoms, Physical functioning, Functional limitations, Physical performance, Older adults, Randomized Clinical Trial, Prevention, Supplementation