The Batten disease protein CLN3 is important for stress granules dynamics and translational activity

The assembly of membrane-less organelles such as stress granules (SGs) is emerging as central in helping cells rapidly respond and adapt to stress. Following stress sensing, the resulting global translational shutoff leads to the condensation of stalled mRNAs and proteins into SGs. By reorganizing cytoplasmic contents, SGs can modulate RNA translation, biochemical reactions, and signaling cascades to promote survival until the stress is resolved. While mechanisms for SG disassembly are not widely understood, the resolution of SGs is important for maintaining cell viability and protein homeostasis. Mutations that lead to persistent or aberrant SGs are increasingly associated with neuropathology and a hallmark of several neurodegenerative diseases. Mutations in CLN3 are causative of juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease affecting children also known as Batten disease. CLN3 encodes a transmembrane lysosomal protein implicated in autophagy, endosomal trafficking, metabolism, and response to oxidative stress. Using a HeLa cell model lacking CLN3, we now show that CLN3KO is associated with an altered metabolic profile, reduced global translation, and altered stress signaling. Furthermore, loss of CLN3 function results in perturbations in SG dynamics, resulting in assembly and disassembly defects, and altered expression of the key SG nucleating factor G3BP1. With a growing interest in SG-modulating drugs for the treatment of neurodegenerative diseases, novel insights into the molecular basis of CLN3 Batten disease may reveal avenues for disease-modifying treatments for this debilitating childhood disease

Mortality From Cardiovascular Diseases in Sub-saharan Africa, 1990-2013: A Systematic Analysis of Data From the Global Burden of Disease Study 2013

Cardiovascular disease (CVD) has been the leading cause of death in developed countries for most of the last century. Most CVD deaths, however, occur in low- and middle-income, developing countries (LMICs) and there is great concern that CVD mortality and burden are rapidly increasing in LMICs as a result of population growth, ageing and health transitions. In sub-Saharan Africa (SSA), where all countries are part of the LMICs, the pattern, magnitude and trends in CVD deaths remain incompletely understood, which limits formulation of data-driven regional and national health policies

Impact of the Specific Mutation in KRAS Codon 12 Mutated Tumors on Treatment Efficacy in Patients with Metastatic Colorectal Cancer Receiving Cetuximab-Based First-Line Therapy: A Pooled Analysis of Three Trials

Purpose: This study investigated the impact of specific mutations in codon 12 of the Kirsten-ras (KRAS) gene on treatment efficacy in patients with metastatic colorectal cancer (mCRC). Patients: Overall, 119 patients bearing a KRAS mutation in codon 12 were evaluated. All patients received cetuximab-based first-line chemotherapy within the Central European Cooperative Oncology Group (CECOG), AIO KRK-0104 or AIO KRK-0306 trials. Results: Patients with KRAS codon 12 mutant mCRC showed a broad range of outcome when treated with cetuximab-based first-line regimens. Patients with tumors bearing a KRAS p.G12D mutation showed a strong trend to a more favorable outcome compared to other mutations (overall survival 23.3 vs. 14-18 months; hazard ratio 0.66, range 0.43-1.03). An interaction model illustrated that KRAS p.G12C was associated with unfavorable outcome when treated with oxaliplatin plus cetuximab. Conclusion: The present analysis suggests that KRAS codon 12 mutation may not represent a homogeneous entity in mCRC when treated with cetuximab-based first-line therapy. Copyright (C) 2012 S. Karger AG, Base

Length of stay in asylum centres and mental health in asylum seekers: a retrospective study from Denmark

<p>Abstract</p> <p>Background</p> <p>The length of stay in asylum centres is generally mentioned as a possible health risk to asylum seekers. Medical staff working with asylum seekers has claimed that long lengths of stay in asylum centres might cause or aggravate mental disorders. We used records from a large, multiethnic group of asylum seekers to study if the incidence of mental disorders increased with length of stay.</p> <p>Methods</p> <p>The study population was asylum seekers in Danish asylum centres run by the Danish Red Cross. General medical care was provided by Red Cross staff who could refer selected cases to medical specialists. If an asylum seeker needed more than three specialist consultations for mental illness or five consultations for physical illness the referrals had to be approved by The Danish Immigration Service. Between July 2001 – December 2002 the Red Cross prospectively registered health related data on all new applications (n = 4516) to the Immigration Service regarding referrals to medical specialists. We used these records to analyse the association between length of stay in the asylum centres and overall rate of referral for mental disorders. Data was analysed using weighted linear regression.</p> <p>Results</p> <p>We found that referrals for mental disorders increased with length of stay in asylum centres in a large, multiethnic population of asylum seekers. The association was found in all the categories of psychiatric illness studied and for a majority of the nationality groups studied.</p> <p>Conclusion</p> <p>Length of stay in asylum centres was associated with an increase in referrals for mental disorders in a large, multiethnic group of asylum seekers. The present study supports the view that prolonged length of stay in an asylum centre is a risk factor for mental health. The risk of psychiatric illness among asylum seekers should be addressed by political and humanitarian means, giving prevention of illness the highest priority.</p

Cancer cells exploit an orphan RNA to drive metastatic progression.

Here we performed a systematic search to identify breast-cancer-specific small noncoding RNAs, which we have collectively termed orphan noncoding RNAs (oncRNAs). We subsequently discovered that one of these oncRNAs, which originates from the 3' end of TERC, acts as a regulator of gene expression and is a robust promoter of breast cancer metastasis. This oncRNA, which we have named T3p, exerts its prometastatic effects by acting as an inhibitor of RISC complex activity and increasing the expression of the prometastatic genes NUPR1 and PANX2. Furthermore, we have shown that oncRNAs are present in cancer-cell-derived extracellular vesicles, raising the possibility that these circulating oncRNAs may also have a role in non-cell autonomous disease pathogenesis. Additionally, these circulating oncRNAs present a novel avenue for cancer fingerprinting using liquid biopsies

Anthropometric indices of Gambian children after one or three annual rounds of mass drug administration with azithromycin for trachoma control.

BACKGROUND: Mass drug administration (MDA) with azithromycin, carried out for the control of blinding trachoma, has been linked to reduced mortality in children. While the mechanism behind this reduction is unclear, it may be due, in part, to improved nutritional status via a potential reduction in the community burden of infectious disease. To determine whether MDA with azithromycin improves anthropometric indices at the community level, we measured the heights and weights of children aged 1 to 4 years in communities where one (single MDA arm) or three annual rounds (annual MDA arm) of azithromycin had been distributed. METHODS: Data collection took place three years after treatment in the single MDA arm and one year after the final round of treatment in the annual MDA arm. Mean height-for-age, weight-for-age and weight-for-height z scores were compared between treatment arms. RESULTS: No significant differences in mean height-for-age, weight-for-age or weight-for-height z scores were found between the annual MDA and single MDA arms, nor was there a significant reduction in prevalence of stunting, wasting or underweight between arms. CONCLUSIONS: Our data do not provide evidence that community MDA with azithromycin improved anthropometric outcomes of children in The Gambia. This may suggest reductions in mortality associated with azithromycin MDA are due to a mechanism other than improved nutritional status

End-to-end Interpretable Learning of Non-blind Image Deblurring

Non-blind image deblurring is typically formulated as a linear least-squares problem regularized by natural priors on the corresponding sharp picture's gradients, which can be solved, for example, using a half-quadratic splitting method with Richardson fixed-point iterations for its least-squares updates and a proximal operator for the auxiliary variable updates. We propose to precondition the Richardson solver using approximate inverse filters of the (known) blur and natural image prior kernels. Using convolutions instead of a generic linear preconditioner allows extremely efficient parameter sharing across the image, and leads to significant gains in accuracy and/or speed compared to classical FFT and conjugate-gradient methods. More importantly, the proposed architecture is easily adapted to learning both the preconditioner and the proximal operator using CNN embeddings. This yields a simple and efficient algorithm for non-blind image deblurring which is fully interpretable, can be learned end to end, and whose accuracy matches or exceeds the state of the art, quite significantly, in the non-uniform case.Comment: Accepted at ECCV2020 (poster

The impact of population heterogeneity on risk estimation in genetic counseling

BACKGROUND: Genetic counseling has been an important tool for evaluating and communicating disease susceptibility for decades, and it has been applied to predict risks for a wide class of hereditary disorders. Most diseases are complex in nature and are affected by multiple genes and environmental conditions; it is highly likely that DNA tests alone do not define all the genetic factors responsible for a disease, so that persons classified into the same risk group by DNA testing actually could have different disease susceptibilities. Ignorance of population heterogeneity may lead to biased risk estimates, whereas additional information on population heterogeneity may improve the precision of such estimates. METHODS: Although DNA tests are widely used, few studies have investigated the accuracy of the predicted risks. We examined the impact of population heterogeneity on predicted disease risks by simulation of three different heterogeneity scenarios and studied the precision and accuracy of the risks estimated from a logistic regression model that ignored population heterogeneity. Moreover, we also incorporated information about population heterogeneity into our original model and investigated the resulting improvement in the accuracy of risk estimation. RESULTS: We found that heterogeneity in one or more categories could lead to biased estimates not only in the "contaminated" categories but also in other homogeneous categories. Incorporating information about population heterogeneity into the original model greatly improved the accuracy of risk estimation. CONCLUSIONS: Our findings imply that without thorough knowledge about genetic basis of the disease, risks estimated from DNA tests may be misleading. Caution should be taken when evaluating the predicted risks obtained from genetic counseling. On the other hand, the improved accuracy of risk estimates after incorporating population heterogeneity information into the model did point out a promising direction for genetic counseling, since more and more new techniques are being invented and disease etiology is being better understood

Spin polarization of the quantum spin Hall edge states

While the helical character of the edge channels responsible for charge transport in the quantum spin Hall regime of a two-dimensional topological insulator is by now well established, an experimental confirmation that the transport in the edge channels is spin-polarized is still outstanding. We report experiments on nanostructures fabricated from HgTe quantum wells with an inverted band structure, in which a split gate technique allows us to combine both quantum spin Hall and metallic spin Hall transport in a single device. In these devices, the quantum spin Hall effect can be used as a spin current injector and detector for the metallic spin Hall effect, and vice versa, allowing for an all-electrical detection of spin polarization.Comment: version 2: supplementary material with additional three figures added. In total 27 pages, 8 figure