ALBERT

Description: Author(s): B. M. Weon, J. T. Kim, J. H. Je, J. M. Yi, S. Wang, and W.-K. Lee We show direct evidence that focused x rays enable us to merge polymer colloidal particles at room temperature. This phenomenon is ascribed to the photochemical scission of colloids with x rays, reducing the molecular weight, glass transition temperature, surface tension, and viscosity of colloids. ... [Phys. Rev. Lett. 107, 018301] Published Fri Jul 01, 2011

Description: Congenital left-sided lesions (LSLs) are serious, heritable malformations of the heart. However, little is known about the genetic causes of LSLs. This study was undertaken to identify common variants acting through the genotype of the affected individual (i.e. case) or the mother (e.g. via an in utero effect) that influence the risk of LSLs. A genome-wide association study (GWAS) was performed using data from 377 LSL case-parent triads, with follow-up studies in an independent sample of 224 triads and analysis of the combined data. Associations with both the case and maternal genotypes were assessed using log-linear analyses under an additive model. An association between LSLs and the case genotype for one intergenic SNP on chromosome 16 achieved genome-wide significance in the combined data (rs8061121, combined P = 4.0 x 10 –9 ; relative risk to heterozygote: 2.6, 95% CI: 1.9–3.7). In the combined data, there was also suggestive evidence of association between LSLs and the case genotype for a variant in the synaptoporin gene (rs1975649, combined P = 3.4 x 10 –7 ; relative risk to heterozygote: 1.6, 95% CI: 1.4–2.0) and between LSLs and the maternal genotype for an intergenic SNP on chromosome 10 (rs11008222, combined P = 6.3 x 10 –7 ; relative risk to heterozygote: 1.6, 95% CI: 1.4–2.0). This is the first GWAS of LSLs to evaluate associations with both the case and maternal genotypes. The results of this study identify three candidate LSL susceptibility loci, including one that appears to be associated with the risk of LSLs via the maternal genotype.

Description: Myotonic dystrophy type 1 (DM1), the most prevalent muscular dystrophy in adults, is characterized by progressive muscle wasting and multi-systemic complications. DM1 is the prototype for disorders caused by RNA toxicity. Currently, no therapies exist. Here, we identify that fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor receptor super-family, is induced in skeletal muscles and hearts of mouse models of RNA toxicity and in tissues from DM1 patients, and that its expression correlates with severity of muscle pathology. This is associated with downstream signaling through the NF-B pathways. In mice with RNA toxicity, genetic deletion of Fn14 results in reduced muscle pathology and better function. Importantly, blocking TWEAK/Fn14 signaling with an anti-TWEAK antibody likewise improves muscle histopathology and functional outcomes in affected mice. These results reveal new avenues for therapeutic development and provide proof of concept for a novel therapeutic target for which clinically available therapy exists to potentially treat muscular dystrophy in DM1.

Description: Latency and ongoing replication have both been proposed to explain the drug-insensitive human immunodeficiency virus (HIV) reservoir maintained during antiretroviral therapy. Here we explore a novel mechanism for ongoing HIV replication in the face of antiretroviral drugs. We propose a model whereby multiple infections per cell lead to reduced sensitivity to drugs without requiring drug-resistant mutations, and experimentally validate the model using multiple infections per cell by cell-free HIV in the presence of the drug tenofovir. We then examine the drug sensitivity of cell-to-cell spread of HIV, a mode of HIV transmission that can lead to multiple infection events per target cell. Infections originating from cell-free virus decrease strongly in the presence of antiretrovirals tenofovir and efavirenz whereas infections involving cell-to-cell spread are markedly less sensitive to the drugs. The reduction in sensitivity is sufficient to keep multiple rounds of infection from terminating in the presence of drugs. We examine replication from cell-to-cell spread in the presence of clinical drug concentrations using a stochastic infection model and find that replication is intermittent, without substantial accumulation of mutations. If cell-to-cell spread has the same properties in vivo, it may have adverse consequences for the immune system, lead to therapy failure in individuals with risk factors, and potentially contribute to viral persistence and hence be a barrier to curing HIV infection.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sigal, Alex -- Kim, Jocelyn T -- Balazs, Alejandro B -- Dekel, Erez -- Mayo, Avi -- Milo, Ron -- Baltimore, David -- HHSN266200500035C/PHS HHS/ -- T32 AI089398/AI/NIAID NIH HHS/ -- England -- Nature. 2011 Aug 17;477(7362):95-8. doi: 10.1038/nature10347.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21849975" target="_blank"〉PubMed〈/a〉

Description: Obesity and its associated comorbidities (for example, diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually and are among the most prevalent and challenging conditions confronting the medical profession. Neurotensin (NT; also known as NTS), a 13-amino-acid peptide predominantly localized in specialized enteroendocrine cells of the small intestine and released by fat ingestion, facilitates fatty acid translocation in rat intestine, and stimulates the growth of various cancers. The effects of NT are mediated through three known NT receptors (NTR1, 2 and 3; also known as NTSR1, 2, and NTSR3, respectively). Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality; however, a role for NT as a causative factor in these diseases is unknown. Here we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates fatty acid absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3 (also known as sortilin). Consistent with the findings in mice, expression of NT in Drosophila midgut enteroendocrine cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Jing -- Song, Jun -- Zaytseva, Yekaterina Y -- Liu, Yajuan -- Rychahou, Piotr -- Jiang, Kai -- Starr, Marlene E -- Kim, Ji Tae -- Harris, Jennifer W -- Yiannikouris, Frederique B -- Katz, Wendy S -- Nilsson, Peter M -- Orho-Melander, Marju -- Chen, Jing -- Zhu, Haining -- Fahrenholz, Timothy -- Higashi, Richard M -- Gao, Tianyan -- Morris, Andrew J -- Cassis, Lisa A -- Fan, Teresa W-M -- Weiss, Heidi L -- Dobner, Paul R -- Melander, Olle -- Jia, Jianhang -- Evers, B Mark -- P01 CA163223/CA/NCI NIH HHS/ -- P20 GM103527/GM/NIGMS NIH HHS/ -- R01 DK048498/DK/NIDDK NIH HHS/ -- R01 ES022191/ES/NIEHS NIH HHS/ -- R01 GM079684/GM/NIGMS NIH HHS/ -- R01 HL073085/HL/NHLBI NIH HHS/ -- R01 HL12050/HL/NHLBI NIH HHS/ -- R01 NS077284/NS/NINDS NIH HHS/ -- R37 AG10885/AG/NIA NIH HHS/ -- T32 CA160003/CA/NCI NIH HHS/ -- T32 CA165990/CA/NCI NIH HHS/ -- U24 DK097215/DK/NIDDK NIH HHS/ -- England -- Nature. 2016 May 11;533(7603):411-5. doi: 10.1038/nature17662.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Surgery, University of Kentucky, Lexington, Kentucky 40536, USA. ; Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA. ; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536, USA. ; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536, USA. ; Department of Clinical Sciences, Lund University, Malmo, 221 00 Lund, Sweden. ; Department of Internal Medicine, Skane University Hospital, Malmo, 205 02 Malmo, Sweden. ; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA. ; Center for Structural Biology, University of Kentucky, Lexington, Kentucky 40536, USA. ; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA. ; Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky and Lexington Veterans Affairs Medical Center, Lexington, Kentucky 40536, USA. ; Department of Biostatistics, University of Kentucky, Lexington, Kentucky 40536, USA. ; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27193687" target="_blank"〉PubMed〈/a〉

Description: Cystatin SN neutralizes the inhibitory effect of cystatin C on cathepsin B activity Cell Death and Disease 4, e974 (December 2013). doi:10.1038/cddis.2013.485 Authors: J-T Kim, S-J Lee, M A Kang, J E Park, B-Y Kim, D-Y Yoon, Y Yang, C-H Lee, Y I Yeom, Y-K Choe & H G Lee