The rockefeller university

Alzheimer's disease (AD) is often characterized by vascular pathology, a procoagulant state, and chronic inflammation. The mechanisms behind these abnormalities in AD are not clear. Here, we review evidence for the role of the AD-associated peptide A beta in promoting inflammation and thrombosis in AD via its interaction with the circulating proteins factor XII and fibrinogen. (C) 2016 Elsevier Ltd. All rights reserved.

Several types of pediatric cancers reportedly contain high-frequency missense mutations in histone H3, yet the underlying oncogenic mechanism remains poorly characterized. Here we report that the H3 lysine 36-to-methionine (H3K36M) mutation impairs the differentiation of mesenchymal progenitor cells and generates undifferentiated sarcoma in vivo. H3K36M mutant nucleosomes inhibit the enzymatic activities of several H3K36 methyltransferases. Depleting H3K36 methyltransferases, or expressing an H3K36I mutant that similarly inhibits H3K36 methylation, is sufficient to phenocopy the H3K36M mutation. After the loss of H3K36 methylation, a genome-wide gain in H3K27 methylation leads to a redistribution of polycomb repressive complex 1 and de-repression of its target genes known to block mesenchymal differentiation. Our findings are mirrored in human undifferentiated sarcomas in which novel K36M/I mutations in H3.1 are identified.

Certain components and functions of the immune system, most notably cytokine production and immune cell migration, are under circadian regulation. Such regulation suggests that circadian rhythms may have an effect on disease onset, progression, and resolution. In the vesicular stomatitis virus (VSV)-induced encephalitis model, the replication, caudal penetration, and survivability of intranasally applied VSV depends on both innate and adaptive immune mechanisms. In the current study, we investigated the effect of circadian time of infection on the progression and outcome of VSV-induced encephalitis and demonstrated a significant decrease in the survival rate in mice infected at the start of the rest cycle, zeitgeber time 0 (ZT0). The lower survival rate in these mice was associated with higher levels of circulating chemokine (C-C motif) ligand 2 (CCL2), a greater number of peripherally derived immune cells accumulating in the olfactory bulb (OB), and increased production of proinflammatory cytokines, indicating an immune-mediated pathology. We also found that the acrophase of molecular circadian clock component REV-ERB alpha mRNA expression in the OB coincides with the start of the active cycle, ZT12, when VSV infection results in a more favorable outcome. This result led us to hypothesize that REV-ERB alpha may mediate the circadian effect on survival following VSV infection. Blocking REV-ERB alpha activity before VSV administration resulted in a significant increase in the expression of CCL2 and decreased survival in mice infected at the start of the active cycle. These data demonstrate that REV-ERB alpha-mediated inhibition of CCL2 expression during viral- induced encephalitis may have a protective effect.

Gestational ex posure to a fat-rich diet, while elevating maternal circulating fatty acids, increases in the offspring's hypothalamus and amygdala the proliferation and density of neurons that express neuropeptides known to stimulate consummatory behavior. To understand the relationship between these phenomena, this study examined in the brain of postnatal offspring (day 15) the effect of prenatal fat exposure on the transcription factor, peroxisome proliferator-activated receptor (PPAR) beta/delta, which is sensitive to fatty acids, and the relationship of PPAR beta/delta to the orexigenic neuropeptides, orexin, melanin-concentrating hormone, and enkephalin. Prenatal exposure to a fat-rich diet compared to low-fat chow increased the density of cells immunoreactive for PPAR beta/delta in the hypothalamic paraventricular nucleus (PVN), perifornical lateral hypothalamus (PFLH), and central nucleus of the amygdala (CeA), but not the hypothalamic arcuate nucleus or basolateral amygdaloid nucleus. It also increased co-labeling of PPAR beta/delta with the cell proliferation marker, BrdU, or neuronal marker, NeuN, and the triple labeling of PPAR beta/delta with BrdU plus NeuN, indicating an increase in proliferation and density of new PPAR beta/delta neurons. Prenatal fat exposure stimulated the double-labeling of PPAR beta/delta with orexin or melanin-concentrating hormone in the PFLH and enkephalin in the PVN and CeA and also triple-labeling of PPAR beta/delta with BrdU and these neuropeptides, indicating that dietary fat increases the genesis of PPAR beta/delta neurons that produce these peptides. These findings demonstrate a close anatomical relationship between PPAR beta/delta and the increased proliferation and density of peptide-expressing neurons in the hypothalamus and amygdala of fat-exposed offspring. (C) 2016 Elsevier Inc. All rights reserved.

RNA-binding proteins (RBPs) control multiple aspects of post-transcriptional gene regulation and function during various biological processes in the nervous system. To further reveal the functional significance of RBPs during neural development, we carried out an in vivo RNAi screen in the dorsal spinal cord interneurons, including the commissural neurons. We found that the NOVA family of RBPs play a key role in neuronal migration, axon outgrowth, and axon guidance. Interestingly, Nova mutants display similar defects as the knockout of the Dcc transmembrane receptor. We show here that Nova deficiency disrupts the alternative splicing of Dcc, and that restoring Dcc splicing in Nova knockouts is able to rescue the defects. Together, our results demonstrate that the production of DCC splice variants controlled by NOVA has a crucial function during many stages of commissural neuron development.

Clinical disease caused by weakly pathogenic mycobacterial species, which is known as Mendelian susceptibility to mycobacterial disease (MSMD), is a rare entity. IFN-gamma and IL-17 production are defective due to insufficient response to IL-2 and IL-23 in IL-12R beta 1 deficiency; so this also causes tendency to intracellular microorganisms and candidal diseases. Here, we present a patient who suffers IL-12R beta 1 deficiency caused by a novel bi-allelic mutation with recurrent salmonellosis, mycobacterial, fungal infections and remained asymptomatic during 13 months of follow-up after hIFN-gamma treatment. In addition she had hemolytic anemia and midline defects like cleft lip and palate which have not been reported in a patient with MSMD in the literature prior to this case report. In conclusion, diagnosis of MSMD should be kept in mind in patients with recurrent salmonellosis, mycobacterial and fungal infections especially in countries with a high consanguinity rate.

Background Assisted Reproductive Technology (ART) reports generated by the Centers for Disease Control and Prevention (CDC) exclude embryo banking cycles from outcome calculations. Methods We examined data reported to the CDC in 2013 for the impact of embryo banking exclusion on national ART outcomes by recalculating autologous oocyte ART live birth rates. Inflation of reported fresh ART cycle live birth rates was assessed for all age groups of infertile women as the difference between fresh cycle live births with reference to number of initiated fresh cycles (excluding embryo banking cycles), as typically reported by the CDC, and fresh cycle live births with reference to total initiated fresh ART cycles (including embryo banking cycles). Results During 2013, out of 121,351 fresh non-donor ART cycles 27,564 (22.7%) involved embryo banking. The proportion of banking cycles increased with female age from 15.5% in women <35 years to 56.5% in women >44 years. Concomitantly, the proportion of thawed cycles decreased with advancing female age (P < 0.0001). Exclusion of embryo banking cycles led to inflation of live birth rates in fresh ART cycles, increasing in size in parallel to advancing female age and utilization of embryo banking, reaching 56.3% in women age >44. The inflation of live birth rates in thawed cycles could not be calculated from the publically available CDC data but appears to be even greater. Conclusions Utilization of embryo banking increased during 2013 with advancing female age, suggesting a potential age selection bias. Exclusion of embryo banking cycles from national ART outcome reports significantly inflated national ART success rates, especially among older women. Precis Exclusion of embryo banking cycles from US National Assisted Reproductive Technology outcome reports significantly inflates reported success rates especially in older women.

Purpose of review Over the last several years, novel immunologic pathways pivotal in the development of the pathobiology of psoriasis and psoriatic arthritis (PsA) have been revealed. These discoveries catalyzed a search for new treatment targets resulting in many new therapies that are now available for patients with psoriatic disease. Recent findings Helper T cells that secrete interleukin-17 (TH17) along with CD8+ cells, innate lymphocyte cells, and gamma delta T cells are important in the pathogenesis of psoriasis and PsA. Recently, agents that target interleukin-17, the interleukin-17 receptor, and interleukin-23 (antip19) have been approved or are in clinical trials. Apremilast, a new oral agent, was approved for the treatment of psoriasis and PsA. Secukinumab, an interleukin-17A antibody, has been approved for treatment of psoriasis and PsA in the United States. It is effective with a good safety profile. Ixekizumab, another anti-interleukin-17A antibody, is currently in clinical trials and brodalumab, an interleukin-17 receptor antagonist, was removed from clinical trials because of safety concerns despite demonstrated efficacy in psoriasis and PsA. Targeting interleukin-23 with antibodies to p19 is another approach with encouraging results in psoriasis. Apremilast, an oral agent, approved to treat psoriasis and PsA demonstrates moderate efficacy with an excellent safety record. The role of tofacitinib in psoriatic disease remains to be determined pending a safety review in psoriasis and completion of PsA trials.

Mitochondrial genomes (mitochondrial DNA, mtDNA) encode essential oxidative phosphorylation (OXPHOS) components. Because hundreds of mtDNAs exist per cell, a deletion in a single mtDNA has little impact. However, if the deletion genome is enriched, OXPHOS declines, resulting in cellular dysfunction. For example, Kearns-Sayre syndrome is caused by a single heteroplasmic mtDNA deletion. More broadly, mtDNA deletion accumulation has been observed in individual muscle cells(1) and dopaminergic neurons(2) during ageing. It is unclear how mtDNA deletions are tolerated or how they are propagated in somatic cells. One mechanism by which cells respond to OXPHOS dysfunction is by activating the mitochondrial unfolded protein response (UPRmt), a transcriptional response mediated by the transcription factor ATFS-1 that promotes the recovery and regeneration of defective mitochondria(3,4). Here we investigate the role of ATFS-1 in the maintenance and propagation of a deleterious mtDNA in a heteroplasmic Caenorhabditis elegans strain that stably expresses wild-type mtDNA and mtDNA with a 3.1-kilobase deletion (Delta mtDNA) lacking four essential genes(5). The heteroplasmic strain, which has 60% Delta mtDNA, displays modest mitochondrial dysfunction and constitutive UPRmt activation. ATFS-1 impairment reduced the Delta mtDNA nearly tenfold, decreasing the total percentage to 7%. We propose that in the context of mtDNA heteroplasmy, UPRmt activation caused by OXPHOS defects propagates or maintains the deleterious mtDNA in an attempt to recover OXPHOS activity by promoting mitochondrial biogenesis and dynamics.