Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA-binding protein (RBP) that controls translation of select mRNAs. We discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is known to enhance translation inhibition of FMRP-bound mRNAs. We show ER stress-induced activation of Inositol requiring enzyme-1 (IRE1), an ER-resident stress-sensing kinase/endoribonuclease, leads to FMRP phosphorylation and to suppression of macrophage cholesterol efflux and apoptotic cell clearance (efferocytosis). Conversely, FMRP deficiency and pharmacological inhibition of IRE1 kinase activity enhances cholesterol efflux and efferocytosis, reducing atherosclerosis in mice. Our results provide mechanistic insights into how ER stress-induced IRE1 kinase activity contributes to macrophage cholesterol homeostasis and suggests IRE1 inhibition as a promising new way to counteract atherosclerosis.

The unfolded protein response (UPR) is an elaborate signaling network that evolved to maintain proteostasis in the endoplasmic reticulum (ER) and mitochondria (mt). These organelles are functionally and physically associated, and consequently, their stress responses are often intertwined. It is unclear how these two adaptive stress responses are coordinated during ER stress. The inositol-requiring enzyme-1 (IRE1), a central ER stress sensor and proximal regulator of the UPRER, harbors dual kinase and endoribonuclease (RNase) activities. IRE1 RNase activity initiates the transcriptional layer of the UPRER, but IRE1’s kinase substrate(s) and their functions are largely unknown. Here, we discovered that sphingosine 1-phosphate (S1P) lyase (SPL), the enzyme that degrades S1P, is a substrate for the mammalian IRE1 kinase. Our data show that IRE1-dependent SPL phosphorylation inhibits SPL’s enzymatic activity, resulting in increased intracellular S1P levels. S1P has previously been shown to induce the activation of mitochondrial UPR (UPRmt) in nematodes. We determined that IRE1 kinase-dependent S1P induction during ER stress potentiates UPRmt signaling in mammalian cells. Phosphorylation of eukaryotic translation initiation factor 2α (eif2α) is recognized as a critical molecular event for UPRmt activation in mammalian cells. Our data further demonstrate that inhibition of the IRE1-SPL axis abrogates the activation of two eif2α kinases, namely double-stranded RNA-activated protein kinase (PKR) and PKR–like ER kinase upon ER stress. These findings show that the IRE1-SPL axis plays a central role in coordinating the adaptive responses of ER and mitochondria to ER stress in mammalian cells.

The double-stranded RNA-dependent protein kinase activating protein (PACT), an RNA-binding protein that is part of the RNA-induced silencing complex, plays a key role in miR-mediated translational repression. Previous studies showed that PACT regulates the expression of various miRs, selects the miR strand to be loaded onto RNA-induced silencing complex, and determines proper miR length. Apart from PACT's role in mediating the antiviral response in immune cells, what PACT does in other cell types is unknown. Strikingly, it has also been shown that cold exposure leads to marked downregulation of PACT protein in mouse brown adipose tissue (BAT), where mitochondrial biogenesis and metabolism play a central role. Here, we show that PACT establishes a posttranscriptional brake on mitochondrial biogenesis (mitobiogenesis) by promoting the maturation of miR-181c, a key suppressor of mitobiogenesis that has been shown to target mitochondrial complex IV subunit I (Mtco1) and sirtuin 1 (Sirt1). Consistently, we found that a partial reduction in PACT expression is sufficient to enhance mitobiogenesis in brown adipocytes in culture as well as during BAT activation in mice. In conclusion, we demonstrate an unexpected role for PACT in the regulation of mitochondrial biogenesis and energetics in cells and BAT.

The ER-bound kinase/endoribonuclease (RNase), inositol-requiring enzyme-1 (IRE1), regulates the phylogenetically most conserved arm of the unfolded protein response (UPR). However, the complex biology and pathology regulated by mammalian IRE1 cannot be fully explained by IRE1's one known, specific RNA target, X box-binding protein-1 (XBP1) or the RNA substrates of IRE1-dependent RNA degradation (RIDD) activity. Investigating other specific substrates of IRE1 kinase and RNase activities may illuminate how it performs these diverse functions in mammalian cells. We report that macrophage IRE1 plays an unprecedented role in regulating phosphatidylinositide-derived signaling lipid metabolites and has profound impact on the downstream signaling mediated by the mammalian target of rapamycin (mTOR). This cross-talk between UPR and mTOR pathways occurs through the unconventional maturation of microRNA (miR) 2137 by IRE1's RNase activity. Furthermore, phosphatidylinositol (3,4,5) phosphate (PI(3,4,5)P3 ) 5-phosphatase-2 (INPPL1) is a direct target of miR-2137, which controls PI(3,4,5)P3 levels in macrophages. The modulation of cellular PI(3,4,5)P3 /PIP2 ratio and anabolic mTOR signaling by the IRE1-induced miR-2137 demonstrates how the ER can provide a critical input into cell growth decisions.

Kizilotesi gudumlu sistemler, hedeften yayilan enerjiyi algilayarak, hedefleri tespit etmek ve etkisiz hale getirmek icin kullanilir. Bu sistemlerde kullanilan optik elemanlar, kubbe, mercekler (ve/veya ayna) ve dedektordur. Calisma kapsaminda, arayici basligin optik tasarimi kizilotesi spektrumun iki bandinda (MWIR–LWIR) calisacak sekilde gerceklestirilmistir. Bu amacla, optik tasarim ve analiz yetenegine sahip Zemax OpticStudio adli program kullanilmistir. Calismaya, iki bantta calisabilen ticari dedektorler arastirilarak baslanmis ve performanslari karsilastirilarak uygun dedektor belirlenmistir. Belirlenen dedektorun ozellikleri ile optik tasarim parametreleri hesaplanarak 3 – 10 µm araliginda calisabilen kizilotesi arayici baslik optik tasarimi yapilmistir. Tasarimin –40 ile +80 °C sicaklik araligindaki optik performanslari, farkli dort govde malzemesi eklenerek incelenmistir. Her bir malzemenin kullanimindaki odak bozulmalari optik pasif atermalizasyon teknigi ile duzeltilmistir. Govde malzemelerinin maliyet ve tedarik imkanlari degerlendirilerek tasarim sonlandirilmistir. Tasarimi yapilan arayici basligin gorus acisi 16° ve modulasyon transfer fonksiyonunun (MTF) %50 oldugunda uzaysal frekansi 23 cc/mm bulunmustur. Yapilan calismanin sonunda arayici baslik optik tasarimi, spot diyagrami, MTF, Seidel diyagrami, enerji dagilimi ile analiz edilmis ve elde edilen sonuclar tartisilmistir.

OBJECTIVE:Saturated and trans fat consumption is associated with increased cardiovascular disease (CVD) risk. Current dietary guidelines recommend low fat and significantly reduced trans fat intake. Full fat dairy can worsen dyslipidemia, but recent epidemiological studies show full-fat dairy consumption may reduce diabetes and CVD risk. This dairy paradox prompted a reassessment of the dietary guidelines. The beneficial metabolic effects in dairy have been claimed for a ruminant-derived, trans fatty acid, trans-C16:1n-7 or trans-palmitoleate (trans-PAO). A close relative, cis-PAO, is produced by de novo lipogenesis and mediates inter-organ crosstalk, improving insulin-sensitivity and alleviating atherosclerosis in mice. These findings suggest trans-PAO may be a useful substitute for full fat dairy, but a metabolic function for trans-PAO has not been shown to date. METHODS:Using lipidomics, we directly investigated trans-PAO's impact on plasma and tissue lipid profiles in a hypercholesterolemic atherosclerosis mouse model. Furthermore, we investigated trans-PAO's impact on hyperlipidemia-induced inflammation and atherosclerosis progression in these mice. RESULTS:Oral trans-PAO supplementation led to significant incorporation of trans-PAO into major lipid species in plasma and tissues. Unlike cis-PAO, however, trans-PAO did not prevent organelle stress and inflammation in macrophages or atherosclerosis progression in mice. CONCLUSIONS:A significant, inverse correlation between circulating trans-PAO levels and diabetes incidence and cardiovascular mortality has been reported. Our findings show that trans-PAO can incorporate efficiently into the same pools that its cis counterpart is known to incorporate into. However, we found trans-PAO's anti-inflammatory and anti-atherosclerotic effects are muted due to its different structure from cis-PAO.

Mevcut makalede sezgisel ve yaratici problem cozme becerilerini olcmede kullanilan Uzak Baglantilar Testi’nin (UBT) Turkce norm ve guvenirlik calismasi rapor edilmistir. UBT icin 120 adet problem (uclu kelime seti) olusturulmustur. Her bir UBT Problemi uc kelimeden olusmakta ve cozum icin bu problem kelimelerinin her biriyle birlikte kullanildiginda anlamli ikili kelime olusturan (ortak) cozum kelimesinin bulunmasi gerekmektedir. Testin guvenirligi icin hesaplanan ic tutarlik katsayisinin (Cronbach α = .87) oldukca yuksek ve anlamli ol- dugu belirlenmistir. Ek olarak UBT problemleri cozum kelimesinin problem kelimesine olan konumuna gore (basta ya da sonda) iki farkli tipte duzenlenmistir. Buna gore; Geriye Dogru UB Problemlerini cozum kelimelerinin uclu problem kelimelerinin onune/basina geldigi prob- lemler; Ileriye Dogru UB Problemlerini ise cozum kelimelerinin uclu problem kelimelerinin sonuna geldigi problemler olusturmustur. Problem yapisina bagli olarak cozulme oranlari incelendiginde ileriye dogru UBT puanlarinin geriye dogru UBT puanlarindan anlamli de- recede daha yuksek oldugu gozlenmistir. Son olarak mevcut bulgular UBT puanlari arasinda cinsiyet acisindan farklilik olmadigini gostermistir.