A hemophagocytic lymphohistiocytosis case with newly defined UNC13D (C.175G>C; p.Ala59Pro) mutation and a rare complication

Hemophagocytic lymphohistiocytosis (HLH) represents a severe hyperinflammatory condition with cardinal symptoms of prolonged fever, cytopenias, hepatosplenomegaly, and hemophagocytosis by activated, morphologically benign macrophages with impaired function of natural killer cells and cytotoxic T lymphocytes. A 2-month-old girl, who was admitted with fever, was diagnosed with HLH and her genetic examination revealed a newly defined mutation in the UNC13D (c.175G>C; p.Ala59Pro) gene. She was treated with dexamethasone, etoposide, and intrathecal methotrexate. During the second week of treatment, after three doses of etoposide, it was noticed that there was a necrotic plaque lesion on the soft palate. Pathologic examination of debrided material in PAS and Grocott staining revealed lots of septated hyphae, which was consistent with aspergillosis infection. Etoposide was stopped and amphotericin B treatment was given for six weeks. HLH 2004 protocol was completed to eight weeks with cyclosporine A orally. There was no patient with invasive aspergillosis infection as severe as causing palate and nasal septum perforation during HLH therapy. In immuncompromised patients, fungal infections may cause nasal septum perforation and treatment could be achieved by antifungal therapy and debridement of necrotic tissue. © 2015 Turkish Society of Hematology. All rights reserved

Two-photon microscopy-guided femtosecond-laser photoablation of avian cardiogenesis: Noninvasive creation of localized heart defects

Yalçın, Hüseyin Çağatay (Dogus Author)Embryonic heart formation is driven by complex feedback between genetic and hemodynamic stimuli. Clinical congenital heart defects (CHD), however, often manifest as localized microtissue malformations with no underlying genetic mutation, suggesting that altered hemodynamics during embryonic development may play a role. An investigation of this relationship has been impaired by a lack of experimental tools that can create locally targeted cardiac perturbations. Here we have developed noninvasive optical techniques that can modulate avian cardiogenesis to dissect relationships between alterations in mechanical signaling and CHD. We used two-photon excited fluorescence microscopy to monitor cushion and ventricular dynamics and femtosecond pulsed laser photoablation to target micrometer-sized volumes inside the beating chick hearts. We selectively photoablated a small (∼100 μm radius) region of the superior atrioventricular (AV) cushion in Hamburger-Hamilton 24 chick embryos. We quantified via ultrasound that the disruption causes AV regurgitation, which resulted in a venous pooling of blood and severe arterial constriction. At 48 h postablation, quantitative X-ray microcomputed tomography imaging demonstrated stunted ventricular growth and pronounced left atrial dilation. A histological analysis demonstrated that the laser ablation produced defects localized to the superior AV cushion: a small quasispherical region of cushion tissue was completely obliterated, and the area adjacent to the myocardial wall was less cellularized. Both cushions and myocardium were significantly smaller than sham-operated controls. Our results highlight that two-photon excited fluorescence coupled with femtosecond pulsed laser photoablation should be considered a powerful tool for studying hemodynamic signaling in cardiac morphogenesis through the creation of localized microscale defects that may mimic clinical CHD

Relationship of vascular variations with liver remnant volume in living liver transplant donors

Background: In this study, we investigated the relationship between the portal vein and hepatic artery variations and the remaining liver volume in living donors in liver transplantation.Materials and methods: In the study, triphasic abdominal computed tomography images of 180 live liver donor candidates were analysed retrospectively. Portal veins were divided into four groups according to the Nakamura classification and seven groups according to the Michels classification. The relationship between vascular variations and remnant liver volume was compared statistically.Results: According to the Nakamura classification, there were 143 (79.4%) type A, 23 (12.7%) type B, 7 (3.9%) type C and 7 (3.9%) type D cases. Using the Michels classification, 129 (71%) type 1, 12 (6.7%) type 2, 24 (13%) type 3, 2 (2.2%) type 4, 10 (5.6%) type 5, 1 (0.6%) type 6, and 2 (1.1%) type 7 cases were detected. There was no significant difference in the percentage of the remaining volume of the left liver lobe between the groups (p = 0.055, p = 0.207, respectively).Conclusions: Variations in the hepatic artery and portal vein do not affect the remaining liver volume in liver transplantation donors

Variant‐specific effects of GBA1 mutations on dopaminergic neuron proteostasis

Glucocerebrosidase 1 (GBA1) mutations are the most important genetic risk factors for Parkinson's disease (PD). Clinically, mild (e.g., p.N370S) and severe (e.g., p.L444P and p.D409H) GBA1 mutations have different PD phenotypes, with differences in age at disease onset, progression, and the severity of motor and non‐motor symptoms. We hypothesize that GBA1 mutations cause the accumulation of α‐synuclein by affecting the cross‐talk between cellular protein degradation mechanisms, leading to neurodegeneration. Accordingly, we tested whether mild and severe GBA1 mutations differentially affect the degradation of α‐synuclein via the ubiquitin–proteasome system (UPS), chaperone‐mediated autophagy (CMA), and macroautophagy and differentially cause accumulation and/or release of α‐synuclein. Our results demonstrate that endoplasmic reticulum (ER) stress and total ubiquitination rates were significantly increased in cells with severe GBA1 mutations. CMA was found to be defective in induced pluripotent stem cell (iPSC)‐derived dopaminergic neurons with mild GBA1 mutations, but not in those with severe GBA1 mutations. When examining macroautophagy, we observed reduced formation of autophagosomes in cells with the N370S and D409H GBA1 mutations and impairments in autophagosome–lysosome fusion in cells with the L444P GBA1 mutation. Accordingly, severe GBA1 mutations were found to trigger the accumulation and release of oligomeric α‐synuclein in iPSC‐derived dopaminergic neurons, primarily as a result of increased ER stress and defective macroautophagy, while mild GBA1 mutations affected CMA, which is mainly responsible for the degradation of the monomeric form of α‐synuclein. Overall, our findings provide new insight into the molecular basis of the clinical variability in PD associated with different GBA1 mutations

Beyond Modes: Building a Secure Record Protocol from a Cryptographic Sponge Permutation

Abstract. BLINKER is a light-weight cryptographic suite and record protocol built from a single permutation. Its design is based on the Sponge construction used by the SHA-3 algorithm KECCAK. We examine the SpongeWrap authen-ticated encryption mode and expand its padding mechanism to offer explicit do-main separation and enhanced security for our specific requirements: shared se-cret half-duplex keying, encryption, and a MAC-and-continue mode. We motivate these enhancements by showing that unlike legacy protocols, the resulting record protocol is secure against a two-channel synchronization attack while also having a significantly smaller implementation footprint. The design facilitates security proofs directly from a single cryptographic primitive (a single security assump-tion) rather than via idealization of multitude of algorithms, paddings and modes of operation. The protocol is also uniquely suitable for an autonomous or semi-autonomous hardware implementation of protocols where the secrets never leave the module, making it attractive for smart card and HSM designs

Authoritarian Neoliberalism and Democratic Backsliding in Turkey: Beyond the Narratives of Progress

Unpacking the core themes that are discussed in this collection, this article both offers a research agenda to re-analyse Turkey’s ‘authoritarian turn’ and mounts a methodological challenge to the conceptual frameworks that reinforce a strict analytical separation between the ‘economic’ and the ‘political’ factors. The paper problematises the temporal break in scholarly analyses of the AKP period and rejects the argument that the party’s methods of governance have shifted from an earlier ‘democratic’ model – defined by ‘hegemony’ – to an emergent ‘authoritarian’ one. In contrast, by retracing the mechanisms of the state-led reproduction of neoliberalism since 2003, the paper demonstrates that the party’s earlier ‘hegemonic’ activities were also shaped by authoritarian tendencies which manifested at various levels of governance

The stable free rank of symmetry of products of spheres

A well known conjecture in the theory of transformation groups states that if p is a prime and (Z/p)^r acts freely on a product of k spheres, then r is less than or equal to k. We prove this assertion if p is large compared to the dimension of the product of spheres. The argument builds on tame homotopy theory for non simply connected spaces.Comment: 30 pages; improved exposition, some details adde

Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins

Axons contain a smooth tubular endoplasmic reticulum (ER) network that is thought to be continuous with ER throughout the neuron; the mechanisms that form this axonal network are unknown. Mutations affecting reticulon or REEP proteins, with intramembrane hairpin domains that model ER membranes, cause an axon degenerative disease, hereditary spastic paraplegia (HSP). We show that Drosophila axons have a dynamic axonal ER network, which these proteins help to model. Loss of HSP hairpin proteins causes ER sheet expansion, partial loss of ER from distal motor axons, and occasional discontinuities in axonal ER. Ultrastructural analysis reveals an extensive ER network in axons, which shows larger and fewer tubules in larvae that lack reticulon and REEP proteins, consistent with loss of membrane curvature. Therefore HSP hairpin-containing proteins are required for shaping and continuity of axonal ER, thus suggesting roles for ER modeling in axon maintenance and function.RCUK | Biotechnology and Biological Sciences Research Council (BBSRC): Lu Zhao, Cahir J O'Kane, BB/L021706/1; Wellcome: Martin Stofanko, Cahir J O'Kane, 08136; European Commission (EC): Lu Zhao, Niamh C O'Sullivan, Sophie Zaessinger, Olivier Blard, MCSA fellowships 220851,220874,236777,660516; Yousef Jameel Foundation: Belgin Yalçın; Singapore A*STAR Scholarship: Zi Han Kang, BM/RES/07/005; Cambridge Commonwealth, European and International Trust (Cambridge Commonwealth, European & International Trust): Belgin Yalçın, Anood Sohail; Pakistan Higher Education Council Scholarship: Anood Sohail; Motor Neurone Disease Association (MNDA): Alex L Patto, Studentship 861-792 The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication