Impaired β-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations.

Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenic GRN mutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia in GRN mutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients with GRN mutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients with GRN mutations (FTD-GRN) also accumulate lipofuscin. The specific lysosomal deficits caused by progranulin insufficiency remain unclear, but emerging data indicate that progranulin insufficiency may impair lysosomal sphingolipid-metabolizing enzymes. We investigated the effects of progranulin insufficiency on sphingolipid-metabolizing enzymes in the inferior frontal gyrus of FTD-GRN patients using fluorogenic activity assays, biochemical profiling of enzyme levels and posttranslational modifications, and quantitative neuropathology. Of the enzymes studied, only β-glucocerebrosidase exhibited impairment in FTD-GRN patients. Brains from FTD-GRN patients had lower activity than controls, which was associated with lower levels of mature β-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated β-glucocerebrosidase. Immunostaining revealed loss of neuronal β-glucocerebrosidase in FTD-GRN patients. To investigate the effects of progranulin insufficiency on β-glucocerebrosidase outside of the context of neurodegeneration, we investigated β-glucocerebrosidase activity in progranulin-insufficient mice. Brains from Grn-/- mice had lower β-glucocerebrosidase activity than wild-type littermates, which was corrected by AAV-progranulin gene therapy. These data show that progranulin insufficiency impairs β-glucocerebrosidase activity in the brain. This effect is strongest in neurons and may be caused by impaired β-glucocerebrosidase processing

Morphological Criteria for Diagnosis of Pulmonary Lesions of Lungs in Tumors Based on Resection Material

Morphological criteria of diagnosis of dust lesions of lungs in tumors on resectionmaterial are considered in the article. It is shown that the complex application of various research methods allows the identification of dust particles in the lung and lymph node tissues, and contributes to the improvement of the diagnosis of dust lesions of the respiratory system. Morphological characteristics of bauxite pneumoconiosis in primary lung cancer on resection material are presented

Diffusion spin echo decay by pulsed magnetic field gradient NMR and some structure features in blockcopolymer solutions

Blockcopolymer solutions were investigated by pulsed field gradient NMR. Nonexponential diffusion decay of solvent molecules and the dependence of it's shape on time of observation uere found out. These features (unusual for solvent molecules) were explained on assumption of the solution heterogeneous structure. Consideration, performed, allow us to estimate the linear dimensions of the heterogeneities, which for concentrated systems occured to be near 10000 A. © 1985 Springer-Verlag

Algorithm of morphological diagnostics of small cell lung cancer on bronchial biopsy

Results of cytologicai, histological and immunohistochemical analyses of bronchial biopsies of 95 patients with small cell lung cancer have been provided in this paper. In 85.3% of the cases small cell lung cancer within optic level has been verified by complex cytologicai and histological diagnosis. In the rest of 14.7% of the cases it has been revealed the necessity of using additional analysis methods to detect a version of small cell lung cancer. In 24 cases immunohistochemical analysis has been made, in 10 of them - to confirm morphological diagnosis of small cell lung cancer, in 14 of them - to detect a version of small cell lung tumour by using different antibodies sets depending on differentially diagnostic series. Immunohistochemical analysis has shown that 20 tumours have immunophenotype of small cell lung cancer, trustworthy lung adenocarcinoma, diffuse large cell В-cell lymphoma and mammary gland carcinoma. It has been worked out an algorithm of complex histological, cytologicai and immunohistochemical methods of diagnostics. Using it allows to improve diagnostics of small cell lung cancer on data of bronchial biopsies.В работе приведены результаты цитологического, гистологического и иммуногистохимического исследований биопсий бронхов 95 больных с мелкоклеточными опухолями легких. В 85,3% случаев достоверно верифицирован мелкоклеточный рак легкого на светооптическом уровне при помощи комплексного цитологического и гистологического исследования, в оставшихся 14,7% случаев выявлена необходимость проведения дополнительных методов исследования для определения варианта мелкоклеточных опухолей легких. В 24 случаях проведено иммуногистохимическое исследование, в 10 случаях - для подтверждения морфологического диагноза мелкоклеточного рака легкого, в 14 — для определения варианта мелкоклеточной опухоли легкого с использованием различных наборов антител в зависимости от дифференциально-диагностическо ряда. В результате иммуногистохимического исследования выявлено, что 20 опухолей имеют иммунофенотип мелкоклеточного рака легкого, оставшиеся четыре мелкоклеточные опухоли — иммунофенотип мелкоклеточного варианта плоскоклеточного рака легкого, низкодифференцированной аденокарциномы легкого солидного строения, крупноклеточной В-клеточной лимфомы и карциномы молочной железы. Сформулирован алгоритм комплексного гистологического, цитологического и иммуногистохимического методов исследования, использование которого позволяет оптимизировать диагностику мелкоклеточного рака легкого по данным биопсий бронхов

Pathomorphology of small cell lung cancer on bronchial biopsy (histological and cytological comparisons)

In the paper there have been shown the results of histological and cytological studies of bronchial biopsies of patients with small cell lung tumors, compared data of histological and cytological studies and defined the structure of small cell lung cancer (variants of cyto-histological structure). In 85.3% of the cases it was managed to verify precisely the small-cell lung cancer, and in the remaining 14.7% of the cases it was revealed the need for immunohistochemical studies to identify the version of small-cell bronchial cancer. In 82.7% of the cases in the structure of small-cell lung cancer there was revealed the prevalence of oat cell variant including oat cell variant proper, oat cell variant with parts of intermediate cellular texture, oat cell variant of lymphocyte-like texture and oat cell variant with parts of both intermediate cellular and lymphocyte-like texture. In 9.9% of the cases small cell lung cancer had intermediate cellular texture, and in 7.4% of the cases variant of small cell lung cancer could not have been identified because of the evident crush phenomenon caused by the fragility of the tumor tissue and its crushing when obtaining biopsy material. In 60.0% of the cases the cytological findings coincided with the histological ones and the tumor structure in the smear test matched histological structure of SCLC. Integrated use of histological and cytological methods makes it possible to improve the diagnostics of small cell lung cancer on bronchial biopsy findings.В работе приведены результаты гистологического и цитологического исследований биопсий бронхов больных с мелко­клеточными опухолями легких, сопоставлены данные гистологического и цитологического исследований и определена структура мелкоклеточного рака легкого (варианты цито-гистологического строения). В 85,3% случаев удалось точно верифицировать мелкоклеточный рак легкого, в оставшихся 14,7% случаев выявлена необходимость иммуногистохимического исследования для определения варианта мелкоклеточных опухолей бронхов. В структуре мелкоклеточного рака легкого в 82,7% случаев выявлено преобладание овсяноклеточного варианта, включающего собственно овсяноклеточный вариант, овсяноклеточный вариант с участками промежуточноклеточного строения, овсяноклеточный вариант с участками лимфоцитоподобного строения и овсяноклеточный вариант с участками промежуточноклеточного и лимфоцитоподобного строения. В 9,9% случаев мелкоклеточный рак имел промежуточноклеточное строение, а в 7,4% случаев вариант мелкоклеточного рака определить не удалось из-за выраженных явлений краш-феномена, обусловленного хрупкостью опухолевой ткани и её раздавливанием при получении биоптата. Цитологические данные в 60,0% случаев совпадали с гистологическими и опухолевые структуры в мазках повторяли гистологическое строение МРЛ. Комплексное использование гистологического и цитологического методов позволяет улучшить диагностику мелкоклеточного рака легкого по данным биопсий бронхов

Morphological diagnostics off small cell lung cancer

Now lung cancer (LC) has remained the most widespread malignant tumour and the most frequent cause of death of people with this disease (this disease) in the world. It's accepted to divide all histological types of LC into small cell and non-small cell variants that is caused by essentially different ways of treatment. Small cell lung cancer (SCLC) is a malignant epithelial tumour of neuroendocrinal nature consisting of small round or oval cells with scant cytoplasm, finely granular nuclear chromatin and absent nucleoli. Necrosis is typically extensive and mitotic activity is high. Combined SCLC contains a component of any non­small cell lung cancer in a tumour structure. Immunohistochemical research of SCLC shows positive reaction on synaptophysin, C056 and chromogranin. The main method to receive material for morphological research at SCLC is bronchoscopy combined with forceps biopsy of affected bronchus. Small size of bronchial biopsy material and its crash during intake make morphological diagnostics difficult. Exact morphological diagnostics of SCLC is essentially important because it defines tactics of treatment which consists mainly in chemotherapy.В настоящее время рак легкого (РЛ) остается наиболее распространенной злокачественной опухолью и наиболее частой причиной смерти больных злокачественными новообразованиями в мире. Принято подразделять все гистологические типы РЛ на мелкоклеточный и немелкоклеточный варианты, что обусловлено принципиально разными подходами к лечению. Мелкоклеточный рак легкого (МРЛ) является злокачественной эпителиальной опухолью нейроэндокринной природы, состоящей из мелких округлых или овальных клеток со скудной цитоплазмой, нежно-гранулированным ядерным хроматином и отсутствием ядрышек. Характерно обилие некрозов и высокая митотическая активность. Комбинированный МРЛ содержит в структуре опухоли компонент любого немелкоклеточного рака. При иммуногистохимическом исследовании МРЛ дает положительную реакцию на синаптофизин, CD56 и хромогранин. Основным методом получения материала для морфологического исследования при МРЛ является бронхоскопия в сочетании со щипцовой биопсией пораженного бронха. Затрудняет морфологическую диагностику малый размер получаемого кусочка ткани и его раздавливание при заборе. Точная морфологическая диагностика МРЛ крайне важна, так как она определяет тактику лечения, которая заключается преимущественно в химиотерапии

LABORATORY MEASUREMENTS OF THE K-SHELL TRANSITION ENERGIES IN L-SHELL IONS OF SI AND S

We have measured the energies of the strongest 1s–2ℓ (ℓ = s, p) transitions in He- through Ne-like silicon and sulfur ions to an accuracy of <1 eV using the Lawrence Livermore National Laboratory's electron beam ion traps, EBIT-I and SuperEBIT, and the NASA/GSFC EBIT Calorimeter Spectrometer (ECS). We identify and measure the energies of 18 and 21 X-ray features from silicon and sulfur, respectively. The results are compared to new Flexible Atomic Code calculations and to semi-relativistic Hartree–Fock calculations by Palmeri et al. (2008). These results will be especially useful for wind diagnostics in high-mass X-ray binaries, such as Vela X-1 and Cygnus X-1, where high-resolution spectral measurements using Chandra's high-energy transmission grating has made it possible to measure Doppler shifts of 100 km s[superscript -1]. The accuracy of our measurements is consistent with that needed to analyze Chandra observations, exceeding Chandra's 100 km s[superscript -1] limit. Hence, the results presented here not only provide benchmarks for theory, but also accurate rest energies that can be used to determine the bulk motion of material in astrophysical sources. We show the usefulness of our results by applying them to redetermine Doppler shifts from Chandra observations of Vela X-1.United States. National Aeronautics and Space Administration (work orders NNX/2AH84G)United States. Department of Energy (Contract DE-AC52-07NA27344)Smithsonian Astrophysical Observatory (contract SV3-73016

NuSTAR and Suzaku observations of the hard state in Cygnus X-1: locating the inner accretion disk

We present simultaneous Nuclear Spectroscopic Telescope Array (NuSTAR ) and Suzaku observations of the X-ray binary Cygnus X-1 in the hard state. This is the first time this state has been observed in Cyg X-1 with NuSTAR, which enables us to study the reflection and broad-band spectra in unprecedented detail. We confirm that the iron line cannot be fit with a combination of narrow lines and absorption features, and instead requires a relativistically blurred profile in combination with a narrow line and absorption from the companion wind. We use the reflection models of Garcia et al. (2014) to simultaneously measure the black hole spin, disk inner radius, and coronal height in a self-consistent manner. Detailed fits to the iron line profile indicate a high level of relativistic blurring, indicative of reflection from the inner accretion disk. We find a high spin, a small inner disk radius, and a low source height, and rule out truncation to greater than three gravitational radii at the 3{\sigma} confidence level. In addition, we find that the line profile has not changed greatly in the switch from soft to hard states, and that the differences are consistent with changes in the underlying reflection spectrum rather than the relativistic blurring. We find that the blurring parameters are consistent when fitting either just the iron line or the entire broad-band spectrum, which is well modelled with a Comptonized continuum plus reflection model.Comment: 12 pages, 7 figures, accepted for publication in Ap

Phase behaviour of charged colloidal sphere dispersions with added polymer chains

We study the stability of mixtures of highly screened repulsive charged spheres and non-adsorbing ideal polymer chains in a common solvent using free volume theory. The effective interaction between charged colloids in an aqueous salt solution is described by a screened-Coulomb pair potential, which supplements the pure hard-sphere interaction. The ideal polymer chains are treated as spheres that are excluded from the colloids by a hard-core interaction, whereas the interaction between two ideal chains is set to zero. In addition, we investigate the phase behaviour of charged colloid-polymer mixtures in computer simulations, using the two-body (Asakura-Oosawa pair potential) approximation to the effective one-component Hamiltonian of the charged colloids. Both our results obtained from simulations and from free volume theory show similar trends. We find that the screened-Coulomb repulsion counteracts the effect of the effective polymer-mediated attraction. For mixtures of small polymers and relatively large charged colloidal spheres, the fluid-crystal transition shifts to significantly larger polymer concentrations with increasing range of the screened-Coulomb repulsion. For relatively large polymers, the effect of the screened-Coulomb repulsion is weaker. The resulting fluid-fluid binodal is only slightly shifted towards larger polymer concentrations upon increasing the range of the screened-Coulomb repulsion. In conclusion, our results show that the miscibility of dispersions containing charged colloids and neutral non-adsorbing polymers increases, upon increasing the range of the screened-Coulomb repulsion, or upon lowering the salt concentration, especially when the polymers are small compared to the colloids.Comment: 25 pages,13 figures, accepted for publication on J.Phys.:Condens. Matte