A new heterozygous compound mutation in the CTSA gene in galactosialidosis

Galactosialidosis is an autosomal recessive lysosomal storage disease caused by the combined deficiency of lysosomal β-galactosidase and neuraminidase due to a defect in the protective protein/cathepsin A. Patients present with various clinical manifestations and are classified into three types according to the age of onset: the early infantile type, the late infantile type, and the juvenile/adult type. We report a Japanese female case of juvenile/adult type galactosialidosis. Clinically, she presented with short stature, coarse facies, angiokeratoma, remarkable action myoclonus, and cerebellar ataxia. The patient was diagnosed with galactosialidosis with confirmation of impaired β-galactosidase and neuraminidase function in cultured skin fibroblasts. Sanger sequencing for CTSA identified a compound heterozygous mutation consisting of NM_00308.3(CTSA):c.746 + 3A>G and c.655-1G>A. Additional analysis of her mother’s DNA sequence indicated that the former mutation originated from her mother, and therefore the latter was estimated to be from the father or was a de novo mutation. Both mutations are considered pathogenic owing to possible splicing abnormalities. One of them (c.655-1G>A) is novel because it has never been reported previously

Neuroendocrine Carcinoma of the Stomach: A Case Study

Gastric neuroendocrine carcinomas are rare and have a poor prognosis, and the diagnostic criteria for this disease have recently changed. We herein report a case of sporadic gastric neuroendocrine carcinoma. A 75-year-old man was referred to our hospital with epigastric pain. Endoscopic examination revealed a localized ulcerative lesion (diameter, 4 cm) at the upper stomach. The diagnosis on biopsy was neuroendocrine carcinoma. Total gastrectomy with D2 lymphadenectomy, splenectomy, and cholecystectomy was performed. Pathologically, the tumor infiltrated the subserosal layer, and 6/49 lymph nodes were involved. The tumor was uniform in shape and arranged in a rosette-like structure to form solid nests, with medium-sized, round-to-cuboid-shaped tumor cells and intense mitosis 46/10 HPF. It was positive for synaptophysin and chromogranin A, and the Ki-67 labeling index was 70–80%. The diagnosis of neuroendocrine carcinoma was made according to the WHO 2010 criteria. The patient was followed up for three years without recurrence

Probing astrophysically important states in the ²⁶Mg nucleus to study neutron sources for the s process

Background: The ²²Ne(α,n) ²⁵Mg reaction is the dominant neutron source for the slow neutron capture process (s process) in massive stars, and contributes, together with C¹³(α,n)O¹⁶, to the production of neutrons for the s process in asymptotic giant branch (AGB) stars. However, the reaction is endothermic and competes directly with ²²Ne(α,γ)²⁶Mg radiative capture. The uncertainties for both reactions are large owing to the uncertainty in the level structure of ²⁶Mg near the α and neutron separation energies. These uncertainties affect the s-process nucleosynthesis calculations in theoretical stellar models. Purpose: Indirect studies in the past have been successful in determining the energies and the γ-ray and neutron widths of the Mg26 states in the energy region of interest. But, the high Coulomb barrier hinders a direct measurement of the resonance strengths, which are determined by the α widths for these states. The goal of the present experiments is to identify the critical resonance states and to precisely measure the α widths by α-transfer techniques. Methods: The α-inelastic scattering and α-transfer measurements were performed on a solid ²⁶Mg target and a ²²Ne gas target, respectively, using the Grand Raiden Spectrometer at the Research Center for Nuclear Physics in Osaka, Japan. The (α,α′) measurements were performed at 0.45°, 4.1°, 8.6°, and 11.1° and the (⁶Li,d) measurements at 0° and 10°. The scattered α particles and deuterons were detected by the focal plane detection system consisting of multiwire drift chambers and plastic scintillators. The focal plane energy calibration allowed the study of ²⁶Mg levels from Eₓ = 7.69–12.06 MeV in the (α,α′) measurement and Eₓ = 7.36–11.32 MeV in the (⁶Li,d) measurement. Results: Six levels (Eₓ = 10717, 10822, 10951, 11085, 11167, and 11317 keV) were observed above the α threshold in the region of interest (10.61–11.32 MeV). The α widths were calculated for these states from the experimental data. The results were used to determine the α-capture induced reaction rates. Conclusion: The energy range above the α threshold in ²⁶Mg was investigated using a high resolution spectrometer. A number of states were observed for the first time in α-scattering and α-transfer reactions. The excitation energies and spin-parities were determined. Good agreement is observed for previously known levels in ²⁶Mg. From the observed resonance levels the Eₓ = 10717 keV state has a negligible contribution to the α-induced reaction rates. The rates are dominated in both reaction channels by the resonance contributions of the states at Ex = 10951, 11167, and 11317 keV. The Eₓ = 11167 keV state has the most appreciable impact on the (α,γ) rate and therefore plays an important role in the prediction of the neutron production in s-process environments

Systems Analysis of ATF3 in Stress Response and Cancer Reveals Opposing Effects on Pro-Apoptotic Genes in p53 Pathway

Stress-inducible transcription factors play a pivotal role in cellular adaptation to environment to maintain homeostasis and integrity of the genome. Activating transcription factor 3 (ATF3) is induced by a variety of stress and inflammatory conditions and is over-expressed in many kinds of cancer cells. However, molecular mechanisms underlying pleiotropic functions of ATF3 have remained elusive. Here we employed systems analysis to identify genome-wide targets of ATF3 that is either induced by an alkylating agent methyl methanesulfonate (MMS) or over-expressed in a prostate tumour cell line LNCaP. We show that stress-induced and cancer-associated ATF3 is recruited to 5,984 and 1,423 targets, respectively, in the human genome, 89% of which are common. Notably, ATF3 targets are highly enriched for not only ATF/CRE motifs but also binding sites of several other stress-inducible transcription factors indicating an extensive network of stress response factors in transcriptional regulation of target genes. Further analysis of effects of ATF3 knockdown on these targets revealed that stress-induced ATF3 regulates genes in metabolic pathways, cell cycle, apoptosis, cell adhesion, and signalling including insulin, p53, Wnt, and VEGF pathways. Cancer-associated ATF3 is involved in regulation of distinct sets of genes in processes such as calcium signalling, Wnt, p53 and diabetes pathways. Notably, stress-induced ATF3 binds to 40% of p53 targets and activates pro-apoptotic genes such as TNFRSF10B/DR5 and BBC3/PUMA. Cancer-associated ATF3, by contrast, represses these pro-apoptotic genes in addition to CDKN1A/p21. Taken together, our data reveal an extensive network of stress-inducible transcription factors and demonstrate that ATF3 has opposing, cell context-dependent effects on p53 target genes in DNA damage response and cancer development

Dipole polarizability of 120Sn and nuclear energy density functionals

The electric dipole strength distribution in 120Sn between 5 and 22 MeV has been determined at RCNP Osaka from a polarization transfer analysis of proton inelastic scattering at E_0 = 295 MeV and forward angles including 0{\deg}. Combined with photoabsorption data an electric dipole polarizability \alpha_D(120Sn) = 8.93(36) fm^3 is extracted. The dipole polarizability as isovector observable par excellence carries direct information on the nuclear symmetry energy and its density dependence. The correlation of the new value with the well established \alpha_D(208Pb) serves as a test of its prediction by nuclear energy density functionals (EDFs). Models based on modern Skyrme interactions describe the data fairly well while most calculations based on relativistic Hamiltonians cannot.Comment: 6 pages, 4 figure