Regulation of Chromatin Structure During Neural Development

The regulation of genome architecture is a key determinant of gene transcription patterns and neural development. Advances in methodologies based on chromatin conformation capture (3C) have shed light on the genome-wide organization of chromatin in developmental processes. Here, we review recent discoveries regarding the regulation of three-dimensional (3D) chromatin conformation, including promoter–enhancer looping, and the dynamics of large chromatin domains such as topologically associated domains (TADs) and A/B compartments. We conclude with perspectives on how these conformational changes govern neural development and may go awry in disease states

JNK antagonizes Akt-mediated survival signals by phosphorylating 14-3-3

Life and death decisions are made by integrating a variety of apoptotic and survival signals in mammalian cells. Therefore, there is likely to be a common mechanism that integrates multiple signals adjudicating between the alternatives. In this study, we propose that 14-3-3 represents such an integration point. Several proapoptotic proteins commonly become associated with 14-3-3 upon phosphorylation by survival-mediating kinases such as Akt. We reported previously that cellular stresses induce c-Jun NH2-terminal kinase (JNK)–mediated 14-3-3ζ phosphorylation at Ser184 (Tsuruta, F., J. Sunayama, Y. Mori, S. Hattori, S. Shimizu, Y. Tsujimoto, K. Yoshioka, N. Masuyama, and Y. Gotoh. 2004. EMBO J. 23:1889–1899). Here, we show that phosphorylation of 14-3-3 by JNK releases the proapoptotic proteins Bad and FOXO3a from 14-3-3 and antagonizes the effects of Akt signaling. As a result of dissociation, Bad is dephosphorylated and translocates to the mitochondria, where it associates with Bcl-2/Bcl-xL. Because Bad and FOXO3a share the 14-3-3–binding motif with other proapoptotic proteins, we propose that this JNK-mediated phosphorylation of 14-3-3 regulates these proapoptotic proteins in concert and makes cells more susceptible to apoptotic signals

Somatostatin induces hyperpolarization in pancreatic islet α cells by activating a G protein-gated K+ channel

AbstractSomatostatin inhibits glucagon-secretion from pancreatic α cells but its underlying mechanism is unknown. In mouse α cells, we found that somatostatin induced prominent hyperpolarization by activating a K+ channel, which was unaffected by tolbutamide but prevented by pre-treating the cells with pertussis toxin. The K+ channel was activated by intracellular GTP (with somatostatin), GTPγS or Gβγ subunits. It was thus identified as a G protein-gated K+ (KG) channel. RT-PCR and immunohistochemical analyses suggested the KG channel to be composed of Kir3.2c and Kir3.4. This study identified a novel ionic mechanism involved in somatostatin-inhibition of glucagon-secretion from pancreatic α cells

TIMP3 promotes the maintenance of neural stem-progenitor cells in the mouse subventricular zone

Adult neural stem cells (NSCs) in the mouse subventricular zone (SVZ) serve as a lifelong reservoir for newborn olfactory bulb neurons. Recent studies have identified a slowly dividing subpopulation of embryonic neural stem-progenitor cells (NPCs) as the embryonic origin of adult NSCs. Yet, little is known about how these slowly dividing embryonic NPCs are maintained until adulthood while other NPCs are extinguished by the completion of brain development. The extracellular matrix (ECM) is an essential component of stem cell niches and thus a key determinant of stem cell fate. Here we investigated tissue inhibitors of metalloproteinases (TIMPs)—regulators of ECM remodeling—for their potential roles in the establishment of adult NSCs. We found that Timp2, Timp3, and Timp4 were expressed at high levels in slowly dividing NPCs compared to rapidly dividing NPCs. Deletion of TIMP3 reduced the number of adult NSCs and neuroblasts in the lateral SVZ. In addition, overexpression of TIMP3 in the embryonic NPCs suppressed neuronal differentiation and upregulated the expression levels of Notch signaling relating genes. These results thus suggest that TIMP3 keeps the undifferentiated state of embryonic NPCs, leading to the establishment and maintenance of adult NSCs

Replicative capacity of SARS-CoV-2 omicron variants BA.5 and BQ.1.1 at elevated temperatures

新型コロナウイルス・オミクロン株のBA.5系統およびBQ.1.1系統が、高温で増殖しづらいことを解明. 京都大学プレスリリース. 2023-04-27

Wide-Field Fundus Autofluorescence Abnormalities and Visual Function in Patients With Cone and Cone-Rod Dystrophies

METHODS. Sixteen patients with cone dystrophy (CD) and 41 patients with cone-rod dystrophy (CRD) were recruited at one institution. The right eye of each patient was included for analysis. We obtained wide-field FAF images using a ultra-widefield retinal imaging device and measured the area of abnormal FAF. The association between the area of abnormal FAF and the results of visual acuity measurements, kinetic perimetry, and electroretinography (ERG) were investigated. RESULTS. The mean age of the participants was 51.4 6 17.4 years, and the mean logarithm of the minimum angle of resolution was 1.00 6 0.57. The area of abnormal FAF correlated with the scotoma measured by the Goldman perimetry I/4e isopter (q ¼ 0.79, P < 0.001). The area also correlated with amplitudes of the rod ERG (q ¼ À0.63, P < 0.001), combined ERG awave (q ¼ À0.72, P < 0.001), combined ERG b-wave (q ¼ À0.66, P < 0.001), cone ERG (q ¼ À0.44, P ¼ 0.001), and flicker ERG (q ¼ À0.47, P < 0.001). CONCLUSIONS. The extent of abnormal FAF reflects the severity of functional impairment in patients with cone-dominant retinal dystrophies. Fundus autofluorescence measurements are useful for predicting retinal function in these patients

Cytology of malignant endocrine tumor of the pancreas : A case report

We report here a case of malignant endocrine tumor of the pancreas with lymph node metastasis in a 67-year-old woman. The cytologic preparations ex-hibited small cells having uniform round eccentrically located nuclei and large cells showing irregular-shaped nuclei with coarse chromatin and pleomorphism. The histologic, immunohistochemical and ultrastructural findings were characte-ristic of pancreatic endocrine tumor, regardless of immunophenotypic hetero-geneity. The heterogeneity observed in cytologic specimens may be important in predicting the malignant potential of this tumor group

Comprehensive molecular diagnosis of a large cohort of Japanese retinitis pigmentosa and Usher syndrome patients by next-generation sequencing. Invest Ophthalmol Vis Sci

PURPOSE. Retinitis pigmentosa (RP), a major cause of blindness in developed countries, has multiple causative genes; its prevalence differs by ethnicity. Usher syndrome is the most common form of syndromic RP and is accompanied by hearing impairment. Although molecular diagnosis is challenging, recent technological advances such as targeted highthroughput resequencing are efficient screening tools. METHODS. We performed comprehensive molecular testing in 329 Japanese RP and Usher syndrome patients by using a custom capture panel that covered the coding exons and exon/ intron boundaries of all 193 known inherited eye disease genes combined with Illumina HiSequation 2500. Candidate variants were screened using systematic data analyses, and their potential pathogenicity was assessed according to the frequency of the variants in normal populations, in silico prediction tools, and compatibility with known phenotypes or inheritance patterns. RESULTS. Molecular diagnoses were made in 115/317 RP patients (36.3%) and 6/12 Usher syndrome patients (50%). We identified 104 distinct mutations, including 66 novel mutations. EYS, USH2A, and RHO were common causative genes. In particular, mutations in EYS accounted for 15.0% of the autosomal recessive/simplex RP patients or 10.7% of the entire RP cohort. Among the 189 previously reported mutations detected in the current study, 55 (29.1%) were found commonly in Japanese or other public databases and were excluded from molecular diagnoses. CONCLUSIONS. By screening a large cohort of patients, this study catalogued the genetic variations involved in RP and Usher syndrome in a Japanese population and highlighted the different distribution of causative genes among populations