scholarly journals Clinical significance of spatiotemporal transcriptional bursting and control

2021 ◽  
Vol 11 (8) ◽  
Author(s):  
Diane Catherine Wang ◽  
Xiangdong Wang
Keyword(s):  
Clinical Significance ◽  
Transcriptional Bursting ◽  
And Control

scholarly journals Comparison of Predictive In Silico Tools on Missense Variants in GJB2, GJB6, and GJB3 Genes Associated with Autosomal Recessive Deafness 1A (DFNB1A)

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Vera G. Pshennikova ◽  
Nikolay A. Barashkov ◽  
Georgii P. Romanov ◽  
Fedor M. Teryutin ◽  
Aisen V. Solov’ev ◽  
...  
Keyword(s):  
Clinical Significance ◽  
In Silico ◽  
Autosomal Recessive ◽  
Area Under The Curve ◽  
Roc Curves ◽  
Missense Variants ◽  
Functional Studies ◽  
Connexin Genes ◽  
Predictive Software ◽  
And Control

In silico predictive software allows assessing the effect of amino acid substitutions on the structure or function of a protein without conducting functional studies. The accuracy of in silico pathogenicity prediction tools has not been previously assessed for variants associated with autosomal recessive deafness 1A (DFNB1A). Here, we identify in silico tools with the most accurate clinical significance predictions for missense variants of the GJB2 (Cx26), GJB6 (Cx30), and GJB3 (Cx31) connexin genes associated with DFNB1A. To evaluate accuracy of selected in silico tools (SIFT, FATHMM, MutationAssessor, PolyPhen-2, CONDEL, MutationTaster, MutPred, Align GVGD, and PROVEAN), we tested nine missense variants with previously confirmed clinical significance in a large cohort of deaf patients and control groups from the Sakha Republic (Eastern Siberia, Russia): Сх26: p.Val27Ile, p.Met34Thr, p.Val37Ile, p.Leu90Pro, p.Glu114Gly, p.Thr123Asn, and p.Val153Ile; Cx30: p.Glu101Lys; Cx31: p.Ala194Thr. We compared the performance of the in silico tools (accuracy, sensitivity, and specificity) by using the missense variants in GJB2 (Cx26), GJB6 (Cx30), and GJB3 (Cx31) genes associated with DFNB1A. The correlation coefficient (r) and coefficient of the area under the Receiver Operating Characteristic (ROC) curve as alternative quality indicators of the tested programs were used. The resulting ROC curves demonstrated that the largest coefficient of the area under the curve was provided by three programs: SIFT (AUC = 0.833, p = 0.046), PROVEAN (AUC = 0.833, p = 0.046), and MutationAssessor (AUC = 0.833, p = 0.002). The most accurate predictions were given by two tested programs: SIFT and PROVEAN (Ac = 89%, Se = 67%, Sp = 100%, r = 0.75, AUC = 0.833). The results of this study may be applicable for analysis of novel missense variants of the GJB2 (Cx26), GJB6 (Cx30), and GJB3 (Cx31) connexin genes.

FAS Mutations Accelerate Lymphoma Growth and Induce Therapeutic Resistance

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3018-3018 ◽  
Author(s):  
Stephanie Totten ◽  
Denis Gaucher ◽  
Ryan D Morin ◽  
Sarit Assouline ◽  
Joseph M. Connors ◽  
...  
Keyword(s):  
Immune Response ◽  
Lymph Node ◽  
B Lymphocytes ◽  
Clinical Significance ◽  
Cell Lines ◽  
Research Funding ◽  
Therapeutic Resistance ◽  
Lymphoma Cells ◽  
And Control

Abstract BACKGROUND: Rituximab-based chemotherapy is effective in inducing remissions in ~85% patients with untreated follicular lymphoma (FL). Primary treatment failure or an early relapse after first-line therapy is associated with a very poor prognosis. Recent sequencing efforts have been successful at identifying recurrent genetic events that contribute to the pathogenesis of FL, but the clinical significance of most of these events, in particular those contributing to therapeutic resistance, remain unknown. We identified a mutation in FAS (Y232*) in a patient with primary-refractory FL. FAS, a key death receptor in the extrinsic apoptotic pathway, plays a fundamental role in immune homeostasis by initiating apoptosis in lymphocytes once activated by FAS ligand (FASL) from neighboring cells. Herein, we show that mutations in FAS contribute to therapeutic resistance in FL. METHODS: We determined the incidence and clinical significance of FAS mutations in an extended cohort of 214 clinically-annotated FL biopsies. We determined the impact of the recurrent FAS(Y232*) mutation on FAS-mediated and chemotherapy-induced apoptosis in lymphoma cell lines. We measured the change in FAS and FASL expression in primary human T and B lymphocytes after exposure to chemotherapy. Finally, we cloned the murine equivalent of FAS(Y232*), Fas(Y224*), in Eu-Myc lymphoma cells and determined its effect on lymphoma growth and response to chemotherapy in immunocompetent C57BL/6 mice (n=36). RESULTS: FAS mutations were identified in 6% of FL patients. Coding FAS mutations were associated with a trend towards an earlier median time to progression (1 y versus 2.8 y, p=0.08) and an increased risk of histological transformation (p=0.036). The recurrent FAS(Y232*) mutation inhibited FAS-mediated apoptosis in cell lines but, unexpectedly, did not inhibit chemotherapy-mediated apoptosis. We hypothesized that in patients, chemotherapy induced a FAS-mediated immune response that was not modeled in vitro. Supporting this concept, we observed an increase in FASL and FAS expression on normal T and B lymphocytes, respectively, after exposure to etoposide. We injected three groups of mice with Eu-Myc lymphoma cells that differed only in their Fas genotype (Fas WT, Fas(Y224*) and an empty vector control) and monitored lymph node volumes before and after therapy. Fas(Y224*) dramatically accelerated lymphoma growth. Lymph node volumes exceeded those measured in Fas wild-type and control mice at all time points beyond the day of injection. The average maximal lymph node volume for the Fas(Y224*) group was 59.9 mm3 compared to 18.9 mm3 and 34.5 mm3 for the Fas WT and control groups, respectively (p < 0.001). Fas mutant lymphomas had an inferior response to doxorubicin and none of the mice in this group achieved a complete remission. Remarkably, the opposite phenotype was observed in the Fas WT group, where the addition of Fas WT inhibited lymphoma growth and induced earlier remissions. CONCLUSION: Mutations in FAS can be clinically important in patients with FL by promoting lymphoma growth and inducing therapeutic resistance. The full malignant phenotype of FAS mutant lymphomas could only be elicited in vivo, and not in vitro, suggesting that a FAS-mediated immune response controls lymphoma growth and actively participates in chemotherapy-induced cell death. Disclosures Connors: Seattle Genetics, Inc.: Research Funding; Roche: Research Funding.

Serum prolactin in uraemia: correlations between bioactivity and activity in two immunoassays

1989 ◽  
Vol 120 (3) ◽  
pp. 295-300 ◽  
Author(s):  
Caroline R. Smith ◽  
Joan Butler ◽  
Neil Iggo ◽  
Michael R. Norman
Keyword(s):  
Biological Activity ◽  
Peritoneal Dialysis ◽  
Clinical Significance ◽  
Elevated Serum ◽  
Biologically Active ◽  
Serum Prolactin ◽  
Immunoradiometric Assay ◽  
Control Subjects ◽  
Significant Difference ◽  
And Control

Abstract. The clinical significance of hyperprolactinaemia in uraemic patients is uncertain and discrepancies between immunoactivity and biological activity of serum hPRL have been reported. We have modified the Nb2 cell bioassay to improve specificity for hPRL and used this assay to measure hPRL bioactivity in sera from 26 uraemic patients and 40 control subjects. Seventeen patients were receiving regular haemodialysis and 9 continuous ambulatory peritoneal dialysis. Levels of hPRL bioactivity were compared with hPRL immunoactivity measured by RIA (PRL-RIA) and by immunoradiometric assay (PRL-IRMA). Serum hPRL levels measured by all three assays were significantly elevated in uraemic patients compared with control subjects (P< 0.001). The immunoradiometric method gave significantly lower results than RIA in control subjects but not in uraemic patients (P< 0.05). There was no significant difference in mean ratio of hPRL bioactivity to PRL-RIA between patients and control subjects (1.18 ± 0.05 vs 1.11 ± 0.03, mean ± sem). The ratio of hPRL bioactivity to PRL-IRMA was slightly decreased in uraemic patients compared with controls (P = 0.05). Serum hPRL bioactivity was closely correlated with immunoactivity in both immunoassays (r ≥ 0.96) in patients and controls. These results confirm that elevated serum hPRL levels in uraemic patients represent biologically active hormone which may contribute to hypogonadism.

Control of Metal Alloy Oxidation with Electric Fields

1973 ◽  
Vol 31 ◽  
pp. 164-165
Author(s):  
R. R. Dils ◽  
P. S. Follansbee
Keyword(s):  
Electric Fields ◽  
Oxidation Process ◽  
Base Alloy ◽  
Oxide Surface ◽  
Platinum Electrodes ◽  
Insulating Layer ◽  
Iron Base Alloy ◽  
Alloy Oxidation ◽  
Aluminum Oxide Layer ◽  
And Control

Electric fields have been applied across oxides growing on a high temperature alloy and control of the oxidation of the material has been demonstrated. At present, three-fold increases in the oxidation rate have been measured in accelerating fields and the oxidation process has been completely stopped in a retarding field.The experiments have been conducted with an iron-base alloy, Pe 25Cr 5A1 0.1Y, although, in principle, any alloy capable of forming an adherent aluminum oxide layer during oxidation can be used. A specimen is polished and oxidized to produce a thin, uniform insulating layer on one surface. Three platinum electrodes are sputtered on the oxide surface and the specimen is reoxidized.

Evidence for a Blood Ganglion Barrier in the Superior Cervical Ganglion of the Rat

1982 ◽  
Vol 40 ◽  
pp. 204-204
Author(s):  
D. M. DePace
Keyword(s):  
Blood Vessels ◽  
Superior Cervical Ganglion ◽  
Peripheral Nerves ◽  
Time Schedule ◽  
Transmission Electron ◽  
Cervical Ganglion ◽  
The Central Nervous System ◽  
Cervical Ganglia ◽  
Capillary Circulation ◽  
And Control

The majority of blood vessels in the superior cervical ganglion possess a continuous endothelium with tight junctions. These same features have been associated with the blood brain barrier of the central nervous system and peripheral nerves. These vessels may perform a barrier function between the capillary circulation and the superior cervical ganglion. The permeability of the blood vessels in the superior cervical ganglion of the rat was tested by intravenous injection of horseradish peroxidase (HRP). Three experimental groups of four animals each were given intravenous HRP (Sigma Type II) in a dosage of.08 to.15 mg/gm body weight in.5 ml of.85% saline. The animals were sacrificed at five, ten or 15 minutes following administration of the tracer. Superior cervical ganglia were quickly removed and fixed by immersion in 2.5% glutaraldehyde in Sorenson's.1M phosphate buffer, pH 7.4. Three control animals received,5ml of saline without HRP. These were sacrificed on the same time schedule. Tissues from experimental and control animals were reacted for peroxidase activity and then processed for routine transmission electron microscopy.

Effects of renovascular hypertension on rat adrenal zona glomerulosa

1978 ◽  
Vol 36 (2) ◽  
pp. 582-583
Author(s):  
G. Mazzocchi ◽  
P. Rebuffat ◽  
C. Robba ◽  
P. Vassanelli ◽  
G. G. Nussdorfer
Keyword(s):  
Renovascular Hypertension ◽  
Left Kidney ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Zona Glomerulosa ◽  
Ultrastructural Changes ◽  
Albino Rats ◽  
Left Renal Artery ◽  
Angiotensin System ◽  
And Control

It is well known that the rat adrenal zona glomerulosa steroidogenic activity is controlled by the renin-angiotensin system. The ultrastructural changes in the rat zona glomerulosa cells induced by renovascular hypertension were described previously, but as far as we are aware no correlated biochemical and morphometric investigations were performed.Twenty adult male albino rats were divided into 2 experimental groups. One group was subjected to restriction of blood flow to the left kidney by the application of a silver clip about the left renal artery. The other group was sham-operated and served as a control. Renovascular hypertension developed in about 10 days: sistolic blood pressure averaged 165 ± 6. 4 mmHg, whereas it was about 110 ± 3. 8 mmHg in the control animals. The hypertensive and control rats were sacrificed 20 days after the operation. The blood was collected and plasma renin activity was determined by radioimmunological methods. The aldosterone concentration was radioimmunologically assayed both in the plasma and in the homogenate of the left capsular adrenal gland.

X-Ray Replication of Submicrometer Linewidth Patterns

1977 ◽  
Vol 35 ◽  
pp. 136-137
Author(s):  
Henry I. Smith ◽  
D.C. Flanders
Keyword(s):  
Electron Beam Lithography ◽  
Cross Sectional ◽  
X Ray ◽  
Electron Backscattering ◽  
Spatial Frequencies ◽  
Cross Sectional Profile ◽  
Carbon Foils ◽  
Sectional Profile ◽  
And Control ◽  
Soft Radiation

Scanning electron beam lithography has been used for a number of years to write submicrometer linewidth patterns in radiation sensitive films (resist films) on substrates. On semi-infinite substrates, electron backscattering severely limits the exposure latitude and control of cross-sectional profile for patterns having fundamental spatial frequencies below about 4000 Å(l),Recently, STEM'S have been used to write patterns with linewidths below 100 Å. To avoid the detrimental effects of electron backscattering however, the substrates had to be carbon foils about 100 Å thick (2,3). X-ray lithography using the very soft radiation in the range 10 - 50 Å avoids the problem of backscattering and thus permits one to replicate on semi-infinite substrates patterns with linewidths of the order of 1000 Å and less, and in addition provides means for controlling cross-sectional profiles. X-radiation in the range 4-10 Å on the other hand is appropriate for replicating patterns in the linewidth range above about 3000 Å, and thus is most appropriate for microelectronic applications (4 - 6).

Ultrastructural changes in sciatic nerve tissue: Effects of passive maternal smoking

1983 ◽  
Vol 41 ◽  
pp. 650-651
Author(s):  
Amankwah K.S. ◽  
A.D. Weberg ◽  
R.C. Kaufmann
Keyword(s):  
Sciatic Nerve ◽  
Maternal Smoking ◽  
Ultrastructural Level ◽  
Uranyl Acetate ◽  
Nerve Tissue ◽  
Ultrastructural Changes ◽  
Cacodylate Buffer ◽  
And Control ◽  
Spontaneous Delivery

Previous research has revealed that passive (involuntary inhalation) tobacco smoking during gestation can have adverse effects upon the developing fetus. These prior investigations did not concentrate on changes in fetal morphology. This study was undertaken to delineate fetal neural abnormalities at the ultrastructural level in mice pups exposed in utero to passive maternal smoking.Pregnant study animals, housed in a special chamber, were subjected to cigarette smoke daily from conception until delivery. Blood tests for determination of carbon monoxide levels were run at 15-18 days gestation. Sciatic nerve tissue from experimental and control animals were obtained following spontaneous delivery and fixed in 2.5% gluteraldehyde in 0.1M cacodylate buffer pH 7.3. The samples were post-fixed in osmium ferrocyanide (1:1 mixture of 1.5% aqueous OSO4 and 2.5% K4 Fe(CN)6). Following dehydration, the tissues were infiltrated with and embedded in Spurr. Sections were stained with uranyl acetate and lead citrate.

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