Glaucoma, the leading cause of irreversible blindness, appears in various forms. Mutations in CYP1B1 result in primary congenital glaucoma (PCG) by an autosomal recessive mode of inheritance while it ...acts as a modifier locus for primary open angle glaucoma (POAG). We investigated the molecular basis of the variable phenotypes resulting from the defects in CYP1B1 by using subclones of 23 CYP1B1 mutants reported in glaucoma patients, in a cell based system by measuring the dual activity of the enzyme to metabolize both retinol and 17β-estradiol. Most variants linked to POAG showed low steroid metabolism while null or very high retinol metabolism was observed in variants identified in PCG. We examined the translational turnover rates of mutant proteins after the addition of cycloheximide and observed that the levels of enzyme activity mostly corroborated the translational turnover rate. We performed extensive normal mode analysis and molecular-dynamics-simulations-based structural analyses and observed significant variation of fluctuation in certain segmental parts of the mutant proteins, especially at the B-C and F-G loops, which were previously shown to affect the dynamic behavior and ligand entry/exit properties of the cytochrome P450 family of proteins. Our molecular study corroborates the structural analysis, and suggests that the pathologic state of the carrier of CYP1B1 mutations is determined by the allelic state of the gene. To our knowledge, this is the first attempt to dissect biological activities of CYP1B1 for correlation with congenital and adult onset glaucomas.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Gene regulation requires selective targeting of DNA regulatory enhancers over megabase distances. Here we show that Evf2, a cloud-forming Dlx5/6 ultraconserved enhancer (UCE) lncRNA, simultaneously ...localizes to activated (Umad1, 1.6 Mb distant) and repressed (Akr1b8, 27 Mb distant) chr6 target genes, precisely regulating UCE-gene distances and cohesin binding in mouse embryonic forebrain GABAergic interneurons (INs). Transgene expression of Evf2 activates Lsm8 (12 Mb distant) but fails to repress Akr1b8, supporting trans activation and long-range cis repression. Through both short-range (Dlx6 antisense) and long-range (Akr1b8) repression, the Evf2-5′UCE links homeodomain and mevalonate pathway-regulated enhancers to IN diversity. The Evf2-3′ end is required for long-range activation but dispensable for RNA cloud localization, functionally dividing the RNA into 3′-activator and 5′UCE repressor and targeting regions. Together, these results support that Evf2 selectively regulates UCE interactions with multi-megabase distant genes through complex effects on chromosome topology, linking lncRNA-dependent topological and transcriptional control with interneuron diversity and seizure susceptibility.
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•Precisely organizes UCE interactions, target genes, and cohesin over an ∼31-Mb domain•Regulates H3K27ac and/or H3K4me3 at cohesin BSs marking domain boundaries•Differential UCE-lncRNA 5′, 3′ end contribution to RNA targeting and UCE activity•Links interneuron diversity and mevalonate pathway; reduces seizure susceptibility
Cajigas et al. provide evidence for RNA-dependent mechanisms that regulate both gene selection and gene activity over unprecedented distances in the genome. These studies reveal that RNA-dependent precise spatial control of genes synergizes with a key DNA regulatory element, contributing to interneuron diversity during development and, ultimately, adult seizure susceptibility.
Helicobacter pylori (H. pylori) is a major causative agent of chronic gastritis, gastric ulcer and gastric carcinoma. H. pylori cytotoxin associated antigen A (CagA) plays a crucial role in the ...development of gastric cancer. Gastric cancer is associated with glycosylation alterations in glycoproteins and glycolipids on the cell surface. H. pylori cytotoxin associated antigen A (CagA) plays a significant role in the progression of gastric cancer through post-translation modification of fucosylation to develop gastric cancer. The involvement of a variety of sugar antigens in the progression and development of gastric cancer has been investigated, including type II blood group antigens. Lewis Y (LeY) is overexpressed on the tumor cell surface either as a glycoprotein or glycolipid. LeY is a difucosylated oligosaccharide, which is catalyzed by fucosyltransferases such as FUT4 (α1,3). FUT4/LeY overexpression may serve as potential correlative biomarkers for the prognosis of gastric cancer. We discuss the various aspects of H. pylori in relation to fucosyltransferases (FUT1-FUT9) and its fucosylated Lewis antigens (LeY, LeX, LeA, and LeB) and gastric cancer. In this review, we summarize the carcinogenic effect of H. pylori CagA in association with LeY and its synthesis enzyme FUT4 in the development of gastric cancer as well as discuss its importance in the prognosis and its inhibition by combination therapy of anti-LeY antibody and celecoxib through MAPK signaling pathway preventing gastric carcinogenesis.
A patient in his 40s with splenic angiosarcoma metastatic to the liver underwent splenectomy, chemotherapy, and partial hepatectomy before being treated on a clinical trial with CTLA4 and PD1 ...inhibitors. He had received pneumococcal and meningococcal vaccines post-splenectomy. On week 10, he developed grade 3 immune-related colitis, successfully treated with the anti-tumor necrosis factor-alpha inhibitor infliximab and steroids. After 4 cycles of treatment, scans showed partial response. He resumed anti-PD1 therapy, and 6 hours after the second dose of anti-PD1 he presented to the emergency room with hematemesis, hematochezia, hypotension, fever, and oxygen desaturation. Laboratory tests demonstrated acute renal failure and septicemia (
). He died 12 hours after the anti-PD1 infusion from overwhelming post-splenectomy infection (OPSI). Autopsy demonstrated non-viable liver tumors among other findings. In conclusion, patients undergoing immunotherapy and with prior history of asplenia should be monitored closely for OPSI as they may be at increased risk.
We report the detection of a very low mass star (VLMS) companion to the primary star 1SWASP J234318.41+295556.5A (J2343+29A), using radial velocity (RV) measurements from the PARAS (PRL Advanced ...Radial-velocity Abu-sky Search) high-resolution echelle spectrograph. The periodicity of the single-lined eclipsing binary (SB1) system, as determined from 20 sets of RV observations from PARAS and 6 supporting sets of observations from SOPHIE data, is found to be 16.953 d as against the 4.24 d period reported from SuperWASP photometry. It is likely that inadequate phase coverage of the transit with SuperWASP photometry led to the incorrect determination of the period for this system. We derive the spectral properties of the primary star from the observed stellar spectra: T
eff = 5125 ± 67 K, Fe/H = 0.1 ± 0.14 and logg = 4.6 ± 0.14, indicating a K1V primary. Applying the Torres relation to the derived stellar parameters, we estimate a primary mass
$0.864_{-0.098}^{+0.097}$
M⊙ and a radius of
$0.854_{-0.060}^{+0.050}$
R⊙. We combine RV data with SuperWASP photometry to estimate the mass of the secondary, M
B
= 0.098 ± 0.007 M⊙, and its radius, R
B
= 0.127 ± 0.007 R⊙, with an accuracy of ∼7 per cent. Although the observed radius is found to be consistent with the Baraffe's theoretical models, the uncertainties on the mass and radius of the secondary reported here are model dependent and should be used with discretion. Here, we establish this system as a potential benchmark for the study of VLMS objects, worthy of both photometric follow-up and the investment of time on high-resolution spectrographs paired with large-aperture telescopes.
In mammalian macrophages, the expression of a number of cytokines is regulated by miRNAs. Upon macrophage activation, proinflammatory cytokine mRNAs are translated, although the expression of miRNAs ...targeting these mRNAs remains largely unaltered. We show that there is a transient reversal of miRNA‐mediated repression during the early phase of the inflammatory response in macrophages, which leads to the protection of cytokine mRNAs from miRNA‐mediated repression. This derepression occurs through Ago2 phosphorylation, which results in its impaired binding to miRNAs and to the corresponding target mRNAs. Macrophages expressing a mutant, non‐phosphorylatable AGO2—which remains bound to miRNAs during macrophage activation—have a weakened inflammatory response and fail to prevent parasite invasion. These findings highlight the relevance of the transient relief of miRNA repression for macrophage function.
During macrophage activation, cytokine mRNAs are translated despite high levels of counteracting miRNAs. Here, phosphorylation of Ago2 is shown to impair its binding to miRNAs and cognate mRNAs, enabling macrophage activation and prevention of pathogen invasion.
We report here strong evidence for a sub-Saturn around EPIC 211945201 and confirm its planetary nature. EPIC 211945201b was found to be a planetary candidate from K2 photometry in Campaigns 5 and 16, ...transiting a bright star (Vmag = 10.15, G0 spectral type) in a 19.492 day orbit. However, the photometric data combined with false positive probability calculations using VESPA was not sufficient to confirm the planetary scenario. Here, we present high-resolution spectroscopic follow up of the target using the PARAS spectrograph (19 radial velocity observations) over a time baseline of 420 days. We conclusively rule out the possibility of an eclipsing binary system and confirm the 2 detection of a sub-Saturn planet. The confirmed planet has a radius of 6.12 0.1 R⊕, and a mass of . We also place an upper limit on the mass (within the 3 confidence interval) at 42 M⊕ above the nominal value. This results in the Saturn-like density of . Based on the mass and radius, we provide a preliminary model-dependent estimate that the heavy element content is 60%-70% of the total mass. This detection is important as it adds to a sparse catalog of confirmed exoplanets with masses between 10 and 70 M⊕ and radii between 4 and 8 R⊕, whose masses and radii are measured to a precision of 50% or better (only 23 including this work).
The
long non-coding RNA directs
ultraconserved enhancer(
)-intrachromosomal interactions, regulating genes across a 27 Mb region on chromosome 6 in mouse developing forebrain. Here, we show that
...long-range gene repression occurs through multi-step mechanisms involving the transcription factor Sox2.
directly interacts with Sox2, antagonizing Sox2 activation of
, and recruits Sox2 to the
shadow enhancer and key
interaction sites. Sox2 directly interacts with Dlx1 and Smarca4, as part of the
ribonucleoprotein complex, forming spherical subnuclear domains (protein pools, PPs).
targets Sox2 PPs to one long-range repressed target gene (
), at the expense of another (
)
and Sox2 shift
interactions towards
, linking
/Sox2 co-regulated topological control and gene repression. We propose a model that distinguishes
gene repression mechanisms at Rbm28 (
position) and Akr1b8 (limited Sox2 availability). Genome-wide control of RNPs (Sox2, Dlx and Smarca4) shows that co-recruitment influences Sox2 DNA binding. Together, these data suggest that
organizes a Sox2 PP subnuclear domain and, through Sox2-RNP sequestration and recruitment, regulates chromosome 6 long-range
targeting and activity with genome-wide consequences.
Crab populations play a major role in net bioturbation of the coastal tracts of the Sagar Island, Hugli Estuary, India. The activities attest to scraping, churning, ingesting, burrowing substrate ...sediment for feeding, dwelling etc. Non-random distribution of bioturbated patches zone averaged for ten spatial zones indicates percent area bioturbation varying between 0.08% and 29.92%. No significant correlation exists between biological vis-a-vis geomorphological or sedimentological parameters as recorded under 12 chosen parameters varying in zones (Z1–Z10) and zone clusters (A, B and C). Bioturbated sediments, however, possess coarser mean size and better sorting than non-bioturbated sediments. We predict genetic link between biogenic coarsening of sediments and selective substrate aggradation as recorded in the zones (Z5 and Z6) of higher bioturbation (by percent area) over a decade (between 2008 and 2018). Onshore sediment transport in the study area appears to be influenced by the biogenic reworking and subsequent textural modifications of the substrate sediment. Fining landward trend is perceptible in the post-monsoon, non-bioturbated sediments that escaped seasonal storm reworking and biogenic reworking. Gradual inundation of the substrate is interpreted from the fining up sediment succession and the plant/animal traces preserved in them. This assay at Sagar Island predicts a constructive role of biogenic reworking by crab populations on sediment transport and substrate aggradation. Outcome of the present study may be applied to reconstruct sedimentation milieu in similar bioturbated and tidally influenced, retreating delta margin settings.
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