Metabolic reprogramming is a hallmark of cancer. Herein we discover that the key glycolytic enzyme pyruvate kinase M2 isoform (PKM2), but not the related isoform PKM1, is methylated by ...co-activator-associated arginine methyltransferase 1 (CARM1). PKM2 methylation reversibly shifts the balance of metabolism from oxidative phosphorylation to aerobic glycolysis in breast cancer cells. Oxidative phosphorylation depends on mitochondrial calcium concentration, which becomes critical for cancer cell survival when PKM2 methylation is blocked. By interacting with and suppressing the expression of inositol-1,4,5-trisphosphate receptors (InsP
Rs), methylated PKM2 inhibits the influx of calcium from the endoplasmic reticulum to mitochondria. Inhibiting PKM2 methylation with a competitive peptide delivered by nanoparticles perturbs the metabolic energy balance in cancer cells, leading to a decrease in cell proliferation, migration and metastasis. Collectively, the CARM1-PKM2 axis serves as a metabolic reprogramming mechanism in tumorigenesis, and inhibiting PKM2 methylation generates metabolic vulnerability to InsP
R-dependent mitochondrial functions.
Summary Autosomal dominant polycystic kidney disease is the most common inherited kidney disease and accounts for 7–10% of all patients on renal replacement therapy worldwide. Although first reported ...500 years ago, this disorder is still regarded as untreatable and its pathogenesis is poorly understood despite much study. During the past 40 years, however, remarkable advances have transformed our understanding of how the disease develops and have led to rapid changes in diagnosis, prognosis, and treatment, especially during the past decade. This Review will summarise the key findings, highlight recent developments, and look ahead to the changes in clinical practice that will likely arise from the adoption of a new management framework for this major kidney disease.
Liver transplantation is the only curative option for patients with polycystic liver disease (PLD). In the United Kingdom, these patients are listed on the variant syndrome list due to their ...preserved liver function reflected in the United Kingdom End-stage Liver Disease (UKELD) score. The transplantation and survival rates for this patient group in the UK have not been previously reported.
A retrospective cross-sectional analysis of patients receiving liver transplantation between 2010 and 2017 was performed using the NHS blood and transplantation database. This database contains the demographic, clinical parameters, indication for transplantation and follow-up of all patients in UK-based transplant centres. Basic statistics was performed using SPSS version 27.
5412 recipients received elective liver allografts in the study period. 1.6% (100) of recipients had PLD as their primary indication for transplantation with 60 receiving liver only allografts and 40 receiving combined liver-kidney allografts. PLD patients had a >3-fold longer mean waiting time for transplantation compared to non-PLD patients, 508 days v 154 days respectively. PLD patients receiving combined liver-kidney allografts had a longer waiting time than those receiving a liver only allograft, 610 days v 438 days respectively. There were comparable patient survival rates for people with PLD and non-PLD primary indications at 30 days (94.0% vs 97.6%) and 1 year (92.0% vs 93.2%) but improved survival rates at 5 years (81.3% vs 76.5%). There were also comparable allograft survival rates for people with PLD and non-PLD primary indications at 30 days (93.9% vs 95.3%) and 1 year (91.9% vs 91.2%) but improved survival rates at 5 years (82.5% vs 77.3%). Transplant centre-level analysis identified variation in the proportion of liver transplantations for people with PLD as their primary listed indication.
Patients with PLD wait significantly longer for liver transplantation compared to other indications. However, transplanted PLD patients demonstrate better longer-term patient and liver allograft survival rates compared to transplanted non-PLD patients. The unexpected variation between individual UK centres transplanting for PLD deserves further study.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
This review investigates the effectiveness of ablative and nonablative fractional photothermolysis (FP) lasers for treating facial acne scars. Twenty‐six studies (13 ablative FP, 13 ...nonablative FP) published between 2003 and January 2011 were reviewed. Quantitative and qualitative data from each article were examined and analysed. Four studies were split‐face randomized controlled studies. While the data analysed were all clinically relevant and significant, there were some methodological differences between the studies. Outcomes included subjective and objective assessment of scar appearance, pre‐ and postoperative treatment, side‐effects and pain scores. A small number of studies used three‐dimensional optical imaging profiling and histology for objective assessment. Even allowing for methodological variability, ablative FP had an improvement range of 26–83% whereas nonablative FP had an improvement range of 26–50%. Patients who underwent treatment with an ablative FP laser experienced erythema for 3–14 days which resolved by 12 weeks, whereas patients who opted for the nonablative FP laser experienced erythema for between 1 and 3 days and this resolved within a week. A higher proportion of patients (up to 92·3%) who underwent ablative FP experienced postinflammatory hyperpigmentation (PIH) than those who had nonablative FP (up to 13%). The maximum duration of PIH in ablative FP was up to 6 months whereas in nonablative FP it lasted for up to 1 week. The procedure with ablative FP was relatively uncomfortable compared with nonablative FP. The pain score with ablative FP ranged from 5·90 to 8·10 (scale 1–10) and with nonablative FP from 3·90 to 5·66 (scale 1–10).
Epithelial tight junctions are compromised in gastrointestinal disease. Processes that contribute to the resulting barrier loss include endocytic occludin removal from the tight junction and reduced ...occludin expression. Nevertheless, the relatively-normal basal phenotype of occludin knockout (KO) mice has been taken as evidence that occludin does not contribute to gastrointestinal barrier function. We asked whether stress could unmask occludin functions within intestinal epithelia.
Wildtype (WT), universal and intestinal epithelial-specific occludin KO, and villin-EGFP-occludin transgenic mice as well as WT and occludin knockdown (KD) Caco-2BBe cell monolayers were challenged with DSS, TNBS, staurosporine, 5-FU, or TNF. Occludin and caspase-3 expression were assessed in patient biopsies.
Intestinal epithelial occludin loss limited severity of DSS- and TNBS-induced colitis due to epithelial resistance to apoptosis; activation of both intrinsic and extrinsic apoptotic pathways was blocked in occludin KO epithelia. Promoter analysis revealed that occludin enhances CASP3 transcription and, conversely, that occludin downregulation reduces caspase-3 expression. Analysis of biopsies from Crohn’s disease and ulcerative colitis patients and normal controls demonstrated that disease-associated occludin downregulation was accompanied by and correlated with reduced caspase-3 expression. In vitro, cytokine-induced occludin downregulation resulted in reduced caspase-3 expression and resistance to intrinsic and extrinsic pathway apoptosis, demonstrating an overall protective effect of inflammation-induced occludin loss.
The tight junction protein occludin regulates apoptosis by enhancing caspase-3 transcription. These data suggest that reduced epithelial caspase-3 expression downstream of occludin downregulation is a previously-unappreciated anti-apoptotic process that contributes to mucosal homeostasis in inflammatory conditions.
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FNR is a well-studied global regulator of anaerobiosis, which is widely conserved across bacteria. Despite the importance of FNR and anaerobiosis in microbial lifestyles, the factors that influence ...its function on a genome-wide scale are poorly understood. Here, we report a functional genomic analysis of FNR action. We find that FNR occupancy at many target sites is strongly influenced by nucleoid-associated proteins (NAPs) that restrict access to many FNR binding sites. At a genome-wide level, only a subset of predicted FNR binding sites were bound under anaerobic fermentative conditions and many appeared to be masked by the NAPs H-NS, IHF and Fis. Similar assays in cells lacking H-NS and its paralog StpA showed increased FNR occupancy at sites bound by H-NS in WT strains, indicating that large regions of the genome are not readily accessible for FNR binding. Genome accessibility may also explain our finding that genome-wide FNR occupancy did not correlate with the match to consensus at binding sites, suggesting that significant variation in ChIP signal was attributable to cross-linking or immunoprecipitation efficiency rather than differences in binding affinities for FNR sites. Correlation of FNR ChIP-seq peaks with transcriptomic data showed that less than half of the FNR-regulated operons could be attributed to direct FNR binding. Conversely, FNR bound some promoters without regulating expression presumably requiring changes in activity of condition-specific transcription factors. Such combinatorial regulation may allow Escherichia coli to respond rapidly to environmental changes and confer an ecological advantage in the anaerobic but nutrient-fluctuating environment of the mammalian gut.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
In the mixed-mode asteroseismology of subgiants and red giants, the coupling between the
p-
and
g-
mode cavities must be understood well in order to derive localized estimates of interior ...rotation from measurements of mode multiplet rotational splittings. There exist now two different descriptions of this coupling: one based on an asymptotic quantization condition, and the other arising from the coupling matrices associated with “acoustic molecular orbitals.” We examine the analytic properties of both, and derive closed-form expressions for various quantities—such as the period-stretching function
τ
—which previously had to be solved for numerically. Using these, we reconcile both formulations for the first time, deriving relations by which quantities in each formulation may be translated to and interpreted within the other. This yields an information criterion for whether a given configuration of mixed modes may meaningfully constrain the parameters of the asymptotic construction, which is likely not satisfied by the majority of first-ascent red giant stars in our observational sample. Since this construction has been already used to make rotational measurements of such red giants, we examine—through a hare-and-hounds exercise—whether, and how, such limitations affect these existing measurements. While averaged estimates of core rotation seem fairly robust, template-matching using the asymptotic construction has difficulty reliably assigning rotational splittings to individual multiplets, or estimating the mixing fractions
ζ
of the most
p
-dominated mixed modes, where such estimates are most needed. We finally discuss implications for extending the two-zone model of radial differential rotation, e.g., via rotational inversions, with these methods.
Abstract
Asteroseismology is our only means of measuring the rotations of stars in their interiors, rather than at their surfaces. Some techniques for measurements of this kind—“rotational ...inversions”—require the shapes of linear response kernels computed from reference stellar models to be representative of those in the stars they are intended to match. This is not the case in evolved stars exhibiting gravitoacoustic mixed modes: we show that the action of the asteroseismic surface term—systematic errors in the modeling of near-surface layers—changes the shapes of their inversion kernels. Corrections for the surface term are not ordinarily considered necessary for rotational inversions. We show how this may have caused previous estimates of red-giant envelope rotation rates from mixed-mode asteroseismic inversions to have been unintentionally contaminated by core rotation as a result, with errors comparable to the entire reported estimates. We derive a mitigation procedure for this hitherto unaccounted systematic error, and demonstrate its viability and effectiveness. We recommend this mitigation be applied when revising existing rotational inversions. Finally, we discuss both the prospects for applying such mitigation to the harder problem of inversions for stellar structure (rather than rotation), as well as the broader implications of this systematic error with regard to the longstanding problem of internal angular momentum transport.
Monolayered boron nitride (BN) quantum dots (QDs; lateral size ≈10 nm) are fabricated using a novel method. Unlike monolayered BN sheets, these BN QDs exhibit blue‐green luminescence due to defects ...formed during preparation. This optical behavior adds significant functionality to a material that is already receiving much attention. It is further shown that the QDs are nontoxic to biological cells and well suited to bio‐imaging.
The search for potential antibody-based diagnostics, vaccines, and therapeutics for pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has focused almost exclusively on the spike ...(S) and nucleocapsid (N) proteins. Coronavirus membrane (M), ORF3a, and ORF8 proteins are humoral immunogens in other coronaviruses (CoVs) but remain largely uninvestigated for SARS-CoV-2. Here, we use ultradense peptide microarray mapping to show that SARS-CoV-2 infection induces robust antibody responses to epitopes throughout the SARS-CoV-2 proteome, particularly in M, in which 1 epitope achieved excellent diagnostic accuracy. We map 79 B cell epitopes throughout the SARS-CoV-2 proteome and demonstrate that antibodies that develop in response to SARS-CoV-2 infection bind homologous peptide sequences in the 6 other known human CoVs. We also confirm reactivity against 4 of our top-ranking epitopes by enzyme-linked immunosorbent assay (ELISA). Illness severity correlated with increased reactivity to 9 SARS-CoV-2 epitopes in S, M, N, and ORF3a in our population. Our results demonstrate previously unknown, highly reactive B cell epitopes throughout the full proteome of SARS-CoV-2 and other CoV proteins.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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