Freedmanbrown8049

The transcription factor TFAM is controlling the transcription of core proteins required for mitochondrial homeostasis. The aim of the current study was to investigate changes in TFAM expression in systemic sclerosis (SSc), to analyze mitochondrial function and to evaluate the consequences for fibroblast activation.

The expression of TFAM was analyzed by immunofluorescence and Western blot. The effects of TFAM knockout were investigated in cultured fibroblasts and in bleomycin-induced skin and lung fibrosis and in TβRI

-induced skin fibrosis.

The expression of TFAM was downregulated in fibroblasts in SSc skin and in cultured SSc fibroblasts. The downregulation of TFAM was associated with decreased mitochondrial number and accumulation of damaged mitochondria with release of mtDNA, accumulation of deletions in mtDNA, metabolic alterations with impaired OXPHOS and release of the mitokine GDF15. Chronic, but not acute, exposure of normal fibroblasts to TGFβ mimicked the finding in SSc fibroblasts with downregulation of TFAM and accumulation of mitochondrial damage. Downregulation of TFAM promotes fibroblast activation with upregulation of fibrosis-relevant GO-terms in RNASeq, partially in a ROS-dependent manner. Mice with fibroblast-specific knockout of TFAM are prone to fibrotic tissue remodeling with fibrotic responses even to NaCl instillation and enhanced sensitivity to bleomycin injection and TβRIact-overexpression. TFAM knockout fosters SMAD3 signaling to promote fibroblast activation.

Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGFβ and associated mitochondrial damage induce transcriptional programs that promote fibroblast-to-myofibroblast transition and drive tissue fibrosis.

Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGFβ and associated mitochondrial damage induce transcriptional programs that promote fibroblast-to-myofibroblast transition and drive tissue fibrosis.High-throughput crop phenotyping, particularly under field conditions, is nowadays perceived as a key factor limiting crop genetic advance. Phenotyping not only facilitates conventional breeding, but it is necessary to fully exploit the capabilities of molecular breeding, and it can be exploited to predict breeding targets for the years ahead at the regional level through more advanced simulation models and decision support systems. In terms of phenotyping, it is necessary to determined which selection traits are relevant in each situation, and which phenotyping tools/methods are available to assess such traits. Remote sensing methodologies are currently the most popular approaches, even when lab-based analyses are still relevant in many circumstances. On top of that, data processing and automation, together with machine learning/deep learning are contributing to the wide range of applications for phenotyping. This review addresses spectral and RGB sensing as the most popular remote sensing approaches, alongside stable isotope composition as an example of a lab-based tool, and root phenotyping, which represents one of the frontiers for field phenotyping. Further, we consider the two most promising forms of aerial platforms (UAV and satellites) and some of the emerging data-processing techniques. The review includes three Boxes that examine specific case studies. This article is protected by copyright. All rights reserved.

To compare 12-month clinical effectiveness of insulin glargine 300 units/mL (Gla-300) versus first-generation basal insulin analogues (BIAs) (insulin glargine 100 units/mL [Gla-100] or insulin detemir [IDet]) in patients with type 2 diabetes (T2D) who were at high risk of hypoglycaemia and switched from one BIA to a different one (Gla-300 or Gla-100/IDet) in a real-world setting.

DELIVER High Risk was a retrospective observational cohort study of 2550 patients with T2D who switched BIA to Gla-300 (Gla-300switchers) and were propensity score-matched (11) to patients who switched to Gla-100 or IDet (Gla-100/IDet switchers). Outcomes were change in glycated haemoglobin A1c (HbA1c), attainment of HbA1c goals (<7% and <8%), and incidence and event rates of hypoglycaemia (all-hypoglycaemia and hypoglycaemia associated with an inpatient/emergency department [ED] contact).

HbA1c reductions were similar following switching to Gla-300 or Gla-100/IDet (-0.51% vs. -0.53%; p=.67), and patients showed similar attainment of HbA1c goals. Patients in both cohorts had comparable all-hypoglycaemia incidence and event rates. However, the Gla-300switcher cohort had a significantly lower risk of inpatient/ED-associated hypoglycaemia (adjusted odds ratio 0.73, 95% confidence interval 0.60-0.89; p=.002) and experienced significantly fewer inpatient/ED-associated hypoglycaemic events (0.21 vs. 0.33 events per patient per year; p<.001).

In patients with T2D at high risk of hypoglycaemia, switching to Gla-300 or Gla-100/IDet achieved similar HbA1c reductions and glycaemic goal attainment, but Gla-300switchers had a significantly lower risk of hypoglycaemia associated with an inpatient/ED contact during 12months after switching.

In patients with T2D at high risk of hypoglycaemia, switching to Gla-300 or Gla-100/IDet achieved similar HbA1c reductions and glycaemic goal attainment, but Gla-300 switchers had a significantly lower risk of hypoglycaemia associated with an inpatient/ED contact during 12 months after switching.The current study aimed to derive site-specific guideline values (SSGVs) for nitrate toxicity that are relevant to high hardness surface waters of the Pilbara region, north-western Australia, many of which receive nitrate-rich mine water discharges. The approach involved deriving SSGVs from a species sensitivity distribution (SSD) based on candidate data sets comprising toxicity data for local Pilbara species tested in local waters and nonlocal species tested under water quality conditions similar to those of local Pilbara waters. Water hardness was identified as the primary toxicity-modifying factor for nitrate that needed to be accounted for, with temperature and pH identified as supporting variables. Using ~10 years of local water quality data, primary and secondary criteria for hardness, temperature and pH were developed and used to select the most relevant toxicity data for the derivation. The selected toxicity data, which included data for four local species tested in local water and 10 nonlocal species tested under representative water quality conditions, were categorized according to the primary and secondary criteria. Using this categorization, four candidate nitrate toxicity data sets (n = 5, 10, 12, and 14) were assessed for their suitability to derive the SSGVs. The SSDs for all data sets yielded similar protective concentration (PC) values. Based on the best balance between the relevance of the toxicity data set to the local water quality conditions and the confidence in the PC values, the PC values based on data set 3 (12 species, six taxonomic groups) were identified as being the most appropriate for the SSGVs. The SSGVs for 99%, 95%, 90%, and 80% species protection were 7.6, 15, 23, and 39 mg/L NO3 -N, respectively. An assessment of the appropriateness of the SSGVs indicated that they were likely to be appropriately protective of nitrate toxicity for the high hardness (i.e., ≥160 mg/L as CaCO3 ) Pilbara receiving waters. Integr Environ Assess Manag 2021;001-12. © 2021 SETAC.

Temporary breast tissue expanders contain a metal port that varies in position throughout the course of radiation treatments. The purpose of this study was to quantify the robustness of the three most common external beam treatment techniques (tangential three-dimensional conformal radiation therapy [3DCRT], volumetric modulated arc therapy [VMAT], and helical tomotherapy) against our measured inter-fractional positional variations of the port.

For eight breast cases, a clinical plan was created for each of the three techniques. The dosimetric effect of our previously measured inter-fractional port errors was evaluated for two classes of error internal port errors (IPEs) and patient registration errors (PREs). For both classes of error, daily variable and systematic errors were modeled, and their cumulative effects were compared against the originally planned doses.

For systematic IPE, the 1%-99% range in point dose differences inside a 5-mm target abutting the implant was the highest for tangential 3DCsage in the shadow of the port. When PREs were modeled, the target coverage and nearby organs were affected the most in VMAT and helical tomotherapy. In reality, port positional errors result from a combination of IPE and PRE, suggesting that VMAT and tomotherapy are more robust when patient registration errors are minimized, despite the presence of IPE.The cGAS-STING pathway discovered ten years ago is an important component of the innate immune system. Activation of cGAS-STING triggers downstream signalling, such as TBK1-IRF3, NF-κB and autophagy, which in turn leads to antipathogen responses, durable antitumour immunity or autoimmune diseases. 2',3'-Cyclic GMP-AMP dinucleotides (2',3'-cGAMP), the key second messengers produced by cGAS, play a pivotal role in cGAS-STING signalling by binding and activating STING. Thus, 2',3'-cGAMP has immunotherapeutic potential, which in turn has stimulated research on the design and synthesis of 2',3'-cGAMP analogues for clinical applications over the past ten years. This review presents the discovery, metabolism, and function of 2',3'-cGAMP in the cGAS-STING innate immune signalling axis. The enzymatic and chemical syntheses of 2',3'-cGAMP analogues as STING-targeting therapeutics are also summarized.

Early warning of disease outbreaks is paramount for health jurisdictions. The objective of the present study was to develop syndromic surveillance monitoring plans from routinely collected ED data with application to detecting disease outbreaks.

The study involved secondary data analysis of ED presentations to major public hospitals in Queensland and South Australia spanning 2017-2020. Monitoring plans were developed for all major Queensland and South Australian public hospitals using an adaptation of Exponentially Weighted Moving Averages - a process control method used in detecting anomalies in industrial production processes. The methods rely on setting a threshold (control limit) relating to the time between an event of interest (e.g. flu outbreak) using ED presentations as a signal to monitor. An outbreak is flagged as this time gets significantly smaller, and each event offers a decision point on whether an outbreak has occurred. The models incorporate differing levels of temporal memory to cover outbreaks of different sizes.

The novel approach to real-time outbreak detection indicates outbreaks for individual hospitals coinciding with the first wave of the COVID-19 outbreak in Queensland and South Australia as well as the large 2017 and 2019 influenza seasons.

Outbreak detection models demonstrate the ability to quickly flag an outbreak based on clinician-assigned ED diagnoses. An implemented syndromic surveillance approach can pick up geographic outbreaks quickly so they can be contained. Such capability can help with surveillance related to the current COVID-19 pandemic and potential future pandemics.

Outbreak detection models demonstrate the ability to quickly flag an outbreak based on clinician-assigned ED diagnoses. An implemented syndromic surveillance approach can pick up geographic outbreaks quickly so they can be contained. MI-503 Such capability can help with surveillance related to the current COVID-19 pandemic and potential future pandemics.