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Various particle accelerators operate in the space plasmas, filling the Galaxy with high-energy particles (primary cosmic rays). Reaching the Earth's atmosphere, these particles originate extensive air showers (EASs) consisting of millions of elementary particles (secondary cosmic rays), covering several km2 on the ground. During thunderstorms, strong electric fields modulate the energy spectra of EAS secondary particles, changing the shower size (number of EAS electrons) and altering the primary particle's estimated energy and frequency of the surface array triggers. Impulse amplifications of particle fluxes (the so-called thunderstorm ground enhancements, TGEs) manifest themselves as large peaks in the time series of count rates of particle detectors located on the Earth's surface. Free electrons are abundant at any altitude in the atmosphere, from small to large EASs. These electrons serve as seeds for electron accelerators, which operate in the thunderous atmosphere and send particle avalanches in the direction of Earth's surface and into space (terrestrial gamma flashes, TGFs). EAS cores randomly hitting arrays of particle detectors also generate short bursts of relativistic particles. For years, particle detectors, electric field sensors, and lightning locators have gathered information about the complex interactions of secondary particle fluxes, electric fields, and lightning flashes. This information is crucial for establishing a field of high-energy physics in the atmosphere. Correlated measurements of particle fluxes modulated by strong atmospheric electric fields, registration of broadband radio and optical emission from atmospheric discharges, and registration of electric fields and various meteorological parameters lead to a better understanding of the complex processes of particle-field interactions in the terrestrial atmosphere. The cooperation of cosmic rays and atmospheric physics has led to the development of models of the origin of particle bursts recorded on the Earth's surface, vertical and horizontal profiles of electric fields, initiation of lightning flashes, etc. Interdisciplinary atmospheric science primarily requires monitoring particle fluxes around the clock by synchronized networks of identical sensors that record and store multidimensional data in databases with open, fast, and reliable access. The advances in multidimensional measurements over the past decade significantly intensified the development of new integrated models of atmospheric electricity and electron acceleration, giving more insight into understanding the modulation effects posed on EAS particles in the strong atmospheric electric fields. [ABSTRACT FROM AUTHOR]

Morphological and structural remodeling of the heart, including cardiac hypertrophy and fibrosis, has been considered as a therapeutic target for heart failure for approximately three decades. Groundbreaking heart failure medications demonstrating reverse remodeling effects have contributed significantly to medical advancements. However, nearly 50% of heart failure patients still exhibit drug resistance, posing a challenge to the healthcare system. Recently, characteristics of heart failure resistant to ARBs and β-blockers have been defined, highlighting preserved systolic function despite impaired diastolic function, leading to the classification of heart failure with preserved ejection fraction (HFpEF). The pathogenesis and aetiology of HFpEF may be related to metabolic abnormalities, as evidenced by its mimicry through endothelial dysfunction and excessive intake of high-fat diets. Our recent findings indicate a significant involvement of mitochondrial hyper-fission in the progression of heart failure. This mitochondrial pathological remodeling is associated with redox imbalance, especially hydrogen sulphide accumulation due to abnormal electron leak in myocardium. In this review, we also introduce a novel therapeutic strategy for heart failure from the current perspective of mitochondrial redox-metabolic remodeling. [ABSTRACT FROM AUTHOR]

It has been revealed previously that chronic liver disease (CLD) may be associated to hormonal fluctuations. The current study, therefore, aimed to evaluate some hormones in CLD patients compared with non-CLD individuals. This case control study was conducted at Gastroenterology and Hepatology Teaching Hospital, Medical city, Baghdad, Iraq during December 2021 to May 2022. One hundred and twenty male patients with CLD (age:14-75 years) and 120 control males (age: 24-70 years) were involved in this study. Serum samples were taken from all individuals and were then analysed for many tests which included hormones (Cortisol, testosterone, prolactin, insulin and thyroid stimulating hormone TSH); biochemical analysis (Prothrombin time PT, international normalized ratio INR and albumin); liver enzymes (aspartate aminotransferase AST, alanine aminotransferase ALT, alkaline phosphatase ALP and gamma glutamyl transferase (GGT)) and interleukins (Interleukin 13 IL-13 and transforming growth factor TGF). Some hormones such as cortisol, prolactin and insulin significantly increased in CLD patients while other hormones (testosterone and TSH) significantly decreased in CLD patients compared with the controls. Results also showed significant increase in liver enzymes among CLD patients. These changes in the hormones and liver enzymes levels may be related with significant increase in INR and albumin which were significantly higher in CLD patients than in the control group. Finally, IL-13 increased significantly in CLD patients while no significant differences were noticed between CLD and control regarding TGF levels. It can, therefore, be concluded that hormonal imbalance can affect people with liver conditions. and that this hormonal imbalance may be associated with high levels of liver enzymes. [ABSTRACT FROM AUTHOR]

The present work investigates the potential role of metformin nanoparticles (MTF-NPs) as a radio-protector against cardiac fibrosis and inflammation induced by gamma radiation via CXCL1/TGF-β pathway. Lethal dose fifty of nano-metformin was determined in mice, then 21 rats (male albino) were equally divided into three groups: normal control (G1), irradiated control (G2), and MTF-NPs + IRR (G3). The possible protective effect of MTF-NPs is illustrated via decreasing cardiac contents of troponin, C-X-C motif Ligand 1 (CXCL1), tumor growth factor β (TGF-β), protein kinase B (AKT), and nuclear factor-κB (NF-κB). Also, the positive effect of MTF-NPs on insulin-like growth factor (IGF) and platelet-derived growth factor (PDGF) in heart tissues using immunohistochemical technique is illustrated in the present study. Histopathological examination emphasizes the biochemical findings. The current investigation suggests that MTF-NPs might be considered as a potent novel treatment for the management of cardiac fibrosis and inflammation in patients who receive radiotherapy or workers who may be exposed to gamma radiation. [ABSTRACT FROM AUTHOR]

Endothelial cells (ECs) are vital structural units of the cardiovascular system possessing two principal distinctive properties: heterogeneity and plasticity. Endothelial heterogeneity is defined by differences in tissue-specific endothelial phenotypes and their high predisposition to modification along the length of the vascular bed. This aspect of heterogeneity is closely associated with plasticity, the ability of ECs to adapt to environmental cues through the mobilization of genetic, molecular, and structural alterations. The specific endothelial cytoarchitectonics facilitate a quick structural cell reorganization and, furthermore, easy adaptation to the extrinsic and intrinsic environmental stimuli, known as the epigenetic landscape. ECs, as universally distributed and ubiquitous cells of the human body, play a role that extends far beyond their structural function in the cardiovascular system. They play a crucial role in terms of barrier function, cell-to-cell communication, and a myriad of physiological and pathologic processes. These include development, ontogenesis, disease initiation, and progression, as well as growth, regeneration, and repair. Despite substantial progress in the understanding of endothelial cell biology, the role of ECs in healthy conditions and pathologies remains a fascinating area of exploration. This review aims to summarize knowledge and concepts in endothelial biology. It focuses on the development and functional characteristics of endothelial cells in health and pathological conditions, with a particular emphasis on endothelial phenotypic and functional heterogeneity. [ABSTRACT FROM AUTHOR]

Context: Altered signalling of androgens, anti-Müllerian hormone or transforming growth factor beta (TGFβ) during foetal development have been implicated in the predisposition to polycystic ovary syndrome (PCOS) in later life, aside from its genetic predisposition. In foetal ovarian fibroblasts, TGFβ1 has been shown to regulate androgen signalling and seven genes located in loci associated with PCOS. Since PCOS exhibits a myriad of symptoms, it likely involves many different organs. Aims: To identify the relationships between TGFβ signalling molecules and PCOS candidate genes in different tissues associated with PCOS. Methods: Using RNA sequencing data, we examined the expression patterns of TGFβ signalling molecules in the human ovary, testis, heart, liver, kidney, brain tissue, and cerebellum from 4 to 20 weeks of gestation and postnatally. We also examined the correlations between gene expression of TGFβ signalling molecules and PCOS candidate genes. Key results: TGFβ signalling molecules were dynamically expressed in most tissues prenatally and/or postnatally. FBN3 , a PCOS candidate gene involved in TGFβ signalling, was expressed during foetal development in all tissues. The PCOS candidate genes HMGA2, YAP1 , and RAD50 correlated significantly (P < 0.01) with most TGFβ signalling molecules in at least four foetal tissues, and specifically with TGFBR1 in six out of the seven tissues examined. Conclusions: This study suggests that possible crosstalk occurs between genes in loci associated with PCOS and TGFβ signalling molecules in multiple tissues, particularly during foetal development. Implications: Thus, alteration in TGFβ signalling during foetal development could affect many tissues contributing to the multiple phenotypes of PCOS in later life. Polycystic ovary syndrome (PCOS) is a complex disorder with an unknown aetiology; although foetal and genetic origins have been implicated. Ovaries of PCOS women are more fibrous, suggesting involvement of transforming growth factor beta (TGFβ) signalling molecules. We identified strong correlations between TGFβ signalling molecules and PCOS candidate genes in multiple human foetal tissues associated with reproduction, metabolism, and neurology. Thus, alteration in TGFβ signalling during foetal development could affectdevelopment of multiple organs leading to the numerous symptoms of PCOS observed in adult life. Image by Katja Hummitzsch. [ABSTRACT FROM AUTHOR]

Hemodialysis is a prevalent treatment for the end-stage chronic kidney disease (CKD) worldwide. The primary arteriovenous fistula (AVF), widely considered the optimal hemodialysis access method, fails to mature in up to two-thirds of the cases. The etiology of the early AVF failure, defined as thrombosis or inability to use within three months post-creation remains less understood, and is influenced by various factors including patient demographics, surgical techniques, and genetic predispositions. Neointimal hyperplasia is a primary histological finding in stenotic lesions leading to the AVF failure. However, there are insufficient data on the cellular phenotypes and the impact of the preexisting CKD-related factors. This study aims to investigate the histological, morphometric, and immunohistochemical alterations in the fistula vein, pre-, peri-, and post-early failure. Eighty-nine stage 4-5 CKD patients underwent standard preoperative assessment, including the Doppler ultrasound, before a typical radio-cephalic AVF creation. Post-failure, a new AVF was created proximally. The vein specimens were collected during the surgery, processed, and analyzed for morphometric analyses and various cellular markers, including Vimentin, TGF, and Ki 67. The study enrolled 89 CKD patients, analyzing various aspects of their condition and AVF failures. The histomorphometric analysis revealed substantial venous luminal stenosis and varied endothelial changes. The immunohistologic analysis showed differential marker expressions pre- and post-AVF creation. This study highlights the complexity of the early AVF failures in CKD patients. The medial hypertrophy emerged as a significant preexisting lesion, while the postoperative analyses indicated a shift towards neointimal hyperplasia. The research underscores the nuanced interplay of vascular remodeling, endothelial damage, and cellular proliferation in the AVF outcomes. [ABSTRACT FROM AUTHOR]

Abstract Purpose To explore the impact of microRNA 146a (miR-146a) and the underlying mechanisms in profibrotic changes following glaucoma filtering surgery (GFS) in rats and stimulation by transforming growth factor (TGF)-β1 in rat Tenon’s capsule fibroblasts. Methods Cultured rat Tenon’s capsule fibroblasts were treated with TGF-β1 and analyzed with microarrays for mRNA profiling to validate miR-146a as the target. The Tenon’s capsule fibroblasts were then respectively treated with lentivirus-mediated transfection of miR-146a mimic or inhibitor following TGF-β1 stimulation in vitro, while GFS was performed in rat eyes with respective intraoperative administration of miR-146a, mitomycin C (MMC), or 5-fluorouracil (5-FU) in vivo. Profibrotic genes expression levels (fibronectin, collagen Iα, NF-KB, IL-1β, TNF-α, SMAD4, and α-smooth muscle actin) were determined through qPCR, Western blotting, immunofluorescence staining and/or histochemical analysis in vitro and in vivo. SMAD4 targeting siRNA was further used to treat the fibroblasts in combination with miR-146a intervention to confirm its role in underlying mechanisms. Results Upregulation of miR-146a reduced the proliferation rate and profibrotic changes of rat Tenon’s capsule fibroblasts induced by TGF-β1 in vitro, and mitigated subconjunctival fibrosis to extend filtering blebs survival after GFS in vivo, where miR-146a decreased expression levels of NF-KB-SMAD4-related genes, such as fibronectin, collagen Iα, NF-KB, IL-1β, TNF-α, SMAD4, and α-smooth muscle actin(α-SMA). Additionally, SMAD4 is a key target gene in the process of miR-146a inhibiting fibrosis. Conclusions MiR-146a effectively reduced TGF-β1-induced fibrosis in rat Tenon’s capsule fibroblasts in vitro and in vivo, potentially through the NF-KB-SMAD4 signaling pathway. MiR-146a shows promise as a novel therapeutic target for preventing fibrosis and improving the success rate of GFS.

Skin ageing is defined, in part, by collagen depletion and fragmentation that leads to a loss of mechanical tension. This is currently believed to reflect, in part, the accumulation of senescent cells. We compared the expression of genes and proteins for components of the extracellular matrix (ECM) as well as their regulators and found that in vitro senescent cells produced more matrix metalloproteinases (MMPs) than proliferating cells from adult and neonatal donors. This was consistent with previous reports of senescent cells contributing to increased matrix degradation with age; however, cells from adult donors proved significantly less capable of producing new collagen than neonatal or senescent cells, and they showed significantly lower myofibroblast activation as determined by the marker α-SMA. Functionally, adult cells also showed slower migration than neonatal cells. We concluded that the increased collagen degradation of aged fibroblasts might reflect senescence, the reduced collagen production likely reflects senescence-independent processes. [ABSTRACT FROM AUTHOR]

Background: TGF-β1 and SMAD3 are particularly pathogenic in the progression of renal fibrosis. Aim: This study aimed to evaluate the kidney protective potentials of silymarin (SM) and exosomes of mesenchymal stem cells against the nephrotoxin thioacetamide (TAA) in rats. Methods: 32 female rats were randomly assigned into four groups: the control group, the TAA group, the TAA + SM group, and the TAA + Exosomes group. The kidney homogenates from all groups were examined for expression levels of TGF-β receptors I and II using real-time PCR, expression levels of collagen type I and CTGF proteins using ELISA, and the expression levels of nuclear SMAD2/3/4, cytoplasmic SMAD2/3, and cytoplasmic SMAD4 proteins using the western blot technique. Results: Compared to the control group, the injection of TAA resulted in a significant increase in serum levels of urea and creatinine, gene expression levels of TβRI and TβRII, protein expression levels of both collagen I and CTGF proteins, cytoplasmic SMAD2/3 complex, and nuclear SMAD2/3/4 (p-value < 0.0001), with significantly decreased levels of the co-SMAD partner, SMAD4 (p-value < 0.0001). Those effects were reversed considerably in both treatment groups, with the superiority of the exosomal treatment regarding the SMAD proteins and the expression levels of the TβRI gene, collagen I, and CTGF proteins returning to near-control values (p-value > 0.05). Conclusion: Using in vitro and in vivo experimental approaches, the research discovered a reno-protective role of silymarin and exosomes of BM-MSCs after thioacetamide-induced renal fibrosis in rats, with the advantage of exosomes. [ABSTRACT FROM AUTHOR]

A newly invented structure called Multi-Fin-based FinFET (M-FinFET) device is a promising candidate for future improvisation of the semiconductor industry. In this article, Multi-channel FinFET (Mch-FinFET) is proposed. A comparative investigation of various DC, analog/linearity attributes is studied for gate length variation and oxide thickness through a Sentaurus TCAD tool. The simulation study concluded that the increased number of channels (= 3no.) has enhanced ION by 409.71% compared to single-channel FinFET. The decreased value of Fin width and Fin height has shown an impressive improvement of sub-threshold swing (SS) and leakage current, which helps achieve a better switching ratio. Mch-FinFET device with lower oxide thickness (Tox=1 nm) enhances the transconductance (Gm), drain conductance (Gd), intrinsic gain (Av), and transconductance gain factor (TGF) by 52.42%, 41.17%, 85.03%, respectively. Various linearity parameters like higher-order harmonics (Gm2 and Gm3), voltage intercepts points (VIP2 and VIP3), and 1-dB compression point has improved by 32.32%, 110.71% 77%, 60.09%, 418.86%, 411.5% respectively gate length of 10 nm. Besides that, a symmetric dual spacer material is introduced to the proposed structure to analyze the importance of spacer engineering. The simulation study reveals that the Mch-FinFET device with HfO2 spacer has improved driving current by 21.42%. The optimization of various short channel effects (SCEs) such as threshold voltage roll-off, sub-threshold swing (SS), and leakage current is reflected in introducing HfO2 spacer material. This detailed study is expected to design low-power RF circuits that would benefit future CMOS technology. [ABSTRACT FROM AUTHOR]

This study was conducted in Baghdad, Iraq from December 2021 to May 2022. The goal was to determine the effect of Toxoplasma gondii on liver function by examining the relationship between Toxoplasma infection and hormones. One hundred and twenty male patients with Chronic liver disease (CLD) (age:14-75 years) and 120 control males (age: 24-70 years) participated in this study. Serum samples were taken from all individuals and were then analysed for anti-Toxoplasma antibodies. Hormonal tests were conducted for all participants which included (Cortisol, testosterone, prolactin, insulin, and thyroid-stimulating hormone TSH). Biochemical tests included (Prothrombin time PT, international normalized ratio INR and albumin); liver enzymes evaluated were (aspartate aminotransferase AST, alanine aminotransferase ALT, alkaline phosphatase ALP and gamma-glutamyl transferase GGT) and interleukins (Interleukin 13 IL-13 and transforming growth factor TGF). According to the anti-Toxoplasma antibodies results, 32 (26% of the control group) of the participants tested positive for anti-Toxoplasma antibodies, compared to 60 (50%) of the CLD patients. Four sub-groups were formed in response to prior results: Control-Toxoplasma positive, control-Toxoplasma negative, CLD-Toxoplasma positive and CLDToxoplasma negative. The seropositive status of T. gondii did not affect the following hormones: cortisol, testosterone, insulin and TSH while it was related significantly to prolactin. The results of liver enzymes showed that T. gondii positive status was significantly related to all enzymes among CLD patients except the GGT enzyme T. gondii positive status was not correlated with the other biochemical (PT, INR, and albumin) and immunological parameters (IL-13 and TGF). [ABSTRACT FROM AUTHOR]

The August 2023 article in Science Signaling , "TGF-β uncouples glycolysis and inflammation in macrophages and controls survival during sepsis," challenges the traditional M1/M2 macrophage classification by investigating the impact of transforming growth factor β on macrophage metabolism and function. Despite its conventional anti-inflammatory role, transforming growth factor β–treated macrophages exhibit a distinct phenotype marked by heightened glycolysis, suppressed proinflammatory cytokines, and increased coagulation factor expression. The study identifies phosphofructokinase, liver type as a crucial glycolytic enzyme regulated by transforming growth factor β via the mTOR–c-MYC pathway. Epigenetic changes induced by transforming growth factor β, such as increased Smad3 activation and reduced proinflammatory transcription factor motif enrichment, contribute to the anti-inflammatory profile. The research extends its implications to sepsis, revealing the role of transforming growth factor β in exacerbating coagulation and reducing survival in mouse models. This effect involves upregulation of coagulation factor F13A1, dependent on phosphofructokinase, liver type activity and glycolysis in macrophages. Connections to COVID-19 pathology are drawn, as transforming growth factor β–treated macrophages and SARS-CoV-2 E protein-exposed cells display similar metabolic profiles. Bioinformatic analysis of COVID-19 patient data suggests correlations between myeloid expression of TGFβR1, PFKL, and F13A1 with disease severity. The study challenges the M1/M2 classification, emphasizing the complexity of macrophage responses influenced by transforming growth factor β, proposing transforming growth factor β as a potential therapeutic target for conditions like sepsis and COVID-19 where dysregulated coagulation is significant. Overall, the research provides valuable insights into transforming growth factor β–mediated immunometabolic regulation, paving the way for future investigations and potential therapeutic interventions. [ABSTRACT FROM AUTHOR]

We observed two Terrestrial Gamma‐ray Flashes (TGFs) in Uchinada, Japan associated with negative cloud‐to‐ground lightning strokes exactly 1 year apart on 18 December 2020 and 2021. The events were remarkable for their lateral distance from the associated strokes—each about 5 km away from the detector site. Not only was that lateral distance remarkable on its own for a ground based detection, but the low‐altitude profile of winter thunderstorms in Japan would suggest the detections occurred at unprecedented nadir angles—73.3° off axis for the 2020 event with the standard assumption of a vertically oriented TGF. Unsurprisingly, Monte Carlo simulations of the straightforward interpretation of these events yield fluences 2 orders of magnitude lower than observed data. We investigate a variety of ways to attempt to resolve the contradiction between expected and observed behavior. Plain Language Summary: We observed two terrestrial gamma‐ray flashes at a distance and angle from which we should have seen nothing given our current understanding of how bright and wide these events can be. We investigate what must have been different about these events to make them visible to our detectors. Key Points: We detected two downward TGFs in Uchinada, Japan, approximately 5 km away laterally from the associated lightning flash's ground strike pointEstimates of the altitude of the tops of the associated leader channels from radio, optical, and climate data suggest we were, remarkably, up to 73.3° off of the vertical axes of the TGFsMonte Carlo simulations show our observations were 1–2 orders of magnitude brighter than what would be expected from a standard TGF at that geometry [ABSTRACT FROM AUTHOR]

In this paper, we present XStorm, a gamma ray spectrometer developed to detect gamma ray glows and terrestrial gamma ray flashes (TGFs) in close proximity. Measurements are mostly planned to take place on balloon campaigns but also on the ground using bigger detectors. The main aim in developing XStorm is to perform new in situ and close proximity measurements of those events to improve the understanding of the physical processes involved. For that, we ensured XStorm reached performances adapted to glow and TGF detections. It detects photons with energy between ∼400 keV and ∼20 MeV. Detected particles are timetagged with a 600 ns precision with respect to UTC. Using two types of scintillator, Bismuth Germanium Oxide and EJ‐276 plastic associated with SiPMs, the instrument is able to discriminate three types of particles involved in those events: photons, neutrons, and electrons. The behavior of the detector under high particle fluxes has been quantified through ground testing using a pulse generator. A triggered detection system has been developed, with different thresholds depending on the target of study. First measurements have been carried out with test flights in fair weather conditions and are presented here. Estimations of the configurations in which a gamma ray glow can be detected by XStorm and of the number of TGFs that could be detected in specific campaigns are also addressed. Plain Language Summary: Terrestrial gamma ray flashes (TGFs) are bursts of high‐energy photons generated in thunderstorms in less than 100 μs, whereas gamma ray glows are enhancement of the high‐energy radiation background in thunderstorms, lasting from seconds to minutes. We present a gamma ray spectrometer, XStorm, designed to detect terrestrial gamma ray flashes (TGFs) and gamma ray glows in close proximity. It is composed of two scintillators of different kinds to allow the detection of TGF and gamma ray glow photons (energies between 400 keV and 20 MeV, with a time precision of 600 ns UTC). XStorm measurements are mainly planned to take place on board balloons, but can also be performed at ground level using bigger scintillators. XStorm is able to discriminate photons, electrons and neutrons, that are particle types involved in TGFs. We show the first measurements in fair weather and configurations allowing the detection of gamma ray glows. We estimate that XStorm will detect ∼0.5 TGF on average over one balloon flight of Stratéole‐2 campaign presented in the scientific objectives. Key Points: Development of a gamma ray spectrometer to detect gamma ray glows and terrestrial gamma ray flashes (TGFs), able to discriminate photons, electrons, and neutronsResults from balloon test flights performed in fair weather conditions, detecting the background radiation level as a function of altitudeEstimation of the detectability of gamma ray glows and TGFs as a function of altitude with XStorm [ABSTRACT FROM AUTHOR]

Abstract Background Preeclampsia is a severe complication of pregnancy which is attributed to placental dysfunction. The retrotransposon, Paternal Expressed Gene 10 (PEG10) harbours critical placental functions pertaining to placental trophoblast cells. Limited evidence exists on whether PEG10 is involved in preeclampsia pathogenesis. This study characterised the expression and regulation of PEG10 in placentas from patients with early-onset preeclampsia compared to gestation-matched controls. Methods PEG10 expression was measured in plasma and placentas collected from patients with early-onset preeclampsia (

The meteorological conditions required for the production of Terrestrial Gamma‐ray Flashes (TGFs) are not well understood. Particularly, the link between TGF production, meteorology, and weather severity is poorly characterized with most works focusing on only a small set of TGF events or isolated storms. This work is a further step toward understanding the general context of the meteorological conditions required for TGF production and if it differs from regular lightning production. We use TGFs observed from AGILE, ASIM, Fermi, and RHESSI to generate the largest catalog of TGFs with associated lightning sferics from either the World Wide Lightning Location Network (WWLLN) or Global Lightning Detection (GLD) combined with geostationary satellite images and meteorological conditions derived from ERA5 reanalysis data. In total we analyze 1582 TGF events and contextualize them in comparison to lightning flashes as characterized by ASIM. In our analysis we consider the proportion of TGFs and lightning coming from systems with overshooting tops as well as the Cloud Top Temperature (CTT) and the Convective Available Potential Energy (CAPE). Our results are consistent with previous studies, finding that TGFs observed from space come from primarily higher cloud tops than regular lightning flashes do. We find that CAPE and the proportion of cells with overshooting tops is similar for both TGF and lightning producing cells. It suggests that TGF observations from space are biased toward systems with higher cloud tops because the attenuation of the gamma‐rays from lower altitude TGFs reduce their intensity below the detection level of LEO instruments. Plain Language Summary: Terrestrial Gamma‐ray Flashes (TGFs) are bursts of high energy radiation associated with only some lightning flashes. Here we seek to determine if the systems which generate TGFs are significantly different from those that generate only lightning flashes. While the general trend of TGF observations indicate that observable TGFs come from systems with higher cloud tops than other lightning, relatively little is understood about how the weather severity impacts the production of TGFs. To explore this we use geostationary satellite images and meteorological data to investigate the systems which generate TGFs compared to those that do not. We find that observed TGFs come from systems with higher cloud tops but not significantly more severe weather systems and that regional differences dominate over seasonal differences. It suggests that TGF observations from space are biased toward systems with higher cloud tops, because lower altitude TGFs cannot be detected from the space observatories. Key Points: Global analysis of TGF cloud characteristics combining AGILE, ASIM, Fermi and RHESSITGF producing cells are higher than lightning producing cells but otherwise their weather severity is similarRegional effects on the meteorological conditions for TGF production are more significant than seasonal effects [ABSTRACT FROM AUTHOR]

Angiogenesis refers to the formation of new blood vessels from existing ones, which can occur in both physiologic and pathologic conditions. Lack of tissue oxygen is the main stimulator of angiogenesis accompanied by increasing in HIF-1α-(hypoxia-inducible factor-1α) expression as a nuclear transcription factor. Other factors such as VEGF (vascular endothelial growth factor), FGF2 (fibroblast growth factor2), and TGF (transforming growth factor) are involved in angiogenesis, too. To control diabetes and tumoral disease, abnormal angiogenesis inhibition can be useful besides stimulation that can be helpful in cardiovascular disease. In this study, we have reviewed the mechanisms and stimulators of angiogenesis and its influential factors. The most important angiogenic factors are MMP, Ang, FGF, and VEGF. Ang is not directly involved in the process of angiogenesis but sometimes destabilize the arteries. In contrast to angiostatin, endostatin TIMP and TSP1 act as the most important angiostatic factors. Many attempts have been made to identify the mechanisms and factors involved in this process but angiogenic inhibitors that inhibit the growth of cancerous masses or tumors in the body have not yet been adequately investigated. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a rare cardiovascular disorder leading to pulmonary hypertension and, often fatal, right heart failure. Sex differences in PAH are evident, which primarily presents with a female predominance and increased male severity. Disturbed signalling of the transforming growth factor-β (TGFβ) family and gene mutations in the bone morphogenetic protein receptor 2 (BMPR2) are risk factors for PAH development, but how sex-specific cues affect the TGFβ family signalling in PAH remains poorly understood. In this review, we aim to explore the sex bias in PAH by examining sex differences in the TGFβ signalling family through mechanistical and translational evidence. Sex hormones including oestrogens, progestogens, and androgens, can determine the expression of receptors (including BMPR2), ligands, and soluble antagonists within the TGFβ family in a tissue-specific manner. Furthermore, sex-related genetic processes, i.e. Y-chromosome expression and X-chromosome inactivation, can influence the TGFβ signalling family at multiple levels. Given the clinical and mechanistical similarities, we expect that the conclusions arising from this review may apply also to hereditary haemorrhagic telangiectasia (HHT), a rare vascular disorder affecting the TGFβ signalling family pathway. In summary, we anticipate that investigating the TGFβ signalling family in a sex-specific manner will contribute to further understand the underlying processes leading to PAH and likely HHT. [ABSTRACT FROM AUTHOR]

Background and Objective: Recent advancements in immunotherapy led to the development of Chimeric antigen receptor (CAR) T‐cell therapy. CAR‐T cell therapy in non‐small cell lung cancer (NSCLC) is hindered by overexpression of transforming growth factor (TGFβ) in the cancer cells that have a negative regulatory role on T‐cells activity. This study characterized CAR‐T with overexpression of mothers against decapentaplegic homologue 7 (SMAD), a negative regulator of TGFβ downstream signalling. Methods: We have generated three types of CAR‐T: epidermal growth factor receptor (EGFR)‐CAR‐T, EGFR‐dominant‐negative TGFbeta receptor 2 (DNR)‐CAR‐T, and EGFR‐SMAD7‐CAR‐T by transducing human T‐cells with the lentivirus constructs. We characterized the proliferation, expression of proinflammatory cytokines, activation profile, and lysis capacity in co‐cultures with A549 lung carcinoma cells with and without TGFβ neutralizing antibodies. We also tested the therapeutic potential of EGFR‐SMAD7‐CAR‐T in the A549 cells tumour‐bearing mice model. Results: Both EGFR‐DNR‐CAR‐T and EGFR‐SMAD7‐CAR‐T demonstrated a higher proliferation rate and lysis capacity to A549 than traditional EGFR‐CAR‐T. Neutralization of TGFβ by the antibodies resulted in increased performance of EGFR‐CAR‐T. In vivo, both EGFR‐DNR‐CAR‐T and EGFR‐SMAD7‐CAR‐T resulted in complete tumour resorption by day 20, whereas conventional CAR‐T only has a partial effect. Conclusion: We demonstrated the high efficacy and resistance to negative TGFβ regulation of EGFR‐SMAD7‐CAR‐T comparable with EGFR‐DNR‐CAR‐T and without the systemic effect of TGFβ inhibition. The efficacy of TGF‐β signalling‐resistant CAR‐T based on SMAD7 overexpression is restricted to CAR‐T cells themselves and potentially reduces systemic effects on TGF‐β signalling. SMAD7‐CAR‐T demonstrates complete elimination of cancer in vivo, high levels of SMAD7‐CAR‐T proliferation, and activation that are not significantly different from the DNR‐CAR‐T design. [ABSTRACT FROM AUTHOR]

Abstract Efforts to develop effective disease-modifying drugs to treat osteoarthritis have so far proved unsuccessful with a number of promising drug candidates from pre-clinical studies failing to show efficacy in clinical trials. It is therefore timely to re-evaluate our current understanding of osteoarthritis pathogenesis and the similarities and differences in disease development between commonly used pre-clinical mouse models and human patients. There is substantial heterogeneity between patients presenting with osteoarthritis and mounting evidence that the pathways involved in osteoarthritis (e.g. Wnt signalling) differ between patient sub-groups. There is also emerging evidence that the pathways involved in osteoarthritis differ between the STR/ort mouse model (the most extensively studied mouse model of spontaneously occurring osteoarthritis) and injury-induced osteoarthritis mouse models. For instance, while canonical Wnt signalling is upregulated in the synovium and cartilage at an early stage of disease in injury-induced osteoarthritis mouse models, this does not appear to be the case in the STR/ort mouse. Such findings may prove insightful for understanding the heterogeneity in mechanisms involved in osteoarthritis pathogenesis in human disease. However, it is important to recognise that there are differences between mice and humans in osteoarthritis pathogenesis. A much more extensive array of pathological changes are evident in osteoarthritic joints in individual mice with osteoarthritis compared to individual patients. There are also specified differences in the pathways involved in disease development. For instance, although increased TGF-β signalling is implicated in osteoarthritis development in both mouse models of osteoarthritis and human disease, in mice, this is mainly mediated through TGF-β3 whereas in humans, it is through TGF-β1. Studies in other tissues have shown TGF-β1 is more potent than TGF-β3 in inducing the switch to SMAD1/5 signalling that occurs in osteoarthritic cartilage and that TGF-β1 and TGF-β3 have opposing effects on fibrosis. It is therefore possible that the relative contribution of TGF-β signalling to joint pathology in osteoarthritis differs between murine models and humans. Understanding the similarities and differences in osteoarthritis pathogenesis between mouse models and humans is critical for understanding the translational potential of findings from pre-clinical studies.

Skin ageing is defined, in part, by collagen depletion and fragmentation that leads to a loss of mechanical tension. This is currently believed to reflect, in part, the accumulation of senescent cells. We compared the expression of genes and proteins for components of the extracellular matrix (ECM) as well as their regulators and found that in vitro senescent cells produced more matrix metalloproteinases (MMPs) than proliferating cells from adult and neonatal donors. This was consistent with previous reports of senescent cells contributing to increased matrix degradation with age; however, cells from adult donors proved significantly less capable of producing new collagen than neonatal or senescent cells, and they showed significantly lower myofibroblast activation as determined by the marker α-SMA. Functionally, adult cells also showed slower migration than neonatal cells. We concluded that the increased collagen degradation of aged fibroblasts might reflect senescence, the reduced collagen production likely reflects senescence-independent processes.

Background: Preeclampsia is a severe complication of pregnancy which is attributed to placental dysfunction. The retrotransposon, Paternal Expressed Gene 10 (PEG10) harbours critical placental functions pertaining to placental trophoblast cells. Limited evidence exists on whether PEG10 is involved in preeclampsia pathogenesis. This study characterised the expression and regulation of PEG10 in placentas from patients with early-onset preeclampsia compared to gestation-matched controls. Methods: PEG10 expression was measured in plasma and placentas collected from patients with early-onset preeclampsia (< 34 weeks') and gestation-matched controls using ELISA (protein) and RT-qPCR (mRNA). First-trimester human trophoblast stem cells (hTSCs) were used for in vitro studies. PEG10 expression was measured during hTSC differentiation and hTSC exposure to hypoxia (1% O2) and inflammatory cytokines (IL-6 and TNFα) using RT-qPCR. Functional studies used PEG10 siRNA to measure the effect of reduced PEG10 on canonical TGF- β signalling and proliferation using luciferase and xCELLigence assays, respectively. Results: PEG10 mRNA expression was significantly reduced in placentas from patients with early-onset preeclampsia (< 34 weeks' gestation) relative to controls (p = 0.04, n = 78 vs n = 18 controls). PEG10 protein expression was also reduced in preeclamptic placentas (p = 0.03, n = 5 vs n = 5 controls, blinded assessment of immunohistochemical staining), but neither PEG10 mRNA nor protein could be detected in maternal circulation. PEG10 was most highly expressed in hTSCs, and its expression was reduced as hTSCs differentiated into syncytiotrophoblasts (p < 0.0001) and extravillous trophoblasts (p < 0.001). Trophoblast differentiation was not altered when hTSCs were treated with PEG10 siRNA (n = 5 vs n = 5 controls). PEG10 was significantly reduced in hTSCs exposed to hypoxia (p < 0.01). PEG10 was also reduced in hTSCs treated with the inflammatory cytokine TNF α (p < 0.01), but not IL-6. PEG10 knocked down (siRNA) in hTSCs showed reduced activation of the canonical TGF-β signalling effector, the SMAD binding element (p < 0.05) relative to controls. PEG10 knockdown in hTSCs however was not associated with any significant alterations in proliferation. Conclusions: Placental PEG10 is reduced in patients with early-onset preeclampsia. In vitro studies suggest that hypoxia and inflammation may contribute to PEG10 downregulation. Reduced PEG10 alters canonical TGF- β signalling, and thus may be involved in trophoblast dysfunction associated with this pathway. [ABSTRACT FROM AUTHOR]

Background and Aim: Human papillomavirus (HPV) is a widespread sexually transmitted infection (STI) with significant health implications. This study aimed to assess the reactivity of TGF, IL10, and MCP-1 with Leukotriene B4 in women diagnosed with cervical HPV infections. Additionally, we considered the histological grade and clinical stage of the patients. Materials and Methods: In this observational study, a total of 50 cervical infection samples from women diagnosed with HPV and 50 samples from healthy controls were collected between January 2nd and August 1st, 2022, from attendees of Al-Elwea Hospital for Delivery and Children. IgM and IgG antibodies against HPV antigens were detected in patient sera. Polymerase chain reaction (PCR) was employed to amplify the IL-6 gene sequences of lengths 249 and 431 base pairs. Interleukin levels were quantified using the enzyme-linked immunosorbent assay (ELISA) technique. HPV infection diagnosis was confirmed using cervical cytology (Pap smear) and HPV DNA testing before study inclusion. Results: The average age of the patients was [35.02±10.73]. The findings revealed that among papillomavirus cases, 30 (85.7%) exhibited normal levels of both IgM and IgG, while 5 cases (14.3%) showed normal IgM levels and elevated IgG levels. Additionally, 10 cases (66.7%) of papilloma demonstrated increased IgM levels and normal IgG levels, in contrast to 5 cases (33.3%) with elevated levels of both IgM and IgG. Importantly, a positive correlation was observed between IgM and IgG levels and the concentrations of TGF, MCP-1, IL-10, and LTB-4 (r=0.896**, 0.678**, 0.692**, 0.894**), (r=0.894**, 0.546**, 0.570**, 0.618**), respectively. Conclusion: The study revealed a significant positive correlation between IgM and IgG levels and the concentrations of TGF, MCP-1, IL-10, and LTB-4, indicating potential immunological interactions in HPV infection. High Ct values for both patients and controls, along with HR-HPV gene expression, suggest a proportional relationship between gene concentration and Ct value. [ABSTRACT FROM AUTHOR]

In this study, we aimed to explore the hepatoprotective effects of the gemmotherapy bud extract of Corylus avellana in a model of liver fibrosis on diabetic mice. An evaluation of total flavonoids and polyphenols contents and LC/MS analyses were performed. Experimental fibrosis was induced with CCl4 (2 mL/kg by i.p. injections twice a week for 7 weeks) in streptozotocin-induced diabetic mice. Our results showed a content of 6–7% flavonoids, while hyperoside and chlorogenic acids were highlighted in the bud extract. Toxic administration of CCl4 increased oxidative stress, mRNA expression of the transforming growth factor-β1 (TGF-β1) and Smad 2/3, and reduced Smad 7 expression. Furthermore, up-regulation of α-smooth muscle actin (α-SMA) revealed an activation of hepatic stellate cells (HSCs), while collagen I (Col I) up-regulation and matrix metalloproteinases (MMPs) unbalance led to an altered extracellular matrix enriched in collagen, confirmed as well by a trichrome stain and electron microscopy analysis. Treatment with gemmotherapy extract significantly restored the liver architecture and the antioxidant balance, and significantly decreased collagen deposits in the liver and improved the liver function. Our results suggest that Corylus avellana gemmotherapy extract may have anti-fibrotic effects and could be useful in the prevention and treatment of liver fibrosis. The hepatoprotective mechanism is based on HSC inhibition, a reduction in oxidative stress and liver damage, a downregulation of the TGF-β1/Smad signaling pathway and a MMPs/TIMP rebalance. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis is a pathological process associated with various forms of heart failure. This study identified latent transforming growth factor-β binding protein 2, cartilage oligomeric matrix protein, and cartilage intermediate layer protein 1 as potential biomarkers for cardiac fibrosis. All 3 encoded proteins showed increased expression in fibroblasts after transforming growth factor-β stimulation in vitro and localized specifically to fibrotic regions in vivo. Of the 3, only the full-length cartilage intermediate layer protein 1 showed a significant decrease in circulating levels in patients with heart failure compared with healthy volunteers. Further studies on these 3 proteins will lead to a better understanding of their biomarker potential for cardiac fibrosis.

Cardiac fibrosis is a pathological process associated with various forms of heart failure. This study identified latent transforming growth factor-β binding protein 2, cartilage oligomeric matrix protein, and cartilage intermediate layer protein 1 as potential biomarkers for cardiac fibrosis. All 3 encoded proteins showed increased expression in fibroblasts after transforming growth factor-β stimulation in vitro and localized specifically to fibrotic regions in vivo. Of the 3, only the full-length cartilage intermediate layer protein 1 showed a significant decrease in circulating levels in patients with heart failure compared with healthy volunteers. Further studies on these 3 proteins will lead to a better understanding of their biomarker potential for cardiac fibrosis.

The tumor microenvironment (TME) plays a pivotal role in cancer progression, and, in ovarian cancer (OvCa), the primary TME is the omentum. Here, we show that the diabetes drug metformin alters mesothelial cells in the omental microenvironment. Metformin interrupts bidirectional signaling between tumor and mesothelial cells by blocking OvCa cell TGF-β signaling and mesothelial cell production of CCL2 and IL-8. Inhibition of tumor-stromal crosstalk by metformin is caused by the reduced expression of the tricarboxylic acid (TCA) enzyme succinyl CoA ligase (SUCLG2). Through repressing this TCA enzyme and its metabolite, succinate, metformin activated prolyl hydroxylases (PHDs), resulting in the degradation of hypoxia-inducible factor 1α (HIF1α) in mesothelial cells. Disruption of HIF1α-driven IL-8 signaling in mesothelial cells by metformin results in reduced OvCa invasion in an organotypic 3D model. These findings indicate that tumor-promoting signaling between mesothelial and OvCa cells in the TME can be targeted using metformin.

Multiple Sclerosis (MS), the leading cause of non-traumatic neurological disability in young adults, is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). Due to the poor accessibility to the target organ, CNS-confined processes underpinning the later progressive form of MS remain elusive thereby limiting treatment options. We aimed to examine DNA methylation, a stable epigenetic mark of genome activity, in glial cells to capture relevant molecular changes underlying MS neuropathology. We profiled DNA methylation in nuclei of non-neuronal cells, isolated from 38 post-mortem normal-appearing white matter (NAWM) specimens of MS patients (n = 8) in comparison to white matter of control individuals (n = 14), using Infinium MethylationEPIC BeadChip. We identified 1,226 significant (genome-wide adjusted P-value < 0.05) differentially methylated positions (DMPs) between MS patients and controls. Functional annotation of the altered DMP-genes uncovered alterations of processes related to cellular motility, cytoskeleton dynamics, metabolic processes, synaptic support, neuroinflammation and signaling, such as Wnt and TGF-β pathways. A fraction of the affected genes displayed transcriptional differences in the brain of MS patients, as reported by publically available transcriptomic data. Cell type-restricted annotation of DMP-genes attributed alterations of cytoskeleton rearrangement and extracellular matrix remodelling to all glial cell types, while some processes, including ion transport, Wnt/TGF-β signaling and immune processes were more specifically linked to oligodendrocytes, astrocytes and microglial cells, respectively. Our findings strongly suggest that NAWM glial cells are highly altered, even in the absence of lesional insult, collectively exhibiting a multicellular reaction in response to diffuse inflammation.

12(S)-hydroxyheptadecatrienoic acid (12-HHT) is a bioactive fatty acid synthesized from arachidonic acid via the cyclooxygenase pathway and serves as an endogenous ligand for the low-affinity leukotriene B4 receptor 2 (BLT2). Although the 12-HHT/BLT2 axis contributes to the maintenance of epithelial homeostasis, 12-HHT metabolism under physiological conditions is unclear. In this study, 12-keto-heptadecatrienoic acid (12-KHT) and 10,11-dihydro-12-KHT (10,11dh-12-KHT) were detected as 12-HHT metabolites in the human megakaryocytic cell line MEG01s. We found that 12-KHT and 10,11dh-12-KHT are produced from 12-HHT by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and prostaglandin reductase 1 (PTGR1), key enzymes in the degradation of prostaglandins, respectively. The 15-PGDH inhibitor SW033291 completely suppressed the production of 12-KHT and 10,11dh-12-KHT in MEG01s cells, resulting in a 9-fold accumulation of 12-HHT. 12-KHT and 10,11dh-12-KHT were produced in mouse skin wounds, and the levels were significantly suppressed by SW033291. Surprisingly, the agonistic activities of 12-KHT and 10,11dh-12-KHT on BLT2 were comparable to that of 12-HHT. Taken together, 12-HHT is metabolized into 12-KHT by 15-PGDH, and then 10,11dh-12-KHT by PTGR1 without losing the agonistic activity. [ABSTRACT FROM AUTHOR]

Introduction: As a kind of human unique benign skin tumour, keloid has caused great trouble to the physical and mental health of patients and is unfavourable for beautiful. The abnormal proliferation of fibroblasts is one of the main causes of keloid formation. TET2 (Ten eleven translocation 2) catalyzes the oxidation of cytosine 5mC to 5hmC which process plays important role in cell proliferation. However, the molecular mechanism of TET2 in keloids is not well-researched. Methods: qPCR was used to detect the mRNA levels and Western blot was used to detect the protein level. DNA Dot blot was used to detect the level of 5hmC. CCK8 was used to examine the cell proliferation rate. EDU/DAPI staining was used to evaluate the living cells' proliferation rate. DNA IP and PCR were used to detect the accumulation of DNA at the target site after 5hmC enrichment. Results: We found that TET2 was highly expressed in keloid tissue. Interestingly, TET2 expression was increased in fibroblasts that were isolated and cultured in vitro compared to the tissue of origin. Knocking down TET2 expression can effectively decrease the modification level of 5hmC and inhibit the proliferation of fibroblasts. Notably, overexpression of DNMT3A inhibited fibroblast proliferation by decreasing 5hmC. The 5hmC-IP assay showed that TET2 could affect the expression of TGFβ by regulating the 5hmC modification level in the promoter region. And by this way, TET2 regulates the proliferation of fibroblasts. Conclusion: This study found new epigenetic mechanisms for keloid formation. [ABSTRACT FROM AUTHOR]

The tubuloglomerular feedback (TGF) mechanism modulates renal hemodynamics and glomerular filtration rate in individual nephrons. Our study aimed to evaluate the TGF‐induced vascular responses by inhibiting Na‐K‐2Cl co‐transporters and sodium‐glucose co‐transporters in rats. We assessed cortical hemodynamics with high‐resolution laser speckle contrast imaging, which enabled the evaluation of blood flow in individual microvessels and analysis of their dynamical patterns in the time‐frequency domain. We demonstrated that a systemic administration of furosemide abolishes TGF‐mediated hemodynamic responses. Furthermore, we showed that the local microcirculatory blood flow decreased, and the TGF‐induced hemodynamic oscillations were sustained but weakened after inhibiting sodium‐glucose co‐transporters in Sprague–Dawley rats. [ABSTRACT FROM AUTHOR]

Acute kidney injury is associated with increased risk of heart failure and mortality. This study demonstrates that acute kidney injury induces remote cardiac dysfunction, damage, injury, and fibrosis via a galectin-3 (Gal-3) dependent pathway. Gal-3 originates from bone marrow-derived immune cells. Cardiac damage could be prevented by blocking this pathway.

Acute kidney injury is associated with increased risk of heart failure and mortality. This study demonstrates that acute kidney injury induces remote cardiac dysfunction, damage, injury, and fibrosis via a galectin-3 (Gal-3) dependent pathway. Gal-3 originates from bone marrow-derived immune cells. Cardiac damage could be prevented by blocking this pathway.

PurposeUnderstanding how differentiation, microenvironment, and hormonal milieu influence human breast cell susceptibility to malignant transformation will require the use of physiologically relevant in vitro systems. We sought to develop a 3D culture model that enables the propagation of normal estrogen receptor alpha (ER) + cells.MethodsWe tested soluble factors and protocols for the ability to maintain progenitor and ER + cells in cultures established from primary cells. Optimized conditions were then used to profile estrogen-induced gene expression changes in cultures from three pathology-free individuals.ResultsLong-term representation of ER + cells was optimal in medium that included three different TGFβ/activin receptor-like kinase inhibitors. We found that omitting the BMP signaling antagonist, Noggin, enhanced the responsiveness of the PGR gene to estradiol exposure without altering the proportions of ER + cells in the cultures. Profiling of estradiol-exposed cultures showed that while all the cultures showed immediate and robust induction of PGR, LRP2, and IGFB4, other responses varied qualitatively and quantitatively across specimens.ConclusionsWe successfully identified conditions for the maintenance and propagation of functional ER + cells from normal human breast tissues. We propose that these 3D cultures will overcome limitations of conventional 2D cultures of partially or fully transformed cell lines by sustaining normal endocrine function and growth regulation of the cell populations that comprise intact breasts.

Abstract The tubuloglomerular feedback (TGF) mechanism modulates renal hemodynamics and glomerular filtration rate in individual nephrons. Our study aimed to evaluate the TGF‐induced vascular responses by inhibiting Na‐K‐2Cl co‐transporters and sodium‐glucose co‐transporters in rats. We assessed cortical hemodynamics with high‐resolution laser speckle contrast imaging, which enabled the evaluation of blood flow in individual microvessels and analysis of their dynamical patterns in the time‐frequency domain. We demonstrated that a systemic administration of furosemide abolishes TGF‐mediated hemodynamic responses. Furthermore, we showed that the local microcirculatory blood flow decreased, and the TGF‐induced hemodynamic oscillations were sustained but weakened after inhibiting sodium‐glucose co‐transporters in Sprague–Dawley rats.

B cells include immune-suppressive fractions, called regulatory B cells (Bregs), which regulate inflammation primarily through an interleukin 10 (IL-10)-mediated inhibitory mechanism. Several B-cell fractions have been reported as IL-10-producing Bregs in murine disease models and human inflammatory responses including autoimmune diseases, infectious diseases, cancer and organ-transplant rejection. Although the suppressive functions of Bregs have been explored through the hallmark molecule IL-10, inhibitory cytokines and membrane-binding molecules other than IL-10 have also been demonstrated to contribute to Breg activities. Transcription factors and surface antigens that are characteristically expressed in Bregs are also being elucidated. Nevertheless, defining Bregs is still challenging because their active periods and differentiation stages vary among disease models. The identity of the diverse Breg fractions is also under debate. In the first place, since regulatory functions of Bregs are mostly evaluated by ex vivo stimulation, the actual in vivo phenotypes and functions may not be reflected by the ex vivo observations. In this article, we provide a historical overview of studies that established the characteristics of Bregs and review the various suppressive mechanisms that have been reported to be used by Bregs in murine and human disease conditions. We are only part-way through but the common phenotypes and functions of Bregs are still emerging. [ABSTRACT FROM AUTHOR]

Simple Summary: The p53 protein family is a class of proteins successively known to be the guardians of the genome, but also depending on the different isoforms have pro-tumoral and pro-metastatic potential. This dual potential is also observed within the TGFb pathway. Several interactions between those two proteins family start to explain this complexity. TP53 (TP53), p73 (TP73), and p63 (TP63) are members of the p53 transcription factor family, which has many activities spanning from embryonic development through to tumor suppression. The utilization of two promoters and alternative mRNA splicing has been shown to yield numerous isoforms in p53, p63, and p73. TAp73 is thought to mediate apoptosis as a result of nuclear accumulation following chemotherapy-induced DNA damage, according to a number of studies. Overexpression of the nuclear ΔNp63 and ΔNp73 isoforms, on the other hand, suppresses TAp73's pro-apoptotic activity in human malignancies, potentially leading to metastatic spread or inhibition. Another well-known pathway that has been associated to metastatic spread is the TGF pathway. TGFs are a family of structurally related polypeptide growth factors that regulate a variety of cellular functions including cell proliferation, lineage determination, differentiation, motility, adhesion, and cell death, making them significant players in development, homeostasis, and wound repair. Various studies have already identified several interactions between the p53 protein family and the TGFb pathway in the context of tumor growth and metastatic spread, beginning to shed light on this enigmatic intricacy. [ABSTRACT FROM AUTHOR]

In this work, gate stacked hetero-junction TFET on SELBOX substrate (GSHJ-STFET) has been proposed. Comparative electrical performance analysis has been performed between proposed GSHJ-STFET structure with fully depleted SOITFET. The optimized proposed TFET structure has been explored for DC, and RF/analog performance matrix such as ION, IOFF, ION/IOFF ratio, subthreshold swing (SS), transconductance (gm), threshold voltage (VT), cut-off frequency (fT), transit time (t), gain bandwidth product (GWB), maximum oscillating frequency (fMAX), TGF, and TFP. It has been found that proposed TFET with SELBOX shows better static performance compared to conventional fully depleted SOI-TFET (FD-SOITFET). Further, the temperature reliability analysis has been extensively investigated for both conventional fully depleted SOI TFET and proposed TFET, respectively. [ABSTRACT FROM AUTHOR]

Multiple Sclerosis (MS), the leading cause of non-traumatic neurological disability in young adults, is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). Due to the poor accessibility to the target organ, CNS-confined processes underpinning the later progressive form of MS remain elusive thereby limiting treatment options. We aimed to examine DNA methylation, a stable epigenetic mark of genome activity, in glial cells to capture relevant molecular changes underlying MS neuropathology. We profiled DNA methylation in nuclei of non-neuronal cells, isolated from 38 post-mortem normal-appearing white matter (NAWM) specimens of MS patients (n = 8) in comparison to white matter of control individuals (n = 14), using Infinium MethylationEPIC BeadChip. We identified 1,226 significant (genome-wide adjusted P-value < 0.05) differentially methylated positions (DMPs) between MS patients and controls. Functional annotation of the altered DMP-genes uncovered alterations of processes related to cellular motility, cytoskeleton dynamics, metabolic processes, synaptic support, neuroinflammation and signaling, such as Wnt and TGF-β pathways. A fraction of the affected genes displayed transcriptional differences in the brain of MS patients, as reported by publically available transcriptomic data. Cell type-restricted annotation of DMP-genes attributed alterations of cytoskeleton rearrangement and extracellular matrix remodelling to all glial cell types, while some processes, including ion transport, Wnt/TGF-β signaling and immune processes were more specifically linked to oligodendrocytes, astrocytes and microglial cells, respectively. Our findings strongly suggest that NAWM glial cells are highly altered, even in the absence of lesional insult, collectively exhibiting a multicellular reaction in response to diffuse inflammation. [ABSTRACT FROM AUTHOR]

Aim: The purpose of this study was to obtain data concerning growth factor release within liquid and solid platelet-rich fibrin (PRF) matrices and to estimate the amount of potential interindividual variations as a basis for further preclinical and clinical trials. Therefore, we aimed to determine possible differences in the release of growth factors between liquid and solid PRF. Materials and Methods: Blood samples obtained from four subjects were processed to both liquid and solid PRF matrices using a standard centrifugation protocol. Five growth factors (vascular endothelial growth factor, VEGF; epidermal growth factor, EGF; platelet-derived growth factor-BB, PDGF-BB; transforming growth factor-β1, TGF-β1; and matrix metallopeptidase 9, MMP-9) have been evaluated at six time points by ELISA over a total observation period of 10 days (1 h, 7 h, 1 d, 2 d, 7 d, and 10 d). Results: Growth factor release could be measured in all samples at each time point. Comparing liquid and solid PRF matrices, no significant differences were detected (p > 0.05). The mean release of VEGF, TGFβ-1, PDGF-BB, and MMP-9 raised to a peak at time point five (day 7) in both liquid and solid PRF matrices. VEGF release was lower in liquid PRF than in solid PRF, whereas those of PDGF-BB and MMP-9 were higher in liquid PRF than in solid PRF at all time points. EGF had its peak release already at time point two after 7 h in liquid and solid matrices (hour 7 EGF solid: mean = 180 pg/mL, SD = 81; EGF liquid: mean = 218 pg/mL, SD = 64), declined rapidly until day 2, and had a second slight peak on day 7 in both groups (day 7 EGF solid: mean = 182 pg/mL, SD = 189; EGF liquid: mean = 81 pg/mL, SD = 70). Conclusions: This study detected growth factor release within liquid and solid PRF matrices with little variations. Further preclinical trials are needed to precisely analyze the growth factor release in larger samples and to better understand their effects on wound healing in different clinical indications. [ABSTRACT FROM AUTHOR]

Asthma is characterized by chronic bronchial inflammation and is a highly heterogeneous disease strongly influenced by both specific and non-specific exogenous factors. The present study was performed to assess the effect of nasal allergen provocation tests and methacholine provocation tests on the mRNA co-expression patterns of genes ( SMAD1/3/6/7 , MPK1/3 and TGFB1/3 ) involved in SMAD and non-SMAD TGF-β signaling pathways in patients with asthma. Reverse transcription-quantitative PCR was performed on blood samples taken pre-provocation and 1 h post-provocation to assess gene expression changes. Of the 59 patients studied, allergen provocations were administered to 27 patients and methacholine provocations to 32 patients. Correlations between expression levels of studied genes were found to be influenced markedly by the challenge administered, challenge test result and time elapsed since challenge. Importantly, increases in expression levels for four gene pairs ( MAPK1-SMAD3, MAPK3-SMAD3, SMAD1-SMAD3 and SMAD3-TGFB1 ) were found to correlate significantly with asthma occurrence in the allergen provocation cohort, but not in the methacholine provocation cohort. The present study allows us to draw the conclusion that both intranasal allergen and bronchial methacholine challenges influence mRNA co-expression patterns of the SMAD1/3/6/7, MPK1/3 and TGFB1/3 genes., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Plichta et al.)