Aim
To understand the direct impact of bradykinin in autonomic control of circulation through baroreflex afferent pathway.
Methods
The mean arterial pressure (MAP) was monitored while bradykinin and ...its agonists were applied via nodose (NG) microinjection, the expression of bradykinin receptors (BRs) in the NG (1st‐order) and nucleus tractus solitarius (NTS, 2nd‐order) were tested in adult male, age‐matched female, and ovariectomized rats under physiological and hypertensive conditions. Additionally, bradykinin‐induced depolarization was also tested in identified baroreceptor and baroreceptive neurons using whole‐cell patch‐clamp technique.
Results
Under physiological condition, bradykinin‐induced dose‐ and estrogen‐dependent reductions of MAP with lower estimated EC50 in females. B2R agonist mediated more dramatic MAP reduction with long‐lasting effect compared with B1R activation. These functional observations were consistent with the molecular and immunostaining evidences. However, under hypertensive condition, the MAP reduction was significantly less dramatic in N’‐Nitro‐L‐Arginine‐methyl ester (L‐NAME) induced secondary and spontaneous hypertension rats in males compared with female rats. Electrophysiological data showed that bradykinin‐elicited concentration‐dependent membrane depolarization with discharges during initial phase in identified myelinated Ah‐types baroreceptor neurons, not myelinated A‐types; while, higher concentration of bradykinin was required for depolarization of unmyelinated C‐types without initial discharges.
Conclusion
These datasets have demonstrated for the first time that bradykinin mediates direct activation of baroreflex afferent function to trigger estrogen‐dependent depressor response, which is due mainly to the direct activation/neuroexcitation of female‐specific myelinated Ah‐type baroreceptor neurons leading to a sexual dimorphism in parasympathetic domination of blood pressure regulation via activation of B2R/B1R expression in baroreflex afferent pathway.
Female‐specific subpolulation of myelinated Ah‐type baroreceptor neurons plays a critical role in BK/BKRs mediated autonomic control of BP regulation.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
For many children with intrahepatic cholestasis and high-serum gamma-glutamyl transferase (GGT) activity, a genetic aetiology of hepatobiliary disease remains undefined. We sought to identify novel ...genes mutated in children with idiopathic high-GGT intrahepatic cholestasis, with clinical, histopathological and functional correlations.
We assembled a cohort of 25 children with undiagnosed high-GGT cholestasis and without clinical features of biliary-tract infection or radiological features of choledochal malformation, sclerosing cholangitis or cholelithiasis. Mutations were identified through whole-exome sequencing and targeted Sanger sequencing. We reviewed histopathological findings and assessed phenotypical effects of ZFYVE19 deficiency in cultured cells by immunofluorescence microscopy.
Nine Han Chinese children harboured biallelic, predictedly complete loss-of-function pathogenic mutations in
(c.314C>G, p.S105X; c.379C>T, p.Q127X; c.514C>T, p.R172X; c.547C>T, p.R183X; c.226A>G, p.M76V). All had portal hypertension and, at liver biopsy, histopathological features of the ductal plate malformation (DPM)/congenital hepatic fibrosis (CHF). Four children required liver transplantation for recurrent gastrointestinal haemorrhage. DPM/CHF was confirmed at hepatectomy, with sclerosing small-duct cholangitis. Immunostaining for two primary-cilium axonemal proteins found expression that was deficient intraluminally and ectopic within cholangiocyte cytoplasm. ZFYVE19 depletion in cultured cells yielded abnormalities of centriole and axoneme.
Biallelic
mutations can lead to high-GGT cholestasis and DPM/CHF in vivo. In vitro, they can lead to centriolar and axonemal abnormalities. These observations indicate that mutation in
results, through as yet undefined mechanisms, in a ciliopathy.
TMEM67 (mecklin or MKS3) locates in the transition zone of cilia. Dysfunction of TMEM67 disrupts cilia‐related signaling and leads to developmental defects of multiple organs in humans. Typical ...autosomal recessive TMEM67 defects cause partial overlapping phenotypes, including abnormalities in the brain, eyes, liver, kidneys, bones, and so forth. However, emerging reports of isolated nephronophthisis suggest the possibility of a broader phenotype spectrum. In this study, we analyzed the genetic data of cholestasis patients with no obvious extrahepatic involvement but with an unexplained high level of gamma‐glutamyl transpeptidase (GGT). We identified five Han Chinese patients from three unrelated families with biallelic nonnull low‐frequency TMEM67 variants. All variants were predicted pathogenic in silico, of which p. Arg820Ile and p. Leu144del were previously unreported. In vitro studies revealed that the protein levels of the TMEM67 variants were significantly decreased; however, their interaction with MKS1 remained unaffected. All the patients, aged 7−39 years old, had silently progressive cholestasis with elevated GGT but had normal bilirubin levels. Histological studies of liver biopsy of patients 1, 3, and 5 showed the presence of congenital hepatic fibrosis. We conclude that variants in TMEM67 are associated with a mild phenotype of unexplained, persistent, anicteric, and high GGT cholestasis without typical symptoms of TMEM67 defects; this possibility should be considered by physicians in gastroenterology and hepatology.
Variants in TMEM67 are associated with ciliopathies, including Meckel syndrome and Joubert syndrome. In this study, we show that variants in TMEM67 are associated with a mild phenotype of unexplained, persistent, anicteric, and high gamma‐glutamyl transpeptidase cholestasis without typical symptoms of TMEM67 defects.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
LSD1 was significantly over-expressed in several cancer types, and its aberrant overexpression was revealed to play a crucial role in the initiation and progression of cancer. Several LSD1 inhibitors ...that were discovered and developed so far were found to be effective in attenuating tumor growth in both in vivo and in vitro studies. However, the major challenge associated with the development of cancer therapies is personalized treatment. Therefore, it is essential to look in detail at how LSD1 plays its part in carcinogenesis and whether there are any different expression levels of LSD1 in different tumors. Here in this review, fresh insight into a list of function correlated LSD1 binding proteins are provided, and we tried to figure out the role of LSD1 in different cancer types, including hematological malignancies and solid tumors. A critical description of mutation preference for LSD1 in different tumors was also discussed. Recent research findings clearly showed that the abrogation of LSD1 demethylase activity via LSD1 inhibitors markedly reduced the growth of cancer cells. But there are still many ambiguities regarding the role of LSD1 in different cancers. Therefore, targeting LSD1 for treating different cancers is still reductionist, and many challenges need to be met to improve the therapeutic outcomes of LSD1 inhibitors.
Display omitted
•LSD1 overexpression is linked with the invasion and migration of cancer cells.•LSD1's critical role in regulating EMT is one of the primary causes of cancer.•Mutations in LSD1 or its effector molecules can cause variety of cancers in humans.•Diverse binding interactions of LSD1 control the fate of target genes in cancer cells.•LSD1 and its partners can serve as potential targets for precision cancer therapy.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Inflammation of the fetal membranes is an indispensable event of parturition, with increasing prostaglandin E2 (PGE2) synthesis as one of the ultimate products that prime labor onset. In addition to ...PGE2, the fetal membranes also boast a large capacity for cortisol regeneration. It is intriguing how increased PGE2 synthesis is achieved in the presence of increasing amounts of classical anti-inflammatory glucocorticoids in the fetal membranes at parturition. 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) synthesized by lipoxygenase 15/15B (ALOX15/15B) has been shown to enhance inflammation-induced PGE2 synthesis in amnion fibroblasts. Here, we examined whether glucocorticoids could induce ALOX15/15B expression and 15(S)-HETE production to promote PGE2 synthesis in amnion fibroblasts at parturition. We found that cortisol and 15(S)-HETE abundance increased parallelly in the amnion at parturition. Cortisol induced ALOX15/15B expression and 15(S)-HETE production paradoxically in amnion fibroblasts. Mechanism study revealed that this paradoxical induction was mediated by p300-mediated histone acetylation and interaction of glucocorticoid receptor with transcription factors CREB and STAT3. Conclusively, cortisol regenerated in the fetal membranes can paradoxically induce ALOX15/15B expression and 15(S)-HETE production in human amnion fibroblasts, which may further assist in the induction of PGE2 synthesis in the inflammatory responses of the fetal membranes for parturition.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background and Purpose
Protein palmitoylation is involved in learning and memory, and in emotional disorders. Yet, the underlying mechanisms in these processes remain unclear. Herein, we describe ...that A‐kinase anchoring protein 150 (AKAP150) is essential and sufficient for depressive‐like behaviours in mice via a palmitoylation‐dependent mechanism.
Experimental Approach
Depressive‐like behaviours in mice were induced by chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS). Palmitoylated proteins in the basolateral amygdala (BLA) were assessed by an acyl‐biotin exchange assay. Genetic and pharmacological approaches were used to investigate the role of the DHHC2‐mediated AKAP150 palmitoylation signalling pathway in depressive‐like behaviours. Electrophysiological recording, western blotting and co‐immunoprecipitation were performed to define the mechanistic pathway.
Key Results
Chronic stress successfully induced depressive‐like behaviours in mice and enhanced AKAP150 palmitoylation in the BLA, and a palmitoylation inhibitor was enough to reverse these changes. Blocking the AKAP150‐PKA interaction with the peptide Ht‐31 abolished the CRS‐induced AKAP150 palmitoylation signalling pathway. DHHC2 expression and palmitoylation levels were both increased after chronic stress. DHHC2 knockdown prevented CRS‐induced depressive‐like behaviours, as well as attenuating AKAP150 signalling and synaptic transmission in the BLA in CRS‐treated mice.
Conclusion and Implications
These results delineate that DHHC2 modulates chronic stress‐induced depressive‐like behaviours and synaptic transmission in the BLA via the AKAP150 palmitoylation signalling pathway, and this pathway may be considered as a promising novel therapeutic target for major depressive disorder.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Female-specific subpopulation of myelinated Ah-type baroreceptor neurons (BRNs) in nodose ganglia is the neuroanatomical base of sexual-dimorphic autonomic control of blood pressure regulation, and ...KCa1.1 is a key player in modulating the neuroexcitation in nodose ganglia. In this study we investigated the exact mechanisms underlying KCa1.1-mediated neuroexcitation of myelinated Ah-type BRNs in the presence or absence of estrogen. BRNs were isolated from adult ovary intact (OVI) or ovariectomized (OVX) female rats, and identified electrophysiologically and fluorescently. Action potential (AP) and potassium currents were recorded using whole-cell recording. Consistently, myelinated Ah-type BRNs displayed a characteristic discharge pattern and significantly reduced excitability after OVX with narrowed AP duration and faster repolarization largely due to an upregulated iberiotoxin (IbTX)-sensitive component; the changes in AP waveform and repetitive discharge of Ah-types from OVX female rats were reversed by G1 (a selective agonist for estrogen membrane receptor GPR30, 100 nM) and/or IbTX (100 nM). In addition, the effect of G1 on repetitive discharge could be completely blocked by G15 (a selective antagonist for estrogen membrane receptor GPR30, 3 μM). These data suggest that estrogen deficiency by removing ovaries upregulates KCa1.1 channel protein in Ah-type BRNs, and subsequently increases AP repolarization and blunts neuroexcitation through estrogen membrane receptor signaling. Intriguingly, this upregulated KCa1.1 predicted electrophysiologically was confirmed by increased mean fluorescent intensity that was abolished by estrogen treatment. These electrophysiological findings combined with immunostaining and pharmacological manipulations reveal the crucial role of KCa1.1 in modulation of neuroexcitation especially in female-specific subpopulation of myelinated Ah-type BRNs and extend our current understanding of sexual dimorphism of neurocontrol of BP regulation.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Electroactive asymmetric bis-carbazole small molecules bearing cyano functional group(s) were conveniently synthesized and fully characterized by physicochemical and electrochemical methods. These ...carbazole-based small molecules are colorless in the neutral states and possess reversible redox processes and outstanding thermal stability. The utilization of these bis-carbazole small molecules as the electrochromic materials for the fabrication of electrochromic devices (ECDs) provided high-performance ECDs of high optical contrast up to 99% switching between colorless bleaching state and dark-red colored state and excellent coloration efficiencies of 412 cm2/C. The present work illuminates the excellent qualification of functionalized carbazole-based small molecules in developing efficient ECDs.
•Cyano-modified bis-carbazole molecules show high thermal stability, colorless neutral state, and excellent redox properties.•The bis-carbazoles based electrochromic devices (ECDs) exhibit striking color change from colorless neutral states to red.•The ECDs show high optical contrast up to 94−99% and coloration efficiencies of 225−412 cm2/C.•The performances of ECDs were markedly improved by increasing of the number of cyano groups incorporated in carbazole unit.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Given the information age, an important educational objective is cultivating innovators who can propose unique ideas. Learner-centred education is a way to achieve this objective; however, what is ...the current effectiveness of learner-centred education? A meta-analysis was conducted to analyse 72 effect sizes from 42 quantitative studies to determine the effect of learner-centred education on students' academic achievement across a 10-year period (2010-2020). The overall effect size was 0.5446 (95% CI 0.3754, 0.7138), which was medium, positive, and significant (P < 0.001). Thus, learner-centred education can significantly improve students' academic achievement. There were significant differences (all P < 0.05) in the influence of learner-centred education on academic achievement among six independent variables (subject, region, education phase, learning environment, teaching strategies, and autonomous learning form). Future research should focus on the positive impact of learner-centred education and choosing teaching strategies and learning forms to the discipline to promote it.
Full text
Available for:
BFBNIB, NUK, PILJ, SAZU, UL, UM, UPUK
Non-academic achievement refers to the positive learning quality, personality, and social adaptability students develop during the learning process, which is essential for growth and social ...development. Can popular student-centered education assume the responsibility of cultivating learners with excellent learning qualities and extraordinary social competencies, as expected by educators globally? Using a meta-analysis, we reviewed and summarized 65 effect sizes from 31 quantitative research papers on the impact of student-centered education on students’ non-academic achievements, published from January 2010 to April 2021. The results showed that student-centered education had a positive impact on students’ non-academic achievements. The impact was greatest at the secondary and higher education levels and over a 3-month experimental period; however, no significant differences were found in curricula, teaching models, teaching strategies, or learning forms. Our results confirm that student-centered education should be widely adopted and accepted in the long term, at secondary and higher education levels.
PDF
