Heart failure is associated with altered gene expression and DNA methylation. De novo DNA methylation is associated with gene silencing, but its role in cardiac pathology remains incompletely ...understood. We hypothesized that inhibition of DNA methyltransferases (DNMT) might prevent the deregulation of gene expression and the deterioration of cardiac function under pressure overload (PO). To test this hypothesis, we evaluated a DNMT inhibitor in PO in rats and analysed DNA methylation in cardiomyocytes.
Young male Wistar rats were subjected to PO by transverse aortic constriction (TAC) or to sham surgery. Rats from both groups received solvent or 12.5 mg/kg body weight of the non-nucleosidic DNMT inhibitor RG108, initiated on the day of the intervention. After 4 weeks, we analysed cardiac function by MRI, fibrosis with Sirius Red staining, gene expression by RNA sequencing and qPCR, and DNA methylation by reduced representation bisulphite sequencing (RRBS). RG108 attenuated the ~70% increase in heart weight/body weight ratio of TAC over sham to 47% over sham, partially rescued reduced contractility, diminished the fibrotic response and the downregulation of a set of genes including Atp2a2 (SERCA2a) and Adrb1 (beta1-adrenoceptor). RG108 was associated with significantly lower global DNA methylation in cardiomyocytes by ~2%. The differentially methylated pathways were “cardiac hypertrophy”, “cell death” and “xenobiotic metabolism signalling”. Among these, “cardiac hypertrophy” was associated with significant methylation differences in the group comparison sham vs. TAC, but not significant between sham+RG108 and TAC+RG108 treatment, suggesting that RG108 partially prevented differential methylation. However, when comparing TAC and TAC+RG108, the pathway cardiac hypertrophy was not significantly differentially methylated.
DNMT inhibitor treatment is associated with attenuation of cardiac hypertrophy and moderate changes in cardiomyocyte DNA methylation. The potential mechanistic link between these two effects and the role of non-myocytes need further clarification.
•Cardiac hypertrophy in rats is associated with altered cardiomyocyte DNA methylation.•DNA methylation changes in cardiomyocytes in hypertrophy map to relevant pathways.•DNA methyltransferase inhibition in all cell types in hypertrophy partially rescues heart function.
Objective:
Multiple studies have compared various optical coherence tomography angiography (OCTA) parameters in participants with systemic hypertension vs. controls and have presented discordant ...findings. We conducted a meta-analysis to pool together data from different studies to generate an overall effect size and find out whether OCTA parameter(s) significantly differed in participants with systemic hypertension as compared to controls.
Methods:
We conducted a literature search through a search of electronic databases to identify studies before 19 June 2021, which compared OCTA parameters in non-diabetic participants with systemic hypertension vs. controls. If the OCTA parameter had a minimum number of 3 studies that analyzed it, the mean difference between participants with systemic hypertension and controls were analyzed using a random-effects model.
Results:
We identified 11 eligible studies. At the macula, 9 studies analyzed vessel density at the superficial capillary plexus (SVD), 7 analyzed vessel density at the deep capillary plexus (DVD), and 6 analyzed the area of the superficial foveal avascular zone (FAZ). Participants with systemic hypertension had significantly lower SVD (standardized mean difference SMD, −0.50 −0.70, −0.30, P < 0.00001,
I
2
= 63%), lower DVD (SMD, −0.38 −0.64, −0.13,
P
= 0.004,
I
2
= 67%) and larger superficial FAZ (SMD, 0.32 0.04, 0.61,
P
= 0.020,
I
2
= 77%).
Conclusion:
The eyes of people with systemic hypertension have robustly lower superficial and deep vascular densities at the macula when compared to control eyes. Our results suggest that OCTA can provide information about pre-clinical microvascular changes from systemic hypertension.
Loss of insulin-secreting pancreatic β cells through apoptosis contributes to the progression of type 2 diabetes, but underlying mechanisms remain elusive. Here, we identify a pathway in which the ...cell death inhibitor ARC paradoxically becomes a killer during diabetes. While cytoplasmic ARC maintains β cell viability and pancreatic architecture, a pool of ARC relocates to the nucleus to induce β cell apoptosis in humans with diabetes and several pathophysiologically distinct mouse models. β cell death results through the coordinate downregulation of serpins (serine protease inhibitors) not previously known to be synthesized and secreted by β cells. Loss of the serpin α1-antitrypsin from the extracellular space unleashes elastase, triggering the disruption of β cell anchorage and subsequent cell death. Administration of α1-antitrypsin to mice with diabetes prevents β cell death and metabolic abnormalities. These data uncover a pathway for β cell loss in type 2 diabetes and identify an FDA-approved drug that may impede progression of this syndrome.
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•Pancreatic β-cells synthesize and secrete the protease inhibitor AAT•The cell death inhibitor ARC translocates to the nucleus of β cells in diabetes•Nuclear ARC downregulates AAT expression and secretion•Loss of AAT disinhibits elastase causing β cell detachment from matrix and cell death
While cytoplasmic ARC maintains survival of insulin-producing pancreatic β cells, McKimpson et al. show that a pool of ARC relocates to the nucleus during diabetes where it paradoxically triggers cell death. The mechanism involves downregulation of AAT expression and secretion unleashing elastase-dependent loss of β cell adhesion and cell death.
Tricho-hepato-enteric syndrome (THE-S) is characterized by severe infantile diarrhea, failure to thrive, dysmorphism, woolly hair, and immune or hepatic dysfunction. We report two cases of East Asian ...descent with THE-S who had remained undiagnosed despite extensive investigations but were diagnosed on whole exome sequencing (WES). Both cases presented with chronic diarrhea, failure to thrive, and recurrent infections. Case 1 had posteriorly rotated low set ears, mild retrognathia, and fine curly hypopigmented hair. She was managed with prolonged total parenteral nutrition and intravenous immunoglobulin infusions. Case 2 had sparse coarse brown hair as well as multiple lentigines and café-au-lait macules. She was managed with amino acid-based formula. For both cases, routine investigations were inconclusive. WES in both cases showed biallelic truncating mutations in
TTC37
(c.3507T>G;p.Y1169X and c.3601C>T;p.R1201X in case 1 and c.3507T>G;p.Y1169X and c.154G>T;p.E52X in case 2), suggesting a diagnosis of THE-S.
Conclusion
: We present novel mutations in the
TTC37
gene in two individuals of East Asian descent with the rare THE-S, detected by WES. Future identification of patients with THE-S and establishing genotype-phenotype correlations will aid in counseling the patients and their families.
What is Known:
•
Tricho-Hepato-Enteric syndrome
(
THE-S
)
is characterized by severe infantile diarrhea
,
failure to thrive
,
dysmorphism
,
woolly hair
,
and immune or hepatic dysfunction
.
•
Complex patients with diagnostic dilemmas undergo extensive investigations
.
What is New:
•
This is a report of novel mutations in TTC37 in individuals of East Asian descent
.
•
Whole exome sequencing (WES) can be useful in certain complex cases with diagnostic dilemmas
.
Antipsychotics are the mainstay in schizophrenia management, and long-acting injectable (LAI) antipsychotics contribute to the successful maintenance of treatment by improving non-adherence and ...preventing relapses. Paliperidone palmitate 3-monthly (PP3M) formulation is the only available LAI antipsychotic that offers an extended 3-month window of stable plasma drug concentration, enabling only four injections per year. This paper summarizes clinically relevant endpoints from available evidence for PP3M to bridge translational research gaps and provide measurable outcomes that can be interpreted in clinical practice. Low number-needed-to-treat (NNT) for relapse prevention (NNT 95% CI 6-month estimate: 4.8 3.2; 10.0; 12-month estimate: 3.4 2.2; 7.0), and high number-needed-to-harm (NNH 95% CI akathisia, 27.1 12.3; -667.1; tremor, 80.0 22.5; 67.3; dyskinesia, -132.6 44.5; -23.2; parkinsonism, 160.0 28.9; -49.8) quantify the relative benefits and low propensity for adverse events with PP3M. Symptom remission and reductions in positive and negative symptoms indicate treatment stability. Additionally, meaningful functional remission, reduced dosing frequency, and freedom from daily negotiations favorably impact patient preference and attenuate burdensome aspects of caregiving, representing important healthcare determinants that enhance prospects of treatment continuity in schizophrenia. This information can potentially improve clinicians' judgment of treatment choices, clinical response, and patient selection in routine care. Taken together, PP3M is a valuable antipsychotic treatment option, meriting consideration for a broader role in the long-term management of schizophrenia; its utility should not be limited to patients with poor adherence or when oral antipsychotics have failed.
Wireless sensor networks (WSNs) could potentially help in the measurement and monitoring of noise levels, an important step in mitigating and fighting noise pollution. Unfortunately, the high energy ...required by the noise measurement process and the reliance of sensor motes on batteries make the management of noise-sensing WSNs cumbersome. Giving motes energy harvesting (EH) capabilities could alleviate such a problem, and several EH-WSNs have already been demonstrated. Nevertheless, the high-frequency nature of the data required to measure noise places significant additional challenges to the design of EH-WSNs. In this paper, we present a design and prototype for a mote extension which enables the mote to detect noise levels while being powered by energy harvesting. The noise level detection carried out by the system relies primarily on the concept of peak detection. Results of performance testing are presented. Aside from the hardware design and prototype, we also discuss methods of assigning charge times for application scenarios where there are multiple pulse loads. We also propose a new opportunistic method for charge time determination. Experiments demonstrate that the new method could improve analytically-derived duty cycles by at least 350%.
Bats are an important animal model with long lifespans, low incidences of tumorigenesis and an ability to asymptomatically harbour pathogens. Currently, in vivo studies of bats are hampered due to ...their low reproduction rates. To overcome this, we transplanted bat cells from bone marrow (BM) and spleen into an immunodeficient mouse strain NOD-scid IL-2R
(NSG), and have successfully established stable, long-term reconstitution of bat immune cells in mice (bat-mice). Immune functionality of our bat-mouse model was demonstrated through generation of antigen-specific antibody response by bat cells following immunization. Post-engraftment of total bat BM cells and splenocytes, bat immune cells survived, expanded and repopulated the mouse without any observable clinical abnormalities. Utilizing bat's remarkable immunological functions, this novel model has a potential to be transformed into a powerful platform for basic and translational research.
The mammalian heart contains heterogeneous cell types contributing to pathological changes in cardiac disease. In this Comment, we explore how single-cell transcriptomic approaches are unveiling ...intricate cellular mechanisms and gene co-expression networks that regulate the workings, and failings, of the heart.
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