Abstract
Huntington’s disease is caused by a CAG repeat expansion in the Huntingtin gene (HTT), coding for polyglutamine in the Huntingtin protein, with longer CAG repeats causing earlier age of ...onset. The variable ‘Age’ × (‘CAG’—L), where ‘Age’ is the current age of the individual, ‘CAG’ is the repeat length and L is a constant (reflecting an approximation of the threshold), termed the ‘CAG Age Product’ (CAP) enables the consideration of many individuals with different CAG repeat expansions at the same time for analysis of any variable and graphing using the CAG Age Product score as the X axis. Structural MRI studies have showed that progressive striatal atrophy begins many years prior to the onset of diagnosable motor Huntington’s disease, confirmed by longitudinal multicentre studies on three continents, including PREDICT-HD, TRACK-HD and IMAGE-HD. However, previous studies have not clarified the relationship between striatal atrophy, atrophy of other basal ganglia structures, and atrophy of other brain regions. The present study has analysed all three longitudinal datasets together using a single image segmentation algorithm and combining data from a large number of subjects across a range of CAG Age Product score. In addition, we have used a strategy of normalizing regional atrophy to atrophy of the whole brain, in order to determine which regions may undergo preferential degeneration. This made possible the detailed characterization of regional brain atrophy in relation to CAG Age Product score. There is dramatic selective atrophy of regions involved in the basal ganglia circuit—caudate, putamen, nucleus accumbens, globus pallidus and substantia nigra. Most other regions of the brain appear to have slower but steady degeneration. These results support (but certainly do not prove) the hypothesis of circuit-based spread of pathology in Huntington’s disease, possibly due to spread of mutant Htt protein, though other connection-based mechanisms are possible. Therapeutic targets related to prion-like spread of pathology or other mechanisms may be suggested. In addition, they have implications for current neurosurgical therapeutic approaches, since delivery of therapeutic agents solely to the caudate and putamen may miss other structures affected early, such as nucleus accumbens and output nuclei of the striatum, the substantia nigra and the globus pallidus.
Liu et al. analysed three large longitudinal Huntington’s disease imaging datasets using a single algorithm. They find dramatic selective atrophy of regions involved in the basal ganglia circuit. These results support the hypothesis of circuit-based spread of pathology in Huntington’s disease and have implications for current neurosurgical therapeutic approaches.
Graphical Abstract
Graphical Abstract
Abstract Colorectal cancer is a leading cause of morbidity and mortality worldwide. Understanding its genetic mechanisms is key to improving risk prediction, prognostication and treatment. Results ...from genome-wide association studies have engendered a growing list of colorectal cancer susceptibility genes whereas the application of genome-wide mutational analysis has enabled the depiction of mutational landscape of colorectal cancer at high resolution. The development of novel technologies, such as metagenomic and single-cell sequencing, is expected to have positive impact on future genetic studies. However, challenges remain to address the changing epidemiology of colorectal cancer, issues on genetic testing, and clinical utilization of genomic data.
Abstract
Background
Exercise is beneficial for pathological myocardial dysfunction and heart failure. We previously reported that miR-17-3p contributed to exercise-induced cardiac growth and ...protected against cardiac ischemia/reperfusion injury. However, if exercise-induced miR-17-3p can prevent pathological myocardial dysfunction is undetermined.
Purpose
To investigate if exercise-induced miR-17-3p can prevent pathological myocardial dysfunction.
Methods
The miR-17-3p expression was examined in phenylephrine (PE, 50μmol/L, 48 h) and angiotensin II (Ang II, 1μmol/L, 48 h) treated primary neonatal rat ventricular cardiomyocytes (NRCM), and the myocardium of thoracic aortic constriction (TAC, 4weeks) or angiotensin II (1.3 mg/kg/day, 4weeks) induced cardiac hypertrophy murine model. miR-17-3p transgenic mice were generated and subjected to TAC or Ang II to investigate the effect of miR-17-3p overexpression in attenuating pathological cardiac dysfunction by echocardiography. Cell area and hypertrophic genes were determined by Wheat Germ Agglutinin (WGA) staining and qRT-PCRs. In addition, cell area and hypertrophic genes (ANP, BNP, β-MHC) were determined by immunolabeling and qRT-PCR in NRCM after the transfection of miR-17-3p mimic or inhibitor. Furthermore, functional rescue assays were performed to identify phosphatase and tensin homolog (PTEN) as a target gene of miR-17-3p, and myocyte enhancer factor 2C (MEF2C) as an upstream regulator of miR-17-3p in pathological cardiac hypertrophy.
Results
The expression of miR-17-3p was significantly decreased in the heart from TAC or Ang II mouse model, and in PE or Ang II-induced cardiomyocyte hypertrophy model. miR-17-3p overexpression mice displayed improved cardiac function and reduced cardiac hypertrophy after TAC or Ang II treatment in vivo. miR-17-3p mimic significantly attenuated PE or Ang II-induced cardiomyocyte hypertrophy in vitro. Based on functional rescue experiments, PTEN was identified as a direct target of miR-17-3p that mediated its protective effects in cardiac hypertrophy. Moreover, MEF2C was identified as a negative upstream regulator of miR-17-3p involved in the control of cardiac hypertrophy.
Proposed mechanism of miR-17-3p
Conclusion
Exercise-induced miR-17-3p can prevent pathological myocardial dysfunction by targeting PTEN. MEF2C was an upstream regulator of miR-17-3p. Targeting MEF2C/miR-17-3p/ PTEN represents a novel therapeutic strategy for pathological myocardial dysfunction.
Acknowledgement/Funding
The grants from National Natural Science Foundation of China (81722008, 91639101 and 81570362 to JJ Xiao)
It has been found that the -2518 C-C motif ligand (CCL)-2 promoter variant increases the risk of developing active tuberculosis (TB).
To study the association between -2518 variants and ...susceptibility to TB.
We searched Medline, PubMed and the Wan Fang databases for human genetic studies on whether the -2518 CCL2 polymorphism influences the expression of active TB. Articles published from January 1998 to November 2010 were included. A random effects model was conducted in the meta-analysis.
The CCL2-2518G allele (OR 1.51, 95%CI 1.11-2.04, P = 0.008) showed significant association with susceptibility to TB. In genotype analysis, the recessive model (CCL2 genotype GG, OR 1.66, 95%CI 1.19-2.33, P = 0.003) was slightly superior to the dominant model (G carrier genotypes OR 1.53, 95%CI 1.07-2.17, P = 0.018). These observations were prominent among Asians and Latin-Americans of Hispanic ancestry, but not in Africans from Ghana and South Africa. The presence of epistatic genes in one population but not in the other, environmental differences and pathogen virulence may account for this.
The CCL2-2518G allele increases the risk of developing TB in Asians and Hispanics.
On 26 February 2008, the THEMIS satellites observed two substorms that occurred at about 0405 and 0455 UT. Angelopoulos et al. (2008) made a comprehensive study of the second event. In this paper we ...display detailed features of the two substorms with emphasis on the first. In both substorms, a distinct auroral intensification occurred during the earliest stage of onset, about 1 to 2 min after midtail reconnection began. This initial intensification was weak and localized and thus had the signatures of a pseudobreakup. In both substorms, a second, major intensification occurred next in the substorm onset sequence, followed by rapid and extensive poleward expansion. This second intensification had the features of the major expansion onset and was nearly coincident with observations of earthward flows and magnetic dipolarization in the near‐Earth tail. During the growth phase of the two substorms, open magnetic flux accumulated in the polar cap; in the expansion/recovery phase the polar cap open flux was quickly reduced. These observations are in agreement with the assertion that tail reconnection initiates the initial pseudobreakup and the ensuing major expansion and releases and transports energy to eventually cause near‐Earth dipolarization and the expansion phase onset of these two substorms.
Objective To explore whether the prevalence of myocardial infarction (MI) was higher in psoriatics than in patients without psoriasis, and whether major cardiovascular risk factors were associated ...with psoriasis in central China.
Methods Data were collected at Medical Records Section of Affiliated Union Hospital, Tongji Hospital, Wuhan Iron and Steel Company General Hospital and No. 1 Hospital of Wuhan between 1999 and 2007. Patients with psoriasis were classified as severe if they ever received a systemic therapy. And patients were classified as having risk factors if they received codes for diabetes, hypertension, hyperlipidemia, or smoking. Controls without psoriasis were randomly selected from the Physical Examination Centre in the Affiliated Union Hospital. Analysis was performed by using conditional logistic regression, and adjustments were made for age and sex.
Results There were 45 MIs (2.96%) within the control population and 97 (6.00%) and 118 (8.01%) MIs within the mild and severe psoriasis groups, respectively. Respective odds ratio (OR) and 95% confidence interval (95% CI) of cardiovascular risk factors in those with mild psoriasis than controls were as follows: obesity (OR, 1.41; 95% CI, 1.08–1.85), diabetes (OR, 1.45; 95% CI, 1.11–1.91), hypertension (OR, 1.39; 95% CI, 1.04–1.85), hyperlipidemia (OR, 1.37; 95% CI, 1.06–1.78) and smoking (OR, 1.35; 95% CI, 1.01–1.80). Patients with severe psoriasis had higher adjusted odds of obesity (OR, 1.51; 95% CI, 1.15–1.98), diabetes (OR, 1.69; 95% CI, 1.32–2.17), hypertension (OR, 1.41; 95% CI, 1.06–1.88), hyperlipidemia (OR, 1.43; 95% CI, 1.11–1.84), and smoking (OR, 1.57; 95% CI, 1.20–2.05) than patients with mild psoriasis and controls. After adjusting for systemic therapies and cardiovascular risk factors (obesity, diabetes, hypertension, hyperlipidemia and smoking) in addition to age and sex, for patients with mild or severe psoriasis, the OR of having an MI was 1.72 (95% CI, 1.29–2.30) and 2.01 (95% CI, 1.45–2.79), respectively.
Conclusions The prevalence of MI is higher in mild andsevere psoriasis than in patients without psoriasis in central China. In addition, MI and major cardiovascular risk factors (e.g. diabetes, hypertension, hyperlipidemia and smoking) are associated with psoriasis in central China.
Highlights ► The neural expression patterns of Thap1 transcript and THAP1 protein were examined in rats. ► Thap1 transcript and THAP1 protein are expressed in the brain, spinal cord and dorsal root ...ganglia. ► THAP1 expression was highest in early development, particularly in the cerebellum at Postnatal Day 7. ► THAP1 immunoreactivity was detected in both the nuclear and cytoplasmic compartments of neurons.
It is found that the photoelectric technology is suitable for the accurate measurement of the frost height. The objectives of this paper are to experimentally investigate the correspondence between ...the output signal of the photoelectric sensor and the frost height, and then develop a generalized correlation to predict the frost height directly and accurately. The experiments are conducted in a wide range of operating conditions for air temperature 17.7 °C–27.2 °C, relative humidity 21.6% RH to 64.9% RH, air velocity 0.5 m/s to 4.5 m/s and cold surface temperature −10.5 °C to −6.5 °C. Based on 21 groups of experiments with total 600 data, a linear correlation with a relative deviation of ±10% is setup. Further validation of this correlation is conducted by comparing the predicted results with 4 additional experiments, and approximately 95% of the predicted frost heights are consistent with the measured data within a relative deviation of ±10%. These results indicate that the photoelectric technology can predict the frost height directly. The application of the proposed correlation to provide defrost control strategy is also discussed in this paper.
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