Introduction
The La ribonucleoprotein 6 (LARP6), an RNA binding protein, increases type I collagen expression by regulating mRNA stability and translation. This is mediated via its interaction with ...the 5’ stem loop (5’SL) structure in collagen I mRNA. Disrupting this interaction by mutating the 5’SL region has been shown to reduce fibrotic remodeling in liver. Therefore, we tested the hypothesis that this interaction plays a role in cardiac fibrosis and stiffening in diet induced obesity in 5’SL mutant and wild‐type littermate mice. In fact, obesity and hypertension promote remodeling and cardiac stiffening due to excess collagen deposition, fibrosis, and microvascular dysfunction, that ultimately lead to diastolic dysfunction.
Methods
Male and female 5’SL mice and wild‐type (WT) littermates were fed a high fat high sucrose (HFHS) or control diet starting at 6 weeks of age. After 28 weeks of feeding, mice were assessed for cardiac function by echocardiography. Hearts were collected and a transverse section of the left and right ventricle was fixed for histology. RNA was isolated from the left ventricle and submitted for mRNA sequencing and qPCR.
Results
Following 28 weeks of a HFHS diet, male and female mice showed increased body weight, cardiac hypertrophy (heart weight normalized to tibia length), and diastolic dysfunction. However, the 5’SL mutation attenuated the impaired diastolic function in male, but not female mice. Surprisingly, cardiac fibrosis was not altered by the HFHS diet. RNA sequencing revealed that HFHS diet altered gene expression associated with glucose and ketone metabolism, as well as inflammation, in male WT littermates. However, the 5’SL mutation enriched gene networks associated with vascular development and angiogenesis.
Conclusions
Chronic HFHS feeding leads to increased body weight, hypertrophic cardiomyopathy, and diastolic dysfunction in both male and female mice. However, the 5’SL mutation blunts dysfunction only in male mice, demonstrating sex‐dependent cardioprotective effects.
N‐methyl‐D‐aspartate receptors are glutamate‐gated, calcium‐permeable ion channels involved in a host of normal brain functions, including neuronal development. Traditionally, the GluN2A subunit, ...encoded by the GRIN2A gene, is thought to signal brain and circuit maturation, given its unique expression pattern where transcripts are low embryonically and then significantly increase during preadolescence in mice. Advances in whole exome sequencing have identified mutations in the GRIN2A gene to be causal to several neuropathological diseases, including epilepsy and intellectual delay. More specifically, 56% of GRIN2A mutations are loss‐of‐function, displaying diminished receptor function and/or surface expression, with Grin2a‐/‐ mice have been reported as having signatures of epileptiform activity. However, little is understood regarding GluN2A’s impact on neurodevelopmental and how its absence may the GABAergic interneuron network. Our data show that Grin2a ‐/‐ mice contain 33% more parvalbumin+ interneurons in the CA1 region of the hippocampus during preadolescence and adulthood. This increase in GABAergic interneuron cell density appears to be unique to parvalbumin+ cells, as cholecystokinin+ and somatostatin+ interneurons are unchanged across Grin2a‐/‐ and wildtype mice. Despite an increased cell count, colocalization staining for parvalbumin+ synaptic densities and measures of parvalbumin cell‐specific tonic inhibition remains unchanged in preadolescence and increases as the animal ages, suggesting delayed maturation. In addition, parvalbumin+ cells from preadolescent Grin2a‐/‐ mice exhibit immature intrinsic and firing properties, such as an increased membrane time constant and input resistance, lower threshold for depolarization‐induced block, and longer action potential half‐widths than age‐matched WT controls, all of which become corrected in adulthood. The sum of these data suggest that the GluN2A subunit is involved in promoting cues for interneuron apoptosis during development, as well as influencing the rate of parvalbumin+ cell functional maturation. The ramifications of these abnormalities are still underexplored, but likely generate a vulnerability time window during preadolescence in which an epileptiform network can manifest. Viral strategies aimed at reintroduction of the GRIN2A gene during this critical time window could represent a viable gene therapy option for loss‐of‐function GRIN2A EE patients.
Seizure induction techniques are used in the epilepsy monitoring unit (EMU) to increase diagnostic yield and reduce length of stay. There are insufficient data on the efficacy of alcohol as an ...induction technique.
We performed a retrospective cohort study using six years of EMU data at our institution. We compared cases who received alcohol for seizure induction to matched controls who did not. The groups were matched on the following variables: age, reason for admission, length of stay, number of antiseizure medications (ASM) at admission, whether ASMs were tapered during admission, and presence of interictal epileptiform discharges. We used both propensity score and exact matching strategies. We compared the likelihood of epileptic seizures and nonepileptic events in cases versus controls using Kaplan-Meier time-to-event analysis, as well as odds ratios for these outcomes occurring at any time during the admission.
We analyzed 256 cases who received alcohol (median dose 2.5 standard drinks) and 256 propensity score-matched controls. Cases who received alcohol were no more likely than controls to have an epileptic seizure (X
(1) = 0.01, p = 0.93) or nonepileptic event (X
(1) = 2.1, p = 0.14) in the first 48 h after alcohol administration. For the admission overall, cases were no more likely to have an epileptic seizure (OR 0.89, 95 % CI 0.61-1.28, p = 0.58), nonepileptic event (OR 0.97, CI 0.62-1.53, p = 1.00), nor require rescue benzodiazepine (OR 0.63, CI 0.35-1.12, p = 0.15). Stratified analyses revealed no increased risk of epileptic seizure in any subgroups. Sensitivity analysis using exact matching showed that results were robust to matching strategy.
Alcohol was not an effective induction technique in the EMU. This finding has implications for counseling patients with epilepsy about the risks of drinking alcohol in moderation in their daily lives.
We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. ...Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10
) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10
). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.
Deep Learning in Natural Language Processing Neterer, Jacob Russell; Guzide, Osman
Proceedings of the West Virginia Academy of Science,
04/2018, Letnik:
90, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The recent leap in the development of deep learning has opened the door to more advanced assistance in natural language processing. In this paper, a rough outline of how the process of deep learning ...functions, how it relates to natural language processing, and examples of deep learning will all be discussed.
Abstract
Aims
Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of ...the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder.
Methods and results
We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors.
Conclusion
We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-β signalling molecules and spectrin β. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.
Structured Graphical Abstract
Structured Graphical Abstract
This study meta-analysed 4884 mitral valve prolapse (MVP) cases versus 434 649 controls, and discovered 16 genetic loci associated to MVP. Downstream analyses implicated candidate genes involved in TGF-beta signalling, cardiomyopathy and the cytoskeleton. The results from the meta-analysis were used to calculate a polygenic risk score (PRS) to aid prediction of MVP. Adding the PRS to a model with age, sex and clinical risk factors improved MVP risk prediction. Abbreviations, MVP, mitral valve prolapse, p, p-value, PRS, polygenic risk score, RF, risk factors.
Currently, the physiological factors responsible for exercise intolerance and bioenergetic alterations with age are poorly understood due, at least in art, to the confounding effect of reduced ...physical activity in the elderly. Thus, in 40 healthy young (22 ± 2 yr) and old (74 ± 8 yr) activity-matched subjects, we assessed the impact of age on: 1) the relative contribution of the three major pathways of ATP synthesis (oxidative ATP synthesis, glycolysis, and the creatine kinase reaction) and 2) the ATP cost of contraction during high-intensity exercise. Specifically, during supramaximal plantar flexion (120% of maximal aerobic power), to stress the functional limits of the skeletal muscle energy systems, we used (31)P-labeled magnetic resonance spectroscopy to assess metabolism. Although glycolytic activation was delayed in the old, ATP synthesis from the main energy pathways was not significantly different between groups. Similarly, the inferred peak rate of mitochondrial ATP synthesis was not significantly different between the young (25 ± 8 mM/min) and old (24 ± 6 mM/min). In contrast, the ATP cost of contraction was significantly elevated in the old compared with the young (5.1 ± 2.0 and 3.7 ± 1.7 mM·min(-1)·W(-1), respectively; P < 0.05). Overall, these findings suggest that, when young and old subjects are activity matched, there is no evidence of age-related mitochondrial and glycolytic dysfunction. However, this study does confirm an abnormal elevation in exercise-induced skeletal muscle metabolic demand in the old that may contribute to the decline in exercise capacity with advancing age.
Apolipoprotein E4 (
), the main susceptibility gene for Alzheimer's disease (AD), leads to vascular dysfunction, amyloid-β pathology, neurodegeneration and dementia. How these different pathologies ...contribute to advanced-stage AD remains unclear. Using aged APOE knock-in mice crossed with
mice, we show that, compared to APOE3, APOE4 accelerates blood-brain barrier (BBB) breakdown, loss of cerebral blood flow, neuronal loss and behavioral deficits independently of amyloid-β. BBB breakdown was associated with activation of the cyclophilin A-matrix metalloproteinase-9 BBB-degrading pathway in pericytes. Suppression of this pathway improved BBB integrity and prevented further neuronal loss and behavioral deficits in APOE4;5FAD mice while having no effect on amyloid-β pathology. Thus, APOE4 accelerates advanced-stage BBB breakdown and neurodegeneration in Alzheimer's mice via the cyclophilin A pathway in pericytes independently of amyloid-β, which has implication for the pathogenesis and treatment of vascular and neurodegenerative disorder in AD.
Abstract only
e15565
Background: KRAS mutations are common oncogenic events across cancers, but effective RAS-directed therapies are lacking. However, recent studies support use of PD-1 blockade in ...most subsets of lung cancer with KRAS short variant mutations (KRAS
SV
) (PMID: 28039262), and preclinical data supports combined MEK and SHP2 inhibition in KRAS amplified ( KRAS
a
) GEA (PMID: 30093730). We sought to explore the landscape of KRAS altered GEA and compare genomic profiles of KRAS-altered and KRAS wild-type (WT) cases for biomarkers of response to targeted therapies and immune checkpoint inhibitors. Methods: 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture-based comprehensive genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 or 114 loci. Descriptive statistics were used to compare among subgroups. Results: KRAS
SV
and KRAS
a
were identified in 11% and 5.8% of gastric adenocarcinoma (GA), respectively, and in 7.2% and 17% of esophageal adenocarcinoma (EA), respectively. KRAS
a
and KRAS
SV
were nearly mutually exclusive, co-occurring in only 4.4% of KRAS altered cases. ERBB2 alterations were less common in KRAS
SV
and KRAS
a
GEA (both 9%) as compared with KRAS WT GEA (19%) (p = 1.9E-16). EGFR
a
was less common in KRAS
SV
vs KRAS
a
GEA (1.9% vs 9.3%, p = 2.6E-8), whereas PIK3CA
SV
was more common in KRAS
SV
vs KRAS
a
(16% vs 5.0%, p = 1.5E-11). Median TMB for all groups was similar; however, KRAS
SV
GEA had a higher mean TMB (9.7 mut/Mb) as compared to KRAS
a
(5.1 mut/Mb, p = 5.0E-12) and KRAS WT cases (5.8 mut/Mb, p = 2.2E-07). KRAS codon 12/13 accounted for > 80% of predicted pathogenic mutations. MSI-high was also more prevalent in KRAS
SV
(11.3%) vs KRAS
a
(0.9%, p = 4.8E-15) and KRAS WT GEA (2.4%, p = 1.8E-25). MSI-high KRAS
SV
GEA was associated with older patient age (median 72 years) and with high TMB (median 40.9 mut/mb). Conclusions: GA was enriched for KRAS mutation whereas EA was enriched for KRAS amplification. KRAS WT vs KRAS
SV
vs KRAS
a
each presented distinct genomic profiles. KRAS
a
in the absence of KRAS mutation exists in 11% of GEA and warrants further exploration to inform combination treatment strategies.
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