Background
APOE‐ε4 is the strongest common genetic risk factor for Alzheimer’s disease (AD) and contributes to worse cognition. However, many carriers of the APOE‐ε4 allele remain cognitively normal ...throughout life, suggesting resilience factors may exist that protect the brain. We leverage a unique statistical design to identify modifiers of APOE effects on cognition by first discovering gene modifiers leveraging RNA sequencing (RNAseq) from whole blood and then replicating any observed modifiers with brain RNAseq from an independent cohort. Transcripts that modify the association between APOE and cognitive decline may highlight pathways of risk or resilience that could be repurposed as targets for intervention.
Method
Cognition, RNAseq from whole blood, and APOE genotype were obtained from 336 individuals from the Vanderbilt Memory and Aging Project (VMAP; mean(SD) age=72.9(7.3), % male=59, % mild cognitive impairment=39). RNAseq data were quantile normalized and batch corrected. Regression and mixed‐effects regression models assessed the interaction between baseline gene expression and APOE‐ε4 or APOE‐ε2 positivity on both baseline and longitudinal decline in memory, adjusting for baseline age and sex. Results were replicated using bulk dorsolateral prefrontal cortex RNAseq data in 618 participants from the Religious Orders Study/Memory and Aging Project (ROS/MAP). Results were corrected for multiple comparisons (60,669 genes) using the false discovery rate method.
Results
Cross‐sectionally, RNASE6 interacted with APOE‐ε4 status on memory (β=‐1.16, p=4.35x10‐8) whereby low RNASE6 expression was associated with better memory performance at baseline among APOE‐ε4 carriers, but high RNASE6 expression was associated with worse memory performance among APOE‐ε4 carriers (Figure 1). These results replicated in brain RNAseq data from ROS/MAP (β=‐0.2, p=0.0009, Figure 2). There were no significant interactions longitudinally or with APOE‐ε2.
Conclusion
RNASE6 encodes a protein involved in innate immunity, including antimicrobial and antiviral activity. It has not been previously associated with AD or AD‐related cognitive decline, though it has been identified in a co‐expression network module with other inflammatory genes, such as TYROBP (DAP12), previously linked to AD. Together, these data implicate neuroinflammatory regulation in cognitive decline, and suggest that innate immune signaling may contribute to the regulation of resilience and susceptibility to AD among APOE‐ε4 carriers.
Introduction
Patterns of atrophy can distinguish normal cognition from Alzheimer's disease (AD), but neuropathological drivers of this pattern are unknown. This study examined associations between ...cerebrospinal fluid biomarkers of AD pathology, synaptic dysfunction, and neuroaxonal injury with two AD imaging signatures.
Methods
Signatures were calculated using published guidelines. Linear regressions related each biomarker to both signatures, adjusting for demographic factors. Bootstrapped analyses tested if associations were stronger with one signature versus the other.
Results
Increased phosphorylated tau (p‐tau), total tau, and neurofilament light (P‐values <.045) related to smaller signatures (indicating greater atrophy). Diagnosis and sex modified associations between p‐tau and neurogranin (P‐values<.05) and signatures, such that associations were stronger among participants with mild cognitive impairment and female participants. The strength of associations did not differ between signatures.
Discussion
Increased evidence of neurodegeneration, axonopathy, and tau phosphorylation relate to greater AD‐related atrophy. Tau phosphorylation and synaptic dysfunction may be more prominent in AD‐affected regions in females.
ABSTRACTAlcohol intoxication at the time of burn injury exacerbates postburn pathogenesis. Recent findings suggest gut barrier integrity is compromised after combined alcohol and burn insult, which ...could contribute to these complications. Tight junction proteins and mucins play critical roles in keeping the gut barrier intact. Therefore, the goal of this study was to examine the effects of alcohol and burn injury on claudin and mucin expression in the intestines. We also evaluated if the combined insult differentially influences their expression in the small and large intestines. Male C57BL/6 mice were given a single dose of 2.9 g/kg ethanol before an approximately 12.5% body area burn. One and three days after injury, we profiled expression of several tight junction proteins, mucin, and bacterial 16S rRNA genes in the small and large intestines, using qPCR. We observed >50% decrease in claudin-4 and claudin-8 genes in both ileal and colonic epithelial cells 1 day after injury. Claudin-2 was significantly upregulated, and occludin was downregulated in the small intestine 1 day after injury. Mucin-3 expression was substantially elevated (>50%) in the small intestine, whereas mucin-2 and mucin-4 were considerably diminished in the colon (>50%) 1 day after injury. Most of the parameters were normalized to sham levels on day 3, except for mucin-3 and claudin-8, which remained decreased in the large intestine. Neither alcohol nor burn alone resulted in changes in junction or mucin gene expression compared to shams. This was accompanied with increases in the family of Gram-negative bacteria, Enterobacteriaceae, in both the small and the large intestines 1 day after injury. These findings suggest that alcohol and burn injury disrupts the normal gut microbiota and alters tight junction and mucin expression in the small and large intestines.
The photovoltaic (PV) system that is based on submodule-integrated converters (subMICs) is capable of maximizing solar energy harvest by eradicating power losses due to intrapanel mismatch. Modeling ...and simulation of subMIC-based systems are important to study the effect of PV partial shading, prove new control strategies, analyze distributed system dynamics, optimize system configurations, and determine system parameters, etc. However, the simulation of such systems can be very challenging due to the large number of switching-mode power units, nonlinear nature of PV generators, and complication of the coordinating control. This paper provides an effective solution to simulate and control single-phase grid-tied PV systems that are based on a practical subMICs configuration. The approach includes the simplified PV cell model and averaged model for power converters, which consider all dynamic interactions among the maximum power point tracking (MPPT), PV submodule voltage regulation, dc-link voltage control, and double frequency ripple. The effectiveness of the proposed simulation and the subMIC system is validated by the comparison with a practical system based on centralized PV inverter under the real-world solar irradiance and various PV mismatch conditions, e.g., partial shading and uneven temperature distribution etc.
Aim Mitral valve pathology in rheumatic heart disease patients is a common cause of secondary pulmonary hypertension (PH). Our aim was to evaluate pulmonary hypertension severity as a predictor of ...in-hospital mortality and early complications following mitral valve replacement. Methods A retrospective review of rheumatic heart disease patients who underwent mitral valve replacement between January 2017 and August 2020 was performed. Systolic pulmonary artery pressure (sPAP) was used to classify patients as no PH (<35 mmHg), mild PH (35-44 mmHg), moderate PH (45-59 mmHg) or severe PH (>60 mmHg). Patients subjected to additional cardiac procedures (such as aortic valve replacement and coronary artery bypass grafting) were excluded from the study sample. Results The study group was composed of 159 patients (mean age: 40; 73 male, 86 female) categorized as no PH (n = 32; 20.1%), mild PH (n = 14; 8.8%), moderate PH (n = 65, 40.9%) and severe PH (n = 48, 30.2%) groups. Patient demographic data and preoperative comorbidities were comparable among the four groups. Use of intraoperative and postoperative blood products was similar in all the groups. Severe PH patients had similar in-hospital mortality (4.2%; p = 0.74) as in groups with lesser degrees of pulmonary hypertension. Likewise, increasing severity of pulmonary hypertension did not confer any significant increase in early postoperative complications, namely prolonged ICU stay (10.4%; p = 0.41), prolonged ventilation (2.1%; p = 0.70), reintubation (4.2%; p = 0.90), reopening for bleeding tamponade (6.3%; p = 0.39), new-onset renal failure (6.3%; p = 0.91), postoperative stroke (4.2%; p = 0.52) or prolonged length of stay (mean: 5.6 + 2.8 days; p = 0.49). Conclusions Increasing severity of pulmonary hypertension does not appear to have a significant impact on in-hospital mortality or early postoperative outcomes of patients undergoing mitral valve replacement.
Late-onset Alzheimer's disease (LOAD) is a polygenic disorder with a long prodromal phase, making early diagnosis challenging. Twin studies estimate LOAD as 60-80% heritable, and while common genetic ...variants can account for 30% of this heritability, nearly 70% remains "missing". Polygenic risk scores (PRS) leverage combined effects of many loci to predict LOAD risk, but often lack sensitivity to preclinical disease changes, limiting clinical utility. Our group has built and published on a resilience phenotype to model better-than-expected cognition give amyloid pathology burden and hypothesized it may assist in preclinical polygenic risk prediction. Thus, we built a LOAD PRS and a resilience PRS and evaluated both in predicting cognition in a dementia-free cohort (N=254). The LOAD PRS had a significant main effect on baseline memory (β=-0.18, P=1.68E-03). Both the LOAD PRS (β=-0.03, P=1.19E-03) and the resilience PRS (β=0.02, P=0.03) had significant main effects on annual memory decline. The resilience PRS interacted with CSF Aβ on baseline memory (β=-6.04E-04, P=0.02), whereby it predicted baseline memory among Aβ+ individuals (β=0.44, P=0.01) but not among Aβ- individuals (β=0.06, P=0.46). Excluding APOE from PRS resulted in mainly LOAD PRS associations attenuating, but notably the resilience PRS interaction with CSF Aβ and selective prediction among Aβ+ individuals was consistent. Although the resilience PRS is currently somewhat limited in scope from the phenotype's cross-sectional nature, our results suggest that the resilience PRS may be a promising tool in assisting in preclinical disease risk prediction among dementia-free and Aβ+ individuals, though replication and fine-tuning are needed.
Laurence Moon Bardet Biedl syndrome is characterized as a rare genetic disorder, with a wide range of presenting symptoms such as mental retardation, decreased visual acuity, obesity, hypogonadism, ...and polydactyly. The diagnosis of this syndrome is easily overlooked due to its rarity, with a prevalence rate of one in 125,000-160,000 reported within Europe. Delayed diagnosis and inappropriate management may lead to an irreversible loss of functions. The most significant of these losses include loss of vision, cardiac problems, and renal abnormalities. These dysfunctions critically impact the mental faculties and personal life of a patient. Our case presented with striking features of this syndrome, but due to a lack of awareness, her family was not adequately counseled. Both the family and the patient were not equipped with the necessary knowledge regarding the nature of her disease and its prognosis. The patient was mismanaged and kept ignorant of the importance of a proper follow-up. This necessitates a multidisciplinary team approach towards such cases so that their disease can be adequately managed. The early diagnosis and symptomatic management of complications as they arise remain the most important and vital step in the management of this illness. We hope that our case sheds further light on the existing knowledge of this syndrome.
Systemic sclerosis is an autoimmune condition that frequently affects women. It is a progressive, debilitating disease that has widespread manifestations, targeting different organs of the body with ...potentially fatal consequences due to lung and kidney involvement. Women with this disease mostly present with Raynaud's phenomenon along with symptoms of gastro-esophageal reflux disease (GERD). Just like any chronic debilitating condition, patients with systemic sclerosis often suffer from mental health issues that can further worsen their condition, significantly affecting their quality of life. Further research regarding the effects and severity of the disease should be encouraged for a better understanding of the illness, its diagnosis, and treatment. We present a rare case of a 55-year-old woman who presented with complaints of a major depressive episode. She was diagnosed with systemic sclerosis last year and has a history of generalized anxiety disorder. She was prescribed Mirtazapine, an antidepressant. On her follow-up after one month, she started complaining of obsessive ruminations that were causing her significant distress. She was prescribed an add-on therapy with a selective serotonin reuptake inhibitor (SSRI) antidepressant with the emphasis being placed on cognitive behavioral therapy (CBT). She reported an improvement in her obsessive symptoms as well as depression after two months.
Isolated unilateral agenesis/atresia of pulmonary artery (IUAPA) is a rare congenital disorder, an uncommon variant of unilateral agenesis of pulmonary artery (UAPA). Patients with IUAPA may remain ...asymptomatic and undiagnosed till late adulthood as they present with vague symptoms which may be overlooked. We report a case of IUAPA of right pulmonary artery in an elderly female who presented with complaints of productive cough and exertional dyspnea. Due to the formation of extensive collaterals, her lung parenchyma was preserved.
Introduction Greying of hair is an inevitable phenomenon that occurs commonly as a person ages. It usually occurs in the fourth decade regardless of gender but now a days, even people in their early ...twenties can experience premature greying. The objective of our study was to determine the frequency of premature greying of hair and its impact on the socio-cultural spheres of life and self-esteem of medical students. Methodology It is a descriptive cross-sectional study conducted at Foundation University Medical College (FUMC) from January to February 2017. All medical students of FUMC who gave their consent were included in the study sample. Students who were absent or unwilling to participate were excluded. Data was collected through a self-administered questionnaire, which was then analysed using SPSS version 17 (SPSS Inc., Chicago, IL). Results Out of 673 students, 210 (31.2%) suffered from premature greying of hair. The prevalence was higher among females (155/73.8%) as compared to males (55/26.2%). There was a statistical difference in perception of both the genders, regarding those with premature greying of hair trying to hide it (p-value = 0.000), premature greying of hair as contagious (p-value = .009) and the affected looking older than their actual age (p-value = 0.036). Conclusion The study showed that premature greying affected the socio-cultural spheres of students' lives. Females were more prone to developing premature greying of hair. Genetics also play a significant role in the phenomenon. No positive correlation was found by using Rosenberg Self-esteem scale.