Ad-Syn-Net: Systematic Identification of alzheimer\u27s Disease-Associated Mutation and Co-Mutation Vulnerabilities Via Deep Learning

Alzheimer\u27s disease (AD) is one of the most challenging neurodegenerative diseases because of its complicated and progressive mechanisms, and multiple risk factors. Increasing research evidence demonstrates that genetics may be a key factor responsible for the occurrence of the disease. Although previous reports identified quite a few AD-associated genes, they were mostly limited owing to patient sample size and selection bias. There is a lack of comprehensive research aimed to identify AD-associated risk mutations systematically. to address this challenge, we hereby construct a large-scale AD mutation and co-mutation framework (\u27AD-Syn-Net\u27), and propose deep learning models named Deep-SMCI and Deep-CMCI configured with fully connected layers that are capable of predicting cognitive impairment of subjects effectively based on genetic mutation and co-mutation profiles. Next, we apply the customized frameworks to data sets to evaluate the importance scores of the mutations and identified mutation effectors and co-mutation combination vulnerabilities contributing to cognitive impairment. Furthermore, we evaluate the influence of mutation pairs on the network architecture to dissect the genetic organization of AD and identify novel co-mutations that could be responsible for dementia, laying a solid foundation for proposing future targeted therapy for AD precision medicine. Our deep learning model codes are available open access here: https://github.com/Pan-Bio/AD-mutation-effectors

Clinical utility of chromogranin A and octreotide in large cell neuro endocrine carcinoma of the uterine corpus

Primary neuroendocrine tumors of the female genital tract have been described in the cervix, ovaries and uterus. Large cell neuroendocrine carcinoma (LCNC) of the uterine corpus is the least common and appears to behave the most aggressively. We report a rare case of a large cell neuroendocrine tumor of the endometrium. These tumors are not well characterized, unlike neuroendocrine tumors of the uterine cervix. Consequently, the optimal management remains still unclear. The treatment of our case consisted of surgery, radiotherapy, chemotherapy, and octreotide. Despite the aggressive treatment, the patient died of disease progression 12 months after the initial diagnosis. We discuss the diagnosis, prognosis, and treatment options for LCNC of the genital tract, and potential future therapeutics

Identification of QTL genes for BMD variation using both linkage and gene-based association approaches

Low bone mineral density (BMD) is a risk factor for osteoporotic fracture with a high heritability. Previous large scale linkage study in Northern Chinese has identified four significant quantitative trait loci (QTL) for BMD variation on chromosome 2q24, 5q21, 7p21 and 13q21. We performed a replication study of these four QTL in 1,459 Southern Chinese from 306 pedigrees. Successful replication was observed on chromosome 5q21 for femoral neck BMD with a LOD score of 1.38 (nominal p value = 0.006). We have previously identified this locus in a genome scan meta-analysis of BMD variation in a white population. Subsequent QTL-wide gene-based association analysis in 800 subjects with extreme BMD identified CAST and ERAP1 as novel BMD candidate genes (empirical p value of 0.032 and 0.014, respectively). The associations were independently replicated in a Northern European population (empirical p value of 0.01 and 0.004 for CAST and ERAP1, respectively). These findings provide further evidence that 5q21 is a BMD QTL, and CAST and ERAP1 may be associated with femoral neck BMD variation

The Rossiter-McLaughlin effect in Exoplanet Research

The Rossiter-McLaughlin effect occurs during a planet's transit. It provides the main means of measuring the sky-projected spin-orbit angle between a planet's orbital plane, and its host star's equatorial plane. Observing the Rossiter-McLaughlin effect is now a near routine procedure. It is an important element in the orbital characterisation of transiting exoplanets. Measurements of the spin-orbit angle have revealed a surprising diversity, far from the placid, Kantian and Laplacian ideals, whereby planets form, and remain, on orbital planes coincident with their star's equator. This chapter will review a short history of the Rossiter-McLaughlin effect, how it is modelled, and will summarise the current state of the field before describing other uses for a spectroscopic transit, and alternative methods of measuring the spin-orbit angle.Comment: Review to appear as a chapter in the "Handbook of Exoplanets", ed. H. Deeg & J.A. Belmont

Sequential multiplex PCR assay for determining capsular serotypes of colonizing S. pneumoniae

Asymptomatic nasopharyngeal carriage represents an important biological marker for monitoring pneumococcal serotype distribution and evaluating vaccine effects. Serotype determination by conventional method (Quellung reaction) is technically and financially challenging. On the contrary, PCR-based serotyping represents a simple, economic and promising alternative method.Evaluation StudiesJournal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting

Validation of a high-confidence regulatory network for gene-to-NUE phenotype in field-grown rice

Nitrogen (N) and Water (W) - two resources critical for crop productivity – are becoming increasingly limited in soils globally. To address this issue, we aim to uncover the gene regulatory networks (GRNs) that regulate nitrogen use efficiency (NUE) - as a function of water availability - in Oryza sativa, a staple for 3.5 billion people. In this study, we infer and validate GRNs that correlate with rice NUE phenotypes affected by N-by-W availability in the field. We did this by exploiting RNA-seq and crop phenotype data from 19 rice varieties grown in a 2x2 N-by-W matrix in the field. First, to identify gene-to-NUE field phenotypes, we analyzed these datasets using weighted gene co-expression network analysis (WGCNA). This identified two network modules ("skyblue" & "grey60") highly correlated with NUE grain yield (NUEg). Next, we focused on 90 TFs contained in these two NUEg modules and predicted their genome-wide targets using the N-and/or-W response datasets using a random forest network inference approach (GENIE3). Next, to validate the GENIE3 TF→target gene predictions, we performed Precision/Recall Analysis (AUPR) using nine datasets for three TFs validated in planta. This analysis sets a precision threshold of 0.31, used to "prune" the GENIE3 network for high-confidence TF→target gene edges, comprising 88 TFs and 5,716 N-and/or-W response genes. Next, we ranked these 88 TFs based on their significant influence on NUEg target genes responsive to N and/or W signaling. This resulted in a list of 18 prioritized TFs that regulate 551 NUEg target genes responsive to N and/or W signals. We validated the direct regulated targets of two of these candidate NUEg TFs in a plant cell-based TF assay called TARGET, for which we also had in planta data for comparison. Gene ontology analysis revealed that 6/18 NUEg TFs - OsbZIP23 (LOC_Os02g52780), Oshox22 (LOC_Os04g45810), LOB39 (LOC_Os03g41330), Oshox13 (LOC_Os03g08960), LOC_Os11g38870, and LOC_Os06g14670 - regulate genes annotated for N and/or W signaling. Our results show that OsbZIP23 and Oshox22, known regulators of drought tolerance, also coordinate W-responses with NUEg. This validated network can aid in developing/breeding rice with improved yield on marginal, low N-input, drought-prone soils

Detection of Central Visual Field Defects in Early Glaucomatous Eyes: comparison of Humphrey and Octopus perimetry

Purpose: To compare the detection rate of central visual field defect (CVFD) between the 30-degree Octopus G1 program (Dynamic strategy) and the HFA 10–2 SITA-Standard test in early glaucoma eyes not showing any CVFD on the HFA 24–2 SITA-Standard test. Methods: One eye of 41 early glaucoma patients without CVFD in the central 10 on HFA 24–2 test was tested with both the HFA 10–2 test and the Octopus G1 program 15 minutes apart, in random order. The primary outcome measure was the comparison of CVFD detection rates. Secondary outcome measures comprised the agreement in detecting CVFD, and the comparison of test durations and the numbers of depressed test points outside the central 10-degree area between the HFA 24–2 test and the Octopus G1 program. Results: The mean age of the population was 65.2±10.1 years, and the mean deviation with HFA 24–2 was -3.26±2.6 dB. The mean test duration was not significantly different between the tests (p = 0.13). A CVFD was present in 33 (80.4%) HFA 10–2 test and in 23 (56.0%) Octopus G1 tests (p = 0.002). The overall agreement between the HFA 10–2 and Octopus G1 examinations in classifying eyes as having or not having CVFD was moderate (Cohen’s kappa 0.47). The Octopus G1 program showed 69.6% sensitivity and 100% specificity to detect CVFD in eyes where the HFA 10–2 test revealed a CVFD. The number of depressed test points (p<5%) outside the central 10 area detected with the Octopus G1 program (19.68±10.6) was significantly higher than that detected with the HFA 24–2 program (11.95±5.5, p<0.001). Conclusion: Both HFA 10–2 and Octopus G1programs showed CVFD not present at HFA 24–2 test although the agreement was moderate. The use of a single Octopus G1 examination may represent a practical compromise for the assessment of both central and peripheral visual field up to 30 eccentricity without any additional testing and increasing the total investigation time

Accounting for quality improvement during the conduct of embedded pragmatic clinical trials within healthcare systems: NIH Collaboratory case studies

Embedded pragmatic clinical trials (ePCTs) and quality improvement (QI) activities often occur simultaneously within healthcare systems (HCSs). Embedded PCTs within HCSs are conducted to test interventions and provide evidence that may impact public health, health system operations, and quality of care. They are larger and more broadly generalizable than QI initiatives, and may generate what is considered high-quality evidence for potential use in care and clinical practice guidelines. QI initiatives often co-occur with ePCTs and address the same high-impact health questions, and this co-occurrence may dilute or confound the ability to detect change as a result of the ePCT intervention. During the design, pilot, and conduct phases of the large-scale NIH Collaboratory Demonstration ePCTs, many QI initiatives occurred at the same time within the HCSs. Although the challenges varied across the projects, some common, generalizable strategies and solutions emerged, and we share these as case studies. KEY LESSONS: Study teams often need to monitor, adapt, and respond to QI during design and the course of the trial. Routine collaboration between ePCT researchers and health systems stakeholders throughout the trial can help ensure research and QI are optimally aligned to support high-quality patient-centered care