scholarly journals Matching drug transcriptional signatures to rare losses disrupting synaptic gene networks identifies known and novel candidate drugs for schizophrenia

2018 ◽  
Author(s):  
Daniele Merico ◽  
Xiao Wang ◽  
Ryan K. C. Yuen ◽  
Stephen W. Scherer ◽  
Anne S. Bassett
Keyword(s):  
Drug Development ◽  
Gene Networks ◽  
Negative Symptoms ◽  
Social Withdrawal ◽  
Global Gene Expression ◽  
Recent Analysis ◽  
P Value ◽  
Copy Number Loss ◽  
Wide Range ◽  
Psychoactive Effects

ABSTRACTSchizophrenia is a complex neuropsychiatric disorder. The etiology is not fully understood, but genetics plays an important role. Pathway analysis of genetic variants have suggested a central role for neuronal synaptic processes. Currently available antipsychotic medications successfully control positive symptoms (hallucinations and delusions) largely by inhibiting the dopamine D2 receptors; however, these drugs have more limited impact on negative symptoms (social withdrawal, flat affections, anhedonia) and cognitive deterioration. Drug development efforts have focused on a wide range of neurotransmitter systems and other agents, with conflicting or inconclusive results. New drug development paradigms are needed. A recent analysis, using common variant association results to match drugs based on their transcriptional perturbation signature, found drugs enriched in known antipsychotics plus novel candidates.We followed a similar approach, but started our analysis from a synaptic gene network implicated by rare copy number loss variants. We found that a significant number of antipsychotics (p-value = 0.0002) and other psychoactive drugs (p-value = 0.0004) upregulate synaptic network genes. Based on global gene expression similarity, active drugs formed two main clusters: one with many known antipsychotics and antidepressants, the other with various drug categories including two nootropics. We specifically recommend further examination of nootropics with limited side effects (meclofenoxate, piracetam and vinpocetine) for combination therapy with antipsychotics to improve cognitive performance. Detailed experimental follow-up is required to further evaluate other candidate drugs lacking an official nervous system indication, although, for at least a few of these, psychoactive effects have been reported in the literature.

Extending the Applicability of the ANI Deep Learning Molecular Potential to Sulfur and Halogens

2020 ◽  
Author(s):  
Christian Devereux ◽  
Justin Smith ◽  
Kate Davis ◽  
Kipton Barros ◽  
Roman Zubatyuk ◽  
...  
Keyword(s):  
Drug Development ◽  
Autonomous Vehicles ◽  
Potential Energy Surfaces ◽  
Organic Molecules ◽  
Chemical Elements ◽  
Molecular Potential ◽  
Wide Range ◽  
Energy Surfaces ◽  
New Applications ◽  
Physical Phenomena

<p>Machine learning (ML) methods have become powerful, predictive tools in a wide range of applications, such as facial recognition and autonomous vehicles. In the sciences, computational chemists and physicists have been using ML for the prediction of physical phenomena, such as atomistic potential energy surfaces and reaction pathways. Transferable ML potentials, such as ANI-1x, have been developed with the goal of accurately simulating organic molecules containing the chemical elements H, C, N, and O. Here we provide an extension of the ANI-1x model. The new model, dubbed ANI-2x, is trained to three additional chemical elements: S, F, and Cl. Additionally, ANI-2x underwent torsional refinement training to better predict molecular torsion profiles. These new features open a wide range of new applications within organic chemistry and drug development. These seven elements (H, C, N, O, F, Cl, S) make up ~90% of drug like molecules. To show that these additions do not sacrifice accuracy, we have tested this model across a range of organic molecules and applications, including the COMP6 benchmark, dihedral rotations, conformer scoring, and non-bonded interactions. ANI-2x is shown to accurately predict molecular energies compared to DFT with a ~10<sup>6</sup> factor speedup and a negligible slowdown compared to ANI-1x. The resulting model is a valuable tool for drug development that can potentially replace both quantum calculations and classical force fields for myriad applications.</p>

scholarly journals Natural Experiment on Trade and Investment Liberalization and Soft Drink Consumption

2020 ◽  
Vol 30 (Supplement_5) ◽  
Author(s):  
Y Tcholakov
Keyword(s):  
Public Health ◽  
International Trade ◽  
Natural Experiment ◽  
Soft Drink ◽  
Trade Agreement ◽  
P Value ◽  
Soft Drink Consumption ◽  
Obesity And Diabetes ◽  
Wide Range ◽  
The Impact

Abstract Background Globalization is recognized to as a contributing factor to a health harming environment through a variety of mechanisms including through changes in food systems and food availability. Sugar-sweetened beverage (SSB) consumption is linked to obesity and diabetes and its regulation is a key priority for public health. The Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CPTPP) is an international trade agreement between 11 countries. Methods This project uses of natural experiment methods to predict the impact of the entry into force of the CPTPP on SSB consumption. These methods allow quantitative inferences to be drawn in the situations where the exposure is not randomly assigned. Soft drink consumption data was collected from the Euromonitor database for 80 countries from all regions. This data was used to estimate the effect of agreements similar to the TPP. Results Eleven country trade agreement pairs were identified. In 5 cases out of the 11, the exposed country had a higher soft drink consumption at five years after the trade agreement. The effect of the trade agreement exposure for an average country in the sample in a trade agreement was found to be 1.10 (95% CI: 1.01-1.18; p-value: 0.03) after adjusting for GDP and the involvement of the US. In 7 of the 11 member-countries soft drink consumption is expected to increase yielding an average increase of 9.0% in those countries; the changes did not yield statistically significant differences in others. Conclusions This projected extended the use of synthetic methods to the projection of future effects of policy implementation. While it showed that there may be increasing trend of SSB consumption in certain scenarios, this could not be generalized to all cases. This illustrates the wide range of effects of international trade liberalization and highlights that national policy probably plays a strong modulating role on the impact that it has on local food environments. Key messages Globalization can lead to health harming environments and its impacts should further be studied by public health professionals and researchers. Many global policies have the potential to lead to significant health impacts but are negotiated without involving public health experts.

P–530 The use of wide thresholds for detecting intermediate chromosomal CNV up to 80% doesn’t improve PGT-A ability to discriminate true mosaic from uniformly aneuploid embryos

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
L Girardi ◽  
M Serdaroğulları ◽  
C Patassini ◽  
S Caroselli ◽  
M Costa ◽  
...  
Keyword(s):  
Inner Cell Mass ◽  
False Negative ◽  
Cell Mass ◽  
Categorical Variables ◽  
P Value ◽  
Sequencing Data ◽  
Preimplantation Genetic Testing ◽  
Exact Test ◽  
Institutional Review ◽  
Wide Range

Abstract Study question What is the effect of varying diagnostic thresholds on the accuracy of Next Generation Sequencing (NGS)-based preimplantation genetic testing for aneuploidies (PGT-A)? Summary answer When single trophectoderm biopsies are tested, the employment of 80% upper threshold increases mosaic calls and false negative aneuploidy results compared to more stringent thresholds. What is known already Trophectoderm (TE) biopsy coupled with NGS-based PGT-A technologies are able to accurately predict Inner Cell Mass’ (ICM) constitution when uniform whole chromosome aneuploidies are considered. However, minor technical and biological inconsistencies in NGS procedures and biopsy specimens can result in subtle variability in analytical results. In this context, the stringency of thresholds employed for diagnostic calls can lead to incorrect classification of uniformly aneuploid embryos into the mosaic category, ultimately affecting PGT-A accuracy. In this study, we evaluated the diagnostic predictivity of different aneuploidy classification criteria by employing blinded analysis of chromosome copy number values (CNV) in multifocal blastocyst biopsies. Study design, size, duration The accuracy of different aneuploidy diagnostic cut-offs was assessed comparing chromosomal CNV in intra-blastocysts multifocal biopsies. Enrolled embryos were donated for research between June and September 2020. The Institutional Review Board at the Near East University approved the study (project: YDU/20l9/70–849). Embryos diagnosed with uniform chromosomal alterations (single or multiple) in their clinical TE biopsy (n = 27) were disaggregated into 5 portions: the ICM and 4 TE biopsies. Overall, 135 specimens were collected and analysed. Participants/materials, setting, methods Twenty-seven donated blastocysts were warmed and disaggregated in TE biopsies and ICM (n = 135 biopsies). PGT-A analysis was performed using Ion ReproSeq PGS kit and Ion S5 sequencer (ThermoFisher). Sequencing data were blindly analysed with Ion-Reporter software. Intra-blastocyst comparison of raw NGS data was performed employing different thresholds commonly used for aneuploidy classification. CNV for each chromosome were reported as aneuploid according to 70% or 80% thresholds. Categorical variables were compared using Fisher’s exact test. Main results and the role of chance In this study, a total of 50 aneuploid patterns in 27 disaggregated embryos were explored. Single TE biopsy results were considered as true positive when they displayed the same alteration detected in the ICM at levels above the 70% or 80% thresholds. Alternatively, alterations detected in the euploid or mosaic range were considered as false negative aneuploidy results. When the 70% threshold was applied, aneuploidy findings were confirmed in 94.5% of TE biopsies analyzed (n = 189/200; 95%CI=90.37–37.22), while 5.5% showed a mosaic profile (50–70%) but uniformly abnormal ICM. Positive (PPV) and negative predictive value (NPV) per chromosome were 100.0% (n = 189/189; 95%CI=98.07–100.00) and 99.5% (n = 2192/2203; 95%CI=99.11–99.75) respectively. When the upper cut-off was experimentally placed at 80% of abnormal cells, a significant decrease (p-value=0.0097) in the percentage of confirmed aneuploid calls was observed (86.5%; n = 173/200; 95%CI=80.97–90.91), resulting in mosaicism overcalling, especially in the high range (50–80%). Less stringent thresholds led to extremely high PPV (100.0%; n = 173/173; 95%CI=97.89–100.00), while NPV decreased to 98.8% (n = 2192/2219; 95%CI=98.30–99.23). Furthermore, no additional true mosaic patterns were identified with the use of wide range thresholds for aneuploidy classification. Limitations, reasons for caution This approach involved the analysis of aneuploidy CNV thresholds at the embryo level and lacked from genotyping-based confirmation analysis. Moreover, aneuploid embryos with known meiotic partial deletion/duplication were not included. Wider implications of the findings: The use of wide thresholds for detecting intermediate chromosomal CNV up to 80% doesn’t improve PGT-A ability to discriminate true mosaic from uniformly aneuploid embryos, lowering overall diagnostic accuracy. Hence, a proportion of the embryos diagnosed as mosaic using wide calling thresholds may actually be uniformly aneuploid and inadvertently transferred. Trial registration number N/A

scholarly journals A Case-Control Study for Assessing Risk Factors for Congenital Anomalies among Children in Sulaimani City

2018 ◽  
pp. 90-95 ◽  
Author(s):  
Niaz Mustafa Kamal ◽  
Nasih Othman
Keyword(s):  
Risk Factors ◽  
Congenital Anomalies ◽  
Maternal Obesity ◽  
Case Control Study ◽  
Significant Risk ◽  
Case Control ◽  
P Value ◽  
Maternal Risk ◽  
Wide Range ◽  
Control Study

Congenital anomalies comprise a wide range of abnormalities in body structure or function that are present at birth and are of prenatal origin. These are defined as structural changes that have significant medical, social or cosmetic consequences for the affected individual, and typically require medical intervention. According to our Knowledge, research is scarce on these conditions in Sulaimaniyah city. Therefore, the current study was conducted to investigate potential risk factors for congenital anomalies. A case-control study was carried out from March to August 2017 involving 400 children (200 cases and 200 controls) aged 0-5 years. Required data were obtained on the risk factors through face to face interviews with mothers of cases and controls. The data were using descriptive statistical methods, Chi-square and Logistic Regression using STATA 11, calculating odds ratios and condensing P value less than 0.05 as statistically significant. The mean age of the children was 1.9 years and age of their mothers at the time of pregnancy was 28 years. Congenital heart anomalies were the commonest type accounting for 27.5%. Significant risk factors for congenital anomalies were family history (OR=2.24, P= 0.007), maternal obesity (OR= 2.26, P= 0.001), mothers age over 30 (OR=2.78, P= 0.002) and mothers not using folic acid during pregnancy (OR=2.12, P= 0.0007). In general, in order to control and prevent the cases of CM, it is important to provide health education and policies to reduce environmental and maternal risk factors. Further, studies with larger sample size are needed to investigate incidence and risk factors of congenital anomalies.

scholarly journals Stigmatization towards persons with mental and intellectual difficulties

Temida ◽  
2013 ◽  
Vol 16 (2) ◽  
pp. 43-56
Author(s):  
Mia Popic ◽  
Snezana Anticevic
Keyword(s):  
Social Withdrawal ◽  
Social Groups ◽  
Careful Analysis ◽  
Self Esteem ◽  
Social Marginalization ◽  
The People ◽  
Wide Range ◽  
Human Tendency ◽  
Seeking Help

Persons with mental and intellectual difficulties are the most stigmatized social groups of all. Consequences of stigma towards these people present themselves in a wide range including social withdrawal; feelings of loneliness; low self-esteem; failure to take care of oneself; avoidance of seeking help; low enrolment in any kind of treatment; financial poverty and total social marginalization. Although most of the attempts to overcome stigmatization towards this population have shown a very pessimistic perspective, it is important to overcome our own helplessness in treating this issue and continue with the efforts to combat stigma. The only way to succeed is through continuous and careful analysis of the factors that contribute to a human tendency to stigmatize that could then be utilized as the ground base in development of mechanisms to battle this issue. This paper summarizes ways that the stigmatization of persons with mental and intellectual difficulties is manifested as well as the negative influences it has on the people who are stigmatized. Factors that contribute to the stigmatization of persons are carefully considered, as well as possible mechanisms that could be utilized as part of efforts to combat stigma.

scholarly journals PENGARUH KONSUMSI KULIT MANGGIS TERHADAP PENURUNAN KADAR GULA DARAH PADA PENDERITA DIABETES MELLITUS DI DESA METESEH BOJA KENDAL TAHUN 2013

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
Budi Herminto ◽  
Diyono ◽  
Shinta Dewi Kusuma
Keyword(s):  
Diabetes Mellitus ◽  
Blood Sugar ◽  
T Test ◽  
P Value ◽  
Average Value ◽  
Mangosteen Peel ◽  
Wide Range ◽  
Before And After ◽  
Sugar Levels ◽  
The Village

Abstract Background. Prevalensidiabetes mellitus in Indonesia potentially increased dramatically from 8.4 million people in 2000 to 21.3 million people in 2030. Diabetes mellitus may develop so bad with various complicated, diabetus mellitus of year to year growing a wide range of treatment options including non- medicinal chemistry ( Hebal ) . One type of therapy is continuously studied using mangosteen peel efectivitness. Research Objectives. Knowing the effect of the consumption of mangosteen rind to decrease blood sugar in the Village District of Boja Meteseh Kendal This is a research Methods. Quasi experiment with pre- post design eksperimental.Responden study are all patients with diabetes mellitus in the village of Boja Meteseh many as 17 people , as many as 16 samples taken. Sampling technic used was simple random sampling . Data obtained by the method of observation of assessing the results of measurements of blood sugar levels before and after taking of mangosteen skin . The data were processed with pairet t - test ( p = 0.05 ) using SPSS 18 . Results : ( 1 ) blood sugar levels before taking mangosteen peel at the most in the range of 301-400 mg / dL with a percentage of 43.75 % , the lowest blood sugar levels in the category of 501-600 mg / dL , with a percentage of 12.5 % , with an average value of 392.63 . ( 2 ) Blood sugar levels after consumption of mangosteen peel at the most in the range of 200-300 mg / dL , the percentage of blood sugar levels are the lowest in the category of 501-600 mg / dL , with a percentage of 12.5 % , with an average value of 371.31 mg / dL ( 3 ) There are significant differences in blood sugar levels before and after consuming mangosteen peel with a value of 0.001 t - Test Conclusion : Consumption of mangosteen peel significant effect on lowering blood sugar levels by t - test results of 5 % ( 0.05), obtained P value of 0.001. Keywords: Blood Sugar Levels, Skin Mangosteen, Diabetes Mellitus

scholarly journals ALS drug development guidances and trial guidelines

Neurology ◽  
2019 ◽  
Vol 93 (2) ◽  
pp. 66-71 ◽  
Author(s):  
Jinsy A. Andrews ◽  
Lucie I. Bruijn ◽  
Jeremy M. Shefner
Keyword(s):  
Drug Development ◽  
External Input ◽  
Draft Guidance ◽  
Current State ◽  
Community Stakeholders ◽  
Predictive Algorithms ◽  
Wide Range ◽  
The Us ◽  
New Treatments ◽  
State Of The Science

The US Food and Drug Administration (FDA) developed a draft guidance for drug development in amyotrophic lateral sclerosis (ALS) that was issued in February 2018. The FDA draft guidance considered the recommendations developed by the ALS community that incorporated the views of a large group of clinical investigators, industry representatives, advocacy groups, patients, and caregivers. This external input from the ALS community reviewed the current state of clinical research in ALS, made suggestions over a wide range of drug development topics, and served as an educational tool to provide the agency with additional inputs about ALS, the state of the science, and the community's views on key topics. In parallel to this effort, there was an independent effort to revise and update the ALS Clinical Trial Guidelines. We discuss the areas of agreement of these 3 documents and the areas that provide opportunities to improve the efficiency of drug development in ALS. It is likely that further research into biomarkers, efficacy endpoints, and predictive algorithms will provide greater alignment among community stakeholders and increase clarity on drug development efforts going forward. Continued patient engagement and inclusion of patient experience data in every aspect of the drug development process will further facilitate the approval of new treatments.

scholarly journals 46 Integration of multiple platforms to discover idh-mutant glioma subtypes

2018 ◽  
Vol 45 (S3) ◽  
pp. S14-S15
Author(s):  
Yasin Mamatjan ◽  
Farshad Nassiri ◽  
Severa Bunda ◽  
Fabio Moraes ◽  
Kenneth D. Aldape ◽  
...  
Keyword(s):  
Hox Genes ◽  
The Cancer Genome Atlas ◽  
Research Network ◽  
P Value ◽  
Biologically Relevant ◽  
Group 4 ◽  
Wide Range ◽  
Diffuse Gliomas ◽  
Cancer Genome Atlas ◽  
Promoter Mutations

Purpose: Diffuse gliomas can be divided on the basis of presence or absence of mutation in IDH genes. IDH-mutant diffuse gliomas represent a wide range of clinical outcome, which is not accounted for by current clinical and pathologic parameters. We aim to identify clinically and biologically relevant subgroups within IDH-mutant gliomas to gain a deeper insight into finer sub-classification. Methods: We used 412 IDH-mutant glioma samples that were profiled by The Cancer Genome Atlas (TCGA) Research Network, utilising methylation/mRNA datasets to identify subtypes with unique molecular signatures. We applied a Similarity Network Fusion (SNF) on individual platforms and their integrations. Results: SNF approach split glioma into four groups. The integrated RNA/methylation subtype produced a highly prognostic groups that predict survival (p-value=0.003) compared to mRNA and methylation alone. We observed a high degree of correlation between integrative subtypes and somatic mutations. Groups 1&4 had higher TERT promoter mutations (35% and 16%, respectively) compared to groups 2&3. Groups 1&4 showed increased TERT expression (34% and 14% respectively), and high percentage of TP53 and ATRX mutations. Multivariate analysis after adjusting for confounding factors including grade and age showed prognostic factors associated with survival (HR=3.2, p-value=0.001) in group 4 versus others. Conclusions: The results indicate that clinically relevant alterations exist within IDH-mutant gliomas that could stratify patients for treatment. Interestingly, group 4 showed high expression of HOX genes (18/18) (p-value=0.01) and higher methylation of Hox genes (21) (p-value=0.01) compared to others. Higher expression of specific Hox genes were associated with worse survival.

scholarly journals The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors

2019 ◽  
Vol 58 ◽  
pp. 1-9 ◽  
Author(s):  
Wolfgang Fleischhacker ◽  
Silvana Galderisi ◽  
István Laszlovszky ◽  
Balázs Szatmári ◽  
Ágota Barabássy ◽  
...  
Keyword(s):  
Negative Symptom ◽  
Repeated Measures ◽  
Negative Symptoms ◽  
Social Withdrawal ◽  
Partial Agonist ◽  
Factor Models ◽  
Symptom Improvement ◽  
Symptom Dimensions ◽  
Intent To Treat ◽  
Post Hoc

AbstractBackground:Negative symptoms in schizophrenia are heterogeneous and multidimensional; effective treatments are lacking. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, was significantly more effective than risperidone in treating negative symptoms in a prospectively designed trial in patients with schizophrenia and persistent, predominant negative symptoms.Methods:Using post hoc analyses, we evaluated change from baseline at week 26 in individual items of the Positive and Negative Syndrome Scale (PANSS) and PANSS-derived factor models using a mixed-effects model for repeated measures (MMRM) in the intent-to-treat (ITT) population (cariprazine = 227; risperidone = 227).Results:Change from baseline was significantly different in favor of cariprazine versus risperidone on PANSS items N1-N5 (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking) (P <.05), but not on N6 (lack of spontaneity/flow of conversation) or N7 (stereotyped thinking). On all PANSS-derived negative symptom factor models evaluated (PANSS-Factor Score for Negative Symptoms, Liemburg factors, Khan factors, Pentagonal Structure Model Negative Symptom factor), statistically significant improvement was demonstrated for cariprazine versus risperidone (P <.01). Small and similar changes in positive/depressive/EPS symptoms suggested that negative symptom improvement was not pseudospecific. Change from baseline was significantly different for cariprazine versus risperidone on PANSS-based factors evaluating other relevant symptom domains (disorganized thoughts, prosocial function, cognition; P <.05).Conclusions:Since items representing different negative symptom dimensions may represent different fundamental pathophysiological mechanisms, significant improvement versus risperidone on most PANSS Negative Subscale items and across all PANSS-derived factors suggests broad-spectrum efficacy for cariprazine in treating negative symptoms of schizophrenia.

Potential SNPs related to microspore culture in Raphanus sativus based on a single-marker analysis

2018 ◽  
Vol 98 (5) ◽  
pp. 1072-1083 ◽  
Author(s):  
Yong Suk Chung ◽  
Yun Gyeong Lee ◽  
Renato Rodrigues Silva ◽  
Suhyoung Park ◽  
Min Young Park ◽  
...  
Keyword(s):  
Raphanus Sativus ◽  
Microspore Culture ◽  
P Value ◽  
Nucleotide Polymorphisms ◽  
Single Marker Analysis ◽  
Regeneration Rate ◽  
Marker Analysis ◽  
Wide Range ◽  
Single Marker ◽  
High Regeneration

Radish (Raphanus sativus) is an economically important crop grown for its edible roots and leaves. It is a self-incompatible, outcrossing species, making the production of homozygous lines and the development of breeding populations difficult. However, this can be overcome with haploids production techniques using isolated microspores, providing the rapid production of homozygous lines for breeding. Thus, it would be useful to identify radishes with a high regeneration rate from microspore culture. In the current study, 96 radish cultivars or germplasms were evaluated for high regeneration rates. Also, a single-marker analysis (SMA) was applied to detect single nucleotide polymorphisms (SNPs) potentially associated with this trait using genotype-by-sequencing (GBS) technology. The regeneration rate from microspore culture of 96 lines showed a wide range, from 0% to 269.5%. From the SMA, 52 markers were detected at a p value of 0.001 and a total of 11 physically nearby genes with high levels of similarity in various species were identified as candidates for high regeneration rates. This result could be used for clarifying the genetic basis underlying these traits and developing molecular markers associated with regeneration rates and would be beneficial for generating homozygous inbred lines.

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