scholarly journals Evaluating Human Mutation Databases for 'Treatability' Using Personalized Antisense Oligonucleotides

2022 ◽  
Author(s):  
Joseph G Gleeson ◽  
Isaac Tang ◽  
Swapnil Mittal
Keyword(s):  
Genome Sequencing ◽  
Genetic Variants ◽  
Loss Of Function ◽  
Regulate Gene Expression ◽  
New Developments ◽  
Human Mutation ◽  
Medical Teams ◽  
The Many ◽  
To Receive ◽  
Collaborative Efforts

Genome sequencing in the clinic often allows patients to receive a molecular diagnosis. However, variants are most often evaluated for pathogenicity, neglecting potential "treatability", and thus often yielding limited clinical benefit. Several collaborative efforts now aim to provide a therapy based upon the genetic variants, even if the drug will benefit only a single patient. Antisense oligonucleotide (ASO) therapies, among others, offer attractive "programmable" and relatively safe platforms for individualized therapy. The landscape of "ASO-treatable" variants is largely uncharted, with new developments emerging for loss-of-function (LOF), haploinsufficient, and gain-of-function (GOF) variants. ASOs can access the genome to target splice-gain variants, poison exons, untranslated/regulatory regions, and naturally-occurring antisense transcripts. Many of these approaches have yet to be proven clinically beneficial, and it is unclear if disease in some patients has progressed past the point where benefit could reasonably be expected. Here we mine public variant databases to identify potential future therapeutic targets. We found that the majority of human pathogenic genetic variants have one or more approaches that could be targeted therapeutically, advantaging the many ways that ASOs can regulate gene expression. The future might see medical teams considering "treatability" when interpreting genome sequencing results, to fully realize benefits for patients.

scholarly journals Whole-genome sequencing reveals KRTAP1-1 as a novel genetic variant associated with antidepressant treatment outcomes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jong-Ho Park ◽  
Shinn-Won Lim ◽  
Woojae Myung ◽  
Inho Park ◽  
Hyeok-Jae Jang ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Treatment Outcomes ◽  
Genetic Markers ◽  
Genome Sequencing ◽  
Genetic Variants ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Remission Rate ◽  
Antidepressant Treatment ◽  
Whole Genome ◽  
Loss Of Function

AbstractAchieving remission following initial antidepressant therapy in patients with major depressive disorder (MDD) is an important clinical result. Making predictions based on genetic markers holds promise for improving the remission rate. However, genetic variants found in previous genetic studies do not provide robust evidence to aid pharmacogenetic decision-making in clinical settings. Thus, the objective of this study was to perform whole-genome sequencing (WGS) using genomic DNA to identify genetic variants associated with the treatment outcomes of selective serotonin reuptake inhibitors (SSRIs). We performed WGS on 100 patients with MDD who were treated with escitalopram (discovery set: 36 remitted and 64 non-remitted). The findings were applied to an additional 553 patients with MDD who were treated with SSRIs (replication set: 185 remitted and 368 non-remitted). A novel loss-of-function variant (rs3213755) in keratin-associated protein 1–1 (KRTAP1-1) was identified in this study. This rs3213755 variant was significantly associated with remission following antidepressant treatment (p = 0.0184, OR 3.09, 95% confidence interval [CI] 1.22–7.80 in the discovery set; p = 0.00269, OR 1.75, 95% CI 1.22–2.53 in the replication set). Moreover, the expression level of KRTAP1-1 in surgically resected human temporal lobe samples was significantly associated with the rs3213755 genotype. WGS studies on a larger sample size in various ethnic groups are needed to investigate genetic markers useful in the pharmacogenetic prediction of remission following antidepressant treatment.

Preferences to Receive Unsolicited Findings of Germline Genome Sequencing in a Large Population of Cancer Patients

2018 ◽  
Author(s):  
R.M. Bijlsma ◽  
R.H.P. Wouters ◽  
H. Wessels ◽  
S. Sleijfer ◽  
L.V. Beerepoot ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Genome Sequencing ◽  
Large Population ◽  
To Receive

scholarly journals Mussolini Predicted a Fascist Century: How Wrong Was He?

Fascism ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Roger Griffin
Keyword(s):  
Twentieth Century ◽  
World Wide ◽  
Local Level ◽  
Modern World ◽  
Benito Mussolini ◽  
New Developments ◽  
The Many ◽  
The Right ◽  
Wide Community

In the entry on ‘Fascism’ published in 1932 in the Enciclopedia Italiana, Benito Mussolini made a prediction. There were, he claimed, good reasons to think that the twentieth century would be a century of ‘authority’, the ‘right’: a fascist century (un secolo fascista). However, after 1945 the many attempts by fascists to perpetuate the dreams of the 1930s have come to naught. Whatever impact they have had at a local level, and however profound the delusion that fascists form a world-wide community of like-minded ultranationalists and racists revolutionaries on the brink of ‘breaking through’, as a factor in the shaping of the modern world, their fascism is clearly a spent force. But history is a kaleidoscope of perspectives that dynamically shift as major new developments force us to rewrite the narrative we impose on it. What if we take Mussolini’s secolo to mean not the twentieth century, but the ‘hundred years since the foundation of Fascism’? Then the story we are telling ourselves changes radically.

The Technique of the Boyne Carvings

1956 ◽  
Vol 21 ◽  
pp. 156-159
Author(s):  
O. G. S. Crawford
Keyword(s):  
Presidential Address ◽  
Time And Space ◽  
East Anglia ◽  
Actual Design ◽  
The Many ◽  
To Receive ◽  
Vast Range ◽  
Made In

The prudent contributor to a Festschrift will select some subject about which he thinks he knows as much as the professor who is to receive it. That is peculiarly difficult here because of the vast range of Professor Childe's knowledge, both in time and space, far exceeding the present contributor's. This Note is offered as a grateful tribute from one of the many who have been intellectually enriched by his writings and encouraged by his devotion to scholarship. It is little more than an amplification and criticism of the Abbé Breuil's classic Presidential Address to the Prehistoric Society of East Anglia, delivered in 1934; but on the strength of observations made in August and September, 1955, I have come to different conclusions.The Abbé Breuil detected five successive techniques, all of them found on the stones of the Boyne Tombs:(1) Incised thin lines (pl. XIX, B).(2) Picked grooves left rough (pl. XVIII).(3, a) Picked grooves afterwards rubbed smooth; in this and the preceding group ‘it is invariably the line (groove) itself on which the pattern depends, which gives and is the design’.(3, b) Picked areas which ‘only define the limits of the pattern, the surface, left in relief by the cutting down of the background, constituting the actual design’ (pl. xx, B).(4) Rectilinear patterns where also the pattern is residual, consisting of raised ribs, forming triangles or lozenges, left standing by picking away the surrounding surface (pl. xx, A).

nterrogative style in the commandments of fathers to children

2021 ◽  
Vol 29 ◽  
Author(s):  
Prof.A.Dr. Nahidha Sattar Hanadi Nizar Abdul-Amir
Keyword(s):  
Arabic Language ◽  
Important Thing ◽  
The Many ◽  
The Mind ◽  
To Receive

In the Arabic language، the question is a method intended to seek knowledge of a specific thing. The most important thing that distinguishes the Arabic language from other languages is the diversity of its methods and its validity for various sciences and arts. God Almighty has honored it by making it the language of the Noble Qur’an، which He revealed to all people، and the many methods and diversity in the language make speech more accurate in approach، fuller in phrase، and systematized path and most sincere outlet. Therefore، the question is one of the pillars of the methods of the construction language، as it is not based on the building only، but the meaning is based on it as well. The most important characteristic that distinguishes the interrogative method from other methods; The high and influential ability in the mind and the soul of the addressee and its appeal to consideration، meditation and contemplation، and the reason for this is that the question is originally issued by a soul wishing to obtain a request for understanding and knowledge; The question arises to alert the mind and provoke feelings، and makes the soul ready to receive the thoughts and images that come out of the person who is casting.

Closing Remarks

2019 ◽  
Vol 15 (S367) ◽  
pp. 515-517
Author(s):  
Debra Meloy Elmegreen
Keyword(s):  
Big Data ◽  
Education Research ◽  
Strategic Plan ◽  
Astronomy Education ◽  
The Public ◽  
The Many ◽  
Collaborative Efforts ◽  
Made In

AbstractThis symposium has highlighted key first steps made in addressing many goals of the IAU Strategic Plan for 2020–2030. Presentations on initiatives regarding education, with applications to development, outreach, equity, inclusion, big data, and heritage, are briefly summarized here. The many projects underway for the public, for students, for teachers, and for astronomers doing astronomy education research provide a foundation for future collaborative efforts, both regionally and globally.

scholarly journals Identification and validation of novel candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas

2021 ◽  
Author(s):  
Guojie Zhong ◽  
Priyanka Ahimaz ◽  
Nicole A. Edwards ◽  
Jacob J. Hagen ◽  
Christophe Faure ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Congenital Anomalies ◽  
De Novo ◽  
Simulation Analysis ◽  
Loss Of Function ◽  
Developmental Defects ◽  
Risk Genes ◽  
Significant Burden ◽  
Background Mutation Rate ◽  
Complex Cases

Esophageal atresias/tracheoesophageal fistulas (EA/TEF) are rare congenital anomalies caused by aberrant development of the foregut. Previous studies indicate that rare or de novo genetic variants significantly contribute to EA/TEF risk, and most individuals with EA/TEF do not have pathogenic genetic variants in established risk genes. To identify novel genetic contributions to EA/TEF, we performed whole genome sequencing of 185 trios (probands and parents) with EA/TEF, including 59 isolated and 126 complex cases with additional congenital anomalies and/or neurodevelopmental disorders. There was a significant burden of protein altering de novo coding variants in complex cases (p=3.3e-4), especially in genes that are intolerant of loss of function variants in the population. We performed simulation analysis of pathway enrichment based on background mutation rate and identified a number of pathways related to endocytosis and intracellular trafficking that as a group have a significant burden of protein altering de novo variants. We assessed 18 variants for disease causality using CRISPR-Cas9 mutagenesis in Xenopus and confirmed 13 with tracheoesophageal phenotypes. Our results implicate disruption of endosome-mediated epithelial remodeling as a potential mechanism of foregut developmental defects. This research may have implications for the mechanisms of other rare congenital anomalies.

High-impact rare genetic variants in severe schizophrenia

2021 ◽  
Vol 118 (51) ◽  
pp. e2112560118
Author(s):  
Anthony W. Zoghbi ◽  
Ryan S. Dhindsa ◽  
Terry E. Goldberg ◽  
Aydan Mehralizade ◽  
Joshua E. Motelow ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Odds Ratio ◽  
High Impact ◽  
Psychiatric Genetics ◽  
Loss Of Function ◽  
Treatment Resistant ◽  
Complex Disorders ◽  
Extreme Phenotype ◽  
Case Selection ◽  
Rare Genetic Variants

Extreme phenotype sequencing has led to the identification of high-impact rare genetic variants for many complex disorders but has not been applied to studies of severe schizophrenia. We sequenced 112 individuals with severe, extremely treatment-resistant schizophrenia, 218 individuals with typical schizophrenia, and 4,929 controls. We compared the burden of rare, damaging missense and loss-of-function variants between severe, extremely treatment-resistant schizophrenia, typical schizophrenia, and controls across mutation intolerant genes. Individuals with severe, extremely treatment-resistant schizophrenia had a high burden of rare loss-of-function (odds ratio, 1.91; 95% CI, 1.39 to 2.63; P = 7.8 × 10−5) and damaging missense variants in intolerant genes (odds ratio, 2.90; 95% CI, 2.02 to 4.15; P = 3.2 × 10−9). A total of 48.2% of individuals with severe, extremely treatment-resistant schizophrenia carried at least one rare, damaging missense or loss-of-function variant in intolerant genes compared to 29.8% of typical schizophrenia individuals (odds ratio, 2.18; 95% CI, 1.33 to 3.60; P = 1.6 × 10−3) and 25.4% of controls (odds ratio, 2.74; 95% CI, 1.85 to 4.06; P = 2.9 × 10−7). Restricting to genes previously associated with schizophrenia risk strengthened the enrichment with 8.9% of individuals with severe, extremely treatment-resistant schizophrenia carrying a damaging missense or loss-of-function variant compared to 2.3% of typical schizophrenia (odds ratio, 5.48; 95% CI, 1.52 to 19.74; P = 0.02) and 1.6% of controls (odds ratio, 5.82; 95% CI, 3.00 to 11.28; P = 2.6 × 10−8). These results demonstrate the power of extreme phenotype case selection in psychiatric genetics and an approach to augment schizophrenia gene discovery efforts.

Occult Spinal Dysraphism: A Series of 73 Cases

PEDIATRICS ◽  
1975 ◽  
Vol 55 (6) ◽  
pp. 826-835 ◽  
Author(s):  
Frank M. Anderson
Keyword(s):  
Distal Part ◽  
Spinal Dysraphism ◽  
Clinical Manifestations ◽  
Dermal Sinus ◽  
Loss Of Function ◽  
Occult Spinal Dysraphism ◽  
Neural Tissues ◽  
The Subject ◽  
The Many ◽  
Developmental Variants

The subject of occult spinal dysraphism or myelodysplasia is reviewed from standpoints of embryology, clinical manifestations, and treatment, and the management of 73 cases summarized. In general, these concealed lesions arise from developmental variants in the most distal part of the neural tube, a situation which may cause distortion or partial absence of neural tissues and also lead to damage from compression or traction. Lipomyelomeningocele and congenital dermal sinus are two examples of the many types of such lesions, but some are more complicated, and borderline myelomeningocele-like forms occur. Incontinence, deformity or weakness of the feet, impaired gait, and other difficulties may appear late and increase with growth. Surgical treatment is advised to reduce chances of delayed or progressive loss of function.

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