scholarly journals Evolutionary history of Alzheimer Disease causing protein family Presenilins with pathological implications

2018 ◽  
Author(s):  
Ammad Aslam Khan ◽  
Bushra Mirza ◽  
Hashim Ali Raja
Keyword(s):  
Alzheimer Disease ◽  
Protein Trafficking ◽  
Developmental Disorders ◽  
Purifying Selection ◽  
Beta Catenin ◽  
Gamma Secretase ◽  
Loss Of Function ◽  
Last Common Eukaryotic Ancestor ◽  
History Of ◽  
Almost All

AbstractPresenilin proteins are type II transmembrane proteins. They make the catalytic component of Gamma secretase, a multiportion transmembrane protease. Amyloid protein, Notch and beta catenin are among more than 90 substrates of Presenilins. Mutations in Presenilins lead to defects in proteolytic cleavage of its substrate resulting in some of the most devastating pathological conditions including Alzheimer disease (AD), developmental disorders and cancer. In addition to catalytic roles, Presenilin protein is also shown to be involved in many non-catalytic roles i.e. calcium homeostasis, regulation of autophagy and protein trafficking etc. These proteolytic proteins are highly conserved, present in almost all the major eukaryotic groups. Studies on wide variety of organisms ranging from human to unicellular dictyostelium have shown the important catalytic and non-catalytic roles of Presenilins. In the current research project, we aimed to elucidate the phylogenetic history of Presenilins. We showed that Presenilins are the most ancient of the Gamma secretase proteins and might have their origin in last common eukaryotic ancestor (LCEA). We also demonstrated that these proteins have been evolving under strong purifying selection. Through evolutionary trace analysis, we showed that Presenilin protein sites which undergoes mutations in Familial Alzheimer Disease are highly conserved in metazoans. Finally, we discussed the evolutionary, physiological and pathological implication of our findings and proposed that evolutionary profile of Presenilins supports the loss of function hypothesis of AD pathogenesis.

From the Tower of London to the Thomas More Society of Buenos Aires: “Give me thy grace, good Lord, to set the world at nought”

Moreana ◽  
2005 ◽  
Vol 42 (Number 164) (4) ◽  
pp. 187-206
Author(s):  
Clare M. Murphy
Keyword(s):  
Buenos Aires ◽  
Short History ◽  
Thomas More ◽  
Tower Of London ◽  
Hebrew Poetry ◽  
Prayer Book ◽  
The World ◽  
History Of ◽  
Book Of Hours ◽  
Almost All

The Thomas More Society of Buenos Aires begins or ends almost all its events by reciting in both English and Spanish a prayer written by More in the margins of his Book of Hours probably while he was a prisoner in the Tower of London. After a short history of what is called Thomas More’s Prayer Book, the author studies the prayer as a poem written in the form of a psalm according to the structure of Hebrew poetry, and looks at the poem’s content as a psalm of lament.

scholarly journals Functional alterations caused by mutations reflect evolutionary trends of SARS-CoV-2

2021 ◽  
Author(s):  
Liang Cheng ◽  
Xudong Han ◽  
Zijun Zhu ◽  
Changlu Qi ◽  
Ping Wang ◽  
...  
Keyword(s):  
Reference Genome ◽  
Sequence Data ◽  
Purifying Selection ◽  
Virus Genome ◽  
Receptor Binding Domain ◽  
Evolutionary Trends ◽  
Synonymous Mutations ◽  
Almost All ◽  
Virus Strains ◽  
New Mutations

Abstract Since the first report of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, the COVID-19 pandemic has spread rapidly worldwide. Due to the limited virus strains, few key mutations that would be very important with the evolutionary trends of virus genome were observed in early studies. Here, we downloaded 1809 sequence data of SARS-CoV-2 strains from GISAID before April 2020 to identify mutations and functional alterations caused by these mutations. Totally, we identified 1017 nonsynonymous and 512 synonymous mutations with alignment to reference genome NC_045512, none of which were observed in the receptor-binding domain (RBD) of the spike protein. On average, each of the strains could have about 1.75 new mutations each month. The current mutations may have few impacts on antibodies. Although it shows the purifying selection in whole-genome, ORF3a, ORF8 and ORF10 were under positive selection. Only 36 mutations occurred in 1% and more virus strains were further analyzed to reveal linkage disequilibrium (LD) variants and dominant mutations. As a result, we observed five dominant mutations involving three nonsynonymous mutations C28144T, C14408T and A23403G and two synonymous mutations T8782C, and C3037T. These five mutations occurred in almost all strains in April 2020. Besides, we also observed two potential dominant nonsynonymous mutations C1059T and G25563T, which occurred in most of the strains in April 2020. Further functional analysis shows that these mutations decreased protein stability largely, which could lead to a significant reduction of virus virulence. In addition, the A23403G mutation increases the spike-ACE2 interaction and finally leads to the enhancement of its infectivity. All of these proved that the evolution of SARS-CoV-2 is toward the enhancement of infectivity and reduction of virulence.

scholarly journals An Emulation of Randomized Trials of Administrating Antipsychotics in PTSD Patients for Outcomes of Suicide-Related Events

2021 ◽  
Vol 11 (3) ◽  
pp. 178
Author(s):  
Noah R. Delapaz ◽  
William K. Hor ◽  
Michael Gilbert ◽  
Andrew D. La ◽  
Feiran Liang ◽  
...  
Keyword(s):  
Randomized Clinical Trials ◽  
Previous History ◽  
Current Treatment ◽  
Careful Consideration ◽  
P Value ◽  
Post Traumatic Stress ◽  
Increased Risk ◽  
History Of ◽  
Almost All

Post-traumatic stress disorder (PTSD) is a prevalent mental disorder marked by psychological and behavioral changes. Currently, there is no consensus of preferred antipsychotics to be used for the treatment of PTSD. We aim to discover whether certain antipsychotics have decreased suicide risk in the PTSD population, as these patients may be at higher risk. A total of 38,807 patients were identified with a diagnosis of PTSD through the ICD9 or ICD10 codes from January 2004 to October 2019. An emulation of randomized clinical trials was conducted to compare the outcomes of suicide-related events (SREs) among PTSD patients who ever used one of eight individual antipsychotics after the diagnosis of PTSD. Exclusion criteria included patients with a history of SREs and a previous history of antipsychotic use within one year before enrollment. Eligible individuals were assigned to a treatment group according to the antipsychotic initiated and followed until stopping current treatment, switching to another same class of drugs, death, or loss to follow up. The primary outcome was to identify the frequency of SREs associated with each antipsychotic. SREs were defined as ideation, attempts, and death by suicide. Pooled logistic regression methods with the Firth option were conducted to compare two drugs for their outcomes using SAS version 9.4 (SAS Institute, Cary, NC, USA). The results were adjusted for baseline characteristics and post-baseline, time-varying confounders. A total of 5294 patients were eligible for enrollment with an average follow up of 7.86 months. A total of 157 SREs were recorded throughout this study. Lurasidone showed a statistically significant decrease in SREs when compared head to head to almost all the other antipsychotics: aripiprazole, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone (p < 0.0001 and false discovery rate-adjusted p value < 0.0004). In addition, olanzapine was associated with higher SREs than quetiapine and risperidone, and ziprasidone was associated with higher SREs than risperidone. The results of this study suggest that certain antipsychotics may put individuals within the PTSD population at an increased risk of SREs, and that careful consideration may need to be taken when prescribed.

scholarly journals Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

2021 ◽  
Vol 22 (7) ◽  
pp. 3786
Author(s):  
Andreas Brodehl ◽  
Alexey Meshkov ◽  
Roman Myasnikov ◽  
Anna Kiseleva ◽  
Olga Kulikova ◽  
...  
Keyword(s):  
Medical History ◽  
Splice Site Mutation ◽  
Pathogenic Mutation ◽  
Large Deletion ◽  
Loss Of Function ◽  
Arrhythmogenic Cardiomyopathy ◽  
Site Mutation ◽  
Snp Arrays ◽  
Number Of Patients ◽  
History Of

About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2–c.378+1G>T) in the first patient and a nonsense mutation (DSG2–p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.

Do Deeper Levels of Cervical Biopsies Preceded by a Pap Smear Diagnosis of LSIL, ASCUS, or NILM/HPV+ Increase the Yield of Identifying Clinically Significant Lesions?

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S163-S164
Author(s):  
K G Manjee ◽  
W G Watkin
Keyword(s):  
Pap Smear ◽  
Past History ◽  
Prior History ◽  
Cervical Biopsy ◽  
P16 Immunohistochemistry ◽  
Hpv Status ◽  
Significant Difference ◽  
History Of ◽  
Clinically Significant ◽  
Almost All

Abstract Introduction/Objective Cervical biopsy is performed following an abnormal pap smear or positive HPV testing in an attempt to uncover clinically significant lesions [HSIL/invasive carcinoma (HSIL+)]. An excisional procedure is considered if biopsy confirms HSIL+. When preceded by pap smear of LSIL, ASCUS, NILM/HPV+ or persistent HPV, continued surveillance is recommended for biopsies showing no SIL or LSIL. In our laboratory, cervical biopsies are routinely sectioned at 3 levels. Deeper levels are often ordered when initial sections are non-diagnostic. p16 immunohistochemistry, with or without deeper levels, is often ordered to confirm HSIL, or to differentiate HSIL from mimics. In this study, we examine whether and in what clinical situations does obtaining additional levels uncover clinically significant lesions. Methods 430 cervical biopsies between January-May 2018, with recent cytology of LSIL, ASCUS or NILM/HPV+ were identified in the pathology database. HPV status (if known), final biopsy diagnosis and past history of LSIL/HSIL were recorded. For each biopsy, orders for additional levels and/or p16 immunohistochemistry were recorded resulting in 4 categories: C1-no additional levels or p16, C2-deeper only, C3-deeper+p16 and C4-p16 only. Final diagnoses were divided into HSIL+, LSIL and no SIL. Results There was no significant difference in prior history of LSIL/HSIL and HPV status between all categories. Biopsy results were as follows: HSIL+: 11/222 (5%) C1; 1/78 (1%) C2; 7/43 (16%) C3; 15/87 (17%) C4 LSIL: 91/222 (41%) C1; 7/78 (9%) C2; 16/43 (37%) C3; 35/87 (40%) C4 No SIL: 120/222 (54%) C1; 70/78 (90%) C2; 20/43 (46%) C3; 37/87 (42%) C4 The average number of additional levels in C2 and C3 was 3.8 and 1.8, respectively. Conclusion Deeper levels alone did not enhance the detection of HSIL+. Almost all LSIL/HSIL were detected when initial levels were diagnostic or suspicious and supported by p16 immunohistochemistry. 3 levels are adequate to detect clinically significant lesions.

scholarly journals On the supposed first stage larva of Leptohylemyia coarctata, Fall.

1917 ◽  
Vol 8 (2) ◽  
pp. 121-123 ◽  
Author(s):  
D. Keilin
Keyword(s):  
Life History ◽  
Recent Work ◽  
European Countries ◽  
Stage Larva ◽  
History Of ◽  
Almost All

It has been well known since the studies of Taschenberg (1864–1872) that the larvae of Leptohylemyia coarctata, Fall., attack wheat and rye. The damage due to this fly has been observed many times in almost all European countries, and many papers have been devoted to its life-history. Of these papers the most important are those of E. Ormerod (1882–1895), S. Rostrup (1905–1911), T. Hedlund (1906- 1907), P. Marchal (1909) and finally the recent work of Kurdjumov (1914).

scholarly journals The sportification of judo: global convergence and evolution

2013 ◽  
Vol 8 (2) ◽  
pp. 299-317 ◽  
Author(s):  
Shohei Sato
Keyword(s):  
Nineteenth Century ◽  
Global Convergence ◽  
Martial Arts ◽  
Way Of Life ◽  
The West ◽  
Modern Times ◽  
The World ◽  
History Of ◽  
Almost All ◽  
Olympic Sport

AbstractThis article re-examines our understanding of modern sport. Today, various physical cultures across the world are practised under the name of sport. Almost all of these sports originated in the West and expanded to the rest of the world. However, the history of judo confounds the diffusionist model. Towards the end of the nineteenth century, a Japanese educationalist amalgamated different martial arts and established judo not as a sport but as ‘a way of life’. Today it is practised globally as an Olympic sport. Focusing on the changes in its rules during this period, this article demonstrates that the globalization of judo was accompanied by a constant evolution of its character. The overall ‘sportification’ of judo took place not as a diffusion but as a convergence – a point that is pertinent to the understanding of the global sportification of physical cultures, and also the standardization of cultures in modern times.

Literary Center of Constructivists on Its Way to the RAPP (From the History of Literary Life at the Turn of the 1920s — 1930s)

2021 ◽  
Vol 6 (3) ◽  
pp. 304-321
Author(s):  
Natalia V. Kornienko ◽  
Ruslan E. Klementiev
Keyword(s):  
Left Wing ◽  
Literary Life ◽  
The Press ◽  
Archival Documents ◽  
History Of ◽  
Almost All ◽  
Russian Association

The article examines one of the episodes of the literary struggle of the late 1920s — early 1930s — the history of the entry of the Literary Center of Constructivists (LCC) into the Russian Association of Proletarian Writers (RAPP). At the beginning of 1930, almost all literary groups and associations faced the need to define a new level of interaction with RAPP. LCC, as one of the literary groups closest to RAPP, seemed to have all the prerequisites for a successful association with the RAPP. But in reality, this did not happen. Members of RAPP are suspicious of constructivists; attacks at LCC are becoming more frequent in the press. Always considered a left-wing association, LLC is declared a petty-bourgeois group, with which, despite its disbandment, an irreconcilable struggle is required. This article bears upon not only the periodicals of 1930 but also and mainly upon the hitherto unstudied transcripts and other archival documents of RAPP. New archival materials reveal internal processes of the literary struggle at the turn of the decade, and make it possible to demonstrate how, even after the acceptance of the Constructivists by RAPP, the former continue to be perceived as a hostile group whose past was to always blame them.

TOOTH-RASHES AS DESCRIBED BY MICHAEL UNDERWOOD (1737-1820), THE FOUNDER OF MODERN PEDIATRICS

PEDIATRICS ◽  
1969 ◽  
Vol 43 (3) ◽  
pp. 459-459
Author(s):  
T. E. C.
Keyword(s):  
Scarlet Fever ◽  
Erythema Nodosum ◽  
Whole Body ◽  
Deciduous Teeth ◽  
History Of ◽  
History Of Pediatrics ◽  
Benign Nature ◽  
Almost All ◽  
As If

I know of no contemporary pediatrician who believes that the cutting of deciduous teeth causes skin rashes. But, almost all the great figures in the history of pediatrics believed firmly that teething was associated with a riety of rashes. Michael Underwood, who more than anyone else laid the foundation of modern pediatrics, wrote about tooth-rashes as follows: A very common rash, appears chiefly in teething children, which yery much resembles the measles, and has been sometimes mistaken for it. It is preceded by sickness at the stomach, but is attended by very little fever; though the rash continues very florid for three days, like the measles, but does not dry off in the manner of that disease. . . . While the double or eye-teeth are cutting, I have noticed a rash Which at its first appearance is very similar to the above, and has likewise been mistaken for the measles. It, however, soon spreads into larger spots and patches of bright red, and afterwards of a darker hue, resembling the ill-looking petechiae which appear in bad fevers, but is, nevertheless, of a benign nature. It is, indeed, attended with some fever, arising possibly from the irritation occasioned by teething, and has been followed by small and hard round tumours on the legs, which softening in two or three days, always appear as if they would suppurate, though I believe they never do . . . [? erythema nodosum, T. E. C., Jr.] I have seen a third kind of rash, in appearance resembling the measles, and, like it, covering the whole body, but with larger intermediate patches, like the eruption in the scarlet fever. . . .

Atopic Dermatitis: Case Series of Individualized Homoeopathic Treatment

2021 ◽  
Vol 11 (11) ◽  
pp. 115-123
Author(s):  
Mousumi Das
Keyword(s):  
Atopic Dermatitis ◽  
Family History ◽  
Case Series ◽  
Calcineurin Inhibitors ◽  
Loss Of Function ◽  
Key Words Atopic Dermatitis ◽  
Topical Calcineurin Inhibitors ◽  
History Of ◽  
Allergic Disorders ◽  
Positive Results

Atopic dermatitis is a common, chronic, intensely pruritic, relapsing inflammatory skin disease that affects both children and adults. Atopic dermatitis is often the originating of a series of allergic disorders, mentioned as the "atopic march".There are numerous risk factors correlated with AD development. However, only two have always been related, and they are (1) family history of atopy and (2) loss of function mutations in the FLG gene. Topical anti-inflammatory therapy with topical corticosteroids or topical calcineurin inhibitors treatment are available in conventional therapy but sometimes it has been reported that patients are also benefited from Homoeopathic treatment. Four patients who presented at the outpatient department at National Institute of Homoeopathy, Saltlake, Kolkata with Atopic dermatitis and a family history of asthma, allergic rhinitis were treated with constitutional homoeopathic medicine. Details of consultations, treatment and assessment are summarized. A constitutional treatment thus eliminates the symptoms locally and internally as well as long-lasting relief from complaints. Common remedies include Mercuris Solubilis, Sulphur. This case series shows positive results of homoeopathy in the treatment of Atopic dermatitis. Key words: Atopic dermatitis, Family history, Individualized Homoeopathic treatment, Case series, repertorisation.

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