partial loss
Recently Published Documents


TOTAL DOCUMENTS

559
(FIVE YEARS 136)

H-INDEX

47
(FIVE YEARS 6)

2022 ◽  
Vol 12 ◽  
Author(s):  
Jamila Zammouri ◽  
Camille Vatier ◽  
Emilie Capel ◽  
Martine Auclair ◽  
Caroline Storey-London ◽  
...  

Lipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed.


Oncogene ◽  
2021 ◽  
Author(s):  
Boris Klimovich ◽  
Nastasja Merle ◽  
Michelle Neumann ◽  
Sabrina Elmshäuser ◽  
Andrea Nist ◽  
...  

AbstractThe tumor suppressive transcription factor p53 is frequently inactivated in cancer cells by missense mutations that cluster in the DNA binding domain. 30% hit mutational hotspot residues, resulting in a complete loss of transcriptional activity and mutant p53-driven chemotherapy resistance. Of the remaining 70% of non-hotspot mutants, many are partial loss-of-function (partial-LOF) mutants with residual transcriptional activity. The therapeutic consequences of a partial-LOF have remained largely elusive. Using a p53 mutation engineered to reduce DNA binding, we demonstrate that partial-LOF is sufficient to enhance oncogene-driven tumorigenesis in mouse models of lung and pancreatic ductal adenocarcinoma and acute myeloid leukemia. Interestingly, mouse and human tumors with partial-LOF mutations showed mutant p53 protein accumulation similar as known for hotspot mutants. Different from the chemotherapy resistance caused by p53-loss, the partial-LOF mutant sensitized to an apoptotic chemotherapy response and led to a survival benefit. Mechanistically, the pro-apoptotic transcriptional activity of mouse and human partial-LOF mutants was rescued at high mutant protein levels, suggesting that accumulation of partial-LOF mutants enables the observed apoptotic chemotherapy response. p53 non-hotspot mutants with partial-LOF, therefore, represent tumorigenic p53 mutations that need to be distinguished from other mutations because of their beneficial impact on survival in a therapy context.


Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2485
Author(s):  
Sabari Nath Neerukonda ◽  
Russell Vassell ◽  
Sabrina Lusvarghi ◽  
Richard Wang ◽  
Fernando Echegaray ◽  
...  

The SARS-CoV-2 B.1.617 lineage variants, Kappa (B.1.617.1) and Delta (B.1.617.2, AY) emerged during the second wave of infections in India, but the Delta variants have become dominant worldwide and continue to evolve. Here, we compared B.1.617 variants for neutralization resistance by convalescent sera, mRNA vaccine-elicited sera, and therapeutic neutralizing antibodies using a pseudovirus neutralization assay. B.1.617.1, B.1.617.2, and AY.1 pseudoviruses showed a modest 1.5- to 4.4-fold reduction in neutralization by convalescent sera and vaccine-elicited sera. In comparison, similar modest reductions were also observed for C.37, P.1, R.1, and B.1.526 pseudoviruses, but 7- and 16-fold reductions for vaccine-elicited and convalescent sera, respectively, were seen for B.1.351 pseudoviruses. Among twenty-three therapeutic antibodies tested, four antibodies showed either complete or partial loss of neutralization against B.1.617.2 pseudoviruses and six antibodies showed either complete or partial loss of neutralization against B.1.617.1 and AY.1 pseudoviruses. Our results indicate that the current mRNA-based vaccines will likely remain effective in protecting against B.1.617 variants. Finally, the P681R substitution confers efficient cleavage of B.1.617 variants’ spike proteins and the spike of Delta variants exhibited greater sensitivity to soluble ACE2 neutralization, as well as fusogenic activity, which may contribute to enhanced spread of Delta variants.


Author(s):  
Daria V. Grigorieva ◽  
Irina V. Gorudko ◽  
Natalia A. Grudinina ◽  
Oleg M. Panasenko ◽  
Igor V. Semak ◽  
...  

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Stefania D’Apice ◽  
Roberta Paolillo ◽  
Lorena Coretti ◽  
Giovanni Esposito ◽  
Francesca Lembo ◽  
...  

Abstract Aims Mitochondrial A-kinase anchoring proteins (mitoAKAP) encoded by the Akap1 gene promote Protein Kinase A mitochondrial targeting, regulating mitochondrial structure and function, reactive oxygen species production, and cardiomyocyte survival. Whether mitoAKAP levels play a role in cardiac ageing, gut barrier integrity and gut microbiota composition is currently unknown. The aim of this study was to highlight the complex interplay between cardiac dysfunction, gut barrier integrity, gut microbiota composition and ageing in young (6-month-old, 6 m) and old (24-month-old, 24 m) wild type (wt) and Akap1 heterozygous mice (Akap1+/−). Methods and results Cardiac function was noninvasively analysed by echocardiography in 6 m and 24 m wt and Akap1+/− mice. Gut microbial DNA was extracted and gut microbiota composition was analysed by Illumina Mi-Seq analysis. Bioinformatics analysis was carried out to identify major intestinal populations. Alpha diversity within each sample was determined, and then analysed according to genotype and age; then, inter-sample diversity was determined. For each dataset, we used UniFrac to calculate the differences between microbial communities based on phylogenetic distance between taxa sets in a phylogenetic tree. Bioinformatics analyses were performed using the analysis of similarities (ANOSIM). To evaluate the role of mitoAKAPs in intestinal permeability, we analysed intestinal junction proteins expression levels in colon samples of all groups. Variance analysis was performed to determine significance among the groups. Partial loss of Akap1 accelerated the progression of cardiac dysfunction in 24 m mice, as demonstrated by a significantly lower % fractional shortening (%FS) compared to 24 m wt mice (%FS, wt 6 m: 60 ± 3; Akap1−/+ 6 m: 58 ± 5; wt 24 m: 49 ± 6*; Akap1−/+ 24 m: 39 ± 12*§; *P < 0.05 vs. wt 6 m; §P < 0.05 vs. wt 24 m). In 24 m Akap1+/− mice, ageing was associated to enhanced colon permeability, as shown by reduced levels of Ocln and Tjp1 mRNA expression. A principal Co-ordinate analysis of faecal samples based on their unweighted UniFrac distances revealed that samples from Akap1+/− 24 m mice cluster apart from wt 24 m samples, suggesting that Akap1+/− 24 m mice exhibit a different assortment of microbial communities. This observation was supported by ANOSIM R statistic that revealed significant differences in gut microbiota composition between wt and Akap1+/− 24 m mice (ANOSIM R = 0.475, P = 0.023), while no significant differences in bacterial assortment were identified between wt and Akap1+/− 6 m mice. We analysed the differences in abundance of all 2042 Operational Taxonomic Units (OTUs) between age-matched wt and Akap1+/−. We identified 10 OTUs differently represented in wt and Akap1+/− 6 m mice, while a bigger set of bacterial OTUs (19) were different between wt and Akap1+/− 24 m mice. Consistent with previous results in patients with heart failure, we identified Clostridiales, Blautia producta, and R. Torques among differently regulated species. These results are in accordance with previous data on patients with heart failure (HF). Conclusions Partial Akap1 deletion plays an important role in the progression towards HF and modulates colon permeability and gut microbiota composition during ageing. This work highlights the complex interplay between gut microbiota and development of cardiac dysfunction, and characterization of these processes might lead to the development of new diagnostic and therapeutic approaches for cardiac dysfunction.


2021 ◽  
Vol 54 ◽  
pp. 101339
Author(s):  
Joan Serrano ◽  
Jaroslava Seflova ◽  
Jihye Park ◽  
Marsha Pribadi ◽  
Keisuke Sanematsu ◽  
...  

2021 ◽  
Vol 4 (2) ◽  
pp. 126
Author(s):  
Mira Zakiah Rahmah ◽  
Aceng Komarudin Mutaqin

<p><strong>Abstract. </strong>This paper discusses the method of limited-fluctuation credibility, also known as classic credibility. Credibility theory is a technique for predicting future premium rates based on past experience data. Limited fluctuation credibility consists of two credibility, namely full credibility if Z = 1 and partial credibility if Z &lt;1. Full credibility is achieved if the amount of recent data is sufficient for prediction, whereas if the latest data is insufficient then the partial credibility approach is used. Calculations for full and partial credibility standards are used for loss measures such as frequency of claims, size of claims, aggregate losses and net premiums. The data used in this paper is secondary data recorded by the company PT. XYZ in 2014. This data contains data on the frequency of claims and the size of the policyholder's partial loss claims for motor vehicle insurance products category 4 areas 1. Based on the results of the application, the prediction of pure premiums for 2015 cannot be fully based on insurance data for 2014 because the credibility factor value is less than 1. So based on the limited-fluctuation credibility method, the prediction of pure premiums for 2015 must be based on manual values for pure premiums as well as insurance data for 2014. If manual values for pure premium is 2,000,000 rupiah, then the prediction of pure premium for 2015 is 1,849,342 rupiah.</p><p><strong>Keywords</strong><strong>: </strong>limited fluctuation credibility, full credibility, partial credibility and partial loss</p>


Author(s):  
Oleksandr Nychyk ◽  
Gabriel L. Galea ◽  
Matteo Molè ◽  
Dawn Savery ◽  
Nicholas D.E. Greene ◽  
...  

Planar cell polarity (PCP) signalling is vital for initiation of mouse neurulation, with diminished convergent extension (CE) cell movements leading to craniorachischisis, a severe neural tube defect (NTD). Some humans with NTDs also have PCP gene mutations but these are heterozygous, not homozygous as in mice. Other genetic or environmental factors may interact with partial loss of PCP function in human NTDs. We found that reduced sulfation of glycosaminoglycans interacts with heterozygosity for the Lp allele of Vangl2 (a core PCP gene), to cause craniorachischisis in cultured mouse embryos, with rescue by exogenous sulphate. We hypothesised this glycosaminoglycan-PCP interaction may regulate CE but, surprisingly, DiO labeling of the embryonic node demonstrates no abnormality of midline axial extension in sulfation-depleted Lp/+ embryos. Positive-control Lp/Lp embryos show severe CE defects. Abnormalities were detected in the size and shape of somites that flank the closing neural tube in sulfation-depleted Lp/+ embryos. We conclude that failure of closure initiation can arise by a mechanism other than faulty neuroepithelial CE, with possible involvement of matrix-mediated somite expansion, adjacent to the closing neural tube.


Author(s):  
L. Bumke ◽  
N. Wolff ◽  
C. Chluba ◽  
T. Dankwort ◽  
L. Kienle ◽  
...  

AbstractSputtered Ti–rich TiNiCu alloys are known to show excellent cyclic stability. Reversibility is mostly influenced by grain size, crystallographic compatibility and precipitates. Isolating their impact on cyclic stability is difficult. Ti2Cu precipitates for instance are believed to enhance reversibility by showing a dual epitaxy with the B2 and B19 lattice. Their influence on the functional fatigue, if they partly lose the coherency is still unknown. In this study, sputtered Ti53.7Ni24.7Cu21.6 films have been annealed at different temperatures leading to a similar compatibility (λ2 ~ 0.99), grain size and thermal cyclic stability. Films annealed at 550 °C exhibit a superior superelastic fatigue resistance but with reduced transformation temperatures and enthalpies. TEM investigations suggest the formation of Guinier–Preston (GP) zone-like plate precipitates and point towards a coherency relation of the B2 phase and finely distributed Ti2Cu precipitates (~ 60 nm). Films annealed at 700 °C result in the growth of Ti2Cu precipitates (~ 280 nm) with an irregular distribution and a partial loss of their coherency. Thus, GP zones are assumed to cause the reduction of transformation temperatures and enthalpies due to increased internal stresses, whereas the coherency relation of both, Ti2Cu and GP zones, help to increase the superelastic stability, well beyond 107 cycles.


2021 ◽  
Author(s):  
Gopinath Chattopadhyay ◽  
Jayantika Bhowmick ◽  
Kavyashree Manjunath ◽  
Shahbaz Ahmed ◽  
Parveen Goyal ◽  
...  

Most amino acid substitutions in a protein either lead to partial loss of function or are near neutral. Several studies have shown the existence of second-site mutations that can rescue defects caused by diverse loss of function mutations. Such global suppressor mutations are key drivers of protein evolution. However, the mechanisms responsible for such suppression remain poorly understood. To address this, we characterized multiple suppressor mutations both in isolation and in combination with inactive mutants. We examined five global suppressors of the bacterial toxin CcdB, the known M182T global suppressor of TEM-1 β-lactamase, the N239Y global suppressor of p53-DBD and three suppressors of the SARS-CoV-2 spike Receptor Binding Domain. The suppressors both alone, and in conjunction with inactive mutants, stabilise the protein both thermodynamically and kinetically in-vitro, predominantly through acceleration of the refolding rate parameters. When coupled to inactive mutants they promote increased in-vivo solubilities as well as regain-of-function phenotypes. Our study also demonstrates that the global suppressor approach can be used to consistently stabilise wild-type proteins, including for downstream translational applications.


Sign in / Sign up

Export Citation Format

Share Document