scholarly journals Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity

2020 ◽  
Author(s):  
Ada Admin ◽  
Hanieh Yaghootkar ◽  
Yiying Zhang ◽  
Cassandra N Spracklen ◽  
Tugce Karaderi ◽  
...  
Keyword(s):  
African Ancestry ◽  
Genetic Regulation ◽  
Missense Variant ◽  
Genetic Studies ◽  
Novel Variants ◽  
The Status ◽  
Fat Stores ◽  
Polygenic Obesity

Leptin influences food intake by informing the brain about the status of body fat stores. Rare <i>LEP</i> mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in <i>LEP, ZNF800, KLHL31</i>, and <i>ACTL9</i>, and one intergenic variant near <i>KLF14.</i> The missense variant Val94Met (rs17151919) in <i>LEP</i> was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10<sup>-16</sup>, n=3,901). Using <i>in vitro</i> analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

scholarly journals Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity

2020 ◽  
Author(s):  
Ada Admin ◽  
Hanieh Yaghootkar ◽  
Yiying Zhang ◽  
Cassandra N Spracklen ◽  
Tugce Karaderi ◽  
...  
Keyword(s):  
African Ancestry ◽  
Genetic Regulation ◽  
Missense Variant ◽  
Genetic Studies ◽  
Novel Variants ◽  
The Status ◽  
Fat Stores ◽  
Polygenic Obesity

Leptin influences food intake by informing the brain about the status of body fat stores. Rare <i>LEP</i> mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in <i>LEP, ZNF800, KLHL31</i>, and <i>ACTL9</i>, and one intergenic variant near <i>KLF14.</i> The missense variant Val94Met (rs17151919) in <i>LEP</i> was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10<sup>-16</sup>, n=3,901). Using <i>in vitro</i> analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

scholarly journals Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity

2020 ◽  
Author(s):  
Ada Admin ◽  
Hanieh Yaghootkar ◽  
Yiying Zhang ◽  
Cassandra N Spracklen ◽  
Tugce Karaderi ◽  
...  
Keyword(s):  
African Ancestry ◽  
Genetic Regulation ◽  
Missense Variant ◽  
Genetic Studies ◽  
Novel Variants ◽  
The Status ◽  
Fat Stores ◽  
Polygenic Obesity

Leptin influences food intake by informing the brain about the status of body fat stores. Rare <i>LEP</i> mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in <i>LEP, ZNF800, KLHL31</i>, and <i>ACTL9</i>, and one intergenic variant near <i>KLF14.</i> The missense variant Val94Met (rs17151919) in <i>LEP</i> was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10<sup>-16</sup>, n=3,901). Using <i>in vitro</i> analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

scholarly journals Comparative Analysis of In Vitro Responses and Regeneration between Diverse Bioenergy Sorghum Genotypes

Plants ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 248
Author(s):  
Barry Flinn ◽  
Savanah Dale ◽  
Andrew Disharoon ◽  
Stephen Kresovich
Keyword(s):  
Plantlet Regeneration ◽  
Induction Phase ◽  
Genetic Studies ◽  
Response Profiles ◽  
The Common ◽  
Parental Lines ◽  
Sorghum Genotypes ◽  
Better Than

Sorghum has been considered a recalcitrant plant in vitro and suffers from a lack of regeneration protocols that function broadly and efficiently across a range of genotypes. This study was initiated to identify differential genotype-in vitro protocol responses across a range of bioenergy sorghum parental lines and the common grain sorghum genotype Tx430 in order to characterize response profiles for use in future genetic studies. Two different in vitro protocols, LG and WU, were used for comparisons. Distinct genotype-protocol responses were observed, and the WU protocol performed significantly better for plantlet regeneration. Most bioenergy genotypes performed as well, if not better than Tx430, with Rio and PI329311 as the top regenerating lines. Genotypes displayed protocol-dependent, differential phenolic exudation responses, as indicated by medium browning. During the callus induction phase, genotypes prone to medium browning exhibited a response on WU medium which was either equal or greater than on LG medium. Genotype- and protocol-dependent albino plantlet regeneration was also noted, with three of the bioenergy genotypes showing albino plantlet regeneration. Grassl, Rio and Pink Kafir were susceptible to albino plantlet regeneration, with the response strongly associated with the WU protocol. These bioenergy parental genotypes, and their differential responses under two in vitro protocols, provide tools to further explore and assess the role of genetic loci, candidate genes, and allelic variants in the regulation of in vitro responsiveness in sorghum.

scholarly journals Wingless-Type MMTV Integration Site Family Member 5a Is a Key Secreted Islet Stellate Cell-Derived Product that Regulates Islet Function

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Wei Xu ◽  
Jun Liang ◽  
H. F. Geng ◽  
Jun Lu ◽  
Rui Li ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Family Member ◽  
Stellate Cell ◽  
Integration Site ◽  
Islet Function ◽  
Insulin Production ◽  
The Status ◽  
Secretory Products

Background. Emerging evidence suggests that T2DM is attributable to the dysfunction of β-cells and the activation of islet stellate cells (ISCs). The wingless-type MMTV integration site family member 5a (Wnt5a)/frizzled 5 (Fzd5) signalling pathway might take part in this process. Our study is aimed at defining the status of ISCs during β-cell insulin secretion homeostasis by determining the role of the Wnt5a protein in the regulation of insulin production. We examined the effects of the status of ISCs on β-cell insulin secretion in normoglycemic db/m and hyperglycaemic db/db mice. Methods. iTRAQ protein screening and RNA interference were used to determine novel ISC-derived secretory products that may use other mechanisms to influence the function of islets. Results. We showed a significant reduction in insulin secretion by β-cells in vitro when they were cocultured with db/db ISCs compared to when they were cocultured with ISCs isolated from normoglycemic db/m mice; in addition, both Wnt5a and its receptor Fzd5 were more highly expressed by quiescent ISCs than by activated db/db ISCs. Treatment with exogenous Wnt5a increased the secretion of insulin in association with the deactivation of ISCs. Conclusion. Our observations revealed that the Wnt5a protein is a key effector of ISC-mediated improvement in islet function.

scholarly journals Molecular mechanism and physiological role of active–deactive transition of mitochondrial complex I

2013 ◽  
Vol 41 (5) ◽  
pp. 1325-1330 ◽  
Author(s):  
Marion Babot ◽  
Alexander Galkin
Keyword(s):  
Complex I ◽  
Physiological Role ◽  
Protective Mechanism ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
The Status ◽  
Nitric Oxide Metabolites

The unique feature of mitochondrial complex I is the so-called A/D transition (active–deactive transition). The A-form catalyses rapid oxidation of NADH by ubiquinone (k ~104 min−1) and spontaneously converts into the D-form if the enzyme is idle at physiological temperatures. Such deactivation occurs in vitro in the absence of substrates or in vivo during ischaemia, when the ubiquinone pool is reduced. The D-form can undergo reactivation given both NADH and ubiquinone availability during slow (k ~1–10 min−1) catalytic turnover(s). We examined known conformational differences between the two forms and suggested a mechanism exerting A/D transition of the enzyme. In addition, we discuss the physiological role of maintaining the enzyme in the D-form during the ischaemic period. Accumulation of the D-form of the enzyme would prevent reverse electron transfer from ubiquinol to FMN which could lead to superoxide anion generation. Deactivation would also decrease the initial burst of respiration after oxygen reintroduction. Therefore the A/D transition could be an intrinsic protective mechanism for lessening oxidative damage during the early phase of reoxygenation. Exposure of Cys39 of mitochondrially encoded subunit ND3 makes the D-form susceptible for modification by reactive oxygen species and nitric oxide metabolites which arrests the reactivation of the D-form and inhibits the enzyme. The nature of thiol modification defines deactivation reversibility, the reactivation timescale, the status of mitochondrial bioenergetics and therefore the degree of recovery of the ischaemic tissues after reoxygenation.

scholarly journals Src-dependent NM2A tyrosine-phosphorylation regulates actomyosin dynamics

2020 ◽  
Author(s):  
Cláudia Brito ◽  
Francisco S. Mesquita ◽  
Daniel S. Osório ◽  
Joana Pereira ◽  
Neil Billington ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Cell Biology ◽  
Bacterial Infections ◽  
Focal Adhesions ◽  
The Status ◽  
Fine Control ◽  
Actomyosin Cytoskeleton

AbstractNon-muscle myosin 2A (NM2A) is a key cytoskeletal enzyme that along with actin assembles into actomyosin filaments inside cells. NM2A is fundamental in cellular processes requiring force generation such as cell adhesion, motility and cell division, and plays important functions in different stages of development and during the progression of viral and bacterial infections. We previously identified at the motor domain of the NM2A, a novel Src-dependent tyrosine phosphorylation on residue 158 (pTyr158), which is promoted by Listeria monocytogenes infection. Despite the central role of NM2A in several cell biology processes, the pTyr at this specific residue had never been reported. Here we showed that LLO, a toxin secreted by Listeria, is sufficient to trigger NM2A pTyr158 by activating Src, which coordinates actomyosin remodeling. We further addressed the role of NM2A pTyr158 on the organization and dynamics of the actomyosin cytoskeleton and found that by controlling the activation of the NM2A, the status of the pTyr158 alters cytoskeletal organization, dynamics of focal adhesions and cell motility, without affecting NM2A enzymatic activity in vitro. Ultimately, by using Caenorhabditis elegans as a model to assess the role of this pTyr158in vivo, we found that the status of the pTyr158 has implications in gonad function and is required for organism survival under stress conditions. We conclude that the fine control of the NM2A pTyr158 is required for cell cytoskeletal remodeling and dynamics, and we propose Src-dependent NM2A pTyr158 as a novel layer of regulation of the actomyosin cytoskeleton.

scholarly journals PLOD1 Is a Prognostic Biomarker and Mediator of Proliferation and Invasion in Osteosarcoma

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Haoli Jiang ◽  
Wei Guo ◽  
Shanyou Yuan ◽  
Lixia Song
Keyword(s):  
Survival Analysis ◽  
Expression Pattern ◽  
Migration And Invasion ◽  
Western Blots ◽  
Primary Bone Tumor ◽  
Kaplan Meier ◽  
The Status ◽  
Public Datasets

Objective. Osteosarcoma is the most common primary bone tumor and most frequently develops during adolescence. PLOD family was mainly involved in lysyl hydroxylation and rarely investigated in cancers, especially in osteosarcoma. The aim of this study was to investigate the expression pattern and oncogenic role of PLODs in osteosarcoma. Methods. GEO datasets (GSE16088, GSE33382, and GSE16091) and validation cohort were used to analyze the expression pattern of PLODs in osteosarcoma. Kaplan-Meier survival analysis was used to explore the prognostic role of PLODs in patients with osteosarcoma. RNA interference of KRT19 was performed using small interfering RNA (siRNA) in MG-63 and U-2OS cells. The proliferation was detected using CCK8, clone formation assay, and EdU staining. Migration and invasion were determined using the transwell assay. Western blots and luciferase assays for β-catenin-T-cell factor protein/β-catenin-lymphoid enhancer factor- (β-catenin-TCF/LEF-) driven transcriptional activity. Results. PLOD1 was upregulated in osteosarcoma tissues compared with control tissues both in public datasets and in in-house cohort. The expression of PLOD1 in osteosarcoma tissues was significantly associated with the status of distance metastasis and Enneking stage, while PLOD2 and PLOD3 expressed no difference between osteosarcoma and benign tissues and showed no correlation with tumor malignancy. Furthermore, Kaplan-Meier survival analysis revealed that patients with a higher level of PLOD1 had worse prognosis than those with a lower level of PLOD1. Downregulation of PLOD1 dramatically inhibited proliferation, migration, and invasion of MG-63 cells and U-2OS cells in vitro. Mechanistically, PLOD1 regulated β-catenin signaling pathway in osteosarcoma. Conclusion. Our results indicated that PLOD1 promoted proliferation, migration, and invasion of osteosarcoma cells. PLOD1 was a novel prognostic marker, as well as a therapeutic target in osteosarcoma.

Implications of genetics for the epidemiology and control of leprosy

1988 ◽  
Vol 321 (1207) ◽  
pp. 365-376 ◽  
Keyword(s):  
Racial Differences ◽  
Genetic Studies ◽  
Disease Clusters ◽  
Hla Dr ◽  
History Of ◽  
Genetic Mechanisms ◽  
Specific Reactions ◽  
And Control

This paper reviews the rationale and history of genetic studies related to leprosy, and considers their implications for the epidemiology and control of the disease. A long tradition of genetic studies in leprosy was initiated by early impressions that the disease clusters within families. Investigations were first motivated by an attempt to understand population patterns, and the focus shifted from investigations of racial differences to investigations of families, of twins and ultimately of genetic markers. The strongest evidence for genetic influence has come from studies of HLA segregation patterns within families, and this has led to elegant in vitro work demonstrating the role of HLA-DR alleles in mediating T-cell reactions in conjunction with antigens of Mycobacterium leprae . The epidemiological implications of this work are not yet clear. The emphasis on family-segregation studies may have given a biased impression because of their requirement for multi-case families. There is evidence that the genetic mechanisms underlying leprosy differ within and between populations. One possible application of the current work would be the use of HLA-DR-specific reactions to identify epitopes of M. leprae which should be excluded from future vaccine preparations.

scholarly journals Human Enteric Defensin 5 Promotes Shigella Infection of Macrophages

2019 ◽  
Vol 88 (1) ◽  
Author(s):  
Dan Xu ◽  
Chongbing Liao ◽  
Jiu Xiao ◽  
Kun Fang ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Intestinal Epithelium ◽  
Protective Factor ◽  
Antimicrobial Activities ◽  
The Status ◽  
Host Defense Peptide ◽  
Type 3 Secretion System ◽  
Type 3

ABSTRACT Human α-defensins are 3- to 5-kDa disulfide-bridged peptides with a multitude of antimicrobial activities and immunomodulatory functions. Recent studies show that human enteric α-defensin 5 (HD5), a host defense peptide important for intestinal homeostasis and innate immunity, aids the highly infectious enteropathogen Shigella in breaching the intestinal epithelium in vitro and in vivo. Whether and how HD5 influences Shigella infection of resident macrophages following its invasion of the intestinal epithelium remain poorly understood. Here, we report that HD5 greatly promoted phagocytosis of Shigella by macrophages by targeting the bacteria to enhance bacterium-to-cell contacts in a structure- and sequence-dependent fashion. Subsequent intracellular multiplication of phagocytosed Shigella led to massive necrotic cell death and release of the bacteria. HD5-promoted phagocytosis of Shigella was independent of the status of the type 3 secretion system. Furthermore, HD5 neither inhibited nor enhanced phagosomal escape of Shigella. Collectively, these findings confirm a potential pathogenic role of HD5 in Shigella infection of not only epithelial cells but also macrophages, illuminating how an enteropathogen exploits a host protective factor for virulence and infection.

scholarly journals Autosomal Recessive Retinitis Pigmentosa Associated with Three Novel REEP6 Variants in Chinese Population

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 537
Author(s):  
Lujia Zhang ◽  
Ya Li ◽  
Litao Qin ◽  
Yu Wu ◽  
Bo Lei
Keyword(s):  
Retinitis Pigmentosa ◽  
Autosomal Recessive ◽  
Cultured Cells ◽  
Missense Variant ◽  
Chinese Families ◽  
Targeted Next Generation Sequencing ◽  
Novel Variants ◽  
Next Generation Sequencing Ngs ◽  
Computational Predictions

Retinitis pigmentosa 77 is caused by mutations of REEP6 (MIM: 609346), which encodes a protein for the development of photoreceptors. Our study was to identify disease-causing variants in three Chinese families using targeted next-generation sequencing (NGS). Multiple lines of computational predictions combined with in vitro cellular experiments were applied to evaluate the pathogenicity of the newly found variants. Three novel variants in REEP6, including one missense variant, c.268G>C, one frameshift variant, c.468delC, and one splicing variant, c.598+1G>C, were found, while c.268G>C was detected in all probands. The three variants were classified as likely pathogenic by the American College of Medical Genetics and Genomics (ACMG). REEP6 variant proteins c.268G>C and c.468delC in cultured cells destabilized the REEP6 protein and induced intracellular inclusions. Our data suggested that REEP6 c.268G>C may be a recurrent causative variant in Chinese autosomal recessive retinitis pigmentosa patients.

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