Input: Psoriasin promotes invasion , aggregation and survival of pancreatic cancer cells ; association with disease progression . Psoriasin ( S100A7 ) is an 11 - kDa small calcium binding protein initially isolated from psoriatic skin lesions . It belongs to the S100 family of proteins which play an important role in a range of cell functions including proliferation , differentiation , migration and apoptosis . Aberrant Psoriasin expression has been implicated in a range of cancers and is often associated with poor prognosis . This study examined the role of Psoriasin on pancreatic cancer cell functions and the implication in progression of the disease . Expression of Psoriasin was determined in a cohort of pancreatic tissues comprised of 126 pancreatic tumours and 114 adjacent non - tumour pancreatic tissues . Knockdown and overexpression of Psoriasin in pancreatic cancer cells was performed using specifically constructed plasmids , which either had anti - Psoriasin ribozyme transgene or the full length human Psoriasin coding sequence . Psoriasin knockdown and overexpression was verified using conventional RT - PCR and qPCR . The effect of manipulating Psoriasin expression on pancreatic cancer cell functions was assessed using several in vitro cell function assays . Local invasive pancreatic cancers extended beyond the pancreas expressed higher levels of Psoriasin transcripts compared with the cancers confined to the pancreas . Primary tumours with distant metastases exhibited a reduced expression of Psoriasin . Psoriasin overexpression cell lines exhibited significantly increased growth and migration compared to control cells . In addition , Psoriasin overexpression resulted in increased pancreatic cancer cell invasion which was associated with upregulation of matrix metalloproteinase - 2 ( MMP - 2 ) and MMP - 9 . Overexpression of Psoriasin also promoted aggregation and survival of pancreatic cancer cells when they lost anchorage . Taken together , higher expression of Psoriasin was associated with local invasion in pancreatic cancers . Psoriasin expression is associated with pancreatic cancer cell growth , migration , cell - matrix adhesion , and invasion via regulation of MMPs . As such , the proposed implications of Psoriasin in invasion , disease progression and as a potential therapeutic target warrant further investigation .

Psoriasin

Psoriasin

calcium binding protein

Psoriasin

Psoriasin

Psoriasin

Psoriasin

Psoriasin

Psoriasin

Psoriasin

Psoriasin

Psoriasin

Psoriasin

Psoriasin

Psoriasin

matrix metalloproteinase - 2

MMP - 2

MMP - 9

Psoriasin

Psoriasin

Psoriasin

MMPs

Psoriasin

pancreatic cancer

psoriatic skin lesions

cancers

pancreatic cancer

pancreatic tumours

pancreatic cancer

pancreatic cancer

pancreatic cancers

cancers

Primary tumours

metastases

pancreatic cancer

pancreatic cancer

pancreatic cancers

pancreatic cancer

human

pancreatic cancer

MMP - 9

pancreatic cancer

MMPs

pancreatic cancer

MMP - 9

pancreatic cancer

MMPs

pancreatic tumours

MMP - 9

pancreatic tumours

MMPs

pancreatic cancer

MMP - 9

pancreatic cancer

MMPs

pancreatic cancer

MMP - 9

pancreatic cancer

MMPs

pancreatic cancers

MMP - 9

pancreatic cancers

MMPs

pancreatic cancer

MMP - 9

pancreatic cancer

MMPs

pancreatic cancer

MMP - 9

pancreatic cancer

MMPs

pancreatic cancers

MMP - 9

pancreatic cancers

MMPs

pancreatic cancer

MMP - 9

pancreatic cancer

MMPs

pancreatic cancer

matrix metalloproteinase - 2

pancreatic cancer

MMP - 2

pancreatic cancer

matrix metalloproteinase - 2

pancreatic cancer

MMP - 2

pancreatic tumours

matrix metalloproteinase - 2

pancreatic tumours

MMP - 2

pancreatic cancer

matrix metalloproteinase - 2

pancreatic cancer

MMP - 2

pancreatic cancer

matrix metalloproteinase - 2

pancreatic cancer

MMP - 2

pancreatic cancers

matrix metalloproteinase - 2

pancreatic cancers

MMP - 2

pancreatic cancer

matrix metalloproteinase - 2

pancreatic cancer

MMP - 2

pancreatic cancer

matrix metalloproteinase - 2

pancreatic cancer

MMP - 2

pancreatic cancers

matrix metalloproteinase - 2

pancreatic cancers

MMP - 2

pancreatic cancer

matrix metalloproteinase - 2

pancreatic cancer

MMP - 2

Psoriasin

MMP - 9

Psoriasin

MMPs

Psoriasin

MMP - 9

Psoriasin

MMPs

MMP - 9

MMPs

calcium binding protein

MMP - 9

calcium binding protein

MMPs

MMP - 9

MMPs

Psoriasin

MMP - 9

Psoriasin

MMPs

Psoriasin

MMP - 9

Psoriasin

MMPs

Psoriasin

MMP - 9

Psoriasin

MMPs

Psoriasin

MMP - 9

Psoriasin

MMPs

Psoriasin

MMP - 9

Psoriasin

MMPs

Psoriasin

MMP - 9

Psoriasin

MMPs

Psoriasin

MMP - 9

Psoriasin

MMPs

Psoriasin

MMP - 9

Psoriasin

MMPs

Psoriasin

MMP - 9

Psoriasin

MMPs

Psoriasin

MMP - 9

Psoriasin

MMPs

Psoriasin

MMP - 9

Psoriasin

MMPs

Psoriasin

MMP - 9

Psoriasin

MMPs

Psoriasin

MMP - 9

Psoriasin

MMPs

Psoriasin

MMP - 9

Psoriasin

MMPs

Psoriasin

MMP - 9

Psoriasin

MMPs

Psoriasin

MMP - 9

Psoriasin

MMPs

Psoriasin

matrix metalloproteinase - 2

Psoriasin

MMP - 2

Psoriasin

matrix metalloproteinase - 2

Psoriasin

MMP - 2

matrix metalloproteinase - 2

MMP - 2

calcium binding protein

matrix metalloproteinase - 2

calcium binding protein

MMP - 2

matrix metalloproteinase - 2

MMP - 2

Psoriasin

matrix metalloproteinase - 2

Psoriasin

MMP - 2

Psoriasin

matrix metalloproteinase - 2

Psoriasin

MMP - 2

Psoriasin

matrix metalloproteinase - 2

Psoriasin

MMP - 2

Psoriasin

matrix metalloproteinase - 2

Psoriasin

MMP - 2

Psoriasin

matrix metalloproteinase - 2

Psoriasin

MMP - 2

Psoriasin

matrix metalloproteinase - 2

Psoriasin

MMP - 2

Psoriasin

matrix metalloproteinase - 2

Psoriasin

MMP - 2

Psoriasin

matrix metalloproteinase - 2

Psoriasin

MMP - 2

Psoriasin

matrix metalloproteinase - 2

Psoriasin

MMP - 2

Psoriasin

matrix metalloproteinase - 2

Psoriasin

MMP - 2

Psoriasin

matrix metalloproteinase - 2

Psoriasin

MMP - 2

Psoriasin

matrix metalloproteinase - 2

Psoriasin

MMP - 2

Psoriasin

matrix metalloproteinase - 2

Psoriasin

MMP - 2

Psoriasin

matrix metalloproteinase - 2

Psoriasin

MMP - 2

Psoriasin

matrix metalloproteinase - 2

Psoriasin

MMP - 2

Psoriasin

matrix metalloproteinase - 2

Psoriasin

MMP - 2

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic tumours

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic tumours

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

pancreatic cancer

pancreatic cancer

pancreatic tumours

pancreatic cancer

pancreatic cancer

pancreatic cancers

pancreatic cancer

pancreatic cancer

pancreatic cancers

pancreatic cancer

calcium binding protein

pancreatic cancer

calcium binding protein

pancreatic cancer

calcium binding protein

pancreatic tumours

calcium binding protein

pancreatic cancer

calcium binding protein

pancreatic cancer

calcium binding protein

pancreatic cancers

calcium binding protein

pancreatic cancer

calcium binding protein

pancreatic cancer

calcium binding protein

pancreatic cancers

calcium binding protein

pancreatic cancer

pancreatic cancer

pancreatic cancer

pancreatic tumours

pancreatic cancer

pancreatic cancer

pancreatic cancers

pancreatic cancer

pancreatic cancer

pancreatic cancers

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic tumours

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic tumours

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic tumours

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic tumours

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic tumours

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic tumours

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic tumours

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic tumours

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic tumours

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic tumours

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic tumours

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic tumours

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic tumours

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic tumours

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic tumours

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic tumours

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancer

Psoriasin

pancreatic cancers

Psoriasin

pancreatic cancer

Psoriasin

cancers

Psoriasin

cancers

Psoriasin

Primary tumours

Psoriasin

cancers

Psoriasin

cancers

Psoriasin

Primary tumours

cancers

cancers

Primary tumours

calcium binding protein

cancers

calcium binding protein

cancers

calcium binding protein

Primary tumours

cancers

cancers

Primary tumours

Psoriasin

cancers

Psoriasin

cancers

Psoriasin

Primary tumours

Psoriasin

cancers

Psoriasin

cancers

Psoriasin

Primary tumours

Psoriasin

cancers

Psoriasin

cancers

Psoriasin

Primary tumours

Psoriasin

cancers

Psoriasin

cancers

Psoriasin

Primary tumours

Psoriasin

cancers

Psoriasin

cancers

Psoriasin

Primary tumours

Psoriasin

cancers

Psoriasin

cancers

Psoriasin

Primary tumours

Psoriasin

cancers

Psoriasin

cancers

Psoriasin

Primary tumours

Psoriasin

cancers

Psoriasin

cancers

Psoriasin

Primary tumours

Psoriasin

cancers

Psoriasin

cancers

Psoriasin

Primary tumours

Psoriasin

cancers

Psoriasin

cancers

Psoriasin

Primary tumours

Psoriasin

cancers

Psoriasin

cancers

Psoriasin

Primary tumours

Psoriasin

cancers

Psoriasin

cancers

Psoriasin

Primary tumours

Psoriasin

cancers

Psoriasin

cancers

Psoriasin

Primary tumours

Psoriasin

cancers

Psoriasin

cancers

Psoriasin

Primary tumours

Psoriasin

cancers

Psoriasin

cancers

Psoriasin

Primary tumours

Psoriasin

cancers

Psoriasin

cancers

Psoriasin

Primary tumours

Psoriasin

psoriatic skin lesions

Psoriasin

psoriatic skin lesions

psoriatic skin lesions

calcium binding protein

psoriatic skin lesions

psoriatic skin lesions

Psoriasin

psoriatic skin lesions

Psoriasin

psoriatic skin lesions

Psoriasin

psoriatic skin lesions

Psoriasin

psoriatic skin lesions

Psoriasin

psoriatic skin lesions

Psoriasin

psoriatic skin lesions

Psoriasin

psoriatic skin lesions

Psoriasin

psoriatic skin lesions

Psoriasin

psoriatic skin lesions

Psoriasin

psoriatic skin lesions

Psoriasin

psoriatic skin lesions

Psoriasin

psoriatic skin lesions

Psoriasin

psoriatic skin lesions

Psoriasin

psoriatic skin lesions

Psoriasin

psoriatic skin lesions

Psoriasin

psoriatic skin lesions


Input: Two novel mutations in SRY gene form Chinese sex reversal XY females . The SRY gene ( sex determining region on Y chromosome ) acts as TDF and is required for regulating male sex determination . SRY represents a transcription factor belonging to the superfamily of genes sharing the HMG - box motif ( high - mobility group - box ) , which acts as DNA binding region . Deletion and inactivating mutations of SRY are among the known causes of XY sex reversal . Here , we described the screening of 10 patients who presented with 46 , XY sex reversal for mutations in open reading frame ( ORF ) of SRY gene . DNA was isolated from blood samples using standard techniques . A 609 bp fragment from the central portion of the SRY gene was amplified , using primers XES - 2 and XES - 7 . The amplified PCR fragments were cloned into the pUCm - T vectors , and direct sequencing were carried out on an ABI 377 - 3 automated DNA sequencer to detect the mutation . PCR - restriction enzyme digestion was applied to detect the results of DNA sequencing . In two patients , de novo mutations led to an amino acid substitution . An A was replaced by a G in codon 38 upstream of the 5 ' border outside the HMG box of the SRY gene , resulting in the replacement of the amino acid glutamate by glycine . Another heterozygous T to A transition at the nucleotide position + 387 which encodes for a Tyrosine ( Tyr ) instead of a Term , whereas her father was proven to have the wild - type sequence . These point mutations have been confirmed with PCR - restrict enzyme method . As demonstrated by the Human Gene Mutation Database analysis , homology search , and review of the literature , these two mutations were not described previously and brought the total number of SRY gene nucleotide substitutions ( missense / nonsense ) to 45 . These findings indicated that these amino acid substitutions may be responsible for the sex reversal , not only inside the HMG - box but also outside the HMG - box . The two novel mutations in SRY gene provided valuable information for understanding the molecular mechanism of the patient with 46 , XY female sex reversal .

SRY

SRY

SRY

SRY

SRY

SRY

SRY

SRY

SRY

sex reversal XY

XY sex reversal

46 , XY sex reversal

sex reversal

46 , XY female sex reversal

patients

patients

Human

patient

A was replaced by a G in codon 38

glutamate by glycine

T to A transition at the nucleotide position + 387

Tyrosine ( Tyr ) instead of a Term

sex reversal XY

A was replaced by a G in codon 38

XY sex reversal

A was replaced by a G in codon 38

46 , XY sex reversal

A was replaced by a G in codon 38

sex reversal

A was replaced by a G in codon 38

46 , XY female sex reversal

A was replaced by a G in codon 38

sex reversal XY

Tyrosine ( Tyr ) instead of a Term

XY sex reversal

Tyrosine ( Tyr ) instead of a Term

46 , XY sex reversal

Tyrosine ( Tyr ) instead of a Term

sex reversal

Tyrosine ( Tyr ) instead of a Term

46 , XY female sex reversal

Tyrosine ( Tyr ) instead of a Term

sex reversal XY

T to A transition at the nucleotide position + 387

XY sex reversal

T to A transition at the nucleotide position + 387

46 , XY sex reversal

T to A transition at the nucleotide position + 387

sex reversal

T to A transition at the nucleotide position + 387

46 , XY female sex reversal

T to A transition at the nucleotide position + 387

sex reversal XY

glutamate by glycine

XY sex reversal

glutamate by glycine

46 , XY sex reversal

glutamate by glycine

sex reversal

glutamate by glycine

46 , XY female sex reversal

glutamate by glycine

sex reversal XY

SRY

sex reversal XY

SRY

sex reversal XY

SRY

sex reversal XY

SRY

sex reversal XY

SRY

sex reversal XY

SRY

sex reversal XY

SRY

sex reversal XY

SRY

sex reversal XY

SRY

XY sex reversal

SRY

XY sex reversal

SRY

XY sex reversal

SRY

XY sex reversal

SRY

XY sex reversal

SRY

XY sex reversal

SRY

XY sex reversal

SRY

XY sex reversal

SRY

XY sex reversal

SRY

46 , XY sex reversal

SRY

46 , XY sex reversal

SRY

46 , XY sex reversal

SRY

46 , XY sex reversal

SRY

46 , XY sex reversal

SRY

46 , XY sex reversal

SRY

46 , XY sex reversal

SRY

46 , XY sex reversal

SRY

46 , XY sex reversal

SRY

sex reversal

SRY

sex reversal

SRY

sex reversal

SRY

sex reversal

SRY

sex reversal

SRY

sex reversal

SRY

sex reversal

SRY

sex reversal

SRY

sex reversal

SRY

46 , XY female sex reversal

SRY

46 , XY female sex reversal

SRY

46 , XY female sex reversal

SRY

46 , XY female sex reversal

SRY

46 , XY female sex reversal

SRY

46 , XY female sex reversal

SRY

46 , XY female sex reversal

SRY

46 , XY female sex reversal

SRY

46 , XY female sex reversal

SRY


Input: A novel missense mutation , F826Y , in the mineralocorticoid receptor gene in Japanese hypertensives : its implications for clinical phenotypes . A gain - of - function mutation resulting in the S810L amino acid substitution in the hormone - binding domain of the mineralocorticoid receptor ( MR , locus symbol NR3C2 ) is responsible for early - onset hypertension that is exacerbated in pregnancy . The objective of this study was to test whether other types of missense mutations in the hormone - binding domain could be implicated in hypertension in Japanese . Here , we screened 942 Japanese patients with hypertension for the S810L mutation in exon 6 in the MR . We did not identify the S810L mutation in our hypertensive population , indicating that S810L does not play a major role in the etiology of essential hypertension in Japanese . However , we identified a novel missense mutation , F826Y , in three patients in a heterozygous state , in addition to four single nucleotide polymorphisms , including one synonymous mutation ( L809L ) . The F826Y mutation is present in the MR hormone - binding domain and might affect the ligand affinity . The F826Y mutation was also identified in 13 individuals ( 5 hypertensives and 8 normotensives ) in a Japanese general population ( n = 3 , 655 ) . The allele frequency was 0 . 00178 . The frequencies of the F826Y mutation in the hypertensive population ( 3 / 942 ) and in the hypertensive group ( 5 / 1 , 480 ) and the normotensive group ( 8 / 2 , 175 ) in the general population were not significantly different , suggesting that this mutation does not greatly affect hypertension . Although it is unclear at present whether or not the F826Y mutation makes a substantial contribution to the mineralocorticoid receptor activity , this missense mutation may contribute , to some extent , to clinical phenotypes through its effects on MR .

mineralocorticoid receptor

mineralocorticoid receptor

MR

MR

MR

mineralocorticoid receptor

MR

hypertensives

hypertension

hypertension

hypertension

hypertensive

essential hypertension

hypertensives

hypertensive

hypertensive

hypertension

patients

patients

hypertensives

hypertension

hypertension

hypertension

hypertensive

hypertensives

hypertensive

hypertensive

hypertension

hypertensives

hypertension

hypertension

hypertension

hypertensive

hypertensives

hypertensive

hypertensive

hypertension

hypertensives

hypertension

hypertension

hypertension

hypertensive

hypertensives

hypertensive

hypertensive

hypertension

hypertensives

hypertension

hypertension

hypertension

hypertensive

hypertensives

hypertensive

hypertensive

hypertension

essential hypertension

mineralocorticoid receptor

hypertensives

mineralocorticoid receptor

hypertension

mineralocorticoid receptor

hypertension

mineralocorticoid receptor

hypertension

mineralocorticoid receptor

hypertensive

mineralocorticoid receptor

hypertensives

mineralocorticoid receptor

hypertensive

mineralocorticoid receptor

hypertensive

mineralocorticoid receptor

hypertension

mineralocorticoid receptor

hypertensives

mineralocorticoid receptor

hypertension

mineralocorticoid receptor

hypertension

mineralocorticoid receptor

hypertension

mineralocorticoid receptor

hypertensive

mineralocorticoid receptor

hypertensives

mineralocorticoid receptor

hypertensive

mineralocorticoid receptor

hypertensive

mineralocorticoid receptor

hypertension

MR

hypertensives

MR

hypertension

MR

hypertension

MR

hypertension

MR

hypertensive

MR

hypertensives

MR

hypertensive

MR

hypertensive

MR

hypertension

hypertensives

hypertension

hypertension

hypertension

hypertensive

hypertensives

hypertensive

hypertensive

hypertension

MR

hypertensives

MR

hypertension

MR

hypertension

MR

hypertension

MR

hypertensive

MR

hypertensives

MR

hypertensive

MR

hypertensive

MR

hypertension

MR

hypertensives

MR

hypertension

MR

hypertension

MR

hypertension

MR

hypertensive

MR

hypertensives

MR

hypertensive

MR

hypertensive

MR

hypertension

mineralocorticoid receptor

hypertensives

mineralocorticoid receptor

hypertension

mineralocorticoid receptor

hypertension

mineralocorticoid receptor

hypertension

mineralocorticoid receptor

hypertensive

mineralocorticoid receptor

hypertensives

mineralocorticoid receptor

hypertensive

mineralocorticoid receptor

hypertensive

mineralocorticoid receptor

hypertension

MR

hypertensives

MR

hypertension

MR

hypertension

MR

hypertension

MR

hypertensive

MR

hypertensives

MR

hypertensive

MR

hypertensive

MR

hypertension

hypertensives

hypertension

hypertension

hypertension

hypertensive

hypertensives

hypertensive

hypertensive

hypertension

hypertensives

hypertension

hypertension

hypertension

hypertensive

hypertensives

hypertensive

hypertensive

hypertension

hypertensives

hypertension

hypertension

hypertension

hypertensive

hypertensives

hypertensive

hypertensive

hypertension

hypertensives

hypertension

hypertension

hypertension

hypertensive

hypertensives

hypertensive

hypertensive

hypertension

hypertensives

hypertension

hypertension

hypertension

hypertensive

hypertensives

hypertensive

hypertensive

hypertension

hypertensives

hypertension

hypertension

hypertension

hypertensive

hypertensives

hypertensive

hypertensive

hypertension


Input: Myocardial Fas ligand expression increases susceptibility to AZT - induced cardiomyopathy . BACKGROUND : Dilated cardiomyopathy ( DCM ) and myocarditis occur in many HIV - infected individuals , resulting in symptomatic heart failure in up to 5 % of patients . Highly active antiretroviral therapy ( HAART ) has significantly reduced morbidity and mortality of acquired immunodeficiency syndrome ( AIDS ) , but has resulted in an increase in cardiac and skeletal myopathies . METHODS AND RESULTS : In order to investigate whether the HAART component zidovudine ( 3 ' - azido - 2 ' , 3 ' - deoxythymidine ; AZT ) triggers the Fas - dependent cell - death pathway and cause cytoskeletal disruption in a murine model of DCM , 8 - week - old transgenic ( expressing Fas ligand in the myocardium : FasL Tg ) and non - transgenic ( NTg ) mice received water ad libitum containing different concentrations of AZT ( 0 , 0 . 07 , 0 . 2 , and 0 . 7 mg / ml ) . After 6 weeks , cardiac function was assessed by echocardiography and morphology was assessed by histopathologic and immunohistochemical methods . NTg and untreated FasL Tg mice showed little or no change in cardiac structure or function . In contrast , AZT - treated FasL Tg mice developed cardiac dilation and depressed cardiac function in a dose - dependent manner , with concomitant inflammatory infiltration of both ventricles . These changes were associated with an increased sarcolemmal expression of Fas and FasL , as well as increased activation of caspase 3 , translocation of calpain 1 to the sarcolemma and sarcomere , and increased numbers of cells undergoing apoptosis . These were associated with changes in dystrophin and cardiac troponin I localization , as well as loss of sarcolemmal integrity . CONCLUSIONS : The expression of Fas ligand in the myocardium , as identified in HIV - positive patients , might increase the susceptibility to HAART - induced cardiomyopathy due to activation of apoptotic pathways , resulting in cardiac dilation and dysfunction .

Fas ligand

Fas

Fas ligand

FasL

FasL

FasL

Fas

FasL

caspase 3

calpain 1

dystrophin

cardiac troponin I

Fas ligand

AZT

zidovudine

3 ' - azido - 2 ' , 3 ' - deoxythymidine

AZT

AZT

AZT

cardiomyopathy

Dilated cardiomyopathy

DCM

myocarditis

HIV - infected

heart failure

acquired immunodeficiency syndrome

AIDS

cardiac and skeletal myopathies

DCM

cardiac dilation

depressed cardiac function

inflammatory

cardiomyopathy

cardiac dilation and dysfunction

patients

murine

mice

mice

mice

HIV

patients

caspase 3

AZT

caspase 3

zidovudine

caspase 3

3 ' - azido - 2 ' , 3 ' - deoxythymidine

caspase 3

AZT

caspase 3

AZT

caspase 3

AZT

AZT

depressed cardiac function

zidovudine

depressed cardiac function

3 ' - azido - 2 ' , 3 ' - deoxythymidine

depressed cardiac function

AZT

depressed cardiac function

AZT

depressed cardiac function

AZT

depressed cardiac function

AZT

Dilated cardiomyopathy

AZT

DCM

AZT

DCM

AZT

cardiac dilation

AZT

cardiac dilation and dysfunction

zidovudine

Dilated cardiomyopathy

zidovudine

DCM

zidovudine

DCM

zidovudine

cardiac dilation

zidovudine

cardiac dilation and dysfunction

3 ' - azido - 2 ' , 3 ' - deoxythymidine

Dilated cardiomyopathy

3 ' - azido - 2 ' , 3 ' - deoxythymidine

DCM

3 ' - azido - 2 ' , 3 ' - deoxythymidine

DCM

3 ' - azido - 2 ' , 3 ' - deoxythymidine

cardiac dilation

3 ' - azido - 2 ' , 3 ' - deoxythymidine

cardiac dilation and dysfunction

AZT

Dilated cardiomyopathy

AZT

DCM

AZT

DCM

AZT

cardiac dilation

AZT

cardiac dilation and dysfunction

AZT

Dilated cardiomyopathy

AZT

DCM

AZT

DCM

AZT

cardiac dilation

AZT

cardiac dilation and dysfunction

AZT

Dilated cardiomyopathy

AZT

DCM

AZT

DCM

AZT

cardiac dilation

AZT

cardiac dilation and dysfunction

AZT

Fas

AZT

Fas

zidovudine

Fas

zidovudine

Fas

3 ' - azido - 2 ' , 3 ' - deoxythymidine

Fas

3 ' - azido - 2 ' , 3 ' - deoxythymidine

Fas

AZT

Fas

AZT

Fas

AZT

Fas

AZT

Fas

AZT

Fas

AZT

Fas

AZT

cardiomyopathy

AZT

cardiomyopathy

zidovudine

cardiomyopathy

zidovudine

cardiomyopathy

3 ' - azido - 2 ' , 3 ' - deoxythymidine

cardiomyopathy

3 ' - azido - 2 ' , 3 ' - deoxythymidine

cardiomyopathy

AZT

cardiomyopathy

AZT

cardiomyopathy

AZT

cardiomyopathy

AZT

cardiomyopathy

AZT

cardiomyopathy

AZT

cardiomyopathy

Fas ligand

AZT

Fas ligand

zidovudine

Fas ligand

3 ' - azido - 2 ' , 3 ' - deoxythymidine

Fas ligand

AZT

Fas ligand

AZT

Fas ligand

AZT

Fas ligand

AZT

Fas ligand

zidovudine

Fas ligand

3 ' - azido - 2 ' , 3 ' - deoxythymidine

Fas ligand

AZT

Fas ligand

AZT

Fas ligand

AZT

Fas ligand

AZT

Fas ligand

zidovudine

Fas ligand

3 ' - azido - 2 ' , 3 ' - deoxythymidine

Fas ligand

AZT

Fas ligand

AZT

Fas ligand

AZT

FasL

depressed cardiac function

FasL

depressed cardiac function

FasL

depressed cardiac function

FasL

depressed cardiac function

FasL

Dilated cardiomyopathy

FasL

DCM

FasL

DCM

FasL

cardiac dilation

FasL

cardiac dilation and dysfunction

FasL

Dilated cardiomyopathy

FasL

DCM

FasL

DCM

FasL

cardiac dilation

FasL

cardiac dilation and dysfunction

FasL

Dilated cardiomyopathy

FasL

DCM

FasL

DCM

FasL

cardiac dilation

FasL

cardiac dilation and dysfunction

FasL

Dilated cardiomyopathy

FasL

DCM

FasL

DCM

FasL

cardiac dilation

FasL

cardiac dilation and dysfunction

depressed cardiac function

calpain 1

depressed cardiac function

caspase 3

depressed cardiac function

Fas

depressed cardiac function

Fas

Dilated cardiomyopathy

calpain 1

DCM

calpain 1

DCM

calpain 1

cardiac dilation

calpain 1

cardiac dilation and dysfunction

calpain 1

Dilated cardiomyopathy

caspase 3

DCM

caspase 3

DCM

caspase 3

cardiac dilation

caspase 3

cardiac dilation and dysfunction

caspase 3

Dilated cardiomyopathy

Fas

Dilated cardiomyopathy

Fas

DCM

Fas

DCM

Fas

DCM

Fas

DCM

Fas

cardiac dilation

Fas

cardiac dilation

Fas

cardiac dilation and dysfunction

Fas

cardiac dilation and dysfunction

Fas

AZT

calpain 1

zidovudine

calpain 1

3 ' - azido - 2 ' , 3 ' - deoxythymidine

calpain 1

AZT

calpain 1

AZT

calpain 1

AZT

calpain 1

AZT

FasL

AZT

FasL

AZT

FasL

AZT

FasL

zidovudine

FasL

zidovudine

FasL

zidovudine

FasL

zidovudine

FasL

3 ' - azido - 2 ' , 3 ' - deoxythymidine

FasL

3 ' - azido - 2 ' , 3 ' - deoxythymidine

FasL

3 ' - azido - 2 ' , 3 ' - deoxythymidine

FasL

3 ' - azido - 2 ' , 3 ' - deoxythymidine

FasL

AZT

FasL

AZT

FasL

AZT

FasL

AZT

FasL

AZT

FasL

AZT

FasL

AZT

FasL

AZT

FasL

AZT

FasL

AZT

FasL

AZT

FasL

AZT

FasL

Fas ligand

cardiac dilation and dysfunction

Fas ligand

cardiac dilation and dysfunction

Fas ligand

cardiac dilation and dysfunction

Fas ligand

Dilated cardiomyopathy

Fas ligand

DCM

Fas ligand

DCM

Fas ligand

cardiac dilation

Fas ligand

Dilated cardiomyopathy

Fas ligand

DCM

Fas ligand

DCM

Fas ligand

cardiac dilation

Fas ligand

Dilated cardiomyopathy

Fas ligand

DCM

Fas ligand

DCM

Fas ligand

cardiac dilation

Fas ligand

cardiomyopathy

Fas ligand

cardiomyopathy

Fas ligand

cardiomyopathy

Fas ligand

cardiomyopathy

Fas ligand

cardiomyopathy

Fas ligand

cardiomyopathy


Input: Familial glucocorticoid receptor haploinsufficiency by non - sense mediated mRNA decay , adrenal hyperplasia and apparent mineralocorticoid excess . Primary glucocorticoid resistance ( OMIM 138040 ) is a rare hereditary disease that causes a generalized partial insensitivity to glucocorticoid action , due to genetic alterations of the glucocorticoid receptor ( GR ) . Investigation of adrenal incidentalomas led to the discovery of a family ( eight affected individuals spanning three generations ) , prone to cortisol resistance , bilateral adrenal hyperplasia , arterial hypertension and hypokalemia . This phenotype exacerbated over time , cosegregates with the first heterozygous nonsense mutation p . R469 [ R , X ] reported to date for the GR , replacing an arginine ( CGA ) by a stop ( TGA ) at amino - acid 469 in the second zinc finger of the DNA - binding domain of the receptor . In vitro , this mutation leads to a truncated 50 - kDa GR lacking hormone and DNA binding capacity , devoid of hormone - dependent nuclear translocation and transactivation properties . In the proband ' s fibroblasts , we provided evidence for the lack of expression of the defective allele in vivo . The absence of detectable mutated GR mRNA was accompanied by a 50 % reduction in wild type GR transcript and protein . This reduced GR expression leads to a significantly below - normal induction of glucocorticoid - induced target genes , FKBP5 in fibroblasts . We demonstrated that the molecular mechanisms of glucocorticoid signaling dysfunction involved GR haploinsufficiency due to the selective degradation of the mutated GR transcript through a nonsense - mediated mRNA Decay that was experimentally validated on emetine - treated propositus ' fibroblasts . GR haploinsufficiency leads to hypertension due to illicit occupation of renal mineralocorticoid receptor by elevated cortisol rather than to increased mineralocorticoid production reported in primary glucocorticoid resistance . Indeed , apparent mineralocorticoid excess was demonstrated by a decrease in urinary tetrahydrocortisone - tetrahydrocortisol ratio in affected patients , revealing reduced glucocorticoid degradation by renal activity of the 11b - hydroxysteroid dehydrogenase type 2 , a GR regulated gene . We propose thus that GR haploinsufficiency compromises glucocorticoid sensitivity and may represent a novel genetic cause of subclinical hypercortisolism , incidentally revealed bilateral adrenal hyperplasia and mineralocorticoid - independent hypertension .

glucocorticoid receptor

glucocorticoid receptor

GR

GR

GR

GR

GR

GR

GR

GR

GR

mineralocorticoid receptor

11b - hydroxysteroid dehydrogenase type 2

GR

GR

adrenal hyperplasia

apparent mineralocorticoid excess

glucocorticoid resistance

OMIM 138040

hereditary disease

adrenal incidentalomas

cortisol resistance

bilateral adrenal hyperplasia

hypertension

hypokalemia

hypertension

glucocorticoid resistance

apparent mineralocorticoid excess

hypercortisolism

bilateral adrenal hyperplasia

hypertension

glucocorticoid

glucocorticoid

glucocorticoid

emetine

cortisol

mineralocorticoid

tetrahydrocortisone

tetrahydrocortisol

glucocorticoid

glucocorticoid

mineralocorticoid

p . R469 [ R , X ]

arginine ( CGA ) by a stop ( TGA ) at amino - acid 469

patients

glucocorticoid resistance

glucocorticoid

glucocorticoid resistance

glucocorticoid

glucocorticoid resistance

glucocorticoid

glucocorticoid resistance

glucocorticoid

glucocorticoid resistance

glucocorticoid

glucocorticoid resistance

glucocorticoid

glucocorticoid resistance

glucocorticoid

glucocorticoid resistance

glucocorticoid

glucocorticoid resistance

glucocorticoid

glucocorticoid resistance

glucocorticoid

11b - hydroxysteroid dehydrogenase type 2

glucocorticoid receptor

11b - hydroxysteroid dehydrogenase type 2

glucocorticoid receptor

11b - hydroxysteroid dehydrogenase type 2

GR

11b - hydroxysteroid dehydrogenase type 2

GR

11b - hydroxysteroid dehydrogenase type 2

GR

11b - hydroxysteroid dehydrogenase type 2

GR

11b - hydroxysteroid dehydrogenase type 2

GR

11b - hydroxysteroid dehydrogenase type 2

GR

11b - hydroxysteroid dehydrogenase type 2

GR

11b - hydroxysteroid dehydrogenase type 2

GR

11b - hydroxysteroid dehydrogenase type 2

GR

11b - hydroxysteroid dehydrogenase type 2

GR

11b - hydroxysteroid dehydrogenase type 2

GR

mineralocorticoid receptor

cortisol

glucocorticoid

hypercortisolism

glucocorticoid

hypercortisolism

glucocorticoid

hypercortisolism

glucocorticoid

hypercortisolism

glucocorticoid

hypercortisolism

adrenal hyperplasia

glucocorticoid

adrenal hyperplasia

glucocorticoid

adrenal hyperplasia

glucocorticoid

adrenal hyperplasia

glucocorticoid

adrenal hyperplasia

glucocorticoid

bilateral adrenal hyperplasia

glucocorticoid

bilateral adrenal hyperplasia

glucocorticoid

bilateral adrenal hyperplasia

glucocorticoid

bilateral adrenal hyperplasia

glucocorticoid

bilateral adrenal hyperplasia

glucocorticoid

bilateral adrenal hyperplasia

glucocorticoid

bilateral adrenal hyperplasia

glucocorticoid

bilateral adrenal hyperplasia

glucocorticoid

bilateral adrenal hyperplasia

glucocorticoid

bilateral adrenal hyperplasia

glucocorticoid

hypertension

cortisol

hypertension

cortisol

hypertension

cortisol

hypertension

mineralocorticoid receptor

hypertension

mineralocorticoid receptor

hypertension

mineralocorticoid receptor

p . R469 [ R , X ]

adrenal hyperplasia

p . R469 [ R , X ]

bilateral adrenal hyperplasia

p . R469 [ R , X ]

bilateral adrenal hyperplasia

arginine ( CGA ) by a stop ( TGA ) at amino - acid 469

adrenal hyperplasia

arginine ( CGA ) by a stop ( TGA ) at amino - acid 469

bilateral adrenal hyperplasia

arginine ( CGA ) by a stop ( TGA ) at amino - acid 469

bilateral adrenal hyperplasia

p . R469 [ R , X ]

adrenal incidentalomas

arginine ( CGA ) by a stop ( TGA ) at amino - acid 469

adrenal incidentalomas

p . R469 [ R , X ]

cortisol resistance

arginine ( CGA ) by a stop ( TGA ) at amino - acid 469

cortisol resistance

p . R469 [ R , X ]

hypokalemia

arginine ( CGA ) by a stop ( TGA ) at amino - acid 469

hypokalemia

p . R469 [ R , X ]

hypertension

p . R469 [ R , X ]

hypertension

p . R469 [ R , X ]

hypertension

arginine ( CGA ) by a stop ( TGA ) at amino - acid 469

hypertension

arginine ( CGA ) by a stop ( TGA ) at amino - acid 469

hypertension

arginine ( CGA ) by a stop ( TGA ) at amino - acid 469

hypertension

apparent mineralocorticoid excess

tetrahydrocortisol

apparent mineralocorticoid excess

tetrahydrocortisol

apparent mineralocorticoid excess

tetrahydrocortisone

apparent mineralocorticoid excess

tetrahydrocortisone

glucocorticoid receptor

glucocorticoid resistance

glucocorticoid receptor

glucocorticoid resistance

glucocorticoid receptor

glucocorticoid resistance

glucocorticoid receptor

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

GR

glucocorticoid resistance

glucocorticoid receptor

hypercortisolism

glucocorticoid receptor

hypercortisolism

GR

hypercortisolism

GR

hypercortisolism

GR

hypercortisolism

GR

hypercortisolism

GR

hypercortisolism

GR

hypercortisolism

GR

hypercortisolism

GR

hypercortisolism

GR

hypercortisolism

GR

hypercortisolism

GR

hypercortisolism

glucocorticoid receptor

mineralocorticoid receptor

glucocorticoid receptor

mineralocorticoid receptor

GR

mineralocorticoid receptor

GR

mineralocorticoid receptor

GR

mineralocorticoid receptor

GR

mineralocorticoid receptor

GR

mineralocorticoid receptor

GR

mineralocorticoid receptor

GR

mineralocorticoid receptor

GR

mineralocorticoid receptor

GR

mineralocorticoid receptor

GR

mineralocorticoid receptor

GR

mineralocorticoid receptor

glucocorticoid receptor

adrenal hyperplasia

glucocorticoid receptor

bilateral adrenal hyperplasia

glucocorticoid receptor

bilateral adrenal hyperplasia

glucocorticoid receptor

adrenal hyperplasia

glucocorticoid receptor

bilateral adrenal hyperplasia

glucocorticoid receptor

bilateral adrenal hyperplasia

GR

adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

adrenal hyperplasia

GR

bilateral adrenal hyperplasia

GR

bilateral adrenal hyperplasia

glucocorticoid receptor

adrenal incidentalomas

glucocorticoid receptor

adrenal incidentalomas

GR

adrenal incidentalomas

GR

adrenal incidentalomas

GR

adrenal incidentalomas

GR

adrenal incidentalomas

GR

adrenal incidentalomas

GR

adrenal incidentalomas

GR

adrenal incidentalomas

GR

adrenal incidentalomas

GR

adrenal incidentalomas

GR

adrenal incidentalomas

GR

adrenal incidentalomas

glucocorticoid receptor

cortisol resistance

glucocorticoid receptor

cortisol resistance

GR

cortisol resistance

GR

cortisol resistance

GR

cortisol resistance

GR

cortisol resistance

GR

cortisol resistance

GR

cortisol resistance

GR

cortisol resistance

GR

cortisol resistance

GR

cortisol resistance

GR

cortisol resistance

GR

cortisol resistance

glucocorticoid receptor

hypokalemia

glucocorticoid receptor

hypokalemia

GR

hypokalemia

GR

hypokalemia

GR

hypokalemia

GR

hypokalemia

GR

hypokalemia

GR

hypokalemia

GR

hypokalemia

GR

hypokalemia

GR

hypokalemia

GR

hypokalemia

GR

hypokalemia

glucocorticoid receptor

hypertension

glucocorticoid receptor

hypertension

glucocorticoid receptor

hypertension

glucocorticoid receptor

hypertension

glucocorticoid receptor

hypertension

glucocorticoid receptor

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

GR

hypertension

glucocorticoid receptor

apparent mineralocorticoid excess

glucocorticoid receptor

apparent mineralocorticoid excess

glucocorticoid receptor

apparent mineralocorticoid excess

glucocorticoid receptor

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

GR

apparent mineralocorticoid excess

glucocorticoid

11b - hydroxysteroid dehydrogenase type 2

glucocorticoid

11b - hydroxysteroid dehydrogenase type 2

glucocorticoid

11b - hydroxysteroid dehydrogenase type 2

glucocorticoid

11b - hydroxysteroid dehydrogenase type 2

glucocorticoid

11b - hydroxysteroid dehydrogenase type 2

glucocorticoid

glucocorticoid

glucocorticoid

glucocorticoid

glucocorticoid

glucocorticoid receptor

glucocorticoid receptor

GR

GR

GR

GR

GR

GR

GR

GR

GR

GR

GR

glucocorticoid receptor

glucocorticoid

glucocorticoid receptor

glucocorticoid

glucocorticoid receptor

glucocorticoid

glucocorticoid receptor

glucocorticoid

glucocorticoid receptor

glucocorticoid

glucocorticoid receptor

glucocorticoid

glucocorticoid receptor

glucocorticoid

glucocorticoid receptor

glucocorticoid

glucocorticoid receptor

glucocorticoid

glucocorticoid receptor

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid

GR

glucocorticoid


Input: Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease ( NAFLD ) . Phosphatidylethanolamine N - methyltransferase ( PEMT ) catalyzes phosphatidylcholine synthesis . PEMT knockout mice have fatty livers , and it is possible that , in humans , nonalcoholic fatty liver disease ( NAFLD ) might be associated with PEMT gene polymorphisms . DNA samples from 59 humans without fatty liver and from 28 humans with NAFLD were genotyped for a single nucleotide polymorphism in exon 8 of PEMT , which leads to a V175M substitution . V175M is a loss of function mutation , as determined by transiently transfecting McArdle - RH7777 cells with constructs of wild - type PEMT open reading frame or the V175M mutant . Met / Met at residue 175 ( loss of function SNP ) occurred in 67 . 9 % of the NAFLD subjects and in only 40 . 7 % of control subjects ( P < 0 . 03 ) . For the first time we report that a polymorphism of the human PEMT gene ( V175M ) is associated with diminished activity and may confer susceptibility to NAFLD .

PEMT

Phosphatidylethanolamine N - methyltransferase

PEMT

PEMT

PEMT

PEMT

PEMT

PEMT

nonalcoholic fatty liver disease

NAFLD

fatty livers

nonalcoholic fatty liver disease

NAFLD

fatty liver

NAFLD

NAFLD

NAFLD

phosphatidylcholine

mice

humans

humans

humans

human

Met / Met at residue 175

McArdle - RH7777

PEMT

fatty livers

PEMT

fatty liver

PEMT

nonalcoholic fatty liver disease

PEMT

NAFLD

PEMT

nonalcoholic fatty liver disease

PEMT

NAFLD

PEMT

NAFLD

PEMT

NAFLD

PEMT

NAFLD

PEMT

nonalcoholic fatty liver disease

PEMT

NAFLD

PEMT

nonalcoholic fatty liver disease

PEMT

NAFLD

PEMT

NAFLD

PEMT

NAFLD

PEMT

NAFLD

Phosphatidylethanolamine N - methyltransferase

nonalcoholic fatty liver disease

Phosphatidylethanolamine N - methyltransferase

NAFLD

Phosphatidylethanolamine N - methyltransferase

nonalcoholic fatty liver disease

Phosphatidylethanolamine N - methyltransferase

NAFLD

Phosphatidylethanolamine N - methyltransferase

NAFLD

Phosphatidylethanolamine N - methyltransferase

NAFLD

Phosphatidylethanolamine N - methyltransferase

NAFLD

PEMT

nonalcoholic fatty liver disease

PEMT

NAFLD

PEMT

nonalcoholic fatty liver disease

PEMT

NAFLD

PEMT

NAFLD

PEMT

NAFLD

PEMT

NAFLD

PEMT

nonalcoholic fatty liver disease

PEMT

NAFLD

PEMT

nonalcoholic fatty liver disease

PEMT

NAFLD

PEMT

NAFLD

PEMT

NAFLD

PEMT

NAFLD

PEMT

nonalcoholic fatty liver disease

PEMT

NAFLD

PEMT

nonalcoholic fatty liver disease

PEMT

NAFLD

PEMT

NAFLD

PEMT

NAFLD

PEMT

NAFLD

PEMT

nonalcoholic fatty liver disease

PEMT

NAFLD

PEMT

nonalcoholic fatty liver disease

PEMT

NAFLD

PEMT

NAFLD

PEMT

NAFLD

PEMT

NAFLD

nonalcoholic fatty liver disease

nonalcoholic fatty liver disease

nonalcoholic fatty liver disease

nonalcoholic fatty liver disease

Met / Met at residue 175

nonalcoholic fatty liver disease

NAFLD

NAFLD

NAFLD

NAFLD

Met / Met at residue 175

NAFLD

nonalcoholic fatty liver disease

nonalcoholic fatty liver disease

nonalcoholic fatty liver disease

nonalcoholic fatty liver disease

Met / Met at residue 175

nonalcoholic fatty liver disease

NAFLD

NAFLD

NAFLD

NAFLD

Met / Met at residue 175

NAFLD

NAFLD

NAFLD

NAFLD

NAFLD

Met / Met at residue 175

NAFLD

NAFLD

NAFLD

NAFLD

NAFLD

Met / Met at residue 175

NAFLD

NAFLD

NAFLD

NAFLD

NAFLD

Met / Met at residue 175

NAFLD

PEMT

phosphatidylcholine

Phosphatidylethanolamine N - methyltransferase

phosphatidylcholine

PEMT

phosphatidylcholine

PEMT

phosphatidylcholine

PEMT

phosphatidylcholine

PEMT

phosphatidylcholine


Input: Polymorphisms in the FOXP3 gene in Han Chinese psoriasis patients . BACKGROUND : Psoriasis is a common dermatological disorder , in which autoimmunity plays an important role . CD4 ( + ) CD25 ( + ) regulatory T cells ( T - regs ) have been suggested to be involved in the pathogenesis of some autoimmune diseases . T - regs express the fork head / winged helix transcription factor , FOXP3 , which appears to be of key importance in the development and function of T - regs . Studies have found that single - nucleotide polymorphisms ( SNPs ) in the FOXP3 gene contribute to susceptibility to some autoimmune disorders . However , information about FOXP3 gene in psoriasis is limited . OBJECTIVE : This study evaluated the association between FOXP3 gene SNPs and susceptibility to psoriasis in a Han Chinese population . METHODS : In a hospital - based case - control study , 524 patients with psoriasis and 549 psoriasis - free controls were recruited according to age and gender . We investigated four SNPs in the FOXP3 gene ( - 6054 , deletion / ATT ; - 3279 , A / C ; - 924 , A / G ; IVS9 + 459 , A / G ) in psoriatic patients , and assessed allele and genotype frequencies in psoriatic patients ( 237 females , 287 males ) and normal controls ( 272 females , 277 males ) . The polymorphisms were genotyped using the PCR sequence - specific primer ( PCR - SSP ) technique and PCR - restriction fragment length polymorphism ( RFLP ) analysis . RESULTS : We found that increased risk of psoriasis was associated with the FOXP3 - 3279 AC genotype ( adjusted OR , 1 . 32 ; 95 % CI , 1 . 01 - 1 . 74 ) and the combined AC + AA genotype ( adjusted OR , 1 . 38 ; 95 % CI , 1 . 07 - 1 . 78 ) , compared with the - 3279 CC genotype . We also found that an increased risk of psoriasis was associated with the FOXP3 IVS9 + 459 GG genotype ( adjusted OR , 2 . 24 ; 95 % CI , 1 . 41 - 3 . 58 ) . However , the combined GA + GG genotype showed no such tendency ( adjusted OR = 1 . 28 ; 95 % CI , 1 . 00 - 1 . 64 ) , compared with the IVS9 + 459 AA genotype . There was no evidence of an increased risk associated with the FOXP3 - 6054 deletion / ATT or FOXP3 - 924 A / G genotype . In combined genotype analyses , the FOXP3 - 3279 AC + AA genotype was more obviously associated in males ( adjusted OR = 1 . 60 , 95 % CI = 1 . 11 - 2 . 31 ) and severe psoriasis patients ( PASI score > 20 ; adjusted OR = 1 . 97 , 95 % CI = 1 . 41 - 2 . 75 ) . Meanwhile , the FOXP3 IVS9 + 459 GA + GG genotype was also associated with severe psoriasis patients ( adjusted OR = 1 . 69 , 95 % CI = 1 . 21 - 2 . 36 ) . CONCLUSIONS : FOXP3 polymorphisms appear to contribute to the risk of psoriasis in a Han Chinese population . Larger studies are needed to confirm these findings .

psoriasis

Psoriasis

dermatological disorder

autoimmune diseases

autoimmune disorders

psoriasis

psoriasis

psoriasis

psoriasis

psoriatic

psoriatic

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

patients

patients

patients

patients

patients

patients

- 6054 , deletion / ATT

- 3279 , A / C

- 924 , A / G

IVS9 + 459 , A / G

- 3279 AC

- 3279 CC

IVS9 + 459 GG

IVS9 + 459 AA

- 6054 deletion / ATT

- 924 A / G

- 3279 AC + AA

IVS9 + 459 GA + GG

IVS9 + 459 GA + GG

psoriasis

IVS9 + 459 GA + GG

Psoriasis

IVS9 + 459 GA + GG

psoriasis

IVS9 + 459 GA + GG

psoriasis

IVS9 + 459 GA + GG

psoriasis

IVS9 + 459 GA + GG

psoriasis

IVS9 + 459 GA + GG

psoriatic

IVS9 + 459 GA + GG

psoriatic

IVS9 + 459 GA + GG

psoriasis

IVS9 + 459 GA + GG

psoriasis

IVS9 + 459 GA + GG

psoriasis

IVS9 + 459 GA + GG

psoriasis

IVS9 + 459 GA + GG

psoriasis

psoriasis

IVS9 + 459 GG

Psoriasis

IVS9 + 459 GG

psoriasis

IVS9 + 459 GG

psoriasis

IVS9 + 459 GG

psoriasis

IVS9 + 459 GG

psoriasis

IVS9 + 459 GG

psoriatic

IVS9 + 459 GG

psoriatic

IVS9 + 459 GG

psoriasis

IVS9 + 459 GG

psoriasis

IVS9 + 459 GG

psoriasis

IVS9 + 459 GG

psoriasis

IVS9 + 459 GG

psoriasis

IVS9 + 459 GG

psoriasis

- 3279 AC

Psoriasis

- 3279 AC

psoriasis

- 3279 AC

psoriasis

- 3279 AC

psoriasis

- 3279 AC

psoriasis

- 3279 AC

psoriatic

- 3279 AC

psoriatic

- 3279 AC

psoriasis

- 3279 AC

psoriasis

- 3279 AC

psoriasis

- 3279 AC

psoriasis

- 3279 AC

psoriasis

- 3279 AC

- 3279 AC + AA

psoriasis

- 3279 AC + AA

Psoriasis

- 3279 AC + AA

psoriasis

- 3279 AC + AA

psoriasis

- 3279 AC + AA

psoriasis

- 3279 AC + AA

psoriasis

- 3279 AC + AA

psoriatic

- 3279 AC + AA

psoriatic

- 3279 AC + AA

psoriasis

- 3279 AC + AA

psoriasis

- 3279 AC + AA

psoriasis

- 3279 AC + AA

psoriasis

- 3279 AC + AA

psoriasis

psoriasis

Psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriatic

psoriatic

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

Psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriatic

psoriatic

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

Psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriatic

psoriatic

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

Psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriatic

psoriatic

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

Psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriatic

psoriatic

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

Psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriatic

psoriatic

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

Psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriatic

psoriatic

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

Psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriatic

psoriatic

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

Psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriatic

psoriatic

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

Psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriatic

psoriatic

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

Psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriatic

psoriatic

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

Psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriatic

psoriatic

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

Psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

psoriatic

psoriatic

psoriasis

psoriasis

psoriasis

psoriasis

psoriasis

autoimmune diseases

autoimmune disorders

autoimmune diseases

autoimmune disorders

autoimmune diseases

autoimmune disorders

autoimmune diseases

autoimmune disorders

autoimmune diseases

autoimmune disorders

autoimmune diseases

autoimmune disorders

autoimmune diseases

autoimmune disorders

autoimmune diseases

autoimmune disorders

autoimmune diseases

autoimmune disorders

autoimmune diseases

autoimmune disorders

autoimmune diseases

autoimmune disorders

autoimmune diseases

autoimmune disorders

autoimmune diseases

autoimmune disorders


Input: Autosomal dominant mutation in the signal peptide of renin in a kindred with anemia , hyperuricemia , and CKD . Homozygous or compound heterozygous mutations in renin ( REN ) cause renal tubular dysgenesis , which is characterized by death in utero due to kidney failure and pulmonary hypoplasia . The phenotype resembles the fetopathy caused by angiotensin - converting enzyme inhibitor or angiotensin receptor blocker intake during pregnancy . Recently , heterozygous REN mutations were shown to result in early - onset hyperuricemia , anemia , and chronic kidney disease ( CKD ) . To date , only 3 different heterozygous REN mutations have been published . We report mutation analysis of the REN gene in 39 kindreds with hyperuricemia and CKD who previously tested negative for mutations in the UMOD ( uromodulin ) and HNF1B ( hepatocyte nuclear factor 1b ) genes . We identified one kindred with a novel thymidine to cytosine mutation at position 28 in the REN complementary DNA , corresponding to a tryptophan to arginine substitution at amino acid 10 , which is found within the signal sequence ( c . 28T > C ; p . W10R ) . On this basis , we conclude that REN mutations are rare events in patients with CKD . Within the kindred , we found affected individuals over 4 generations who carried the novel REN mutation and were characterized by significant anemia , hyperuricemia , and CKD . Anemia was severe and disproportional to the degree of decreased kidney function . Because all heterozygous REN mutations that have been described are localized in the signal sequence , screening of the REN gene for patients with CKD with hyperuricemia and anemia may best be focused on sequencing of exon 1 , which encodes the signal peptide .

renin

renin

REN

REN

REN

REN

UMOD

uromodulin

hepatocyte nuclear factor 1b

REN

REN

REN

REN

REN

anemia

hyperuricemia

CKD

renal tubular dysgenesis

death

kidney failure

pulmonary hypoplasia

fetopathy

hyperuricemia

anemia

chronic kidney disease

CKD

hyperuricemia

CKD

CKD

anemia

hyperuricemia

CKD

Anemia

CKD

hyperuricemia

anemia

angiotensin - converting enzyme inhibitor

angiotensin receptor blocker

thymidine to cytosine mutation at position 28

tryptophan to arginine substitution at amino acid 10

c . 28T > C

p . W10R

patients

patients

tryptophan to arginine substitution at amino acid 10

CKD

tryptophan to arginine substitution at amino acid 10

chronic kidney disease

tryptophan to arginine substitution at amino acid 10

CKD

tryptophan to arginine substitution at amino acid 10

CKD

tryptophan to arginine substitution at amino acid 10

CKD

tryptophan to arginine substitution at amino acid 10

CKD

tryptophan to arginine substitution at amino acid 10

CKD

p . W10R

CKD

p . W10R

chronic kidney disease

p . W10R

CKD

p . W10R

CKD

p . W10R

CKD

p . W10R

CKD

p . W10R

CKD

tryptophan to arginine substitution at amino acid 10

anemia

tryptophan to arginine substitution at amino acid 10

anemia

tryptophan to arginine substitution at amino acid 10

anemia

tryptophan to arginine substitution at amino acid 10

Anemia

tryptophan to arginine substitution at amino acid 10

anemia

p . W10R

anemia

p . W10R

anemia

p . W10R

anemia

p . W10R

Anemia

p . W10R

anemia

tryptophan to arginine substitution at amino acid 10

hyperuricemia

tryptophan to arginine substitution at amino acid 10

hyperuricemia

tryptophan to arginine substitution at amino acid 10

hyperuricemia

tryptophan to arginine substitution at amino acid 10

hyperuricemia

tryptophan to arginine substitution at amino acid 10

hyperuricemia

p . W10R

hyperuricemia

p . W10R

hyperuricemia

p . W10R

hyperuricemia

p . W10R

hyperuricemia

p . W10R

hyperuricemia

thymidine to cytosine mutation at position 28

CKD

thymidine to cytosine mutation at position 28

chronic kidney disease

thymidine to cytosine mutation at position 28

CKD

thymidine to cytosine mutation at position 28

CKD

thymidine to cytosine mutation at position 28

CKD

thymidine to cytosine mutation at position 28

CKD

thymidine to cytosine mutation at position 28

CKD

c . 28T > C

CKD

c . 28T > C

chronic kidney disease

c . 28T > C

CKD

c . 28T > C

CKD

c . 28T > C

CKD

c . 28T > C

CKD

c . 28T > C

CKD

thymidine to cytosine mutation at position 28

anemia

thymidine to cytosine mutation at position 28

anemia

thymidine to cytosine mutation at position 28

anemia

thymidine to cytosine mutation at position 28

Anemia

thymidine to cytosine mutation at position 28

anemia

c . 28T > C

anemia

c . 28T > C

anemia

c . 28T > C

anemia

c . 28T > C

Anemia

c . 28T > C

anemia

thymidine to cytosine mutation at position 28

hyperuricemia

thymidine to cytosine mutation at position 28

hyperuricemia

thymidine to cytosine mutation at position 28

hyperuricemia

thymidine to cytosine mutation at position 28

hyperuricemia

thymidine to cytosine mutation at position 28

hyperuricemia

c . 28T > C

hyperuricemia

c . 28T > C

hyperuricemia

c . 28T > C

hyperuricemia

c . 28T > C

hyperuricemia

c . 28T > C

hyperuricemia

fetopathy

angiotensin receptor blocker

fetopathy

angiotensin - converting enzyme inhibitor

renin

renal tubular dysgenesis

renin

renal tubular dysgenesis

REN

renal tubular dysgenesis

REN

renal tubular dysgenesis

REN

renal tubular dysgenesis

REN

renal tubular dysgenesis

REN

renal tubular dysgenesis

REN

renal tubular dysgenesis

REN

renal tubular dysgenesis

REN

renal tubular dysgenesis

REN

renal tubular dysgenesis

renin

CKD

renin

chronic kidney disease

renin

CKD

renin

CKD

renin

CKD

renin

CKD

renin

CKD

renin

CKD

renin

chronic kidney disease

renin

CKD

renin

CKD

renin

CKD

renin

CKD

renin

CKD

REN

CKD

REN

chronic kidney disease

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

chronic kidney disease

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

chronic kidney disease

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

chronic kidney disease

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

chronic kidney disease

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

chronic kidney disease

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

chronic kidney disease

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

chronic kidney disease

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

chronic kidney disease

REN

CKD

REN

CKD

REN

CKD

REN

CKD

REN

CKD

renin

anemia

renin

anemia

renin

anemia

renin

Anemia

renin

anemia

renin

anemia

renin

anemia

renin

anemia

renin

Anemia

renin

anemia

REN

anemia

REN

anemia

REN

anemia

REN

Anemia

REN

anemia

REN

anemia

REN

anemia

REN

anemia

REN

Anemia

REN

anemia

REN

anemia

REN

anemia

REN

anemia

REN

Anemia

REN

anemia

REN

anemia

REN

anemia

REN

anemia

REN

Anemia

REN

anemia

REN

anemia

REN

anemia

REN

anemia

REN

Anemia

REN

anemia

REN

anemia

REN

anemia

REN

anemia

REN

Anemia

REN

anemia

REN

anemia

REN

anemia

REN

anemia

REN

Anemia

REN

anemia

REN

anemia

REN

anemia

REN

anemia

REN

Anemia

REN

anemia

REN

anemia

REN

anemia

REN

anemia

REN

Anemia

REN

anemia

renin

hyperuricemia

renin

hyperuricemia

renin

hyperuricemia

renin

hyperuricemia

renin

hyperuricemia

renin

hyperuricemia

renin

hyperuricemia

renin

hyperuricemia

renin

hyperuricemia

renin

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia

REN

hyperuricemia


Input: On the pivotal role of PPARa in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury . The role of peroxisome proliferator - activated receptor a ( PPARa ) - mediated metabolic remodeling in cardiac adaptation to hypoxia has yet to be defined . Here , mice were housed in hypoxia for 3 wk before in vivo contractile function was measured using cine MRI . In isolated , perfused hearts , energetics were measured using ( 31 ) P magnetic resonance spectroscopy ( MRS ) , and glycolysis and fatty acid oxidation were measured using [ ( 3 ) H ] labeling . Compared with a normoxic , chow - fed control mouse heart , hypoxia decreased PPARa expression , fatty acid oxidation , and mitochondrial uncoupling protein 3 ( UCP3 ) levels , while increasing glycolysis , all of which served to maintain normal ATP concentrations ( [ ATP ] ) and thereby , ejection fractions . A high - fat diet increased cardiac PPARa expression , fatty acid oxidation , and UCP3 levels with decreased glycolysis . Hypoxia was unable to alter the high PPARa expression or reverse the metabolic changes caused by the high - fat diet , with the result that [ ATP ] and contractile function decreased significantly . The adaptive metabolic changes caused by hypoxia in control mouse hearts were found to have occurred already in PPARa - deficient ( PPARa ( - / - ) ) mouse hearts and sustained function in hypoxia despite an inability for further metabolic remodeling . We conclude that decreased cardiac PPARa expression is essential for adaptive metabolic remodeling in hypoxia , but is prevented by dietary fat . - Cole , M . A . , Abd Jamil , A . H . , Heather , L . C . , Murray , A . J . , Sutton , E . R . , Slingo , M . , Sebag - Montefiore , L . , Tan , S . C . , Aksentijevic , D . , Gildea , O . S . , Stuckey , D . J . , Yeoh , K . K . , Carr , C . A . , Evans , R . D . , Aasum , E . , Schofield , C . J . , Ratcliffe , P . J . , Neubauer , S . , Robbins , P . A . , Clarke , K . On the pivotal role of PPARa in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury .

PPARa

peroxisome proliferator - activated receptor a

PPARa

PPARa

mitochondrial uncoupling protein 3

PPARa

PPARa

PPARa

PPARa

PPARa

PPARa

hypoxia

hypoxic

hypoxia

hypoxia

hypoxia

Hypoxia

hypoxia

hypoxia

hypoxia

hypoxia

hypoxic

mice

mouse

mouse

mouse

fatty acid

( 3 ) H

fatty acid

ATP

ATP

fatty acid

ATP

mitochondrial uncoupling protein 3

ATP

mitochondrial uncoupling protein 3

ATP

mitochondrial uncoupling protein 3

ATP

ATP

ATP

ATP

ATP

ATP

ATP

fatty acid

ATP

fatty acid

ATP

fatty acid

ATP

fatty acid

ATP

fatty acid

ATP

fatty acid

ATP

fatty acid

ATP

fatty acid

ATP

fatty acid

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

peroxisome proliferator - activated receptor a

ATP

peroxisome proliferator - activated receptor a

ATP

peroxisome proliferator - activated receptor a

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

PPARa

ATP

hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

hypoxic

ATP

hypoxic

ATP

hypoxic

ATP

hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

Hypoxia

ATP

Hypoxia

ATP

Hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

hypoxia

ATP

hypoxic

ATP

hypoxic

ATP

hypoxic

ATP

hypoxia

mitochondrial uncoupling protein 3

hypoxia

hypoxia

hypoxic

mitochondrial uncoupling protein 3

hypoxic

hypoxic

hypoxia

mitochondrial uncoupling protein 3

hypoxia

hypoxia

hypoxia

mitochondrial uncoupling protein 3

hypoxia

hypoxia

hypoxia

mitochondrial uncoupling protein 3

hypoxia

hypoxia

Hypoxia

mitochondrial uncoupling protein 3

Hypoxia

Hypoxia

hypoxia

mitochondrial uncoupling protein 3

hypoxia

hypoxia

hypoxia

mitochondrial uncoupling protein 3

hypoxia

hypoxia

hypoxia

mitochondrial uncoupling protein 3

hypoxia

hypoxia

hypoxia

mitochondrial uncoupling protein 3

hypoxia

hypoxia

hypoxic

mitochondrial uncoupling protein 3

hypoxic

hypoxic

hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxic

fatty acid

hypoxic

fatty acid

hypoxic

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

Hypoxia

fatty acid

Hypoxia

fatty acid

Hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxia

fatty acid

hypoxic

fatty acid

hypoxic

fatty acid

hypoxic

fatty acid

hypoxia

PPARa

hypoxia

peroxisome proliferator - activated receptor a

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxic

PPARa

hypoxic

peroxisome proliferator - activated receptor a

hypoxic

PPARa

hypoxic

PPARa

hypoxic

PPARa

hypoxic

PPARa

hypoxic

PPARa

hypoxic

PPARa

hypoxic

PPARa

hypoxic

PPARa

hypoxia

PPARa

hypoxia

peroxisome proliferator - activated receptor a

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

peroxisome proliferator - activated receptor a

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

peroxisome proliferator - activated receptor a

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

Hypoxia

PPARa

Hypoxia

peroxisome proliferator - activated receptor a

Hypoxia

PPARa

Hypoxia

PPARa

Hypoxia

PPARa

Hypoxia

PPARa

Hypoxia

PPARa

Hypoxia

PPARa

Hypoxia

PPARa

Hypoxia

PPARa

hypoxia

PPARa

hypoxia

peroxisome proliferator - activated receptor a

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

peroxisome proliferator - activated receptor a

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

peroxisome proliferator - activated receptor a

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

peroxisome proliferator - activated receptor a

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxia

PPARa

hypoxic

PPARa

hypoxic

peroxisome proliferator - activated receptor a

hypoxic

PPARa

hypoxic

PPARa

hypoxic

PPARa

hypoxic

PPARa

hypoxic

PPARa

hypoxic

PPARa

hypoxic

PPARa

hypoxic

PPARa


Input: Gartanin induces cell cycle arrest and autophagy and suppresses migration involving PI3K / Akt / mTOR and MAPK signalling pathway in human glioma cells . In central nervous system , glioma is the most common primary brain tumour . The diffuse migration and rapid proliferation are main obstacles for successful treatment . Gartanin , a natural xanthone of mangosteen , suppressed proliferation , migration and colony formation in a time - and concentration - dependent manner in T98G glioma cells but not in mouse normal neuronal HT22 cells . Gartanin , at low micromole , led to cell cycle arrest in G1 phase accompanied by inhibited expression level of G1 cell cycle regulatory proteins cyclin D1 , while increased expression level of cyclin - dependent kinase inhibitor p27Kip1 . In addition , the secretion and activity of matrix metalloproteinases 2 / 9 ( MMP - 2 / - 9 ) were significantly suppressed in T98G cells treated with gartanin , and it might result from modulating mitogen - activated protein kinases ( MAPK ) signalling pathway in T98G glioma cells . Moreover , gartanin significantly induced autophagy in T98G cells and increased GFP - LC3 punctate fluorescence accompanied by the increased expression level of Beclin 1 and LC3 - II , while suppressed expression level of p62 . Gartanin treatment resulted in obvious inhibition of PI3K / Akt / mTOR signalling pathway , which is important in modulating autophagy . Notably , gartanin - mediated anti - viability was significantly abrogated by autophagy inhibitors including 3 - methyladenine ( 3 - MA ) and chloroquine ( CQ ) . These results indicate that anti - proliferation effect of gartanin in T98G cells is most likely via cell cycle arrest modulated by autophagy , which is regulated by PI3K / Akt / mTOR signalling pathway , while anti - migration effect is most likely via suppression of MMP - 2 / - 9 activity which is involved in MAPK signalling pathway .

Gartanin

Gartanin

xanthone

Gartanin

gartanin

gartanin

Gartanin

gartanin

3 - methyladenine

3 - MA

chloroquine

CQ

gartanin

Akt

mTOR

MAPK

cyclin D1

cyclin - dependent kinase

matrix metalloproteinases 2 / 9

MMP - 2 / - 9

mitogen - activated protein kinases

MAPK

Beclin 1

Akt

mTOR

Akt

mTOR

MMP - 2 / - 9

MAPK

human

mangosteen

mouse

glioma

glioma

primary brain tumour

glioma

glioma

cyclin - dependent kinase

Gartanin

chloroquine

Gartanin

CQ

Gartanin

chloroquine

Gartanin

CQ

Gartanin

chloroquine

Gartanin

CQ

gartanin

chloroquine

gartanin

CQ

gartanin

chloroquine

gartanin

CQ

Gartanin

chloroquine

Gartanin

CQ

gartanin

chloroquine

gartanin

CQ

gartanin

chloroquine

gartanin

CQ

Gartanin

3 - methyladenine

Gartanin

3 - MA

Gartanin

3 - methyladenine

Gartanin

3 - MA

Gartanin

3 - methyladenine

Gartanin

3 - MA

gartanin

3 - methyladenine

gartanin

3 - MA

gartanin

3 - methyladenine

gartanin

3 - MA

Gartanin

3 - methyladenine

Gartanin

3 - MA

gartanin

3 - methyladenine

gartanin

3 - MA

gartanin

3 - methyladenine

gartanin

3 - MA

Gartanin

Gartanin

Gartanin

gartanin

gartanin

Gartanin

gartanin

gartanin

Gartanin

matrix metalloproteinases 2 / 9

Gartanin

MMP - 2 / - 9

Gartanin

MMP - 2 / - 9

Gartanin

matrix metalloproteinases 2 / 9

Gartanin

MMP - 2 / - 9

Gartanin

MMP - 2 / - 9

Gartanin

matrix metalloproteinases 2 / 9

Gartanin

MMP - 2 / - 9

Gartanin

MMP - 2 / - 9

gartanin

matrix metalloproteinases 2 / 9

gartanin

MMP - 2 / - 9

gartanin

MMP - 2 / - 9

gartanin

matrix metalloproteinases 2 / 9

gartanin

MMP - 2 / - 9

gartanin

MMP - 2 / - 9

Gartanin

matrix metalloproteinases 2 / 9

Gartanin

MMP - 2 / - 9

Gartanin

MMP - 2 / - 9

gartanin

matrix metalloproteinases 2 / 9

gartanin

MMP - 2 / - 9

gartanin

MMP - 2 / - 9

gartanin

matrix metalloproteinases 2 / 9

gartanin

MMP - 2 / - 9

gartanin

MMP - 2 / - 9

Gartanin

cyclin D1

Gartanin

cyclin D1

Gartanin

cyclin D1

gartanin

cyclin D1

gartanin

cyclin D1

Gartanin

cyclin D1

gartanin

cyclin D1

gartanin

cyclin D1

Gartanin

glioma

Gartanin

glioma

Gartanin

glioma

Gartanin

glioma

Gartanin

glioma

Gartanin

glioma

Gartanin

glioma

Gartanin

glioma

Gartanin

glioma

Gartanin

glioma

Gartanin

glioma

Gartanin

glioma

gartanin

glioma

gartanin

glioma

gartanin

glioma

gartanin

glioma

gartanin

glioma

gartanin

glioma

gartanin

glioma

gartanin

glioma

Gartanin

glioma

Gartanin

glioma

Gartanin

glioma

Gartanin

glioma

gartanin

glioma

gartanin

glioma

gartanin

glioma

gartanin

glioma

gartanin

glioma

gartanin

glioma

gartanin

glioma

gartanin

glioma

xanthone

glioma

xanthone

glioma

xanthone

glioma

xanthone

glioma

Akt

mTOR

Akt

mTOR

Akt

mTOR

Akt

mTOR

Akt

mTOR

Akt

mTOR

Akt

mTOR

Akt

mTOR

Akt

mTOR

mTOR

mTOR

mTOR

mTOR

mTOR

mTOR

mTOR

mTOR

mTOR

Akt

Akt

Akt

Akt

Akt

Akt

Akt

Akt

Akt

Gartanin

Gartanin

Gartanin

Gartanin

Gartanin

Gartanin

gartanin

gartanin

gartanin

gartanin

Gartanin

Gartanin

gartanin

gartanin

gartanin

gartanin

Gartanin

Beclin 1

Gartanin

Beclin 1

Gartanin

Beclin 1

gartanin

Beclin 1

gartanin

Beclin 1

Gartanin

Beclin 1

gartanin

Beclin 1

gartanin

Beclin 1

Gartanin

Gartanin

Gartanin

gartanin

gartanin

Gartanin

gartanin

gartanin


Input: Gene therapy for cystic fibrosis airway disease - is clinical success imminent ? Cystic fibrosis ( CF ) was one of the first inherited disorders for which gene therapy was seriously considered as a realistic option for treatment , and as such , it has long provided a paradigm for gene therapy of inherited diseases . However , despite the cloning of the cystic fibrosis transmembrane conductance regulator gene in 1989 , over 15 years later a practical gene therapy for CF has not eventuated . There are a number of reasons for this , and analysis of the specific issues that have delayed the successful development of gene therapy for CF also provides general insights into the practical complexities involved in the development of gene therapy for inherited disorders . The issues which have prevented the application of gene therapy for CF to date include the lack of suitable gene delivery technologies , the complexities of the interactions between the host and vector , the biology of the lung airways , and the nature of the pathology found in individuals with CF . We will discuss the history of CF gene therapy with specific reference to these and other issues that pre - occupy the field at present : namely , the question of what vectors appear to be suitable for airway gene delivery in CF , what cells must be targeted , how airway epithelium defences can be overcome or eluded to allow efficient gene delivery , how to ensure safe and long - term transgene expression and the need to identify relevant surrogate success measures that can be used to assess the outcome of gene therapy in CF patients .

cystic fibrosis

Cystic fibrosis

CF

inherited disorders

inherited diseases

CF

CF

inherited disorders

CF

CF

CF

CF

CF

cystic fibrosis transmembrane conductance regulator

patients

cystic fibrosis transmembrane conductance regulator

cystic fibrosis

cystic fibrosis transmembrane conductance regulator

Cystic fibrosis

cystic fibrosis transmembrane conductance regulator

CF

cystic fibrosis transmembrane conductance regulator

CF

cystic fibrosis transmembrane conductance regulator

CF

cystic fibrosis transmembrane conductance regulator

CF

cystic fibrosis transmembrane conductance regulator

CF

cystic fibrosis transmembrane conductance regulator

CF

cystic fibrosis transmembrane conductance regulator

CF

cystic fibrosis transmembrane conductance regulator

CF


Input: Mutation in the auxiliary calcium - channel subunit CACNA2D4 causes autosomal recessive cone dystrophy . Retinal signal transmission depends on the activity of high voltage - gated l - type calcium channels in photoreceptor ribbon synapses . We recently identified a truncating frameshift mutation in the Cacna2d4 gene in a spontaneous mouse mutant with profound loss of retinal signaling and an abnormal morphology of ribbon synapses in rods and cones . The Cacna2d4 gene encodes an l - type calcium - channel auxiliary subunit of the alpha ( 2 ) delta type . Mutations in its human orthologue , CACNA2D4 , were not yet known to be associated with a disease . We performed mutation analyses of 34 patients who received an initial diagnosis of night blindness , and , in two affected siblings , we detected a homozygous nucleotide substitution ( c . 2406C - - > A ) in CACNA2D4 . The mutation introduces a premature stop codon that truncates one - third of the corresponding open reading frame . Both patients share symptoms of slowly progressing cone dystrophy . These findings represent the first report of a mutation in the human CACNA2D4 gene and define a novel gene defect that causes autosomal recessive cone dystrophy .

calcium

calcium

l - type calcium - channel auxiliary subunit of the alpha ( 2 ) delta type

cone dystrophy

night blindness

cone dystrophy

cone dystrophy

mouse

human

patients

patients

human

c . 2406C - - > A

l - type calcium - channel auxiliary subunit of the alpha ( 2 ) delta type

l - type calcium - channel auxiliary subunit of the alpha ( 2 ) delta type

c . 2406C - - > A

night blindness

night blindness

night blindness

night blindness

night blindness

cone dystrophy

cone dystrophy

cone dystrophy

cone dystrophy

cone dystrophy

cone dystrophy

cone dystrophy

cone dystrophy

cone dystrophy

cone dystrophy

cone dystrophy

cone dystrophy

calcium

calcium

calcium

calcium

calcium

calcium

calcium

calcium

c . 2406C - - > A

cone dystrophy

c . 2406C - - > A

cone dystrophy

c . 2406C - - > A

cone dystrophy


Input: A homozygous mutation in LYRM7 / MZM1L associated with early onset encephalopathy , lactic acidosis , and severe reduction of mitochondrial complex III activity . Mutations in nuclear genes associated with defective complex III ( cIII ) of the mitochondrial respiratory chain are rare , having been found in only two cIII assembly factors and , as private changes in single families , three cIII structural subunits . Recently , human LYRM7 / MZM1L , the ortholog of yeast MZM1 , has been identified as a new assembly factor for cIII . In a baby patient with early onset , severe encephalopathy , lactic acidosis and profound , isolated cIII deficiency in skeletal muscle , we identified a disease - segregating homozygous mutation ( c . 73G > A ) in LYRM7 / MZM1L , predicting a drastic change in a highly conserved amino - acid residue ( p . Asp25Asn ) . In a mzm1D yeast strain , the expression of a mzm1 ( D25N ) mutant allele caused temperature - sensitive respiratory growth defect , decreased oxygen consumption , impaired maturation / stabilization of the Rieske Fe - S protein , and reduced complex III activity and amount . LYRM7 / MZM1L is a novel disease gene , causing cIII - defective , early onset , severe mitochondrial encephalopathy .

cIII

cIII

cIII

Rieske Fe - S protein

complex III

encephalopathy

lactic acidosis

reduction of mitochondrial complex III

defective complex III ( cIII ) of the mitochondrial

encephalopathy

lactic acidosis

cIII deficiency

respiratory growth defect

cIII - defective

mitochondrial encephalopathy

human

yeast

patient

yeast

c . 73G > A

p . Asp25Asn

oxygen

c . 73G > A

oxygen

p . Asp25Asn

oxygen

oxygen

respiratory growth defect

respiratory growth defect

respiratory growth defect

respiratory growth defect

respiratory growth defect

respiratory growth defect

respiratory growth defect

respiratory growth defect

oxygen

oxygen

oxygen

Rieske Fe - S protein

Rieske Fe - S protein

Rieske Fe - S protein

respiratory growth defect

respiratory growth defect

respiratory growth defect

mitochondrial encephalopathy

mitochondrial encephalopathy

mitochondrial encephalopathy

mitochondrial encephalopathy

mitochondrial encephalopathy

mitochondrial encephalopathy

mitochondrial encephalopathy

mitochondrial encephalopathy

cIII

cIII

cIII

complex III

cIII

cIII

cIII

complex III

cIII

cIII

cIII

complex III

cIII

cIII

cIII

complex III

cIII

cIII

cIII

complex III

cIII

cIII

cIII

complex III

cIII

cIII

cIII

complex III

cIII

cIII

cIII

complex III

lactic acidosis

lactic acidosis

lactic acidosis

lactic acidosis

lactic acidosis

lactic acidosis

lactic acidosis

lactic acidosis

lactic acidosis

lactic acidosis

lactic acidosis

lactic acidosis

lactic acidosis

lactic acidosis

lactic acidosis

lactic acidosis

reduction of mitochondrial complex III

defective complex III ( cIII ) of the mitochondrial

cIII deficiency

cIII - defective

reduction of mitochondrial complex III

defective complex III ( cIII ) of the mitochondrial

cIII deficiency

cIII - defective

reduction of mitochondrial complex III

defective complex III ( cIII ) of the mitochondrial

cIII deficiency

cIII - defective

reduction of mitochondrial complex III

defective complex III ( cIII ) of the mitochondrial

cIII deficiency

cIII - defective

reduction of mitochondrial complex III

defective complex III ( cIII ) of the mitochondrial

cIII deficiency

cIII - defective

reduction of mitochondrial complex III

defective complex III ( cIII ) of the mitochondrial

cIII deficiency

cIII - defective

reduction of mitochondrial complex III

defective complex III ( cIII ) of the mitochondrial

cIII deficiency

cIII - defective

reduction of mitochondrial complex III

defective complex III ( cIII ) of the mitochondrial

cIII deficiency

cIII - defective

encephalopathy

encephalopathy

encephalopathy

encephalopathy

encephalopathy

encephalopathy

encephalopathy

encephalopathy

encephalopathy

encephalopathy

encephalopathy

encephalopathy

encephalopathy

encephalopathy

encephalopathy

encephalopathy

c . 73G > A

respiratory growth defect

p . Asp25Asn

respiratory growth defect

respiratory growth defect

c . 73G > A

encephalopathy

c . 73G > A

encephalopathy

p . Asp25Asn

encephalopathy

p . Asp25Asn

encephalopathy

encephalopathy

encephalopathy

lactic acidosis

c . 73G > A

lactic acidosis

p . Asp25Asn

lactic acidosis

lactic acidosis

c . 73G > A

lactic acidosis

p . Asp25Asn

lactic acidosis

reduction of mitochondrial complex III

c . 73G > A

reduction of mitochondrial complex III

p . Asp25Asn

reduction of mitochondrial complex III

defective complex III ( cIII ) of the mitochondrial

c . 73G > A

defective complex III ( cIII ) of the mitochondrial

p . Asp25Asn

defective complex III ( cIII ) of the mitochondrial

cIII deficiency

c . 73G > A

cIII deficiency

p . Asp25Asn

cIII deficiency

cIII - defective

c . 73G > A

cIII - defective

p . Asp25Asn

cIII - defective

cIII

cIII

cIII

complex III

cIII

cIII

cIII

complex III

cIII

cIII

cIII

complex III

reduction of mitochondrial complex III

cIII

reduction of mitochondrial complex III

cIII

reduction of mitochondrial complex III

cIII

reduction of mitochondrial complex III

complex III

defective complex III ( cIII ) of the mitochondrial

cIII

defective complex III ( cIII ) of the mitochondrial

cIII

defective complex III ( cIII ) of the mitochondrial

cIII

defective complex III ( cIII ) of the mitochondrial

complex III

cIII deficiency

cIII

cIII deficiency

cIII

cIII deficiency

cIII

cIII deficiency

complex III

cIII - defective

cIII

cIII - defective

cIII

cIII - defective

cIII

cIII - defective

complex III


Input: Comparison of sequential cytomegalovirus isolates in a patient with lymphoma and failing antiviral therapy . BACKGROUND : Long - term anti - cytomegalovirus ( CMV ) treatments in immunocompromised patients are hampered by resistance to antiviral drugs . Longitudinal changes in the resistance genotype may depend on changes in selective pressure and the complexity of CMV isolates . OBJECTIVE : To evaluate longitudinal changes in the CMV resistance genotype and phenotype along with strain - specific variability in a patient with non - Hodgkin ' s lymphoma in whom successive anti - CMV treatments failed . STUDY DESIGN : The resistance phenotype and genotype of seven CMV isolates collected from one patient during a 2 - year follow - up period were retrospectively analysed . In parallel , we used glycoprotein B ( gB ) genotyping , and a - and UL10 - 13 - sequence analysis to study CMV interstrain variability . RESULTS : The patient was infected by at least three CMV strains plus variants of the parental strains . Resistance to ganciclovir , cidofovir and foscarnet was successively detected during the follow - up period . UL97 protein kinase changes responsible for resistance to ganciclovir were initially detected at residues 591 and 592 , and then at position 594 . Decreased sensitivity to foscarnet coincided with the appearance of amino acid substitution N495K in DNA polymerase , whereas cross - resistance to ganciclovir and cidofovir was due to the L501I substitution . CONCLUSIONS : The CMV isolates obtained from our patient were complex mixtures of strains . Changes in resistance genotypes depended on resistance selective pressure and were not linked to interstrain variation .

cytomegalovirus

patient

patients

patient

patient

patient

patient

lymphoma

Long - term anti - cytomegalovirus

CMV

CMV

CMV

non - Hodgkin ' s lymphoma

CMV

CMV

CMV

CMV

CMV

glycoprotein B

gB

UL97 protein kinase

ganciclovir

cidofovir

foscarnet

ganciclovir

foscarnet

ganciclovir

cidofovir

UL97 protein kinase

foscarnet

UL97 protein kinase

foscarnet

UL97 protein kinase

cidofovir

UL97 protein kinase

cidofovir

UL97 protein kinase

ganciclovir

UL97 protein kinase

ganciclovir

UL97 protein kinase

ganciclovir

glycoprotein B

Long - term anti - cytomegalovirus

glycoprotein B

CMV

glycoprotein B

CMV

glycoprotein B

CMV

glycoprotein B

CMV

glycoprotein B

CMV

glycoprotein B

CMV

glycoprotein B

CMV

glycoprotein B

CMV

gB

Long - term anti - cytomegalovirus

gB

CMV

gB

CMV

gB

CMV

gB

CMV

gB

CMV

gB

CMV

gB

CMV

gB

CMV

foscarnet

foscarnet

cidofovir

cidofovir

ganciclovir

ganciclovir

ganciclovir

Long - term anti - cytomegalovirus

foscarnet

Long - term anti - cytomegalovirus

foscarnet

CMV

foscarnet

CMV

foscarnet

CMV

foscarnet

CMV

foscarnet

CMV

foscarnet

CMV

foscarnet

CMV

foscarnet

CMV

foscarnet

CMV

foscarnet

CMV

foscarnet

CMV

foscarnet

CMV

foscarnet

CMV

foscarnet

CMV

foscarnet

CMV

foscarnet

CMV

foscarnet

Long - term anti - cytomegalovirus

cidofovir

Long - term anti - cytomegalovirus

cidofovir

CMV

cidofovir

CMV

cidofovir

CMV

cidofovir

CMV

cidofovir

CMV

cidofovir

CMV

cidofovir

CMV

cidofovir

CMV

cidofovir

CMV

cidofovir

CMV

cidofovir

CMV

cidofovir

CMV

cidofovir

CMV

cidofovir

CMV

cidofovir

CMV

cidofovir

CMV

cidofovir

Long - term anti - cytomegalovirus

ganciclovir

Long - term anti - cytomegalovirus

ganciclovir

Long - term anti - cytomegalovirus

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir

CMV

ganciclovir


Input: Coincidence of mutations in different connexin genes in Hungarian patients . Mutations in the GJB2 gene are the most common cause of hereditary prelingual sensorineural hearing impairment in Europe . Several studies indicate that different members of the connexin protein family interact to form gap junctions in the inner ear . Mutations in different connexin genes may accumulate and , consequently lead to hearing impairment . Therefore , we screened 47 Hungarian GJB2 - heterozygous ( one mutation in coding exon of the GJB2 gene ) patients with hearing impairment for DNA changes in two further connexin genes ( GJB6 and GJB3 ) and in the 5 ' non - coding region of GJB2 including the splice sites . Eleven out of 47 GJB2 - heterozygous patients analyzed carried the splice site mutation - 3170G > A in the 5 ' UTR region of GJB2 . One out of these 11 patients showed homozygous - 3170G > A genotype in combination with p . R127H . Next to the GJB2 mutations we noted 2 cases of deletion in GJB6 [ Delta ( GJB6 - D13S1830 ) ] and 3 ( 2 new and 1 described ) base substitutions in GJB3 [ c . 357C > T , c . 798C > T and c . 94C > T ( p . R32W ) ] which are unlikely disease - causing . Our results suggest the importance of routine screening for the rather frequent - 3170G > A mutation ( in addition to c . 35delG ) in patients with hearing impairment .

patients

patients

patients

patients

patients

sensorineural hearing impairment

hearing impairment

hearing impairment

hearing impairment

- 3170G > A

- 3170G > A

p . R127H

c . 357C > T

c . 798C > T

c . 94C > T

p . R32W

- 3170G > A

c . 35delG

c . 35delG

sensorineural hearing impairment

c . 35delG

hearing impairment

c . 35delG

hearing impairment

c . 35delG

hearing impairment

- 3170G > A

sensorineural hearing impairment

- 3170G > A

hearing impairment

- 3170G > A

hearing impairment

- 3170G > A

hearing impairment

- 3170G > A

sensorineural hearing impairment

- 3170G > A

hearing impairment

- 3170G > A

hearing impairment

- 3170G > A

hearing impairment

- 3170G > A

sensorineural hearing impairment

- 3170G > A

hearing impairment

- 3170G > A

hearing impairment

- 3170G > A

hearing impairment

sensorineural hearing impairment

hearing impairment

hearing impairment

hearing impairment

sensorineural hearing impairment

hearing impairment

hearing impairment

hearing impairment

sensorineural hearing impairment

hearing impairment

hearing impairment

hearing impairment

sensorineural hearing impairment

hearing impairment

hearing impairment

hearing impairment

sensorineural hearing impairment

hearing impairment

hearing impairment

hearing impairment

sensorineural hearing impairment

hearing impairment

hearing impairment

hearing impairment

sensorineural hearing impairment

hearing impairment

hearing impairment

hearing impairment