scholarly journals The PfAP2-HS transcription factor protects malaria parasites from febrile temperatures

2021 ◽  
Author(s):  
Elisabet Tintó-Font ◽  
Lucas Michel-Todó ◽  
Timothy J. Russell ◽  
Núria Casas-Vila ◽  
David J. Conway ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Periodic Fever ◽  
Clinical Feature ◽  
Protective Response ◽  
Malaria Parasites ◽  
Growth Defects ◽  
Characteristic Clinical Feature ◽  
Full Complement ◽  
Increased Sensitivity ◽  
Febrile Episodes

Periodic fever is the most characteristic clinical feature of human malaria1-3, but how parasites survive febrile episodes is not known. While Plasmodium spp. genomes encode a full complement of chaperones4, they lack an ortholog of the conserved transcription factor HSF1, which in most eukaryotes activates the expression of key chaperones upon heat shock (HS)5-8. Here we identified PfAP2-HS, a transcription factor of the ApiAP2 family9-11, as the key regulator of the P. falciparum protective HS response. The PfAP2-HS-dependent HS response is largely restricted to rapid activation of hsp70-1, the predominant direct target of PfAP2-HS, and hsp90. Deletion of PfAP2-HS dramatically reduced HS survival and also resulted in severe growth defects at 37°C, but not at 35°C, and increased sensitivity to imbalances in protein homeostasis (proteostasis) produced by artemisinin, the current frontline antimalarial drug12,13. These results demonstrate that PfAP2-HS contributes to general maintenance of proteostasis and drives a rapid chaperone-based protective response against febrile temperatures. While several ApiAP2 transcription factors regulate life cycle transitions in malaria parasites11,14,15, PfAP2-HS is the first identified Plasmodium transcription factor that controls a protective response to a within-host environmental challenge.

scholarly journals A Novel Group of Glutaredoxins in the cis-Golgi Critical for Oxidative Stress Resistance

2008 ◽  
Vol 19 (6) ◽  
pp. 2673-2680 ◽  
Author(s):  
Nikola Mesecke ◽  
Anne Spang ◽  
Marcel Deponte ◽  
Johannes M. Herrmann
Keyword(s):  
Disulfide Bonds ◽  
Secretory Pathway ◽  
Reduced Glutathione ◽  
General Role ◽  
Growth Defects ◽  
Early Secretory Pathway ◽  
Full Complement ◽  
Increased Sensitivity ◽  
Substrate Proteins

Glutaredoxins represent a ubiquitous family of proteins that catalyze the reduction of disulfide bonds in their substrate proteins by use of reduced glutathione. In an attempt to identify the full complement of glutaredoxins in baker's yeast, we found three so-far uncharacterized glutaredoxin-like proteins that we named Grx6, Grx7, and Grx8. Grx6 and Grx7 represent closely related monothiol glutaredoxins that are synthesized with N-terminal signal sequences. Both proteins are located in the cis-Golgi, thereby representing the first glutaredoxins found in a compartment of the secretory pathway. In contrast to formerly described monothiol glutaredoxins, Grx6 and Grx7, showed a high glutaredoxin activity in vitro. Grx6 and Grx7 overlap in their activity and deletion mutants lacking both proteins show growth defects and a strongly increased sensitivity toward oxidizing agents such as hydrogen peroxide or diamide. Our observations suggest that Grx6 and Grx7 do not play a general role in the oxidative folding of proteins in the early secretory pathway but rather counteract the oxidation of specific thiol groups in substrate proteins.

scholarly journals An R2R3-type myeloblastosis transcription factor MYB103 is involved in phosphorus remobilization

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Fangwei Yu ◽  
Shenyun Wang ◽  
Wei Zhang ◽  
Hong Wang ◽  
Li Yu ◽  
...  
Keyword(s):  
Cell Wall ◽  
Transcription Factor ◽  
Abiotic Stresses ◽  
Myb Transcription Factor ◽  
Ethylene Signaling ◽  
Biotic And Abiotic Stresses ◽  
P Deficiency ◽  
P Concentration ◽  
Increased Sensitivity

Abstract The members of myeloblastosis transcription factor (MYB TF) family are involved in the regulation of biotic and abiotic stresses in plants. However, the role of MYB TF in phosphorus remobilization remains largely unexplored. In the present study, we show that an R2R3 type MYB transcription factor, MYB103, is involved in phosphorus (P) remobilization. MYB103 was remarkably induced by P deficiency in cabbage (Brassica oleracea var. capitata L.). As cabbage lacks the proper mutant for elucidating the mechanism of MYB103 in P deficiency, another member of the crucifer family, Arabidopsis thaliana was chosen for further study. The transcript of its homologue AtMYB103 was also elevated in response to P deficiency in A. thaliana, while disruption of AtMYB103 (myb103) exhibited increased sensitivity to P deficiency, accompanied with decreased tissue biomass and soluble P concentration. Furthermore, AtMYB103 was involved in the P reutilization from cell wall, as less P was released from the cell wall in myb103 than in wildtype, coinciding with the reduction of ethylene production. Taken together, our results uncover an important role of MYB103 in the P remobilization, presumably through ethylene signaling.

scholarly journals Multicopy FZF1 (SUL1) Suppresses the Sulfite Sensitivity but Not the Glucose Derepression or Aberrant Cell Morphology of a grr1 Mutant of Saccharomyces cerevisiae

Genetics ◽  
1996 ◽  
Vol 144 (2) ◽  
pp. 511-521 ◽  
Author(s):  
Dorina Avram ◽  
Alan T Bakalinsky
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Transcription Factor ◽  
Glucose Metabolism ◽  
Cell Morphology ◽  
Glucose Repression ◽  
Carbon Sources ◽  
Single Copy ◽  
Aberrant Cell ◽  
Growth Defects ◽  
Putative Transcription Factor

Abstract An ssu2 mutation in Sacccharomyces cermisiae, previously shown to cause sulfite sensitivity, was found to be allelic to GRR1, a gene previously implicated in glucose repression. The suppressor rgt1, which suppresses the growth defects of grr1 strains on glucose, did not fully suppress the sensitivity on glucose or nonglucose carbon sources, indicating that it is not strictly linked to a defect in glucose metabolism. Because the Cln1 protein was previously shown to be elevated in grr1 mutants, the effect of CLN1 overexpression on sulfite sensitivity was investigated. Overexpression in GRR1 cells resulted in sulfite sensitivity, suggesting a connection between CLN1 and sulfite metabolism. Multicopy FZF1, a putative transcription factor, was found to suppress the sulfite sensitive phenotype of grr1 strains, but not the glucose derepression or aberrant cell morphology. Multicopy FZF1 was also found to suppress the sensitivity of a number of other unrelated sulfite-sensitive mutants, but not that of ssu1 or met20, implying that FZF1 may act through Ssulp and Met20p. Disruption of FZF1 resulted in sulfite sensitivity when the construct was introduced in single copy at the FZF1 locus in a GRR1 strain, providing evidence that FZF1 is involved in sulfite metabolism.

Malaria parasites possess a telomere repeat-binding protein that shares ancestry with transcription factor IIIA

2017 ◽  
Vol 2 (6) ◽  
Author(s):  
Nicole L. Bertschi ◽  
Christa G. Toenhake ◽  
Angela Zou ◽  
Igor Niederwieser ◽  
Rob Henderson ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Binding Protein ◽  
Malaria Parasites ◽  
Telomere Repeat ◽  
Transcription Factor Iiia

Abstract 14308: Integrative Epigenomic Analysis Identifies Enhancer Modifying Variants Linked to Cardiomyopathy Genes

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Anthony M Gacita ◽  
Dominic Fullenkamp ◽  
Joyce C Ohiri ◽  
Tess Pottinger ◽  
Megan Puckelwartz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transcription Factor ◽  
Clinical Care ◽  
Phenotypic Expression ◽  
Transcription Factor Binding ◽  
Clinical Feature ◽  
Protein Coding ◽  
Human Cardiomyocytes ◽  
Factor Binding ◽  
Enhancer Function

Introduction: Inherited cardiomyopathy is caused by mutations in more than 100 genes. A well-recognized clinical feature of genetic cardiomyopathy is varying phenotypic expression. Even with identical primary mutations, there is a range of clinical outcomes. Genetic variants in protein coding regions have been shown to alter the phenotypic expression of primary cardiomyopathy-causing mutations. However, the contribution of noncoding variation has been less well studied. Methods and Results: We used an integrative analysis of >20 publicly-available heart enhancer function and enhancer target datasets to identify genomic regions predicted to regulate the cardiomyopathy genes, MYH7 and LMNA . We identified two candidate enhancer clusters around the MYH7 gene and three clusters around the LMNA gene. We tested enhancers in these clusters using reporter assays and CRISPr-mediated deletion in human cardiomyocytes derived from induced pluripotent stem cells (iCMs). We identified a super enhancer upstream of MYH7 that is necessary for high MYH7 expression in iCMs. These regulatory regions contained sequence variants within transcription factor binding sites that altered enhancer function. We created an informatic pipeline that extended this strategy genomewide to identify an additional enhancer modifying variant upstream of MYH7 . This variant disrupts a transcription factor binding site upstream of MYH7 and limits MYH7 upregulation. We extended these analyses by examining clinical correlates, finding that this variant correlated with a more dilated left ventricle over time in patients with cardiomyopathy. Conclusions: We identified two enhancer regions important for MYH7 expression in iCMs. These enhancer regions may be utilized to induce MYH7 during human development and heart failure. MYH7 changes in heart failure have been linked to cardiomyopathy phenotypes. The variant upstream of MYH7 likely alters these changes and results in a more severe phenotype. These findings demonstrate that noncoding variants have clinical utility and targeted assessment of noncoding modifiers may become integrated into clinical care.

Embryonic Liver Degeneration and Increased Sensitivity Towards Heavy Metal and H2O2 in Mice Lacking the Metal-Responsive Transcription Factor MTF-1

1999 ◽  
pp. 339-352
Author(s):  
Peter Lichtlen ◽  
Çagatay Günes ◽  
Rainer Heuchel ◽  
Oleg Georgiev ◽  
Karl-Heinz Müller ◽  
...  
Keyword(s):  
Heavy Metal ◽  
Transcription Factor ◽  
Embryonic Liver ◽  
Increased Sensitivity ◽  
Liver Degeneration

scholarly journals The landscape of circulating platelet aggregates in COVID-19

2021 ◽  
Author(s):  
Yuqi Zhou ◽  
Masako Nishikawa ◽  
Hiroshi Kanno ◽  
Tinghui Xiao ◽  
Takuma Suzuki ◽  
...  
Keyword(s):  
Large Scale ◽  
Multiorgan Failure ◽  
Young Patients ◽  
Clinical Feature ◽  
Platelet Activity ◽  
Multiple Organs ◽  
Characteristic Clinical Feature ◽  
Circulating Platelet Aggregates ◽  
Platelet Aggregates ◽  
D Dimer

A characteristic clinical feature of COVID-19 is the frequent occurrence of thrombotic events. Furthermore, many cases of multiorgan failure are thrombotic in nature. Since the outbreak of COVID-19, D-dimer testing has been used extensively to evaluate COVID-19-associated thrombosis, but does not provide a complete view of the disease because it probes blood coagulation, but not platelet activity. Due to this limitation, D-dimer testing fails to account for thrombotic events which occur despite low D-dimer levels, such as sudden stroke in young patients and autopsy-identified widespread microthrombi in multiple organs. Here we report the landscape of circulating platelet aggregates in COVID-19 obtained by large-scale single-cell image-based profiling and temporal monitoring of the blood of COVID-19 patients (n = 110). Surprisingly, our analysis shows the anomalous presence of excessive platelet aggregates in nearly 90% of all COVID-19 patients, including those who were not clinically diagnosed with thrombosis and those with low D-dimer levels (less than 1 ug/mL). Additionally, results indicate a strong link between the concentration of platelet aggregates and the severity and mortality of COVID-19. Finally, high-dimensional analysis and comparison with other diseases reveal that COVID-19 behaves as a product of thrombosis (localized) and infectious diseases (systemic), as a cause of systemic thrombosis.

scholarly journals Role of therapeutic phlebotomy in management of case of porphyria cutanea tarda (PCT) admitted in tertiary care hospital Vadodara  

2020 ◽  
Vol 8 (1) ◽  
pp. 4-6
Author(s):  
Ashu Dogra
Keyword(s):  
Aminolevulinic Acid ◽  
Tertiary Care Hospital ◽  
Porphyria Cutanea Tarda ◽  
Tertiary Care ◽  
Skin Lesions ◽  
Clinical Feature ◽  
Care Hospital ◽  
Skin Symptoms ◽  
Characteristic Clinical Feature

Porphyria cutanea tarda is the most frequent type of Porphyria worldwide & presents with skin symptoms mainly. Porphyrias can affect peripheral, autonomic and central nervous system. In Porphyria conditions there is accumulation of heme precursors 5 Aminolevulinic acid, Porphobilinogen and porphyrins which are associated with characteristic clinical feature with acute neurovisceral attacks and skin lesions. This case report summarizes Case of PCT that was successfully managed with Therapeutic Phlebotomy.

scholarly journals Mid-Frequency Hearing Loss Is Characteristic Clinical Feature of OTOA-Associated Hearing Loss

Genes ◽  
2019 ◽  
Vol 10 (9) ◽  
pp. 715 ◽  
Author(s):  
Sugiyama ◽  
Moteki ◽  
Kitajiri ◽  
Kitano ◽  
Nishio ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Clinical Features ◽  
Autosomal Recessive ◽  
Japanese Patients ◽  
Copy Number Variations ◽  
Clinical Feature ◽  
Single Nucleotide Variants ◽  
Characteristic Clinical Feature ◽  
Or Gene ◽  
Homozygous Deletions

The OTOA gene (Locus: DFNB22) is reported to be one of the causative genes for non-syndromic autosomal recessive hearing loss. The copy number variations (CNVs) identified in this gene are also known to cause hearing loss, but have not been identified in Japanese patients with hearing loss. Furthermore, the clinical features of OTOA-associated hearing loss have not yet been clarified. In this study, we performed CNV analyses of a large Japanese hearing loss cohort, and identified CNVs in 234 of 2262 (10.3%, 234/2262) patients with autosomal recessive hearing loss. Among the identified CNVs, OTOA gene-related CNVs were the second most frequent (0.6%, 14/2262). Among the 14 cases, 2 individuals carried OTOA homozygous deletions, 4 carried heterozygous deletions with single nucleotide variants (SNVs) in another allele. Additionally, 1 individual with homozygous SNVs in the OTOA gene was also identified. Finally, we identified 7 probands with OTOA-associated hearing loss, so that its prevalence in Japanese patients with autosomal recessive hearing loss was calculated to be 0.3% (7/2262). As novel clinical features identified in this study, the audiometric configurations of patients with OTOA-associated hearing loss were found to be mid-frequency. This is the first study focused on the detailed clinical features of hearing loss caused by this gene mutation and/or gene deletion.

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