High temperature requirement A1 in cancer: biomarker and therapeutic target

As the life expectancy of the population increases worldwide, cancer is becoming a substantial public health problem. Considering its recurrence and mortality rates, most cancer cases are difficult to cure. In recent decades, a large number of studies have been carried out on different cancer types; unfortunately, tumor incidence and mortality have not been effectively improved. At present, early diagnostic biomarkers and accurate therapeutic strategies for cancer are lacking. High temperature requirement A1 (HtrA1) is a trypsin-fold serine protease that is also a chymotrypsin-like protease family member originally discovered in bacteria and later discovered in mammalian systems. HtrA1 gene expression is decreased in diverse cancers, and it may play a role as a tumor suppressor for promoting the death of tumor cells. This work aimed to examine the role of HtrA1 as a cell type-specific diagnostic biomarker or as an internal and external regulatory factor of diverse cancers. The findings of this study will facilitate the development of HtrA1 as a therapeutic target.

Dissecting the role of interprotomer cooperativity in the activation of oligomeric high-temperature requirement A2 protein

The human high-temperature requirement A2 (HtrA2) mitochondrial protease is critical for cellular proteostasis, with mutations in this enzyme closely associated with the onset of neurodegenerative disorders. HtrA2 forms a homotrimeric structure, with each subunit composed of protease and PDZ (PSD-95, DLG, ZO-1) domains. Although we had previously shown that successive ligand binding occurs with increasing affinity, and it has been suggested that allostery plays a role in regulating catalysis, the molecular details of how this occurs have not been established. Here, we use cysteine-based chemistry to generate subunits in different conformational states along with a protomer mixing strategy, biochemical assays, and methyl-transverse relaxation optimized spectroscopy–based NMR studies to understand the role of interprotomer allostery in regulating HtrA2 function. We show that substrate binding to a PDZ domain of one protomer increases millisecond-to-microsecond timescale dynamics in neighboring subunits that prime them for binding substrate molecules. Only when all three PDZ-binding sites are substrate bound can the enzyme transition into an active conformation that involves significant structural rearrangements of the protease domains. Our results thus explain why when one (or more) of the protomers is fixed in a ligand-binding–incompetent conformation or contains the inactivating S276C mutation that is causative for a neurodegenerative phenotype in mouse models of Parkinson’s disease, transition to an active state cannot be formed. In this manner, wild-type HtrA2 is only active when substrate concentrations are high and therefore toxic and unregulated proteolysis of nonsubstrate proteins can be suppressed.

Molecular Engineering for High-Performance Fullerene Broadband Photodetector

Broadband photodetectors fabricated with organic molecules have the advantages of low cost, high flexibility, easy processing and low-temperature requirement. Fullerene molecules, due to the electron acceptor and photoinduced electron transfer...

High-temperature requirement factor A1 rs11200638 polymorphism and age-related macular degenerative from a comprehensive analysis about 15316 subjects

Background: The high-temperature requirement factor A1 (HTRA1) gene at the 10q26 locus has been associated with age-related macular degenerative (AMD) risk, with the significantly associated polymorphism being (rs11200638, -625G/A), however, above association is not consistent. We investigated an updated meta-analysis to evaluate the association between rs11200638 polymorphism and AMD risk thoroughly addressing this issue. Methods: An identification was covered with the Pubmed and Chinese Wanfang databases through 27th Jan, 2020. Odds ratios (OR) and 95% confidence intervals (CI) were used to assess the strength of associations. After a thorough and meticulous search, 35 different articles (33 case-control studies with HWE, 22 case-control studies about wet/dry AMD) were retrieved. Results: Individuals carrying A-allele or AA genotype may have an increased risk to be AMD disease. For example, there has a significantly increased relationship between rs11200638 polymorphism and AMD both for Asians (OR: 2.51, 95%CI: 2.22-2.83 for A-allele vs. G-allele) and Caucasians (OR: 2.63, 95%CI: 2.29-3.02 for A-allele vs. G-allele). Moreover, a similar trend in the source of control subgroup was detected. To classify the type of AMD, increased association was also observed in both wet (OR: 3.40, 95%CI: 2.90-3.99 for dominant model) and dry (OR: 2.08, 95%CI: 1.24-3.48 for dominant model) AMD. Finally, based on the different genotyping methods, increased relationships were identified by sequencing, TaqMan, PCR-RFLP and RT-PCR. Conclusions: Our present meta-analysis suggests that the HTRA1 rs11200638 polymorphism are potentially associated with the risk of AMD development, especially about individuals carrying A-allele or AA genotype, who may be as identified targets to detect and intervene in advance. Further studies using larger sample sizes and including information about gene-environment interactions should be conducted to elucidate.

High-temperature requirement factor A1 rs11200638 polymorphism and age-related macular degenerative from a comprehensive analysis about 15316 subjects

Background: The high-temperature requirement factor A1 (HTRA1) gene at the 10q26 locus has been associated with age-related macular degenerative (AMD) risk, with the significantly associated polymorphism being (rs11200638, -625G/A), however, above association is not consistent. We investigated an updated meta-analysis to evaluate the association between rs11200638 polymorphism and AMD risk thoroughly addressing this issue. Methods: An identification was covered with the Pubmed and Chinese Wanfang databases through 27th Jan, 2020. Odds ratios (OR) and 95% confidence intervals (CI) were used to assess the strength of associations. After a thorough and meticulous search, 35 different articles (33 case-control studies with HWE, 22 case-control studies about wet/dry AMD) were retrieved. Results: Individuals carrying A-allele or AA genotype may have an increased risk to be AMD disease. For example, there has a significantly increased relationship between rs11200638 polymorphism and AMD both for Asians (OR: 2.51, 95%CI: 2.22-2.83 for A-allele vs. G-allele) and Caucasians (OR: 2.63, 95%CI: 2.29-3.02 for A-allele vs. G-allele). Moreover, a similar trend in the source of control subgroup was detected. To classify the type of AMD, increased association was also observed in both wet (OR: 3.40, 95%CI: 2.90-3.99 for dominant model) and dry (OR: 2.08, 95%CI: 1.24-3.48 for dominant model) AMD. Finally, based on the different genotyping methods, increased relationships were identified by sequencing, TaqMan, PCR-RFLP and RT-PCR. Conclusions: Our present meta-analysis suggests that the HTRA1 rs11200638 polymorphism are potentially associated with the risk of AMD development, especially about individuals carrying A-allele or AA genotype, who may be as identified targets to detect and intervene in advance. Further studies using larger sample sizes and including information about gene-environment interactions should be conducted to elucidate.

High-temperature requirement factor A1 rs11200638 polymorphism and age-related macular degenerative from a comprehensive analysis about 15316 subjects

Background The high-temperature requirement factor A1 (HTRA1) gene at the 10q26 locus has been associated with age-related macular degenerative (AMD) risk, with the significantly associated polymorphism being (rs11200638, -625G/A), however, above association is not consistent. We investigated an updated meta-analysis to evaluate the association between rs11200638 polymorphism and AMD risk thoroughly addressing this issue. Methods An identification was covered with the Pubmed and Chinese Wanfang databases through 27th Jan, 2020. Odds ratios (OR) and 95% confidence intervals (CI) were used to assess the strength of associations. After a thorough and meticulous search, 35 different articles (33 case-control studies with HWE, 22 case-control studies about wet/dry AMD) were retrieved. Results Individuals carrying A-allele or AA genotype may have an increased risk to be AMD disease. For example, there has a significantly increased relationship between rs11200638 polymorphism and AMD both for Asians (OR: 2.50, 95%CI: 2.22-2.80 for A-allele vs. G-allele) and Caucasians (OR: 2.11, 95%CI: 1.43-3.13 for A-allele vs. G-allele). Moreover, a similar trend in the source of control subgroup was detected. To classify the type of AMD, increased association was also observed in both wet (OR: 3.40, 95%CI: 2.90-3.99 for dominant model) and dry (OR: 2.08, 95%CI: 1.24-3.48 for dominant model) AMD. Finally, based on the different genotyping methods, increased relationships were identified by sequencing, TaqMan, PCR-RFLP. Conclusions Our present meta-analysis suggests that the HTRA1 rs11200638 polymorphism are potentially associated with the risk of AMD development, especially about individuals carrying A-allele or AA genotype, who may be as identified targets to detect and intervene in advance. Further studies using larger sample sizes and including information about gene-environment interactions should be conducted to elucidate.