18 research outputs found
Synergistic effects of putative Ca<sup>2+</sup>-binding sites of calmodulin in fungal development, temperature stress and virulence of <i>Aspergillus fumigatus</i>
In pathogenic fungi, calcium-calmodulin-dependent serine-threonine-specific phosphatase calcineurin is involved in morphogenesis and virulence. Therefore, calcineurin and its tightly related protein complexes are attractive antifungal drug targets. However, there is limited knowledge available on the relationship between in vivo Ca2+-binding sites of calmodulin (CaM) and its functions in regulating stress responses, morphogenesis, and pathogenesis. In the current study, we demonstrated that calmodulin is required for hyphal growth, conidiation, and virulence in the human fungal pathogen, Aspergillus fumigatus. Site-directed mutations of calmodulin revealed that a single Ca2+-binding site mutation had no significant effect on A. fumigatus hyphal development, but multiple Ca2+-binding site mutations exhibited synergistic effects, especially when cultured at 42 °C, indicating that calmodulin function in response to temperature stress depends on its Ca2+-binding sites. Western blotting implied that mutations in Ca2+-binding sites caused highly degraded calmodulin fragments, suggesting that the loss of Ca2+-binding sites results in reduced protein stability. Moreover, normal intracellular calcium homeostasis and the nuclear translocation of the transcriptional factor CrzA are dependent on Ca2+-binding sites of AfCaM, demonstrating that Ca2+-binding sites of calmodulin are required for calcium signalling and its major transcription factor CrzA. Importantly, in situ mutations for four Ca2+-binding sites of calmodulin resulted in an almost complete loss of virulence in the Galleria mellonella wax moth model. This study shed more light on the functional characterization of putative calcium-binding sites of calmodulin in the morphogenesis and virulence of A. fumigatus, which enhances our understanding of calmodulin biological functions in cells of opportunistic fungal pathogens.</p
Association of polymorphisms in heat shock protein 70 genes with the susceptibility to noise-induced hearing loss: A meta-analysis
<div><p>Background</p><p>Several case-control studies reported the relationship between single nucleotide polymorphisms (SNPs) in HSP70 genes and noise-induced hearing loss (NIHL). However, their conclusions are conflicting. This meta-analysis aims to identify the association of HSP70 variants and NIHL susceptibility.</p><p>Method</p><p>A systematical literature search was performed in PubMed, Web of Science, EMBASE, and Wanfang Chinese database. The pooled odds radio (OR), 95% confidence interval (CI) and p value were calculated in fixed- or random-effects model according to the I<sup>2</sup> value in the heterogeneity test.</p><p>Results</p><p>Four articles containing five studies, including 633 cases and 926 controls, were included. Under the allele, homozygote and dominant model, the pooled ORs (95%CI, p-value) of rs1061581 were 1.32 (1.06–1.67, p = 0.019), 1.93 (1.10–3.36, p = 0.021) and 1.455 (1.408–2.019, p = 0.025), respectively. In addition, a significant association was found between rs2227956 in Caucasians and the NIHL susceptibility under all five genetic models. We did not discover evidence sufficient to prove the associations between the other three SNPs (rs1043618, rs2763979 and rs2075800) and the NIHL susceptibility.</p><p>Conclusion</p><p>This meta-analysis indicated that the two HSP70 variants, rs1061581 and rs2227956, may serve as genetic susceptibility factors for NIHL. Larger scale studies are required to further update the results.</p></div
Table_1_Large-scale correlation analysis of deep venous thrombosis and gut microbiota.XLS
ObjectiveAlthough previous studies have shown that gut microbiota may be involved in the occurrence of deep venous thrombosis (DVT), the specific link between the two remains unclear. The present study aimed to explore this question from a genetic perspective.Materials and methodsGenome-wide association study (GWAS) summary data of DVT were obtained from the UK Biobank (N = 9,059). GWAS summary data of the gut microbiota were obtained from the Flemish Gut Flora Project (N = 2,223) and two German cohorts (FoCus, N = 950; PopGen, N = 717). All the participants were of European ancestry. Linkage disequilibrium score (LDSC) regression has great potential for analyzing the heritability of disease or character traits. LDSC regression was used to analyze the genetic correlation between DVT and the gut microbiota based on the GWAS summary data obtained from previous studies. Mendelian randomization (MR) was used to analyze the genetic causal relationship between DVT and the gut microbiota. We used the random effects inverse variance weighted, MR Egger, weighted median, simple mode, and weighted mode to perform MR analysis. We performed a sensitivity analysis of the MR analysis results by examining heterogeneity and horizontal pleiotropy.ResultsLinkage disequilibrium score analysis showed that Streptococcaceae (correlation coefficient = −0.542, SE = 0.237, P = 0.022), Dialister (correlation coefficient = −0.623, SE = 0.316, P = 0.049), Streptococcus (correlation coefficient = −0.576, SE = 0.264, P = 0.029), and Lactobacillales (correlation coefficient = −0.484, SE = 0.237, P = 0.042) had suggestive genetic correlation with DVT. In addition, the MR analysis showed that Streptococcaceae had a positive genetic causal relationship with DVT (P = 0.027, OR = 1.005). There was no heterogeneity or horizontal pleiotropy in the MR analysis (P > 0.05).ConclusionIn this study, four gut microbes (Streptococcaceae, Dialister Streptococcus, Lactobacillales) had suggestive genetic correlations with DVT, and Streptococcaceae had a positive causal relationship with DVT. Our findings provide a new research direction for the further study of and prevention of DVT.</p
Overall analysis of the association between HSP70 SNPs and NIHL susceptibility.
<p>Overall analysis of the association between HSP70 SNPs and NIHL susceptibility.</p
The association between rs1061581 and NIHL susceptibility in different genetic models.
<p>The association between rs1061581 and NIHL susceptibility in different genetic models.</p
Characteristics of the five SNPs in HSP70 genes.
<p>Characteristics of the five SNPs in HSP70 genes.</p
Endogenous Enzyme-Activatable Spherical Nucleic Acids for Spatiotemporally Controlled Signal Amplification Molecular Imaging and Combinational Tumor Therapy
Due to the adjustable hybridization activity, antinuclease
digestion
stability, and superior endocytosis, spherical nucleic acids (SNAs)
have been actively developed as probes for molecular imaging and the
development of noninvasive diagnosis and image-guided surgery. However,
since highly expressed biomarkers in tumors are not negligible in
normal tissues, an inevitable background signal and the inability
to precisely release probes at the chosen region remain a challenge
for SNAs. Herein, we proposed a rationally designed, endogenous enzyme-activatable
functional SNA (Ep-SNA) for spatiotemporally controlled signal amplification
molecular imaging and combinational tumor therapy. The self-assembled
amphiphilic polymer micelles (SM-ASO), which were obtained by a simple
and rapid copper-free strain-promoted azide–alkyne cycloaddition
click reaction between dibenzocyclooctyne-modified antisense oligonucleotide
and azide-containing aliphatic polymer polylactic acid, were introduced
as the core elements of Ep-SNA. This Ep-SNA was then constructed by
connecting two apurinic/apyrimidinic (AP) site-containing trailing
DNA hairpins, which could occur via a hybridization chain reaction
in the presence of low-abundance survivin mRNA to SM-ASO through complementary
base pairing. Notably, the AP site-containing trailing DNA hairpins
also empowered the SNA with the feasibility of drug delivery. Once
this constructed intelligent Ep-SNA nanoprobe was specifically cleaved
by the highly expressed cytoplasmic human apurinic/apyrimidinic endonuclease
1 in tumor cells, three key elements (trailing DNA hairpins, antisense
oligonucleotide, and doxorubicin) could be released to enable subsequent
high-sensitivity survivin mRNA imaging and combinational cancer therapy
(gene silencing and chemotherapy). This strategy shows great application
prospects of SNAs as a precise platform for the integration of disease
diagnosis and treatment and can contribute to basic biomedical research