In this research, we developed a robust two-layer classifier that can accurately classify normal hearing (NH) from hearing impaired (HI) infants with congenital sensori-neural hearing loss (SNHL) ...based on their Magnetic Resonance (MR) images. Unlike traditional methods that examine the intensity of each single voxel, we extracted high-level features to characterize the structural MR images (sMRI) and functional MR images (fMRI). The Scale Invariant Feature Transform (SIFT) algorithm was employed to detect and describe the local features in sMRI. For fMRI, we constructed contrast maps and detected the most activated/de-activated regions in each individual. Based on those salient regions occurring across individuals, the bag-of-words strategy was introduced to vectorize the contrast maps. We then used a two-layer model to integrate these two types of features together. With the leave-one-out cross-validation approach, this integrated model achieved an AUC score of 0.90. Additionally, our algorithm highlighted several important brain regions that differentiated between NH and HI children. Some of these regions, e.g. planum temporale and angular gyrus, were well known auditory and visual language association regions. Others, e.g. the anterior cingulate cortex (ACC), were not necessarily expected to play a role in differentiating HI from NH children and provided a new understanding of brain function and of the disorder itself. These important brain regions provided clues about neuroimaging markers that may be relevant to the future use of functional neuroimaging to guide predictions about speech and language outcomes in HI infants who receive a cochlear implant. This type of prognostic information could be extremely useful and is currently not available to clinicians by any other means.
Background: The haplotype based association method offers a powerful approach to complex disease gene mapping. In this method, a few common haplotypes that account for the vast majority of ...chromosomes in the populations are usually examined for association with disease phenotypes. This brings us to a critical question of whether rare haplotypes play an important role in influencing disease susceptibility and thus should not be ignored in the design and execution of association studies. Methods: To address this question we surveyed, in a large sample of 1873 white subjects, six candidate genes for osteoporosis (a common late onset bone disorder), which had 29 SNPs, an average marker density of 13 kb, and covered a total of 377 kb of the DNA sequence. Results: Our empirical data demonstrated that two rare haplotypes of the parathyroid hormone (PTH)/PTH related peptide receptor type 1 and vitamin D receptor genes (PTHR1 and VDR) with frequencies of 1.1% and 2.9%, respectively, had significant effects on osteoporosis phenotypes (p = 4.2 × 10−6 and p = 1.6 × 10−4, respectively). Large phenotypic differences (4.0∼5.0%) were observed between carriers of these rare haplotypes and non-carriers. Carriers of the two rare haplotypes showed quantitatively continuous variation in the population and were derived from a wide spectrum rather than from one extreme tail of the population phenotype distribution. Conclusions: These findings indicate that rare haplotypes/variants are important for disease susceptibility and cannot be ignored in genetics studies of complex diseases. The study has profound implications for association studies and applications of the HapMap project.
There are many difficulties and uncertainties in the early diagnosis of neonatal sepsis. The aim of this study was to determine whether albumin (ALB) is useful for the early diagnosis of neonatal ...sepsis using ALB, C-reactive protein (CRP) and procalcitonin (PCT) together.
ALB, CRP, PCT and white blood cell (WBC) data from 732 patients with neonatal sepsis and 1317 neonatal infection patients hospitalized in Foshan Maternal and Child Health Hospital from 2011 to 2022 were collected. Receiver operating characteristic (ROC) and logistic regression analyses were performed to assess the diagnostic value of ALB, CRP, PCT and the WBC count for neonatal sepsis. The roles of ALB, CRP, PCT and the WBC count in the diagnosis of neonatal sepsis were analysed by using subject working characteristics (ROC) and areas under the curve (AUCs), and the variables were combined to determine which combination had the best diagnostic efficacy.
In the sepsis group, the ALB, CRP, and PCT levels and the WBC count were significantly higher than those in the infection group (
<0.001). In all infants, the sensitivities and specificities of ALB, CRP, PCT, and WBC count were 0.411, 0.596, 0.483 and 0.411, respectively, and 0.833, 0.846, 0.901 and 0.796, respectively. With a sensitivity of 0.646, a specificity of 0.929, and an AUC of 0.834, the best combination was that of ALB, CRP, and PCT, which was better than that of CRP + PCT, CRP + ALB and PCT + ALB.
In neonatal sepsis, in the absence of blood culture results, the combination of ALB, CRP, and PCT is more reliable than CRP, PCT, or CRP+PCT alone. These results suggest that ALB is a useful inflammatory biomarker for the early diagnosis of neonatal sepsis, and can improve the diagnostic efficiency.
The unfolded protein response (UPR) is a network of intracellular signaling pathways that supports the ability of the secretory pathway to maintain a balance between the load of proteins entering the ...endoplasmic reticulum (ER) and the protein folding capacity of the ER lumen. Current evidence indicates that several pathogenic fungi rely heavily on this pathway for virulence, but there is limited understanding of the mechanisms involved. The best known functional output of the UPR is transcriptional upregulation of mRNAs involved in ER homeostasis. However, this does not take into account mechanisms of translational regulation that involve differential loading of ribosomes onto mRNAs. In this study, a global analysis of transcript-specific translational regulation was performed in the pathogenic mold Aspergillus fumigatus to determine the nature and scope of the translational response to ER stress.
ER stress was induced by treating the fungus with dithiothreitol, tunicamycin, or a thermal up-shift. The mRNAs were then fractionated on the basis of ribosome occupancy into an under-translated pool (U) and a well-translated pool (W). The mRNAs were used to interrogate microarrays and the ratio of the hybridization signal (W/U) was used as an indicator of the relative translational efficiency of a mRNA under each condition. The largest category of translationally upregulated mRNAs during ER stress encoded proteins involved in translation. Components of the ergosterol and GPI anchor biosynthetic pathways also showed increased polysome association, suggesting an important role for translational regulation in membrane and cell wall homeostasis. ER stress induced limited remodeling of the secretory pathway translatome. However, a select group of transcription factors was translationally upregulated, providing a link to subsequent modification of the transcriptome. Finally, we provide evidence that one component of the ER stress translatome is a novel mRNA isoform from the yvc1 gene that is induced by ER stress in a UPR-dependent manner.
Together, these findings define a core set of mRNAs subject to translational control during the adaptive response to acute ER stress in A. fumigatus and reveal a remarkable breadth of functions that are needed to resolve ER stress in this organism.
Background: Osteoporosis, mainly characterised by low bone mineral density (BMD), is a serious public health problem. The collagen type I alpha 1 (COL1A1) gene is a prominent candidate gene for ...osteoporosis. Here, we examined whether genetic variants at the COL1A1 gene can influence BMD variation. Methods: BMD was measured at nine skeletal sites in 313 Caucasian males and 308 Caucasian females. We screened four single nucleotide polymorphisms (SNPs) at the COL1A1 gene: PCOL2 (-1997 G/T) in the promoter, Sp1 (1546 G/T) in the intron 1, Gly19Cys (3911 G/A) in exon 8, and Ala897Thr (13 773 G/A) in exon 45. Univariate and multivariate association approaches were used in the analyses. Results: In multivariate analyses, we found a strong association between the PCOL2 SNP and BMD (p = 0.007 to 0.024) and a suggestive association between the Sp1 SNP and BMD (p = 0.023 to 0.048) in elderly Caucasian females. Interestingly, the interaction of these two SNPs was highly significantly associated with BMD variation (p = 0.001 to 0.003). The haplotype GG at the two SNPs had, on average, 2.7% higher BMD than non-carriers (p = 0.006 to 0.026). Conclusions: Our data suggested that the common genetic variants at the PCOL2 and Sp1 sites, and importantly, their interactive effects, may contribute to BMD variation in elderly Caucasian females. Further studies are necessary to delineate the mechanisms underlying the effects of these common variants on BMD variation and to test their clinical relevance for general populations. In addition, our study highlighted the importance of multivariate analyses when multiple correlated phenotypes are under study.
We have previously established a model for postmenopausal, hormone-dependent breast cancer in nude mice which is responsive to both antiestrogens and aromatase inhibitors. In this model, MCF-7 human ...breast carcinoma cells transfected with the aromatase gene (MCF-7CA) synthesize sufficient estrogen to form tumors in ovariectomized nude mice. In the present study we used this intratumoral aromatase model to investigate the effects on tumor growth of the new nonsteroidal aromatase inhibitors letrozole (CGS 20,267) and anastrozole (ZD 1033) and the antiestrogens tamoxifen (ICI 47,474) and faslodex (ICI 182,780). Furthermore, we determined whether the inhibition of estrogen synthesis together with inhibition of estrogen action would be more effective in controlling breast tumor growth. The results of our studies indicate that the aromatase inhibitors anastrozole and letrozole, as well as the new pure antiestrogen faslodex, have potent antitumor effects in the mouse model. In the treatment of mice with mammary tumors, letrozole was more effective in suppressing tumor growth than anastrozole. This was consistent with the Ki values of these inhibitors against placental aromatase and the IC50 values in cell culture (MCF-7CA), which indicated the greater potency of letrozole as an aromatase inhibitor. Letrozole also had greater antitumor effects than tamoxifen and faslodex. The antitumor effect of letrozole was substantial, making it difficult to detect any additional effect on the tumors when letrozole was combined with the antiestrogens. However, the combined treatment of anastrozole + tamoxifen and anastrozole + faslodex also did not increase efficacy compared to the aromatase inhibitor alone. In addition, combining the two antiestrogens did not suppress tumor growth more effectively than faslodex alone. Our results show that treatment with the combinations of aromatase inhibitors with either tamoxifen or faslodex are not more effective in blocking estrogen stimulation of tumor growth than the aromatase inhibitors alone.
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome which develops in patients with severe liver diseases and/or portal-systemic shunting. Minimal HE, the earliest manifestation of HE, has ...drawn increasing attention in the last decade. Minimal HE is associated with a series of brain functional changes, such as attention, working memory, and so on. Blood oxygen level dependent (BOLD) functional MRI (fMRI), especially resting-state fMRI has been used to explore the brain functional changes of HE, yielding important insights for understanding pathophysiological mechanisms and functional reorganization of HE. This paper briefly reviews the principles of BOLD fMRI, potential applications of resting-state fMRI with advanced post-processing algorithms such as regional homogeneity, amplitude of low frequency fluctuation, functional connectivity and future research perspective in this field.
In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified 3 genetic loci newly associated with breast cancer risk, including ...rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene; P=8.82×10(-9)), rs10474352 at 5q14.3 (near the ARRDC3 gene; P=1.67×10(-9)) and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene; P=4.25×10(-8)). We replicated these associations in 16,003 cases and 41,335 controls of European ancestry (P=0.030, 0.004 and 0.010, respectively). Data from the ENCODE Project suggest that variants rs4951011 and rs10474352 might be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer.
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