Expression Evolution of Mammalian Genes.

Comparing the expression-profiles of over 10,000 genes from the human and mouse genomes, I address fundamental questions on mammalian gene expression. First, I demonstrate that over 80% of human-mouse orthologous genes are evolutionarily conserved in their expression-profiles. This result highlights the importance of proper gene expression to fitness. Second, I show that highly expressed and tissue-specific genes tend to evolve slowly in expression-profile, implying that the expression pattern is of particular importance to highly expressed and tissue-specific genes. I then investigate the potential roles that gene expression plays in protein sequence evolution, dynamics of genome organization, and evolutionary changes of gene essentiality in mammals. My results indicate that tissue-specificity is a stronger determinant on protein evolutionary rate than gene expression level, a factor that is known to be the most important rate determinant in yeasts. The result suggests a great variation in rate determinants of protein sequence evolution between unicellular and multicellular organisms. Subsequently, my analyses on the origin of co-expressed gene clusters indicate that co-expression of linked genes is a form of transcriptional interference that is disadvantageous to organisms, suggesting that transcriptional interference may promote recurrent relocations of genes in the genome. Lastly, I study underlying mechanisms of the evolution of gene essentiality. The results show that the changes of gene essentiality appear to be associated with adaptive evolution at the protein-sequence level, while gene duplication and gene expression evolution plays a negligible role. Together, my studies help understand patterns, mechanisms and consequences of gene expression evolution.Ph.D.Ecology and Evolutionary BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/60816/1/liaoby_1.pd

Impact of Extracellularity on the Evolutionary Rate of Mammalian Proteins

It is of fundamental importance to understand the determinants of the rate of protein evolution. Eukaryotic extracellular proteins are known to evolve faster than intracellular proteins. Although this rate difference appears to be due to the lower essentiality of extracellular proteins than intracellular proteins in yeast, we here show that, in mammals, the impact of extracellularity is independent from the impact of gene essentiality. Our partial correlation analysis indicated that the impact of extracellularity on mammalian protein evolutionary rate is also independent from those of tissue-specificity, expression level, gene compactness, and the number of protein–protein interactions and, surprisingly, is the strongest among all the factors we examined. Similar results were also found from principal component regression analysis. Our findings suggest that different rules govern the pace of protein sequence evolution in mammals and yeasts

Integrated single-cell and bulk RNA sequencing analyses reveal a prognostic signature of cancer-associated fibroblasts in head and neck squamous cell carcinoma

Objectives: To identify a prognosis-related subtype of cancer-associated fibroblasts (CAFs) in head and neck squamous cell carcinoma (HNSCC) and comprehend its contributions to molecular characteristics, immune characteristics, and their potential benefits in immunotherapy and chemotherapy for HNSCC.Materials and Methods: We performed single-cell RNA sequencing (scRNA-seq) analysis of CAFs from the samples of HNSCC patients derived from Gene Expression Omnibus (GEO), to identify the prognosis-related subtype of CAFs. CAFs were clustered into five subtypes, and a prognosis-related subtype was identified. Univariate and multivariate cox regression analyses were performed on the cohort selected from The Cancer Genome Atlas (TCGA) to determine signature construction, which was validated in GSE65858 and GSE42743. A prognostic signature based on 4 genes was constructed, which were derived from prognosis-related CAFs. The molecular characteristics, immune characteristics as well as the predicted chemosensitivity and immunotherapeutic response in the signature-defined subgroups were analyzed subsequently.Results: The patients with higher CAF scores correlated with poor survival outcomes. Additionally, a high CAF score correlated with lower infiltration levels of many immune cells including M1 macrophages, CD8+ T cells, follicular T helper cells, monocytes, and naïve B cells. High CAF score also demonstrated different enrichment pathways, mutation genes and copy number variated genes. Furthermore, patients with high CAF scores showed lower sensitivity for chemotherapy and immunotherapy than those with low CAF scores.Conclusion: The results of our study indicate the potential of the CAF signature as a biomarker for the prognosis of HNSCC patients. Furthermore, the signature could be a prospective therapeutic target in HNSCC

A plausible microtubule-based mechanism for cell division orientation in plant embryogenesis

Oriented cell divisions are significant in plant morphogenesis because plant cells are embedded in cell walls and cannot relocate. Cell divisions follow various regular orientations, but the underlying mechanisms have not been clarified. We propose that cell-shape-dependent self-organization of cortical microtubule arrays is able to provide a mechanism for determining planes of early tissue-generating divisions and may form the basis for robust control of cell division orientation in the embryo. To show this, we simulate microtubules on actual cell surface shapes, from which we derive a minimal set of three rules for proper array orientation. The first rule captures the effects of cell shape alone on microtubule organization, the second rule describes the regulation of microtubule stability at cell edges, and the third rule includes the differential effect of auxin on local microtubule stability. These rules generate early embryonic division plane orientations and potentially offer a framework for understanding patterned cell divisions in plant morphogenesis. Chakrabortty et al. show that a computational model for dynamic self-organization of cortical microtubules on experimentally extracted cell shapes provides a plausible molecular mechanism for division plane orientation in the first four divisions of early stage A. thaliana embryos, in WT as well as two developmental mutants bodenlos and clasp

Inflammatory Marker but Not Adipokine Predicts Mortality among Long-Term Hemodialysis Patients

Aims: chronic inflammation contributes significantly to the morbidity and mortality of chronic hemodialysis patients. A recent research has shown that adipokines were associated with inflammation in these patients. We aim to investigate whether biomarkers of inflammation, adipokines, and clinical features can predict the outcome of hemodialysis patients. Materials and methods: we enrolled 181 hemodialysis patients (men: 97, mean age: 56.3±13.6) and analyzed predictors of long-term outcomes. Results: during the 3-year followup period, 41 patients died; the main causes of death were infection and cardiovascular disease. Elevated serum levels of hsCRP and albumin and advanced age were highly associated with death (all P<.001). Leptin and adiponectin levels were not significantly different between deceased patients and survivors. Cox-regression analysis indicated that age, diabetes, albumin level, and hsCRP were independent factors predicting mortality. Conclusion: the presence of underlying disease, advanced age, and markers of chronic inflammation is strongly related to survival rate in long-term hemodialysis patients

Differential expression profile of CXCR3 splicing variants is associated with thyroid neoplasia. Potential role in papillary thyroid carcinoma oncogenesis?

Indexación: Scopus.Papillary thyroid cancer (PTC) is the most prevalent endocrine neoplasia. The increased incidence of PTC in patients with thyroiditis and the frequent immune infiltrate found in PTC suggest that inflammation might be a risk factor for PTC development. The CXCR3-ligand system is involved in thyroid inflammation and CXCR3 has been found upregulated in many tumors, suggesting its pro-tumorigenic role under the inflammatory microenvironment. CXCR3 ligands (CXCL4, CXCL9, CXCL10 and CXCL11) trigger antagonistic responses partly due to the presence of two splice variants, CXCR3A and CXCR3B. Whereas CXCR3A promotes cell proliferation, CXCR3B induces apoptosis. However, the relation between CXCR3 variant expression with chronic inflammation and PTC development remains unknown. Here, we characterized the expression pattern of CXCR3 variants and their ligands in benign tumors and PTC. We found that CXCR3A and CXCL10 mRNA levels were increased in non-metastatic PTC when compared to non-neoplastic tissue. This increment was also observed in a PTC epithelial cell line (TPC-1). Although elevated protein levels of both isoforms were detected in benign and malignant tumors, the CXCR3A expression remained greater than CXCR3B and promoted proliferation in Nthy-ori-3-1 cells. In non-metastatic PTC, inflammation was conditioning for the CXCR3 ligands increased availability. Consistently, CXCL10 was strongly induced by interferon gamma in normal and tumor thyrocytes. Our results suggest that persistent inflammation upregulates CXCL10 expression favoring tumor development via enhanced CXCR3A-CXCL10 signaling. These findings may help to further understand the contribution of inflammation as a risk factor in PTC development and set the basis for potential therapeutic studies.http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=23502&path[]=7402

Mammalian Genes Preferentially Co-Retained in Radiation Hybrid Panels Tend to Avoid Coexpression

Coexpression has been frequently used to explore modules of functionally related genes in eukaryotic genomes. However, we found that genetically interacting mammalian genes identified through radiation hybrid (RH) genotypes tend not to be coexpressed across tissues. This pattern remained unchanged after controlling for potential confounding factors, including chromosomal linkage, chromosomal distance, and gene duplication. Because >99.9% of the genetically interacting genes were identified according to the higher co-retention frequencies, our observation implies that coexpression is not necessarily an indication of the need for the co-presence of two genes in the genome, which is a prerequisite for cofunctionality of their coding proteins in the cell. Therefore, coexpression information must be applied cautiously to the exploration of the functional relatedness of genes in a genome

Scanning for the Signatures of Positive Selection for Human-Specific Insertions and Deletions

Human-specific small insertions and deletions (HS indels, with lengths <100 bp) are reported to be ubiquitous in the human genome. However, whether these indels contribute to human-specific traits remains unclear. Here we employ a modified McDonald–Kreitman (MK) test and a combinatorial population genetics approach to infer, respectively, the occurrence of positive selection and recent selective sweep events associated with HS indels. We first extract 625,890 HS indels from the human–chimpanzee–macaque–mouse multiple alignments and classify them into nonpolymorphic (41%) and polymorphic (59%) indels with reference to the human indel polymorphism data. The modified MK test is then applied to 100-kb partially overlapped sliding windows across the human genome to scan for the signs of positive selection. After excluding the possibility of biased gene conversion and controlling for false discovery rate, we show that HS indels are potentially positively selected in about 10 Mb of the human genome. Furthermore, the indel-associated positively selected regions overlap with genes more often than expected. However, our result suggests that the potential targets of positive selection are located in noncoding regions. Meanwhile, we also demonstrate that the genomic regions surrounding HS indels are more frequently involved in recent selective sweep than the other regions. In addition, HS indels are associated with distinct recent selective sweep events in different human subpopulations. Our results suggest that HS indels may have been associated with human adaptive changes at both the species level and the subpopulation level

Jointly optimizing lot sizing and maintenance policy for a production system with two failure modes

In the reliability literature, there are studies that jointly study maintenance and production and that is typically restricted to one failure mode, and fail to address the case where multiple failure modes exist. This study in-vestigates the problem of joint optimization of lot sizing and maintenance policy for a multi-product produc-tion system subject to two failure modes. The failure of the first mode refers to the soft failure that occurs af-ter defects arrive. The failure of the second mode is a hard failure that occurs without any early warning sig-nals. Products are sequentially produced by the system and a complete run of all products forms a production cycle. The system needs to be re-set up before producing a different product. Both the production cycle and the set-up point depend on the lot sizes of products. Models are proposed for two maintenance policies: 1) arranging the maintenance to be at the end of each production cycle; 2) arranging the maintenance to be at set-up points. The expected profit per unit time is formulated to obtain the optimal lot sizing and maintenance policy. Some properties of proposed models are proved, which show that the optimal lot sizing and mainte-nance policy can be obtained under certain conditions. Case studies and sensitivity analyses are presented to illustrate the proposed models of two maintenance policies. Basically, the results show that the producer will gain the most profit if the optimal lot sizing and maintenance policy are adopted. The results of comparing both maintenance policies reveal that the excessive maintenance is not economic. The sensitivity analyses il-lustrate that reducing the cost caused by failures and improving system reliability are effective ways to in-crease the expected profit per unit time