Construction and Validation of a Nomogram for the Preoperative Prediction of Lymph Node Metastasis in Gastric Cancer.

BACKGROUND: Increasing evidence indicated that the tumor microenvironment (TME) plays a critical role in tumor progression. This study aimed to identify and evaluate mRNA signature involved in lymph node metastasis (LNM) in TME for gastric cancer (GC). METHODS: Gene expression and clinical data were downloaded from The Cancer Genome Atlas (TCGA). The ESTIMATE algorithm was used to evaluate the TME of GC. The heatmap and Venn plots were applied for visualizing and screening out intersect differentially expressed genes (DEGs) involved in LNM in TME. Functional enrichment analysis, gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) network were also conducted. Furthermore, binary logistic regression analysis were employed to develop a 4-mRNAs signature for the LNM prediction. ROC curves were applied to validate the LNM predictive ability of the riskscore. Nomogram was constructed and calibration curve was plotted to verify the predictive power of nomogram. RESULTS: A total of 88 LNM related DEGs were identified. Functional enrichment analysis and GSEA implied that those genes were associated with some biological processes, such as ion transportation, lipid metabolism and thiolester hydrolase activity. After univariate and multivariate logistic regression analysis, 4 mRNAs (RASSF2, MS4A2, ANKRD33B and ADH1B) were eventually screened out to develop a predictive model. ROC curves manifested the good performance of the 4-mRNAs signature. The proportion of patients with LNM in high-risk group was significantly higher than that in low-risk group. The C-index of nomogram from training and test cohorts were 0.865 and 0.765, and the nomogram was well calibrated. CONCLUSIONS: In general, we identified a 4-mRNAs signature that effectively predicted LNM in GC patients. Moreover, the 4-mRNAs signature and nomogram provide a guidance for the preoperative evaluation and postoperative treatment of GC patients.

Effects of a high body mass index on the short-term outcomes and prognosis after radical gastrectomy.

PURPOSE: This study aimed to investigate the effects of a high body mass index (BMI) on the outcomes of radical gastrectomy for gastric cancer. METHODS: We conducted a retrospective cohort study of 1729 patients with stage I to III gastric cancer who received open radical gastrectomy from February 2003 to August 2011. The patients were divided into 3 groups according to their BMI: a low BMI group (BMI < 18.5 kg/m2), normal BMI group (18.5 ≤ BMI < 25 kg/m2), and high BMI group (BMI ≥ 25 kg/m2). RESULTS: A total of 871 patients were included in the final analysis, of which the median BMI was 22.7 kg/m2 (range 13.6-44.9 kg/m2). A high BMI increased the risk of postoperative intestinal fistula but not the risk of a reduced number of examined lymph nodes or hospital death. Furthermore, a high BMI did not negatively affect the overall survival (OS) of gastric cancer patients. CONCLUSIONS: A high BMI increased the operative morbidity after radical gastrectomy for gastric cancer. However, a high BMI did not negatively affect the quality of lymphadenectomy or the OS of gastric cancer patients in experienced high-volume centers. A careful approach during operation and meticulous perioperative management are required for gastric cancer patients with a high BMI.

The insulin signaling pathway in Drosophila melanogaster: A nexus revealing an "Achilles' heel" in DDT resistance.

Insecticide resistance is an ongoing challenge in agriculture and disease vector control. Here, we demonstrate a novel strategy to attenuate resistance. We used genomics tools to target fundamental energy-associated pathways and identified a potential "Achilles' heel" for resistance, a resistance-associated protein that, upon inhibition, results in a substantial loss in the resistance phenotype. Specifically, we compared the gene expression profiles and structural variations of the insulin/insulin-like growth factor signaling (IIS) pathway genes in DDT-susceptible (91-C) and -resistant (91-R) Drosophila melanogaster (Drosophila) strains. A total of eight and seven IIS transcripts were up- and down-regulated, respectively, in 91-R compared to 91-C. A total of 114 nonsynonymous mutations were observed between 91-C and 91-R, of which 51.8% were fixed. Among the differentially expressed transcripts, phosphoenolpyruvate carboxykinase (PEPCK), down-regulated in 91-R, encoded the greatest number of amino acid changes, prompting us to perform PEPCK inhibitor-pesticide exposure bioassays. The inhibitor of PEPCK, hydrazine sulfate, resulted in a 161- to 218-fold decrease in the DDT resistance phenotype (91-R) and more than a 4- to 5-fold increase in susceptibility in 91-C. A second target protein, Glycogen synthase kinase 3ß (GSK3ß-PO), had one amino acid difference between 91-C and 91-R, and the corresponding transcript was also down-regulated in 91-R. A GSK3ß-PO inhibitor, lithium chloride, likewise reduced the resistance but to a lesser extent than did hydrazine sulfate for PEPCK. We demonstrate the potential role of IIS genes in DDT resistance and the potential discovery of an "Achilles' heel" against pesticide resistance in this pathway.

Dietary antioxidant vitamin C influences the evolutionary path of insecticide resistance in Drosophila melanogaster.

Herbivorous insects encounter a variety of toxic environmental substances ranging from ingested plant defensive compounds to human-introduced insecticidal agents. Dietary antioxidants are known to reduce the negative physiological impacts of toxins in mammalian systems through amelioration of reactive oxygen-related cellular damage. The analogous impacts to insects caused by multigenerational exposure to pesticides and the effects on adaptive responses within insect populations, however, are currently unknown. To address these research gaps, we used Drosophila as a model system to explore adaptive phenotypic responses to acute dichlorodiphenyltrichloroethane (DDT) exposure in the presence of the dietary antioxidant vitamin C and to examine the structural genomic consequences of this exposure. DDT resistance increased significantly among four replicates exposed to a low concentration of DDT for 10 generations. In contrast, dietary intake of vitamin C significantly reduced DDT resistance after mutigenerational exposure to the same concentration of DDT. As to the genomic consequences, no significant differences were predicted in overall nucleotide substitution rates across the genome between any of the treatments. Despite this, replicates exposed to a low concentration of DDT without vitamin C showed the highest number of synonymous and non-synonymous variants (3196 in total), followed by the DDT plus vitamin C (1174 in total), and vitamin C alone (728 in total) treatments. This study demonstrates the potential role of diet (specifically, antioxidant intake) on adaptive genome responses, and thus on the evolution of pesticide resistance within insect populations.

Prognostic impact of D2-plus lymphadenectomy and optimal extent of lymphadenectomy in advanced gastric antral carcinoma: Propensity score matching analysis.

OBJECTIVE: To investigate the prognostic impact of D2-plus lymphadenectomy including the posterior (No. 8p, No. 12b/p, No. 13, and No. 14v), and para-aortic (No. 16a2, and No. 16b1) lymph nodes (LNs) in subtotal gastrectomy for advanced gastric antral carcinoma. METHODS: A total of 203 patients with advanced gastric cancer (GC) located in the antrum, who underwent R0 gastrectomy with D2 or D2-plus lymphadenectomy between January 2003 and December 2011 were enrolled. Propensity score matching was used to reduce the strength of the confounding factors to accurately evaluate prognoses. The therapeutic value index (TVI) was calculate to evaluate the survival benefit of dissecting each LN station. RESULTS: Of 102 patients with D2-plus lymphadenectomy, 21 (20.59%) were pathologically identified as having LN metastases beyond the extent of D2 lymphadenectomy. After matching, the overall survival (OS) was significantly better in the D2-plus than the D2 group (P=0.030). In the multivariate survival analysis, D2-plus lymphadenectomy (hazard ratio, 0.516; P=0.006) was confirmed to significantly improve the survival rate. In the logistic regression analysis, pN stage [odds ratio (OR), 2.533; 95% confidence interval (95% CI), 1.368-4.691; P=0.003] and extent of LNs metastasis (OR, 5.965; 95% CI, 1.335-26.650; P=0.019) were identified as independent risk factors for LN metastases beyond the extent of D2 lymphadenectomy. The TVI of patient with metastasis to LNs station was 7.1 (No. 8p), 5.7 (No. 12p), 5.1 (No. 13), and 7.1 (both No. 16a2 and No. 16b1), respectively. CONCLUSIONS: D2-plus lymphadenectomy may improve the prognoses of some patients with advanced GC located in the antrum, especially for No. 8p, No. 12b, No. 13, and No. 16.

Variation in Mitochondria-Derived Transcript Levels Associated With DDT Resistance in the 91-R Strain of Drosophila melanogaster (Diptera: Drosophilidae).

The organochloride insecticide dichlorodiphenyltrichloroethane (DDT) and its metabolites can increase cellular levels of reactive oxygen species (ROS), cause mitochondrial dysfunction, and induce apoptosis. The highly DDT-resistant Drosophila melanogaster Meigen 1830 (Drosophila) strain, 91-R, and its susceptible control, 91-C, were used to investigate functional and structural changes among mitochondrial-derived pathways. Resequencing of mitochondrial genomes (mitogenomes) detected no structural differences between 91-R and 91-C, whereas RNA-seq suggested the differential expression of 221 mitochondrial-associated genes. Reverse transcriptase-quantitative PCR validation of 33 candidates confirmed that transcripts for six genes (Cyp12d1-p, Cyp12a4, cyt-c-d, COX5BL, COX7AL, CG17140) were significantly upregulated and two genes (Dif, Rel) were significantly downregulated in 91-R. Among the upregulated genes, four genes are duplicated within the reference genome (cyt-c-d, CG17140, COX5BL, and COX7AL). The predicted functions of the differentially expressed genes, or known functions of closely related genes, suggest that 91-R utilizes existing ROS regulation pathways of the mitochondria to combat increased ROS levels from exposure to DDT. This study represents, to our knowledge, the initial investigation of mitochondrial genome sequence variants and functional adaptations in responses to intense DDT selection and provides insights into potential adaptations of ROS management associated with DDT selection in Drosophila.

Facile preparation of a novel nickel-containing metallopolymer via RAFT polymerization.

While the metallocene polymers were comprehensively studied, other metallopolymers are rarely explored. The major challenge is the lack of a synthetic platform for the preparation of metal coordinated derivatives, monomers, and polymers. Therefore, the development of a facile synthesis of new metal coordinated monomers and polymers is critically needed. A novel successfully synthesized methacrylate-containing nickel complex is reported in this communication. Controlled RAFT polymerizations are further carried out to prepare a series of side-chain nickel containing polymers with different molecular weight and narrow Polydispersity Index (PDI). This new metallopolymer performs specific electrochemical and excellent thermal properties. This study provides a novel and convenient strategy to prepare metallopolymer with controllable molecular weight, which has potential applications in assembled, catalytic and magnetic materials.

Incorporation of zinc into the coccoliths of the microalga Emiliania huxleyi.

The coccolithophore Emiliania huxleyi is covered with elaborated calcite plates, the so-called coccoliths, which are produced inside the cells. We investigated the incorporation of zinc into the coccoliths of E. huxleyi by applying different zinc and calcium amounts via the culture media and subsequently analyzing the zinc content in the cells and the Zn/Ca ratio of the coccoliths. To investigate the Zn/Ca ratio of coccoliths built in the manipulated media, the algae have first to be decalcified, i.e. coccolith free. We used a newly developed decalcification method to obtain 'naked' cells for cultivation. E. huxleyi proliferated and produced new coccoliths in all media with manipulated Zn/Ca ratios. The cells and the newly built coccoliths were investigated regarding their zinc content and their Zn/Ca ratio, respectively. High zinc amounts were taken up by the algae. The Zn/Ca ratio of the coccoliths was positively correlated to the Zn/Ca ratio of the applied media. The unique feature of the coccoliths was maintained also at high Zn/Ca ratios. We suggest the following pathway of the zinc ions into the coccoliths: first, the zinc ions are bound to the cell surface, followed by their transportation into the cytoplasm. Obviously, the zinc ions are removed afterwards into the coccolith vesicle, where the zinc is incorporated into the calcite coccoliths which are then extruded. The incorporation of toxic zinc ions into the coccoliths possibly due to a new function of the coccoliths as detoxification sites is discussed.

Validation of the Chinese version of EORTC QLQ-BM22 in patients with bone metastases.

PURPOSE: Our aim is to test the validity, reliability, and acceptability of the Chinese version of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Bone Metastases 22 (EORTC QLQ-BM22) module to assess health-related quality of life (HRQOL) in patients with bone metastases in China. METHODS: Patients with histological confirmation of malignancy and bone metastases from Tianjin Cancer Institution and Hospital from June 2013 to April 2014 were enrolled in this study. All patients self-administered the EORTC QLQ-BM22 and the EORTC QLQ-C30. The Karnofsky Performance Scale (KPS) was performed to evaluate scores. The reliability and validity tests of the questionnaires were based on Cronbach's α coefficients, Pearson correlation test, and Wilcoxon rank sum nonparametric test. RESULTS: Internal consistency reliabilities of all the four scales were acceptable. Scales measuring similar HRQOL aspects were found to correlate with one another between EORTC QLQ-BM22 and EORTC QLQ-C30, but differences still existed. Significant differences were demonstrated in the scores of all four subscales of the QLQ-BM22 between the two KPS subgroups (KPS ≤ 80; KPS > 80). Meanwhile, the compliance for item completion of the QLQ-BM22 was satisfactory. CONCLUSIONS: The Chinese version of EORTC QLQ-BM22 is a reliable and valid instrument, which is appropriate for measuring the HRQOL of patients with bone metastases in China.

Cross-cultural verification of the EORTC QLQ-C15-PAL questionnaire in mainland China.

BACKGROUND: Simplified by European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30), EORTC Quality-of-Life Questionnaire Core 15 Palliative Care (QLQ-C15-PAL) is specifically applied to evaluating palliative care patients' quality of life. AIM: This study examined cross-cultural adaptability and validity of QLQ-C15-PAL for evaluating quality of life of palliative care patients with advanced cancer in mainland China. PARTICIPANTS AND DESIGN: From May to October 2013, 243 palliative care patients in Tianjin Cancer Hospital completed the EORTC QLQ-C30. We extracted QLQ-C15-PAL data for analysis. Physicians completed the Eastern Cooperative Oncology Group Performance Status score and mental state assessment for each patient. RESULTS: A total of 243 patients completed the study. The compliance rate was high, with missing rate for each item ranging from 0% to 2.1%. In addition to emotional function, the remaining dimensions demonstrated a high reliability (Cronbach's alpha > 0.7). Whether we divided patients into two groups according to their Eastern Cooperative Oncology Group Performance Status or divided patients into three groups according to mental status, both sets of results showed significant differences in QLQ-C15-PAL subscale scores (p < 0.05), indicating that the QLQ-C15-PAL scale could be used to distinguish between the aforementioned subgroups. Overall quality of life was moderately correlated with fatigue (r = -0.406) but weakly correlated with other subscales. The proportion of variance (R(2)) ranged from 0.848 to 0.903, which showed that QLQ-C15-PAL subscale scores explained between 84.8% and 90.3% of the original QLQ-C30 score distribution. CONCLUSION: The Chinese version of the EORTC QLQ-C15-PAL questionnaire has high reliability and validity and is therefore suitable for clinical use in China to determine health-related quality of life in Chinese patients with advanced cancer.

Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2.

Although the Hsp90 chaperone family, comprised in humans of four paralogs, Hsp90α, Hsp90ß, Grp94 and Trap-1, has important roles in malignancy, the contribution of each paralog to the cancer phenotype is poorly understood. This is in large part because reagents to study paralog-specific functions in cancer cells have been unavailable. Here we combine compound library screening with structural and computational analyses to identify purine-based chemical tools that are specific for Hsp90 paralogs. We show that Grp94 selectivity is due to the insertion of these compounds into a new allosteric pocket. We use these tools to demonstrate that cancer cells use individual Hsp90 paralogs to regulate a client protein in a tumor-specific manner and in response to proteome alterations. Finally, we provide new mechanistic evidence explaining why selective Grp94 inhibition is particularly efficacious in certain breast cancers.

RNAi validation of resistance genes and their interactions in the highly DDT-resistant 91-R strain of Drosophila melanogaster.

4,4'-dichlorodiphenyltrichloroethane (DDT) has been re-recommended by the World Health Organization for malaria mosquito control. Previous DDT use has resulted in resistance, and with continued use resistance will increase in terms of level and extent. Drosophila melanogaster is a model dipteran that has many available genetic tools, numerous studies done on insecticide resistance mechanisms, and is related to malaria mosquitoes allowing for extrapolation. The 91-R strain of D. melanogaster is highly resistant to DDT (>1500-fold), however, there is no mechanistic scheme that accounts for this level of resistance. Recently, reduced penetration, increased detoxification, and direct excretion have been identified as resistance mechanisms in the 91-R strain. Their interactions, however, remain unclear. Use of UAS-RNAi transgenic lines of D. melanogaster allowed for the targeted knockdown of genes putatively involved in DDT resistance and has validated the role of several cuticular proteins (Cyp4g1 and Lcp1), cytochrome P450 monooxygenases (Cyp6g1 and Cyp12d1), and ATP binding cassette transporters (Mdr50, Mdr65, and Mrp1) involved in DDT resistance. Further, increased sensitivity to DDT in the 91-R strain after intra-abdominal dsRNA injection for Mdr50, Mdr65, and Mrp1 was determined by a DDT contact bioassay, directly implicating these genes in DDT efflux and resistance.

Differential effects of RNAi treatments on field populations of the western corn rootworm.

RNA interference (RNAi) mediated crop protection against insect pests is a technology that is greatly anticipated by the academic and industrial pest control communities. Prior to commercialization, factors influencing the potential for evolution of insect resistance to RNAi should be evaluated. While mutations in genes encoding the RNAi machinery or the sequences targeted for interference may serve as a prominent mechanism of resistance evolution, differential effects of RNAi on target pests may also facilitate such evolution. However, to date, little is known about how variation of field insect populations could influence the effectiveness of RNAi treatments. To approach this question, we evaluated the effects of RNAi treatments on adults of three western corn rootworm (WCR; Diabrotica virgifera virgifera LeConte) populations exhibiting different levels of gut cysteine protease activity, tolerance of soybean herbivory, and immune gene expression; two populations were collected from crop rotation-resistant (RR) problem areas and one from a location where RR was not observed (wild type; WT). Our results demonstrated that RNAi targeting DvRS5 (a highly expressed cysteine protease gene) reduced gut cysteine protease activity in all three WCR populations. However, the proportion of the cysteine protease activity that was inhibited varied across populations. When WCR adults were treated with double-stranded RNA of an immune gene att1, different changes in survival among WT and RR populations on soybean diets occurred. Notably, for both genes, the sequences targeted for RNAi were the same across all populations examined. These findings indicate that the effectiveness of RNAi treatments could vary among field populations depending on their physiological and genetic backgrounds and that the consistency of an RNAi trait's effectiveness on phenotypically different populations should be considered or tested prior to wide deployment. Also, genes that are potentially subjected to differential selection in the field should be avoided for RNAi-based pest control.

Chemical and Geological Properties of Shale Gas: In Situ Desorption of Lower Cambrian Niutitang Shale in the Micangshan Tectonic Zone of South Shaanxi, China.

Shale gas was recently found in the Lower Cambrian Niutitang Formation (LCNF) of the Micangshan tectonic zone of south Shaanxi (MTZSS), but not in commercial quantities. To determine the laws governing the generation, enrichment, and desorption of shale gases in overmatured shale strata in the LCNF of MTZSS, we carried out in situ desorption experiments on nine shale core samples and got 168 desorbed gas samples at different phases of desorption. Also measured were the chemical and carbon isotopic compositions of these desorbed gas samples and the geochemical parameters of the shale core samples. CH4 was the predominant hydrocarbon shale gas identified in the 82.06-98.48% range, suggesting that the gases were mainly dry. The nonhydrocarbon gases found were CO2 and H2. The CH4 content of the desorbed gas samples dropped continuously during desorption, lowering the dryness index to 98.48 and 92.26% of the first and last desorbed shale gas, respectively. The change in the gas ratio during shale gas desorption proved that the adsorbability of the LCNF to the various gases follows the trend H2 > CO2 > C2H6 > CH4 > He. Further, δ13C2H6 and δ13CH4 become heavier during desorption, showing isotopic fractionation arising from the desorption-diffusion coeffect. As the desorption temperature increases, the value of δ13CH4 increases because 12CH4 is more sensitive to temperature than 13CH4, so it is with the ethane. Similar to the LCNF shale gas in other areas of China, the desorbed shale gases are characteristic of carbon isotope reversal (CIR) (δ13CH4 > δ13C2H6). The cracking of the residual soluble organic matter at the high overmaturity stage mixed with the cracking of kerogen at the early stage of maturation, causing CIR. Furthermore, the desorbed gas content was proportionally and inversely related to the CIR degree and final dryness index of the desorbed gas, respectively. Moreover, the carbon isotope fractionation degree of CH4 and δ13C1 of the last desorbed gas correlated positively with the desorbed gas content and the desorbed time of the gas. In conclusion, the four parameters are effective parameters for identifying shale gas sweet spots.

Clinical outcome and prognostic factors of T4N0M0 colon cancer after R0 resection: A retrospective study.

BACKGROUND: Paradoxically, patients with T4N0M0 (stage II, no lymph node metastasis) colon cancer have a worse prognosis than those with T2N1-2M0 (stage III). However, no previous report has addressed this issue. AIM: To screen prognostic risk factors for T4N0M0 colon cancer and construct a prognostic nomogram model for these patients. METHODS: Two hundred patients with T4N0M0 colon cancer were treated at Tianjin Medical University General Hospital between January 2017 and December 2021, of which 112 patients were assigned to the training cohort, and the remaining 88 patients were assigned to the validation cohort. Differences between the training and validation groups were analyzed. The training cohort was subjected to multivariate analysis to select prognostic risk factors for T4N0M0 colon cancer, followed by the construction of a nomogram model. RESULTS: The 3-year overall survival (OS) rates were 86.2% and 74.4% for the training and validation cohorts, respectively. Enterostomy (P = 0.000), T stage (P = 0.001), right hemicolon (P = 0.025), irregular review (P = 0.040), and carbohydrate antigen 199 (CA199) (P = 0.011) were independent risk factors of OS in patients with T4N0M0 colon cancer. A nomogram model with good concordance and accuracy was constructed. CONCLUSION: Enterostomy, T stage, right hemicolon, irregular review, and CA199 were independent risk factors for OS in patients with T4N0M0 colon cancer. The nomogram model exhibited good agreement and accuracy.

Identification of differentially expressed miRNAs associated with diamide detoxification pathways in Spodoptera frugiperda.

The fall armyworm (FAW) Spodoptera frugiperda is a severe economic pest of multiple crops globally. Control of this pest is often achieved using insecticides; however, over time, S. frugiperda has developed resistance to new mode of action compounds, including diamides. Previous studies have indicated diamide resistance is a complex developmental process involving multiple detoxification genes. Still, the mechanism underlying the possible involvement of microRNAs in post-transcriptional regulation of resistance has not yet been elucidated. In this study, a global screen of microRNAs (miRNAs) revealed 109 known and 63 novel miRNAs. Nine miRNAs (four known and five novel) were differentially expressed between insecticide-resistant and -susceptible strains. Gene Ontology analysis predicted putative target transcripts of the differentially expressed miRNAs encoding significant genes belonging to detoxification pathways. Additionally, miRNAs are involved in response to diamide exposure, indicating they are probably associated with the detoxification pathway. Thus, this study provides comprehensive evidence for the link between repressed miRNA expression and induced target transcripts that possibly mediate diamide resistance through post-transcriptional regulation. These findings highlight important clues for further research to unravel the roles and mechanisms of miRNAs in conferring diamide resistance.

Genome sequences of the human body louse and its primary endosymbiont provide insights into the permanent parasitic lifestyle.

As an obligatory parasite of humans, the body louse (Pediculus humanus humanus) is an important vector for human diseases, including epidemic typhus, relapsing fever, and trench fever. Here, we present genome sequences of the body louse and its primary bacterial endosymbiont Candidatus Riesia pediculicola. The body louse has the smallest known insect genome, spanning 108 Mb. Despite its status as an obligate parasite, it retains a remarkably complete basal insect repertoire of 10,773 protein-coding genes and 57 microRNAs. Representing hemimetabolous insects, the genome of the body louse thus provides a reference for studies of holometabolous insects. Compared with other insect genomes, the body louse genome contains significantly fewer genes associated with environmental sensing and response, including odorant and gustatory receptors and detoxifying enzymes. The unique architecture of the 18 minicircular mitochondrial chromosomes of the body louse may be linked to the loss of the gene encoding the mitochondrial single-stranded DNA binding protein. The genome of the obligatory louse endosymbiont Candidatus Riesia pediculicola encodes less than 600 genes on a short, linear chromosome and a circular plasmid. The plasmid harbors a unique arrangement of genes required for the synthesis of pantothenate, an essential vitamin deficient in the louse diet. The human body louse, its primary endosymbiont, and the bacterial pathogens that it vectors all possess genomes reduced in size compared with their free-living close relatives. Thus, the body louse genome project offers unique information and tools to use in advancing understanding of coevolution among vectors, symbionts, and pathogens.

Evolutionary toxicogenomics: diversification of the Cyp12d1 and Cyp12d3 genes in Drosophila species.

Gene duplication and divergence are overwhelmingly considered to be the primary mechanisms by which cytochrome P450 monooxygenases (P450s) have radiated into a large and diverse gene superfamily. To address how environmental stress drives the fixation and diversification of gene duplications, we have analyzed Cyp12d1 and Cyp12d3, a pair of duplicated genes found in the sequenced Drosophila genomes of the melanogaster group. The paralog Cyp12d3, which is not found in Drosophila melanogaster, is basal to the melanogaster group, after it split from the obscura group (ca. 50 mya), and has a significant signature of positive selection in two species (D. sechellia and D. ananassae). Examination of the Cyp12d1 region in D. melanogaster wildtype and isoline populations revealed variation both in copy number and sequence, including splice-site variations, which certainly alter gene function. Further investigations of several strains have identified three cases in which differences in the Cyp12d1 gene region are associated with the differences in transcript abundance and transcriptional responses to the environmental stresses that have not been seen for other detoxificative loci. Together, these data highlight the value of using both macro- and microevolutionary approaches in studying the duplication and divergence events associated with detoxification genes and lay important groundwork for future studies in the field of evolutionary toxicogenomics, which uses the principles of phylogenetic analysis to predict possible enzymatic functions.

Heat shock protein gp96 regulates Toll-like receptor 9 proteolytic processing and conformational stability.

Nucleic acid-sensing Toll-like receptors (TLRs) initiate innate immune responses to foreign RNA and DNA, yet can detect and respond to host DNA. To avoid autoimmune pathologies, nucleic acid sensing TLRs are tightly regulated. TLR9 primarily resides in the endoplasmic reticulum, traffics to endosomes, is proteolytically processed and responds to DNA. The heat shock protein gp96 is one of several accessory proteins that regulate intracellular trafficking of TLR9. In the absence of gp96, TLR9 fails to exit the endoplasmic reticulum, and therefore gp96-deficient macrophages fail to respond to CpG DNA. However, absence of gp96 precludes studies on potential chaperoning functions of gp96 for TLR9. Here we demonstrate that pharmacologic interference with gp96 function inhibits TLR9 signaling. TLR9 remains associated with gp96 during intracellular trafficking, and gp96-specific inhibitors increase TLR9 sensitivity to proteolytic degradation. We propose that gp96 is critical for both TLR9 egress from the ER, and for protein conformational stability in the endosomal compartment. These studies highlight the importance of examining gp96-specific inhibitors for modulating TLR9 activation, and the treatment autoimmune diseases.

A nomogram to predict the risk of colorectal anastomotic leakage combining inflammatory-nutritional and abdominal aorta calcium index.

Background: Anastomotic leakage is a serious complication after colorectal cancer surgery, which affects the quality of life and the prognosis. This study aims to create a novel nomogram to predict the risk of anastomotic leakage for patients with colorectal cancer based on the preoperative inflammatory-nutritional index and abdominal aorta calcium index. Methods: 292 patients at Tianjin Medical University General Hospital (Tianjin, China) from January 2018 to October 2021 who underwent colorectal cancer surgery with a primary anastomosis were retrospectively reviewed. A nomogram was constructed based on the results of multivariate logistic regression model. The calibration curves and receiver operating characteristic curves were used to verify the efficacy of the nomogram. Results: Univariate and multivariate analyses showed that tumor location (P = 0.002), preoperative albumin (P = 0.006), preoperative lymphocyte (P = 0.035), preoperative neutrophil to lymphocyte ratio (P = 0.024), and superior mesenteric artery calcium volumes score (P = 0.004) were identified as the independent risk factors for postoperative anastomotic leakage in patients with colorectal carcinoma. A nomogram was constructed based on the results of the multivariate analysis, and the C-index of the calibration curves was 0.913 (95%CI: 0.870-0.957) in the training cohort and 0.840 (95%CI: 0.753-0.927) in the validation cohort. Conclusion: The nomogram, combining basic variables, inflammatory-nutritional index and abdominal aorta calcium index, could effectively predict the possibility of postoperative anastomotic leakage for patients with colorectal cancer, which could guide surgeons to carry out the appropriate treatment for the prevention of anastomotic leakage.