Genome-wide analysis sheds light on the high-altitude adaptation of the buff-throated partridge (Tetraophasis szechenyii).

The buff-throated partridge (Tetraophasis szechenyii) is a hypoxia-tolerant bird living in an extremely inhospitable high-altitude environment, which has high ultraviolet (UV) radiation as well as a low oxygen supply when compared with low-altitude areas. To further understand the molecular genetic mechanisms of the high-altitude adaptation of the buff-throated partridges, we de novo assembled the complete genome of the buff-throated partridge. Comparative genomics revealed that positively selected hypoxia-related genes in the buff-throated partridge were distributed in the HIF-1 signaling pathway (map04066), response to hypoxia (GO:0001666), response to oxygen-containing compound (GO:1901700), ATP binding (GO:0005524), and angiogenesis (GO:0001525). Of these positively selected hypoxia-related genes, one positively selected gene (LONP1) had one buff-throated partridge-specific missense mutation which was classified as deleterious by PolyPhen-2. Moreover, positively selected genes in the buff-throated partridge were enriched in cellular response to DNA damage stimulus (corrected P value: 0.028006) and DNA repair (corrected P value: 0.044549), which was related to the increased exposure of the buff-throated partridge to UV radiation. Compared with other avian genomes, the buff-throated partridge showed expansion in genes associated with steroid hormone receptor activity and contractions in genes related to immune and olfactory perception. Furthermore, comparisons between the buff-throated partridge genome and red junglefowl genome revealed a conserved genome structure and provided strong evidence of the sibling relationship between Tetraophasis and Lophophorus. Our data and analysis contributed to the study of Phasianidae evolutionary history and provided new insights into the potential adaptation mechanisms to the high altitude employed by the buff-throated partridge.

Interleukin-17D Aggravates Sepsis by Inhibiting Macrophage Phagocytosis.

OBJECTIVES: Interleukin-17D has been shown to participate in the control of viral infections and cancer. Here we hypothesized that interleukin-17D may play a potential role in sepsis. DESIGN: Prospective randomized animal investigation and in vitro human blood studies. SETTING: Research laboratory from a university hospital. SUBJECTS: Female C57BL/6J mice, sepsis patients by Sepsis-3 definitions, ICU patient controls, and healthy individuals. INTERVENTIONS: Serum concentrations of interleukin-17D were measured and analyzed in human sepsis patients, patient controls, and healthy individuals. The contribution of interleukin-17D to sepsis-related survival, bacterial burden, and organ injury was assessed in a murine model of cecal ligation and puncture-induced polymicrobial sepsis by the use of anti-interleukin-17D antibody and recombinant interleukin-17D protein. The effects of interleukin-17D on bacterial phagocytosis by macrophages were also investigated using in vitro cell models. MEASUREMENTS AND MAIN RESULTS: On the day of ICU admission (day 0), septic patients had significantly higher serum concentrations of interleukin-17D than patient controls and healthy individuals. Serum interleukin-17D levels remained significantly elevated in septic patients from ICU admission to day 3 and correlated with Sequential (Sepsis-related) Organ Failure Assessment scores and documented bacteremia on day 0. Furthermore, nonsurvivors of septic patients displayed significantly higher interleukin-17D levels compared with survivors of septic patients on days 0 and 1 of ICU admission. In animal models of sepsis, treatment with anti-interleukin-17D antibody protected mice from cecal ligation and puncture-induced severe sepsis, which was associated with improved bacterial clearance and organ injury. Conversely, administration of recombinant interleukin-17D protein aggravated cecal ligation and puncture-induced nonsevere sepsis. Furthermore, we found that interleukin-17D impaired bacterial phagocytosis by macrophages. Phagocytosis inhibition by interleukin-17D involved its ability to down-regulate the activation of nuclear factor-κB signaling pathway in macrophages upon bacterial infection. CONCLUSIONS: This study indicates a previously undescribed role of interleukin-17D in sepsis and identifies a new target for antisepsis treatment.

Progranulin aggravates pulmonary immunopathology during influenza virus infection.

Progranulin (PGRN) exerts multiple functions in various inflammatory diseases. However, the role of PGRN in the pathogenesis of virus infection is unknown. Here, we demonstrated that PGRN production was up-regulated in clinical and experimental influenza, which contributed to the deleterious inflammatory response after influenza virus infection in mice. PGRN-deficient mice were protected from influenza virus-induced lung injury and mortality. Decreased mortality was associated with significantly reduced influx of neutrophils and monocytes/macrophages, release of cytokines and chemokines, and permeability of the alveolar-epithelial barrier without affecting viral clearance. Our findings suggest that PGRN exacerbates pulmonary immunopathology during influenza virus infection.

Genome-wide analysis reveals the genomic features of the turkey vulture (Cathartes aura) as a scavenger.

Cathartidae is a small family of large-bodied carrion-feeding birds, of which the turkey vulture (Cathartes aura, Cathartidae) is the most widespread distributed. To investigate the chemoreception system, detoxification system, and immune system in the turkey vulture, we compared its genome to 14 other avian genomes. Comparative genomics demonstrated the expansion in the chemoreception system, especially the olfactory receptors, while the genes in the detoxification system of the turkey vulture did not show apparent expansion. We identified five positively selected genes associated with the immune system in the turkey vulture, which was likely to strengthen the immune defense against pathogenic invasion. Functional enrichment analysis indicated that many positively selected genes were involved in the regulation of immune system processes, implying important reorganization of the immune system in the turkey vulture. The turkey vulture-specific missense mutations were found in one positively selected gene (BCL6), and all the missense mutations were classified as deleterious by PolyPhen-2, possibly contributing to immune adaptation to the carrion feeding. Furthermore, we identified four turkey vulture-specific missense mutations in three ß-defensin genes of the turkey vulture, which was an indispensable part in the innate immunity (a natural barrier against invasive microbes including bacteria, fungi, and viruses). Our genomic analyses in the turkey vulture provided insights into the genetic signatures of the adaptation to the carrion feeding.

Interleukin-26 is overexpressed in human sepsis and contributes to inflammation, organ injury, and mortality in murine sepsis.

BACKGROUND: Sepsis is a serious syndrome that is caused by an unbalanced host inflammatory response to an infection. The cytokine network plays a pivotal role in the orchestration of inflammatory response during sepsis. IL-26 is an emerging proinflammatory member of the IL-10 cytokine family with multifaceted actions in inflammatory disorders. However, its role in the pathogenesis of sepsis remains unknown. METHODS: Serum IL-26 level was measured and analyzed in 52 septic patients sampled on the day of intensive care unit (ICU) admission, 18 non-septic ICU patient controls, and 30 healthy volunteers. In addition, the effects of recombinant human IL-26 on host inflammatory response in cecal ligation and puncture (CLP)-induced polymicrobial sepsis were determined. RESULTS: On the day of ICU admission, the patients with sepsis showed a significant increase in serum IL-26 levels compared with ICU patient controls and healthy volunteers, and the serum IL-26 levels were related to the severity of sepsis. Nonsurvivors of septic patients displayed significantly higher serum IL-26 levels compared with survivors. A high serum IL-26 level on ICU admission was associated with 28-day mortality, and IL-26 was found to be an independent predictor of 28-day mortality in septic patients by logistic regression analysis. Furthermore, administration of recombinant human IL-26 increased lethality in CLP-induced polymicrobial sepsis. Despite a lower bacterial load, septic mice treated with recombinant IL-26 had higher concentrations of IL-1ß, IL-4, IL-6, IL-10, IL-17A, TNF-α, CXCL1, and CCL2 in peritoneal lavage fluid and blood and demonstrated more severe multiple organ injury (including lung, liver and kidney) as indicated by clinical chemistry and histopathology. Furthermore, septic mice treated with recombinant human IL-26 showed an increased neutrophil recruitment to the peritoneal cavity. CONCLUSIONS: Septic patients had elevated serum IL-26 levels, which may correlate with disease severity and mortality. In experimental sepsis, we demonstrated a previously unrecognized role of IL-26 in increasing lethality despite promoting antibacterial host responses.

Interleukin 38 Protects Against Lethal Sepsis.

Background: Interleukin 38 (IL-38) is the most recently characterized cytokine of the interleukin 1 family. However, its role in sepsis remains unknown. Methods: Circulating IL-38 levels were measured in 2 cohorts of adult and pediatric patients with sepsis. Using 2 murine models of lipopolysaccharide (LPS)-induced endotoxemia and cecal ligation and puncture (CLP)-induced sepsis, the effects of IL-38 on survival, inflammation, tissue injury, and bacterial clearance were assessed. Results: Serum IL-38 concentrations were significantly elevated in adult and pediatric patients with sepsis relative to corresponding healthy adult and pediatric controls, respectively. An increased IL-38 level negatively correlated with the number of blood leukocytes and with the level of inflammatory cytokines, including interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) in clinical sepsis. Anti-IL-38 antibody impaired survival and while recombinant IL-38 improved survival in the 2 murine models of LPS-induced endotoxemia and CLP-induced sepsis. IL-38 administration decreased the inflammatory response, as reflected by lower levels of cytokines and chemokines (including IL-6, TNF-α, interleukin 10, interleukin 17, interleukin 27, CXCL1, and CCL2), and less damage to tissues (including lung, liver, and kidney) in CLP-induced sepsis. Furthermore, IL-38 augmented bacterial clearance in CLP-induced polymicrobial sepsis. Conclusions: These findings suggest that IL-38 attenuates sepsis by decreasing inflammation and increasing bacterial clearance, thus providing a novel tool for antisepsis therapy.

Combinations of plasma cfDNA concentration, integrity and tumor markers are promising biomarkers for early diagnosis of non-small cell lung cancer.

Background: Circulating cell-free DNA (cfDNA) concentration and integrity as noninvasive biomarkers play an important role in cancer diagnosis, prognosis and therapy monitoring. However, few studies have been conducted on the combination of plasma cfDNA concentration, integrity and tumor markers (CEA, CA125, NSE and CYFRA21-1) for cancer detection. Thus, the purpose of this study was to investigate the diagnostic value of combining plasma cfDNA concentration, integrity and tumor markers in early detection of non-small cell lung cancer (NSCLC). Methods: Plasma cfDNA concentration from 50 healthy controls and 84 NSCLC patients were assessed by quantitative real-time PCR of ALU repeated sequence. Plasma cfDNA integrity was calculated as the ratio of long to short fragments (ALU115/60). Results: Plasma cfDNA concentration (ALU60 and ALU115) and integrity ALU115/60 were significantly higher in NSCLC patients with stage III/IV than in healthy controls (p = 0.0002, p < 0.0001, and p = 0.0093, respectively). The receiver operating characteristic (ROC) curve for discriminating NSCLC patients from healthy controls had an area under the curve (AUC) of 0.936 (95 % CI, 0.939-0.996). Moreover, the combination of plasma cfDNA concentration, integrity and tumor markers (CEA, CA125, NSE and CYFRA21-1) had higher diagnostic performance than either plasma cfDNA concentration alone, integrity alone or tumor markers alone, with sensitivity, specificity and AUC value of 94.05%, 90.00% and 0.968, respectively. These results demonstrated that the combination of plasma cfDNA concentration, integrity and tumor markers could significantly improve the diagnostic accuracy of NSCLC. Conclusion: Combination of plasma cfDNA concentration, integrity and tumor markers is a promising biomarker for early diagnosis of NSCLC.

Large-scale genetic surveys for main extant population of wild giant panda (Ailuropoda melanoleuca) reveals an urgent need of human management.

There are only six isolated living giant panda populations, and a comprehensive understanding of their genetic health status is crucial for the conservation of this vulnerable species. Liangshan Mountains is one of the main distribution areas of living giant pandas and is outside the newly established Giant panda national park. In this study, 971 giant panda fecal samples were collected in the heartland of Liangshan Mountains (Mabian Dafengding Nature Reserve: MB; Meigu Dafengding Nature Reserve: MG; and Heizhugou Nature Reserve: HZG). Microsatellite markers and mitochondrial D-loop sequences were used to estimate population size and genetic diversity. We identified 92 individuals (MB: 27, MG: 22, HZG: 43) from the three reserves. Our results showed that: (1) genetic diversity of three giant panda populations was moderate; (2) several loci deviated significantly from the Hardy-Weinberg equilibrium and almost all these deviated loci showed significant heterozygote deficiencies and inbreeding; (3) three giant panda populations have substantial genetic differentiation with the most differentiation between MB and the two other populations; and (4) a large amount of giant panda feces outside the three reserves were found, implying the existence of protection gap. These results indicated that under stochastic events, the giant panda populations in Liangshan Mountains are at risk of genetic decline or extinction and urgent need of human management. This study revealed that high attention should be paid to the protection of these giant panda populations outside the Giant panda national park, to ensure their survival in their distribution areas.

Genomic evidence sheds light on the genetic mechanisms of musk secretion in muskrats.

Adult male muskrat (Ondatra zibethicus) has a pair of scent glands which secret musk to attract females during the breeding stage. The goal of the present study was to investigate the genetic mechanisms of musk secretion of muskrats at the whole genome level. Comparative genomics illustrated obvious expansion in 809 gene families, of which nine gene families played pivotal roles in steroid biosynthesis, possibly related to muskrat musk secretion. We identified 1112 positively selected genes (PSGs) in the muskrat, including estrogen receptor 1 (ER1), an important influencing factor to the weight and size of the scented glands of muskrats. HSD17B3, HSD17B4, CYP7B1 and CYP17B1, crucial to steroid hormone biosynthesis, were under strong positive selection in the muskrat, and phylogenetic analysis of HSD and CYP450 classes revealed high gene diversity. Functional enrichment revealed many pathways associated with musk secretion and/or growth and degeneration of scented gland significantly, such as peroxisome, PI3K-Akt signaling pathway, apoptosis, and prostate cancer. Two muskrat-specific missense mutations (Pro237Thr and Ser297Ile) were detected in LIPC, which were reported to be involved cholesterol metabolic process. More importantly, the missense mutations discovered in LIPC were classified as deleterious by PolyPhen-2, possibly affecting the musk secretion of muskrats.

Elevated serum CXCL10 in patients with Clostridium difficile infection are associated with disease severity.

Clostridium difficile infection (CDI) is the primary cause of community- and health care-associated diarrhea. CXCL10, also known as IFN-γ-inducible protein of 10 (IP-10), is involved in various inflammatory diseases, but its role in CDI remains unknown. In this study, We determined the serum concentration of CXCL10 in 80 CDI patients and 76 sex & age-matched diarrhea patients by enzyme-linked immunosorbent assay (ELISA) and analyzed the correlation between CXCL10 levels and CDI disease severity parameters. Besides, we also measured the level of other cytokines and/or chemokines in CDI patients, such as IL-1ß, IL-6, TNF-α and CXCL9. We found that serum CXCL10 in CDI patients was significantly higher compared with those in non-C. difficile diarrhea patients, especially in the moderate disease. Elevated serum CXCL10 correlated positively and significantly with severity score index (SSI) score in all CDI patients. CXCL10 levels were also positively correlated with WBC count, creatinine and inflammatory cytokines including, IL-1ß, IL-6 and CXCL9, but negatively correlated with albumin. Furthermore, serum CXCL10 concentration could be significantly decreased after effective treatment of CDI. Therefore, the above results suggest that the up-regulated release of CXCL10 is important in the immunopathogenesis of CDI, and may be served as a potential alternative biomarker for the monitoring of CDI disease severity and therapeutic efficacy.

The complete mitochondrial genome of Aquila nipalensis and its phylogenetic position.

Mitochondrial genome sequences are valuable resources for systematics and conservation biology studies. In this paper, we present the complete mitogenome of Aquila nipalensis which was 18,450 bp in length. The gene content and arrangement were typical for avian mtDNA. The overall A + T content of was 54.1%, and the AT skew was calculated as 0.12 for the complete mitogenome of A. nipalensis. The maximum-likelihood (ML) tree based on the concatenated 12 protein-coding genes (PCGs) revealed the basal phylogenetic position of A. nipalensis in Aquila.

The Draft Genome of the Endangered Sichuan Partridge (Arborophila rufipectus) with Evolutionary Implications.

The Sichuan partridge (Arborophila rufipectus, Phasianidae, Galliformes) is distributed in south-west China, and classified as endangered grade. To examine the evolution and genomic features of Sichuan partridge, we de novo assembled the Sichuan partridge reference genome. The final draft assembly consisted of approximately 1.09 Gb, and had a scaffold N50 of 4.57 Mb. About 1.94 million heterozygous single-nucleotide polymorphisms (SNPs) were detected, 17,519 protein-coding genes were predicted, and 9.29% of the genome was identified as repetitive elements. A total of 56 olfactory receptor (OR) genes were found in Sichuan partridge, and conserved motifs were detected. Comparisons between the Sichuan partridge genome and chicken genome revealed a conserved genome structure, and phylogenetic analysis demonstrated that Arborophila possessed a basal phylogenetic position within Phasianidae. Gene Ontology (GO) enrichment analysis of positively selected genes (PSGs) in Sichuan partridge showed over-represented GO functions related to environmental adaptation, such as energy metabolism and behavior. Pairwise sequentially Markovian coalescent analysis revealed the recent demographic trajectory for the Sichuan partridge. Our data and findings provide valuable genomic resources not only for studying the evolutionary adaptation, but also for facilitating the long-term conservation and genetic diversity for this endangered species.