Data_Sheet_1_RIOK-1 Is a Suppressor of the p38 MAPK Innate Immune Pathway in Caenorhabditis elegans.DOCX

<p>Innate immunity is the primary defense mechanism against infection in metazoans. However, aberrant upregulation of innate immune-signaling pathways can also be detrimental to the host. The p38 MAPK/PMK-1 innate immune-signaling pathway has been demonstrated to play essential roles in cellular defenses against numerous infections in metazoans, including Caenorhabditis elegans. However, the negative regulators that maintain the homeostasis of this important innate immune pathway remain largely understudied. By screening a focused RNAi library against the kinome of C. elegans, we identified RIOK-1, a human RIO kinase homolog, as a novel suppressor of the p38 MAPK/PMK-1 signal pathway. We demonstrated that the suppression of riok-1 confers resistance to Aeromonas dhakensis infection in C. elegans. Using quantitative real time-PCR and riok-1 reporter worms, we found the expression levels of riok-1 to be significantly upregulated in worms infected with A. dhakensis. Our genetic epistasis analysis suggested that riok-1 acts on the upstream of the p38 MAPK/pmk-1 genetic pathway. Moreover, the suppression of riok-1 enhanced the p38 MAPK signal, suggesting that riok-1 is a negative regulator of this innate pathway in C. elegans. Our epistatic results put riok-1 downstream of skn-1, which encodes a p38 MAPK downstream transcription factor and serves as a feedback loop to the p38 MAPK pathway during an A. dhakensis infection. In conclusion, riok-1 is proposed as a novel innate immune suppressor and as a negative feedback loop model involving p38 MAPK, SKN-1, and RIOK-1 in C. elegans.</p

Table_1_RIOK-1 Is a Suppressor of the p38 MAPK Innate Immune Pathway in Caenorhabditis elegans.XLSX

<p>Innate immunity is the primary defense mechanism against infection in metazoans. However, aberrant upregulation of innate immune-signaling pathways can also be detrimental to the host. The p38 MAPK/PMK-1 innate immune-signaling pathway has been demonstrated to play essential roles in cellular defenses against numerous infections in metazoans, including Caenorhabditis elegans. However, the negative regulators that maintain the homeostasis of this important innate immune pathway remain largely understudied. By screening a focused RNAi library against the kinome of C. elegans, we identified RIOK-1, a human RIO kinase homolog, as a novel suppressor of the p38 MAPK/PMK-1 signal pathway. We demonstrated that the suppression of riok-1 confers resistance to Aeromonas dhakensis infection in C. elegans. Using quantitative real time-PCR and riok-1 reporter worms, we found the expression levels of riok-1 to be significantly upregulated in worms infected with A. dhakensis. Our genetic epistasis analysis suggested that riok-1 acts on the upstream of the p38 MAPK/pmk-1 genetic pathway. Moreover, the suppression of riok-1 enhanced the p38 MAPK signal, suggesting that riok-1 is a negative regulator of this innate pathway in C. elegans. Our epistatic results put riok-1 downstream of skn-1, which encodes a p38 MAPK downstream transcription factor and serves as a feedback loop to the p38 MAPK pathway during an A. dhakensis infection. In conclusion, riok-1 is proposed as a novel innate immune suppressor and as a negative feedback loop model involving p38 MAPK, SKN-1, and RIOK-1 in C. elegans.</p

<i>Clostridium difficile</i> Infections in Medical Intensive Care Units of a Medical Center in Southern Taiwan: Variable Seasonality and Disease Severity

<div><p>Critical patients are susceptible to <i>Clostridium difficile</i> infections (CDIs), which cause significant morbidity and mortality in the hospital. In Taiwan, the epidemiology of CDI in intensive care units (ICUs) is not well understood. This study was aimed to describe the incidence and the characteristics of CDI in the ICUs of a medical center in southern Taiwan. Adult patients with diarrhea but without colostomy/colectomy or laxative use were enrolled. Stool samples were collected with or without 5 ml alcohol and were plated on cycloserine-cefoxitin-fructose agar. <i>C</i>. <i>difficile</i> identification was confirmed by polymerase chain reaction. There were 1,551 patients admitted to ICUs, 1,488 screened, and 145 with diarrhea. A total of 75 patients were excluded due either to laxative use, a lack of stool samples, or refusal. Overall, 70 patients were included, and 14 (20%) were diagnosed with CDI, with an incidence of 8.8 cases per 10,000 patient-days. The incidence of CDI was found to be highest in March 2013 and lowest in the last quarter of 2013. The cases were categorized as the following: 5 severe, complicated, 5 severe, and 4 mild or moderate diseases. Among the 14 cases of CDI, the median patient age was 74 (range: 47–94) years, and the median time from admission to diarrhea onset was 16.5 (4–53) days. Eight cases received antimicrobial treatment (primarily metronidazole), and the time to diarrheal resolution was 11.5 days. Though 6 cases were left untreated, no patients died of CDI. The in-hospital mortality of CDI cases was 50%, similar to that of patients without CDI (46.4%; <i>P</i> = 1.0). We concluded that the overall incidence of CDI in our medical ICUs was low and there were variable seasonal incidences and disease severities of CDI.</p></div

Symptoms associated with adverse dengue fever prognoses at the time of reporting in the 2015 dengue outbreak in Taiwan

<div><p>Background</p><p>Tainan experienced the most severe dengue epidemic in Taiwan in 2015. This study investigates the association between the signs and symptoms at the time of reporting with the adverse dengue prognoses.</p><p>Methods</p><p>A descriptive study was conducted using secondary data from the Dengue Disease Reporting System in Tainan, Taiwan, between January 1 and December 31, 2015. A multivariate stepwise logistic regression was used to identify the risk factors for the adverse prognoses: ICU admissions and mortality.</p><p>Results</p><p>There were 22,777 laboratory-confirmed reported cases (mean age 45.6 ± 21.2 years), of which 3.7% were admitted to intensive care units (ICU), and 0.8% were fatal. The most common symptoms were fever (92.8%), myalgia (26.6%), and headache (22.4%). The prevalence of respiratory distress, altered consciousness, shock, bleeding, and thrombocytopenia increased with age. The multivariate analysis indicated that being in 65–89 years old age group [Adjusted Odds Ratio (aOR):4.95], or the 90 years old and above age group (aOR: 9.06), and presenting with shock (aOR: 8.90) and respiratory distress (aOR: 5.31) were significantly associated with the risk of ICU admission. While old age (aOR: 1.11), respiratory distress (aOR: 9.66), altered consciousness (aOR: 7.06), and thrombocytopenia (aOR: 2.55) were significantly associated with the risk of mortality.</p><p>Conclusions</p><p>Dengue patients older than 65 and those with severe and non-specific signs and symptoms at the time of reporting were at a higher risk of ICU admission and mortality. First-line healthcare providers need to be aware of the varied presentations between the different age groups to allow early diagnosis and in-time management, which would prevent ICU admissions and fatalities in dengue patients.</p></div

Multivariate stepwise logistic regression analysis for mortality (N = 22, 767).

<p>Multivariate stepwise logistic regression analysis for mortality (N = 22, 767).</p

Characteristics of the 22,777 patients with dengue in Tainan.

<p>Characteristics of the 22,777 patients with dengue in Tainan.</p

The incidences of <i>Clostridium difficile</i> infection (CDI) in different clinical settings.

<p>The incidences of CDI in a medical center (NCKUH) and a regional hospital (TH) between March 2013 and March 2014. CDI was diagnosed by the presence of toxigenic <i>C</i>. <i>difficile</i> isolates (Culture+) or <i>C</i>. <i>difficile</i> toxin (Toxin+) in stools. mICUs = medical intensive care units.</p

Distribution of the signs and symptoms by organ systems at the time of reporting in dengue patients in different age groups.

<p>Distribution of the signs and symptoms by organ systems at the time of reporting in dengue patients in different age groups.</p

Signs and symptoms at the time of reporting in the 22,777 dengue patients in Tainan.

<p>Signs and symptoms at the time of reporting in the 22,777 dengue patients in Tainan.</p

Characteristics of the patients with or without <i>Clostridium difficile</i> infection (CDI) in intensive care units (ICUs).

<p>Characteristics of the patients with or without <i>Clostridium difficile</i> infection (CDI) in intensive care units (ICUs).</p