The Stimulator of Interferon Genes (STING) pathway initiates potent immune responses upon recognition of DNA. To initiate signaling, serine 365 (S365) in the C-terminal tail (CTT) of STING is ...phosphorylated, leading to induction of type I interferons (IFNs). Additionally, evolutionary conserved responses such as autophagy also occur downstream of STING, but their relative importance during in vivo infections remains unclear. Here we report that mice harboring a serine 365-to-alanine (S365A) mutation in STING are unexpectedly resistant to Herpes Simplex Virus (HSV)-1, despite lacking STING-induced type I IFN responses. By contrast, resistance to HSV-1 is abolished in mice lacking the STING CTT, suggesting that the STING CTT initiates protective responses against HSV-1, independently of type I IFNs. Interestingly, we find that STING-induced autophagy is a CTT- and TBK1-dependent but IRF3-independent process that is conserved in the STING S365A mice. Thus, interferon-independent functions of STING mediate STING-dependent antiviral responses in vivo.
Although antibiotic-induced dysbiosis has been demonstrated to exacerbate intestinal inflammation, it has been suggested that antibiotic prophylaxis may be beneficial in certain clinical conditions ...such as acute pancreatitis (AP). However, whether broad-spectrum antibiotics, such as meropenem, influence the dissemination of multidrug-resistant (MDR) bacteria during severe AP has not been addressed. In the currently study, a mouse model of obstructive severe AP was employed to investigate the effects of pretreatment with meropenem on bacteria spreading and disease outcome. As expected, animals subjected to biliopancreatic duct obstruction developed severe AP. Surprisingly, pretreatment with meropenem accelerated the mortality of AP mice (survival median of 2 days) when compared to saline-pretreated AP mice (survival median of 7 days). Early mortality was associated with the translocation of MDR strains, mainly
into the blood stream. Induction of AP in mice with guts that were enriched with
recapitulated the increased mortality rate observed in the meropenem-pretreated AP mice. Furthermore, naïve mice challenged with a mouse or a clinical strain of
succumbed to infection through a mechanism involving toll-like receptor-2. These results confirm that broad-spectrum antibiotics may lead to indirect detrimental effects during inflammatory disease and reveal an intestinal pathobiont that is associated with the meropenem pretreatment during obstructive AP in mice.
SARS coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic with significant mortality and morbidity. At this time, the only FDA-approved therapeutic for COVID-19 is remdesivir, a ...broad-spectrum antiviral nucleoside analog. Efficacy is only moderate, and improved treatment strategies are urgently needed. To accomplish this goal, we devised a strategy to identify compounds that act synergistically with remdesivir in preventing SARS-CoV-2 replication. We conducted combinatorial high-throughput screening in the presence of submaximal remdesivir concentrations, using a human lung epithelial cell line infected with a clinical isolate of SARS-CoV-2. This identified 20 approved drugs that act synergistically with remdesivir, many with favorable pharmacokinetic and safety profiles. Strongest effects were observed with established antivirals, Hepatitis C virus nonstructural protein 5A (HCV NS5A) inhibitors velpatasvir and elbasvir. Combination with their partner drugs sofosbuvir and grazoprevir further increased efficacy, increasing remdesivir's apparent potency > 25-fold. We report that HCV NS5A inhibitors act on the SARS-CoV-2 exonuclease proofreader, providing a possible explanation for the synergy observed with nucleoside analog remdesivir. FDA-approved Hepatitis C therapeutics Epclusa® (velpatasvir/sofosbuvir) and Zepatier® (elbasvir/grazoprevir) could be further optimized to achieve potency and pharmacokinetic properties that support clinical evaluation in combination with remdesivir.
Proinflammatory cytokines are critical mediators that control Mycobacterium tuberculosis (Mtb) growth during active tuberculosis (ATB). To further inhibit bacterial proliferation in diseased ...individuals, drug inhibitors of cell wall synthesis such as isoniazid (INH) are employed. However, whether INH presents an indirect effect on bacterial growth by regulating host cytokines during ATB is not well known. To examine this hypothesis, we used an in vitro human granuloma system generated with primary leukocytes from healthy donors adapted to model ATB. Intense Mtb proliferation in cell cultures was associated with monocyte/macrophage activation and secretion of IL‐1β and TNF. Treatment with INH significantly reduced Mtb survival, but altered neither T‐cell‐mediated Mtb killing, nor production of IL‐1β and TNF. However, blockade of both IL‐1R1 and TNF signaling rescued INH‐induced killing, suggesting synergistic roles of these cytokines in mediating control of Mtb proliferation. Additionally, mycobacterial killing by INH was highly dependent upon drug activation by the pathogen catalase‐peroxidase KatG and involved a host PI3K‐dependent pathway. Finally, experiments using coinfected (KatG‐mutated and H37Rv strains) cells suggested that active INH does not directly enhance host‐mediated killing of Mtb. Our results thus indicate that Mtb‐stimulated host IL‐1 and TNF have potential roles in TB chemotherapy.
Bafica and colleagues show that the anti‐TB drug isoniazid does not enhance the production of cytokines IL‐1 and TNF by human leukocytes in a granuloma system. However, control of infection by the drug does require involvement of the cytokines.
Although research on coral diseases is increasing worldwide, it remains limited in Taiwan. Taiwan is located at the Tropic of Cancer and contains both tropical and subtropical reefs. We conducted ...spatial and cross-seasonal surveys in Taiwan in 2018 and identified 7 types of disease and nondisease lesions and 6 potential factors influencing coral health. The overall mean prevalence of disease and nondisease lesions varied considerably across the reef regions, and host susceptibility differed among the coral taxa. The overall mean prevalence of disease and nondisease lesions was highest in Kenting (mean ± SEM: 8.58 ± 1.81%) and lowest on the Southern Islands (2.12 ± 0.73%). Although the prevalence of diseases did not differ significantly between the seasons, cyanobacteria-related diseases—including black band disease (BBD), BBD-like syndrome, and other cyanobacterial syndromes—were slightly more prevalent in autumn than in spring. Furthermore, 3 of the potential factors influencing coral health (i.e. turf algae, bioeroding sponges, and coral bleaching) were strong predictors of disease and nondisease lesion prevalence. These results advance our understanding of coral disease ecology in Taiwan and highlight the need for further research on the correlations between diseases, hosts, and environment.
Introduction Pathogenesis of cutaneous leishmaniases involves parasite growth, persistent inflammation, and likely participation of lipoproteins (LP). The cholesteryl ester transfer protein (CETP), ...involved in LP remodeling, has been shown to participate in the inflammatory response and the evolution of infectious conditions. Methods We evaluated the impact of the presence of CETP on infection by Leishmania (L.) amazonensis in an experimental model of cutaneous leishmaniasis using C57BL6/J mice transgenic for human CETP (CETP), having as control their littermates that do not express the protein, wild-type (WT) mice. The progression of the lesion after infection in the footpad was monitored for 12 weeks. Two groups of animals were formed to collect the plantar pad in the 4th and 12th week post-infection. Results The lesion increased from the 3rd week onwards, in both groups, with a gradual decrease from the 10th week onwards in the CETP group compared to the WT group, showing a reduction in parasitism and an improvement in the healing process, a reduction in CD68+ cells, and an increase in CD163+ and CD206, characterizing a population of M2 macrophages. A reduction in ARG1+ cells and an increase in INOS+ cells were observed. During infection, the LP profile showed an increase in triglycerides in the VLDL fraction in the CETP group at 12 weeks. Gene expression revealed a decrease in the CD36 receptor in the CETP group at 12 weeks, correlating with healing and parasite reduction. In vitro , macrophages derived from bone marrow cells from CETP mice showed lower parasite load at 48 h and, a reduction in arginase activity at 4 h accompanied by increased NO production at 4 and 24 h compared to WT macrophages, corroborating the in vivo findings. Discussion The data indicate that the presence of CETP plays an important role in resolving Leishmania (L.) amazonensis infection, reducing parasitism, and modulating the inflammatory response in controlling infection and tissue repair.
This article provides an overview of the state of the field of racial and other minorities in Japan – a field that has developed in English mostly since the 1990s. The construction of race in Japan ...conflates race, ethnicity, language, culture, class, and citizenship. As a result, the majority “Japanese” are constructed against “foreigners,” both categories implying the aforementioned characteristics. Minorities in Japan lack some or all of the aforementioned traits: most are seen as racially different from Japanese but some are marginalized in other ways that support hierarchical social organization. After reviewing scholarship that analyzes the meaning of race in Japan, I briefly describe the major minority groups: Ainu, Okinawans, Burakumin, ethnic Koreans, foreign workers, Japanese Brazilians and mixed race Japanese.
Abstract
Background. Indocyanine green (ICG) fluorescence method (ICG-f) has been recently widely used in sentinel lymph node (SLN) detection. The advantages of ICG-f are no radiation exposure, no ...limitation to use in high-volume medical centers without radioactive facility, and to confirm lymph flow as a real-time image from outside the body. ICG-f identified an average of 2.3-3.4 SLNs and the detection rate was 99%, compared to 1.7-2 SLNs by RI methods. Long-term observation after SNB using ICG-f has not been reported, including arm lymphedema as the complication of this method.We evaluate the usefulness of SLN biopsy (SNB) for cN0 breast cancer patients from data of multicenter cohort study on long-term results after negative SNB by ICG-f.
Methods. Eleven hundred and thirty-two women were enrolled who had histologically proved clinical stage T1-4, pN0, M0 primary invasive breast cancer with SNB using ICG-f (ICG alone or combination of RI/blue dye method) sparing axillary lymph node dissection from May 2007 to December 2015. This study is retrospective, multicenter cohort study conducted at 6 centers in Japan. Primary endpoint is axillary recurrence rate. We analyzed the correlation with the axillary recurrence and adjuvant systemic therapy, adjuvant radiotherapy, and the clinicopathological characteristics. Secondary endpoint is lymphedema.
Results and Discussion. The median follow-up time was 41 (range 21-117) months, and axillary recurrence was found in 6 patients (0.53%). Five out of 6 patients were not received standard adjuvant systemic therapy or adjuvant radiation therapy after breast conserving surgerybecause of patient's preference or old age. Lymphedema was identified only 4 patients in 632 patients. It is reported that axillary recurrence after SNB was 0.3-1.65%, which was consistent with our result. Lymphedema was not frequent in patients received SNB using ICG-f, because SLNs are removed along with lymphatic ducts in the limited area of axillary adipose tissue.
Conclusion.Axillary recurrence after negative SNB using ICG-f was comparable to RI or blue dye method. It might be important to perform appropriate adjuvant medication or radiation therapy for preventing axillary recurrence after SNB using ICG-f.
Next, ICG-f after neoadjuvant chemotherapy is to be investigated, because itis reported that removing more than 2 SLNs were associated with a lower likelihood of false negative ratio in patients with clinically node-positive disease converted to clinically node-negative after chemotherapy, and ICG-f might overcome this issue.
Citation Format: Maeshima Y, Takahara S, Yamauchi A, Yamagami K, Sugie T, Yamashiro H, Kato H, Torii M, Takada M, Torii M. Usefulness of sentinel lymph node biopsy by indocyanine green fluorescence method for cN0 breast cancer patients abstract. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-03-21.
This article examines Japanese Americans in Japan to illuminate how 'Japanese American' - an ethnic minority identity in the US - is reconstructed in Japan as a racialized national identity. Based on ...fifty interviews with American citizens of Japanese ancestry conducted between 2004 and 2007, I demonstrate how interactions with Japanese in Japan shape Japanese Americans' racial and national understandings of themselves. After laying out a theoretical framework for understanding the shifting intersection of race, ethnicity, and nationality, I explore the interactive process of racial categorization and ethnic identity assertion for Japanese American transnationals in Japan. This process leads to what I call racialized national identities - the intersection of racial and national identities in an international context - and suggests that US racial minority identities are constructed not only within the US, but abroad as well.
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