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Radiation therapy (RT) has the potential to activate the tumor-microenvironment (TME) and promote the efficacy of immune checkpoint blockade therapy. Tumor cell-intrinsic expression of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) plays an important role in regulations of radiation-induced activation of immune cells in the TME. However, the role of tumor cell-intrinsic cGAS-STING in radiation-mediated remodeling of the TME in esophageal squamous cell carcinoma (ESCC) is not completely understood; thus, we investigated its effect on the radiation-mediated remodeling of the TME in ESCC.We assessed the effect of tumor cell-intrinsic cGAS-STING on the expression of mediators of the immune system, including type I interferon, T-cell chemo-attractants, colony-stimulating factor-1, and interleukin 34 (IL-34), induced by radiation in ESCC cell lines. We also quantified the association between tumor cell-intrinsic expression of cGAS-STING and infiltrations of immune cells, including CD8We found that tumor cell-intrinsic expression of cGAS-STING was involved in radiation-induced infiltration of CD8The tumor cell-intrinsic expression of cGAS-STING is essential for radiation-induced activation of immune cells in the TME, but it is also involved in the recruitment of tumor-promoting M2-TAMs in ESCC. Therefore, blocking of M2-TAM infiltration by targeting IL-34 might improve the efficacy of RT and combination therapy of RT with immune checkpoint inhibitors in ESCC.

Revocation functionality is vital to real-world cryptographic systems for managing their reliability. In the context of identity-based encryption (IBE), Boldyreva, Goyal, and Kumar (ACM CCS 2008) first showed an efficient revocation method for IBE, and such an IBE scheme with the scalable revocation method is called revocable IBE (RIBE). Seo and Emura (PKC 2013) introduced a new security notion, called decryption key exposure resistance (DKER), which is a desirable security notion for RIBE. However, all existing RIBE schemes that achieve adaptive security with DKER require long public parameters or composite-order bilinear groups. In this paper, we first show an RIBE scheme that (1) satisfies adaptive security; (2) achieves DKER; (3) realizes constant-size public parameters; and (4) is constructed over prime-order bilinear groups. Our core technique relies on Seo and Emura's one (PKC 2013), which transform the Waters IBE (EUROCRYPT 2005) to the corresponding RIBE scheme. Specifically, we construct an IBE scheme that satisfies constant-size public parameters over prime-order groups and some requirements for the Seo-Emura technique, and then transform the IBE scheme to an RIBE scheme. We also discuss how to extend the proposed RIBE scheme to a chosen-ciphertext secure one and server-aided one (ESORICS 2015).

Patients with severe COVID-19 exhibit a cytokine storm characterized by greatly elevated levels of cytokines. Despite this, the interferon (IFN) response is delayed, contributing to disease progression. Here, we report that SARS-CoV-2 excessively generates small viral RNAs (svRNAs) encoding exact 5' ends of positive-sense genes in human cells

Avian influenza viruses can adapt to infect humans by accumulating mutations or reassortments, potentially leading to a pandemic. However, the adaptation dynamics of zoonotic avian influenza viruses in their transition from animal hosts to human hosts remains largely unknown. In a recent PNAS report, Liu et al. have presented deep sequencing data showing host adaptation by “genetic tuning” of a zoonotic H7N9 avian influenza virus to cross the species barrier to infect humans. This provides the first in-depth data on avian influenza virus adaptation at the bird-human interface. As a one-health approach, the deep sequencing approach as implemented by Liu et al. is applicable to the study of emerging zoonotic viruses and provides valuable data on “genetic tuning” in virus-host adaptation. This experimental design should be useful for studying other zoonotic viruses, including SARS-CoV-2 and the novel swine influenza virus, and helpful for mitigating future pandemic public health risks.

Highlights • Splenogonadal fusion is a malformation in which the spleen is connected to the gonad. • We report a case of Splenogonadal fusion which was incidentally detected by TAPP and this is the first report of this condition. • The potential for incidental diagnoses of Splenogonadal fusion by TAPP may be increasing. • A therapeutic strategy for incidentally detected Splenogonadal fusion is unclear, but we show one successful experience., Introduction Splenogonadal fusion (SGF) is a rare congenital malformation in which the spleen is connected to the gonad. Few SGF cases have been reported in the English scientific literature, and we are unaware of any previous case reports of SGF with inguinal hernia by laparoscopic transabdominal preperitoneal hernia repair (TAPP). Here, we report a case of SGF that was incidentally detected during a TAPP procedure, with an uneventful postoperative course without complications. Presentation of case A 76-year-old male presented with a 10-year history of left inguinal swelling. He was diagnosed with a left inguinal hernia, and we performed TAPP. Laparoscopy revealed the left inguinal hernia and two reddish-purple masses, one located close to the left inguinal ring. A cord of soft tissue extended cranially from the mass to the spleen, and passed through the left internal inguinal ring caudally. We cut the cord for mesh placement and to make an accurate diagnosis of the mass. Pathological and intraoperative findings indicated a diagnosis of continuous SGF. Discussion We observed two important clinical issues in this case. First, the potential for incidental diagnoses of SGF may be increasing. Second, to our knowledge, this is the first case report of a patient with SGF identified by TAPP. Such a therapeutic strategy for incidentally detected SGF has not been described; here we report a successful experience. Conclusion To our knowledge, this is the first report of a patient with SGF diagnosed by a TAPP procedure. The postoperative course was uneventful using our method.

The highly pathogenic avian influenza (AI) virus, H5N1, is a serious threat to public health worldwide. Both the currently circulating H5N1 and previously circulating AI viruses recognize avian-type receptors; however, only the H5N1 is highly infectious and virulent in humans. The mechanism(s) underlying this difference in infectivity remains unclear. The aim of this study was to clarify the mechanisms responsible for the difference in infectivity between the current and previously circulating strains. Primary human small airway epithelial cells (SAECs) were transformed with the SV40 large T-antigen to establish a series of clones (SAEC-Ts). These clones were then used to test the infectivity of AI strains. Human SAEC-Ts could be broadly categorized into two different types based on their susceptibility (high or low) to the viruses. SAEC-T clones were poorly susceptible to previously circulating AI but were completely susceptible to the currently circulating H5N1. The hemagglutinin (HA) of the current H5N1 virus showed greater membrane fusion activity at higher pH levels than that of previous AI viruses, resulting in broader cell tropism. Moreover, the endosomal pH was lower in high susceptibility SAEC-T clones than that in low susceptibility SAEC-T clones. Taken together, the results of this study suggest that the infectivity of AI viruses, including H5N1, depends upon a delicate balance between the acid sensitivity of the viral HA and the pH within the endosomes of the target cell. Thus, one of the mechanisms underlying H5N1 pathogenesis in humans relies on its ability to fuse efficiently with the endosomes in human airway epithelial cells.

Correlative light-electron microscopy of cells in a natural environment of aqueous liquid facilitates high-throughput observation of protein complex formation. ASEM allows the inverted SEM to observe the wet sample from below, while an optical microscope observes it from above quasi-simultaneously. The disposable ASEM dish with a silicon nitride (SiN) film window can be coated variously to realize the primary-culture of substrate-sensitive cells in a few milliliters of culture medium in a stable incubator environment. Neuron differentiation, neural networking, proplatelet-formation and phagocytosis were captured by optical or fluorescence microscopy, and imaged at high resolution by gold-labeled immuno-ASEM with/without metal staining. Fas expression on the cell surface was visualized, correlated to the spatial distribution of F-actin. Axonal partitioning was studied using primary-culture neurons, and presynaptic induction by GluRδ2-N-terminus-linked fluorescent magnetic beads was correlated to the presynaptic-marker Bassoon. Further, megakaryocytes secreting proplatelets were captured, and P-selectins with adherence activity were localized to some of the granules present by immuno-ASEM. The phagocytosis of lactic acid bacteria by dendritic cells was also imaged. Based on these studies, ASEM correlative microscopy promises to allow the study of various mesoscopic-scale dynamics in the near future.

Highly pathogenic avian influenza A virus subtype H5N1 has been endemic in some bird species since its emergence in 1996 and its ecology, genetics and antigenic properties have continued to evolve. This has allowed diverse virus strains to emerge in endemic areas with altered receptor specificity, including a new H5 sublineage with enhanced binding affinity to the human-type receptor. The pandemic potential of H5N1 viruses is alarming and may be increasing. We review here the complex dynamics and changing nature of the H5N1 virus that may contribute to the emergence of pandemic strains.

We sought to determine whether a clinical association exists between osteoarthritis (OA)-associated knee pain and adenosine triphosphate (ATP) levels in synovial fluid (SF). A total of 28 patients with 28 primary OA knees were included. They routinely received intra-articular injection of high-molecular-weight hyaluronic acid (HA) once weekly for 5 weeks (treated group). Eight patients without knee pain who had undergone an operation for anterior or posterior cruciate ligament reconstruction 2 years ago were also examined (control group). SF and blood ATP concentrations, total amount of ATP, total SF volume, and Visual Analogue Scale (VAS) scores in all patients were measured and we compared pre-treatment values with those 1 week after the final treatment. We evaluated the correlation of change in total ATP (ΔATP) and change in VAS score (ΔVAS), ΔVAS and change in SF volume (ΔSF), and ATP concentration in SF and blood. In the treated group, SF ATP concentration, total amount of ATP, SF volume, and VAS score were all significantly lower post-treatment than pre-treatment (p = 0.0005, 0.0003, 0.0022, and < 0.0001, respectively). In treated group, ΔVAS was significantly associated with ΔATP (r = 0.56, p = 0.0032), ΔSF was significantly associated with ΔVAS (r = 0.78, p < 0.0001), and total amount of SF ATP and SF volume at pre-treatment were significantly higher than the control group (p < 0.0001, p < 0.0001) We demonstrated an association between SF ATP level changes and OA knee pain, which should facilitate a further understanding of OA pain mechanisms.

The epitope sequences within the hemagglutinin (HA) of influenza A virus H3N2 at amino acid residues 173-181 and 227-239 that forms anti-parallel beta-sheet structure are similarly recognized by human monoclonal antibodies (HuMAbs), B-1 and D-1 that we recently obtained using the peripheral blood lymphocytes from two influenza-vaccinated volunteers. Both HuMAbs showed strong global neutralization of H3N2 strains. Here we show the significant conservation of the beta-sheet region consisting of the above-mentioned two epitope regions in H3N2. In addition, we also identified the corresponding regions with similar structure in other subtypes such as H1N1 and H5N1. These two regions are similarly located underneath the receptor-binding sites of individual subtypes. Analysis of those regions using sequences available from the Influenza Virus Resource at the National Center for Biotechnology Information revealed that compared with those in the known neutralizing epitopes A-E, those sequences were fairly conserved in human H3N2 (n=7955), swine H1N1 (n=360) and swine H3N2 (n=235); and highly conserved in human H1N1 (n=2722), swine-origin pandemic H1N1 (n=1474), human H5N1 (n=319) and avian H5N1 (n=2349). Phylogenetic tree for these regions formed clearly separable clusters for H1N1, H3N2 and H5N1, irrespective of different host origin. These data may suggest a possible significance of those regions for development of alternative vaccine that could induce neutralizing antibodies reactive against wide-range of influenza virus strains.

Some cases of seasonal influenza virus (human influenza A virus (IAV)/human influenza B virus (IBV)) are associated with abdominal symptoms. Although virus RNA has been detected in faeces, intestinal infection has not been clearly demonstrated. We aimed to provide evidence that IAV/IBV infects the human intestine. This prospective observational study measured virus RNA in faecal and sputum samples from 22 patients infected with IAV/IBV (19 IAV positive and three IBV positive). Nineteen patients were included in the analysis and were assigned to faecal IAV-positive and -negative groups. Virus kinetics were examined in faecal samples from an IAV-infected patient (patient 1) and an IBV-infected patient (patient 2). Finally, intestinal tissue from an IAV-diagnosed patient who developed haemorrhagic colitis and underwent colonoscopy was examined for the presence of replicating IAV (patient 3). Virus RNA was detected in faecal samples from 8/22 IAV/IBV-infected patients (36.4%). Diarrhoea occurred significantly more often in the faecal IAV-positive group (p 0.002). In patients 1 and 2, virus RNA became undetectable in sputum on days 7 and 10 after infection, respectively, but was detected in faeces for a further 2 weeks. Virus mRNA and antigens were detected in intestinal tissues (mucosal epithelium of the sigmoid colon) from patient 3. These findings suggest that IAV/IBV infects within the intestinal tract; thus, the human intestine may be an additional target organ for IAV/IBV infection.