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Increasing human population size and mobility have accelerated the translocation of nonnative species globally, which has become a major threat to conservation of biodiversity and ecosystem services. Introduced species can disrupt species interactions of the recipient ecosystem, triggering system‐wide events, and amplify or dampen effects of existing pressures. We show how two pervasive intercontinental invasive consumers in North American lakes, dreissenids (filter‐feeding mussels) and Bythotrephes (carnivorous zooplankton), nonlinearly modify consumer–resource dynamics and undermine management interventions to rebuild cold‐water predatory fish biomass. Synthesizing 30 yr (1986–2015) of lake‐wide monitoring data with a dynamic mass‐balance food‐web model (consisting of 61 species and trophic groups), we reconstructed historical food‐web dynamics of Lake Simcoe, a large, temperate lake in Ontario, Canada that has shifted from a turbid to clear‐water state. We then analyzed patterns of biomass fluctuations of three recreationally harvested, ecologically connected populations; lake trout (Salvelinus namaycush , a piscivore), lake whitefish (Coregonus clupeaformis , a benthivore), and cisco (C. artedi , a planktivore) before and after the invasions by testing hypotheses on their delayed recoveries under management interventions–predator manipulations (fishery removal and stocking) and nutrient (phosphorus) load reduction. Analyses suggest that fishery harvest primarily regulated early recovery trajectories of the piscivore and planktivore, weakening top‐down control prior to the establishment of the invasive consumers. By contrast, the benthivore biomass patterns were shaped, in part, by the invasive mussels (via diet shift), independently of management actions. Although improved water quality (with reduced hypoxia in deeper water) and, in turn, higher macrophyte production are projected to expand the predation refuge for young fish, intensified planktivory (by Bythotrephes ) and herbivory (by dreissenids) have triggered shifts in community composition (from pelagic to demersal dominance). These system‐wide shifts, in turn, have substantially diminished ecosystem productivity, thereby shrinking fishery yields. Novel consumers can rewire food webs, disrupt energy flows, and suppress predator recoveries, underscoring the need to account for altered ecological reality when sustainably managing fishery resources in invaded ecosystems.

Several effective drugs have been identified for the treatment of systemic sclerosis (SSc). However, in advanced cases, not only their effectiveness is reduced but they may be also harmful due to their side-effects. Therefore, early diagnosis and early treatment is most important for the treatment of SSc. We established diagnostic criteria for SSc in 2003 and early diagnostic criteria for SSc in 2011, for the purpose of developing evaluation of each organ in SSc. Moreover, in November 2013, the American College of Rheumatology and the European Rheumatology Association jointly developed new diagnostic criteria for increasing their sensitivity and specificity, so we revised our diagnostic criteria and severity classification of SSc. Furthermore, we have revised the clinical guideline based on the newest evidence. In particular, the clinical guideline was established by clinical questions based on evidence-based medicine according to the New Minds Clinical Practice Guideline Creation Manual (version 1.0). We aimed to make the guideline easy to use and reliable based on the newest evidence, and to present guidance as specific as possible for various clinical problems in treatment of SSc.

Objectives Several studies report on the outcomes of self-expandable metallic stents (SEMSs) deployment for malignant gastric outlet obstruction (GOO). However, data was mostly based on the analysis of single-center studies including only a small number of patients. This study aimed to evaluate clinical outcomes after the deployment of SEMS in patients with malignant GOO and to compare the clinical outcomes of two metallic stents with different designs. Methods Altogether 125 consecutive patients from five institutions were included. Clinical outcomes were evaluated according to technical success, clinical success, stent patency period, survival period and complications. A comparison of clinical outcomes between Niti-S pyloric/duodenal and WallFlex duodenal stents was also undertaken. Results Rates for clinical and technical success were 100% and 92.0%, respectively. The median stent patency and survival periods were 72.0 days (range 3–775 days) and 75.0 days (range 3–775 days), respectively. The rate of overall adverse events was 28.8%. The rate of stent dysfunction was 16.8%, and that of adverse events, except stent dysfunction was 12.0%. Massive bleeding occurred in two patients as a late complication. The clinical success rate for Niti-S stent was significantly higher than that for WallFlex stent (96.2% vs 84.8%, P = 0.023). Conclusions We successfully deployed a SEMS in malignant GOO. The selection of a SEMS with a lower axial force may be important for patients to resume the oral food intake. Additionally, consideration must be given to the appropriate management of fatal bleeding as a late complication.

Aims We aimed to compare the efficacy and safety of mirabegron, a β3-adrenoceptor agonist, and imidafenacin, an anticholinergic agent, in overactive bladder patients. Methods We conducted a multicenter, prospective randomized cross-over study at 5 hospitals in Japan from December 2012 to June 2015. We enrolled female patients with overactive bladder aged ≥50 years, who had never received treatment for the condition. The patients were assigned to Group A or B. Group A patients were administered mirabegron (50 mg per day) for 8 weeks, followed by a 2-week washout period, and then imidafenacin (0.2 mg per day) for 8 weeks. This order of drug administration was reversed in Group B. Results A total of 33 and 18 patients in Group A and 37 and 26 patients in Group B continued to receive treatment at weeks 8 and 18, respectively. Mirabegron administration significantly improved overactive bladder symptom score (OABSS), the urinary frequency per 24 hr, voided volume per micturition, and number of nocturia episodes per night at week 8. Moreover, imidafenacin administration improved all these variables, except for the number of nocturia episodes per night at week 8. No significant difference was observed in the drug effects between mirabegron and imidafenacin. Although imidafenacin administration significantly increased the scores for dry mouth, blurred vision, and constipation, mirabegron administration did not. Conclusions Mirabegron and imidafenacin have the same efficacy. Imidafenacin administration is associated with a higher rate of dry mouth, blurred vision, and constipation as compared to mirabegron administration. Neurourol. Urodynam. 36:1097–1103, 2017. © 2016 Wiley Periodicals, Inc.

Aim: It is reported that in salivary glands of Sjogren’s syndrome (SS), interferon gamma (IFNγ) and IFNγ-inducible genes containing signal transducers and activators of transcription 1 (STAT1) are upregulated and play a crucial role in the pathogenesis of SS. The aim of this study is to clarify which phosphorylation of STAT1, serine727 (Ser727) or tyrosine701 (Tyr701) of STAT1, is important for IFNγ signaling and IFNγ-induced apoptosis in salivary gland cells. Methods: We established STAT1 Tyr701 variant (tyrosine to phenylalanine; Y701F) and STAT1 Ser727 variant (serine to alanine; S727A), which were transfected into human salivary gland (HSG) cells. HSG cells transfected with these mutant-STAT1 were analyzed on the expression of IFNγ-inducible genes and apoptosis after stimulation with IFNγ. Results: In Y701F mutant-STAT1 transfected HSG cells (Ser727-dominant HSG cells), IFNγ-inducible genes such as IP10, IRF1, and Fas expression were increased after stimulation with IFNγ. In Ser727-dominant HSG cells, the induction of apoptosis after stimulation with IFNγ was also increased compared with S727A mutant-STAT1 transfected HSG cells (Tyr701-dominant HSG cells). Conclusion: Phosphorylation of Ser727 in STAT1 might be more important in IFNγ signaling and the induction of apoptosis in HSG cells than phosphorylation of Tyr701. Accordingly, we propose that phosphorylation of Ser727 in STAT1 could be a potentially suitable new therapeutic target for SS patients to prevent the destruction of salivary glands.

A case of a 37-year-old pregnant patient with antiphospholipid syndrome (APS), who has a medical history of both thrombosis and recurrent fetal loss, is presented. She was treated with predonisolone and fixed-dose unfractionated heparin (UFH) infusion, followed by plasmaphereses and fixed-dose low-molecular-weight heparin infusion during her fourth pregnancy. Unfortunately, this treatment did not have beneficial effects, resulting in intrauterine growth restriction and finally neonatal death. Continuous intravenous UFH infusion and low-dose aspirin were administrated under the monitoring of the activated partial thromboplastin time to achieve a target level of 120 s during her fifth pregnancy. A healthy baby weighing 1818 g at birth was delivered by Cesarean section at the 34th week of pregnancy. High-dose UFH infusion may be considered to be one of the preferable options to manage pregnant patients with refractory APS.

Objective Recent genome-wide association studies identified an association between single-nucleotide polymorphisms (SNPs) in the C8orf13 region of BLK, the B lymphoid tyrosine kinase gene, with systemic lupus erythematosus (SLE) in Caucasians. The purpose of this study was to evaluate the significance of this region in the genetic background of Japanese patients with SLE. Methods Fourteen tag SNPs in the C8orf13–BLK region were genotyped in 327 Japanese patients with SLE and 322 healthy Japanese controls. The population-attributable risk percentage (PAR%) of rs13277113 in Japanese was compared with that in Caucasians as well as with that of other SLE susceptibility genes in Japanese. Results As in Caucasians, rs13277113A demonstrated the strongest association in Japanese (P = 1.73 × 10–6 for the genotype frequency, P = 4.75 × 10–7 for the allele frequency, odds ratio [OR] 2.44 [95% confidence interval (95% CI) 1.43–4.16]). The association in Japanese was consistent with a recessive model (P = 2.74 × 10–7, OR 2.27 [95% CI 1.66–3.11]). In contrast to the Caucasian population, this risk allele was the major allele in the Japanese population. Because both the risk allele frequency and the OR were higher in Japanese than in Caucasians, the PAR% of rs13277113 was estimated to be much higher in Japanese (35.4%) than in Caucasians (16.2%), and the second highest among the 6 confirmed SLE susceptibility genes in Japanese. Conclusion The association of the C8orf13–BLK region with SLE was replicated in a Japanese population. Contribution of this region to the genetic predisposition to SLE appeared to be greater in Japanese than in Caucasians.

Objective To clarify the glucose-6-phosphate isomerase (GPI)–specific CD4+ T cell lineage involved in GPI-induced arthritis and to investigate their pathologic and regulatory roles in the induction of the disease. Methods DBA/1 mice were immunized with GPI to induce arthritis. CD4+ T cells and antigen-presenting cells were cocultured with GPI, and cytokines in the supernatant were analyzed by enzyme-linked immunosorbent assay. Anti–interferon-γ (anti-IFNγ) monoclonal antibody (mAb), anti–interleukin-17 (anti–IL-17) mAb, or the murine IL-6 receptor (IL-6R) mAb MR16-1 was injected at different time points, and arthritis development was monitored visually. After MR16-1 was injected, percentages of Th1, Th2, Th17, and Treg cells were analyzed by flow cytometry, and CD4+ T cell proliferation was analyzed using carboxyfluorescein diacetate succinimidyl ester. Results GPI-specific CD4+ T cells were found to be differentiated to Th1 and Th17 cells, but not Th2 cells. Administration of anti–IL-17 mAb on day 7 significantly ameliorated arthritis (P < 0.01), whereas administration of anti-IFNγ mAb exacerbated arthritis. Neither anti–IL-17 mAb nor anti-IFNγ mAb administration on day 14 ameliorated arthritis. Administration of MR16-1 on day 0 or day 3 protected against arthritis induction, and MR16-1 administration on day 8 significantly ameliorated existing arthritis (P < 0.05). After administration of MR16-1, there was marked suppression of Th17 differentiation, without an increase in Th1, Th2, or Treg cells, and CD4+ T cell proliferation was also suppressed. Conclusion IL-6 and Th17 play an essential role in GPI-induced arthritis. Since it has previously been shown that treatment with a humanized anti–IL-6R mAb has excellent effects in patients with rheumatoid arthritis (RA), we propose that the IL-6/IL-17 axis might also be involved in the generation of RA, especially in the early effector phase.

Objective To clarify the molecular mechanisms of Sjogren's syndrome (SS), we analyzed the functional role of the STAT-1 gene, one of the interferon-γ (IFNγ)–inducible genes, in labial salivary glands (LSGs) from SS patients. Methods The expression of STAT-1 messenger RNA (mRNA) was examined by real-time polymerase chain reaction (PCR) analysis, and the phosphorylation of STAT-1 protein (Tyr701 and Ser727 pSTAT-1) was investigated by Western blot and immunohistochemical analyses. The expression of IFNγ-inducible 10-kd protein (IP-10), IFN regulatory factor 1 (IRF-1), and Fas was also examined by real-time PCR and immunohistochemical analyses. Results STAT-1α and STAT-1β mRNA were highly expressed in LSGs from SS patients. The level of STAT-1α protein in SS LSGs was higher than that in 3 control LSGs, whereas STAT-1β protein was not clearly detected by Western blot analysis. Moreover, Tyr701 and Ser727 pSTAT-1α proteins were specifically detected in SS LSGs. Immunohistochemical analysis showed localization of Tyr701 pSTAT-1 in infiltrating lymphocytes and the adjacent ductal epithelium from SS patients. Ser727 pSTAT-1 was localized only in the ductal epithelium of SS LSGs. The STAT-1–inducible genes IP-10 and IRF-1 and the Fas genes were highly expressed in SS LSGs and were colocalized with Ser727 pSTAT-1–positive, but not Tyr701 pSTAT-1–positive, cells. Conclusion We found evidence of the up-regulation of STAT-1α mRNA and protein in LSGs from SS patients, as well as the presence of pSTAT-1α in ductal epithelium from SS patients. Our findings suggest that STAT-1α, especially Ser727 pSTAT-1, may function as a key molecule in the pathogenesis of SS.

TGF-beta is a potent inhibitor of cell growth, and accumulating evidence suggests that perturbation of the TGF-beta signaling pathway leads to tumorigenesis. Smads are recently identified proteins that mediate intracellular signaling of the TGF-beta superfamily. Smads 2 and 3 are phosphorylated by the TGF-beta type I receptor. Smad4 was originally identified as a candidate tumor suppressor gene in pancreatic cancers. Smads 2 and 3 form complexes with Smad4 upon TGF-beta stimulation. The heteromeric Smad complexes translocate into the nucleus, where they activate expression of target genes. Our recent study demonstrated that Smads exist as monomers in the absence of TGF-beta. Smads 2 and 3 form homo- as well as hetero-oligomers with Smad4 upon ligand stimulation. Both homo-oligomers and hetero-oligomers directly bind to DNA, suggesting that the signaling pathway of Smads may be multiplex. Smads 2 and 3 associate with transcriptional coactivators such as p300 in a ligand-dependent manner, p300 enhances transactivation by TGF-beta, suggesting that coactivators link Smads to the basal transcriptional machinery. A missense mutation of Smad2 identified in colorectal and lung cancers was introduced to Smad3. The mutant, Smad3(DE), blocked the activation of wild-type Smad2 and Smad3. Thus, the missense mutation not only disrupts the function of the wild-type Smad but also creates a dominant-negative Smad, which could actively contribute to oncogenesis.

Electronic states and spin operation in coupled quantum dots are numerically studied, considering realistic shape of quantum dots and electron-electron interaction. (i) We evaluate the spin coupling J between two electron spins, as a function of magnetic field perpendicular to the quantum dots. We observe a transition from antiferromagnetic coupling (J > 0) to ferromagnetic coupling (J < 0) at magnetic field of a few Tesla. The spin coupling is hardly influenced by the size difference between the quantum dots if the energy levels are matched. (ii) We simulate SWAP gate operations by calculating the time development of two electron spins. We show that a sudden change of tunnel barrier may result in the gate errors. The spin exchange is incomplete in the presence of strong spin-orbit interaction in InGaAs. (© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Alkyl sulfonates (R 1 -OSO 2 R 2 ) react with carbon monoxide and alcohol (R 3 -OH) in the presence of catalytic amounts of Co complex and Nal to afford the corresponding esters (R 1 -COOR 3 ) in moderate to good yields.