Light-induced silencing of neural activity in Rosa26 knock-in and BAC transgenic mice conditionally expressing the microbial halorhodopsin eNpHR3

An engineered light-inducible chloride pump, Natronomonas pharaonis halorhodopsin 3 (eNpHR3) enables temporally and spatially precise inhibition of genetically defined cell populations in the intact nervous tissues. In this report, we show the generation of new mouse strains that express eNpHR3-EYFP fusion proteins after Cre- and/or Flp-mediated recombination to optically inhibit neuronal activity. In these mouse strains, Cre/Flp recombination induced high levels of opsin expression. We confirmed their light-induced activities by brain slice whole-cell patch clamp experiments. eNpHR3-expressing neurons were optically hyperpolarized and silenced from firing action potentials. In prolonged silencing of action potentials, eNpHR3 was superior to eNpHR2, a former version of the engineered pump. Thus, these eNpHR3 mouse strains offer reliable genetic tools for light-induced inhibiting of neuronal activity in defined sets of neurons

Molecular targeting of hepatocyte growth factor by an antagonist, NK4, in the treatment of rheumatoid arthritis

INTRODUCTION: Hepatocyte growth factor (HGF) is a potent proangiogenic molecule that induces neovascularization. The HGF antagonist, NK4, competitively antagonizes HGF binding to its receptor. In the present study, we determined the inhibitory effect of NK4 in a rheumatoid arthritis (RA) model using SKG mice. METHODS: Arthritis was induced in SKG mice by a single intraperitoneal injection of β-glucan. Recombinant adenovirus containing NK4 cDNA (AdCMV.NK4) was also injected intravenously at the time of or 1 month after β-glucan injection. Ankle bone destruction was examined radiographically. The histopathologic features of joints were examined using hematoxylin and eosin and immunohistochemical staining. Enzyme-linked immunosorbent assays were used to determine the serum levels of HGF, interferon γ (IFN-γ, interleukin 4 (IL-4) and IL-17 production by CD4(+ )T cells stimulated with allogeneic spleen cells. RESULTS: The intravenous injection of AdCMV.NK4 into SKG mice suppressed the progression of β-glucan-induced arthritis. Bone destruction was also inhibited by NK4 treatment. The histopathologic findings of the ankles revealed that angiogenesis, inflammatory cytokines and RANKL expression in synovial tissues were significantly inhibited by NK4 treatment. Recombinant NK4 (rNK4) proteins inhibited IFN-γ, IL-4 and IL-17 production by CD4(+ )T cells stimulated with allogeneic spleen cells. CONCLUSIONS: These results indicate that NK4 inhibits arthritis by inhibition of angiogenesis and inflammatory cytokine production by CD4(+ )T cells. Therefore, molecular targeting of angiogenic inducers by NK4 can potentially be used as a novel therapeutic approach for the treatment of RA

Study protocol for endoscopic ultrasonography-guided ethanol injection therapy for patients with pancreatic neuroendocrine neoplasm: a multicentre prospective study

Introduction The management of small pancreatic neuroendocrine neoplasms (PNENs) remains controversial. The standard treatment for PNENs is surgical resection; however, invasiveness of surgical procedure remains higher and the incidence of postoperative adverse events is still high. Recently, the efficacy and safety of endoscopic ultrasonography (EUS)-guided ethanol injection for small PNENs has been preliminarily demonstrated. Thus, a multicentre prospective study is being conducted to evaluate the efficacy and safety of EUS-guided ethanol injection therapy for small PNENs. Methods and analysis The major eligibility criteria are the presence of pathologically diagnosed grade (G) 1 tumour, a tumour size of <= 15 mm and non-functional PNEN or insulinoma. For treatment, we will use a 25-gauge needle and pure ethanol. Contrast-enhanced CT (CE-CT) will be performed on postoperative day 3-5, and if enhanced areas of the tumour are still apparent, an additional session is scheduled during the same hospitalisation period. We set the total amount of ethanol per session to 2 mL. To evaluate the efficacy and safety, CE-CT will be performed at 1 and 6 months after treatment. The primary endpoint is the percentage of subjects who achieved all of the following evaluated points. Efficacy will be evaluated based on the achievement of complete ablation (defined as no enhanced area within the tumour on CE-CT) at 1 and 6 months. Safety will be evaluated based on the avoidance of severe adverse events within 1 month after treatment, continuing severe pancreatic fistula at 1 month after treatment and the incidence and/or exacerbation of diabetes mellitus at 6 months after treatment. Ethics and dissemination This protocol has been approved by Okayama University Certified Review Board (approval number. CRB19-007). The results will be submitted to peer-reviewed journals and will be presented at international conferences

Postoperative Coagulation Changes in Patients with esophageal carcinoma

Postoperative coagulation changes were studied in 50 patients with esophageal carcinomas for 7 days following operation. Of these, 12 patients were examined further for changes in platelet aggregation rate as an index of platelet function. Just after operation, both platelet count and aggregation rate decreased, but at day 2 when the platelet count reached its lowest point, platelet aggregation returned to the preoperative level. Altough platelet aggregation decreased again, it recovered to the preoperative level earlier than did the platelet count. Changes in prothrombin time, activated partial thromboplastin time and fibrinogen and FDP-E levels may suggest pre-DIC state

Anomalous Flux Flow Resistivity in Two Gap Superconductor MgB_2

The flux flow resistivity associated with purely viscous motion of vortices in high-quality MgB_2 was measured by microwave surface impedance. Flux flow resistivity exhibits unusual field dependence with strong enhancement at low field, which is markedly different to conventional s-wave superconductors. A crossover field which separates two distinct flux flow regimes having different flux flow resistivity slopes was clearly observed in H//ab-plane. The unusual H-dependence indicates that two very differently sized superconducting gaps in MgB_2 manifest in the vortex dynamics and almost equally contribute to energy dissipation. The carrier scattering rate in two different bands is also discussed with the present results, compared to heat capacity and thermal conductivity results.Comment: 4 pages, 3figure

Stop the Top Background of the Stop Search

The main background for the supersymmetric stop direct production search comes from Standard Model ttbar events. For the single-lepton search channel, we introduce a few kinematic variables to further suppress this background by focusing on its dileptonic and semileptonic topologies. All are defined to have end points in the background, but not signal distributions. They can substantially improve the stop signal significance and mass reach when combined with traditional kinematic variables such as the total missing transverse energy. Among them, our variable M^W_T2 has the best overall performance because it uses all available kinematic information, including the on-shell mass of both W's. We see 20%-30% improvement on the discovery significance and estimate that the 8 TeV LHC run with 20 fb-1 of data would be able to reach an exclusion limit of 650-700 GeV for direct stop production, as long as the stop decays dominantly to the top quark and a light stable neutralino. Most of the mass range required for the supersymmetric solution of the naturalness problem in the standard scenario can be covered.Comment: 16 pages, 5 figure

Label-Free Electrical Detection Using Carbon Nanotube-Based Biosensors

Label-free detections of biomolecules have attracted great attention in a lot of life science fields such as genomics, clinical diagnosis and practical pharmacy. In this article, we reviewed amperometric and potentiometric biosensors based on carbon nanotubes (CNTs). In amperometric detections, CNT-modified electrodes were used as working electrodes to significantly enhance electroactive surface area. In contrast, the potentiometric biosensors were based on aptamer-modified CNT field-effect transistors (CNTFETs). Since aptamers are artificial oligonucleotides and thus are smaller than the Debye length, proteins can be detected with high sensitivity. In this review, we discussed on the technology, characteristics and developments for commercialization in label-free CNT-based biosensors

CLE Peptides can Negatively Regulate Protoxylem Vessel Formation via Cytokinin Signaling

Cell–cell communication is critical for tissue and organ development. In plants, secretory CLAVATA3/EMBRYO SURROUNDING REGION-related (CLE) peptides function as intercellular signaling molecules in various aspects of tissue development including vascular development. However, little is known about intracellular signaling pathways functioning in vascular development downstream of the CLE ligands. We show that CLE peptides including CLE10, which is preferentially expressed in the root vascular system, inhibit protoxylem vessel formation in Arabidopsis roots. GeneChip analysis displayed that CLE10 peptides repressed specifically the expression of two type-A Arabidopsis Response Regulators (ARRs), ARR5 and ARR6, whose products act as negative regulators of cytokinin signaling. The arr5 arr6 roots exhibited defective protoxylem vessel formation. These results indicate that CLE10 inhibits protoxylem vessel formation by suppressing the expression of type-A ARR genes including ARR5 and ARR6. This was supported by the finding that CLE10 did not suppress protoxylem vessel formation in a background of arr10 arr12, a double mutant of type-B ARR genes. Thus, our results revealed cross-talk between CLE signaling and cytokinin signaling in protoxylem vessel formation in roots. Taken together with the indication that cytokinin signaling functions downstream of the CLV3/WUS signaling pathway in the shoot apical meristem, the cross-talk between CLE and cytokinin signaling pathways may be a common feature in plant development

Real-world management of treatment-naïve diabetic macular oedema : 2-year visual outcome focusing on the starting year of intervention from STREAT-DMO study

Background/aims To investigate the yearly change of real-world outcomes for best corrected visual acuity (BCVA) after 2-year clinical intervention for treatment-naïve diabetic macular oedema (DMO). Methods Retrospective analysis of aggregated, longitudinal medical records obtained from 27 retina specialised institutions in Japan from Survey of Treatment for DMO database. A total of 2049 treatment-naïve centre involving DMO eyes of which the initial intervention started between 2010 and 2015, and had been followed for 2 years, were eligible. As interventions, antivascular endothelial growth factor (VEGF) agents, local corticosteroids, macular photocoagulation and vitrectomy were defined. In each eye, baseline and final BCVA, the number of each intervention for 2 years was extracted. Each eye was classified by starting year of interventional treatment. Results Although baseline BCVA did not change by year, 2-year improvement of BCVA had been increased, and reached to +6.5 letters in the latest term. There is little difference among starting year about proportions of eyes which BCVA gained >15 letters, in contrast to those which lost >15 letters were decreased by year. The proportion of eyes receiving anti-VEGF therapy was dramatically increased, while those receiving the other therapies were gradually decreased. The proportion of eyes which maintained socially good vision of BCVA>20/40 has been increased and reached to 59.0% in the latest term. Conclusion For recent years, treatment patterns for DMO have been gradually but certainly changed; as a result, better visual gain, suppression of worsened eyes and better final BCVA have been obtained. Anti-VEGF therapy has become the first-line therapy and its injection frequency has been increasing