Gating Charge Immobilization in Kv4.2 Channels: The Basis of Closed-State Inactivation

Kv4 channels mediate the somatodendritic A-type K+ current (ISA) in neurons. The availability of functional Kv4 channels is dynamically regulated by the membrane potential such that subthreshold depolarizations render Kv4 channels unavailable. The underlying process involves inactivation from closed states along the main activation pathway. Although classical inactivation mechanisms such as N- and P/C-type inactivation have been excluded, a clear understanding of closed-state inactivation in Kv4 channels has remained elusive. This is in part due to the lack of crucial information about the interactions between gating charge (Q) movement, activation, and inactivation. To overcome this limitation, we engineered a charybdotoxin (CTX)-sensitive Kv4.2 channel, which enabled us to obtain the first measurements of Kv4.2 gating currents after blocking K+ conduction with CTX (Dougherty and Covarrubias. 2006J. Gen. Physiol. 128:745–753). Here, we exploited this approach further to investigate the mechanism that links closed-state inactivation to slow Q-immobilization in Kv4 channels. The main observations revealed profound Q-immobilization at steady-state over a range of hyperpolarized voltages (−110 to −75 mV). Depolarization in this range moves <5% of the observable Q associated with activation and is insufficient to open the channels significantly. The kinetics and voltage dependence of Q-immobilization and ionic current inactivation between −153 and −47 mV are similar and independent of the channel's proximal N-terminal region (residues 2–40). A coupled state diagram of closed-state inactivation with a quasi-absorbing inactivated state explained the results from ionic and gating current experiments globally. We conclude that Q-immobilization and closed-state inactivation at hyperpolarized voltages are two manifestations of the same process in Kv4.2 channels, and propose that inactivation in the absence of N- and P/C-type mechanisms involves desensitization to voltage resulting from a slow conformational change of the voltage sensors, which renders the channel's main activation gate reluctant to open

Surf Sled

This Final Design Review document outlines the process by which we designed and built a surfboard sled, nicknamed the “Beachin’ Buggy”, for the AmpSurf program. The document describes the goals and services that AmpSurf provides for those living with disabilities, and the current methods that volunteers use to transport people from to beach to the water and onto a surfboard. It then identifies the need for a new system for beach-to-water transportation, along with all specifications, constraints, and goals for the system. Background research will be introduced to relate similar products to this project, and their relevant features and parameters will be detailed. The final design that has been chosen through a documented process will be presented, as well as the completed manufacturing. Finally, the yet to be completed aspects due to the coronavirus situation will be explained along with instructions to complete them

Knowledge management as intellectual property: Evidence from Mexican manufacturing SMEs

© 2016, © Emerald Group Publishing Limited. Purpose: The purpose of this paper is to explore the relationship between knowledge management and creation of intellectual property within the context of small and medium size manufacturing enterprises. Design/methodology/approach: A hypothesis was formulated and tested using structural equation modelling. Data were collected through an instrument that was developed based on key constructs adapted from the literature and that was first validated using Confirmatory Factor Analysis. A Cronbach’s alpha test was also conducted and the Composite Reliability Index was calculated to ensure reliability of the theoretical model. The instrument was distributed among manufacturing small and medium enterprises (SMEs) in the Aguascalientes region of Mexico, from were 125 valid responses were obtained. Findings: In general, the results indicate that knowledge management has positive effects on the creation of intellectual property in manufacturing SMEs. This suggests that SMEs can create more intellectual property if they dedicate more efforts to the management of knowledge. Practical implications: The implication of this research and its findings may inform the strategies formulated by policy makers, and the managerial practices that manufacturing SMEs can adopt to protect their knowledge. Originality/value: Evidence suggests that studies focused on investigating the relationship between knowledge and intellectual property are limited. This paper provides a refined understanding of the relationship between knowledge management and intellectual property creation

The Luminous Type Ic SN 1992ar at z=0.145

We present spectroscopic and photometric observations of SN1992ar, the more distant SN in the Calan/Tololo Survey. We compare its spectrum with those of nearby Type Ia and Ic SNe and conclude that the latter type is a better match to SN 1992ar. Using K-corrections based on the spectra of well observed Type Ic and Ia SNe we compute different possible rest frame light curves of SN 1992ar and compare them with those of representative SNe of each type observed in the nearby universe. From the photometry and the spectra, we are able to conclude that SN 1992ar cannot be matched by any known example of a Type Ia SN. Even though the data set collected is fairly complete (one spectrum and 10 photometric points), it is not possible to decide whether SN 1992ar was a fast Type Ic SN, like SN 1994I, or a slow one, like SN 1983V. The absolute V magnitudes at maximum implied by each of these possibilities are -19.2 and -20.2, respectively. The latter would make SN 1992ar one of the brightest SNe on record. SN 1992ar, hence, illustrates the problem of contamination faced by the high z Type Ia SNe samples whose luminosity distances are used to determine the cosmological parameters of the Universe. We present observational criteria to distinguish the two SN types when the SiII 6355 line is redshifted out of the sensitivity range of typical CCD detectors, and discuss the effect that these luminous Type Ic SNe would have on the measured cosmological parameters, if not removed from the High-z Type Ia SN samples.Comment: 40 pages, 9 figures. Accepted for publication in Astrophysical Journa

Spectroscopy of High-Redshift Supernovae from the ESSENCE Project: The First Two Years

We present the results of spectroscopic observations of targets discovered during the first two years of the ESSENCE project. The goal of ESSENCE is to use a sample of ~200 Type Ia supernovae (SNe Ia) at moderate redshifts (0.2 < z < 0.8) to place constraints on the equation of state of the Universe. Spectroscopy not only provides the redshifts of the objects, but also confirms that some of the discoveries are indeed SNe Ia. This confirmation is critical to the project, as techniques developed to determine luminosity distances to SNe Ia depend upon the knowledge that the objects at high redshift are the same as the ones at low redshift. We describe the methods of target selection and prioritization, the telescopes and detectors, and the software used to identify objects. The redshifts deduced from spectral matching of high-redshift SNe Ia with low-redshift SNe Ia are consistent with those determined from host-galaxy spectra. We show that the high-redshift SNe Ia match well with low-redshift templates. We include all spectra obtained by the ESSENCE project, including 52 SNe Ia, 5 core-collapse SNe, 12 active galactic nuclei, 19 galaxies, 4 possibly variable stars, and 16 objects with uncertain identifications.Comment: 38 pages, 9 figures (many with multiple parts), submitted to A

Optical Light Curve of the Type Ia Supernova 1998bu in M96 and the Supernova Calibration of the Hubble Constant

We present the UBVRI light curves of the Type Ia supernova SN 1998bu which appeared in the nearby galaxy M96 (NGC 3368). M96 is a spiral galaxy in the Leo I group which has a Cepheid-based distance. Our photometry allows us to calculate the absolute magnitude and reddening of this supernova. These data, when combined with measurements of the four other well-observed supernovae with Cepheid based distances, allow us to calculate the Hubble constant with respect to the Hubble flow defined by the distant Calan/Tololo Type Ia sample. We find a Hubble constant of 64.0 +/- 2.2(internal) +/- 3.5(external) km/s/Mpc, consistent with most previous estimates based on Type Ia supernovae. We note that the two well-observed Type Ia supernovae in Fornax, if placed at the Cepheid distance to the possible Fornax spiral NGC 1365, are apparently too faint with respect to the Calan/Tololo sample calibrated with the five Type Ia supernovae with Cepheid distances to the host galaxies.Comment: AAS LaTeX, 20 pages, 4 figures, 6 tables, accepted for publication in the Astronomical Journal. Figure 1 (finding chart) not include

Tofacitinib or adalimumab versus placebo: patient-reported outcomes from OPAL Broaden-a phase III study of active psoriatic arthritis in patients with an inadequate response to conventional synthetic disease-modifying antirheumatic drugs.

Objectives: Tofacitinib is an oral Janus kinase inhibitor for treatment of psoriatic arthritis (PsA). We evaluated patient-reported outcomes (PROs) in patients with PsA refractory to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR) and tumour necrosis factor inhibitor-naïve in a 12-month, phase III randomised controlled trial (OPAL Broaden [NCT01877668]). Methods: Patients (N=422) received tofacitinib 5 mg or 10 mg twice daily, adalimumab 40 mg subcutaneously every 2 weeks or placebo advancing to tofacitinib 5 mg or 10 mg twice daily at month 3. Least squares mean changes from baseline and percentages of patients reporting improvements ≥minimum clinically important differences (MCID); and scores ≥normative values in: Patient Global Assessment of disease activity (PtGA), Pain, Patient Global Joint and Skin Assessment (PGJS), Short Form-36 Health Survey version 2 (SF-36v2), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), EuroQol 5-Dimensions-3-level questionnaire (EQ-5D-3L) and Ankylosing Spondylitis Quality of Life (ASQoL) were determined. Nominal p values were cited without multiple comparison adjustments. Results: At month 3, PtGA, Pain, PGJS, FACIT-Fatigue, EQ-5D-3L, ASQoL and SF-36v2 Physical Component Summary (PCS), physical functioning (PF), bodily pain (BP) and vitality domain scores exceeded placebo with both tofacitinib doses (p≤0.05); SF-36v2 social functioning with 5 mg twice daily (p≤0.05). Percentages reporting improvements ≥MCID in PtGA, Pain, PGJS, FACIT-Fatigue, ASQoL and SF-36v2 PCS, PF, BP and general health scores exceeded placebo with both tofacitinib doses (p≤0.05) and were similar with adalimumab. Conclusion: csDMARD-IR patients with active PsA reported statistically and clinically meaningful improvements in PROs with tofacitinib compared with placebo at Month 3

Efficacy, safety, tolerability and population pharmacokinetics of tedizolid, a novel antibiotic, in Latino patients with acute bacterial skin and skin structure infections

AbstractAcute bacterial skin and skin structure infections are caused mainly by Gram-positive bacteria which are often treated with intravenous vancomycin, daptomycin, or linezolid, with potential step down to oral linezolid for outpatients. Tedizolid phosphate 200mg once daily treatment for six days demonstrated non-inferior efficacy, with a favourable safety profile, compared with linezolid 600mg twice daily treatment for 10 days in the Phase 3 ESTABLISH-1 and -2 trials. The objective of the current post-hoc analysis of the integrated dataset of ESTABLISH-1 and -2 was to evaluate the efficacy and safety of tedizolid (N=182) vs linezolid (N=171) in patients of Latino origin enrolled into these trials. The baseline demographic characteristics of Latino patients were similar between the two treatment groups. Tedizolid demonstrated comparable efficacy to linezolid at 48–72h in the intent-to-treat population (tedizolid: 80.2% vs linezolid: 81.9%). Sustained clinical success rates were comparable between tedizolid- and linezolid-treated Latino patients at end-of-therapy (tedizolid: 86.8% vs linezolid: 88.9%). Tedizolid phosphate treatment was well tolerated by Latino patients in the safety population with lower abnormal platelet counts at end-of-therapy (tedizolid: 3.4% vs linezolid: 11.3%, p=0.0120) and lower incidence of gastrointestinal adverse events (tedizolid: 16.5% vs linezolid: 23.5%). Population pharmacokinetic analysis suggested that estimated tedizolid exposure measures in Latino patients vs non-Latino patients were similar. These findings demonstrate that tedizolid phosphate 200mg, once daily treatment for six days was efficacious and well tolerated by patients of Latino origin, without warranting dose adjustment

Gene Silencing of \u3ci\u3eArgonaute5\u3c/i\u3e Negatively Affects the Establishment of the Legume-Rhizobia Symbiosis

The establishment of the symbiosis between legumes and nitrogen-fixing rhizobia is finely regulated at the transcriptional, posttranscriptional and posttranslational levels. Argonaute5 (AGO5), a protein involved in RNA silencing, can bind both viral RNAs and microRNAs to control plant-microbe interactions and plant physiology. For instance, AGO5 regulates the systemic resistance of Arabidopsis against Potato Virus X as well as the pigmentation of soybean (Glycine max) seeds. Here, we show that AGO5 is also playing a central role in legume nodulation based on its preferential expression in common bean (Phaseolus vulgaris) and soybean roots and nodules. We also report that the expression of AGO5 is induced after 1 h of inoculation with rhizobia. Down-regulation of AGO5 gene in P. vulgaris and G. max causes diminished root hair curling, reduces nodule formation and interferes with the induction of three critical symbiotic genes: Nuclear Factor Y-B (NF-YB), Nodule Inception (NIN) and Flotillin2 (FLOT2). Our findings provide evidence that the common bean and soybean AGO5 genes play an essential role in the establishment of the symbiosis with rhizobia

Effect of tofacitinib on patient-reported outcomes in patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors in the phase III, randomised controlled trial: OPAL Beyond.

Objectives: Tofacitinib is an oral Janus kinase inhibitor for treatment of psoriatic arthritis (PsA). Patient-reported outcomes (PROs) were evaluated in patients with PsA with inadequate responses to tumour necrosis factor inhibitors (TNFi-IR) in a 6-month, phase III randomised controlled trial (OPAL Beyond [NCT01882439]). Methods: Patients (N=394) received tofacitinib 5 or 10 mg twice daily or placebo (advancing to tofacitinib 5 or 10 mg twice daily at month 3). Least squares mean changes from baseline and percentages of patients reporting improvements ≥minimum clinically important differences and scores ≥normative values were determined in Patient Global Assessment of disease activity (PtGA), Pain, Patient Global Joint and Skin Assessment (PGJS), Short Form-36 Health Survey version 2 (SF-36v2), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), EuroQol 5-Dimensions-3-level (EQ-5D-3L), EQ-VAS and Ankylosing Spondylitis Quality of Life (ASQoL). Nominal p values are without multiple comparison adjustments. Results: At month 3, PtGA, Pain, PGJS, SF-36v2 Physical Component Summary (PCS), physical functioning (PF), bodily pain (BP), vitality and social functioning (SF) domains, FACIT-Fatigue Total score, EQ-5D-3L pain/discomfort, EQ-VAS and ASQoL scores exceeded placebo with both tofacitinib doses (role physical [RP] with 10 mg twice daily only; p≤0.05). Patients reporting improvements ≥MCID (%) in PtGA, PGJS, Pain, ASQoL and SF-36v2 PCS, PF, RP, BP, SF (both tofacitinib doses) exceeded placebo (p≤0.05). Conclusion: TNFi-IR patients with PsA receiving tofacitinib reported statistically and clinically meaningful improvements in PROs versus placebo over 3 months, which were maintained to month 6. Despite lower baseline scores, these improvements were similar to the csDMARD-IR TNFi-naive OPAL Broaden trial