We explore the new physics reach for the off-shell Higgs boson measurement in the pp→H⁎→Z(ℓ+ℓ−)Z(νν¯) channel at the high-luminosity LHC. The new physics sensitivity is parametrized in terms of the ...Higgs boson width, effective field theory framework, and a non-local Higgs-top coupling form factor. Adopting Machine-learning techniques, we demonstrate that the combination of a large signal rate and a precise phenomenological probe for the process energy scale, due to the transverse ZZ mass, leads to significant sensitivities beyond the existing results in the literature for the new physics scenarios considered.
Despite successful clinical applications, teleoperated robotic surgical systems face particular limitations in the functional endoscopic sinus surgery (FESS) in terms of incompatible instrument ...dimensions and robot set-up. The endoscope remains manually handled by an assistant when the surgeon performs bimanual operations. This paper introduces the development of the Foot-controlled Robot-Enabled EnDOscope Manipulator (FREEDOM) designed for FESS. The system features clinical considerations that inform the design for providing reliable and safe endoscope positioning with minimal obstruction to the routine practice. The robot structure is modular and compact to ensure coaxial instrument manipulation through the nostril for manual procedures. To avoid rigid endoscope motions, a new compliant endoscope holder is proposed that passively limits the lens-tissue contact forces under collisions for patient-side protection. To facilitate hands-free endoscope manipulation that imposes minimal distractions to the surgeon, a foot-wearable interface is further designed to relieve the assistant's workload. The foot control method owns a short learning curve (mean 3.4 mins), and leads the task to be more ergonomic and surgeon-centered. Cadaver and clinical studies were both conducted to evaluate the surgical applicability of the FREEDOM to assist endoscope manipulation in FESS. The system was validated to be safe (IEC-60601-1) and easy for set up (mean 3.6 mins), from which the surgeon could perform various three-handed procedures alone in FESS without disrupting the routine practice.
An implant (porous polyethylene) is an alternative to rib cartilage for microtia reconstruction but carries a risk of extrusion.
To evaluate the outcome of a hybrid framework of implant with rib ...cartilage for microtia reconstruction.
Patients who underwent Nagata's technique for microtia reconstruction were reviewed for complications and aesthetic score. In stage 1, a rib cartilage framework or a hybrid framework of implant with rib cartilage was used. In stage 2, the framework was elevated and supported by an implant for projection. Postoperative outcomes were reported for both groups.
Forty-four ears of 40 patients underwent surgery. Eleven ears received a rib auricular framework and 33 ears a hybrid auricular framework. The mean postoperative follow-up for the rib and hybrid groups was 76.3 and 43.1 months, respectively. No supporting postauricular implant extruded, whereas stainless-steel wires extruded in seven ears (15.9%). Five (15.2%) hybrid frameworks were removed due to infection or extrusion. Mean operating time was 2 h shorter in the hybrid group. Aesthetic outcomes were similar for both groups.
A hybrid framework of rib and implant that requires less harvested cartilage is feasible for microtia reconstruction, but caution should be used due to its higher explantation rate.
MEK1 and MEK2 are closely related, dual-specificity tyrosine/threonine protein kinases found in the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. Approximately 30% of all ...human cancers have a constitutively activated MAPK pathway, and constitutive activation of MEK1 results in cellular transformation. Here we present the X-ray structures of human MEK1 and MEK2, each determined as a ternary complex with MgATP and an inhibitor to a resolution of 2.4 A and 3.2 A, respectively. The structures reveal that MEK1 and MEK2 each have a unique inhibitor-binding pocket adjacent to the MgATP-binding site. The presence of the potent inhibitor induces several conformational changes in the unphosphorylated MEK1 and MEK2 enzymes that lock them into a closed but catalytically inactive species. Thus, the structures reported here reveal a novel, noncompetitive mechanism for protein kinase inhibition.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Janus kinases (JAKs) are critical regulators of cytokine pathways and attractive targets of therapeutic value in both inflammatory and myeloproliferative diseases. Although the crystal structures of ...active JAK1 and JAK2 kinase domains have been reported recently with the clinical compound CP-690550, the structures of both TYK2 and JAK3 with CP-690550 have remained outstanding. Here, we report the crystal structures of TYK2, a first in class structure, and JAK3 in complex with PAN-JAK inhibitors CP-690550 ((3R,4R)-3-4-methyl-3-
N-methyl-
N-(7H-pyrrolo2,3-dpyrimidin-4-yl)aminopiperidin-1-yl-3-oxopropionitrile) and CMP-6 (tetracyclic pyridone 2-t-butyl-9-fluoro-3,6-dihydro-7H-benzh-imidaz4,5-fisoquinoline-7-one), both of which bind in the ATP-binding cavities of both JAK isozymes in orientations similar to that observed in crystal structures of JAK1 and JAK2. Additionally, a complete thermodynamic characterization of JAK/CP-690550 complex formation was completed by isothermal titration calorimetry, indicating the critical role of the nitrile group from the CP-690550 compound. Finally, computational analysis using WaterMap further highlights the critical positioning of the CP-690550 nitrile group in the displacement of an unfavorable water molecule beneath the glycine-rich loop. Taken together, the data emphasize the outstanding properties of the kinome-selective JAK inhibitor CP-690550, as well as the challenges in obtaining JAK isozyme-selective inhibitors due to the overall structural and sequence similarities between the TYK2, JAK1, JAK2 and JAK3 isozymes. Nevertheless, subtle amino acid variations of residues lining the ligand-binding cavity of the JAK enzymes, as well as the global positioning of the glycine-rich loop, might provide the initial clues to obtaining JAK-isozyme selective inhibitors.
Past research on pathways to cultural influence on judgment has compared the explanatory power of personal preferences, perceived descriptive norms and institutionalization. Positive education is an ...education movement inspired by Western positive psychology. The present study examined how these factors jointly predict Hong Kong teachers’ evaluation of imported positive education programs in their schools. In a field study, we measured teachers’ personal endorsement of growth mindset (a positive psychology construct developed in the US) and their evaluation of adopting positive education programs in their schools. We also measured teachers’ perception of the extent of institutional and normative support for positive education in their schools. The results show that teachers’ personal preferences for growth mindset predict more favorable evaluation of positive education programs when institutional and normative support for positive education programs are
both
weak,
or
when they are
both
strong. We interpret these effects from the perspectives of the strong situation hypothesis and the intersubjective theory of culture.
We explore the sensitivity to new physics for the coupling of the Higgs boson (h) and top quark (t) at high energy scales with the process pp→tt¯h at the high-luminosity LHC. This process probes the ...coupling in both the space-like and time-like domains at a high scale, complementary to the off-shell Higgs processes in the time-like domain. The effects from physics beyond the Standard Model are parametrized in terms of the effective field theory framework and a non-local Higgs-top form factor. Focusing on the boosted Higgs regime in association with jet substructure techniques, we show that the present search can directly probe the Higgs-top coupling to good precision, providing a strong sensitivity to the new physics scale.
Increasing the level of correspondence between measures of growth mindset and their related outcomes could afford more precise prediction of the relationships between growth mindset and ...social-emotional outcomes. To illustrate the value of measurement correspondence, two studies were conducted in Hong Kong. Study 1 showed that an agent-correspondent growth mindset measure (parents’ perception of the malleability of their children's personal qualities), compared to an agent-non-correspondent one (parents’ belief in the malleability of personal qualities of a generalized other), had stronger predictive relationship with children's likelihood of displaying difficult behaviors. Study 2 found that children's self-theories about the malleability of their intelligence (an intrapersonal construct) had stronger predictive relationship with academic engagement (an intrapersonal outcome) than did their perception of growth mindset norm (a normative construct). However, perceived growth mindset norm regarding personal qualities had stronger predictive relationship with peer relationship quality (an interpersonal outcome). Together these results demonstrated that when corresponding measures of growth mindset were used to predict an outcome, more reliable growth mindset effects would emerge.
Introduction. Screening and brief intervention (SBI) for alcohol consumption in primary care have been shown to be effective in reducing drinking. This role has not been taken up by community ...pharmacists. This study aimed to explore attitudes, knowledge, barriers and incentives towards involvement of community pharmacists in New Zealand with problem drinkers. Method. A postal survey (three mailshots) of community pharmacies was undertaken in Auckland, New Zealand, followed by a 10% random sample non-responder-follow-up. Results. A response rate of 39.1% to the postal survey was obtained. In general, knowledge of alcohol content of drinks and recommended safe drinking limits was poor. Respondents were generally well motivated towards undertaking this role, but lacked knowledge, skills and confidence. On follow-up, non-responders were found to be less knowledgeable, but had similar attitudes to respondents, indicating potential for extrapolation with regard to beliefs and views on this subject. Discussion. This novel study has found that there is potential for involvement of community pharmacists in New Zealand in SBI for problem drinkers. Lack of knowledge can be remedied relatively easily; greater hurdles such as lack of skills, and lack of confidence may be offset by the high level of motivation of this group. This is an area where community pharmacists can further their professional scope of practice by being in an essential position to provide this service. Sheridan J, Wheeler A, Ju-Hsing Chen L, Chen-Yun Huang A, Nga-Yee Leung I, Yow-Chyi Tien K. Screening and brief interventions for alcohol: attitudes, knowledge and experience of community pharmacists in Auckland, New Zealand. Drug Alcohol Rev 2008;27:380-387
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