1,286 research outputs found
Epilepsy in older people
Globally, as populations age there will be challenges and opportunities to deliver optimal health care to senior citizens. Epilepsy, a condition characterised by spontaneous recurrent seizures, is common in older adults (aged >65 years) and yet has received comparatively little attention in this age group. In this Review, we evaluate the underlying causes of epilepsy in older people, explore difficulties in establishing a diagnosis of epilepsy in this population, discuss appropriate antiseizure medications, and evaluate potential surgical treatment options. We consider cognitive, psychological, and psychosocial comorbidities and the effect that epilepsy might have on an older person's broader social or care network in high-income versus middle-income and low-income countries. We emphasise the need for clinical trials to be more inclusive of older people with epilepsy to help inform therapeutic decision making and discuss whether measures to improve vascular risk factors might be an important strategy to reduce the probability of developing epilepsy
Electron dose calculations using the Method of Moments
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134898/1/mp7920.pd
Structural and functional analysis of mRNA export regulation by the nuclear pore complex
The nuclear pore complex (NPC) controls the passage of macromolecules between the nucleus and cytoplasm, but how the NPC directly participates in macromolecular transport remains poorly understood. In the final step of mRNA export, the DEAD-box helicase DDX19 is activated by the nucleoporins Gle1, Nup214, and Nup42 to remove Nxf1•Nxt1 from mRNAs. Here, we report crystal structures of Gle1•Nup42 from three organisms that reveal an evolutionarily conserved binding mode. Biochemical reconstitution of the DDX19 ATPase cycle establishes that human DDX19 activation does not require IP_6, unlike its fungal homologs, and that Gle1 stability affects DDX19 activation. Mutations linked to motor neuron diseases cause decreased Gle1 thermostability, implicating nucleoporin misfolding as a disease determinant. Crystal structures of human Gle1•Nup42•DDX19 reveal the structural rearrangements in DDX19 from an auto-inhibited to an RNA-binding competent state. Together, our results provide the foundation for further mechanistic analyses of mRNA export in humans
Suspended liminality: Vacillating affects in cyberbullying/research
This paper develops a concept of liminal hotspots in the context of i) a secondary analysis of a cyberbullying case involving a group of school children from a Danish school, and ii) an altered auto-ethnography in which the authors ‘entangle’ their own experiences with the case analysis. These two sources are used to build an account of a liminal hotspot conceived as an occasion of troubled and suspended transformative transition in which a liminal phase is extended and remains unresolved. The altered auto-ethnography is used to explore the affectivity at play in liminal hotspots, and this liminal affectivity is characterised in terms of volatility, vacillation, suggestibility and paradox
Cryo-EM Structures of HIV-1 trimer bound to CD4-mimetics M48U1 and BNM-III-170 adopt a CD4-bound open conformation
Human Immunodeficiency Virus-1 (HIV-1), the causative agent of AIDS, impacts millions of people. Entry into target cells is mediated by the HIV-1 envelope (Env) glycoprotein interacting with host receptor CD4, which triggers conformational changes allowing binding to a coreceptor and subsequent membrane fusion. Small molecule or peptide CD4-mimetic drugs mimic CD4’s Phe43 interaction with Env by inserting into the conserved Phe43 pocket on Env subunit gp120. Here, we present single-particle cryo-EM structures of CD4-mimetics BNM-III-170 and M48U1 bound to a BG505 native-like Env trimer plus the CD4-induced antibody 17b at 3.7Å and 3.9Å resolution, respectively. CD4-mimetic-bound BG505 exhibits canonical CD4-induced conformational changes including trimer opening, formation of the 4-stranded gp120 bridging sheet, displacement of the V1V2 loop, and formation of a compact and elongated gp41 HR1C helical bundle. We conclude that CD4-induced structural changes on both gp120 and gp41 Env subunits are induced by binding to the gp120 Phe43 pocket
Registration between DCT and EBSD datasets for multiphase microstructures
The ability to characterise the three-dimensional microstructure of
multiphase materials is essential for understanding the interaction between
phases and associated materials properties. Here, laboratory-based
diffraction-contrast tomography (DCT), a recently-established materials
characterization technique that can determine grain phases, morphologies,
positions and orientations in a voxel-based reconstruction method, was used to
map part of a dual-phase steel alloy sample. To assess the resulting
microstructures that were produced by the DCT technique, an EBSD map was
collected within the same sample volume. To identify the 2D slice of the 3D DCT
reconstruction that best corresponded to the EBSD map, a novel registration
technique based solely on grain-averaged orientations was developed -- this
registration technique requires very little a priori knowledge of dataset
alignment and can be extended to other techniques that only recover
grain-averaged orientation data such as far-field 3D X-ray diffraction
microscopy. Once the corresponding 2D slice was identified in the DCT dataset,
comparisons of phase balance, grain size, shape and texture were performed
between DCT and EBSD techniques. More complicated aspects of the
microstructural morphology such as grain boundary shape and grains less than a
critical size were poorly reproduced by the DCT reconstruction, primarily due
to the difference in resolutions of the technique compared with EBSD. However,
lab-based DCT is shown to accurately determine the centre-of-mass position,
orientation, and size of the large grains for each phase present, austenite and
martensitic ferrite. The results reveals a complex ferrite grain network of
similar crystal orientations that are absent from the EBSD dataset. Such detail
demonstrates that lab-based DCT, as a technique, shows great promise in the
field of multi-phase material characterization.Comment: 15 pages, 11 figures. Preprint submitted to Materials
Characterizatio
First-principles calculations of the self-trapped exciton in crystalline NaCl
The atomic and electronic structure of the lowest triplet state of the
off-center (C2v symmetry) self-trapped exciton (STE) in crystalline NaCl is
calculated using the local-spin-density (LSDA) approximation. In addition, the
Franck-Condon broadening of the luminescence peak and the a1g -> b3u absorption
peak are calculated and compared to experiment. LSDA accurately predicts
transition energies if the initial and final states are both localized or
delocalized, but 1 eV discrepancies with experiment occur if one state is
localized and the other is delocalized.Comment: 4 pages with 4 embeddded figure
Inhibition of the epidermal growth factor receptor by erlotinib prevents immortalization of human cervical cells by Human Papillomavirus type 16
AbstractThe Human Papillomavirus type-16 (HPV-16) E6 and E7 oncogenes are selectively retained and expressed in cervical carcinomas, and expression of E6 and E7 is sufficient to immortalize human cervical epithelial cells. Expression of the epidermal growth factor receptor (EGFR) is often increased in cervical dysplasia and carcinoma, and HPV oncoproteins stimulate cell growth via the EGFR pathway. We found that erlotinib, a specific inhibitor of EGFR tyrosine kinase activity, prevented immortalization of cultured human cervical epithelial cells by the complete HPV-16 genome or the E6/E7 oncogenes. Erlotinib stimulated apoptosis in cells that expressed HPV-16 E6/E7 proteins and induced senescence in a subpopulation of cells that did not undergo apoptosis. Since immortalization by HPV E6/E7 is an important early event in cervical carcinogenesis, the EGFR is a potential target for chemoprevention or therapy in women who have a high risk for cervical cancer
Neuropsychiatric adverse drug reactions associated with low dose methotrexate in rheumatoid arthritis patients
BACKGROUND: Neuropsychiatric adverse drug reactions (NPADRs) are not commonly associated with low dose methotrexate (LDMTX) in patients with rheumatoid arthritis (RA). RESEARCH DESIGN AND METHODS: In this case series assessment, we described the nature and frequency of NPADRs with LDMTX in the Dutch DREAM-RA registry, including causality of NPADRs, the impact on further LDMTX treatment and the impact on patient reported Health Related Quality of Life (HRQoL). RESULTS: A total of 71 NPADRs (frequency 6.8%) associated with LDMTX were captured in the DREAM-RA registry. NPADRs were registered for 62 (5.9%) out of 1048 patients with 10.9 NPADRs per 1000 patient years. Headache, dizziness and depression were most frequently reported. The causality was considered probable for 67 NPADRs (94.4%) and definite for 1 NPADR (1.4%). NPADRs led to LDMTX withdrawal in 34 cases (47.9%) and was not restarted in 16 cases (47.1%). Median mental HRQoL was significantly decreased around the occurrence of the NPADR and remained significantly lower after the event. Median physical HRQoL was not significantly affected. CONCLUSIONS: Knowledge on the nature, frequency and impact of the demonstrated NPADRs during LDMTX therapy will enhance attention toward these potential ADRs allowing better risk assessment and communication to patients
- …