In this work, lamellar composite sheets combining one of two fully hexagonal magnesium-lithium alloys (Mg–4Li and Mg–5Li wt%) and pure niobium (Nb) are manufactured via accumulative roll bonding ...(ARB). With extreme straining of over two true strain, the individual layers were refined to 200 μm. The strength differential between co-deforming phases with strain is characterized to be low enough to facilitate bonding without instabilities. Additionally, homogeneity in deformation was enhanced by intermediate annealing, especially for the Mg-xLi phase. Diffraction methods and polycrystal modeling are employed to study the microstructure and texture evolution of the individual phases after each subsequent ARB pass. Characterization by electron backscatter diffraction and neutron diffraction reveals substantial changes in microstructure and texture in both phases and very little deformation twinning in the Mg-xLi phase. Evolution of grain morphology and the number of grains that span a layer with ARB and annealing are determined and discussed. To link texture evolution to slip-based deformation mechanisms during the processing, a multiscale polycrystalline model of the two-phase Mg–4Li/Nb composite was developed, which included a relative directional compliance (RDC) method to account for anisotropic interactions in the phases, allowing appropriate slip sensitivity to dislocation density based hardening on the multiple slip modes in Mg–4Li and in Nb. The model indicates that the deformation of the Mg–4Li phase during ARB cycles was accommodated by more basal and progressively smaller amounts of prismatic , pyramidal <c+a>, and twinning than previously reported for rolling of Mg–4Li. The experimental textures cannot be entirely explained by grain shape and an increase in pyramidal and prismatic slip resistance are required as expected with a small grain size. Consistent with measurements, the model predicts that c-axis of the Mg–4Li phase tilts from the sheet's normal direction towards the rolling direction, and that the strong γ-fiber and the unusually weak α-fiber should develop in Nb with large ARB straining of the Mg-xLi/Nb composites.
Aconite poisoning refers to toxicity resulting from plants belonging to the Aconitum genus, which comprises over 350 different species of perennial flowering plants that grow in temperate mountainous ...areas of the northern hemisphere (North America, Europe, Asia). These plants contain a group of toxins known as aconite alkaloids, which encompass numerous closely related toxic compounds. Conventional teaching from toxicology textbooks has broadly classified these alkaloids based on their mechanism of action, often simplifying them as substances that prevent sodium channel inactivation. However, this is an oversimplified and sometimes inaccurate description, as some aconite alkaloids can act as sodium channel blockers. Aconite alkaloids have a long history of use as poisonous substances and have been historically employed for hunting, assassinations, traditional medicine, and self-inflicted harm. Toxicity can occur due to the consumption of traditional medicines derived from aconitum plants or the ingestion of aconite plants and their derivatives. The clinical manifestations of aconite poisoning may encompass gastrointestinal symptoms, sensory alterations, seizures, and life-threatening dysrhythmias that may not respond to standard treatments. Treatment is primarily supportive however evaluation and management of these patients should be personalized and carried out in collaboration with a toxicologist.
Acute carbon monoxide (CO) poisoning due to smoking hookah has been reported and may present similarly to other causes of acute carbon monoxide poisoning with nausea, headache, and loss of ...consciousness 1. In the acute poisoned patient, immediate removal from the carbon monoxide source is paramount in addition to administration of oxygen and possible hyperbaric oxygen therapy (HBO) in certain situations. However, cases of chronic CO poisoning, treatment options, and long-term adverse health effects are far less reported but may include atherosclerosis and vague neurologic symptoms 2. We present a case of a patient who chronically smoked hookah creating a condition of chronic carboxyhemoglobinemia which was discovered during work up for unexplained polycythemia. While being seen in the hematology clinic, he was found to have a blood carboxyhemoglobin of level 33.6% despite being asymptomatic. This is the highest recorded hookah-related carboxyhemoglobin concentration in the medical literature; and the significant chronic carboxyhemoglobinemia explained his polycythemia. This case illustrates that a social history is crucial when assessing the patient with severe carboxyhemoglobinemia as HBO is not indicated in chronic CO poisoning in an asymptomatic patient.
All animal cells use the motor cytoplasmic dynein 1 (dynein) to transport diverse cargo toward microtubule minus ends and to organize and position microtubule arrays such as the mitotic spindle. ...Cargo-specific adaptors engage with dynein to recruit and activate the motor, but the molecular mechanisms remain incompletely understood. Here, we use structural and dynamic nuclear magnetic resonance (NMR) analysis to demonstrate that the C-terminal region of human dynein light intermediate chain 1 (LIC1) is intrinsically disordered and contains two short conserved segments with helical propensity. NMR titration experiments reveal that the first helical segment (helix 1) constitutes the main interaction site for the adaptors Spindly (SPDL1), bicaudal D homolog 2 (BICD2), and Hook homolog 3 (HOOK3). In vitro binding assays show that helix 1, but not helix 2, is essential in both LIC1 and LIC2 for binding to SPDL1, BICD2, HOOK3, RAB-interacting lysosomal protein (RILP), RAB11 family-interacting protein 3 (RAB11FIP3), ninein (NIN), and trafficking kinesin-binding protein 1 (TRAK1). Helix 1 is sufficient to bind RILP, whereas other adaptors require additional segments preceding helix 1 for efficient binding. Point mutations in the C-terminal helix 1 of Caenorhabditis elegans LIC, introduced by genome editing, severely affect development, locomotion, and life span of the animal and disrupt the distribution and transport kinetics of membrane cargo in axons of mechanosensory neurons, identical to what is observed when the entire LIC C-terminal region is deleted. Deletion of the C-terminal helix 2 delays dynein-dependent spindle positioning in the one-cell embryo but overall does not significantly perturb dynein function. We conclude that helix 1 in the intrinsically disordered region of LIC provides a conserved link between dynein and structurally diverse cargo adaptor families that is critical for dynein function in vivo.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
UK Biobank is a well-characterised cohort of over 500 000 participants including genetics, environmental data and imaging. An online mental health questionnaire was designed for UK Biobank ...participants to expand its potential.
Describe the development, implementation and results of this questionnaire.
An expert working group designed the questionnaire, using established measures where possible, and consulting a patient group. Operational criteria were agreed for defining likely disorder and risk states, including lifetime depression, mania/hypomania, generalised anxiety disorder, unusual experiences and self-harm, and current post-traumatic stress and hazardous/harmful alcohol use.
A total of 157 366 completed online questionnaires were available by August 2017. Participants were aged 45-82 (53% were ≥65 years) and 57% women. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status. Lifetime depression was a common finding, with 24% (37 434) of participants meeting criteria and current hazardous/harmful alcohol use criteria were met by 21% (32 602), whereas other criteria were met by less than 8% of the participants. There was extensive comorbidity among the syndromes. Mental disorders were associated with a high neuroticism score, adverse life events and long-term illness; addiction and bipolar affective disorder in particular were associated with measures of deprivation.
The UK Biobank questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed because of selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health.
Bupropion is an antidepressant medication with expanding indications including smoking cessation, weight loss, attention-deficit/hyperactivity disorder, seasonal affective disorder, and amphetamine ...dependence. Despite its increasing popularity among providers, it has a well-known narrow therapeutic window that can lead to delayed onset of symptoms with extended-release formulations and devastating consequences in overdose. We have noticed some patients misusing bupropion via insufflation, which added a layer of complexity with regards to the therapeutic application of the drug. This route of use created difficult decisions regarding clinical monitoring in these patients.
To determine if prolonged observation is required after insufflation of bupropion and to further describe effects from this route of use.
This is a retrospective observational study reviewing all the cases of insufflated bupropion use reported to a single poison center without any other coingestants.
The majority (85.7%) of patients had mild or moderate effects, and seizures occurred in 19.6% of cases; and the vast majority of patients were symptomatic by the time of the initial call to the poison center. We did not encounter any delayed effects after this route of use.
This report describes the clinical effects reported, and the timing of these effects, after insufflation of bupropion.
Bupropion is an antidepressant medication with expanding indications including smoking cessation, weight loss, attention-deficit/hyperactivity disorder, seasonal affective disorder, and amphetamine ...dependence. Despite its increasing popularity among providers, it has a well-known narrow therapeutic window which can lead to delayed onset of symptoms with extended-release formulations and devastating consequences in overdose. We have noticed some patients misusing bupropion via intravenous use and had difficulty guiding decisions regarding clinical monitoring in these patients. As this route entirely changes the kinetics of bupropion, this has caused concern within our group. We reviewed all the cases of intravenous bupropion use reported to a single poison center without any other coingestants. The majority (66.7%) of patients had moderate effects and one patient had a seizure. No deaths were reported. All patients were symptomatic by the time of initial call to the poison center if they had any reported symptoms due to bupropion. This case series describes the clinical effects reported, and the timing of these effects, after intravenous bupropion use.
How IGF-1 activates its receptor Kavran, Jennifer M; McCabe, Jacqueline M; Byrne, Patrick O ...
eLife,
09/2014, Letnik:
3
Journal Article
Recenzirano
Odprti dostop
The type I insulin-like growth factor receptor (IGF1R) is involved in growth and survival of normal and neoplastic cells. A ligand-dependent conformational change is thought to regulate IGF1R ...activity, but the nature of this change is unclear. We point out an underappreciated dimer in the crystal structure of the related Insulin Receptor (IR) with Insulin bound that allows direct comparison with unliganded IR and suggests a mechanism by which ligand regulates IR/IGF1R activity. We test this mechanism in a series of biochemical and biophysical assays and find the IGF1R ectodomain maintains an autoinhibited state in which the TMs are held apart. Ligand binding releases this constraint, allowing TM association and unleashing an intrinsic propensity of the intracellular regions to autophosphorylate. Enzymatic studies of full-length and kinase-containing fragments show phosphorylated IGF1R is fully active independent of ligand and the extracellular-TM regions. The key step triggered by ligand binding is thus autophosphorylation.
A general aim of studies of signal transduction is to identify mediators of specific signals, order them into pathways, and understand the nature of interactions between individual components and how ...these interactions alter pathway behavior. Despite years of intensive study and its central importance to animal development and human health, our understanding of the Hedgehog (Hh) signaling pathway remains riddled with gaps, question marks, assumptions, and poorly understood connections. In particular, understanding how interactions between Hh and Patched (Ptc), a 12-pass integral membrane protein, lead to modulation of the function of Smoothened (Smo), a 7-pass integral membrane protein, has defied standard biochemical characterization. Recent structural and biochemical characterizations of Smoothened domains have begun to unlock this riddle, however, and lay the groundwork for improved cancer therapies.
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