Background Stroke thrombolysis with alteplase is currently recommended 0-4•5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4•5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis.Methods In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged ≥18 years) with ischaemic stroke treated more than 4•5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0-1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036. FindingsWe identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1•86, 95% CI 1•15-2•99, p=0•011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [<1%] of 201 patients in the placebo group; adjusted OR 9•7, 95% CI 1•23-76•55, p=0•031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1•55, 0•81-2•96, p=0•66).Interpretation Patients with ischaemic stroke 4•5-9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis.
Mutations of parkin, a protein-ubiquitin isopeptide ligase (E3), appear to be the most frequent cause of familial Parkinson's disease (PD). Our previous studies have demonstrated that parkin binds strongly to ␣/ tubulin heterodimers and microtubules. Here we show that the strong binding between parkin and tubulin, as well as that between parkin and microtubules, was mediated by three independent domains: linker, RING1, and RING2. These redundant strong interactions made it virtually impossible to separate parkin from microtubules by high concentrations of salt (3.8 M) or urea (0.5 M). Parkin co-purified with tubulin and was found in highly purified tubulin preparation. Expression of either full-length parkin or any of its three microtubulebinding domains significantly attenuated colchicine-induced microtubule depolymerization. The abilities of parkin to bind to and stabilize microtubules were not affected by PD-linked mutations that abrogate its E3 ligase activity. Thus, the tubulin/microtubule-binding activity of parkin and its E3 ligase activity are independent. The strong binding between parkin and tubulin/microtubules through three redundant interaction domains may not only stabilize microtubules but also guarantee the anchorage of this E3 ligase on microtubules. Because many misfolded proteins are transported on microtubules, the localization of parkin on microtubules may provide an important environment for its E3 ligase activity toward misfolded substrates.
The transfer reactions of 11 B(d,p) 12 B and 12 C(d,p) 13 C, at incident energy of 11.8 MeV, have been used to extract asymptotic normalization coefficients and root-mean-square radii for the last neutron in 12 B and 13 C. It is found experimentally that the second (J ϭ2 Ϫ ) and third (J ϭ1 Ϫ ) excited states in 12 B and the first (J ϭ1/2 ϩ ) excited state in 13 C are the neutron halo states, whereas the third (J ϭ5/2 ϩ ) excited state in 13 C is a neutron skin state.
Mitogen-activated protein kinases, originally known as microtubule-associated protein (MAP) kinases, are activated in response to a variety of stimuli. Here we report that microtubule-depolymerizing agents such as colchicine or nocodazole induced strong activation of MAP kinases including JNK, ERK, and p38. This effect was markedly attenuated by parkin, whose mutations are linked to Parkinson disease (PD). Our previous study has shown that parkin stabilizes microtubules through strong interactions mediated by three independent domains. We found that each of the three microtubule-binding domains of parkin was sufficient to reduce MAP kinase activation induced by microtubule depolymerization. The ability to attenuate microtubule depolymerization and the ensuing MAP kinase activation was abrogated in B-lymphocytes and fibroblasts derived from PD patients with parkin mutations such as exon 4 deletion. Such mutations produced truncated parkin proteins lacking any microtubule binding domain and prevented parkin from protecting midbrain dopaminergic neurons against microtubule-depolymerizing toxins such as rotenone or colchicine. Consistent with these, blocking MAP kinase activation in midbrain dopaminergic neurons by knocking down MAP kinase kinases (MKK) significantly reduced the selective toxicity of rotenone or colchicine. Conversely, overexpression of MAP kinases caused marked toxicities that were significantly attenuated by parkin. Thus, the results suggest that parkin protects midbrain dopaminergic neurons against microtubule-depolymerizing PD toxins such as rotenone by stabilizing microtubules to attenuate MAP kinase activation.Mitogen-activated protein kinases are a superfamily of kinases that include the extracellular signal-related kinases (ERK1/2), 2 Jun N-terminal kinases (JNK1/2/3), and p38 proteins (p38␣//␥/␦) in mammalian species (1). Initially, MAP kinase stood for microtubule-associated protein kinase because microtubule-associated proteins such as MAP2 are excellent substrates of MAP kinases (2, 3). Previous studies have shown that a significant portion of ERK is associated with microtubules (4). It has also been shown that JNK1 is required for the maintenance of microtubule integrity in neurons through controlling the phosphorylation states of MAP2 and MAP1B (5). Phosphorylation of tau, an axon-enriched MAP, by p38␦ promotes microtubule assembly (6). All MAP kinases are prolinedirected kinases, preferring serine or threonine residues followed by proline. The abundance of such sites on many microtubule-associated proteins suggests that MAP kinases play critical roles in regulating the phosphorylation states of MAPs; hence, the dynamic properties of microtubules. The selective loss of dopaminergic (DA) neurons in substantia nigra is the pathological hallmark of Parkinson disease and directly contributes to its locomotor symptoms. Nigral DA neurons project to striatal target areas with very long axons, which rely on microtubules to transport dopamine vesicles over long distances. Our previous studies ...
Summary Wireless body area network (WBAN) is a special wireless mobile sensor network, which is mainly applied to the medical field. It can monitor the physical condition of patients and send this vital and sensitive information to a server that provides medical and health services. Because of the openness and mobility of WBAN, it is easier for the adversary to obtain, corrupt, or replace the data transmitted in the channel, or launch various attacks. Therefore, data security and privacy issues are the most challenging problems in WBANs. Moreover, most wearable sensors in WBAN are resource‐constrained devices, traditional security schemes may not be suitable for WBAN. Therefore, in this paper, we propose a lightweight anonymous mutual authentication and key agreement scheme for WBAN. This scheme uses only hash function operations and XOR operations. We use the automatic security verification tool ProVerif to verify the security properties of our scheme and informal security analysis is discussed. We also compared the proposed scheme with many related works and the results indicate that our scheme has either more advantages in terms of computation cost, energy consumption, and communication cost or lower security risk.
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