The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay -these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions.Experiments carried out over the past half century have revealed that neutrinos are found in three states, or flavors, and can transform from one flavor into another. These results indicate that each neutrino flavor state is a mixture of three different nonzero mass states, and to date offer the most compelling evidence for physics beyond the Standard Model. In a single experiment, LBNE will enable a broad exploration of the three-flavor model of neutrino physics with unprecedented detail. Chief among its potential discoveries is that of matter-antimatter asymmetries (through the mechanism of charge-parity violation) in neutrino flavor mixing -a step toward unraveling the mystery of matter generation in the early Universe. Independently, determination of the unknown neutrino mass ordering and precise measurement of neutrino mixing parameters by LBNE may reveal new fundamental symmetries of Nature.Grand Unified Theories, which attempt to describe the unification of the known forces, predict rates for proton decay that cover a range directly accessible with the next generation of large underground detectors such as LBNE's. The experiment's sensitivity to key proton decay channels will offer unique opportunities for the ground-breaking discovery of this phenomenon.Neutrinos emitted in the first few seconds of a core-collapse supernova carry with them the potential for great insight into the evolution of the Universe. LBNE's capability to collect and analyze this high-statistics neutrino signal from a supernova within our galaxy would provide a rare opportunity to peer inside a newly-formed neutron star and potentially witness the birth of a black hole.To achieve its goals, LBNE is conceived around three central components: (1) a new, highintensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a fine-grained near neutrino detector installed just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is ∼1,300 km from the neutrino source at Fermilab -a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions.With its exceptional combi...

Campbell, B. C.V. et al. (2019) Penumbral imaging and functional outcome in patients with anterior circulation ischaemic stroke treated with endovascular thrombectomy versus medical therapy: a meta-analysis of individual patient-level data.ABSTRACT Background: CT-perfusion (CTP) and MRI may assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of ischaemic core and penumbra volumes were associated with functional outcomes and treatment effect.

Cyclin-dependent kinases (CDKs) are commonly known to regulate cell proliferation. However, previous reports suggest that in cultured postmitotic neurons, activation of CDKs is a signal for death rather than cell division. We determined whether CDK activation occurs in mature adult neurons during focal stroke in vivo and whether this signal was required for neuronal death after reperfusion injury. Cdk4͞cyclin D1 levels and phosphorylation of its substrate retinoblastoma protein (pRb) increase after stroke. Deregulated levels of E2F1, a transcription factor regulated by pRb, are also observed. Administration of a CDK inhibitor blocks pRb phosphorylation and the increase in E2F1 levels and dramatically reduces neuronal death by 80%. These results indicate that CDKs are an important therapeutic target for the treatment of reperfusion injury after ischemia.T he mechanism by which stroke-induced neuronal death occurs is complex and is likely dependent upon the severity and duration of ischemic insult and an elaborate interplay between ischemic death initiators such as excitotoxicity, oxidative stress, DNA damage, and inflammatory responses (1-3). Neurons that survive the acute ischemic injury undergo a delayed cell death that exhibits some characteristics of apoptosis (1-3). This delayed cell death is dependent upon selected death-signaling elements such as caspases, poly(ADP-ribose) polymerase, and p53 (4). The identification of signaling molecules that control delayed neuronal death has led to the hope that some of these death-signaling elements may serve as useful therapeutic targets for the reduction of neuropathology and behavioral deficits associated with stroke injury. The mechanism by which stroke-evoked delayed death occurs, however, is not fully understood.The cell cycle is a highly coordinated process regulated by the appropriate and timely activation of cyclin-dependent kinases (CDKs) (5). Regulation of CDKs is complex and includes binding to their obligate cyclin partner, activating and inhibitory phosphorylation events, and endogenous inhibitors of CDK activity. Distinct CDKs regulate progressive phases of the cell cycle. Generally, it is thought that the Cdk4͞6͞cyclin D1 complex regulates the G 0 to G 1 , Cdk2͞cyclin E and Cdk3 control G 1 to S, and Cdk2͞cyclin A and Cdk1͞cyclin B control G 2 and M progressions. Although the downstream targets of CDKs are not fully characterized, one important substrate is the tumor suppresser retinoblastoma protein (pRb), which is phosphorylated by activated Cdk4͞6͞cyclin D complex (6). Once hyperphosphorylated, pRb is released from the transcription factor complex E2F͞DP, which then activates genes required for S phase transition (7-9).Paradoxically, increasing evidence suggests that CDKs may have functions beyond that of cell cycle regulation. Numerous reports indicate the requirement of CDK signals for death of cultured postmitotic neurons exposed to select death insults. For example, inappropriate cyclin B and cyclin D1 transcripts have been observed in neuronal P...

Background and Purpose-We investigated whether computed tomography (CT) perfusion-derived cerebral blood flow (CBF) and cerebral blood volume (CBV) could be used to differentiate between penumbra and infarcted gray matter in a limited, exploratory sample of acute stroke patients. Methods-Thirty patients underwent a noncontrast CT (NCCT), CT angiography (CTA), and CT perfusion (CTP) scan within 7 hours of stroke onset, NCCT and CTA at 24 hours, and NCCT at 5 to 7 days. Twenty-five patients met the criteria for inclusion and were subsequently divided into 2 groups: those with recanalization at 24 hours (nϭ16) and those without (nϭ9). Penumbra was operationally defined as tissue with an admission CBF Ͻ25 mL ⅐ 100 g Ϫ1 ⅐ min