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The brains of humans and other mammals are highly vulnerable to interruptions in blood flow and decreases in oxygen levels. Here we describe the restoration and maintenance of microcirculation and molecular and cellular functions of the intact pig brain under ex vivo normothermic conditions up to four hours post-mortem. We have developed an extracorporeal pulsatile-perfusion system and a haemoglobin-based, acellular, non-coagulative, echogenic, and cytoprotective perfusate that promotes recovery from anoxia, reduces reperfusion injury, prevents oedema, and metabolically supports the energy requirements of the brain. With this system, we observed preservation of cytoarchitecture; attenuation of cell death; and restoration of vascular dilatory and glial inflammatory responses, spontaneous synaptic activity, and active cerebral metabolism in the absence of global electrocorticographic activity. These findings demonstrate that under appropriate conditions the isolated, intact large mammalian brain possesses an underappreciated capacity for restoration of microcirculation and molecular and cellular activity after a prolonged post-mortem interval. A specialized technology can restore and preserve microcirculation and cellular functions hours post-mortem in an isolated pig brain.

Idiopathic trigeminal neuralgia (TN) is a debilitating pain disorder characterized by episodic unilateral facial pain along the territory of branches of the trigeminal nerve. Human pain disorders, but not TN, have been linked to gain-of-function mutations in peripheral voltage-gated sodium channels (Na V 1.7, Na V 1.8 and Na V 1.9). Gain-of-function mutations in Na V 1.6, which is expressed in myelinated and unmyelinated central nervous system (CNS) and peripheral nervous system neurons and supports neuronal high-frequency firing, have been linked to epilepsy but not to pain. Here, we describe an individual who presented with evoked and spontaneous paroxysmal unilateral facial pain and carried a diagnosis of TN. Magnetic resonance imaging showed unilateral neurovascular compression, consistent with pain in areas innervated by the second branch of the trigeminal nerve. Genetic analysis as part of a phase 2 clinical study in patients with TN conducted by Convergence Pharmaceuticals Ltd revealed a previously undescribed de novo missense mutation in Na V 1.6 (c.A406G; p.Met136Val). Whole-cell voltage-clamp recordings show that the Met136Val mutation significantly increases peak current density (1.5-fold) and resurgent current (1.6-fold) without altering gating properties. Current-clamp studies in trigeminal ganglia (TRG) neurons showed that Met136Val increased the fraction of high-firing neurons, lowered the current threshold and increased the frequency of evoked action potentials in response to graded stimuli. Our results demonstrate a novel Na V 1.6 mutation in TN, and show that this mutation potentiates transient and resurgent sodium currents and leads to increased excitability in TRG neurons. We suggest that this gain-of-function Na V 1.6 mutation may exacerbate the pathophysiology of vascular compression and contribute to TN.

Inhibitors of voltage-gated sodium channels (Nav) have been used as anticonvulsants since the 1940s, while potassium channel activators have only been investigated more recently. We here describe the discovery of 2-amino-6-trifluoromethylthio-benzothiazole (SKA-19), a thioanalog of riluzole, as a potent, novel anticonvulsant, which combines the two mechanisms. SKA-19 is a use-dependent NaV channel blocker and an activator of small-conductance Ca2+-activated K+ channels. SKA-19 reduces action potential firing and increases medium afterhyperpolarization in CA1 pyramidal neurons in hippocampal slices. SKA-19 is orally bioavailable and shows activity in a broad range of rodent seizure models. SKA-19 protects against maximal electroshock-induced seizures in both rats (ED50 1.6 mg/kg i.p.; 2.3 mg/kg p.o.) and mice (ED50 4.3 mg/kg p.o.), and is also effective in the 6-Hz model in mice (ED50 12.2 mg/kg), Frings audiogenic seizure-susceptible mice (ED50 2.2 mg/kg), and the hippocampal kindled rat model of complex partial seizures (ED50 5.5 mg/kg). Toxicity tests for abnormal neurological status revealed a therapeutic index (TD50/ED50) of 6–9 following intraperitoneal and of 33 following oral administration. SKA-19 further reduced acute pain in the formalin pain model and raised allodynic threshold in a sciatic nerve ligation model. The anticonvulsant profile of SKA-19 is comparable to riluzole, which similarly affects NaV and KCa2 channels, except that SKA-19 has a ~4-fold greater duration of action owing to more prolonged brain levels. Based on these findings we propose that compounds combining KCa2 channel-activating and Nav channel-blocking activity exert broad-spectrum anticonvulsant and analgesic effects.

The brains of humans and other mammals are highly vulnerable to interrupted blood flow and decreased oxygen levels. Here, we describe the restoration and maintenance of microcirculation and molecular and cellular functions of the intact porcine brain under ex vivo normothermic conditions up to 4-hours postmortem. We developed an extracorporeal pulsatile-perfusion system and a hemoglobin-based, acellular, non-coagulative, echogenic, and cytoprotective perfusate that promotes recovery from anoxia, reduces reperfusion injury, prevents edema, and metabolically supports the energy requirements of the brain. Employing this system, we observe preservation of cytoarchitecture; attenuation of cell death; and restoration of vascular dilatory and glial inflammatory responses, spontaneous synaptic activity, as well as active cerebral metabolism in the absence of global electrocorticographic activity. These findings demonstrate that under appropriate conditions the isolated, intact large mammalian brain possesses a yet underappreciated capacity for restoration of microcirculation and molecular and cellular activity after a prolonged postmortem interval.

Issue Title: Rethinking Alzheimer's Disease Therapies Inhibitors of voltage-gated sodium channels (Na^sub v^) have been used as anticonvulsants since the 1940s, while potassium channel activators have only been investigated more recently. We here describe the discovery of 2-amino-6-trifluoromethylthio-benzothiazole (SKA-19), a thioanalog of riluzole, as a potent, novel anticonvulsant, which combines the two mechanisms. SKA-19 is a use-dependent Na^sub v^ channel blocker and an activator of small-conductance Ca^sup 2+^-activated K^sup +^ channels. SKA-19 reduces action potential firing and increases medium afterhyperpolarization in CA1 pyramidal neurons in hippocampal slices. SKA-19 is orally bioavailable and shows activity in a broad range of rodent seizure models. SKA-19 protects against maximal electroshock-induced seizures in both rats (ED^sub 50^ 1.6 mg/kg i.p.; 2.3 mg/kg p.o.) and mice (ED^sub 50^ 4.3 mg/kg p.o.), and is also effective in the 6-Hz model in mice (ED^sub 50^ 12.2 mg/kg), Frings audiogenic seizure-susceptible mice (ED^sub 50^ 2.2 mg/kg), and the hippocampal kindled rat model of complex partial seizures (ED^sub 50^ 5.5 mg/kg). Toxicity tests for abnormal neurological status revealed a therapeutic index (TD^sub 50^/ED^sub 50^) of 6-9 following intraperitoneal and of 33 following oral administration. SKA-19 further reduced acute pain in the formalin pain model and raised allodynic threshold in a sciatic nerve ligation model. The anticonvulsant profile of SKA-19 is comparable to riluzole, which similarly affects Na^sub v^ and KCa2 channels, except that SKA-19 has a ~4-fold greater duration of action owing to more prolonged brain levels. Based on these findings we propose that compounds combining KCa2 channel-activating and Na^sub v^ channel-blocking activity exert broad-spectrum anticonvulsant and analgesic effects.

To characterize the proteomic signature of chronological age, 1,301 proteins were measured in plasma using the SOMAscan assay (SomaLogic, Boulder, CO, USA) in a population of 240 healthy men and women, 22–93 years old, who were disease‐ and treatment‐free and had no physical and cognitive impairment. Using a p ≤ 3.83 × 10−5 significance threshold, 197 proteins were positively associated, and 20 proteins were negatively associated with age. Growth differentiation factor 15 (GDF15) had the strongest, positive association with age (GDF15; 0.018 ± 0.001, p = 7.49 × 10−56). In our sample, GDF15 was not associated with other cardiovascular risk factors such as cholesterol or inflammatory markers. The functional pathways enriched in the 217 age‐associated proteins included blood coagulation, chemokine and inflammatory pathways, axon guidance, peptidase activity, and apoptosis. Using elastic net regression models, we created a proteomic signature of age based on relative concentrations of 76 proteins that highly correlated with chronological age (r = 0.94). The generalizability of our findings needs replication in an independent cohort.

While it is well known that during RCF tests the formation of nascent catalytic sites on the wear track can break down hydrocarbon molecules to release atomic hydrogen, the potential of the hydrogen environment in fuel cells to hydrocrack the hydrocarbon lubricant in high pressure rolling contacts has so far been ignored. Here we investigate for the first time the ability of the hydrogen environment to generate a chemical tribofilm on the wear track most likely through lubricant hydrocracking, as compared with argon and air environments. Despite the ability of the hydrogen environment to generate a notably larger amount of atomic hydrogen, the chemical tribofilm significantly prevents the formation of atomic hydrogen and its subsequent diffusion through the lattice of steel rolling element bearings. This is of great importance in the lubrication of hydrogen technology and the prevention of Hydrogen embrittlement (HE). An investigation into the prospects of high energy micro-computed-tomography (Micro-CT) as a non-destructive technique for sub-surface damage characterisation in RCF was comparatively performed alongside traditional sectioning methods.

BackgroundIn the phase III open-label KEYNOTE-426 (NCT02853331) study, first-line pembrolizumab and axitinib improved overall survival (OS) and progression-free survival (PFS) versus sunitinib for metastatic renal cell carcinoma (mRCC). KEYNOTE-426 evaluated patients enrolled from 25 sites in Japan.MethodsPatients enrolled in Japan were included in this post hoc subgroup analysis. Adults with clear cell mRCC were randomly assigned 1:1 to receive intravenous pembrolizumab 200 mg every 3 weeks plus oral axitinib 5 mg twice daily or oral sunitinib 50 mg once daily (4 weeks on/2 weeks off). Dual primary endpoints were OS and PFS as assessed by blinded independent central review. Objective response rate (ORR) and safety were secondary endpoints.ResultsThe Japanese subgroup comprised 94 patients (pembrolizumab–axitinib, n = 44; sunitinib, n = 50; 11% of the intent-to-treat population). Median time from randomization to data cutoff (January 6, 2020) was 29.5 months (range 24.6–37.3). Consistent with the intent-to-treat population, the OS, PFS, and ORR suggested improvement with pembrolizumab–axitinib versus sunitinib in the Japanese subgroup. Grade ≥ 3 treatment-related adverse events (TRAEs) occurred in 70% of patients receiving pembrolizumab–axitinib versus 78% receiving sunitinib; 11 (25%) patients receiving pembrolizumab–axitinib and 13 (27%) patients receiving sunitinib discontinued the study medication due to AEs. TRAEs led to the discontinuation of pembrolizumab, axitinib, pembrolizumab–axitinib, or sunitinib in 32%, 34%, 14%, and 20%, respectively. No deaths from TRAEs occurred.ConclusionsEfficacy outcomes for the Japanese subgroup were consistent with those of the global population. Safety in Japanese patients was consistent with the results from the global population.

As ocean temperatures continue to rise, coral bleaching events around the globe are becoming stronger and more frequent. High-resolution temperature data is therefore critical for monitoring reef conditions to identify indicators of heat stress. Satellite and in situ measurements have historically been relied upon to study the thermal tolerances of coral reefs, but these data are quite limited in their spatial and temporal coverage. Ocean circulation models could provide an alternative or complement to these limited data, but a thorough evaluation against in situ measurements has yet to be conducted in any Pacific Islands region. Here we compared subsurface temperature measurements around the nearshore Main Hawaiian Islands (MHI) from 2010 to 2017 with temperature predictions from an operational Regional Ocean Modeling System (ROMS) to evaluate the potential utility of this model as a tool for coral reef management. We found that overall, the ROMS reanalysis presents accurate subsurface temperature predictions across the nearshore MHI region and captures a significant amount of observed temperature variability. The model recreates several temperature metrics used to identify coral heat stress, including predicting the 2014 and 2015 bleaching events around Hawaiʻi during the summer and fall months of those years. The MHI ROMS simulation proves to be a useful tool for coral reef management in the absence of, or to supplement, subsurface and satellite measurements across Hawaiʻi and likely for other Pacific Island regions.

The concept of the neurovascular unit emphasizes the importance of cell-cell signaling between neural, glial, and vascular compartments. In neurogenesis, for example, brain endothelial cells play a key role by supplying trophic support to neural progenitors. Here, we describe a surprising phenomenon where brain endothelial cells may release trans-differentiation signals that convert astrocytes into neural progenitor cells in male mice after stroke. After oxygen-glucose deprivation, brain endothelial cells release microvesicles containing pro-neural factor Ascl1 that enter into astrocytes to induce their trans-differentiation into neural progenitors. In mouse models of focal cerebral ischemia, Ascl1 is upregulated in endothelium prior to astrocytic conversion into neural progenitor cells. Injecting brain endothelial-derived microvesicles amplifies the process of astrocyte trans-differentiation. Endothelial-specific overexpression of Ascl1 increases the local conversion of astrocytes into neural progenitors and improves behavioral recovery. Our findings describe an unexpected vascular-regulated mechanism of neuroplasticity that may open up therapeutic opportunities for improving outcomes after stroke. Damaged brains try to repair themselves by producing neurons in areas where neurogenesis does not normally occur. Here, the authors show that brain endothelial cells provide microvesicle-encased signals that convert parenchymal astrocytes into neural progenitors, thus improving outcomes after stroke.