Stroke in the Time of Circadian Medicine.

Time-of-day significantly influences the severity and incidence of stroke. Evidence has emerged not only for circadian governance over stroke risk factors, but also for important determinants of clinical outcome. In this review, we provide a comprehensive overview of the interplay between chronobiology and cerebrovascular disease. We discuss circadian regulation of pathophysiological mechanisms underlying stroke onset or tolerance as well as in vascular dementia. This includes cell death mechanisms, metabolism, mitochondrial function, and inflammation/immunity. Furthermore, we present clinical evidence supporting the link between disrupted circadian rhythms and increased susceptibility to stroke and dementia. We propose that circadian regulation of biochemical and physiological pathways in the brain increase susceptibility to damage after stroke in sleep and attenuate treatment effectiveness during the active phase. This review underscores the importance of considering circadian biology for understanding the pathology and treatment choice for stroke and vascular dementia and speculates that considering a patient's chronotype may be an important factor in developing precision treatment following stroke.

Potent halogenated xanthone derivatives: synthesis, molecular docking and study on antityrosinase activity.

Tyrosinase inhibitors can reduce melanin production for skin whitening, but some existing products may harm the skin. This study discovered six compounds that inhibit tyrosinase in the mushroom Agaricus bisporus by over 50%. Compound 11 displayed strong inhibition (92.2% and 86.7%) for L-tyrosine and L-DOPA substrates, while compound 13 showed high inhibition (96.0% and 62.0%) for both substrates. Molecular docking simulations revealed compounds 11 and 13 bind at the allosteric site of the enzyme. Xanthone derivatives, based on these findings, hold potential as safe skin whitening agents and for pigmentation-related diseases in the cosmetic industry.

Frequency-Dependent Squeezed Vacuum Source for the Advanced Virgo Gravitational-Wave Detector.

In this Letter, we present the design and performance of the frequency-dependent squeezed vacuum source that will be used for the broadband quantum noise reduction of the Advanced Virgo Plus gravitational-wave detector in the upcoming observation run. The frequency-dependent squeezed field is generated by a phase rotation of a frequency-independent squeezed state through a 285 m long, high-finesse, near-detuned optical resonator. With about 8.5 dB of generated squeezing, up to 5.6 dB of quantum noise suppression has been measured at high frequency while close to the filter cavity resonance frequency, the intracavity losses limit this value to about 2 dB. Frequency-dependent squeezing is produced with a rotation frequency stability of about 6 Hz rms, which is maintained over the long term. The achieved results fulfill the frequency dependent squeezed vacuum source requirements for Advanced Virgo Plus. With the current squeezing source, considering also the estimated squeezing degradation induced by the interferometer, we expect a reduction of the quantum shot noise and radiation pressure noise of up to 4.5 dB and 2 dB, respectively.

Posterior circulation ischaemic stroke diagnosis and management.

This narrative review provides an overview of the posterior circulation and the clinical features of common posterior circulation stroke (PCS) syndromes in the posterior arterial territories and how to distinguish them from mimics. We outline the hyperacute management of patients with suspected PCS with emphasis on how to identify those who are likely to benefit from intervention based on imaging findings. Finally, we review advances in treatment options, including developments in endovascular thrombectomy (EVT) and intravenous thrombolysis (IVT), and the principles of medical management and indications for neurosurgery. Observational and randomised clinical trial data have been equivocal regarding EVT in PCS, but more recent studies strongly support its efficacy. There have been concomitant advances in imaging of posterior stroke to guide optimal patient selection for thrombectomy. Recent evidence suggests that clinicians should have a heightened suspicion of posterior circulation events with the resultant implementation of timely, evidence-based management.

Placental capillary pericytes release excess extracellular vesicles under hypoxic conditions inducing a pro-angiogenic profile in term pregnancy.

Pericytes are multifunctional cells wrapped around capillary endothelia, essential for vascular health, development, and blood flow regulation, although their role in human placental chorionic villi has not been fully explored. The second half of normal pregnancy is characterized by a progressive decline in placental and fetal oxygen levels which, by term, comprises a substantial degree of hypoxia. We hypothesized this hypoxia would stimulate pericyte regulation of chorionic villous capillary function. This study's objective was to investigate the role of hypoxia on normal term placental pericytes (PLVP) and their signaling to endothelial cells. First, we confirmed fetoplacental hypoxia at term by a new analysis of umbilical arterial blood oxygen tension of 3,010 healthy singleton neonates sampled at caesarean section and before labor. We then measured the release of cytokines, chemokines, and small extracellular vesicles (PLVPsv), from PLVP cultured at 20%, 8% and 1% O2. As O2 levels decreased, secreted cytokines and chemokines [interleukin-6 (IL-6), interleukin-1α (IL-1α) and vascular endothelial growth factor (VEGF)], and small extracellular vesicle markers, (Alix, Syntenin and CD9) increased significantly in the culture supernatants. When primary human umbilical vein endothelial cells (HUVEC) were cultured with PLVPsv, polygon formation, number, and tube formation length was significantly increased compared to cells not treated with PLVPsv, indicating PLVPsv stimulated angiogenesis. We conclude that adding PLVPsv stimulates angiogenesis and vessel stabilization on neighboring endothelial cells in response to hypoxia in term pregnancy compared to no addition of PLVPsv. Our finding that PLVP can release angiogenic molecules via extracellular vesicles in response to hypoxia may apply to other organ systems.

Search for Subsolar-Mass Binaries in the First Half of Advanced LIGO's and Advanced Virgo's Third Observing Run.

We report on a search for compact binary coalescences where at least one binary component has a mass between 0.2 M_{⊙} and 1.0 M_{⊙} in Advanced LIGO and Advanced Virgo data collected between 1 April 2019 1500 UTC and 1 October 2019 1500 UTC. We extend our previous analyses in two main ways: we include data from the Virgo detector and we allow for more unequal mass systems, with mass ratio q≥0.1. We do not report any gravitational-wave candidates. The most significant trigger has a false alarm rate of 0.14 yr^{-1}. This implies an upper limit on the merger rate of subsolar binaries in the range [220-24200] Gpc^{-3} yr^{-1}, depending on the chirp mass of the binary. We use this upper limit to derive astrophysical constraints on two phenomenological models that could produce subsolar-mass compact objects. One is an isotropic distribution of equal-mass primordial black holes. Using this model, we find that the fraction of dark matter in primordial black holes in the mass range 0.2 M_{⊙}

Automated quantification of atrophy and acute ischemic volume for outcome prediction in endovascular thrombectomy.

Background: Short- and long-term outcomes from endovascular thrombectomy (EVT) for large vessel occlusion stroke remain variable. Numerous relevant predictors have been identified, including severity of neurological deficits, age, and imaging features. The latter is typically defined as acute changes (most commonly Alberta Stroke Programme Early CT Score, ASPECTS, at presentation), but there is little information on the impact of imaging assessment of premorbid brain health as a determinant of outcome. Aims: To examine the impact of automated measures of stroke severity and underlying brain frailty on short- and long-term outcomes in acute stroke treated with EVT. Methods: In 215 patients with anterior circulation stroke, who subsequently underwent EVT, automated analysis of presenting non-contrast CT scans was used to determine acute ischemic volume (AIV) and e-ASPECTS as markers of stroke severity, and cerebral atrophy as a marker of brain frailty. Univariate and multivariate logistic regression were used to identify significant predictors of NIHSS improvement, modified Rankin scale (mRS) at 90 and 30 days, mortality at 90 days and symptomatic intracranial hemorrhage (sICH) following successful EVT. Results: For long-term outcome, atrophy and presenting NIHSS were significant predictors of mRS 0-2 and death at 90 days, whereas age did not reach significance in multivariate analysis. Conversely, for short-term NIHSS improvement, AIV and age were significant predictors, unlike presenting NIHSS. The interaction between age and NIHSS was similar to the interaction of AIV and atrophy for mRS 0-2 at 90 days. Conclusion: Combinations of automated software-based imaging analysis and clinical data can be useful for predicting short-term neurological outcome and may improve long-term prognostication in EVT. These results provide a basis for future development of predictive tools built into decision-aiding software in stroke.

Constraints on Cosmic Strings Using Data from the Third Advanced LIGO-Virgo Observing Run.

We search for gravitational-wave signals produced by cosmic strings in the Advanced LIGO and Virgo full O3 dataset. Search results are presented for gravitational waves produced by cosmic string loop features such as cusps, kinks, and, for the first time, kink-kink collisions. A template-based search for short-duration transient signals does not yield a detection. We also use the stochastic gravitational-wave background energy density upper limits derived from the O3 data to constrain the cosmic string tension Gµ as a function of the number of kinks, or the number of cusps, for two cosmic string loop distribution models. Additionally, we develop and test a third model that interpolates between these two models. Our results improve upon the previous LIGO-Virgo constraints on Gµ by 1 to 2 orders of magnitude depending on the model that is tested. In particular, for the one-loop distribution model, we set the most competitive constraints to date: Gµâ‰²4×10^{-15}. In the case of cosmic strings formed at the end of inflation in the context of grand unified theories, these results challenge simple inflationary models.

Growth Differentiation Factor-11 Causes Neurotoxicity During Ischemia in vitro.

Age-related neuronal dysfunction can be overcome by circulating factors present in young blood. Growth differentiation factor-11 (GDF-11), a systemic factor that declines with age, can reverse age-related dysfunction in brain, heart and skeletal muscle. Given that age increases susceptibility to stroke, we hypothesized that GDF-11 may be directly protective to neurons following ischemia. Primary cortical neurons were isolated from E18 Wistar rat embryos and cultured for 7-10 days. Neurons were deprived of oxygen and glucose (OGD) to simulate ischemia. Neuronal death was assessed by lactate dehydrogenase, propidium iodide or CellTox™ green cytotoxicity assays. 40 ng/mL GDF-11 administration during 2 h OGD significantly increased neuronal death following 24 h recovery. However, GDF-11 pre-treatment did not affect neuronal death during 2 h OGD. GDF-11 treatment during the 24 h recovery period after 2 h OGD also did not alter death. Real-time monitoring for 24 h revealed that by 2 h OGD, GDF-11 treatment had increased neuronal death which remained raised at 24 h. Co-treatment of 1 µM SB431542 (ALK4/5/7 receptor inhibitor) with GDF-11 prevented GDF-11 neurotoxicity after 2 h OGD and 24 h OGD. Transforming growth factor beta (TGFß) did not increase neuronal death to the same extent as GDF-11 following OGD. GDF-11 neurotoxicity was also exhibited following neuronal exposure to hydrogen peroxide. These results reveal for the first time that GDF-11 is neurotoxic to primary neurons in the acute phase of simulated stroke through primarily ALK4 receptor signaling.

Prospects for observing and localizing gravitational-wave transients with Advanced LIGO, Advanced Virgo and KAGRA.

We present our current best estimate of the plausible observing scenarios for the Advanced LIGO, Advanced Virgo and KAGRA gravitational-wave detectors over the next several years, with the intention of providing information to facilitate planning for multi-messenger astronomy with gravitational waves. We estimate the sensitivity of the network to transient gravitational-wave signals for the third (O3), fourth (O4) and fifth observing (O5) runs, including the planned upgrades of the Advanced LIGO and Advanced Virgo detectors. We study the capability of the network to determine the sky location of the source for gravitational-wave signals from the inspiral of binary systems of compact objects, that is binary neutron star, neutron star-black hole, and binary black hole systems. The ability to localize the sources is given as a sky-area probability, luminosity distance, and comoving volume. The median sky localization area (90% credible region) is expected to be a few hundreds of square degrees for all types of binary systems during O3 with the Advanced LIGO and Virgo (HLV) network. The median sky localization area will improve to a few tens of square degrees during O4 with the Advanced LIGO, Virgo, and KAGRA (HLVK) network. During O3, the median localization volume (90% credible region) is expected to be on the order of 10 5 , 10 6 , 10 7 Mpc 3 for binary neutron star, neutron star-black hole, and binary black hole systems, respectively. The localization volume in O4 is expected to be about a factor two smaller than in O3. We predict a detection count of 1 - 1 + 12 ( 10 - 10 + 52 ) for binary neutron star mergers, of 0 - 0 + 19 ( 1 - 1 + 91 ) for neutron star-black hole mergers, and 17 - 11 + 22 ( 79 - 44 + 89 ) for binary black hole mergers in a one-calendar-year observing run of the HLV network during O3 (HLVK network during O4). We evaluate sensitivity and localization expectations for unmodeled signal searches, including the search for intermediate mass black hole binary mergers.

Quantum Backaction on kg-Scale Mirrors: Observation of Radiation Pressure Noise in the Advanced Virgo Detector.

The quantum radiation pressure and the quantum shot noise in laser-interferometric gravitational wave detectors constitute a macroscopic manifestation of the Heisenberg inequality. If quantum shot noise can be easily observed, the observation of quantum radiation pressure noise has been elusive, so far, due to the technical noise competing with quantum effects. Here, we discuss the evidence of quantum radiation pressure noise in the Advanced Virgo gravitational wave detector. In our experiment, we inject squeezed vacuum states of light into the interferometer in order to manipulate the quantum backaction on the 42 kg mirrors and observe the corresponding quantum noise driven displacement at frequencies between 30 and 70 Hz. The experimental data, obtained in various interferometer configurations, is tested against the Advanced Virgo detector quantum noise model which confirmed the measured magnitude of quantum radiation pressure noise.

GW190521: A Binary Black Hole Merger with a Total Mass of 150 M_{⊙}.

On May 21, 2019 at 03:02:29 UTC Advanced LIGO and Advanced Virgo observed a short duration gravitational-wave signal, GW190521, with a three-detector network signal-to-noise ratio of 14.7, and an estimated false-alarm rate of 1 in 4900 yr using a search sensitive to generic transients. If GW190521 is from a quasicircular binary inspiral, then the detected signal is consistent with the merger of two black holes with masses of 85_{-14}^{+21} M_{⊙} and 66_{-18}^{+17} M_{⊙} (90% credible intervals). We infer that the primary black hole mass lies within the gap produced by (pulsational) pair-instability supernova processes, with only a 0.32% probability of being below 65 M_{⊙}. We calculate the mass of the remnant to be 142_{-16}^{+28} M_{⊙}, which can be considered an intermediate mass black hole (IMBH). The luminosity distance of the source is 5.3_{-2.6}^{+2.4} Gpc, corresponding to a redshift of 0.82_{-0.34}^{+0.28}. The inferred rate of mergers similar to GW190521 is 0.13_{-0.11}^{+0.30} Gpc^{-3} yr^{-1}.

Search for Subsolar Mass Ultracompact Binaries in Advanced LIGO's Second Observing Run.

We present a search for subsolar mass ultracompact objects in data obtained during Advanced LIGO's second observing run. In contrast to a previous search of Advanced LIGO data from the first observing run, this search includes the effects of component spin on the gravitational waveform. We identify no viable gravitational-wave candidates consistent with subsolar mass ultracompact binaries with at least one component between 0.2 M_{⊙}-1.0 M_{⊙}. We use the null result to constrain the binary merger rate of (0.2 M_{⊙}, 0.2 M_{⊙}) binaries to be less than 3.7×10^{5} Gpc^{-3} yr^{-1} and the binary merger rate of (1.0 M_{⊙}, 1.0 M_{⊙}) binaries to be less than 5.2×10^{3} Gpc^{-3} yr^{-1}. Subsolar mass ultracompact objects are not expected to form via known stellar evolution channels, though it has been suggested that primordial density fluctuations or particle dark matter with cooling mechanisms and/or nuclear interactions could form black holes with subsolar masses. Assuming a particular primordial black hole (PBH) formation model, we constrain a population of merging 0.2 M_{⊙} black holes to account for less than 16% of the dark matter density and a population of merging 1.0 M_{⊙} black holes to account for less than 2% of the dark matter density. We discuss how constraints on the merger rate and dark matter fraction may be extended to arbitrary black hole population models that predict subsolar mass binaries.

Tests of General Relativity with GW170817.

The recent discovery by Advanced LIGO and Advanced Virgo of a gravitational wave signal from a binary neutron star inspiral has enabled tests of general relativity (GR) with this new type of source. This source, for the first time, permits tests of strong-field dynamics of compact binaries in the presence of matter. In this Letter, we place constraints on the dipole radiation and possible deviations from GR in the post-Newtonian coefficients that govern the inspiral regime. Bounds on modified dispersion of gravitational waves are obtained; in combination with information from the observed electromagnetic counterpart we can also constrain effects due to large extra dimensions. Finally, the polarization content of the gravitational wave signal is studied. The results of all tests performed here show good agreement with GR.

Constraining the p-Mode-g-Mode Tidal Instability with GW170817.

We analyze the impact of a proposed tidal instability coupling p modes and g modes within neutron stars on GW170817. This nonresonant instability transfers energy from the orbit of the binary to internal modes of the stars, accelerating the gravitational-wave driven inspiral. We model the impact of this instability on the phasing of the gravitational wave signal using three parameters per star: an overall amplitude, a saturation frequency, and a spectral index. Incorporating these additional parameters, we compute the Bayes factor (lnB_{!pg}^{pg}) comparing our p-g model to a standard one. We find that the observed signal is consistent with waveform models that neglect p-g effects, with lnB_{!pg}^{pg}=0.03_{-0.58}^{+0.70} (maximum a posteriori and 90% credible region). By injecting simulated signals that do not include p-g effects and recovering them with the p-g model, we show that there is a ≃50% probability of obtaining similar lnB_{!pg}^{pg} even when p-g effects are absent. We find that the p-g amplitude for 1.4 M_{⊙} neutron stars is constrained to less than a few tenths of the theoretical maximum, with maxima a posteriori near one-tenth this maximum and p-g saturation frequency ∼70 Hz. This suggests that there are less than a few hundred excited modes, assuming they all saturate by wave breaking. For comparison, theoretical upper bounds suggest ≲10^{3} modes saturate by wave breaking. Thus, the measured constraints only rule out extreme values of the p-g parameters. They also imply that the instability dissipates ≲10^{51} erg over the entire inspiral, i.e., less than a few percent of the energy radiated as gravitational waves.

Functional Outcomes 6 Months After Severe Traumatic Brain Injury Following Admission Into Intensive Care Unit: A Cohort Study in Two Tertiary Hospitals.

Severe traumatic brain injury (TBI) survivors show physical and functional improvements but continue to have cognitive and psychosocial problems throughout recovery. However, the functional outcome of severe TBI in Malaysia is unknown. The objective of this study is to measure the functional outcomes of severe TBI within 6 months post-injury. A cohort study was done on 33 severe TBI survivors. The Glasgow Outcome Scale-Extended (GOSE) was used in this study. The mean age of the participants was 31.79 years (range: 16-73 years). The logistic regression model was statistically significant, χ²(5, N = 33) = 29.09, p < .001. The length of stay (LOS) in incentive care unit (p = .049, odds ratio = 6.062) and duration on ventilator (p = .048, odds ratio = 0.083) were good predictors of the functional outcomes. Future research should focus on larger sample size of severe TBI in Malaysia.

Rapamycin in ischemic stroke: Old drug, new tricks?

The significant morbidity that accompanies stroke makes it one of the world's most devastating neurological disorders. Currently, proven effective therapies have been limited to thrombolysis and thrombectomy. The window for the administration of these therapies is narrow, hampered by the necessity of rapidly imaging patients. A therapy that could extend this window by protecting neurons may improve outcome. Endogenous neuroprotection has been shown to be, in part, due to changes in mTOR signalling pathways and the instigation of productive autophagy. Inducing this effect pharmacologically could improve clinical outcomes. One such therapy already in use in transplant medicine is the mTOR inhibitor rapamycin. Recent evidence suggests that rapamycin is neuroprotective, not only via neuronal autophagy but also through its broader effects on other cells of the neurovascular unit. This review highlights the potential use of rapamycin as a multimodal therapy, acting on the blood-brain barrier, cerebral blood flow and inflammation, as well as directly on neurons. There is significant potential in applying this old drug in new ways to improve functional outcomes for patients after stroke.

Development of Highly Sensitive Immunosensor for Clenbuterol Detection by Using Poly(3,4-ethylenedioxythiophene)/Graphene Oxide Modified Screen-Printed Carbon Electrode.

Clenbuterol (CLB) is an antibiotic and illegal growth promoter drug that has a long half-life and easily remains as residue and contaminates the animal-based food product that leads to various health problems. In this work, electrochemical immunosensor based on poly(3,4-ethylenedioxythiophene)/graphene oxide (PEDOT/GO) modified screen-printed carbon electrode (SPCE) for CLB detection was developed for antibiotic monitoring in a food product. The modification of SPCE with PEDOT/GO as a sensor platform was performed through electropolymerization, while the electrochemical assay was accomplished while using direct competitive format in which the free CLB and clenbuterol-horseradish peroxidase (CLB-HRP) in the solution will compete to form binding with the polyclonal anti-clenbuterol antibody (Ab) immobilized onto the modified electrode surface. A linear standard CLB calibration curve with R² = 0.9619 and low limit of detection (0.196 ng mL-1) was reported. Analysis of milk samples indicated that this immunosensor was able to detect CLB in real samples and the results that were obtained were comparable with enzyme-linked immunosorbent assays (ELISA).

Search for Subsolar-Mass Ultracompact Binaries in Advanced LIGO's First Observing Run.

We present the first Advanced LIGO and Advanced Virgo search for ultracompact binary systems with component masses between 0.2 M_{⊙}-1.0 M_{⊙} using data taken between September 12, 2015 and January 19, 2016. We find no viable gravitational wave candidates. Our null result constrains the coalescence rate of monochromatic (delta function) distributions of nonspinning (0.2 M_{⊙}, 0.2 M_{⊙}) ultracompact binaries to be less than 1.0×10^{6} Gpc^{-3} yr^{-1} and the coalescence rate of a similar distribution of (1.0 M_{⊙}, 1.0 M_{⊙}) ultracompact binaries to be less than 1.9×10^{4} Gpc^{-3} yr^{-1} (at 90% confidence). Neither black holes nor neutron stars are expected to form below ∼1 M_{⊙} through conventional stellar evolution, though it has been proposed that similarly low mass black holes could be formed primordially through density fluctuations in the early Universe and contribute to the dark matter density. The interpretation of our constraints in the primordial black hole dark matter paradigm is highly model dependent; however, under a particular primordial black hole binary formation scenario we constrain monochromatic primordial black hole populations of 0.2 M_{⊙} to be less than 33% of the total dark matter density and monochromatic populations of 1.0 M_{⊙} to be less than 5% of the dark matter density. The latter strengthens the presently placed bounds from microlensing surveys of massive compact halo objects (MACHOs) provided by the MACHO and EROS Collaborations.