Low-latency gravitational wave alert products and their performance at the time of the fourth LIGO-Virgo-KAGRA observing run.

Multimessenger searches for binary neutron star (BNS) and neutron star-black hole (NSBH) mergers are currently one of the most exciting areas of astronomy. The search for joint electromagnetic and neutrino counterparts to gravitational wave (GW)s has resumed with ALIGO's, AdVirgo's and KAGRA's fourth observing run (O4). To support this effort, public semiautomated data products are sent in near real-time and include localization and source properties to guide complementary observations. In preparation for O4, we have conducted a study using a simulated population of compact binaries and a mock data challenge (MDC) in the form of a real-time replay to optimize and profile the software infrastructure and scientific deliverables. End-toend performance was tested, including data ingestion, running online search pipelines, performing annotations, and issuing alerts to the astrophysics community. We present an overview of the low-latency infrastructure and the performance of the data products that are now being released during O4 based on the MDC. We report the expected median latency for the preliminary alert of full bandwidth searches (29.5 s) and show consistency and accuracy of released data products using the MDC. We report the expected median latency for triggers from early warning searches (-3.1 s), which are new in O4 and target neutron star mergers during inspiral phase. This paper provides a performance overview for LIGO-Virgo-KAGRA (LVK) low-latency alert infrastructure and data products using theMDCand serves as a useful reference for the interpretation of O4 detections.

Angular Power Spectrum of Gravitational-Wave Transient Sources as a Probe of the Large-Scale Structure.

We present a new, simulation-based inference method to compute the angular power spectrum of the distribution of foreground gravitational-wave transient events. As a first application of this method, we use the binary black hole mergers observed during the LIGO, Virgo, and KAGRA third observation run to test the spatial distribution of these sources. We find no evidence for anisotropy in their angular distribution. We discuss further applications of this method to investigate other gravitational-wave source populations and their correlations to the cosmological large-scale structure.

Toward a holographic brain paradigm: a lipid-centric model of brain functioning.

Due to the stimulation of neuronal membrane dipoles by action potentials, under suitable conditions coherent dipole oscillations can be formed. We argue that these dipole oscillations satisfy the weak Bose-Einstein condensate criteria of the Froehlich model of biological coherence. They can subsequently generate electromagnetic fields (EMFs) propagating in the inter-neuronal space. When neighboring neurons fire synchronously, EMFs can create interference patterns and hence form holographic images containing analog information about the sensory inputs that trigger neuronal activity. The mirror pattern projected by EMFs inside the neuron can encode information in the neuronal cytoskeleton. We outline an experimental verification of our hypothesis and its consequences for anesthesia, neurodegenerative diseases, and psychiatric states.

Alteration of lipid bilayer mechanics by volatile anesthetics: Insights from µs-long molecular dynamics simulations.

Very few drugs in clinical practice feature the chemical diversity, narrow therapeutic window, unique route of administration, and reversible cognitive effects of volatile anesthetics. The correlation between their hydrophobicity and their potency and the increasing amount of evidence suggesting that anesthetics exert their action on transmembrane proteins, justifies the investigation of their effects on phospholipid bilayers at the molecular level, given the strong functional and structural link between transmembrane proteins and the surrounding lipid matrix. Molecular dynamics simulations of a model lipid bilayer in the presence of ethylene, desflurane, methoxyflurane, and the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (also called F6 or 2N) at different concentrations highlight the structural consequences of VA partitioning in the lipid phase, with a decrease of lipid order and bilayer thickness, an increase in overall lipid lateral mobility and area-per-lipid, and a marked reduction in the mechanical stiffness of the membrane, that strongly correlates with the compounds' hydrophobicity.

ALS2-Related Motor Neuron Diseases: From Symptoms to Molecules.

Infantile-onset Ascending Hereditary Spastic Paralysis, Juvenile Primary Lateral Sclerosis and Juvenile Amyotrophic Lateral Sclerosis are all motor neuron diseases related to mutations on the ALS2 gene, encoding for a 1657 amino acids protein named Alsin. This ~185 kDa multi-domain protein is ubiquitously expressed in various human tissues, mostly in the brain and the spinal cord. Several investigations have indicated how mutations within Alsin's structured domains may be responsible for the alteration of Alsin's native oligomerization state or Alsin's propensity to interact with protein partners. In this review paper, we propose a description of differences and similarities characterizing the above-mentioned ALS2-related rare neurodegenerative disorders, pointing attention to the effects of ALS2 mutation from molecule to organ and at the system level. Known cases were collected through a literature review and rationalized to deeply elucidate the neurodegenerative clinical outcomes as consequences of ALS2 mutations.

Insights into the interaction dynamics between volatile anesthetics and tubulin through computational molecular modelling.

General anesthetics, able to reversibly suppress all conscious brain activity, have baffled medical science for decades, and little is known about their exact molecular mechanism of action. Given the recent scientific interest in the exploration of microtubules as putative functional targets of anesthetics, and the involvement thereof in neurodegenerative disorders, the present work focuses on the investigation of the interaction between human tubulin and four volatile anesthetics: ethylene, desflurane, halothane and methoxyflurane. Interaction sites on different tubulin isotypes are predicted through docking, along with an estimate of the binding affinity ranking. The analysis is expanded by Molecular Dynamics simulations, where the dimers are allowed to freely interact with anesthetics in the surrounding medium. This allowed for the determination of interaction hotspots on tubulin dimers, which could be linked to different functional consequences on the microtubule architecture, and confirmed the weak, Van der Waals-type interaction, occurring within hydrophobic pockets on the dimer. Both docking and MD simulations highlighted significantly weaker interactions of ethylene, consistent with its far lower potency as a general anesthetic. Overall, simulations suggest a transient interaction between anesthetics and microtubules in general anesthesia, and contact probability analysis shows interaction strengths consistent with the potencies of the four compounds.Communicated by Ramaswamy H. Sarma.

JAK inhibitors in immune-mediated rheumatic diseases: From a molecular perspective to clinical studies.

The Janus Kinase signalling pathway is implicated in the pathogenesis of immune-related diseases. The potency of small-molecule Janus Kinase inhibitors in the treatment of inflammatory diseases demonstrates that this pathway can be successfully targeted for therapeutic purposes. The outstanding relevant questions concerning drugs' efficacy and toxicity challenge the research to enhance the selectivity of these drugs. The promising results of computational techniques, such as Molecular Dynamics and Molecular Docking, coupled with experimental studies, can improve the understanding of the molecular mechanism of Janus Kinase pathway and thus enable the rational design of new more selective inhibitor molecules.

Prediction of Protein-Protein Interactions Between Alsin DH/PH and Rac1 and Resulting Protein Dynamics.

Alsin is a protein of 1,657 amino acids known for its crucial role in vesicular trafficking in neurons thanks to its ability to interact with two guanosine triphosphatases, Rac1 and Rab5. Evidence suggests that Rac1 can bind Alsin central region, composed by a Dbl Homology (DH) domain followed by a Pleckstrin Homology (PH) domain, leading to Alsin relocalization. However, Alsin three-dimensional structure and its relationship with known biological functions of this protein are still unknown. In this work, a homology model of the Alsin DH/PH domain was developed and studied through molecular dynamics both in the presence and in the absence of its binding partner, Rac1. Due to different conformations of DH domain, the presence of Rac1 seems to stabilize an open state of the protein, while the absence of its binding partner results in closed conformations. Furthermore, Rac1 interaction was able to reduce the fluctuations in the second conserved region of DH motif, which may be involved in the formation of a homodimer. Moreover, the dynamics of DH/PH was described through a Markov State Model to study the pathways linking the open and closed states. In conclusion, this work provided an all-atom model for the DH/PH domain of Alsin protein; moreover, molecular dynamics investigations suggested underlying molecular mechanisms in the signal transduction between Rac1 and Alsin, providing the basis for a deeper understanding of the whole structure-function relationship for Alsin protein.

Noninvasive mechanical ventilation in the COVID-19 era: Proposal for a continuous positive airway pressure closed-loop circuit minimizing air contamination, oxygen consumption, and noise.

Noninvasive continuous positive airway pressure (NIV-CPAP) is effective in patients with hypoxemic respiratory failure. Building evidence during the COVID-19 emergency reported that around 50% of patients in Italy treated with NIV-CPAP avoided the need for invasive mechanical ventilation. Standard NIV-CPAP systems operate at high gas flow rates responsible for noise generation and inadequate humidification. Furthermore, open-configuration systems require a high concentration of oxygen to deliver the desired FiO2 . Concerns outlined the risk for aerosolization in the ambient air and the possible pressure drop in hospital supply pipes. A new NIV-CPAP system is proposed that includes automatic control of patient respiratory parameters. The system operates as a closed-loop breathing circuit that can be assembled, combining a sleep apnea machine with existing commercially available components. Analytical simulation of a breathing patient and simulation with a healthy volunteer at different FiO2 were performed. Inspired and expired oxygen fraction and inspired and expired carbon dioxide pressure were recorded at different CPAP levels with different oxygen delivery. Among the main findings, we report (a) a significant (up to 30-fold) reduction in oxygen feeding compared to standard open high flow NIV-CPAP systems, to assure the same FiO2 levels, and (b) a negligible production of the noise generated in ventilatory systems, and consequent minimization of patients' discomfort. The proposed NIV-CPAP circuit, reshaped in closed-loop configuration with the blower outside of the circuit, has the advantages of minimizing aerosol generation, environmental contamination, oxygen consumption, and noise to the patient. The system is easily adaptable and can be implemented using standard CPAP components.

Personalized therapy design for systemic lupus erythematosus based on the analysis of protein-protein interaction networks.

We analyzed protein expression data for Lupus patients, which have been obtained from publicly available databases. A combination of systems biology and statistical thermodynamics approaches was used to extract topological properties of the associated protein-protein interaction networks for each of the 291 patients whose samples were used to provide the molecular data. We have concluded that among the many proteins that appear to play critical roles in this pathology, most of them are either ribosomal proteins, ubiquitination pathway proteins or heat shock proteins. We propose some of the proteins identified in this study to be considered for drug targeting.

Using the Gibbs Function as a Measure of Human Brain Development Trends from Fetal Stage to Advanced Age.

We propose to use a Gibbs free energy function as a measure of the human brain development. We adopt this approach to the development of the human brain over the human lifespan: from a prenatal stage to advanced age. We used proteomic expression data with the Gibbs free energy to quantify human brain's protein-protein interaction networks. The data, obtained from BioGRID, comprised tissue samples from the 16 main brain areas, at different ages, of 57 post-mortem human brains. We found a consistent functional dependence of the Gibbs free energies on age for most of the areas and both sexes. A significant upward trend in the Gibbs function was found during the fetal stages, which is followed by a sharp drop at birth with a subsequent period of relative stability and a final upward trend toward advanced age. We interpret these data in terms of structure formation followed by its stabilization and eventual deterioration. Furthermore, gender data analysis has uncovered the existence of functional differences, showing male Gibbs function values lower than female at prenatal and neonatal ages, which become higher at ages 8 to 40 and finally converging at late adulthood with the corresponding female Gibbs functions.

Ultrasonic waves effect on S-shaped ß-amyloids conformational dynamics by non-equilibrium molecular dynamics.

Ultrasound-based technologies are widely adopted in the clinical practice. Recently, the ultrasound stable cavitation has been proposed as a strategy to destabilize amyloid aggregates in Alzheimer disease. However, the molecular mechanisms driving ultrasound-induced amyloid destabilization are not fully clarified yet. Here, molecular dynamics is applied to investigate in silico the conformational dynamics induced by ultrasound stable cavitation on S-shaped Aß1-42 amyloid fibrils, which has been highlighted as a more stable architecture with respect to U-shaped Aß1-42. The findings of the study suggested that ultrasound exposure could affect S-shaped aggregates folding dynamics and kinetics, with a marked dependence on the fibril polymorphism. More in detail, here we suggest that the molecular mechanisms of amyloid destabilization could be driven by residues not involved in defined secondary structures, with unstructured amyloid regions acting as source of instability for the overall fibril by opening a nanofracture able to propagate into the protein, until the complete unfolding of the molecular assembly takes place.

Black hole particle emission in higher-dimensional spacetimes.

In models with extra dimensions, a black hole evaporates both in the bulk and on the visible brane, where standard model fields live. The exact emissivities of each particle species are needed to determine how the black hole decay proceeds. We compute and discuss the absorption cross sections, the relative emissivities, and the total power output of all known fields in the evaporation phase. Graviton emissivity is highly enhanced as the spacetime dimensionality increases. Therefore, a black hole loses a significant fraction of its mass in the bulk. This result has important consequences for the phenomenology of black holes in models with extra dimensions and black hole detection in particle colliders.

Increased transcription factor expression and permeability of the blood brain barrier associated with cardiopulmonary bypass in lambs.

BACKGROUND: The pathophysiology of neurocognitive dysfunction and developmental delay after cardiopulmonary bypass (CPB) in infants is not known. It is known that head trauma, stroke, and seizures cause dysfunction of the blood brain barrier (BBB) that is associated with increased inducible transcription factor gene expression in the cells of the barrier. The purpose of this study was to determine the effects of CPB and hypothermic circulatory arrest on expression of the transcription factor FOS and the function of the BBB in an infant animal model. METHODS: Infant lambs (n = 36; 10-12 days) were exposed to 0, 15, 30, 60, or 120 minutes of normothermic (38 degrees C) CPB or 2 hours of hypothermic circulatory arrest at 16 degrees C. After terminating bypass 15 animals had their brains perfusion-fixed and removed for immunohistochemical analysis of expression of the transcription factor FOS. The other animals were perfused with fluorescent albumin to visualize the brain microvasculature. Brain sections were analyzed with a laser scanning confocal microscope. RESULTS: Control animals (n = 6, sham operated and cannulated) exhibited normal vasculature with negligible leakage and no FOS protein expression in neurons or endothelial cells anywhere in the brain. Significant FOS expression in barrier-associated structures including the blood vessels, choroid plexus, and ependyma but not neurons occurred at all times on bypass. CPB caused leakage of fluorescent albumin from blood vessels in all animals. Two hours of normothermic CPB (n = 4) caused significant (p < 0.01) leakage in the cerebellum, cortex, hippocampus, and corpus callosum. Animals exposed to circulatory arrest experienced severe leakage throughout the brain (p < 0.001) and FOS expression in all cells. CONCLUSIONS: These experiments indicate that the BBB is dysfunctional after all time points on normothermic CPB, BBB dysfunction is worsened by hypothermic circulatory arrest, and BBB dysfunction is associated with intense molecular activity within the barrier-forming cells. Dysfunction of the BBB may contribute to neurologic complications after heart surgery.

Peripheral markers of blood-brain barrier damage.

Neurological diseases are often associated with cerebrovascular dysfunction and changes in blood-brain barrier (BBB) function. This is important for two seemingly conflicting reasons. On the one hand, a leaky BBB may lead to brain disease by allowing extravasation of cells and molecules normally segregated in the periphery, while on the other hand an intact BBB may hamper drug delivery to the ailing brain. Under both circumstances, it would be desirable to follow closely over time BBB "tightness". Several lines of evidence have suggested that the astrocytic protein S100beta is a potentially useful peripheral marker of BBB permeability. Other markers of brain-to-blood barriers have been recently discovered by a proteomic approach. These proteins are virtually absent in normal blood, appear in serum from patients with cerebral lesions, and can be easily detected. We will present clinical and laboratory evidence supporting the use of these markers as modern neurodiagnostic tools.

Peripheral markers of brain damage and blood-brain barrier dysfunction.

PURPOSE: Occurrence of brain damage is frequently associated with abnormal blood-brain barrier (BBB) function. Two brain-specific proteins, S100beta and neuron-specific enolase (NSE) are released systemically in a variety of neurological diseases, but S100beta levels sometimes rise in the absence of neuronal damage, suggesting that S100beta is a marker of BBB rather than neuronal damage. METHODS: We measured both proteins in the serum of patients undergoing iatrogenic BBB disruption with intrarterial mannitol, followed by chemotherapy. RESULTS: Serum S100beta increased significantly after mannitol infusion (p<0.05) while NSE did not. Furthermore, in a model of intracerebral hemorrhage, S100beta increases in CSF did not lead to serum changes at a time when the BBB was intact. Modeling of S100beta release from the CNS suggested that low (<0.34 ng/ml) serum levels of S100beta are consistent with BBB opening without CNS damage, while larger increases imply synthesis and release from presumable damaged glia. CONCLUSIONS: Thus, S100beta in serum is an early marker of BBB openings that may precede neuronal damage and may influence therapeutic strategies. Secondary, massive elevations in S100beta are indicators of prior brain damage and bear clinical significance as predictors of poor outcome or diagnostic means to differentiate extensive damage from minor, transient impairment.

A glial-derived protein, S100B, in neonates and infants with congenital heart disease: evidence for preexisting neurologic injury.

UNLABELLED: The glial-derived protein S100B is a serum marker of cerebral ischemia and correlates with negative neurological outcome after cardiopulmonary bypass (CPB) in adults. We sought to characterize the S100B release pattern before and after CPB in neonates and infants with congenital heart disease and correlate it with surgical mortality. Serum was collected before surgery and at 24 postoperative h from 109 neonates and infants with congenital heart disease. All patients had presurgical transthoracic echocardiograms and CPB with or without hypothermic circulatory arrest. S100B concentrations were determined using a two-site immunoluminometric assay (Sangtec 100). Thirty-day surgical mortality was observed. All neonates had significantly increased S100B concentrations before surgery that decreased by 24 postoperative h. Preoperative S100B concentrations in 32 neonates with hypoplastic left heart syndrome correlated inversely with the forward flow and size of the ascending aorta and postoperative mortality (r(2) = -0.63; P = 0.03). Among infants, increased pulmonary blood flow was associated with higher S100B levels before surgery than cyanosis. There was no correlation with postoperative S100B and time on CPB, hypothermic circulatory arrest, or 30-day surgical mortality. In conclusion, preoperative S100B concentrations correlate inversely with the size of the ascending aorta in hypoplastic left heart syndrome and may serve as a marker for preexisting brain injury and mortality. IMPLICATIONS: Neonates with hypoplastic left heart syndrome and no forward flow in the ascending aorta may have brain injury at birth before heart surgery.