Leveraging Non-negative Matrix Tri-Factorization and Knowledge-Based Embeddings for Drug Repurposing: an Application to Parkinson's Disease

Drug repurposing, which involves using already approved drugs for new clinical targets, represents a cost-effective alternative to the development of new drugs. In this study, we introduce an innovative computational strategy, which uses Non-negative Matrix Tri-Factorization (NMTF) to generate vector embeddings of given sizes for drugs and drug targets; vector embeddings are then employed to generate predictions for drug repurposing using conventional classifiers, like random forest, logistic regression, and multi-layer perceptron. Our approach leverages the NMTF method within a new approach to classification, named two-tower architecture, which is effective in solving complex tasks, such as the optimal prediction of targets for already approved drugs. This approach produces robust models, with AUROC reaching 0.90, which outperform traditional NMTF. We evaluate our method in the context of Parkinson's Disease; within the newly revealed drug-target predictions, we highlight compounds that exhibit potential in mitigating neurodegeneration, thereby revealing a potentially useful drug in relationships with a well-identified target

Two-dimensional non-commutative Yang-Mills theory: coherent effects in open Wilson line correlators

A perturbative calculation of the correlator of three parallel open Wilson lines is performed for the U(N) theory in two non-commutative space-time dimensions. In the large-N planar limit, the perturbative series is fully resummed and asymptotically leads to an exponential increase of the correlator with the lengths of the lines, in spite of an interference effect between lines with the same orientation. This result generalizes a similar increase occurring in the two-line correlator and is likely to persist when more lines are considered provided they share the same direction.Comment: 22 pages, 1 figure, typeset in JHEP styl

How the heterogeneity of the severely injured brain affects hybrid 2 diffuse optical signals: case examples and guidelines

Significance: A shortcoming for the routine clinical use of diffuse optics (DO) in the injured head has been that the results from commercial near-infrared spectroscopy-based devices are not reproducible, often give phys iologically invalid values and differ between systems. Besides the limitations due to the physics of continuous23 wave light sources, one culprit is the head heterogeneity and the underlying morphological and functional abnor malities of the probed tissue. Aim: To investigate the effect that different tissue alterations in the damaged head has on DO signals and provide guidelines to avoid data misinterpretation. Approach: DO measurements and computed tomography scans were acquired on brain-injured patients. The relationship between the signals and the underlying tissue types was classified on a case-by-case basis. Results: Examples and suggestions to establish quality control routines were provided. The findings suggested guidelines for carrying out DO measurements and speculations towards improved devices. Conclusions: This study advocates for the standardization of the DO measurements to secure a role for DO in neurocritical care. We suggest that blind measurements are unacceptably problematic due to confounding effects and care using a priori and a posteriori quality control routines that go beyond an assessment of the signal-to-noise ratio that is typically utilized.Preprin

Oxygen Sensing in Neurodegenerative Diseases: Current Mechanisms, Implication of Transcriptional Response, and Pharmacological Modulation

: Significance: Oxygen (O2) sensing is the fundamental process through which organisms respond to changes in O2 levels. Complex networks exist allowing the maintenance of O2 levels through the perception, capture, binding, transport, and delivery of molecular O2. The brain extreme sensitivity to O2 balance makes the dysregulation of related processes crucial players in the pathogenesis of neurodegenerative diseases (NDs). In this study, we wish to review the most relevant advances in O2 sensing in relation to Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Recent Advances: Over the years, it has been clarified that most NDs share common pathways, a great number of which are in relation to O2 imbalance. These include hypoxia, hyperoxia, reactive oxygen species production, metabolism of metals, protein misfolding, and neuroinflammation. Critical Issues: There is still a gap in knowledge concerning how O2 sensing plays a role in the above indicated neurodegenerations. Specifically, O2 concentrations are perceived in body sites that are not limited to the brain, but primarily reside in other organs. Moreover, the mechanisms of O2 sensing, gene expression, and signal transduction seem to correlate with neurodegeneration, but many aspects are mechanistically still unexplained. Future Directions: Future studies should focus on the precise characterization of O2 level disruption and O2 sensing mechanisms in NDs. Moreover, advances need to be made also concerning the techniques used to assess O2 sensing dysfunctions in these diseases. There is also the need to develop innovative therapies targeting this precise mechanism rather than its secondary effects, as early intervention is necessary. Antioxid. Redox Signal. 38, 160-182

Transcranial, noninvasive evaluation of the potential misery perfusion during hyperventilation therapy of traumatic brain injury patients

Hyperventilation (HV) therapy uses vasoconstriction to reduce intracranial pressure (ICP) by reducing cerebral blood volume. However, as HV also lowers cerebral blood flow (CBF), it may provoke misery perfusion (MP) where the decrease in CBF is coupled with increased oxygen extraction fraction (OEF). MP may rapidly lead to the exhaustion of brain energy metabolites, making it vulnerable to ischemia. MP is difficult to detect at the bedside, which is where transcranial hybrid, near-infrared spectroscopies are promising since they noninvasively measure OEF and CBF.Peer ReviewedPostprint (author's final draft

Non-invasive estimation of intracranial pressure by diffuse optics: a proof-of-concept study

Intracranial pressure (ICP) is an important parameter to monitor in several neuropathologies. However, because current clinically accepted methods are invasive, its monitoring is limited to patients in critical conditions. On the other hand, there are other less critical conditions for which ICP monitoring could still be useful; therefore, there is a need to develop non-invasive methods. We propose a new method to estimate ICP based on the analysis of the non-invasive measurement of pulsatile, microvascular cerebral blood flow with diffuse correlation spectroscopy. This is achieved by training a recurrent neural network using only the cerebral blood flow as the input. The method is validated using a 50% split sample method using the data from a proof-of-concept study. The study involved a population of infants (n = 6) with external hydrocephalus (initially diagnosed as benign enlargement of subarachnoid spaces) as well as a population of adults (n = 6) with traumatic brain injury. The algorithm was applied to each cohort individually to obtain a model and an ICP estimate. In both diverse cohorts, the non-invasive estimation of ICP was achieved with an accuracy of 0.9) and good concordance (Lin's concordance correlation coefficient >0.9) in comparison with standard clinical, invasive ICP monitoring. This preliminary work paves the way for further investigations of this tool for the non-invasive, bedside assessment of ICP.This work leading to the results was funded by the European Union’s Horizon 2020 project “BitMap: Brain injury and trauma monitoring using advanced photonics” (No. 675332); Fundació CELLEX Barcelona; Ministerio de Economía y Competitividad /FEDER (PHOTODEMENTIA, DPI2015-64358-C2-1-R); Instituto de Salud Carlos III / FEDER (MEDPHOTAGE, DTS16/00087 and PI18/00468); the “Severo Ochoa” Programme for Centers of Excellence in R&D (SEV-2015-0522); the Obra social “laCaixa” Foundation (LlumMedBcn); Institució CERCA, AGAUR-Generalitat (2017 SGR 1380); LASERLAB-EUROPE IV; KidsBrainIT (ERA-NET NEURON) and la Fundació La Marató de TV3 (201709.31 and 201724.31).Peer ReviewedPostprint (author's final draft

Identification of a novel pathway in sporadic Amyotrophic Lateral Sclerosis mediated by the long non-coding RNA ZEB1-AS1

Background: Deregulation of transcription in the pathogenesis of sporadic Amyotrophic Lateral Sclerosis (sALS) is taking central stage with RNA-sequencing analyses from sALS patients tissues highlighting numerous deregulated long non-coding RNAs (lncRNAs). The oncogenic lncRNA ZEB1-AS1 is strongly downregulated in peripheral blood mononuclear cells of sALS patients. In addition, in cancer-derived cell lines, ZEB1-AS1 belongs to a negative feedback loop regulation with hsa-miR-200c, acting as a molecular sponge for this miRNA. The role of the lncRNA ZEB1-AS1 in sALS pathogenesis has not been characterized yet, and its study could help identifying a possible disease-modifying target. Methods: the implication of the ZEB1-AS1/ZEB1/hsa-miR-200c/BMI1 pathway was investigated in multiple patients-derived cellular models (patients-derived peripheral blood mononuclear cells and induced pluripotent stem cells-derived neural stem cells) and in the neuroblastoma cell line SH-SY5Y, where its function was inhibited via RNA interference. Molecular techniques such as Real Time PCR, Western Blot and Immunofluorescence were used to assess the pathway dysregulation. Results: Our results show a dysregulation of a signaling pathway involving ZEB1-AS1/hsa-miR-200c/β-Catenin in peripheral blood mononuclear cells and in induced pluripotent stem cells-derived neural stem cells from sALS patients. These results were validated in vitro on the cell line SH-SY5Y with silenced expression of ZEB1-AS1. Moreover, we found an increase for ZEB1-AS1 during neural differentiation with an aberrant expression of β-Catenin, highlighting also its aggregation and possible impact on neurite length. Conclusions: Our results support and describe the role of ZEB1-AS1 pathway in sALS and specifically in neuronal differentiation, suggesting that an impairment of β-Catenin signaling and an alteration of the neuronal phenotype are taking place

The role of scatterometry in ocean model forcing

VI Expanding Ocean Frontiers Conference, 5-7 July 2021, Barcelona, Spain.-- 25 page

Transcriptional regulatory logic of the diurnal cycle in the mouse liver.

Many organisms exhibit temporal rhythms in gene expression that propel diurnal cycles in physiology. In the liver of mammals, these rhythms are controlled by transcription-translation feedback loops of the core circadian clock and by feeding-fasting cycles. To better understand the regulatory interplay between the circadian clock and feeding rhythms, we mapped DNase I hypersensitive sites (DHSs) in the mouse liver during a diurnal cycle. The intensity of DNase I cleavages cycled at a substantial fraction of all DHSs, suggesting that DHSs harbor regulatory elements that control rhythmic transcription. Using chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq), we found that hypersensitivity cycled in phase with RNA polymerase II (Pol II) loading and H3K27ac histone marks. We then combined the DHSs with temporal Pol II profiles in wild-type (WT) and Bmal1-/- livers to computationally identify transcription factors through which the core clock and feeding-fasting cycles control diurnal rhythms in transcription. While a similar number of mRNAs accumulated rhythmically in Bmal1-/- compared to WT livers, the amplitudes in Bmal1-/- were generally lower. The residual rhythms in Bmal1-/- reflected transcriptional regulators mediating feeding-fasting responses as well as responses to rhythmic systemic signals. Finally, the analysis of DNase I cuts at nucleotide resolution showed dynamically changing footprints consistent with dynamic binding of CLOCK:BMAL1 complexes. Structural modeling suggested that these footprints are driven by a transient heterotetramer binding configuration at peak activity. Together, our temporal DNase I mappings allowed us to decipher the global regulation of diurnal transcription rhythms in the mouse liver