•Data-driven model reduction for deterministic and random dynamical systems.•A precise formulation of data-driven modeling based on discrete-time Mori-Zwanzig formalism.•A Wiener projection ...construction unifying data-driven model reduction strategies.•Derivation of the NARMAX representation of stochastic processes from underlying dynamical model.
Model reduction methods aim to describe complex dynamic phenomena using only relevant dynamical variables, decreasing computational cost, and potentially highlighting key dynamical mechanisms. In the absence of special dynamical features such as scale separation or symmetries, the time evolution of these variables typically exhibits memory effects. Recent work has found a variety of data-driven model reduction methods to be effective for representing such non-Markovian dynamics, but their scope and dynamical underpinning remain incompletely understood. Here, we study data-driven model reduction from a dynamical systems perspective. For both chaotic and randomly-forced systems, we show the problem can be naturally formulated within the framework of Koopman operators and the Mori-Zwanzig projection operator formalism. We give a heuristic derivation of a NARMAX (Nonlinear Auto-Regressive Moving Average with eXogenous input) model from an underlying dynamical model. The derivation is based on a simple construction we call Wiener projection, which links Mori-Zwanzig theory to both NARMAX and to classical Wiener filtering. We apply these ideas to the Kuramoto-Sivashinsky model of spatiotemporal chaos and a viscous Burgers equation with stochastic forcing.
Understanding information processing in the brain requires monitoring neuronal activity at high spatiotemporal resolution. Using an ultrafast two-photon fluorescence microscope empowered by ...all-optical laser scanning, we imaged neuronal activity in vivo at up to 3,000 frames per second and submicrometer spatial resolution. This imaging method enabled monitoring of both supra- and subthreshold electrical activity down to 345 μm below the brain surface in head-fixed awake mice.
Annually in the United States, at least 3.5 million people seek medical attention for traumatic brain injury (TBI). The development of therapies for TBI is limited by the absence of diagnostic and ...prognostic biomarkers. Microtubule-associated protein tau is an axonal phosphoprotein. To date, the presence of the hypophosphorylated tau protein (P-tau) in plasma from patients with acute TBI and chronic TBI has not been investigated.
To examine the associations between plasma P-tau and total-tau (T-tau) levels and injury presence, severity, type of pathoanatomic lesion (neuroimaging), and patient outcomes in acute and chronic TBI.
In the TRACK-TBI Pilot study, plasma was collected at a single time point from 196 patients with acute TBI admitted to 3 level I trauma centers (<24 hours after injury) and 21 patients with TBI admitted to inpatient rehabilitation units (mean SD, 176.4 44.5 days after injury). Control samples were purchased from a commercial vendor. The TRACK-TBI Pilot study was conducted from April 1, 2010, to June 30, 2012. Data analysis for the current investigation was performed from August 1, 2015, to March 13, 2017.
Plasma samples were assayed for P-tau (using an antibody that specifically recognizes phosphothreonine-231) and T-tau using ultra-high sensitivity laser-based immunoassay multi-arrayed fiberoptics conjugated with rolling circle amplification.
In the 217 patients with TBI, 161 (74.2%) were men; mean (SD) age was 42.5 (18.1) years. The P-tau and T-tau levels and P-tau-T-tau ratio in patients with acute TBI were higher than those in healthy controls. Receiver operating characteristic analysis for the 3 tau indices demonstrated accuracy with area under the curve (AUC) of 1.000, 0.916, and 1.000, respectively, for discriminating mild TBI (Glasgow Coma Scale GCS score, 13-15, n = 162) from healthy controls. The P-tau level and P-tau-T-tau ratio were higher in individuals with more severe TBI (GCS, ≤12 vs 13-15). The P-tau level and P-tau-T-tau ratio outperformed the T-tau level in distinguishing cranial computed tomography-positive from -negative cases (AUC = 0.921, 0.923, and 0.646, respectively). Acute P-tau levels and P-tau-T-tau ratio weakly distinguished patients with TBI who had good outcomes (Glasgow Outcome Scale-Extended GOS-E, 7-8) (AUC = 0.663 and 0.658, respectively) and identified those with poor outcomes (GOS-E, ≤4 vs >4) (AUC = 0.771 and 0.777, respectively). Plasma samples from patients with chronic TBI also showed elevated P-tau levels and a P-tau-T-tau ratio significantly higher than that of healthy controls, with both P-tau indices strongly discriminating patients with chronic TBI from healthy controls (AUC = 1.000 and 0.963, respectively).
Plasma P-tau levels and P-tau-T-tau ratio outperformed T-tau level as diagnostic and prognostic biomarkers for acute TBI. Compared with T-tau levels alone, P-tau levels and P-tau-T-tau ratios show more robust and sustained elevations among patients with chronic TBI.
Purpose
Fibroblast activation protein (FAP) is a membrane-bound protease that has limited expression in normal adult tissues but is highly expressed in the tumor microenvironment of many solid ...cancers. FAP-2286 is a FAP-binding peptide coupled to a radionuclide chelator that is currently being investigated in patients as an imaging and therapeutic agent. The potency, selectivity, and efficacy of FAP-2286 were evaluated in preclinical studies.
Methods
FAP expression analysis was performed by immunohistochemistry and autoradiography on primary human cancer specimens. FAP-2286 was assessed in biochemical and cellular assays and in
in vivo
imaging and efficacy studies, and was further evaluated against FAPI-46, a small molecule–based FAP-targeting agent.
Results
Immunohistochemistry confirmed elevated levels of FAP expression in multiple tumor types including pancreatic, breast, and sarcoma, which correlated with FAP binding by FAP-2286 autoradiography. FAP-2286 and its metal complexes demonstrated high affinity to FAP recombinant protein and cell surface FAP expressed on fibroblasts. Biodistribution studies in mice showed rapid and persistent uptake of
68
Ga-FAP-2286,
111
In-FAP-2286, and
177
Lu-FAP-2286 in FAP-positive tumors, with renal clearance and minimal uptake in normal tissues.
177
Lu-FAP-2286 exhibited antitumor activity in FAP-expressing HEK293 tumors and sarcoma patient-derived xenografts, with no significant weight loss. In addition, FAP-2286 maintained longer tumor retention and suppression in comparison to FAPI-46.
Conclusion
In preclinical models, radiolabeled FAP-2286 demonstrated high tumor uptake and retention, as well as potent efficacy in FAP-positive tumors. These results support clinical development of
68
Ga-FAP-2286 for imaging and
177
Lu-FAP-2286 for therapeutic use in a broad spectrum of FAP-positive tumors.
Spontaneous canine cancers are valuable but relatively understudied and underutilized models. To enhance their usage, we reanalyze whole exome and genome sequencing data published for 684 cases of >7 ...common tumor types and >35 breeds, with rigorous quality control and breed validation. Our results indicate that canine tumor alteration landscape is tumor type-dependent, but likely breed-independent. Each tumor type harbors major pathway alterations also found in its human counterpart (e.g., PI3K in mammary tumor and p53 in osteosarcoma). Mammary tumor and glioma have lower tumor mutational burden (TMB) (median < 0.5 mutations per Mb), whereas oral melanoma, osteosarcoma and hemangiosarcoma have higher TMB (median ≥ 1 mutations per Mb). Across tumor types and breeds, TMB is associated with mutation of TP53 but not PIK3CA, the most mutated genes. Golden Retrievers harbor a TMB-associated and osteosarcoma-enriched mutation signature. Here, we provide a snapshot of canine mutations across major tumor types and breeds.
Biologically detailed models of brain circuitry are challenging to build and simulate due to the large number of neurons, their complex interactions, and the many unknown physiological parameters. ...Simplified mathematical models are more tractable, but harder to evaluate when too far removed from neuroanatomy/physiology. We propose that a multiscale model, coarse-grained (CG) while preserving local biological details, offers the best balance between biological realism and computability. This paper presents such a model. Generally, CG models focus on the interaction between groups of neurons—here termed “pixels”—rather than individual cells. In our case, dynamics are alternately updated at intra- and interpixel scales, with one informing the other, until convergence to equilibrium is achieved on both scales. An innovation is how we exploit the underlying biology: Taking advantage of the similarity in local anatomical structures across large regions of the cortex, we model intrapixel dynamics as a single dynamical system driven by “external” inputs. These inputs vary with events external to the pixel, but their ranges can be estimated a priori . Precomputing and tabulating all potential local responses speed up the updating procedure significantly compared to direct multiscale simulation. We illustrate our methodology using a model of the primate visual cortex. Except for local neuron-to-neuron variability (necessarily lost in any CG approximation) our model reproduces various features of large-scale network models at a tiny fraction of the computational cost. These include neuronal responses as a consequence of their orientation selectivity, a primary function of visual neurons.
Over the past few years, the application of camera-equipped Unmanned Aerial Vehicles (UAVs) for visually monitoring construction and operation of buildings, bridges, and other types of civil ...infrastructure systems has exponentially grown. These platforms can frequently survey construction sites, monitor work-in-progress, create documents for safety, and inspect existing structures, particularly for hard-to-reach areas. The purpose of this paper is to provide a concise review of the most recent methods that streamline collection, analysis, visualization, and communication of the visual data captured from these platforms, with and without using Building Information Models (BIM) as
a priori
information. Specifically, the most relevant works from Civil Engineering, Computer Vision, and Robotics communities are presented and compared in terms of their potential to lead to automatic construction monitoring and civil infrastructure condition assessment.
Tauopathies are a class of neurodegenerative disorders characterized by abnormal deposition of post-translationally modified tau protein in the human brain. Tauopathies are associated with ...Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and other diseases. Hyperphosphorylation increases tau tendency to aggregate and form neurofibrillary tangles (NFT), a pathological hallmark of AD. In this study, okadaic acid (OA, 100 nM), a protein phosphatase 1/2A inhibitor, was treated for 24h in mouse neuroblastoma (N2a) and differentiated rat primary neuronal cortical cell cultures (CTX) to induce tau-hyperphosphorylation and oligomerization as a cell-based tauopathy model. Following the treatments, the effectiveness of different kinase inhibitors was assessed using the tauopathy-relevant tau antibodies through tau-immunoblotting, including the sites: pSer202/pThr205 (AT8), pThr181 (AT270), pSer202 (CP13), pSer396/pSer404 (PHF-1), and pThr231 (RZ3). OA-treated samples induced tau phosphorylation and oligomerization at all tested epitopes, forming a monomeric band (46-67 kDa) and oligomeric bands (170 kDa and 240 kDa). We found that TBB (a casein kinase II inhibitor), AR and LiCl (GSK-3 inhibitors), cyclosporin A (calcineurin inhibitor), and Saracatinib (Fyn kinase inhibitor) caused robust inhibition of OA-induced monomeric and oligomeric p-tau in both N2a and CTX culture. Additionally, a cyclin-dependent kinase 5 inhibitor (Roscovitine) and a calcium chelator (EGTA) showed contrasting results between the two neuronal cultures. This study provides a comprehensive view of potential drug candidates (TBB, CsA, AR, and Saracatinib), and their efficacy against tau hyperphosphorylation and oligomerization processes. These findings warrant further experimentation, possibly including animal models of tauopathies, which may provide a putative Neurotherapy for AD, CTE, and other forms of tauopathy-induced neurodegenerative diseases.
Constraining the many biological parameters that govern cortical dynamics is computationally and conceptually difficult because of the curse of dimensionality. This paper addresses these challenges ...by proposing (1) a novel data-informed mean-field (MF) approach to efficiently map the parameter space of network models; and (2) an organizing principle for studying parameter space that enables the extraction biologically meaningful relations from this high-dimensional data. We illustrate these ideas using a large-scale network model of the Macaque primary visual cortex. Of the 10-20 model parameters, we identify 7 that are especially poorly constrained, and use the MF algorithm in (1) to discover the firing rate contours in this 7D parameter cube. Defining a "biologically plausible" region to consist of parameters that exhibit spontaneous Excitatory and Inhibitory firing rates compatible with experimental values, we find that this region is a slightly thickened codimension-1 submanifold. An implication of this finding is that while plausible regimes depend sensitively on parameters, they are also robust and flexible provided one compensates appropriately when parameters are varied. Our organizing principle for conceptualizing parameter dependence is to focus on certain 2D parameter planes that govern lateral inhibition: Intersecting these planes with the biologically plausible region leads to very simple geometric structures which, when suitably scaled, have a universal character independent of where the intersections are taken. In addition to elucidating the geometry of the plausible region, this invariance suggests useful approximate scaling relations. Our study offers, for the first time, a complete characterization of the set of all biologically plausible parameters for a detailed cortical model, which has been out of reach due to the high dimensionality of parameter space.
ATHENA (ClinicalTrials.gov identifier: NCT03522246) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without
or
(BRCA) mutations or ...other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA-MONO comparison of rucaparib versus placebo.
Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population.
As of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185
49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank
= .0004; hazard ratio HR, 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank
< .0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade ≥ 3 treatment-emergent adverse events were anemia (rucaparib, 28.7%
placebo, 0%) and neutropenia (14.6%
0.9%).
Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD.
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