PANAMA-enabled high-sensitivity dual nanoflow LC-MS metabolomics and proteomics analysis.

High-sensitivity nanoflow liquid chromatography (nLC) is seldom employed in untargeted metabolomics because current sample preparation techniques are inefficient at preventing nanocapillary column performance degradation. Here, we describe an nLC-based tandem mass spectrometry workflow that enables seamless joint analysis and integration of metabolomics (including lipidomics) and proteomics from the same samples without instrument duplication. This workflow is based on a robust solid-phase micro-extraction step for routine sample cleanup and bioactive molecule enrichment.

Corrigendum: Integrated metabolomics and proteomics reveal biomarkers associated with hemodialysis in end-stage kidney disease.

[This corrects the article DOI: 10.3389/fphar.2023.

A Commentary on Fasting of Nonclinical Research Animals.

This commentary discusses the implementation of fasting in nonclinical animal experimental subjects. The short-term removal of food from cages of experimental animals is in all respects innocuous. The term "stress" is ill-defined and the statutes and regulations governing animal research laboratories that exert their authority in the performance of their operations do so without substantive grounds to base compliance.

Integrated metabolomics and proteomics reveal biomarkers associated with hemodialysis in end-stage kidney disease.

We hypothesize that the poor survival outcomes of end-stage kidney disease (ESKD) patients undergoing hemodialysis are associated with a low filtering efficiency and selectivity. The current gold standard criteria using single or several markers show an inability to predict or disclose the treatment effect and disease progression accurately. We performed an integrated mass spectrometry-based metabolomic and proteomic workflow capable of detecting and quantifying circulating small molecules and proteins in the serum of ESKD patients.

Characterization and root cause analysis of immunogenicity to pasotuxizumab (AMG 212), a prostate-specific membrane antigen-targeting bispecific T-cell engager therapy.

Introduction: In oncology, anti-drug antibody (ADA) development that significantly curtails response durability has not historically risen to a level of concern. The relevance and attention ascribed to ADAs in oncology clinical studies have therefore been limited, and the extant literature on this subject scarce. In recent years, T cell engagers have gained preeminence within the prolific field of cancer immunotherapy.

Distortion Product Otoacoustic Emission Test is Not the Test to Use in Nonclinical Safety Assessment.

Ototoxicity and ocular toxicity screening are but two examples of specialty product lines that are often employed as Tier II or III nonclinical safety/hazard screening assessments. Compared to the regulatory guidelines that govern over standard toxicology or neurotoxicology programs, there is a paucity of regulatory strategies to address these specialized product lines. With respect to ototoxicity testing, we argue for the inclusion of the "least burdensome principles" adopted by the US FDA in providing the most pragmatic, efficient, and directed identification of potential harm to auditory function in the nonclinical safety arena.

Machine learning-guided, big data-enabled, biomarker-based systems pharmacology: modeling the stochasticity of natural history and disease progression.

The incidence of systemic and metabolic co-morbidities increases with aging. The purpose was to investigate a novel paradigm for modeling the orchestrated changes in many disease-related biomarkers that occur during aging. A hybrid strategy that integrates machine learning and stochastic modeling was evaluated for modeling the long-term dynamics of biomarker systems.

The cholesterol autoxidation products, 7-ketocholesterol and 7β-hydroxycholesterol are associated with serum neurofilaments in multiple sclerosis.

Background: Serum neurofilament light chain (sNfL) is an established marker of neuroaxonal injury in multiple sclerosis (MS).

Objectives: To investigate if oxysterols produced from non-enzymatic and enzymatic cholesterol oxidation are differentially associated with sNfL measurements in MS.

Methods: This longitudinal study included 62 relapsing-remitting (RR-MS) and 36 progressive MS (PMS) patients with baseline and 5-year follow-up measures of serum levels of 6 oxysterols, sNfL and lipids.

Machine learning in pharmacometrics: Opportunities and challenges.

The explosive growth in medical devices, imaging and diagnostics, computing, and communication and information technologies in drug development and healthcare has created an ever-expanding data landscape that the pharmacometrics (PMX) research community must now traverse. The tools of machine learning (ML) have emerged as a powerful computational approach in other data-rich disciplines but its effective utilization in the pharmaceutical sciences and PMX modelling is in its infancy. ML-based methods can complement PMX modelling by enabling the information in diverse sources of big data, e.

Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2.

Human transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative pathogen of the COVID-19 pandemic, exerts a massive health and socioeconomic crisis. The virus infects alveolar epithelial type 2 cells (AT2s), leading to lung injury and impaired gas exchange, but the mechanisms driving infection and pathology are unclear. We performed a quantitative phosphoproteomic survey of induced pluripotent stem cell-derived AT2s (iAT2s) infected with SARS-CoV-2 at air-liquid interface (ALI).

Prescribing Pattern of Oral Anticoagulants in Patients With Obesity.

Introduction: There is limited efficacy and safety data for direct oral anticoagulants (DOACs) in patients with obesity, and it has been suggested to avoid DOACs in this patient population.

Objective: Describe the prescribing pattern of oral anticoagulants in obese patients in an urban university setting and assess efficacy, safety, and adherence.

Methods: Retrospective, cohort study in patients ≥18 years with a history of VTE and/or atrial fibrillation.

Neuroprotective associations of apolipoproteins A-I and A-II with neurofilament levels in early multiple sclerosis.

Background: The role of cholesterol homeostasis in neuroaxonal injury in multiple sclerosis is not known.

Objective: The objective of the study is to investigate the associations of cerebrospinal fluid (CSF) and serum neurofilament light chain levels (CSF-NfL and sNfL, respectively), which are biomarkers of neuroaxonal injury, with cholesterol biomarkers at the clinical onset of multiple sclerosis.

Methods: sNfL, serum cholesterol profile (total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), serum apolipoprotein (Apo) levels (ApoA-I, ApoA-II, ApoB, and ApoE), and albumin quotient were obtained for 133 patients (63% female, age: 29.

Apolipoproteins AI and E are associated with neuroaxonal injury to gray matter in multiple sclerosis.

Purpose To investigate the associations between longitudinal changes in lipid biomarkers and serum neurofilament (sNfL) levels in multiple sclerosis (MS) neurodegeneration and disease progression. Methods 5-year prospective, longitudinal study included 75 relapsing-remitting MS (RR-MS) and 37 progressive-MS (P-MS) patients. sNfL, plasma total cholesterol (TC), high-density (HDL-C) and low-density (LDL-C) lipoprotein cholesterol, apolipoproteins (Apo), ApoA-I, Apo-II, ApoB, ApoC-II and ApoE were measured at baseline and 5-years.

Osteocytes control myeloid cell proliferation and differentiation through Gsα-dependent and -independent mechanisms.

Osteocytes, the bone cells embedded in the mineralized matrix, control bone modeling, and remodeling through direct contact with adjacent cells and via paracrine and endocrine factors that affect cells in the bone marrow microenvironment or distant organs. Osteocytes express numerous G protein-coupled receptors (GPCRs) and thus mice lacking the stimulatory subunit of G-protein (Gsα) in osteocytes (Dmp1-Gsα mice) have abnormal myelopoiesis, osteopenia, and reduced adipose tissue. We previously reported that the severe osteopenia and the changes in adipose tissue present in these mice were mediated by increased sclerostin, which suppress osteoblast functions and promote browning of white adipocytes.

Neurofilament levels are associated with blood-brain barrier integrity, lymphocyte extravasation, and risk factors following the first demyelinating event in multiple sclerosis.

Background: Increased blood brain barrier (BBB) permeability, CNS inflammation and neuroaxonal damage are pathological hallmarks in early multiple sclerosis (MS).

Objective: To investigate the associations of neurofilament light chain (NfL) levels with measures of BBB integrity and central nervous system (CNS) inflammation in MS during the first demyelinating event.

Methods: Blood and cerebrospinal fluid (CSF) were obtained from 142 MS (McDonald 2017) treatment-naive patients from the SET study (63% female; age: 29.

Lionfish (Pterois volitans) as biomonitoring species for oil pollution effects in coral reef ecosystems.

With oil spills, and other sources of aromatic hydrocarbons, being a continuous threat to coral reef systems, and most reef fish species being protected or difficult to collect, the use of the invasive lionfish (Pterois volitans) might be a good model species to monitor biomarkers in potentially exposed fish in the Caribbean and western Atlantic. The rapid expansion of lionfish in the Caribbean and western Atlantic, and the unregulated fishing for this species, would make the lionfish a suitable candidate as biomonitoring species for oil pollution effects. However, to date little has been published about the responses of lionfish to environmental pollutants.

Generalized Pharmacometric Modeling, a Novel Paradigm for Integrating Machine Learning Algorithms: A Case Study of Metabolomic Biomarkers.

There is an unmet need for identifying innovative machine learning (ML) strategies to improve drug treatment regimens and therapeutic outcomes. We investigate Generalized Pharmacometric Modeling (GPM), a novel paradigm that integrates ML algorithms with pharmacokinetic and pharmacodynamic structural models, population covariate modeling, and "big data," and enables identification of patient-specific factors contributing to drug disposition. We hypothesize that GPM will enhance forecasting of drug outcomes in diverse populations.

Correction to: Behavioral Artistry: Examining the Relationship Between the Interpersonal Skills and Effective Practice Repertoires of Applied Behavior Analysis Practitioners.

The article Behavioral Artistry: Examining the Relationship Between the Interpersonal Skills and Effective Practice Repertoires of Applied Behavior Analysis Practitioners, written by Kevin Callahan, was originally published electronically on the publisher's internet portal (currently SpringerLink) on August 29, 2019 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on August, 2019 to © The Author(s) 2019 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.

Behavioral Artistry: Examining the Relationship Between the Interpersonal Skills and Effective Practice Repertoires of Applied Behavior Analysis Practitioners.

This study investigated interpersonal skills associated with the concept of behavioral artistry (BA), a repertoire of practitioner behaviors including care, attentiveness, and creativity, among others, associated with the effective delivery of applied behavior analysis (ABA) treatment. Survey results indicated parents of children with autism preferred BA descriptors for ABA therapists over non-BA descriptors. A separate survey of 212 university students on a standardized personality assessment revealed students majoring and/or working in the field of ABA had lower levels of BA than those in other human services professions.

Altered Domain Structure of the Prion Protein Caused by Cu Binding and Functionally Relevant Mutations: Analysis by Cross-Linking, MS/MS, and NMR.

The cellular isoform of the prion protein (PrP) serves as precursor to the infectious isoform (PrP), and as a cell-surface receptor, which binds misfolded protein oligomers as well as physiological ligands such as Cu ions. PrP consists of two domains: a flexible N-terminal domain and a structured C-terminal domain. Both the physiological and pathological functions of PrP depend on intramolecular interactions between these two domains, but the specific amino acid residues involved have proven challenging to define.