Directing B7-H3 chimeric antigen receptor T cell homing through IL-8 induces potent antitumor activity against pediatric sarcoma.

Background: Advances in pediatric oncology have occurred for some cancers; however, new therapies for sarcoma have been inadequate. Cellular immunotherapy using chimeric antigen receptor (CAR) T cells has shown dramatic benefits in leukemia, lymphoma, and multiple myeloma but has been far less successful in pediatric solid tumors such as rhabdomyosarcoma (RMS) and osteosarcoma (OS). Balancing issues of "on-target, off-tumor toxicity", investigators have identified B7-H3 as a broadly expressed tumor antigen with otherwise restricted expression on normal tissues.

The Use of Parenteral Nutrition and Disparities in Its Allocation Following Traumatic Injury.

Introduction: Severe traumatic injury requires rapid and extensive deployment of resources to save the lives of the critically injured. The sequelae of traumatic injuries frequently require extensive intervention obligating patients to a complicated recovery process devoid of meaningful nutrition. In this setting, parenteral nutrition (PN) is key in enabling appropriate wound healing, recovery, and rehabilitation.

High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways.

Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel in vivo functional analysis of 10 ASD genes at the behavioral, structural, and circuit levels in zebrafish mutants, revealing both unique and overlapping effects of gene loss of function. Whole-brain mapping identifies the forebrain and cerebellum as the most significant contributors to brain size differences, while regions involved in sensory-motor control, particularly dopaminergic regions, are associated with altered baseline brain activity.

Capturing Fleeting Intermediates in a Claisen Rearrangement Using Nonequilibrium Droplet Imbibition Reaction Conditions.

The Claisen rearrangement of aromatic allyl phenyl ether to 2-allyl phenol is known to be induced by heat, acid, and air-water interfacial (on-water) effects. In this work, we show that the combination of acid and interfacial effects in an "on-droplet" experiment accelerates this reaction even further (by a factor >10×). The reaction acceleration was achieved through a droplet imbibition mass spectrometry (MS) experiment that allows reactants to be deposited on rapidly moving (100 m/s), charged microdroplets while avoiding turbulent mixing.

Anchor-based bisulfite sequencing determines genome-wide DNA methylation.

Whole Genome Bisulfite Sequencing (WGBS) is the current standard for DNA methylation profiling. However, this approach is costly as it requires sequencing coverage over the entire genome. Here we introduce Anchor-Based Bisulfite Sequencing (ABBS).

Molecular Docking as a Tool to Examine Organic Cation Sorption to Organic Matter.

Molecular docking simulations were performed to examine the structural effects of organic cations on their sorption to organic matter. A set of benzylamine compounds was used to assess the sorption trends arising from the systematic structural differences between ring or nitrogen substituents. Binding simulations were performed using AutoDock 4.

Defining variant-resistant epitopes targeted by SARS-CoV-2 antibodies: A global consortium study.

Antibody-based therapeutics and vaccines are essential to combat COVID-19 morbidity and mortality after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Multiple mutations in SARS-CoV-2 that could impair antibody defenses propagated in human-to-human transmission and spillover or spillback events between humans and animals. To develop prevention and therapeutic strategies, we formed an international consortium to map the epitope landscape on the SARS-CoV-2 spike protein, defining and structurally illustrating seven receptor binding domain (RBD)–directed antibody communities with distinct footprints and competition profiles.

Longitudinal auditory pathophysiology following mild blast-induced trauma.

Blast-induced hearing difficulties affect thousands of veterans and civilians. The long-term impact of even a mild blast exposure on the central auditory system is hypothesized to contribute to lasting behavioral complaints associated with mild blast traumatic brain injury (bTBI). Although recovery from mild blast has been studied separately over brief or long time windows, few, if any, studies have investigated recovery longitudinally over short-term and longer-term (months) time windows.

Alkynyl-Based Covalent Organic Frameworks as High-Performance Anode Materials for Potassium-Ion Batteries.

The development of high-performance organic electrodes for potassium-ion batteries (KIBs) is attracting interest due to their sustainability and low costs. However, the electrolyte systems and moieties that generally proved to be successful in high-performance Li-ion batteries have found relatively little success in KIBs. Herein, two alkynyl-based covalent organic frameworks (COFs) containing 1,3,5-tris(arylethynyl)benzene (TAEB) and dehydrobenzoannulene (DBA) units are utilized as bulk anode materials for KIBs in a localized high-concentration electrolyte.

A simple and effective F0 knockout method for rapid screening of behaviour and other complex phenotypes.

Hundreds of human genes are associated with neurological diseases, but translation into tractable biological mechanisms is lagging. Larval zebrafish are an attractive model to investigate genetic contributions to neurological diseases. However, current CRISPR-Cas9 methods are difficult to apply to large genetic screens studying behavioural phenotypes.

Stem cell-derived polarized hepatocytes.

Human stem cell-derived hepatocyte-like cells (HLCs) offer an attractive platform to study liver biology. Despite their numerous advantages, HLCs lack critical in vivo characteristics, including cell polarity. Here, we report a stem cell differentiation protocol that uses transwell filters to generate columnar polarized HLCs with clearly defined basolateral and apical membranes separated by tight junctions.

Acrolein-mediated alpha-synuclein pathology involvement in the early post-injury pathogenesis of mild blast-induced Parkinsonian neurodegeneration.

Survivors of blast-induced traumatic brain injury (bTBI) have increased susceptibility to Parkinson's disease (PD), characterized by α-synuclein aggregation and the progressive degeneration of nigrostriatal dopaminergic neurons. Using an established bTBI rat model, we evaluated the changes of α-synuclein and tyrosine hydroxylase (TH), known hallmarks of PD, and acrolein, a reactive aldehyde and marker of oxidative stress, with the aim of revealing key pathways leading to PD post-bTBI. Indicated in both animal models of PD and TBI, acrolein is likely a point of pathogenic convergence.

Stereo- and Regioselective Synthesis of Molecular Baskets.

We describe a stereoselective method for obtaining multigram quantities of molecular basket 1 in overall 11% yield, using inexpensive cyclopentadiene and diethyl fumarate as starting materials. First, an asymmetric synthesis of enantioenriched bromo(trimethylstannyl)alkene (-)-8 was accomplished by the stereoselective bromination of dibromonorbornene (+)-4 guided by anchimeric assistance and subsequent syn- exo-elimination of tetrabromonorbornane (-)-5a as the key steps. Subsequent Cu(I)-catalyzed cyclotrimerization of (-)-8 was optimized to give 1 in 85% yield and 1:1 ratio of diastereomers.

Functional Peptide Nanofibers with Unique Tumor Targeting and Enzyme-Induced Local Retention Properties.

An effective tumoral delivery system should show minimal removal by the reticuloendothelial system (RES), promote tumor uptake and penetration, and minimize on-site clearance. This study reports the design and synthesis of advanced self-assembling peptide nanofiber precursor (NFP) analogues. The peptidic nature of NFP offers the design flexibility for on-demand customization with imaging agents and surface charges while maintaining a set size, allowing for real-time monitoring of kinetic and dynamic tumoral delivery by multimodal fluorescence/positron emission tomography/computed tomography (fluo/PET/CT) imaging, for formulation optimization.

Selective Enrichment and Direct Analysis of Protein S-Palmitoylation Sites.

S-Fatty-acylation is the covalent attachment of long chain fatty acids, predominately palmitate (C16:0, S-palmitoylation), to cysteine (Cys) residues via a thioester linkage on proteins. This post-translational and reversible lipid modification regulates protein function and localization in eukaryotes and is important in mammalian physiology and human diseases. While chemical labeling methods have improved the detection and enrichment of S-fatty-acylated proteins, mapping sites of modification and characterizing the endogenously attached fatty acids are still challenging.

IKKβ is a β-catenin kinase that regulates mesenchymal stem cell differentiation.

Mesenchymal stem cells (MSCs) can give rise to both adipocytes and osteoblasts, but the molecular mechanisms underlying MSC fate determination remain poorly understood. IκB kinase β (IKKβ), a central coordinator of inflammation and immune responses through activation of NF-κB, has been implicated as a critical molecular link between obesity and metabolic disorders. Here, we show that IKKβ can reciprocally regulate adipocyte and osteoblast differentiation of murine and human MSCs through an NF-κB-independent mechanism.

αIIbβ3 binding to a fibrinogen fragment lacking the γ-chain dodecapeptide is activation dependent and EDTA inducible.

Platelet integrin receptor αIIbβ3 supports platelet aggregation by binding fibrinogen. The interaction between the fibrinogen C-terminal γ-chain peptide composed of residues γ-404-411 (GAKQAGDV) and the Arg-Gly-Asp (RGD) binding pocket on αIIbβ3 is required for fibrinogen-mediated platelet aggregation, but data suggest that other ancillary binding sites on both fibrinogen and αIIbβ3 may lead to higher-affinity fibrinogen binding and clot retraction. To identify additional sites, we analyzed the ability of platelets and cells expressing normal and mutant αIIbβ3 to adhere to an immobilized fibrinogen plasmin fragment that lacks intact γ-404-411 ('D98').

Pathological correlations between traumatic brain injury and chronic neurodegenerative diseases.

Traumatic brain injury is among the most common causes of death and disability in youth and young adults. In addition to the acute risk of morbidity with moderate to severe injuries, traumatic brain injury is associated with a number of chronic neurological and neuropsychiatric sequelae including neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. However, despite the high incidence of traumatic brain injuries and the established clinical correlation with neurodegeneration, the causative factors linking these processes have not yet been fully elucidated.

Chemical proteomics reveals ADP-ribosylation of small GTPases during oxidative stress.

ADP-ribosylation is a post-translational modification that is known to be involved in cellular homeostasis and stress but has been challenging to analyze biochemically. To facilitate the detection of ADP-ribosylated proteins, we show that an alkyne-adenosine analog, N-propargyl adenosine (NpA), is metabolically incorporated in mammalian cells and enables fluorescence detection and proteomic analysis of ADP-ribosylated proteins. Notably, our analysis of NpA-labeled proteins that are upregulated by oxidative stress revealed differential ADP-ribosylation of small GTPases.

Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2.

Autism spectrum disorders (ASDs) are a group of devastating neurodevelopmental syndromes that affect up to 1 in 68 children. Despite advances in the identification of ASD risk genes, the mechanisms underlying ASDs remain unknown. Homozygous loss-of-function mutations in Contactin Associated Protein-like 2 (CNTNAP2) are strongly linked to ASDs.

Zero-Aliasing Correlation Filters for Object Recognition.

Correlation filters (CFs) are a class of classifiers that are attractive for object localization and tracking applications. Traditionally, CFs have been designed in the frequency domain using the discrete Fourier transform (DFT), where correlation is efficiently implemented. However, existing CF designs do not account for the fact that the multiplication of two DFTs in the frequency domain corresponds to a circular correlation in the time/spatial domain.

Evaluation of a collagen-coated, resorbable fiber scaffold loaded with a peptide basic fibroblast growth factor mimetic in a sheep model of rotator cuff repair.

Background: A new scaffold design combined with a peptide growth factor was tested prospectively for safety and for improved tendon healing in sheep.

Methods: The infraspinatus tendon was detached and then surgically repaired to the humerus using sutures and anchors in 50 adult sheep. The repairs in 40 of these sheep were reinforced with a scaffold containing F2A, a peptide mimetic of basic fibroblast growth factor.

A novel class of ion displacement ligands as antagonists of the αIIbβ3 receptor that limit conformational reorganization of the receptor.

A collection of αIIbβ3 integrin receptor antagonists possessing a unique MIDAS metal ion displacement mechanism of action is presented. Insight into these agents' structure-activity relationships, binding modality, and pharmacokinetic and pharmacodynamic profiles highlight the potential of these small molecule ion displacement ligands as attractive candidates for clinical development.