Structuring lipid nanoparticles, DNA, and protein corona into stealth bionanoarchitectures for in vivo gene delivery.

Lipid nanoparticles (LNPs) play a crucial role in addressing genetic disorders, and cancer, and combating pandemics such as COVID-19 and its variants. Yet, the ability of LNPs to effectively encapsulate large-size DNA molecules remains elusive. This is a significant limitation, as the successful delivery of large-size DNA holds immense potential for gene therapy.

Sex differences in the molecular profile of adult diffuse glioma are shaped by IDH status and tumor microenvironment.

Background: Sex differences in adult diffuse glioma (ADG) are well-established clinically, yet the underlying molecular mechanisms remain inadequately understood. Here, we aim to reveal molecular features and cellular compositions unique to each sex in ADG to comprehend the role of sex in disease etiology.

Methods: We quantified sex differences in transcriptome of ADG using multiple independent glioma patient datasets.

Segmentation of supragranular and infragranular layers in ultra-high-resolution 7T ex vivo MRI of the human cerebral cortex.

Accurate labeling of specific layers in the human cerebral cortex is crucial for advancing our understanding of neurodevelopmental and neurodegenerative disorders. Building on recent advancements in ultra-high-resolution ex vivo MRI, we present a novel semi-supervised segmentation model capable of identifying supragranular and infragranular layers in ex vivo MRI with unprecedented precision. On a dataset consisting of 17 whole-hemisphere ex vivo scans at 120 $\mu $m, we propose a Multi-resolution U-Nets framework that integrates global and local structural information, achieving reliable segmentation maps of the entire hemisphere, with Dice scores over 0.

Enhancing Immune Responses against SARS-CoV-2 Variants in Aged Mice with INDUK: A Chimeric DNA Vaccine Encoding the Spike S1-TM Subunits.

Currently available vaccines against COVID-19 showed high efficacy against the original strain of SARS-CoV-2 but progressively lower efficacy against new variants. In response to emerging SARS-CoV-2 strains, we propose chimeric DNA vaccines encoding the spike antigen, including a combination of selected key mutations from different variants of concern. We developed two DNA vaccines, pVAX-S1-TM-D614G and pVAX-S1-TM-INDUK (INDUK), encoding the SARS-CoV-2 S1 spike subunit in fusion with the transmembrane region that allows protein trimerization as predicted by analysis.

Reduction of Filamin C Results in Altered Proteostasis, Cardiomyopathy, and Arrhythmias.

Background: Many cardiomyopathy-associated pathogenic variants are heterozygous truncations, and pathogenic variants are associated with arrhythmias. Arrhythmia triggers in filaminopathy are incompletely understood.

Methods And Results: We describe an individual with biallelic pathogenic variants, p.

Pioglitazone Phases and Metabolic Effects in Nanoparticle-Treated Cells Analyzed via Rapid Visualization of FLIM Images.

Fluorescence lifetime imaging microscopy (FLIM) has proven to be a useful method for analyzing various aspects of material science and biology, like the supramolecular organization of (slightly) fluorescent compounds or the metabolic activity in non-labeled cells; in particular, FLIM phasor analysis (phasor-FLIM) has the potential for an intuitive representation of complex fluorescence decays and therefore of the analyzed properties. Here we present and make available tools to fully exploit this potential, in particular by coding via hue, saturation, and intensity the phasor positions and their weights both in the phasor plot and in the microscope image. We apply these tools to analyze FLIM data acquired via two-photon microscopy to visualize: (i) different phases of the drug pioglitazone (PGZ) in solutions and/or crystals, (ii) the position in the phasor plot of non-labelled poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), and (iii) the effect of PGZ or PGZ-containing NPs on the metabolism of insulinoma (INS-1 E) model cells.

Expansion and Light-Sheet Microscopy for Nanoscale 3D Imaging.

Expansion Microscopy (ExM) and Light-Sheet Fluorescence Microscopy (LSFM) are forefront imaging techniques that enable high-resolution visualization of biological specimens. ExM enhances nanoscale investigation using conventional fluorescence microscopes, while LSFM offers rapid, minimally invasive imaging over large volumes. This review explores the joint advancements of ExM and LSFM, focusing on the excellent performance of the integrated modality obtained from the combination of the two, which is refer to as ExLSFM.

Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations.

Polygenic risk scores (PRSs) have improved in predictive performance, but several challenges remain to be addressed before PRSs can be implemented in the clinic, including reduced predictive performance of PRSs in diverse populations, and the interpretation and communication of genetic results to both providers and patients. To address these challenges, the National Human Genome Research Institute-funded Electronic Medical Records and Genomics (eMERGE) Network has developed a framework and pipeline for return of a PRS-based genome-informed risk assessment to 25,000 diverse adults and children as part of a clinical study. From an initial list of 23 conditions, ten were selected for implementation based on PRS performance, medical actionability and potential clinical utility, including cardiometabolic diseases and cancer.

Stereocontrolled Self-Assembly of a Helicate-Bridged CuL Cage That Emits Circularly Polarized Light.

Control over the stereochemistry of metal-organic cages can give rise to useful functions that are entwined with chirality, such as stereoselective guest binding and chiroptical applications. Here, we report a chiral CuL pseudo-octahedral cage that self-assembled from condensation of triaminotriptycene, aminoquinaldine, and diformylpyridine subcomponents around Cu templates. The corners of this cage consist of six head-to-tail dicopper(I) helicates whose helical chirality can be controlled by the addition of enantiopure 1,1'-bi-2-naphthol (BINOL) during the assembly process.

The impact of damaging epilepsy and cardiac genetic variant burden in sudden death in the young.

Background: Sudden unexpected death in children is a tragic event. Understanding the genetics of sudden death in the young (SDY) enables family counseling and cascade screening. The objective of this study was to characterize genetic variation in an SDY cohort using whole genome sequencing.

Segmentation of supragranular and infragranular layers in ultra-high resolution 7T MRI of the human cerebral cortex.

Accurate labeling of specific layers in the human cerebral cortex is crucial for advancing our understanding of neurodevelopmental and neurodegenerative disorders. Leveraging recent advancements in ultra-high resolution MRI, we present a novel semi-supervised segmentation model capable of identifying supragranular and infragranular layers in MRI with unprecedented precision. On a dataset consisting of 17 whole-hemisphere scans at 120 m, we propose a multi-resolution U-Nets framework (MUS) that integrates global and local structural information, achieving reliable segmentation maps of the entire hemisphere, with Dice scores over 0.

A cellular resolution atlas of Broca's area.

Brain cells are arranged in laminar, nuclear, or columnar structures, spanning a range of scales. Here, we construct a reliable cell census in the frontal lobe of human cerebral cortex at micrometer resolution in a magnetic resonance imaging (MRI)-referenced system using innovative imaging and analysis methodologies. MRI establishes a macroscopic reference coordinate system of laminar and cytoarchitectural boundaries.

Fluorescence Lifetime Nanoscopy of Liposomal Irinotecan Onivyde: From Manufacturing to Intracellular Processing.

Onivyde was approved by the Food and Drug Administration (FDA) in 2015 for the treatment of solid tumors, including metastatic pancreatic cancer. It is designed to encapsulate irinotecan at high concentration, increase its blood-circulation lifetime, and deliver it to cells where it is enzymatically converted into SN-38, a metabolite with 100- to 1000-fold higher anticancer activity. Despite a rewarding clinical path, little is known about the physical state of encapsulated irinotecan within Onivyde and how this synthetic identity changes throughout the process from manufacturing to intracellular processing.

Into the dynamics of rotaxanes at atomistic resolution.

Mechanically-interlocked molecules (MIMs) are at the basis of artificial molecular machines and are attracting increasing interest for various applications, from catalysis to drug delivery and nanoelectronics. MIMs are composed of mechanically-interconnected molecular sub-parts that can move with respect to each other, imparting these systems innately dynamical behaviors and interesting stimuli-responsive properties. The rational design of MIMs with desired functionalities requires studying their dynamics at sub-molecular resolution and on relevant timescales, which is challenging experimentally and computationally.

Echographic characterization of extraocular muscles in pediatric patients with thyroid dysfunction.

Purpose: To characterize the size of extraocular muscles (EOMs) in a pediatric population with thyroid dysfunction using orbital echography.

Methods: Patients under age 18 with thyroid dysfunction who presented to an academic ophthalmology department from 2009 to 2020 and received orbital echography were included in this IRB-approved retrospective study. Data collected included age, clinical activity score (CAS), thyroid stimulating immunoglobulin (TSI), and extraocular recti muscle thickness on echography.

Emerging Activity Patterns and Synaptogenesis in Dissociated Hippocampal Cultures.

Cultures of dissociated hippocampal neurons display a stereotypical development of network activity patterns within the first three weeks of maturation. During this process, network connections develop and the associated spiking patterns range from increasing levels of activity in the first two weeks to regular bursting activity in the third week of maturation. Characterization of network structure is important to examine the mechanisms underlying the emergent functional organization of neural circuits.

The Value of Adding Scribe Services to 2 Distinct Pediatric Subspecialties in the Era of the Electronic Medical Record.

To evaluate the impact of adding medical scribes to 2 distinct outpatient pediatric subspecialty clinics on provider burnout, visit length, and patient satisfaction. A total of 2 pediatric endocrinologists and 2 developmental-behavioral pediatrics/pediatrician (DBP) were randomly assigned based on days of the week to see patients aged 0 to 21 years in their clinics with and without in-person medical scribes from February 2019 to February 2020. Parent satisfaction rates were examined through pre- and postappointment surveys.

The impact of damaging epilepsy and cardiac genetic variant burden in sudden death in the young.

Background: Sudden unexpected death in children is a tragic event. Understanding the genetics of sudden death in the young (SDY) enables family counseling and cascade screening. The objective of this study was to characterize genetic variation in an SDY cohort using whole genome sequencing.

Innate dynamics and identity crisis of a metal surface unveiled by machine learning of atomic environments.

Metals are traditionally considered hard matter. However, it is well known that their atomic lattices may become dynamic and undergo reconfigurations even well below the melting temperature. The innate atomic dynamics of metals is directly related to their bulk and surface properties.