Magnetic Nanoparticle-Assisted Non-Viral CRISPR-Cas9 for Enhanced Genome Editing to Treat Rett Syndrome.

The CRISPR-Cas9 technology has the potential to revolutionize the treatment of various diseases, including Rett syndrome, by enabling the correction of genes or mutations in human patient cells. However, several challenges need to be addressed before its widespread clinical application. These challenges include the low delivery efficiencies to target cells, the actual efficiency of the genome-editing process, and the precision with which the CRISPR-Cas system operates.

Anti-TIGIT antibody improves PD-L1 blockade through myeloid and T cells.

Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone. However, there remains little consensus on the mechanism(s) of response with this combination.

IMI 2023 Digest.

Myopia is a dynamic and rapidly moving field, with ongoing research providing a better understanding of the etiology leading to novel myopia control strategies. In 2019, the International Myopia Institute (IMI) assembled and published a series of white papers across relevant topics and updated the evidence with a digest in 2021. Here, we summarize findings across key topics from the previous 2 years.

Stroke genetics informs drug discovery and risk prediction across ancestries.

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.

Structural and functional characterization of a monoclonal antibody blocking TIGIT.

TIGIT is an immune checkpoint receptor that is expressed on subsets of activated T cells and natural killer (NK) cells. Several ligands for TIGIT, including poliovirus receptor (PVR), are expressed on cancer cells and mediate inhibitory signaling to suppress antitumor activities of the immune cells. Many studies support that the TIGIT signaling is a potential target for cancer immunotherapy.

Digital printing of shape-morphing natural materials.

We demonstrate how programmable shape evolution and deformation can be induced in plant-based natural materials through standard digital printing technologies. With nonallergenic pollen paper as the substrate material, we show how specific geometrical features and architectures can be custom designed through digital printing of patterns to modulate hygrophobicity, geometry, and complex shapes. These autonomously hygromorphing configurations can be "frozen" by postprocessing coatings to meet the needs of a wide spectrum of uses and applications.

Discovery of the First Selective M Muscarinic Acetylcholine Receptor Antagonists with Antiparkinsonian and Antidystonic Efficacy.

Nonselective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson's disease and dystonia. Despite their efficacy in these and other central nervous system disorders, antimuscarinic therapy has limited utility due to severe adverse effects that often limit their tolerability by patients. Recent advances in understanding the roles that each mAChR subtype plays in disease pathology suggest that highly selective ligands for individual subtypes may underlie the antiparkinsonian and antidystonic efficacy observed with the use of nonselective antimuscarinic therapeutics.

Lipid bilayer coatings for rapid enzyme-linked immunosorbent assay.

The enzyme-linked immunosorbent assay (ELISA) is a widely used method for protein detection and relies on the specific capture of target proteins while minimizing the nonspecific binding of other interfering proteins and biomolecules. To prevent nonspecific binding events, blocking agents such as bovine serum albumin (BSA) protein, mixtures of proteins in media such as milk or serum, and/or surfactants are typically added to ELISA plates after probe attachment and before analyte capture. Herein, we developed a streamlined ELISA strategy in which readily prepared lipid nanoparticles are utilized as the blocking agent and are added together with the probe molecule to the ELISA plate, resulting in fewer processing steps, quicker protocol time, and superior detection performance compared to conventional BSA blocking.

Metabolic and enzymatic elucidation of cooperative degradation of red seaweed agarose by two human gut bacteria.

Various health beneficial outcomes associated with red seaweeds, especially their polysaccharides, have been claimed, but the molecular pathway of how red seaweed polysaccharides are degraded and utilized by cooperative actions of human gut bacteria has not been elucidated. Here, we investigated the enzymatic and metabolic cooperation between two human gut symbionts, Bacteroides plebeius and Bifidobacterium longum ssp. infantis, with regard to the degradation of agarose, the main carbohydrate of red seaweed.

Activation of Autophagic Flux Blunts Cardiac Ischemia/Reperfusion Injury.

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A Wide-Field Optical Coherence Tomography Normative Database Considering the Fovea-Disc Relationship for Glaucoma Detection.

Purpose: One purpose of this study was to collect wide-field swept-source optical coherence tomography (SS-OCT) data from healthy eyes and build a wide-filed normative database. Another purpose was to compare the glaucoma diagnostic ability of new parameters based on this normative database to the parameters that are currently in use, such as the peripapillary retinal nerve fiber layer (RNFL), macular ganglion cell-inner plexiform layer, and ganglion cell complex (GCC) thickness.

Methods: This study had 220 healthy eyes and 292 eyes with early-stage glaucoma (EG) and moderate-stage glaucoma (MG) enrolled.

Clinical Application of Virtual Reality for Upper Limb Motor Rehabilitation in Stroke: Review of Technologies and Clinical Evidence.

Neurorehabilitation for stroke is important for upper limb motor recovery. Conventional rehabilitation such as occupational therapy has been used, but novel technologies are expected to open new opportunities for better recovery. Virtual reality (VR) is a technology with a set of informatics that provides interactive environments to patients.

Lipid-Bicelle-Coated Microfluidics for Intracellular Delivery with Reduced Fouling.

Innovative technologies for intracellular delivery are ushering in a new era for gene editing, enabling the utilization of a patient's own cells for stem cell and immunotherapies. In particular, cell-squeezing platforms provide unconventional forms of intracellular delivery, deforming cells through microfluidic constrictions to generate transient pores and to enable effective diffusion of biomolecular cargo. While these devices are promising gene-editing platforms, they require frequent maintenance due to the accumulation of cellular debris, limiting their potential for reaching the throughputs necessary for scalable cellular therapies.

Respiratory Syncytial Virus Vaccination during Pregnancy and Effects in Infants.

Background: Respiratory syncytial virus (RSV) is the dominant cause of severe lower respiratory tract infection in infants, with the most severe cases concentrated among younger infants.

Methods: Healthy pregnant women, at 28 weeks 0 days through 36 weeks 0 days of gestation, with an expected delivery date near the start of the RSV season, were randomly assigned in an overall ratio of approximately 2:1 to receive a single intramuscular dose of RSV fusion (F) protein nanoparticle vaccine or placebo. Infants were followed for 180 days to assess outcomes related to lower respiratory tract infection and for 364 days to assess safety.

Excessive Astrocytic GABA Causes Cortical Hypometabolism and Impedes Functional Recovery after Subcortical Stroke.

Glucose hypometabolism in cortical structures after functional disconnection is frequently reported in patients with white matter diseases such as subcortical stroke. However, the molecular and cellular mechanisms have been poorly elucidated. Here we show, in an animal model of internal capsular infarct, that GABA-synthesizing reactive astrocytes in distant cortical areas cause glucose hypometabolism via tonic inhibition of neighboring neurons.

Actuation and locomotion driven by moisture in paper made with natural pollen.

Here we describe the development of a humidity-responsive sheet of paper that is derived solely from natural pollen. Adaptive soft material components of the paper exhibit diverse and well-integrated responses to humidity that promote shape reconfiguration, actuation, and locomotion. This mechanically versatile and nonallergenic paper can generate a cyclically high contractile stress upon water absorption and desorption, and the rapid exchange of water drives locomotion due to hydrodynamic effects.

Transformation of hard pollen into soft matter.

Pollen's practically-indestructible shell structure has long inspired the biomimetic design of organic materials. However, there is limited understanding of how the mechanical, chemical, and adhesion properties of pollen are biologically controlled and whether strategies can be devised to manipulate pollen beyond natural performance limits. Here, we report a facile approach to transform pollen grains into soft microgel by remodeling pollen shells.

Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation.

Background: Relationships between microbiota composition and clinical outcomes after allogeneic hematopoietic-cell transplantation have been described in single-center studies. Geographic variations in the composition of human microbial communities and differences in clinical practices across institutions raise the question of whether these associations are generalizable.

Methods: The microbiota composition of fecal samples obtained from patients who were undergoing allogeneic hematopoietic-cell transplantation at four centers was profiled by means of 16S ribosomal RNA gene sequencing.

Robotic fluidic coupling and interrogation of multiple vascularized organ chips.

Organ chips can recapitulate organ-level (patho)physiology, yet pharmacokinetic and pharmacodynamic analyses require multi-organ systems linked by vascular perfusion. Here, we describe an 'interrogator' that employs liquid-handling robotics, custom software and an integrated mobile microscope for the automated culture, perfusion, medium addition, fluidic linking, sample collection and in situ microscopy imaging of up to ten organ chips inside a standard tissue-culture incubator. The robotic interrogator maintained the viability and organ-specific functions of eight vascularized, two-channel organ chips (intestine, liver, kidney, heart, lung, skin, blood-brain barrier and brain) for 3 weeks in culture when intermittently fluidically coupled via a common blood substitute through their reservoirs of medium and endothelium-lined vascular channels.

Hypersensitivity Reactions to Iodinated Contrast Media: A Multicenter Study of 196 081 Patients.

Background Multicenter studies may be required for establishing guidelines for safe usage of iodinated contrast media (ICM). Purpose To identify the prevalence, patterns, risk factors, and preventive measures for ICM-related hypersensitivity reactions (HSRs). Materials and Methods Between March 2017 and October 2017, a total of 196 081 patients who underwent ICM administration were enrolled from seven participating institutions.

Recovery of Motor Function after Mixed and Motor Nerve Repair with Processed Nerve Allograft.

Background: Severe trauma often results in the transection of major peripheral nerves. The RANGER Registry is an ongoing observational study on the use and outcomes of processed nerve allografts (PNAs; Avance Nerve Graft, AxoGen, Inc., Alachua, Fla.