EBP1 potentiates amyloid β pathology by regulating γ-secretase.

The abnormal deposition of amyloid β (Aβ), produced by proteolytic cleavage events of amyloid precursor protein involving the protease γ-secretase and subsequent polymerization into amyloid plaques, plays a key role in the neuropathology of Alzheimer's disease (AD). Here we show that ErbB3 binding protein 1 (EBP1)/proliferation-associated 2G4 (PA2G4) interacts with presenilin, a catalytic subunit of γ-secretase, inhibiting Aβ production. Mice lacking forebrain Ebp1/Pa2g4 recapitulate the representative phenotypes of late-onset sporadic AD, displaying an age-dependent increase in Aβ deposition, amyloid plaques and cognitive dysfunction.

Immune cell-enriched single-cell RNA sequencing unveils the interplay between infiltrated CD8 T resident memory cells and choroid plexus epithelial cells in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurological disorder and the leading cause of dementia. Despite significant efforts, treatment strategies targeting amyloid-β have been less successful than anticipated. Recently, the role of neuroinflammation and adaptive immune response in AD pathogenesis has gained attention.

In vivo adenine base editing rescues adrenoleukodystrophy in a humanized mouse model.

X-linked adrenoleukodystrophy (ALD), an inherited neurometabolic disorder caused by mutations in ABCD1, which encodes the peroxisomal ABC transporter, mainly affects the brain, spinal cord, adrenal glands, and testes. In ALD patients, very-long-chain fatty acids (VLCFAs) fail to enter the peroxisome and undergo subsequent β-oxidation, resulting in their accumulation in the body. It has not been tested whether in vivo base editing or prime editing can be harnessed to ameliorate ALD.

CRISPR-based editing strategies to rectify complex genomic rearrangement linked to haploinsufficiency.

Pathogenic structure variations (SVs) are associated with various types of cancer and rare genetic diseases. Recent studies have used Cas9 nuclease with paired guide RNAs (gRNAs) to generate targeted chromosomal rearrangements, focusing on producing fusion proteins that cause cancer, whereas research on precision genome editing for rectifying SVs is limited. In this study, we identified a novel complex genomic rearrangement (CGR), specifically an inversion with a deletion, implicated in branchio-oto-renal/branchio-oto syndrome.

Precise editing of pathogenic nucleotide repeat expansions in iPSCs using paired prime editor.

Nucleotide repeat expansion disorders, a group of genetic diseases characterized by the expansion of specific DNA sequences, pose significant challenges to treatment and therapy development. Here, we present a precise and programmable method called prime editor-mediated correction of nucleotide repeat expansion (PE-CORE) for correcting pathogenic nucleotide repeat expansion. PE-CORE leverages a prime editor and paired pegRNAs to achieve targeted correction of repeat sequences.

Integrated NLRP3, AIM2, NLRC4, Pyrin inflammasome activation and assembly drive PANoptosis.

Inflammasomes are important sentinels of innate immune defense; they sense pathogens and induce the cell death of infected cells, playing key roles in inflammation, development, and cancer. Several inflammasome sensors detect and respond to specific pathogen- and damage-associated molecular patterns (PAMPs and DAMPs, respectively) by forming a multiprotein complex with the adapters ASC and caspase-1. During disease, cells are exposed to several PAMPs and DAMPs, leading to the concerted activation of multiple inflammasomes.

Interventional Heartworm Extraction in Two Dogs: The Clinical Application of Impedance Cardiography.

Unlabelled: Heartworm (HW) disease, caused by , is a life-threatening ailment in dogs. HW disrupts blood flow and decreases cardiac output (CO). The accurate monitoring of CO during HW extraction is pivotal for patient survival and overall health.

β-arrestin 2 negatively regulates lung cancer progression by inhibiting the TRAF6 signaling axis for NF-κB activation and autophagy induced by TLR3 and TLR4.

β-arrestin 2 (ARRB2) is functionally implicated in cancer progression via various signaling pathways. However, its role in lung cancer remains unclear. To obtain clinical insight on its function in lung cancer, microarray data from lung tumor tissues (LTTs) and matched lung normal tissues (mLNTs) of primary non-small cell lung cancer (NSCLC) patients (n = 37) were utilized.

FFAR2 antagonizes TLR2- and TLR3-induced lung cancer progression via the inhibition of AMPK-TAK1 signaling axis for the activation of NF-κB.

Background: Free fatty acid receptors (FFARs) and toll-like receptors (TLRs) recognize microbial metabolites and conserved microbial products, respectively, and are functionally implicated in inflammation and cancer. However, whether the crosstalk between FFARs and TLRs affects lung cancer progression has never been addressed.

Methods: We analyzed the association between FFARs and TLRs using The Cancer Genome Atlas (TCGA) lung cancer data and our cohort of non-small cell lung cancer (NSCLC) patient data (n = 42), and gene set enrichment analysis (GSEA) was performed.

DNA double-strand break-free CRISPR interference delays Huntington's disease progression in mice.

Huntington's disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. CRISPR-Cas9 nuclease causes double-strand breaks (DSBs) in the targeted DNA that induces toxicity, whereas CRISPR interference (CRISPRi) using dead Cas9 (dCas9) suppresses the target gene expression without DSBs. Delivery of dCas9-sgRNA targeting CAG repeat region does not damage the targeted DNA in HEK293T cells containing CAG repeats.

Selective-Area Growth Mechanism of GaN Microrods on a Plateau Patterned Substrate.

This study provides experimental evidence regarding the mechanism of gallium nitride (GaN) selective-area growth (SAG) on a polished plateau-patterned sapphire substrate (PP-PSS), on which aluminum nitride (AlN) buffer layers are deposited under the same deposition conditions. The SAG of GaN was only observed on the plateau region of the PP-PSS, irrespective of the number of growth cycles. Indirect samples deposited on the bare c-plane substrate were prepared to determine the difference between the AlN buffer layers in the plateau region and silicon oxide (SiO2).

Profiling Genome-Wide Specificity of dCpf1 Cytidine Base Editors Using Digenome-Seq.

Digenome-seq is a powerful approach for determining the genome-wide specificity of programmable nuclease including CRISPR-Cas9 and CRISPR-Cpf1 (also known as Cas12a) and programmable deaminase including cytosine base editors (CBEs) and adenine base editors (ABEs). To define the genome-wide specificity of dLbCpf1-BE (also known as dLbCas12a-BE), genomic DNA is first incubated with dLbCpf1-BE, which induces C-to-U conversion at on-target and off-target sites, and then treated with a mixture of E. coli uracil DNA glycosylase (UDG) and Endonuclease VIII, which creates single-strand breaks (SSBs) by removing uracil in vitro.

Horticultural Therapy for Improving the Work Performance and Interpersonal Relationships of Persons with Intellectual Disabilities.

For the occupational adaptation and social integration of the intellectually disabled, it is helpful to improve their work performance and interpersonal skills. The purpose of the study was to evaluate the effectiveness of horticultural therapy (HT) programs to improve work performance and interpersonal relationships of persons with intellectual disabilities. Based on observations and analyses of how people with intellectual disabilities work, we have developed a 12-session HT program that includes upper limb movements and physical activities to improve hand function.

Expanded targeting scope of LbCas12a variants allows editing of multiple oncogenic mutations.

RNA-guided CRISPR-Cas12a endonucleases are promising tools for genome engineering. Here we demonstrate that LbCas12a variants derived from show a broad PAM preference, recognizing certain non-canonical PAMs with high efficiency. Furthermore, we engineered LbABE8e to carry G532R and/or K595R mutations, altering its original PAM specificities; these variants exhibited superior base editing activity in human cells compared with wild-type LbABE8e at sites with non-canonical PAMs.

Targeted genomic translocations and inversions generated using a paired prime editing strategy.

A variety of cancers have been found to have chromosomal rearrangements, and the genomic abnormalities often induced expression of fusion oncogenes. To date, a pair of engineered nucleases including ZFNs, TALENs, and CRISPR-Cas9 nucleases have been used to generate chromosomal rearrangement in living cells and organisms for disease modeling. However, these methods induce unwanted indel mutations at the DNA break junctions, resulting in incomplete disease modeling.

Clinical application of both amniotic membranes and adipose derived mesenchymal stem cells in a cat with a large skin defect.

Surgical procedures on large skin defects can be challenging in the short term due to the size of the lesion, infection, and tissue defect. A regenerative therapy for skin wounds has been applied to promote the healing process. An 8-month-old, Korean domestic short-haired female cat, weighing 3 kg, was rescued with extensive defects on the right flank to right inguinal region caused by bite wounds.

Electronic Skin Based on a Cellulose/Carbon Nanotube Fiber Network for Large-Area 3D Touch and Real-Time 3D Surface Scanning.

Electronic skin (E-skin) based on tactile sensors has great significance in next-generation electronics such as biomedical application and artificial intelligence that requires interaction with humans. To mimic the properties of human skin, high flexibility, excellent sensing capability, and sufficient spatial resolution through high-level sensor integration are required. Here, we report a highly sensitive pressure sensor matrix based on a piezoresistive cellulose/single-walled carbon nanotube-entangled fiber network, which forms its own porous structure enabling a superior pressure sensor with a high sensitivity (9.

Efficient CRISPR editing with a hypercompact Cas12f1 and engineered guide RNAs delivered by adeno-associated virus.

Gene therapy would benefit from a miniature CRISPR system that fits into the small adeno-associated virus (AAV) genome and has high cleavage activity and specificity in eukaryotic cells. One of the most compact CRISPR-associated nucleases yet discovered is the archaeal Un1Cas12f1. However, Un1Cas12f1 and its variants have very low activity in eukaryotic cells.

Application of prime editing to the correction of mutations and phenotypes in adult mice with liver and eye diseases.

The use of prime editing-a gene-editing technique that induces small genetic changes without the need for donor DNA and without causing double strand breaks-to correct pathogenic mutations and phenotypes needs to be tested in animal models of human genetic diseases. Here we report the use of prime editors 2 and 3, delivered by hydrodynamic injection, in mice with the genetic liver disease hereditary tyrosinemia, and of prime editor 2, delivered by an adeno-associated virus vector, in mice with the genetic eye disease Leber congenital amaurosis. For each pathogenic mutation, we identified an optimal prime-editing guide RNA by using cells transduced with lentiviral libraries of guide-RNA-encoding sequences paired with the corresponding target sequences.

Stamp-Perforation-Inspired Micronotch for Selectively Tearing Fiber-Bridged Carbon Nanotube Thin Films and Its Applications for Strain Classification.

Cracks typically deteriorate the structural and electrical properties of materials when not properly controlled. A few papers recently reported the controlling methods of crack formation in the brittle materials utilizing the lateral V-notch structure. For ductile materials, however, there have been few papers reporting cracking phenomenon, but full cracking control including predesigned initiation, propagation, and termination has not been reported yet.

Migration Behavior of Lubricants in Polypropylene Composites under Accelerated Thermal Aging.

The surface migration of lubricants degrades the quality of thermoplastic polymer composites. In this study, the surface migration of lubricants in polypropylene composites were studied to improve the quality of the composites. Polypropylene (PP)/lubricant composites were manufactured using a co-rotating twin-screw extruder and injection molding, and the migration phenomena of the lubricant in the PP/lubricant composites were investigated under accelerated aging conditions with temperatures in the range of 20 to 90 °C and humidity of 100% for 72 h.

Prostaglandin E receptor PTGER4-expressing macrophages promote intestinal epithelial barrier regeneration upon inflammation.

Objective: Dysfunctional resolution of intestinal inflammation and altered mucosal healing are essential features in the pathogenesis of inflammatory bowel disease (IBD). Intestinal macrophages are vital in the process of inflammation resolution, but the mechanisms underlying their mucosal healing capacity remain elusive.

Design: We investigated the role of the prostaglandin E (PGE) receptor PTGER4 on the differentiation of intestinal macrophages in patients with IBD and mouse models of intestinal inflammation.

Identifying genome-wide off-target sites of CRISPR RNA-guided nucleases and deaminases with Digenome-seq.

Digested genome sequencing (Digenome-seq) is a highly sensitive, easy-to-carry-out, cell-free method for experimentally identifying genome-wide off-target sites of programmable nucleases and deaminases (also known as base editors). Genomic DNA is digested in vitro using clustered regularly interspaced short palindromic repeats ribonucleoproteins (RNPs; plus DNA-modifying enzymes to cleave both strands of DNA at sites containing deaminated base products, in the case of base editors) and subjected to whole-genome sequencing (WGS) with a typical sequencing depth of 30×. A web-based program is available to map in vitro cleavage sites corresponding to on- and off-target sites.

Case Report: Surgical Treatment of Severe Facial Wounds and Proptosis in a Dog Due to a Traffic Accident.

Although facial wounds caused by traffic accidents in dogs are common, the surgical management of severe facial injuries involving the soft tissue, bone, dentition, nose and orbit are challenging. A 2 year-old Korean Jindo dog was diagnosed with severe skin defects of the face and proptosis caused by a vehicular accident. Along the left lateral maxilla, severe injury involving the overlying skin and platysma muscle occurred, to the extent that the middle part of the sphincter colli profundus pars intermedia muscle was exposed.

Highly efficient and safe genome editing by CRISPR-Cas12a using CRISPR RNA with a ribosyl-2'-O-methylated uridinylate-rich 3'-overhang in mouse zygotes.

The CRISPR-Cas12a system has been developed to harness highly specific genome editing in eukaryotic cells. Given the relatively small sizes of Cas12a genes, the system has been suggested to be most applicable to gene therapy using AAV vector delivery. Previously, we reported that a U-rich crRNA enabled highly efficient genome editing by the CRISPR-Cas12a system in eukaryotic cells.