Stargardt disease is a currently untreatable, inherited neurodegenerative disease that leads to macular degeneration and blindness due to loss-of-function mutations in the ABCA4 gene. We have designed a dual adeno-associated viral vector encoding a split-intein adenine base editor to correct the most common mutation in ABCA4 (c.5882G>A, p.Gly1961Glu). We optimized ABCA4 base editing in human models, including retinal organoids, induced pluripotent stem cell-derived retinal pigment epithelial (RPE) cells, as well as adult human retinal explants and RPE/choroid explants in vitro. The resulting gene therapy vectors achieved high levels of gene correction in mutation-carrying mice and in female nonhuman primates, with average editing of 75% of cones and 87% of RPE cells in vivo, which has the potential to translate to a clinical benefit. No off-target editing was detectable in human retinal explants and RPE/choroid explants. The high editing rates in primates show promise for efficient gene editing in other ocular diseases that are targetable by base editing.

Olfactory neuroblastoma (ONB) is a rare malignant tumor originating from the olfactory neuroepithelium, typically within the sinonasal cavity. Cases of ONB originating outside of the olfactory cleft area are extremely rare and are referred to as "ectopic" (eONB), in contrast to "orthotopic" tumors (oONB). ONB has been associated with paraneoplastic syndromes (PNSs), including the syndrome of inappropriate antidiuretic hormone secretion (SIADH). This study investigate the association between eONB and SIADH and compared the prognosis of eONB to oONB.

Brugada syndrome (BrS) is an inherited channelopathy characterized by right precordial ST-segment elevation. This study investigates the clinical and genetic characteristics of children with BrS in Hong Kong.

Inflammation is the critical component of neuropathic pain; therefore, this study aimed to assess the potential anti-inflammatory effects of L. extracts in a vincristine-induced model of neuropathic pain. The effects of different doses (5.0-40.0 mg/kg) of two L. extracts (B and D) on COX-1, COX-2, TNF-α, and NF-κB mRNA and protein levels were examined in the rat hippocampus, cerebral cortex, and blood lymphocytes. There were statistically significant differences in COX-1, COX-2, and TNF-α mRNA and protein expression in the hippocampus and cerebral cortex, with significant differences in COX-2 and TNF-α in the lymphocytes. Extract D dose-dependently increased COX-1 mRNA and protein in the hippocampus and cortex. In contrast, Extract B dose-dependently increased COX-1 mRNA and decreased COX-2 mRNA (in a dose of 7.5 mg/kg) and TNF-α protein levels in the cortex. L. extracts significantly influenced the expression of inflammatory genes and proteins, with effects varying based on dose and tissue type. The increased expression of COX-1, COX-2, and TNF-α (in comparison to groups receiving NaCl, vincristine, and gabapentin) in the rat hippocampus and COX-1 in the cerebral cortex suggests that may have a pro-inflammatory effect. Due to species specificity, the results of our research based on rats require confirmation in humans. However, should be recommended with caution for treating pain with an inflammatory component.

Acute myeloid leukemia (AML) is an aggressive neoplasm. Although most patients respond to induction therapy, they commonly relapse due to recurrent disease in the bone marrow microenvironment (BMME). So, the disruption of the BMME, releasing tumor cells into the peripheral circulation, has therapeutic potential.

This report presents two phased chromosome-scale genome assemblies of allotetraploid Salsola tragus (2n=4x=36) and fills the current genomics resource gap for this species. Flow cytometry estimated 1C genome size was 1.319 Gbp. PacBio HiFi reads were assembled and scaffolded with Hi-C chromatin contact mapping and Bionano optical mapping data. For annotation, a PacBio Iso-Seq library was generated from root, stem, leaf, and floral tissues followed by annotation using a modified Maker pipeline. The assembled haploid S. tragus genomes contained 18 chromosomes each, with 9 chromosomes assigned to subgenome A and 9 chromosomes to subgenome B. Each haplome assembly represented 95% of the total flow cytometry estimated genome size. Haplome 1 and haplome 2 contained 43,354 and 42,221 annotated genes, respectively. The availability of high-quality reference genomes for this economically important weed will facilitate future omics analysis of S. tragus and a better understanding of chenopod plants.

Efficient degradation of sulfur mustard is essential owing to its extreme toxicity and widespread use as a chemical warfare agent. However, current degradation methods often lack selectivity and generate highly toxic by-products. Herein, we demonstrate an approach for the selective photodegradation of a sulfur mustard simulant using singlet oxygen (O) produced by a methylene blue (MB)-modified UiO-66-(COOH) (UC, a classical metal-organic framework) composite, termed as MB@UC. The composite was prepared adsorption of MB onto the surface of UC through strong electrostatic interactions. The MB@UC composite demonstrates high O generation, enabling selective detoxification of a sulfur mustard simulant (2-chloroethyl ethyl sulfide) into relatively non-toxic sulfoxide, with a half-life of 1.8 minutes under ambient conditions. Compared to traditional detoxifying agents, the MB@UC composite offers superior selectivity, rapid degradation, and excellent recyclability, maintaining its performance over multiple cycles. This work presents a promising strategy for the development of advanced heterogeneous photosensitizers for the detoxification of chemical warfare agents.

Using an optimized CRISPR/Cas9 system to knock out the BTB-POZ and MATH domain gene BoBPM6 and the DOWNY MILDEW RESISTANCE 6 gene in Brassica oleracea resulted in new lines with broad-spectrum disease resistance.

Endoscopic resection (ER) of non-ampullary duodenal epithelial tumors (NADETs) is associated with a high incidence of delayed bleeding (DB). While previous reports have identified composite risk factors for delayed adverse events, including both DB and delayed perforation, the specific factors associated with DB remain unclear. This study aimed to identify factors associated with DB after ER of NADETs.

The mitochondrial unfolded protein response (UPR) maintains mitochondrial quality control and proteostasis under stress conditions. However, the role of UPR in aggressive and resistant prostate cancer is not clearly defined. We show that castration-resistant neuroendocrine prostate cancer (CRPC-NE) harbored highly dysfunctional oxidative phosphorylation (OXPHOS) Complexes. However, biochemical and protein analyses of CRPC-NE tumors showed upregulation of nuclear-encoded OXPHOS proteins and UPR in this lethal subset of prostate cancer suggestive of compensatory upregulation of stress signaling. Genetic deletion and pharmacological inhibition of the main chaperone of UPR heat shock protein 60 (HSP60) reduced neuroendocrine prostate cancer (NEPC) growth in vivo as well as reverted NEPC cells to a more epithelial-like state. HSP60-dependent aggressive NEPC phenotypes was associated with upregulation of β-catenin signaling both in cancer cells and in vivo tumors. HSP60 expression rendered enrichment of aggressive prostate cancer signatures and metastatic potential were inhibited upon suppression of UPR. We discovered that UPR promoted OXPHOS functions including mitochondrial bioenergetics in CRPC-NE via regulation of β-catenin signaling. Mitochondrial biogenesis facilitated cisplatin resistance and inhibition of UPR resensitizes CRPC-NE cells to cisplatin. Together, our findings demonstrated that UPR promotes mitochondrial health via upregulating β-catenin signaling and UPR represents viable therapeutic target for NEPC.

Patients with lupus nephritis (LN), including those below age 50, face significantly higher risk of atherosclerotic cardiovascular disease (ASCVD) vs. peers. This highlights the need for identifying specific ASCVD risk factors in LN. Renal arteriosclerosis in kidney biopsies (subclinical arteriosclerosis) may be able to predict future clinical ASCVD events. However, renal arteriosclerosis is under-reported in LN biopsies and is not taken into consideration when ASCVD risk is calculated. Therefore, we aimed to systematically grade renal arteriosclerosis in kidney biopsies at LN diagnosis and examined associations with 10- & 20-year ASCVD occurrence.

In Diffuse Large B-cell Lymphoma (DLBCL), elevated anti-apoptotic BCL2-family proteins (e.g., MCL1, BCL2, BCLXL) and NF-κB subunits (RelA, RelB, cRel) confer poor prognosis. Heterogeneous expression, regulatory complexity, and redundancy offsetting the inhibition of individual proteins, complicate the assignment of targeted therapy. We combined flow cytometry 'fingerprinting', immunofluorescence imaging, and computational modeling to identify therapeutic vulnerabilities in DLBCL. The combined workflow predicted selective responses to BCL2 inhibition (venetoclax) and non-canonical NF-κB inhibition (Amgen16). Within the U2932 cell line we identified distinct resistance mechanisms to BCL2 inhibition in cellular sub-populations recapitulating intratumoral heterogeneity. Co-cultures with CD40L-expressing stromal cells, mimicking the tumor microenvironment (TME), induced resistance to BCL2 and BCLXL targeting BH3-mimetics via cell-type specific upregulation of BCLXL or MCL1. Computational models, validated experimentally, showed that basal NF-κB activation determined whether CD40 activation drove BH3-mimetic resistance through upregulation of RelB and BCLXL, or cRel and MCL1. High basal NF-κB activity could be overcome by inhibiting BTK to resensitize cells to BH3-mimetics in CD40L co-culture. Importantly, non-canonical NF-κB inhibition overcame heterogeneous compensatory BCL2 upregulation, restoring sensitivity to both BCL2-and BCLXL-targeting BH3-mimetics. Combined molecular fingerprinting and computational modelling provides a strategy for the precision use of BH3-mimetics and NF-κB inhibitors in DLBCL.

Neoadjuvant pembrolizumab plus chemotherapy and adjuvant pembrolizumab have been established as the optimal systemic therapies for patients with early stage triple-negative breast cancer (TNBC); however, their efficacy and feasibility in the Japanese population remain unexplored.

To determine the epidemiological cut-off (ECOFF) values of etimicin against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Acinetobacter baumannii and Staphylococcus aureus.

Borgs are huge extrachromosomal elements of anaerobic methane-oxidizing archaea. They exist in exceedingly complex microbiomes, lack cultivated hosts and have few protein functional annotations, precluding their classification as plasmids, viruses or other. Here, we used structure prediction methods to investigate potential roles for ∼10,000 Borg proteins. Prioritizing analysis of multicopy genes that could signal importance for Borg lifestyles, we uncovered highly represented de-ubiquitination-like Zn-metalloproteases that may counter host targeting of Borg proteins for proteolysis. Also prevalent are clusters of multicopy genes for production of diverse glycoconjugates that could contribute to decoration of the host cell surface, or of putative capsid proteins that we predict multimerize into hexagonal arrays. Features including megabase-scale linear genomes with inverted terminal repeats, genomic repertoires for energy metabolism, central carbon compound transformations and translation, and pervasive direct repeat regions are shared with giant viruses of eukaryotes, although analyses suggest that these parallels arose via convergent evolution. If Borgs are giant archaeal viruses they would fill the gap in the tri(um)virate of giant viruses of all three domains of life.

Optical diagnosis of superficial nonampullary duodenal epithelial tumors using white-light imaging (WLI) and/or narrow-band imaging with magnifying endoscopy (NBI-ME) is used to guide the treatment strategy and avoid biopsy-induced fibrosis. However, the effectiveness of this approach has not been elucidated. We conducted a systematic review and meta-analysis aiming to investigate the diagnostic yield between Vienna classification category 3 (VCL C3) and categories 4 or 5 (VCL C4/C5) using biopsy, WLI, NBI-ME, and WLI + NBI-ME.

Radiomics has revolutionized clinical research by enabling objective measurements of imaging-derived biomarkers. However, the true potential of radiomics necessitates a comprehensive understanding of the biological basis of extracted features to serve as a clinical decision support. In this work, we propose an end-to-end framework for the in silico simulation of [F]FLT PET imaging process in Pancreatic Ductal Adenocarcinoma, accounting for the biological characterization of tissues (including perfusion and fibrosis) on tracer delivery. We thus establish a direct association between radiomics features and the underlying biological properties of tissues.

Chestnut honey has various benefits, such as antioxidative, anti-inflammatory, immunomodulatory, antibacterial, and antiviral effects. However, the effects of chestnut honey or the ethyl acetate fraction of chestnut honey (EACH) on neurodegenerative diseases and their related cognitive impairment and neurotoxicity have not yet been established. Therefore, in this study, we investigated the mitigating effect of the EACH on scopolamine (SCO)-injected cognitive decline in mice and glutamate-exposed neurotoxicity in HT22 cells. EACH administration significantly reversed SCO-induced cognitive decline in mice, as demonstrated through the Morris water maze and passive avoidance tests. The EACH treatment showed a significant alleviation effect by recovering more than 80% of the cell viability decrease induced by glutamate exposure in the HT22 neuronal cell model. Furthermore, the EACH significantly reduced reactive oxygen species accumulation, lactate dehydrogenase release, mitochondrial depolarization, and neuronal apoptosis. The EACH regulated the level of apoptosis-related proteins, induced the nuclear translocation of nuclear factor-E2-related factor 2 (Nrf-2) and the expression of related antioxidant proteins, and induced the phosphorylation of tropomyosin-related kinase receptor B (TrkB)/cAMP-calcium response element-binding protein (CREB) and the expression of brain-derived neurotrophic factor. These data indicate that the EACH can prevent neurons from oxidative damage and improve cognitive dysfunction by activating Nrf-2 and TrkB/CREB signaling pathways. Therefore, the EACH demonstrates potential therapeutic value in mitigating oxidative stress-induced neurotoxicity, cognitive decline, and related neurodegenerative diseases.

Diabetic retinopathy (DR) is a complication of diabetes and a primary cause of visual impairment amongst working-age individuals. DR is a degenerative condition in which hyperglycaemia results in morphological and functional changes in certain retinal cells. Existing treatments mainly address the advanced stages of the disease, which involve vascular defects or neovascularization. However, it is now known that retinal neurodegeneration and inflammation precede these vascular changes as early events of DR. Therefore, there is a pressing need to develop a reliable human in vitro model that mimics the early stage of DR to identify new therapeutic approaches to prevent and delay its progression.

To investigate the osteogenic potential of human embryonic stem cell-derived exosomes (hESC-Exos) and their effects on the differentiation of human umbilical cord mesenchymal stem cells (hUCMSCs).