Development of a Dihydrofolate Reductase Selection System for .

, the only commercially available probiotic yeast, has gained attention as a recombinant live biotherapeutic product (rLBP) empowered with the expression of heterologous therapeutic proteins for treating gastrointestinal diseases. However, the genetic modification of intended for clinical use is hindered by regulatory and technical challenges. In this study, we developed a dihydrofolate reductase (DHFR)-based selection system as an innovative alternative to traditional auxotrophic selection strategies for engineering .

Therapeutic assessment of a novel mitochondrial complex I inhibitor in and models of Alzheimer's disease.

Despite recent approval of monoclonal antibodies that reduce amyloid (Aβ) accumulation, the development of disease-modifying strategies targeting the underlying mechanisms of Alzheimer's disease (AD) is urgently needed. We demonstrate that mitochondrial complex I (mtCI) represents a druggable target, where its weak inhibition activates neuroprotective signaling, benefiting AD mouse models with Aβ and p-Tau pathologies. Rational design and structure-activity relationship studies yielded novel mtCI inhibitors profiled in a drug discovery funnel designed to address their safety, selectivity, and efficacy.

Sparse deconvolution beamforming with non-negative L1-αL2 regularization for acoustic source localization.

This letter proposed a sparse deconvolution localization method (FFT-L1ML2) driven by non-convex L1-αL2 regularization that more closely approximates the ideal L0 norm. It is an alternative that explores the sparse structure of sound sources to enhance localization accuracy, while the original sparse deconvolution beamforming lacks a sufficiently accurate sparse description. An optimization solver composed of forward gradient descent and backward proximal operator is then developed for the FFT-L1ML2 model to reconstruct the beamforming map.

Amyloid pathology and cognitive impairment in hAβ-KI and APP-KI mouse models of Alzheimer's disease.

The hAβ-KI and APP-KI are two amyloid models that harbor mutations in the endogenous mouse App gene. Both hAβ-KI and APP-KI mice contain a humanized Aβ sequence, and APP-KI mice carry three additional familial AD mutations. We herein report that the Aβ levels and Aβ42/Aβ40 ratio in APP-KI homozygotes are dramatically higher than those in hAβ-KI homozygotes at 14 months of age.

Modeling Lewy body disease with triplication iPSC-derived cortical organoids and identifying therapeutic drugs.

Aggregated α-synuclein (α-SYN) proteins, encoded by the gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we recapitulated α-SYN pathologies in human induced pluripotent stem cells (iPSCs)-derived cortical organoids generated from patients with LBD with gene triplication.

Metformin promotes the survival of random skin flaps via the activation of Nrf2/HO-1 signaling.

The random flap is one of the commonly used techniques for tissue defect repair in surgery and orthopaedics, however the risk of ischaemic necrosis at the distal end of the flap limits its size and clinical application. Metformin (Met) is a first-line medication in the treatment of type 2 diabetes, with additional effects such as anti-tumor, anti-aging, and neuroprotective properties. In this study, we aimed to investigate the biological effects and potential mechanisms of Met in improving the survival of random skin flaps.

A novel histone deacetylase inhibitor W2A-16 improves the barrier integrity in brain vascular endothelial cells.

The maturation of brain microvascular endothelial cells leads to the formation of a tightly sealed monolayer, known as the blood-brain barrier (BBB). The BBB damage is associated with the pathogenesis of age-related neurodegenerative diseases including vascular cognitive impairment and Alzheimer's disease. Growing knowledge in the field of epigenetics can enhance the understanding of molecular profile of the BBB and has great potential for the development of novel therapeutic strategies or targets to repair a disrupted BBB.

Dose-dependent effects of polystyrene nanoplastics on growth, photosynthesis, and astaxanthin synthesis in Haematococcus pluvialis.

Microalgae play an important role in aquatic ecosystems, but the widespread presence of micro- and nano-plastics (MNPs) poses significant threats to them. Haematococcus pluvialis is well-known for its ability to produce the antioxidant astaxanthin when it experiences stress from environmental conditions. Here we examined the effects of polystyrene nanoplastics (PS-NPs) at concentrations of 0.

Micro-and nano-plastics induce kidney damage and suppression of innate immune function in zebrafish (Danio rerio) larvae.

Aquatic environments serve as critical repositories for pollutants and have significantly accumulated micro- and nanoplastics (MNPs) due to the extensive production and application of plastic products. While the disease resistance and immunity of fish are closely linked to the condition of their aquatic habitats, the specific effects of nanoplastics (NPs) and microplastics (MPs) within these environments on fish immune functions are still not fully understood. The present study utilized zebrafish (Danio rerio) embryos and larvae as model organisms to examine the impacts of polystyrene NPs (100 nm) and MPs (5 μm) on fish immune responses.

ABCA7 deficiency causes neuronal dysregulation by altering mitochondrial lipid metabolism.

ABCA7 loss-of-function variants are associated with increased risk of Alzheimer's disease (AD). Using ABCA7 knockout human iPSC models generated with CRISPR/Cas9, we investigated the impacts of ABCA7 deficiency on neuronal metabolism and function. Lipidomics revealed that mitochondria-related phospholipids, such as phosphatidylglycerol and cardiolipin were reduced in the ABCA7-deficient iPSC-derived cortical organoids.

WGCNA and transcriptome profiling reveal hub genes for key development stage seed size/oil content between wild and cultivated soybean.

Background: Soybean is one of the most important oil crops in the world. The domestication of wild soybean has resulted in significant changes in the seed oil content and seed size of cultivated soybeans. To better understand the molecular mechanisms of seed formation and oil content accumulation, WDD01514 (E1), ZYD00463 (E2), and two extreme progenies (E23 and E171) derived from RILs were used for weighted gene coexpression network analysis (WGCNA) combined with transcriptome analysis.

APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids.

Background: The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease (AD); however, how it modulates brain homeostasis is not clear. The apoE protein is a major lipid carrier in the brain transporting lipids such as cholesterol among different brain cell types.

Methods: We generated three-dimensional (3-D) cerebral organoids from human parental iPSC lines and its isogenic APOE-deficient (APOE) iPSC line.

Upregulation of sFRP1 Is More Profound in Female than Male 5xFAD Mice and Positively Associated with Amyloid Pathology.

The prevalence of Alzheimer's disease is greater in women, but the underlying mechanisms remain to be elucidated. We herein demonstrated that α-secretase ADAM10 was downregulated and ADAM10 inhibitor sFRP1 was upregulated in 5xFAD mice. While there were no sex effects on ADAM10 protein and sFRP1 mRNA levels, female 5xFAD and age-matched non-transgenic mice exhibited higher levels of sFRP1 protein than corresponding male mice.

Evaluation of Lipid Droplet Size and Fusion in Bovine Hepatic Cells.

Lipid droplets (LDs) are organelles that play an important role in lipid metabolism and neutral lipid storage in cells. They are associated with a variety of metabolic diseases, such as obesity, fatty liver disease, and diabetes. In hepatic cells, the sizes and numbers of LDs are signs of fatty liver disease.

Proteomic analysis of milk fat globule membranes from small-sized milk fat globules and their function in promoting lipid droplet fusion in bovine mammary epithelial cells.

In mammary epithelial cells, milk fat is synthesized as lipid droplets and secreted in the form of globules. Milk fat globules (MFGs) are covered by a lipid-protein membrane known as the milk fat globule membrane (MFGM). We randomly divided 12 Holstein cows into control and conjugated linoleic acid (CLA) groups.

Comparisons of constitutive resistances to soybean cyst nematode between PI 88788- and Peking-type sources of resistance in soybean by transcriptomic and metabolomic profilings.

Soybean cyst nematode (SCN) is a serious damaging disease in soybean worldwide. Peking- and PI 88788-type sources of resistance are two most important germplasm used in breeding resistant soybean cultivars against this disease. However, until now, no comparisons of constitutive resistances to soybean cyst nematode between these two types of sources had been conducted, probably due to the influences of different backgrounds.

Size, number and phospholipid composition of milk fat globules are affected by dietary conjugated linoleic acid.

Milk fat globules (MFGs) surround the triacylglycerol core that composes milk fat. The aim of this study is to induce milk fat depression via dietary conjugated linoleic acid (CLA) supplementation to study MFG size parameters, number and glycerophospholipid composition. Eighteen Holstein dairy cows (136 ± 28 days in milk, 571 ± 37.

Suppression of Wnt/β-Catenin Signaling Is Associated with Downregulation of Wnt1, PORCN, and Rspo2 in Alzheimer's Disease.

Wnt and R-spondin (Rspo) proteins are two major types of endogenous Wnt/β-catenin signaling agonists. While Wnt/β-catenin signaling is greatly diminished in Alzheimer's disease (AD), it remains to be elucidated whether the inhibition of this pathway is associated with dysregulation of Wnt and Rspo proteins. By analyzing temporal cortex RNA-seq data of the human postmortem brain samples, we found that WNT1 and RRPO2 were significantly downregulated in human AD brains.

Milk fat globule membrane proteins are involved in controlling the size of milk fat globules during conjugated linoleic acid-induced milk fat depression.

Milk fat globule membrane (MFGM) proteins surround the triacylglycerol core comprising milk fat globules (MFG). We previously detected a decrease in the size of fat globules during conjugated linoleic acid (CLA)-induced milk fat depression (MFD), and other studies have reported that some MFGM proteins play a central role in regulating mammary cellular lipid droplet size. However, little is known about the relationship between MFD, MFG size, and MFGM proteins in bovine milk.

LRP1 is a neuronal receptor for α-synuclein uptake and spread.

Background: The aggregation and spread of α-synuclein (α-Syn) protein and related neuronal toxicity are the key pathological features of Parkinson's disease (PD) and Lewy body dementia (LBD). Studies have shown that pathological species of α-Syn and tau can spread in a prion-like manner between neurons, although these two proteins have distinct pathological roles and contribute to different neurodegenerative diseases. It is reported that the low-density lipoprotein receptor-related protein 1 (LRP1) regulates the spread of tau proteins; however, the molecular regulatory mechanisms of α-Syn uptake and spread, and whether it is also regulated by LRP1, remain poorly understood.

HMGA1 chromatin regulators induce transcriptional networks involved in GATA2 and proliferation during MPN progression.

Myeloproliferative neoplasms (MPNs) transform to myelofibrosis (MF) and highly lethal acute myeloid leukemia (AML), although the actionable mechanisms driving progression remain elusive. Here, we elucidate the role of the high mobility group A1 (HMGA1) chromatin regulator as a novel driver of MPN progression. HMGA1 is upregulated in MPN, with highest levels after transformation to MF or AML.

Endovascular Aneurysm Treatment with the Numen Coil Embolization System: A Prospective Randomized Controlled Open-Label Multicenter Noninferiority Trial in China.

Objective: We investigated the safety and efficacy of the Numen coil compared with the Axium coil in the treatment of intracranial aneurysms.

Methods: Because CATCH (Coil Application Trial in China) is a prospective randomized controlled open-label noninferiority trial conducted in 10 centers across China, patients who fulfilled the inclusion and exclusion criteria were randomized 1:1 to either a test group (Numen) or a control group (Axium). The primary outcome was based on successful aneurysm occlusion at 6 months follow-up, whereas secondary outcomes included technical success, the recanalization and retreatment rates, and the rate of serious adverse events (SAEs) at 6 months and 12 months follow-up.

-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia.

Apolipoprotein E () genetic variants have been shown to modify Alzheimer’s disease (AD) risk. We previously identified an variant (3-V236E), named -Jacksonville (-Jac), associated with healthy brain aging and reduced risk for AD and dementia with Lewy bodies (DLB). Herein, we resolved the functional mechanism by which APOE3-Jac reduces APOE aggregation and enhances its lipidation in human brains, as well as in cellular and biochemical assays.