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The systemic delivery of oligonucleotide therapeutics to the brain is challenging but highly desirable for the treatment of brain diseases undruggable with traditional small‐molecule drugs. In this study, a set of DNA nanostructures is prepared and screened them to develop a protein corona‐assisted platform for the brain delivery of oligonucleotide therapeutics. The biodistribution analysis of intravenously injected DNA nanostructures reveals that a cube‐shaped DNA nanostructure (D‐Cb) can penetrate the brain‐blood barrier (BBB) and reach the brain tissue. The brain distribution level of D‐Cb is comparable to that of other previous nanoparticles conjugated with brain‐targeting ligands. Proteomic analysis of the protein corona formed on D‐Cb suggests that its brain distribution is driven by endothelial receptor‐targeting ligands in the protein corona, which mediate transcytosis for crossing the BBB. D‐Cb is subsequently used to deliver an antisense oligonucleotide (ASO) to treat glioblastoma multiforme (GBM) in mice. While free ASO is unable to reach the brain, ASO loaded onto D‐Cb is delivered efficiently to the brain tumor region, where it downregulates the target gene and exerts an anti‐tumor effect on GBM. D‐Cb is expected to serve as a viable platform based on protein corona formation for systemic brain delivery of oligonucleotide therapeutics. [ABSTRACT FROM AUTHOR]

Simple Summary: In veterinary medicine, intrahepatic cholelithiasis is a difficult disease to manage. Previously, treatment methods such as medical management or a liver lobectomy were suggested, although they cannot be used to treat some patients. Here, we describe the use of intrahepatic duct incision and closure to remove most of the cholelithiasis in the hepatic ducts of the left medial and lateral liver lobes in a dog with untreated hypothyroidism and multiple cholelithiasis. To our knowledge, this is the first report of this procedure in veterinary medicine. The findings from this case suggest that this technique can be used as a safe and feasible option in veterinary medicine as well as human medicine. However, because it often cannot remove all intrahepatic cholelithiasis, physicians must be cautious when choosing this treatment method. Although it is not the best way to treat intrahepatic duct cholelithiasis, it can be a new treatment option for patients who cannot receive conventional treatment methods. This report describes the successful intrahepatic duct incision and closure for the treatment of multiple cholelithiasis in a dog with untreated hypothyroidism. A 12-year-old spayed female Spitz dog weighing 11.3 kg was diagnosed with multiple cholelithiasis, and a quadrate liver lobectomy and cholecystectomy were performed. Large gallstones were located in the left liver lobe's intrahepatic duct distal to the anastomosis of the intrahepatic ducts of the left medial and lateral lobes. The dilated intrahepatic duct was packed off with wet gauze, and incision and closure were performed on the most dilated section, which was proximal to the largest gallstone. After surgery, the patient showed normal liver function and was discharged with normal total bilirubin and C-reactive protein levels. On postoperative day 83, no stones were observed in the dilated common bile duct (CBD), and the degree of dilatation of the CBD had decreased from 9 mm to 4 mm, with no obstructions. Right intrahepatic gallstones were confirmed without dilatation. Hypothyroidism was managed medically. Hepatic duct incision and closure can be performed in dogs with multiple cholelithiasis. Although not the first option, intrahepatic bile duct incision proves to be a new alternative for the successful treatment of cholelithiasis in dogs. [ABSTRACT FROM AUTHOR]

A new alkaloid, neohelicomyine A (1), along with two known alkaloids (2–3), were isolated from the fermentation of Neohelicomyces hyalosporus PF11-1. The structures of these compounds were elucidated by extensive analyses of spectroscopic methods including 1 D and 2 D NMR, HRESIMS and ECD. The bioactivities of all compounds were evaluated using cellular assays, and compounds 2 and 3 displayed moderate cytotoxicities against human cancer (A549, TCA, RD) cells with IC50 values of 26–87 μg/mL. [ABSTRACT FROM AUTHOR]

Glaucoma remains the primary cause of long-term blindness. While diabetes mellitus (DM) and hypertension (HTN) are known to influence glaucoma, other factors such as age and sex may be involved. In this retrospective study, we aimed to investigate the associations between age, sex, DM, HTN, and glaucoma risk. We employed optical coherence tomography (OCT) conducted using a 200 × 200-pixel optic cube (Cirrus HD OCT 6000, version 10.0; Carl Zeiss Meditec, Dublin, CA, USA). Effects obscured by low-test signals were disregarded. Data were amassed from 1337 patients. Among them, 218 and 402 patients had DM and HTN, respectively, with 133 (10%) exhibiting both. A sex-based comparison revealed slightly greater retinal nerve fiber layer (RNFL) and ganglion cell–inner plexiform layer (GCIPL) thickness in females. Patients without DM and HTN were predominantly in their 50 s and 60 s, whereas DM and HTN were most prevalent in those in their 60 s and 70 s. Both RNFL and GCIPL thicknesses decreased with advancing age in most patients. The study revealed that older individuals were more prone to glaucoma than younger individuals, with a higher incidence among patients with DM and HTN and reduced RNFL and GCIPL thicknesses. Furthermore, early detection before advancing age could furnish valuable preventive insights. [ABSTRACT FROM AUTHOR]

Introduction: The Phosphoinositide 3-kinase (PI3K) signaling pathway plays an important role in skeletal muscle insulin-stimulated glucose uptake. While whole-body and tissue specific knockout (KO) of individual or combinations of the regulatory subunits of PI3K (p85α, p55α, and p50α or p85β); increase insulin sensitivity, no study has examined whether increasing the expression of the individual regulatory subunits would inhibit insulin action in vivo. Therefore, the objective of this study was to determine whether skeletal muscle-specific overexpression of the p55α regulatory subunit of PI3K impairs skeletal muscle insulin sensitivity, or prevents its enhancement by caloric restriction. Methods: We developed a novel floxed mouse that, through the Cre-LoxP approach, allows for tamoxifen (TMX)-inducible and skeletal muscle-specific overexpression of the p55α subunit of PI3K (referred to as, p55α-mOX). Beginning at 10 weeks of age, p55α-mOX mice and their floxed littermates (referred to as wildtype [WT]) either continued with free access to food (ad libitum; AL), or were switched to a calorie restricted diet (CR; 60% of AL intake) for 20 days. We measured body composition, whole-body energy expenditure, oral glucose tolerance and ex vivo skeletal muscle insulin sensitivity in isolated soleus and extensor digitorum longus muscles using the 2-deoxy-glucose (2DOG) uptake method. Results: p55α mRNA and protein expression was increased ∼2 fold in muscle from p55α-mOX versus WT mice. There were no differences in energy expenditure, total activity, or food intake of AL-fed mice between genotypes. Body weight, fat and lean mass, tissue weights, and fasting glucose and insulin were comparable between p55α-mOX and WT mice on AL, and were decreased equally by CR. Interestingly, overexpression of p55α did not impair oral glucose tolerance or skeletal muscle insulin signaling or sensitivity, nor did it impact the ability of CR to enhance these parameters. Conclusion: Skeletal muscle-specific overexpression of p55α does not impact skeletal muscle insulin action, suggesting that p85α and/or p50α may be more important regulators of skeletal muscle insulin signaling and sensitivity.

Deciphering neuronal networks governing specific brain functions is a longstanding mission in neuroscience, yet global manipulation of protein functions pharmacologically or genetically lacks sufficient specificity to reveal a neuronal protein's function in a particular neuron or a circuitry. Photostimulation presents a great venue for researchers to control neuronal proteins with high temporal and spatial resolution. Recently, an approach to optically control the function of a neuronal protein directly in neurons has been demonstrated using genetically encoded light-sensitive Unnatural amino acids (Uaas). Here, we describe procedures for genetically incorporating Uaas into target neuronal proteins in neurons in vitro and in embryonic mouse brain. As an example, a photocaged Uaa was incorporated into an inwardly rectifying potassium channel Kir2.1 to render Kir2.1 photo-activatable. This method has the potential to be generally applied to many neuronal proteins to achieve optical regulation of different processes in brains. Uaas with other properties can be similarly incorporated into neuronal proteins in neurons for various applications.