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Veterinary drugs are used to treat livestock and aquatic diseases and thus are introduced into animal-derived foods, endangering consumer health and safety. Antibiotic resistance is rapidly becoming a major worldwide problem, and there has been a steady increase in the number of pathogens that show multi-drug resistance. Illegal and excessive use of veterinary drugs in animals and aquaculture has serious adverse effects on humans and on all other environmental organisms. It is necessary to develop simple extraction methods and fast analytical methods to effectively detect veterinary drug residues in animal-derived foods. This review summarizes the application of various sample extraction techniques and detection and quantification methods for veterinary drug residues reported in the last decade (2010-2020). This review compares the advantages and disadvantages of various extraction techniques and detection methods and describes advanced methods, such as those that use electrochemical biosensors, piezoelectric biosensors, optical biosensors, and molecularly imprinted polymer biosensors. Finally, the future prospects and trends related to extraction methods, detection methods and advanced methods for the analysis of veterinary drug residues in animal-derived foods are summarized.

Synthetic retinoid compounds can kill both growing and persister MRSA cells by disrupting the membrane lipid bilayer, and are effective in a mouse model of chronic MRSA infection. Drugs to beat persistence Bacterial persisters are a subpopulation of cells that can survive lethal antibiotics and other stresses. They are a major challenge for antimicrobial therapy as they cannot be killed by traditional therapeutic agents. Eleftherios Mylonakis and colleagues have developed retinoid compounds that can kill both growing and persister MRSA cells by disrupting the membrane. They develop one of these compounds with an improved cytotoxicity profile, and show that it is effective in treating a mouse model of chronic MRSA infection. Further development of these antibiotics is required to improve safety margins to move the antibiotics closer to being viable clinical candidates. A challenge in the treatment of Staphylococcus aureus infections is the high prevalence of methicillin-resistant S. aureus (MRSA) strains and the formation of non-growing, dormant ‘persister’ subpopulations that exhibit high levels of tolerance to antibiotics 1 , 2 , 3 and have a role in chronic or recurrent infections 4 , 5 . As conventional antibiotics are not effective in the treatment of infections caused by such bacteria, novel antibacterial therapeutics are urgently required. Here we used a Caenorhabditis elegans –MRSA infection screen 6 to identify two synthetic retinoids, CD437 and CD1530, which kill both growing and persister MRSA cells by disrupting lipid bilayers. CD437 and CD1530 exhibit high killing rates, synergism with gentamicin, and a low probability of resistance selection. All-atom molecular dynamics simulations demonstrated that the ability of retinoids to penetrate and embed in lipid bilayers correlates with their bactericidal ability. An analogue of CD437 was found to retain anti-persister activity and show an improved cytotoxicity profile. Both CD437 and this analogue, alone or in combination with gentamicin, exhibit considerable efficacy in a mouse model of chronic MRSA infection. With further development and optimization, synthetic retinoids have the potential to become a new class of antimicrobials for the treatment of Gram-positive bacterial infections that are currently difficult to cure.

A novel quinophthalone derivative, 4,5,6,7-tetrachloro-2-(2-(3-hydroxy-1-oxo-1H-cyclopenta[b]naphthalen-2-yl)quinolin-4-yl)isoindoline-1,3-dione (TCHCQ), was designed and synthesized as a yellow colorant additive for green color filters in image sensors. The characteristics of the new material were evaluated in terms of optical, thermal, and chemical properties under solution and color filter film conditions. TCHCQ exhibited a significantly enhanced molar extinction coefficient in solution, being 1.21 times higher than that of the commercially used yellow colorant Y138. It also demonstrated excellent thermal stability, with a decomposition temperature (Td) exceeding 450 °C. Utilizing the nano-pigmentation process, TCHCQ was used to prepare nano-sized particles with an excellent average size of 35 nm. This enabled the fabrication of a color filter film with outstanding properties. The optical properties of the produced film revealed outstanding yellow colorant transmittance of 0.97% at 435 nm and 91.2% at 530 nm. The color filter film exhibited similar optical and thermal stability to Y138, with an improved chemical stability, as evidenced by a ΔEab value of 0.52. The newly synthesized TCHCQ is considered a promising candidate for use as a yellow colorant additive in image sensor color filters, demonstrating superior optical, thermal, and chemical stability.

Background Acupuncture, practiced for millennia, lacks a clear anatomical definition for acupoints. A prevailing theory suggests that acupoints overlap with skin areas with higher mast cell density. Skin spots stained with intravenously infused Evans blue (EB), indicative of neurogenic inflammation, have recently been posited as acupoints in rats. Objectives To demonstrate the concordance between EB-reactive skin spots and mast cell–enriched acupoints. Methods We employed staining and RNA-seq analysis to delineate the morphological characteristics and gene expression profiles of EB-reactive skin spots in rats. Results EB infusion revealed a novel nodal structure on the rat skin surface, visible to the naked eye, with dimensions of approximately 1 mm in both diameter and height. Around 30 such nodes were identified on one side of the abdominal area, spaced roughly 3 mm apart, excluding the linea alba. RNA-seq analysis indicated that the gene expression patterns within these nodes markedly differed from both non-nodal skin areas and lymph nodes. Histological examination using toluidine blue revealed a significantly greater mast cell count in the nodes than in non-nodal skin regions. Additionally, the nodes stained positively with Alcian blue and Hemacolor, reagents known to mark primo vascular tissues. Conclusion Our findings suggest that EB-reactive nodes are indeed rich in mast cells. Further research is warranted to establish these skin nodes as surface primo nodes.

In this study, we introduced the weak electron-accepting oxazole derivative 4,5-diphenyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazole (TPO) into both anthracene and pyrene moieties of a dual core structure. Ultimately, we developed 2-(4-(6-(anthracen-9-yl)pyren-1-yl)phenyl)-4,5-diphenyloxazole (AP-TPO) as the substitution on the second core, pyrene, and 4,5-diphenyl-2-(4-(10-(pyren-1-yl)anthracen-9-yl)phenyl)oxazole (TPO-AP) as the substitution on the first core, anthracene. Both materials exhibited maximum photoluminescence wavelengths at 433 and 443 nm in solution and emitted deep blue light with high photoluminescence quantum yields of 82% and 88%, respectively. When used as the emitting layer in non-doped devices, TPO-AP outperformed AP-TPO, achieving a current efficiency of 5.49 cd/A and an external quantum efficiency of 4.26% in electroluminescence. These materials introduce a new category of deep blue emitters in the organic light-emitting diodes field, combining characteristics related to the electron transport layer.

Mammalian embryo development is initiated by the union of paternal and maternal gametes. Upon fertilization, their epigenome landscape is transformed through a series of finely orchestrated mechanisms that are crucial for survival and successful embryogenesis. Specifically, maternal or oocyte-specific reprogramming factors modulate germ cell specific epigenetic marks into their embryonic states. Rapid and dynamic changes in epigenetic marks such as DNA methylation and histone modifications are observed during early embryo development. These changes govern the structure of embryonic genome prior to zygotic genome activation. Differential changes in epigenetic marks are observed between paternal and maternal genomes because the structure of the parental genomes allows interaction with specific oocyte reprogramming factors. For instance, the paternal genome is targeted by the TET family of enzymes which oxidize the 5-methylcytosine (5mC) epigenetic mark into 5-hydroxymethylcytosine (5hmC) to lower the level of DNA methylation. The maternal genome is mainly protected from TET3-mediated oxidation by the maternal factor, STELLA. The TET3-mediated DNA demethylation occurs at the global level and is clearly observed in many mammalian species. Other epigenetic modulating enzymes, such as DNA methyltransferases, provide fine tuning of the DNA methylation level by initiating de novo methylation. The mechanisms which initiate the epigenetic reprogramming of gametes are critical for proper activation of embryonic genome and subsequent establishment of pluripotency and normal development. Clinical cases or diseases linked to mutations in reprogramming modulators exist, emphasizing the need to understand mechanistic actions of these modulators. In addition, embryos generated via in vitro embryo production system often present epigenetic abnormalities. Understanding mechanistic actions of the epigenetic modulators will potentially improve the well-being of individuals suffering from these epigenetic disorders and correct epigenetic abnormalities in embryos produced in vitro . This review will summarize the current understanding of epigenetic reprogramming by TET enzymes during early embryogenesis and highlight its clinical relevance and potential implication for assisted reproductive technologies.

Preclinical animal models are essential for the development of effective treatments. For instance, the 5xFAD mouse model successfully represents the pathophysiology of Alzheimer's disease (AD). Expression of humanized APP (K670N/M671L - Swedish, I716V - Florida, V717I - London) and PSEN1 (M146L and L286V), found in early onset AD patients, induces the production of amyloid-β 42 (Aβ42) and amyloid deposition, gliosis, and progressive neuronal loss. While these mouse models are necessary to identify mechanisms of the disease progression, translating the findings by using large animal models such as pigs allows us to explore treatments under clinical conditions, and therefore, improve the success of clinical trial outcomes. For example, the gray-to-white matter ratio and the complexity of the distribution of crossing fibers in the pig brain is more similar to humans than are rodents. Phenotypes of previous swine models carrying humanized APP and PSEN1 to mimic the 5xFAD mouse model did not align with the mouse model, presumably due to differences in aging rates or variation in the expression level of the genes. To accelerate the impact of the humanized APP and PSEN1, we first inactivated endogenous porcine APP and PSEN1 genes by using the CRISPR/Cas9 system in fetal fibroblast cells. Subsequently, constructs designed to express human APP and PSEN1 under the control of the neuron specific Thy1 promoter were transfected into the cells. Cells carrying the humanized APP and PSEN1 genes and the cells were used for somatic cell nuclear transfer to produce AD swine model. Thirteen piglets were born from a single pregnant sow and the genotyping of the piglets indicated that the piglets carried inactivated porcine APP and PSEN1 and carry humanized APP/PSEN1 as expected. Immunohistochemistry on the brain of the newborn AD piglets revealed an elevated abundance of Aβ42 compared to the wild type. Production of the novel AD swine model will offer a new pre-clinical animal resource to expand our understanding of Alzheimer's disease pathogenesis and develop effective treatments against the disease.

Pigs are an important resource in agriculture and serve as a model for human diseases. Due to their physiological and anatomical similarities with humans, pigs can recapitulate symptoms of human diseases, making them a useful model in biomedicine. However, in the past pig models have not been widely used partially because of the difficulty in genetic modification. The lack of true embryonic stem cells in pigs forced researchers to utilize genetic modification in somatic cells and somatic cell nuclear transfer (SCNT) to generate genetically engineered (GE) pigs carrying site-specific modifications. Although possible, this approach is extremely inefficient and GE pigs born through this method often presented developmental defects associated with the cloning process. Advancement in the gene-editing systems such as Zinc-Finger Nucleases (ZFNs), Transcription activator-like effector nucleases (TALENs), and the Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated 9 (Cas9) system have dramatically increased the efficiency of producing GE pigs. These gene-editing systems, specifically engineered endonucleases, are based on inducing double-stranded breaks (DSBs) at a specific location, and then site-specific modifications can be introduced through one of the two DNA repair pathways: non-homologous end joining (NHEJ) or homology direct repair (HDR). Random insertions or deletions (indels) can be introduced through NHEJ and specific nucleotide sequences can be introduced through HDR, if donor DNA is provided. Use of these engineered endonucleases provides a higher success in genetic modifications, multiallelic modification of the genome, and an opportunity to introduce site-specific modifications during embryogenesis, thus bypassing the need of SCNT in GE pig production. This review will provide a historical prospective of GE pig production and examples of how the gene-editing system, led by engineered endonucleases, have improved GE pig production. We will also present some of our current progress related to the optimal use of CRISPR/Cas9 system during embryogenesis.

Membrane-damaging antimicrobial agents have great potential to treat multidrug-resistant or multidrug-tolerant bacteria against which conventional antibiotics are not effective. However, their therapeutic applications are often hampered due to their low selectivity to bacterial over mammalian membranes or their potential for cross-resistance to a broad spectrum of cationic membrane-active antimicrobial agents. We discovered that the diarylurea derivative compound PQ401 has antimicrobial potency against multidrug-resistant and multidrug-tolerant Staphylococcus aureus . PQ401 selectively disrupts bacterial membrane lipid bilayers in comparison to mammalian membranes. Unlike cationic membrane-active antimicrobials, the neutral form of PQ401 rather than its cationic form exhibits maximum membrane activity. Overall, our results demonstrate that PQ401 could be a promising lead compound that overcomes the current limitations of membrane selectivity and cross-resistance. Also, this work provides deeper insight into the design and development of new noncharged membrane-targeting therapeutics to combat hard-to-cure bacterial infections. Resistance or tolerance to traditional antibiotics is a challenging issue in antimicrobial chemotherapy. Moreover, traditional bactericidal antibiotics kill only actively growing bacterial cells, whereas nongrowing metabolically inactive cells are tolerant to and therefore “persist” in the presence of legacy antibiotics. Here, we report that the diarylurea derivative PQ401, previously characterized as an inhibitor of the insulin-like growth factor I receptor, kills both antibiotic-resistant and nongrowing antibiotic-tolerant methicillin-resistant Staphylococcus aureus (MRSA) by lipid bilayer disruption. PQ401 showed several beneficial properties as an antimicrobial lead compound, including rapid killing kinetics, low probability for resistance development, high selectivity to bacterial membranes compared to mammalian membranes, and synergism with gentamicin. In contrast to well-studied membrane-disrupting cationic antimicrobial low-molecular-weight compounds and peptides, molecular dynamic simulations supported by efficacy data demonstrate that the neutral form of PQ401 penetrates and subsequently embeds into bacterial lipid bilayers more effectively than the cationic form. Lastly, PQ401 showed efficacy in both the Caenorhabditis elegans and Galleria mellonella models of MRSA infection. These data suggest that PQ401 may be a lead candidate for repurposing as a membrane-active antimicrobial and has potential for further development as a human antibacterial therapeutic for difficult-to-treat infections caused by both drug-resistant and -tolerant S. aureus . IMPORTANCE Membrane-damaging antimicrobial agents have great potential to treat multidrug-resistant or multidrug-tolerant bacteria against which conventional antibiotics are not effective. However, their therapeutic applications are often hampered due to their low selectivity to bacterial over mammalian membranes or their potential for cross-resistance to a broad spectrum of cationic membrane-active antimicrobial agents. We discovered that the diarylurea derivative compound PQ401 has antimicrobial potency against multidrug-resistant and multidrug-tolerant Staphylococcus aureus . PQ401 selectively disrupts bacterial membrane lipid bilayers in comparison to mammalian membranes. Unlike cationic membrane-active antimicrobials, the neutral form of PQ401 rather than its cationic form exhibits maximum membrane activity. Overall, our results demonstrate that PQ401 could be a promising lead compound that overcomes the current limitations of membrane selectivity and cross-resistance. Also, this work provides deeper insight into the design and development of new noncharged membrane-targeting therapeutics to combat hard-to-cure bacterial infections.