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Preclinical Look at [64Cu]NOTA-CP01 as being a Puppy Imaging Adviser with regard to Metastatic Esophageal Squamous Cell Carcinoma.
ion to hypophosphataemia and hypokalaemia, altered glucose homeostasis and organ damage involving the liver and kidneys were common. Cats with RS appear to have a good prognosis, but prolonged intensive care is required.Alzheimer disease (AD) is usually accompanied by two prominent pathological features, cerebral accumulation of amyloid-β (Aβ) plaques and presence of MAPT/tau neurofibrillary tangles. Dysregulated clearance of Aβ largely contributes to its accumulation and plaque formation in the brain. Macroautophagy/autophagy is a lysosomal degradative process, which plays an important role in the clearance of Aβ. Failure of autophagic clearance of Aβ is currently acknowledged as a contributing factor to increased accumulation of Aβ in AD brains. In this study, we have identified crocetin, a pharmacologically active constituent from the flower stigmas of Crocus sativus, as a potential inducer of autophagy in AD. In the cellular model, crocetin induced autophagy in N9 microglial and primary neuron cells through STK11/LKB1 (serine/threonine kinase 11)-mediated AMP-activated protein kinase (AMPK) pathway activation. Autophagy induction by crocetin significantly increased Aβ clearance in N9 cells. Moreover, crocetin crossed the blood-brain barrier and induced autophagy in the brains' hippocampi of wild-type male C57BL/6 mice. Further studies in transgenic male 5XFAD mice, as a model of AD, revealed that one-month treatment with crocetin significantly reduced Aβ levels and neuroinflammation in the mice brains and improved memory function by inducing autophagy that was mediated by AMPK pathway activation. Our findings support further development of crocetin as a pharmacological inducer of autophagy to prevent, slow down progression, and/or treat AD.Combining targeted therapeutic agents is an attractive cancer treatment strategy associated with high efficacy and low toxicity. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is an essential factor in DNA damage repair. Studies from us and others have revealed that DNA-PKcs also plays an important role in normal mitosis progression. Histone deacetylase (HDACs) inhibitors commonly lead to mitotic aberration and have been approved for treating various cancers in the clinic. We showed that DNA-PKcs depletion or kinase activity inhibition increases cancer cells' sensitivity to HDACs inhibitors in vitro and in vivo. DNA-PKcs deficiency significantly enhances HDACs inhibitors (HDACi)-induced mitotic arrest and is followed by apoptotic cell death. Mechanistically, we found that DNA-PKcs binds to HDAC6 and facilitates its acetylase activity. HDACi is more likely to impair HDAC6-induced deacetylation of HSP90 and abrogate HSP90's chaperone function on Aurora A, a critical mitotic kinase that regulates centrosome separation and mitotic spindle assembly in DNA-PKcs-deficient cells. Our current work indicates crosstalk between DNA-PKcs and HDACs signaling pathways, and highlights that the combined targeting of DNA-PKcs and HDACs can be used in cancer therapy. Abbreviations DNA-PKcs, DNA-dependent protein kinase catalytic subunit, HDACs, Histone deacetylases, DSBs, DNA double-strand breaks, ATM, ataxia telangiectasia mutated, ATR, ATM-Rad3-related.We investigated in larval and adult Drosophila models whether loss of the mitochondrial chaperone Hsc70-5 is sufficient to cause pathological alterations commonly observed in Parkinson disease. At affected larval neuromuscular junctions, no effects on terminal size, bouton size or number, synapse size, or number were observed, suggesting that we studied an early stage of pathogenesis. At this stage, we noted a loss of synaptic vesicle proteins and active zone components, delayed synapse maturation, reduced evoked and spontaneous excitatory junctional potentials, increased synaptic fatigue, and cytoskeleton rearrangements. The adult model displayed ATP depletion, altered body posture, and susceptibility to heat-induced paralysis. Adult phenotypes could be suppressed by knockdown of dj-1β, Lrrk, DCTN2-p50, DCTN1-p150, Atg1, Atg101, Atg5, Atg7, and Atg12. The knockdown of components of the macroautophagy/autophagy machinery or overexpression of human HSPA9 broadly rescued larval and adult phenotypes, while disease-associated HSPA9 variants did not. Overexpression of Pink1 or promotion of autophagy exacerbated defects.Abbreviations AEL after egg laying; AZ active zone; brp bruchpilot; Csp cysteine string protein; dlg discs large; eEJPs evoked excitatory junctional potentials; GluR glutamate receptor; H2O2 hydrogen peroxide; mEJP miniature excitatory junctional potentials; MT microtubule; NMJ neuromuscular junction; PD Parkinson disease; Pink1 PTEN-induced putative kinase 1; PSD postsynaptic density; SSR subsynaptic reticulum; SV synaptic vesicle; VGlut vesicular glutamate transporter.Five series of novel carbazole derivatives containing an aminoguanidine, dihydrotriazine, thiosemicarbazide, semicarbazide or isonicotinic moiety were designed, synthesised and evaluated for their antimicrobial activities. Most of the compounds exhibited potent inhibitory activities towards different bacterial strains (including one multidrug-resistant clinical isolate) and one fungal strain with minimum inhibitory concentrations (MICs) between 0.5 and 16 µg/ml. Compounds 8f and 9d showed the most potent inhibitory activities (MICs of 0.5-2 µg/ml). Furthermore, compounds 8b, 8d, 8f, 8k, 9b and 9e with antimicrobial activities were not cytotoxic to human gastric cancer cell lines (SGC-7901 and AGS) or a normal human liver cell line (L-02). Structure-activity relationship analyses and docking studies implicated the dihydrotriazine group in increasing the antimicrobial potency and reducing the toxicity of the carbazole compounds. In vitro enzyme activity assays suggested that compound 8f binding to dihydrofolate reductase might account for the antimicrobial effect.Loquat (Eriobotrya japonica), a native fruit tree to China, is a popular edible fruit with medicinal properties (Badenes et al. 2013). A 2016-2019 field survey of ~13,000 loquat trees in two orchards in Chongqing and Fujian provinces showed about 5 to 10% root rot disease incidence. The disease symptoms included leaf yellowing, wilting, rotting of main root, and cracking of lateral roots, eventually leading to defoliation and death. To determine the causative agent, diseased roots from six trees were collected, washed in tap water, cut into 2-3 mm pieces, and disinfected for 3 min in 75% (v/v) EtOH. After rinsing in sterilized water, the root pieces were soaked in 10% NaClO (w/v) for 5-10 min, rinsed thrice in sterile water, and plated on potato dextrose agar (PDA). After 7 days of incubation at 25°C, individual spores were collected from the fungal colonies and replated. Single spore cultures growing on PDA gave rise to woolly-cottony, cream-white colored aerial mycelium and a yellowish pigmented mycelium. Ts (TEF-1, RPB1 and RPB2), the re-isolated pathogen from diseased plants was identical to the R4 isolate used for inoculation and the disease assays were repeated thrice. FSSC was recently reported to cause fruit rot disease on loquat in Pakistan (Abbas et al. 2017). Identifying Fusarium solani species complex as a disease agent in Chinese loquat will assist in future development of improved germplasm for this important worldwide tree crop.Sclerotinia sclerotiorum is a devastating plant pathogen with a broad host range and worldwide distribution. The application of chemical fungicides is a primary strategy for controlling this pathogen. However, under the high selective pressure of chemical fungicides, fungicide resistance has emerged and gradually increased, resulting in the failure to control S. sclerotiorum in the field. Quinofumelin is a novel quinoline fungicide, but its antifungal activities against plant pathogens have been rarely reported. Here, we determined the antifungal activity of quinofumelin against S. sclerotiorum in vitro and in planta. The EC50 values ranged from 0.0004 to 0.0059 μg mL-1 with a mean EC50 of 0.0017 ± 0.0009 μg mL-1 and were normally distributed (P=0.402). In addition, no cross-resistance was observed between quinofumelin and other fungicides, dimethachlone, boscalid, or carbendazim, which are commonly used to manage S. sclerotiorum. Quinofumelin did not affect glycerol and oxalic acid production of either carbendazim-sensitive or -resistant isolates. Moreover, quinofumelin exhibited excellent protective, curative, and translaminar activity against S. sclerotiorum on oilseed rape leaves. Protective activity was higher than curative activity. Interestingly, quinofumelin inhibited the formation of the infection cushion in S. selleck kinase inhibitor sclerotiorum, which may contribute to the control efficacy of quinofumelin against S. sclerotiorum in the field. Our findings indicate that quinofumelin has excellent control efficacy against S. sclerotiorum in vitro and in planta as compared with the currently extensively used fungicides and could be used to manage carbendazim- and dimethachlone-resistance in S. sclerotiorum in the field.Field observations suggest that reduced fungicide sensitivity exists in field populations of Podosphaera aphanis, the causal agent of strawberry powdery mildew (SPM). SPM is one of the most common diseases in strawberry production and is controlled using foliar fungicide applications. This study characterizes the sensitivity of 19 P. aphanis isolates to the most common fungicides used against SPM in California. Isolates were collected from commercial fruit production fields in Oxnard, Ventura, Santa Maria, Salinas, and Watsonville, and from a plant nursery in Balico, California. Healthy, unfurled strawberry leaves (cv. Monterey) free of any visual disease symptoms were removed from actively growing plants and treated with one of six commercially formulated fungicides using the minimum labeled rate and inoculated with conidia of P. aphanis. Inoculated leaves were incubated at 20°C under 16/8 hours of day/night lighting and assessed for disease incidence (%) after 14 days. Pathogen growth on the treated leaflets constituted a measure of insensitivity to the fungicide. The six fungicide treatments and their average disease incidence on treated leaves for the 19 isolates are penthiopyrad (51.4%), quinoxyfen (41.5%), myclobutanil (39.8%), trifloxystrobin (19.8%), cyflufenamid (19.3%), and fluopyram + trifloxystrobin (3.5%). The average disease incidence for the trifloxystrobin treatment was raised significantly by two isolates considered to be resistant to the product (disease incidence > 66.6%). Two isolates collected from organic production systems were sensitive to all fungicides. We document compromised fungicide efficacy due to resistance to most of the fungicides currently used for control of SPM in California. This is the first report of resistance in P. aphanis to any fungicide in California and the first report of resistance in P. aphanis to penthiopyrad and quinoxyfen worldwide.On the North China Plain, one of the most water-deficient regions in China, bare fallow has been implemented over a large-scale area to conserve water during the growth season of water-intensive winter wheat since 2015. However, the effects of this bare fallow on fungal community and the occurrence of crop diseases are poorly understood. Here we measured soil chemical properties, fungal community composition and the occurrence of crop diseases after 15 years of long-term fallow (continuous maize or soybean) and non-fallow (maize-wheat rotation; soybean-wheat rotation) cropping systems. Bare fallow during the winter-wheat growth season significantly decreased soil organic matter, available nitrogen and phosphorus. It also changed the composition of soil fungal communities, i.e., increased relative abundances of some potentially pathogenic species of Lectera, Fusarium and Volutella but decreased beneficial Cladorrhium and Schizothecium. Meanwhile, the epidemic tendency of maize diseases changed correspondingly the disease index of southern corn leaf blight and maize brown spot increased, but the incidence of stalk rot decreased compared with the non-fallow system.
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