By using a cell-based high throughput screening campaign, a novel angelicin derivative 6a was identified to inhibit influenza A (H1N1) virus induced cytopathic effect in Madin−Darby canine kidney ...cell culture in low micromolar range. Detailed structure−activity relationship studies of 6a revealed that the angelicin scaffold is essential for activity in pharmacophore B, while meta-substituted phenyl/2-thiophene rings are optimal in pharmacophore A and C. The optimized lead 4-methyl-9-phenyl-8-(thiophene-2-carbonyl)-furo2,3-hchromen-2-one (8g, IC50 = 70 nM) showed 64-fold enhanced activity compared to the high throughput screening (HTS) hit 6a. Also, 8g was found effective in case of influenza A (H3N2) and influenza B virus strains similar to approved anti-influenza drug zanamivir (4). Preliminary mechanistic studies suggest that these compounds act as anti-influenza agents by inhibiting ribonucleoprotein (RNP) complex associated activity and have the potential to be developed further, which could form the basis for developing additional defense against influenza pandemics.
The aim of this study was to develop a multivariate logistic regression model with least absolute shrinkage and selection operator (LASSO) to make valid predictions about the incidence of ...moderate-to-severe patient-rated xerostomia among head and neck cancer (HNC) patients treated with IMRT.
Quality of life questionnaire datasets from 206 patients with HNC were analyzed. The European Organization for Research and Treatment of Cancer QLQ-H&N35 and QLQ-C30 questionnaires were used as the endpoint evaluation. The primary endpoint (grade 3(+) xerostomia) was defined as moderate-to-severe xerostomia at 3 (XER3m) and 12 months (XER12m) after the completion of IMRT. Normal tissue complication probability (NTCP) models were developed. The optimal and suboptimal numbers of prognostic factors for a multivariate logistic regression model were determined using the LASSO with bootstrapping technique. Statistical analysis was performed using the scaled Brier score, Nagelkerke R(2), chi-squared test, Omnibus, Hosmer-Lemeshow test, and the AUC.
Eight prognostic factors were selected by LASSO for the 3-month time point: Dmean-c, Dmean-i, age, financial status, T stage, AJCC stage, smoking, and education. Nine prognostic factors were selected for the 12-month time point: Dmean-i, education, Dmean-c, smoking, T stage, baseline xerostomia, alcohol abuse, family history, and node classification. In the selection of the suboptimal number of prognostic factors by LASSO, three suboptimal prognostic factors were fine-tuned by Hosmer-Lemeshow test and AUC, i.e., Dmean-c, Dmean-i, and age for the 3-month time point. Five suboptimal prognostic factors were also selected for the 12-month time point, i.e., Dmean-i, education, Dmean-c, smoking, and T stage. The overall performance for both time points of the NTCP model in terms of scaled Brier score, Omnibus, and Nagelkerke R(2) was satisfactory and corresponded well with the expected values.
Multivariate NTCP models with LASSO can be used to predict patient-rated xerostomia after IMRT.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The programmed cell death-1 receptor/programmed cell death-1 ligand (PD-1/PD-L1) pathway plays a crucial role in tumor evasion from host immunity. This study was designed to evaluate the association ...between circulating PD-L1/PD-1 and prognosis after cryoablation in patients with HBV-related hepatocellular carcinoma (HCC).
In the present study, 141 HBV-related HCC patients were enrolled and of those 109 patients received cryoablation. Circulating PD-L1/PD-1 expression was tested by flow cytometry, and 23 patients were simultaneously evaluated for intratumoral PD-L1 expression by immunohistochemical staining. Circulating PD-1/PD-L1 expression was associated with severity of diseases in patients with HCC, and the circulating PD-L1 expression was closely correlated with intratumoral PD-L1 expression. Of the clinical parameters, PD-1/PD-L1 expression was associated with tumor size, blood vessel invasion and BCLC staging. Moreover, PD-1/PD-L1 expression dropped after cryoablation while being elevated at the time of tumor recurrence. Patients with higher expression of circulating PD-L1, as well as circulating PD-1, had a significantly shorter overall survival and tumor-free survival than those with lower expression. Multivariate analysis confirmed that circulating PD-L1 could serve as an independent predictor of overall survival and tumor-recurrence survival in HCC patients after cryoablation.
Upregulation of circulating PD-L1/PD-1 is associated with poor post-cryoablation prognosis in patients with HBV-related hepatocellular carcinoma.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
1,3-xylan is present in the cell walls of some red and green algae and is an important organic carbon in the ocean. However, information on its bacterial degradation is quite limited. Here, after ...enrichment with 1,3-xylan, the diversity of bacteria recovered from marine algae collected in Hainan, China, was analyzed with both the 16S rRNA gene amplicon sequencing and the culture-dependent method. Bacteria recovered were affiliated with more than 19 families mainly in phyla
Proteobacteria
and
Bacteroidetes
, suggesting a high bacterial diversity. Moreover, 12 strains with high 1,3-xylanase-secreting ability from genera
Vibrio
,
Neiella
,
Alteromonas
, and
Gilvimarinus
were isolated from the enrichment culture. The extracellular 1,3-xylanases secreted by
Vibrio
sp. EA2,
Neiella
sp. GA3,
Alteromonas
sp. CA13-2, and
Gilvimarinus
sp. HA3-2, which were taken as representatives due to their efficient utilization of 1,3-xylan for growth, were further characterized. The extracellular 1,3-xylanases secreted by these strains showed the highest activity at pH 6.0–7.0 and 30–40°C in 0–0.5M NaCl, exhibiting thermo-unstable and alkali-resistant characters. Their degradation products on 1,3-xylan were mainly 1,3-xylobiose and 1,3-xylotriose. This study reveals the diversity of marine bacteria involved in the degradation and utilization of 1,3-xylan, helpful in our understanding of the recycling of 1,3-xylan driven by bacteria in the ocean and the discovery of novel 1,3-xylanases.
Decreased heart rate variability (HRV) leads to cardiovascular diseases and increased mortality in clinical studies. However, the underlying mechanisms are still inconclusive. Systemic ...inflammation-induced neuroinflammation is known to impair the autonomic center of cardiovascular regulation. The dynamic stability of blood pressure and heart rate (HR) is regulated by modulation of the reciprocal responses of sympathetic and parasympathetic tone by the baroreflex, which is controlled by the nucleus of the solitary tract (NTS).
Systemic inflammation was induced by E. coli lipopolysaccharide (LPS, 1.2 mg/kg/day, 7 days) peritoneal infusion via an osmotic minipump in normotensive Sprague-Dawley rats. Systolic blood pressure (SBP) and HR were measured by femoral artery cannulation and recorded on a polygraph under anesthesia. The low-frequency (LF; 0.25-0.8 Hz) and high-frequency (HF; 0.8-2.4 Hz) components of SBP were adopted as the indices for sympathetic vasomotor tone and parasympathetic vasomotor tone, while the baroreflex effectiveness index (BEI) was adopted from the analysis of SBP and pulse interval (PI). The plasma levels of proinflammatory cytokines and mitochondrial DNA (mtDNA) oxidative damage were analyzed by ELISA. Protein expression was evaluated by Western blot. The distribution of oxidative mtDNA was probed by immunofluorescence. Pharmacological agents were delivered via infusion into the cisterna magna with an osmotic minipump.
The suppression of baroreflex sensitivity was concurrent with increased SBP and decreased HR. Neuroinflammatory factors, including TNF-α, CD11b, and Iba-1, were detected in the NTS of the LPS group. Moreover, indices of mtDNA damage, including 8-OHdG and γ-H2AX, were significantly increased in neuronal mitochondria. Pentoxifylline or minocycline intracisternal (IC) infusion effectively prevented mtDNA damage, suggesting that cytokine and microglial activation contributed to mtDNA damage. Synchronically, baroreflex sensitivity was effectively protected, and the elevated blood pressure was significantly relieved. In addition, the mtDNA repair mechanism was significantly enhanced by pentoxifylline or minocycline.
These results suggest that neuronal mtDNA damage in the NTS induced by neuroinflammation could be the core factor in deteriorating baroreflex desensitization and subsequent cardiovascular dysfunction. Therefore, the enhancement of base excision repair (BER) signaling in mitochondria could be a potential therapeutic strategy for cardiovascular reflex dysregulation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We sought to explore the prevalence and immediate clinical implications of acute myocardial injury in a cohort of patients with COVID-19 in a region of China where medical resources are less stressed ...than in Wuhan (the epicentre of the pandemic).
We prospectively assessed the medical records, laboratory results, chest CT images and use of medication in a cohort of patients presenting to two designated covid-19 treatment centres in Sichuan, China. Outcomes of interest included death, admission to an intensive care unit (ICU), need for mechanical ventilation, treatment with vasoactive agents and classification of disease severity. Acute myocardial injury was defined by a value of high-sensitivity troponin T (hs-TnT) greater than the normal upper limit.
A total of 101 cases were enrolled from January to 10 March 2020 (average age 49 years, IQR 34-62 years). Acute myocardial injury was present in 15.8% of patients, nearly half of whom had a hs-TnT value fivefold greater than the normal upper limit. Patients with acute myocardial injury were older, with a higher prevalence of pre-existing cardiovascular disease and more likely to require ICU admission (62.5% vs 24.7%, p=0.003), mechanical ventilation (43.5% vs 4.7%, p<0.001) and treatment with vasoactive agents (31.2% vs 0%, p<0.001). Log hs-TnT was associated with disease severity (OR 6.63, 95% CI 2.24 to 19.65), and all of the three deaths occurred in patients with acute myocardial injury.
Acute myocardial injury is common in patients with COVID-19 and is associated with adverse prognosis.
MYB transcription factors (TFs) participate in many biological processes. However, the molecular mechanisms by which MYB TFs affect plant resistance to apple ring rot remain poorly understood. Here, ...the R2R3-MYB gene
was cloned from "
" apples and functionally characterized as a positive regulator of the defense response to
. qRT-PCR and GUS staining demonstrated that
was strongly induced in apple fruits and transgenic calli after inoculation with
.
overexpression improved resistance to
in apple calli and fruits, while
suppression weakened. Increased resistance to
was also observed in
-expressing
. Interestingly, salicylic acid (SA) contents and the expression levels of genes related with SA synthesis and signaling were greater in
-overexpressing plant materials compared to wild-type controls after inoculation, suggesting that MdMYB73 might enhance resistance to
the SA pathway. Finally, we discovered that MdMYB73 interacts with MdWRKY31, a positive regulator of
. Together, MdWRKY31 and MdMYB73 enhanced
resistance in apples. Our results clarify the mechanisms by which MdMYB73 improves resistance to
and suggest that resistance may be affected by regulating the SA pathway.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
Late Paleozoic sedimentary strata outcrop extensively in central Inner Mongolia, and are a key to understanding the tectonic evolution of the southeastern Central Orogenic Belt. A combined analysis ...of petrography, whole-rock major and trace element, and Nd isotope is carried out on representative sandstones from the Late Paleozoic sedimentary strata (420–270 Ma). The sandstones are mainly wackes and litharenites in lithology, with low SiO2/Al2O3 of 2.85–9.47 (averagely 5.22) and poor textural and compositional maturities, implying short sediment transportation between the depositional basins and provenances. The trace element compositions are generally comparable to that of the average upper continent crust (UCC), with negatively-sloping chondrite-normalized rare earth element distribution patterns ((La/Yb)N = 3.43–11; averagely 6.94) and flat UCC-normalized trace element distribution patterns. The Nd isotopic compositions show great variation (ԐNd(t) = −5.01 to 5.35) with depositional time of the sandstones, and coincide well with the arc magmatic phases in central Inner Mongolia. The geochemical signatures of the sandstones indicate that the dominant provenances are intermediate to felsic arc magmatic rocks that have ages approximating the deposition, although old, recycled sediments may have made a minor contribution. An active continental arc setting during the Late Paleozoic in central Inner Mongolia, controlled by the northward subduction of the Paleo-Asian oceanic slab, was the most likely depositional tectonic setting of the sandstones. This active continental arc setting continued to at least 270 Ma, implying that the final closure of the Paleo-Asian Ocean along the Solonker suture zone most likely occurred sometime during the Late Permian to Early Triassic. The northward subduction of the Paleo-Asian Ocean is likely of West Pacific-style, in which the present-day Baolidao arc has a close genetic link with the South Mongolian microcontinent and, likely, the former originally formed as the arc margin of the latter.
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•First reported Nd isotope on Late Paleozoic sandstones in central Inner Mongolia•A dominant arc provenance and tectonic setting of the sandstones are proposed.•A west Pacific-style northward subduction of Paleo-Asian Ocean continued to 270 Ma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Curcumin, a constituent of the turmeric plant, has antitumor, anti‐inflammatory, and antioxidative effects, but its effects on wound healing are unclear. We created back wounds in 72 mice and treated ...them with or without topical curcumin (0.2 mg/mL) in Pluronic F127 gel (20%) daily for 3, 5, 7, 9, and 12 days. Healing in wounds was evaluated from gross appearance, microscopically by haematoxylin and eosin staining, by immunohistochemistry for tumour necrosis factor alpha and alpha smooth muscle actin, and by polymerase chain reaction amplification of mRNA expression levels. Treatment caused fast wound closure with well‐formed granulation tissue dominated by collagen deposition and regenerating epithelium. Curcumin increased the levels of tumour necrosis factor alpha mRNA and protein in the early phase of healing, which then decreased significantly. However, these levels remained high in controls. Levels of collagen were significantly higher in curcumin‐treated wounds. Immunohistochemical staining for alpha smooth muscle actin was increased in curcumin‐treated mice on days 7 and 12. Curcumin treatment significantly suppressed matrix metallopeptidase‐9 and stimulated alpha smooth muscle levels in tumour necrosis factor alpha‐treated fibroblasts via nuclear factor kappa B signalling. Thus, topical curcumin accelerated wound healing in mice by regulating the levels of various cytokines.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Maternal nutrient intake influences the health of the offspring via microenvironmental systems in digestion and absorption. Maternal high fructose diet (HFD) impairs hippocampus-dependent memory in ...adult female rat offspring. However, the underlying mechanisms remain largely unclear. Maternal HFD causes microbiota dysbiosis. In this study, we find that the plasma level of butyrate, a major metabolite of microbiota, is significantly decreased in the adult female maternal HFD offspring. In these rats, GPR43, a butyrate receptor was downregulated in the hippocampus. Moreover, the expressions of mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) were downregulated in the hippocampus. The decreases of these functional proteins were reversed by fructooligosaccharides (FOS, a probiotic) treatment in adulthood. Astrocytes are critical for energy metabolism in the brain. Primary astrocyte culture from female maternal HFD offspring indicated that GPR43 and the mitochondrial biogenesis were significantly suppressed, which was reversed by supplemental butyrate incubation. The oxygen consumption rate (OCR) was reduced in the HFD group and rescued by butyrate. Intriguingly, the nuclear histone deacetylase 4 (HDAC4) was enhanced in the HFD group, suggesting an inhibitory role of butyrate on histone deacetylase activity. Inhibition of HDAC4 effectively restored the OCR, bioenergetics, and biogenesis of mitochondria. Together, these results suggested that the impaired butyrate signaling by maternal HFD could underlie the reduced mitochondrial functions in the hippocampus via HDAC4-mediated epigenetic changes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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