Serial Endosymbiosis Theory, or SET, was conceived and developed by Lynn Margulis, to explain the greatest discontinuity in the history of life, the origin of eukaryotic cells. Some predictions of SET, namely the origin of mitochondria and chloroplasts, withstood the test of the most recent evidence from a variety of disciplines including phylogenetics, biochemistry, and cell biology. Even though some other predictions fared less well, SET remains a seminal theory in biology. In this paper, I focus on two aspects of SET. First, using the concept of "universal symbiogenesis", developed by Freeman Dyson to search for commonalities in astronomy and biology, I propose that SET can be extended beyond eukaryogenesis. The extension refers to the possibility that even prokaryotic organisms, themselves subject to the process of symbiogenesis in SET, could have emerged symbiotically. https://www.selleckchem.com/products/5-cholesten-3beta-ol-7-one.html Second, I contrast a recent "viral eukaryogenesis" hypothesis, according to which the nucleus evolved from a complex DNA virus, with a view closer to SET, according to which the nucleus evolved through the interplay of the archaeal host, the eubacterial symbiont, and a non-LTR transposon, or telomerase. Viruses joined in later, through the process of viral endogenization, to shape eukaryotic chromosomes in the process of karyotype evolution. These two proposals based on SET are a testament to its longevity as a scientific theory.The emergence of antibiotic-resistant strains of Mycobacterium tuberculosis and the decelerating development of new and effective antibiotics has impaired the treatment of tuberculosis (TB). Efflux pump inhibitors (EPIs) have the potential to improve the efficacy of existing anti-TB drugs although with toxicity limitations. Peptide nucleic acids (PNAs), oligonucleotide mimics, by virtue of their high nucleic acid binding specificity have the capability to overcome this drawback. We, therefore, investigated the efflux pump inhibitory properties of a PNA designed against an efflux pump of Mycobacterium smegmatis. LfrA, an efflux pump found in M. smegmatis, is majorly involved in conferring innate drug resistance to this strain and, therefore, was selected as a target for gene silencing via PNA. qRT-PCR and EtBr assays confirmed the EPI activity of the anti-lfrA PNA. On testing the effect of the anti-lfrA PNA on the bactericidal activity of a fluoroquinolone, norfloxacin, we observed that 5 μM of anti-lfrA PNA in combination with norfloxacin led to an enhanced killing of up to 2.5 log-fold against wild-type and a lab-generated multidrug resistant strain, exemplifying its potential in countering resistance. Improved efficacy was also observed against intra-macrophage mycobacteria, where the drug-PNA combination enhanced bacterial clearance by 1.3 log-fold. Further, no toxicity was observed with PNA concentrations up to 4 times higher than the efficacious anti-lfrA PNA concentration. Thus, PNA, as an adjuvant, presents a novel and viable approach to rejuvenate anti-TB therapeutics.Mango is one of the important commercially cultivated fruit crops in southern China. In continuing research on foliar diseases of mango in south of China during 2016-2017, leaf spot disease was common at all mango orchards investigated. The purpose of this study was to investigate Fusarium species associated with leaf spots of mango in the main production areas of China, and to identify them to species. Twenty-two Fusarium isolates were obtained from diseased leaves from seven provinces (Fujian, Guangdong, Guangxi, Guizhou, Hainan, Sichuan and Yunnan), and then identified using morphological characteristics and phylogenetic analysis. These isolates were from seven species F. concentricum, F. hainanense, F. mangiferae, F. pernambucanum, F. proliferatum, F. sulawesiense, and F. verticillioides. We found all 22 isolates to be capable of causing leaf spot symptoms on artificially wounded leaves. To our knowledge, this is the first report of F. concentricum, F. hainanense, F. mangiferae, F. pernambucanum, F. sulawesiense and F. verticillioides associated with leaf spots on mango in China, and the first for F. concentricum, F. hainanense, F. pernambucanum, F. sulawesiense from mango worldwide. This is one of the few reports on Fusarium species as potential causal agents of mango leaf spots.Immunostimulant and protective effects of Yarrowia lipolytica glucans against important pathogens, such as Escherichia coli, have not been investigated in goats and other ruminants. This study aimed to characterize Y. lipolytica N6-glucan (Yl-glucan) and its possible role in immunological signaling pathway activation and immunoprotection against E. coli in goat leukocytes. Characterization analyses showed that Y. lipolytica content had a mix of β and α-D-glucans, molecular weight of 3301.53 kDa and low solubility after the heat treatment. The stimulation of goat leukocytes with Yl-glucan induced protection against E. coli challenge. Remarkably, Yl-glucan and E. coli interaction increased gene expression of dectin-1 and TLR-2 receptors, signaling pathway Syk/NFκB, and cytokines, such as TNF-α and IL-10. As a consequence of signaling activation, phagocytosis, and nitric oxide production enhanced killing of pathogens. Altogether, Y. lipolytica-glucan demonstrated to possess an immunoprotective potential against E. coli through innate immune response modulation in goat leukocytes.
Radiation recall pneumonitis (RRP) is a delayed radiation-induced lung toxicity triggered by systemic agents, typically anticancer drugs. Immune checkpoint inhibitors (ICIs) have recently been identified as potential causal agents of RRP but its real incidence and potential risk factors remain unknown.
Medical records and CTs of patients treated with programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors for advanced lung cancer between 2014 and 2019 at our tertiary center, and who had a previous history of lung irradiation were retrospectively analyzed. We identified RRP as lung CT modifications occurring in the irradiation field >6months after conventionally fractionated radiotherapy completion and >1year after stereotactic body radiation therapy. Clinical and dosimetric data were analyzed to identify potential risk factors for RRP.
Among 348 patients treated with ICIs, data from 80 eligible patients were analyzed (median age, 69years [interquartile range, 11]; 45 men). Fifteen patients (18.8%) presented with RRP. Median time between end of radiotherapy and RRP was 450days (range, 231-1859). No risk factor was significantly associated with RRP. ICI-related pneumonitis was associated with RRP in 33.3% of cases (p=0.0021), developing either concomitantly or after RRP. Incidence of grade≥3 pneumonitis in the RRP population was 13.3 %.
We demonstrated a high incidence of RRP (18.8%) in our population of previously irradiated patients treated with ICIs for lung cancer. We identified no risk factors for RRP, but an association was noted between RRP and ICI-related pneumonitis.
We demonstrated a high incidence of RRP (18.8%) in our population of previously irradiated patients treated with ICIs for lung cancer. We identified no risk factors for RRP, but an association was noted between RRP and ICI-related pneumonitis.
Multiple large trials have established the non-inferiority of hypofractionated radiotherapy compared to conventional fractionation. This study will determine real-world hypofractionation adoption across different geographic regions for breast, prostate, cervical cancer, and bone metastases, and identify barriers and facilitators to its use.
An anonymous, electronic survey was distributed from January 2018 through January 2019 to radiation oncologists through the ESTRO-GIRO initiative. Predictors of hypofractionation were identified in univariable and multivariable regression analyses.
2316 radiation oncologists responded. Hypofractionation was preferred in node-negative breast cancer following lumpectomy (82·2% vs. 46·7% for node-positive; p<0.001), and in low- and intermediate-risk prostate cancer (57·5% and 54·5%, respectively, versus 41·2% for high-risk (p<0.001)). Hypofractionation was used in 32·3% of cervix cases in Africa, but <10% in other regions (p<0.001). For palliative indicationr concordance in palliation. Using inadequate fractionation schedules may impede the delivery of affordable and accessible radiotherapy. Greater regionally-targeted and disease-specific education on evidence-based fractionation schedules is needed to improve utilization, along with best-case examples addressing practice barriers and supporting policy reform.
The Neoadjuvant rectal (NAR) score is a new surrogate endpoint to be used in clinical trials for early determination of treatment response to different preoperative therapies. The aim is to further validate the NAR-score, primarily developed using chemoradiotherapy (CRT) with a delay to surgery 6-8weeks, and explore its value using other schedules.
The study included all 9978 patients diagnosed with non-metastasized RC in 2007-2015 that had undergone surgery and was registered in the Swedish Colorectal Cancer Registry. The patients of interest had either short-course radiotherapy (scRT)/CRT+delayed surgery, long-course radiotherapy (RT)+delayed surgery, (C)RT+additional chemotherapy, primary surgery, or scRT+immediate surgery. The scRT/CRT+delayed surgery groups were further divided based on time to surgery.
Mean NAR-score differed significantly (p<0.0001) between different treatments. (C)RT+additional chemotherapy had the lowest mean score of 16.3 and CRT+delayed surgery had 17.7. There was a significant difference (p<0.05) in overall survival (OS) and time to recurrence (TTR) of patients with a Low NAR-score (<8) compared to those with a High score (>16) for both CRT- and scRT, with a stronger correlation for CRT-patients. C-index for the NAR-score model (0.623) was not superior to when only pathological T- and N-stage was used (0.646).
The NAR-score is prognostic, but it is not better than pT- and pN-stage. However, the NAR-score can still discriminate between two treatments that have different cell killing effect and may still be of value in clinical trials as an easier method than pT- and N-stage.
The NAR-score is prognostic, but it is not better than pT- and pN-stage. However, the NAR-score can still discriminate between two treatments that have different cell killing effect and may still be of value in clinical trials as an easier method than pT- and N-stage.The refinement of OECD 402 study design and criteria under which the study can be waived has been welcomed in some regulatory regions but met with uncertainty in others. To address these human safety concerns, previously available in vivo acute oral and acute dermal toxicity data was evaluated from a total of 597 agrochemical active ingredients and products. It was identified that all active ingredients and 99.6% of products had an acute dermal classification equal to or less toxic than their acute oral classification, confirming that waiving the acute dermal study and basing the outcome on the acute oral toxicity result has no impact on human health assessment. Additionally, automated Acute Toxicity Estimate (ATE) calculations were conducted on 440 products to evaluate if the predicted dermal toxicity resulted in the same in vivo classification. 93% of ATE predictions provided excellent correlation to the in vivo result and 6.4% resulted in a more conservative prediction. It is therefore clear that the results of this investigation, should remove any regulatory concerns and that OECD 402 can be confidently eliminated in its entirety from testing requirements globally.