A comprehensive understanding of the sources and distribution of antibiotic resistance risk is essential for controlling antibiotic pollution and resistance. Based on surface water samples collected ...from the Fenhe River basin in the flood season, using the positive matrix factorization (PMF) model, the risk quotient (RQ) method and the multiple attribute decision making (MADM) method, the resistance risk and source-specific resistance risk of antibiotics were analyzed in this study. The results showed that sulfonamides (SAs) were the dominant antibiotics with a mean concentration of 118.30 ng/L, whereas tetracyclines (TCs) and macrolides (MLs) had the highest detection frequencies (100%). The significant resistance risk rate of antibiotics in the entire river basin was 48%, but no high risk occurred. The significant resistance risk rate of quinolones (QNs) was the highest (100%), followed by that of MLs and TCs. Owing to human activities, the most serious resistance risk occurred in the midstream of the river basin. The resistance risk was the lowest upstream. The antibiotics were mainly contributed by six sources. Pharmaceutical wastewater was the main source, accounting for 30%, followed by livestock discharge (22%). The resistance risk from the six sources showed clear differences, but none of the sources caused a high risk of antibiotic resistance. Pharmaceutical wastewater poses the greatest risk of antibiotic resistance in the Fenhe River basin and is widely distributed. The second greatest source was livestock discharge, which was mainly concentrated in the upstream and midstream areas. The critical sources upstream, midstream, and downstream were all pharmaceutical wastewater, whereas the sequences of other sources were different because different areas were affected by different human activities. The proposed method might provide an important reference for the identification the key source of antibiotics and management of antibiotic pollution, as well as help for the management of antibiotics in Fenhe and Shanxi Province.
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•ARR and source-specific ARR were analyzed based on RQ method and PMF model.•Affected by human activities, ARR was mainly distributed in midstream.•Six sources were identified, the contributions varied with sources and locations.•Pharmaceutical wastewater was critical sources, livestock discharge was the second.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To date, the known models applied in China to risk assessment and cleanup level estimation still have uncertainties. To solve this problem, this study combined the advantages of the traditional model ...and the probabilistic risk assessment model to create a new model that fits China’s exposure scenarios and enhance the accuracy of health risk assessment and cleanup level estimation. The results of applying the traditional model to the health risk assessment and cleanup level estimate in coking plants showed that the selection of point estimates influenced the results, which increased the uncertainty in the outcome of the risk assessment and cleanup level estimates. The risk assessment result of the new model adopted the 95th percentile distribution range to establish a confidence interval to solve the uncertainty of the traditional model. The cancer risk results calculated using the new model were one-fifth to one-third of those calculated using the traditional model. The results showed that using the new model could eliminate the conservativeness of the traditional model. For the cleanup level estimation, the cleanup levels calculated by the new model can control the risk by 95% for the coking plant, but the results calculated by the traditional model can only control the risk by 69–80%. Therefore, the cleanup levels obtained using the traditional model may underestimate the exposure risk of pollutants. The concentration of contaminants in the surface soil was the most sensitive variable in terms of risk outcomes, but the most important parameter for cleanup level estimation was exposure duration. This study highlighted the positive role of the new model in improving the accuracy of risk assessments and cleanup level estimation.
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CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Parkinson's disease (PD) is a progressive neurodegenerative disorder. The classical behavioral defects of PD patients involve motor symptoms such as bradykinesia, tremor, and rigidity, as well as ...non-motor symptoms such as anosmia, depression, and cognitive impairment. Pathologically, the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN) and the accumulation of α-synuclein (α-syn)-composed Lewy bodies (LBs) and Lewy neurites (LNs) are key hallmarks. Glia are more than mere bystanders that simply support neurons, they actively contribute to almost every aspect of neuronal development and function; glial dysregulation has been implicated in a series of neurodegenerative diseases including PD. Importantly, amounting evidence has added glial activation and neuroinflammation as new features of PD onset and progression. Thus, gaining a better understanding of glia, especially neuron-glia crosstalk, will not only provide insight into brain physiology events but also advance our knowledge of PD pathologies. This review addresses the current understanding of α-syn pathogenesis in PD, with a focus on neuron-glia crosstalk. Particularly, the transmission of α-syn between neurons and glia, α-syn-induced glial activation, and feedbacks of glial activation on DA neuron degeneration are thoroughly discussed. In addition, α-syn aggregation, iron deposition, and glial activation in regulating DA neuron ferroptosis in PD are covered. Lastly, we summarize the preclinical and clinical therapies, especially targeting glia, in PD treatments.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Left ventricular (LV) diastolic dysfunction is an independent predictor of future cardiovascular events. Early detection of patients with LV diastolic dysfunction can improve clinical outcomes ...through active management. However, the assessment of diastolic function is very complicated, and there are currently lack of effective biomarkers to assess the risk of LV diastolic dysfunction. Connective tissue growth factor (CTGF) plays a significant role in cardiac remodeling and dysfunction. We aimed to investigate the associations between plasma CTGF level and the risk of LV diastolic dysfunction in this study and judge its effectiveness in diagnosing LV diastolic dysfunction.
A total of 169 patients with overt hyperthyroidism were included. LV diastolic function was evaluated and the subjects were divided into normal LV diastolic function group and LV diastolic dysfunction group. Routine clinical medical data, biochemical data, thyroid related parameters and echocardiographic parameters were recorded for analysis.
Compared with normal LV diastolic function group, the LV diastolic dysfunction group had higher age and BMI, as well as lower heart rate, lower serum albumin, lower eGFR, higher serum TgAb and BNP level, and the incidences of hypertension were also higher (all
<0.05). Circulating plasma CTGF levels in the LV diastolic dysfunction group were significantly higher (normal LV diastolic function group: 7.026 5.567-8.895, LV diastolic dysfunction group: 8.290 7.054-9.225 ng/ml, median (Interquartile range),
= 0.004); Compared with the lowest quartile group, the crude odds ratios (OR) of LV diastolic dysfunction in the second, third, and fourth quartile group were 3.207, 5.032 and 4.554, respectively (all
<0.05). After adjustment for the potentially confounding variables, the adjusted OR values of the third and fourth quartile group had no obvious change. The results of ROC showed that the plasma CTGF had the largest area under the ROC curve, and the value was 0.659 (
= 0.005).
The level of circulating plasma CTGF in the LV diastolic dysfunction group was significantly increased. Plasma CTGF level is an independent risk factor for LV diastolic dysfunction. Compared with serum BNP level, the plasma CTGF level may have auxiliary diagnostic value for LV diastolic dysfunction in hyperthyroid patients.
MicroRNAs (miRNAs) widely participate in plant growth and development. The miR396 family, one of the most conserved miRNA families, remains poorly understood in sorghum. To reveal the evolution and ...expression pattern of Sbi-miR396 gene family in sorghum, bioinformatics analysis and target gene prediction were performed on the sequences of the Sbi-miR396 gene family members. The results showed that five Sbi-miR396 members, located on chromosomes 4, 6, and 10, were identified at the whole-genome level. The secondary structure analysis showed that the precursor sequences of all five Sbi-miR396 potentially form a stable secondary stem-loop structure, and the mature miRNA sequences were generated on the 5' arm of the precursors. Sequence analysis identified the mature sequences of the five sbi-miR396 genes were high identity, with differences only at the 1st, 9th and 21st bases at the 5' end. Phylogenetic analysis revealed that Sbi-miR396a, Sbi-miR396b, and Sbi-miR396c were clustered into Group I, and Sbi-miR396d and Sbi-miR396e were clustered into Group II, and all five sbi-miR396 genes were closely related to those of maize and foxtail millet. Expression analysis of different tissue found that Sbi-miR396d/e and Sbi-miR396a/b/c were preferentially and barely expressed, respectively, in leaves, flowers, and panicles. Target gene prediction indicates that the growth-regulating factor family members (SbiGRF1/2/3/4/5/6/7/8/10) were target genes of Sbi-miR396d/e. Thus, Sbi-miR396d/e may affect the growth and development of sorghum by targeting SbiGRFs. In addition, expression analysis of different tissues and developmental stages found that all Sbi-miR396 target genes, SbiGRFs, were barely expressed in leaves, root and shoot, but were predominantly expressed in inflorescence and seed development stage, especially SbiGRF1/5/8. Therefore, inhibition the expression of sbi-miR396d/e may increase the expression of SbiGRF1/5/8, thereby affecting floral organ and seed development in sorghum. These findings provide the basis for studying the expression of the Sbi-mir396 family members and the function of their target genes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BackgroundIn locally advanced rectal cancer (LARC), preoperative short-course radiotherapy (SCRT) with delayed surgery has been shown to be as effective as long-course chemoradiotherapy, with only ...modest benefits. This study aimed to evaluate the efficacy and safety of preoperative SCRT combined with subsequent CAPOX (capecitabine and oxaliplatin) and the anti-PD-1 antibody camrelizumab in patients with LARC.MethodsThis was a prospective, single-arm, phase II trial. Treatment-naïve patients with histologically confirmed T3-4N0M0 or T1-4N+M0 rectal adenocarcinoma received 5×5 Gy SCRT with two subsequent 21-day cycles of CAPOX plus camrelizumab after 1 week, followed by radical surgery after 1 week. The primary endpoint was pathological complete response (pCR) rate. Biomarker analysis was performed to identify a potential predictor of pCR to treatment.ResultsFrom November 7, 2019 to September 14, 2020, 30 patients were enrolled, and 27 patients received at least one dose of CAPOX plus camrelizumab. Surgery was performed in 27 (100%) patients. The pCR (ypT0N0) rate was 48.1% (13/27), including 46.2% (12/26) for proficient mismatch repair (MMR) tumors and 100% (1/1) for deficient MMR tumors. Immune-related adverse events were all grade 1–2, with the most common being reactive cutaneous capillary endothelial proliferation (81.5%). No grade 4/5 adverse events occurred. Biomarker analysis showed patients without FGFR1–3 deletions had a better tendency for pCR.ConclusionsSCRT combined with subsequent CAPOX plus camrelizumab followed by delayed surgery showed a favorable pCR rate with good tolerance in patients with LARC, especially in the proficient MMR setting. A randomized controlled trial is ongoing to confirm these results.Trial registration numberClinicalTrials.gov identifier: NCT04231552.
40-50% of colorectal cancer (CRC) patients develop metastatic disease; the presence of metastasis hinders the effective treatment of cancer through surgery, chemotherapy and radiotherapy, which makes ...5-year survival rate extremely low; therefore, studying CRC metastasis is crucial for disease therapy. In the present study, we investigated the role of rhomboid domain containing 1 (RHBDD1) in tumor metastasis of CRC.
The expression of RHBDD1 was analyzed in 539 colorectal tumor tissues for its correlation with lymphatic metastasis and distal metastasis. Transwell assay in vitro and pleural metastasis analysis in vivo were performed to determine the functions of RHBDD1 during CRC cells metastasis. RNA-seq analysis, TOP/FOP flash reporter assay, western blot and transwell assay were performed to investigate the underlying mechanism for the function of RHBDD1 on Wnt signaling pathway. Bioinformatics analysis was conducted to investigate epithelial-mesenchymal transition (EMT) and stemness in HCT-116 cells. Tissue microarray analysis, Q-PCR and western blot were performed to determine the correlation of RHBDD1 and Zinc Finger E-Box Binding Homeobox 1 (ZEB1).
In this study, we found that RHBDD1 expression was positively correlated with lymphatic metastasis and distal metastasis in 539 colorectal tumor tissues. RHBDD1 expression can promote CRC cells metastasis in vitro and in vivo. RNA-Seq analysis showed that the Wnt signaling pathway played a key role in this metastatic regulation. RHBDD1 mainly regulated ser552 and ser675 phosphorylation of β-catenin to activate the Wnt signaling pathway. Rescuing ser552 and ser675 phosphorylation of β-catenin resulted in the recovery of signaling pathway activity, migration, and invasion in CRC cells. RHBDD1 promoted EMT and a stem-like phenotype of CRC cells. RHBDD1 regulated the Wnt/β-catenin target gene ZEB1, a potent EMT activator, at the RNA and protein levels. Clinically, RHBDD1 expression was positively correlated with ZEB1 at the protein level in 71 colon tumor tissues.
Our findings therefore indicated that RHBDD1 can promote CRC metastasis through the Wnt signaling pathway and ZEB1. RHBDD1 may become a new therapeutic target or clinical biomarker for metastatic CRC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Through exomic sequencing of ten hepatitis C virus (HCV)-associated hepatocellular carcinomas (HCC) and subsequent evaluation of additional affected individuals, we discovered novel inactivating ...mutations of ARID2 in four major subtypes of HCC (HCV-associated HCC, hepatitis B virus (HBV)-associated HCC, alcohol-associated HCC and HCC with no known etiology). Notably, 18.2% of individuals with HCV-associated HCC in the United States and Europe harbored ARID2 inactivation mutations, suggesting that ARID2 is a tumor suppressor gene that is relatively commonly mutated in this tumor subtype.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
TRIM proteins play important roles in a wide range of biological processes, including cell proliferation, dif- ferentiation, development, apoptosis, oncogenesis and innate immunity 1, 2. The ...N-terminal regions of all TRIM proteins contain a RING finger domain followed by one or two B-box domains and a coiled-coil domain （CCD）. The RING-finger domain comprises conserved cysteine and histidine residues that bind two zinc atoms in a ＇cross-brace＇ arrangement, and is essential for recruiting the ubiquitin-charged ubiquitin-conjugating enzymes （E2-Ub）.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Long noncoding RNAs (lncRNAs) have emerged as diverse functional regulators involved in mammalian development; however, large-scale functional investigation of lncRNAs in mammalian spermatogenesis in ...vivo is lacking. Here, we delineated the global lncRNA expression landscape in mouse spermatogenesis and identified 968 germ cell signature lncRNAs. By combining bioinformatics and functional screening, we identified three functional lncRNAs (
,
, and
) that directly influence spermatogenesis in vivo. Knocking down
hampered the development of round spermatids into elongating spermatids and disrupted key spermatogenic gene expression. Mechanistically, lncRNA
localized in the nucleus of round spermatids and occupied the genomic regulatory region of important spermatogenic genes including
and
These findings provide a valuable resource and framework for future functional analysis of lncRNAs in spermatogenesis and their potential roles in other biological processes.
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