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Colostrum is essential for immune system development and has a protective role for infants in early life. However, the lipid compositions of human and ewe colostra have not been characterized. We hypothesized that lipidomics can be used to compare lipids in two mammalian colostra. Herein, 1004 lipids assigned to 26 subclasses were identified in both human and ewe colostra using a quantitative lipidomics approach. In total, 173 significantly different lipids (SDLs) were investigated (variable importance in projection 1.1, fold change (FC) ≥ 2 or ≤0.5, and P 0.0001). Four potential lipid biomarkers, namely, DG (19:0/18:0), TG (10:0/15:0/16:0), FFA (22:0), and TG (18:1/24:1/18:2), were selected from the 173 SDLs based on FC values. These different lipids were involved in 44 metabolic pathways, of which sphingolipid metabolism and glycerophospholipid metabolism were the major pathways. Our results improve the understanding of the differences between human and ewe colostra lipids.

Objective: To assess the correlations of type 2 diabetic retinopathy (DR) severity with vascular endothelial growth factor (VEGF), IL-6, IL-1β and TNF-α and oxidative stress. Methods: 80 patients with type 2 DR were divided into non-proliferative DR (NPDR) group [NPDR+/diabetic macular edema (DME) − group], NPDR with DME group (NPDR+/DME+ group), proliferative DR (PDR) group (PDR+/DME− group) and PDR with DME group (PDR+/DME+ group) according to non-mydriatic fundus examination and angiography. Another 20 patients without DR and DME were selected as control group (DR−/DME− group). VEGF, inflammatory factors (IL-6, IL-1β and TNF-α) and mal-ondialdehyde (MDA) and superoxide dismutase (SOD) were measured. Changes in hemodynamic parameters were detected by color Doppler ultrasound. Results: Compared with those in control group, the inflammatory factors, VEGF, MDA and SOD were significantly increased in the other four groups of patients with RD, in which inflammatory factors and VEGF level were significantly higher in PDR patients than those in NPDR, and higher in DME patients than patients without DME. However, the hemodynamic parameters showed a significantly decreasing trend (all P < 0.05). A positive correlation of VEGF with inflammatory factors was found in aqueous humor. Conclusion: Inflammatory reactions, oxidative stress and angiogenesis are found in DR patients at early stage and during the disease progression. Combined monitoring of their changes is helpful for the early diagnosis of DR. Meanwhile, anti-inflammation, anti-oxidative stress and reversing of angiogenesis treatment might delay DR progression.

Purpose Telomerase is reactivated in non-small cell lung cancer (NSCLC), and it increases cell resistance to irradiation through protecting damaged telomeres and enhancing DNA damage repair. We investigated the radiosensitizing effect of BIBR1532, a highly selective telomerase inhibitor, and its corresponding mechanism in NSCLC. Methods and Materials Cell proliferation, telomerase activity, and telomere dysfunction-induced foci were measured with CCK-8 assay, real-time fluorescent quantitative polymerase chain reaction, and immunofluorescence. The effect of BIBR1532 on the response of NSCLC cells to radiation was analyzed using clonogenic survival and xenograft tumor assays. Cell death and cell senescence induced by BIBR1532 or ionizing radiation (IR), or both, were detected with western blotting, flow cytometry, and senescence-association β-galactosidase staining assay. Results We observed dose-dependent direct cytotoxicity of BIBR1532 at relatively high concentrations in NSCLC cells. Low concentrations of BIBR1532 did not appear toxic to NSCLC cells; however, they substantially increased the therapeutic efficacy of IR in vitro by enhancing IR-induced apoptosis, senescence, and mitotic catastrophe. Moreover, in a mouse xenograft model, BIBR1532 treatment synergized with IR at nontoxic dose levels promoted the antitumor efficacy of IR without toxicity to hematologic and internal organs. Mechanistically, lower concentrations of BIBR1532 effectively inhibited telomerase activity and increased IR-induced telomere dysfunction, resulting in disruption of chromosomal stability and inhibition of the ATM/CHK1 (ataxia-telangiectasia-mutated/Checkpoint kinase 1) pathway, which impaired DNA damage repair. Conclusions Our findings demonstrate that disturbances in telomerase function by nontoxic dose levels of BIBR1532 effectively enhance the radiosensitivity of NSCLC cells. This finding provides a rationale for the clinical assessment of BIBR1532 as a radiosensitizer.

This paper shows that CH4 produced in the heartwood of living trees in upland forests is of microbial origin, and that microbial CH4 production may be suppressed in the heartwood with more phenolic compounds than carbohydrates. Methane (CH4) is a potent greenhouse gas that exerts large effects on atmospheric chemistry and the global warming. Living trees in upland forests might contribute to the global CH4 emissions but the contribution is poorly understood and the mechanisms of CH4 production in their heartwood are not completely clear. Using gene sequencing and a series of laboratory incubations, this study addressed whether CH4 produced in the heartwood of living trees in upland forests is microbial in origin and how the CH4 production is affected by secondary metabolites. Both the response of CH4 production to temperatures and the presence of methanogenic archaea indicate that the CH4 produced in heartwood was microbial in origin. Methanobacterium was the dominant methanogens in the heartwood of Populus canadensis which had high concentrations of CH4, and was absent from the heartwood of Pinus tabuliformis and Salix matsudana which produced negligible or very low CH4. Water- and ethanol-soluble extractives enhanced microbial CH4 production in heartwood incubations but acetone-soluble extractives inhibited the production. Since acetone-soluble extractives inhibited the production of microbial CH4, it is assumed that the CH4 production may be suppressed from heartwood with phenolic compounds that act as an antibiotic for methanogenic archaea in most living trees in upland forests. The inhibitory effects of secondary metabolites on microbial CH4 production in heartwood reduce the CH4 emissions from the stems of living trees in upland forests.

Purpose Multiple anthropogenic disturbances, such as climate warming and nitrogen deposition are affecting terrestrial ecosystems. Different disturbances may have some consistent effects on the soil microbial community, which remains largely unexplored. Methods We mimicked 16 anthropogenic disturbances in a steppe ecosystem, and measured the absolute abundance and taxonomic composition of soil bacterial communities with qPCR and amplicon sequencing, respectively. Results We found that while the absolute abundance of each of the four dominant bacterial phyla did not show a consistent response to these disturbances, that of the five subdominant phyla showed a consistent increase. Meanwhile, these disturbances consistently stimulated the relative abundances of metabolic functions for high-growth-yield, including the transport/metabolism of amino acids and carbohydrates. Stochastic processes (e.g., random birth) played more critical roles in structuring the subdominant than dominant phyla, and the disturbances promoted the stochastic processes. Conclusions Overall, the high-yield traits and stochasticity of subdominant phyla led to their positive responses to disturbances. Furthermore, our findings indicate that the intensifying human activities are likely to cause a high-yield-strategies-toward shift in soil microbial composition in the Eurasian steppe ecosystem.

Background: To investigate the etiologies and clinical characteristics of full-thickness macular hole (FTMH) patients at Shanxi eye hospital of North China. Methods: Patients diagnosed with FTMH and treated with surgery from 2012 to 2020 were included, and the etiologies and clinical features of different types of MHs were analysed in the 8-years cross sectional retrospective study. Multivariate correlation analysis was used to predict the related factors affecting baseline vision.Results: A total of 752 cases (776 eyes) were analysed. The top three causes of MH were idiopathic (IMH, 64.4%), myopic (MMH, 21.1%) and traumatic (TMH, 3.7%). Among these three causes’ groups, there were significant differences in sex distribution, age, and baseline BCVA. Female was predominated in IMH and MMH, while it was the opposite in TMH. The age of onset in IMH was older than MMH and TMH. The baseline Logarithm of the Minimum Angle of Resolution (logMAR) best-corrected visual acuity (BCVA) in IMH (Z=8.9, pConclusions: The most common etiologies in MH were idiopathic, myopic and traumatic, which contributed to the different clinical features. Female was more common in IMH and MMH, and patients with MMH were 6.5 years earlier than IMH in onset. Therefore earlier monitoring fundus for female and people with high myopia is helpful for early detection and timely treatment.

American ginseng (Panax quinquefolius L.) is a perennial medicinal plant that has a long usage history in China. However, root rot, which is mainly caused by Fusarium solani can severely reduce the yield and quality of American ginseng, but no disease-resistant variety of American ginseng exists, and the resistance against this disease is not yet well understood. Thus, it is very urgent to analyze the interaction mechanism regulating the interactions between American ginseng and F. solani to mine disease resistance genes. Using transcriptome data and quantitative polymerase chain reaction (qPCR), we screened the transcription factor PqbZIP1 in response to induction by chitin. Yeast self-activation and subcellular localization experiments proved that PqbZIP1 showed transcriptional activity and was localized in the plant nucleus. In addition, qPCR showed that the highest relative expression level was in the roots, wherein chitin and F. solani inhibited and activated the expression of PqbZIP1, respectively, in American ginseng. Additionally, PqbZIP1 significantly inhibited the growth of the Pseudomonas syringae pv. tomato D36E strain in Nicotiana benthamiana, where expressing PqbZIP1 in N. benthamiana increased the jasmonic acid, salicylic acid, and abscisic acid content. Furthermore, PqbZIP1 expression was continually increased upon inoculation with F. solani. Hence, this study revealed that the PqbZIP1 transcription factor might mediate multiple hormonal signaling pathway to modulate root rot disease resistance in American ginseng, and provided important information to breed disease-resistant American ginseng.

Helicobacter pylori antibiotic resistance is a serious concern in China, where it severely influences treatment for H. pylori infection. To overcome this, it is essential to apply personalized therapies based on local or individual data on antibiotic-resistant phenotypes or genotypes. We conducted a large-scale multi-center study with a retrospective cross-sectional observational design to investigate the antibiotic-resistant phenotypes and genotypes of H. pylori in China. Strains were isolated from the gastric biopsy samples of H. pylori-infected patients from five different regions in China. The strains were tested for antibiotic-resistant phenotypes and genotypes, and the agreement between the two was assessed. In total, 4242 H. pylori strains were isolated and cultured, with an 84.43% success rate. The primary and secondary antibiotic resistance rates of H. pylori were 37.00% and 76.93% for clarithromycin, 34.21% and 61.58% for levofloxacin, 2.20% and 6.12% for amoxicillin, 1.61% and 3.11% for furazolidone, 1.18% and 3.31% for tetracycline, and 87.87% and 93.48% for metronidazole, respectively. The dual-resistance patterns for metronidazole/clarithromycin, metronidazole/levofloxacin, and clarithromycin/levofloxacin were 43.6%, 38.4%, and 26.1%, respectively. Clarithromycin- and levofloxacin-resistant H. pylori phenotypes and genotypes showed satisfactory agreement. Based on these findings, clarithromycin- and levofloxacin-resistant genotype testing could partially replace traditional antibiotic susceptibility testing in China. Continuous monitoring and personalized treatments based on individual and local H. pylori antibiotic-resistance data remain necessary.

Random migration often plays important roles in soil microbial community assembly. However, it remains unexplored that whether its role is affected by anthropogenic disturbances, and whether the effects of different disturbances are consistent. Here, we report a novel and general pattern that different disturbances consistently restrain the role of migration in soil bacterial community assembly. We mimicked 16 types of anthropogenic disturbances relevant to a Eurasian steppe ecosystem, including removing different number of plant functional groups, mowing, adding nitrogen, adding phosphorus, watering, warming, and some of their combinations. The estimated migration rates in soil bacterial community assembly with Stephen Hubbell’s neutral model decreased by 0.19–6.29% under these disturbances. The relative change in migration rate was correlated with the deterministic change in community composition and the relative change in soil pH. Our results suggested that the intensifying anthropogenic disturbances may restrain the random dispersal, colonization and distribution of soil microorganisms.

Backgrounds: With the excellent local control in T1 to T3 nasopharyngeal carcinoma (NPC) treated with intensity modulated radiotherapy (IMRT), the importance of toxicities is increasingly being recognised. This retrospective propensity score analysis sought to assess whether moderate dose reduction compromised long-term outcome compared with standard dose in T1-3 NPCs. Materials and Methods: A total of 266 patients (67 female, 199 male) with a median age of 50 years between June 2011 and June 2015 were analysed. All were treated with IMRT, with or without systemic chemotherapy. The prescription radiation dose to gross tumor is 70Gy/2.12Gy/33F in our institution. Results: With a median follow-up time of 50 months, the 5-year loco-regional failure-free survival (LRFS) and overall survival (OS) were 93.5% and 81.8%, respectively. 32 patients received radiation dose less than prescription dose, with a median dose of 63.6Gy (53-67Gy). Another 234 patients received exactly the prescription dose of 70Gy. Propensity scores were computed (32 patients treated with de-escalated dose and 64 patients with standard dose), there was no significant difference in 5-year LRFS and 5-year OS between the two groups (92.5% and 91.7% with standard dose; 82.1% and 85.7% with de-escalation dose; p=0.863 for LRFS and 0.869 for OS). No independent prognostic factor was associated with loco-regional failure in univariate analysis. Conclusions: T1-3 nasopharyngeal carcinoma presenting with superior locoregional control, a moderately reduced dose (about 10%) delivered with IMRT resulted in comparable prognosis to those with prescription dose of 70Gy.

BACKGROUND This research aimed to determine high-risk factors of supraclavicular recurrence for limited-stage small cell lung cancer (LS-SCLC) patients to discover a potential subpopulation that can benefit from prophylactic supraclavicular irradiation (PSCI). MATERIAL AND METHODS Between July 2006 and July 2011, LS-SCLC patients without supraclavicular lymph node (SCLN) involvement consecutively treated with concurrent chemo-radiation but without PSCI in the Radiotherapy Department of the Cancer Institute and Hospital of Tianjin Medical University, were retrospectively analyzed. SCLN recurrence rate, overall survival (OS), and distant metastasis-free survival (DMFS) were assessed. Binary logistic regression analysis was conducted to discover the high-risk factors related to the SCLN recurrence. The receiver operating characteristic (ROC) curves were drawn to evaluate logistic regression model prediction performance. RESULTS Eighty-eight LS-SCLC patients were analyzed in this study. During 99 months (ranging from 72 months to 124 months) for survivors, 28 (31.8%) had SCLN recurrence. There were significant differences for median DMFS and OS between LS-SCLC patients with and without SCLN recurrence. The logistic regression model revealed that lymphadenopathy at mediastinal level 2 and level 3 prior to chemotherapy were significantly associated with SCLN recurrence, which was validated by ROC. CONCLUSIONS Lymphadenopathy at mediastinal level 2 and level 3 prior to chemotherapy were the high-risk factors associated with SCLN recurrence for patients with LS-SCLC. Further work is needed to determine whether patients with these factors can benefit from PSCI.

N2O emissions have increased significantly over the last decades, with much of the increase being ascribed to the expansion in agricultural land. Agricultural water management has significant influence on N2O emissions, hence the investigation of N2O emissions and the underlying production mechanisms under different irrigation managements would provide insights for N2O emission reduction and rational water usage. Here, we used the stable isotope method to evaluate the N2O isotopic signatures and the site preference, to clarify the N2O emission dynamics and the N2O source partitioning under different irrigation managements. We applied a furrow irrigation system and a drip irrigation system to maintain two different soil water conditions, allowance of dry-wet cycles and relatively stable water conditions, respectively. We found that the N2O emission was significantly decreased under drip irrigation compared to furrow irrigation with cumulated N2O flux of 526.3 mg m−2 and 571.0 mg m−2, respectively. In general, furrow irrigation with its dry-wet alternations promoted N2O emissions, while drip irrigation created a relatively stable environment that reduced N2O emissions. The intramolecular 15N isotopic composition of N2O was used to partition the relative contribution of denitrification and nitrification. Nitrification dominated the processes driving N2O production under both treatments, nearly accounting for 76% up to 100% during the initial N2O peaks. Effective measure for mitigating N2O emissions from the investigated vegetable field could be obtained by replacing the traditional furrow irrigation with drip irrigation.

Purpose To determine the efficacy and late toxicities of moderate (2.5-4 Gy) hypofractionated radiotherapy (H-RT) in localized prostate cancer, a meta-analysis of published randomized clinical trials comparing moderate H-RT with conventional fractionated RT (C-RT) was performed. Materials and methods Systematic search on published randomized clinical trials in English according to Cochrane review guidelines in databases of Pubmed, Embase, Cochrane, web of science, and Wiley Online Library was carried out. Outcomes of interests were biochemical and clinical disease failure (BCDF), biochemical failure (BF), overall survival (OS), and late toxicities. Results Seven of the 365 studies fulfilled inclusion criteria with 8,156 participants. Compared with C-RT, moderate H-RT showed a lower BF rate (risk ratio [RR] =0.80, 95% CI: 0.68-0.95, P=0.009), while did not improve OS (RR =0.68, 95% CI: 0.78-1.02, P=0.10). There was no significant difference in BCDF rates between H-RT and C-RT (RR =0.92, 95% CI: 0.82-1.02, P=0.12). The H-RT was deeply grouped into dose-escalated H-RT (with a higher biologically effective dose [BED1.5] than C-RT) and no dose-escalated H-RT; dose-escalated H-RT significantly decreased BCDF rate compared with C-RT (RR =0.84, 95% CI: 0.73-0.96, P=0.01). Regarding late toxicities, there is no significant difference in late gastrointestinal (GI; RR =0.97, 95% CI: 0.71-1.33, P=0.85) and genitourinary (GU) toxicities (RR =1.04, 95% CI: 0.87-1.24, P=0.69). When subgrouped into dose-escalated H-RT (with a higher BED5 compared with C-RT) and no dose-escalated H-RT, dose-escalated H-RT increased GI toxicity (RR =1.62, 95% CI: 1.26-2.09, P=0.0002) and GU toxicity (RR =1.28, 95% CI: 1.05-1.55, P=0.01), while no dose-escalated H-RT significantly lowered GI toxicity (RR =0.81, 95% CI: 0.70-0.94, P=0.005) and placed no influence on GU toxicity (RR =1.02, 95% CI: 0.88-1.20, P=0.77). Conclusion This meta-analysis provides reliable evidence that moderate H-RT decreases BF rate, while does not improve OS. Compared with C-RT, H-RT with an increase in BED1.5 improved BCDF rates significantly, and accordingly, an increase in BED5 will result in elevated late GI and GU toxicities.

In the Loess Plateau of China, conventional tillage is defined as the tillage without crop residues left on the soil surface and ploughed twice a year. The use of alternative practices is a way to reduce soil erosion. Our objectives were to assess the long-term impacts of different soil tillage systems on soil physical and hydraulic characteristics, emphasizing management practices to improve the soil physical qualities (reduce bulk density and increase stability of aggregate) under the conservation tillage system in the Loess Plateau of China. Conventional tillage (CT), no tillage (NT), and sub-soiling (SS) were applied in this experiment. Soil wet aggregates distribution and stability, soil organic carbon (SOC) content, soil water retention curves and pore size distributions were measured. The results showed that in the 0–10 cm and 10–20 cm depth soil layers, NT and SS treatments showed a significantly higher proportion of wet aggregates >250 μm (macroaggregates) compared to CT. In these two layers, the proportion of wet aggregates 250 μm than within the 250–53 μm and

e18031 Background: Immune-checkpoint inhibitor (ICI) in combination with antiangiogenic therapy have the potential for synergistic activity. We report the results of camrelizumab plus famitinib for the treatment of recurrent or metastatic, ICI-resistant nasopharyngeal carcinoma (NPC) from an open-label, multicenter, phase II basket trial. Methods: Patients (pts) with histologically confirmed recurrent or metastatic NPC (nonkeratinizing carcinoma, WHO type II-III), who had been treated with platinum-based chemotherapy and ICIs (≤2 lines of systemic treatment), were enrolled to receive camrelizumab (200 mg intravenously every 3 weeks) and famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per RECIST version 1.1, and secondary endpoints included duration of response (DoR), disease control rate (DCR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and safety. Results: Between Oct 23, 2020, and Sep 24, 2021, 15 recurrent or metastatic NPC pts were enrolled. Among them, 12 (80.0%) and 3 (20.0%) pts had received their prior 1st-line and 2nd-line treatment, respectively. All pts were pretreated with anti-PD-1/PD-L1 immunotherapy (toripalimab, n = 9; tislelizumab, n = 4; sintilimab, n = 1; pembrolizumab, n = 1). As of Nov 30, 2021, median time from enrollment to data cutoff was 6.3 months (range, 2.2-13.3). No pt had a complete response, 5 (33.3%) pts had a confirmed partial response, 7 (46.7%) pts had stable disease, 2 (13.3%) pts had progressive disease and 1 (6.7%) pt was not evaluable. The ORR was 33.3% (95% confidence interval [CI], 11.8-61.6), the DCR was 80.0% (95% CI, 51.9-95.7). Most pts (73.3%) experienced reduction in target lesion size from baseline, with a median change of -36.0%. The median DoR was 4.2 months (95% CI, 2.1-not reached [NR]), median PFS was 6.3 months (95% CI, 4.1-NR), and median OS has not been reached. Treatment-related adverse events (TRAEs) of grade 3 or higher were reported in 7 (46.7%) pts, mainly decreased platelet count (13.3%), decreased neutrophil count (13.3%) and palmar-plantar erythrodysaesthesia syndrome (13.3%). Treatment interruption and discontinuation due to TRAEs occurred in 11 (73.3%) and 1 (6.7%) pts, respectively. Five (33.3%) pts had serious TRAEs (grade 2 platelet count decreased, grade 2 pharyngeal necrosis, grade 2 pulmonary tuberculosis, grade 3 left ventricular dysfunction, grade 3 pharyngeal hemorrhage; n = 1 for each), and no treatment-related death was reported. Conclusions: Camrelizumab plus famitinib showed encouraging antitumor activity in recurrent or metastatic NPC patients who were resistant to ICI treatment, with an acceptable and manageable safety profile. This combination might provide a novel alternative treatment strategy in this challenging disease setting and support further investigation. Clinical trial information: NCT04346381.

6066 Background: For elderly patients with locally advanced head and neck squamous cell carcinoma (HNSCC), the role of postoperative concurrent chemotherapy was controversial since the intolerable toxicities and increased acute mortality, thus, radiotherapy alone was recommended. Aimed to seek out a feasible regimen for concurrent treatment, we evaluated the feasibility and quality of life of postoperative concurrent radiotherapy and toripalimab (anti-PD-1 antibody) in elderly HNSCC patients. Methods: The IMPORT trial was an investigator-initiated, multicentre, open-label, parallel-group, phase 2, randomized study. Patients were enrolled at 3 hospitals in China. We randomly assigned (1:1) patients aged＞65 years, with ECOG Performance Status(PS) of 0–2, and with postoperative Stage III-IV (AJCC 8th Staging system) HNSCC to concurrent radiotherapy (60-66Gy) and toripalimab (240mg on D0, D21 and D42)(RT+PD-1 group) or radiotherapy alone(RT group). Following stratification by PS(0-1 vs 2) and pathological adverse features (extranodal extension or positive margin vs others), patients were randomly assigned using a computer-generated randomization list. Acute toxicities were reported. Quality of life were evaluated by EORTC QLQ-C30 and QLQ-H&N35 at baseline, week3, week6 and 1 month after radiotherapy, and the standard scores were compared between groups by linear mixed-effects models. Results: Between September 2020 and December 2021, 38 patients randomly assigned(19 per group). The median age were 70 years (range 66-81) for the RT+PD-1 group and 73 years (range 67-78 years) for RT group. 16 (84.2%) patients in the RT+PD-1 group and 15 (78.9%) patients in the RT group complete the planed radiation dose. In the RT+PD-1 group, 13 (68.4%) patients completed 3 cycles of toripalimab, 3 (15.8%) patients completed 2 cycles due to adverse events and 3 (15.8%) patients declined toripalimab; The most common adverse events of grade 3-5 was oral mucositis (55.6% vs 58.8%) and lymphocyte count decreased(61.1% and 41.2%) in RT+PD-1 group and RT group. In the RT+PD-1 group, only 1 patients experienced grade 3 immune-related enteritis. As to the quality of life scores evaluated by QLQ-C30, no difference was found in standard score of global health status, as well as in most functional scales including: physical, emotion, cognitive and social, except for role functioning (p = 0.045). As to the symptom scale scores evaluated by QLQ-H&N35, no difference was found in standard score of pain, swallowing, dry mouth, opening mouth, and stick saliva, except for speech problem (p = 0.032). Conclusions: For elderly patients with locally advanced HNSCC, postoperative concurrent radiotherapy and toripalimab was safe and feasible. Concurrent toripalimab did not worsen quality of life scores in the majority of cases. Clinical trial information: NCT04523883.

Fertigation can improve water use efficiency (WUE) compared with conventional separate supply of water and fertilizers to plants. Yet the mechanisms underlying the improved WUE under fertigation remain largely elusive. Therefore, the impact of water and nitrogen (N) on leaf gas exchange, plant water relations, ABA signaling and WUE as well as leaf δ13C and δ18O were investigated in order to unravel how water and N modulate plant WUE. Results showed that reduced soil water regimes under N fertigation caused partial closure of stomata via decreased plant water status and intensified root-to-shoot ABA signaling, resulting in improved intrinsic WUE (WUEi). Decreased soil water regimes increased plant WUE (WUEp) and leaf δ13C, and the increased leaf δ13C was due to reduced gs and/or higher specific leaf N content enhanced photosynthetic capacity. Leaf δ18O and δ13C further indicated that the significant increase in leaf δ13C under the reduced water regimes was caused primarily by reductions in gs compared with N nutrition. Therefore, gs rather than N nutrition predominated regulation of plant WUE under fertigation. Moderate soil water regimes with sufficient N supply are recommended for fertigation in terms of achieving high fresh fruit yield, WUE and nutrient uptake.

Many anthropogenic environmental changes are leading to a rapid decline in soil microbial functional diversity. However, ecological mechanisms that can serve to counteract/resist the diversity loss remain largely underexplored. In particular, although intermediate disturbance and increased amount of effective resources can promote the diversity of higher organisms, the potential role of these factors, and their combination, in maintaining microbial functional diversity is poorly studied. We conducted a 5-year experiment in a Eurasian steppe, manipulating mowing, nitrogen addition, phosphorus addition and their combinations. Nitrogen addition decreased soil pH by ~0.6 and bacterial abundance by ~19.5%, causing a disturbance effect. Phosphorus addition significantly decreased the effective amount of soil carbon-, nitrogen-, phosphorus- and water-relevant resources. Across all nitrogen-addition treatments subject to intermediate disturbance, there was a significant positive correlation between soil effective resource amount and microbial gene richness (r > 0.6, p < 0.01), which was elevated, in part, due to the increased fungal abundance. In contrast, significant correlations between gene richness and resource amount were not found under low-disturbance conditions. Overall, gene richness was greatest under conditions of both intermediate disturbance and ample effective resources, suggesting that the two factors could be manipulated in combination for the maintenance of microbial functional diversity.

Purpose Nitrogen deposition at rate not more than 50 kg ha−1 year−1 is generally considered to stimulate soil nitrifying and denitrifying microorganisms via increases in soil nitrogen content. However, this phenomenon in alpine ecosystems remains largely untested. Methods We conducted an 8-year nitrogen deposition experiment on the Qinghai–Tibetan Plateau, with four nitrogen deposition rates of 10 (atmospheric deposition), 20, 30, and 50 kg ha−1 year−1. Results The abundances of two nitrifying genes and four denitrifying genes and the N2O emission rate initially increased and subsequently decreased as the nitrogen deposition rate increased. The observed decrease in these indices at the rate of 50 kg ha−1 year−1 was caused by the toxicity of excessive NH4+. Conclusions Our study demonstrates the vulnerability of alpine microorganisms under global changes.

FGIN-1-27 is a synthetic mitochondrial diazepam binding inhibitor receptor (MDR) agonist that has demonstrated pro-apoptotic, anti-anxiety, and steroidogenic activity in various studies. Here we report, for the first time, the anti-melanogenic efficacy of FGIN-1-27 in vitro and in vivo. FGIN-1-27 significantly inhibited basal and α-melanocyte-stimulating hormone (α-MSH)-, 1-Oleoyl-2-acetyl-sn-glycerol (OAG)- and Endothelin-1 (ET-1)-induced melanogenesis without cellular toxicity. Mushroom tyrosinase activity assay showed that FGIN-1-27 did not directly inhibit tyrosinase activity, which suggested that FGIN-1-27 was not a direct inhibitor of tyrosinase. Although it was not capable of modulating the catalytic activity of mushroom tyrosinase in vitro, FGIN-1-27 downregulated the expression levels of key proteins that function in melanogenesis. FGIN-1-27 played these functions mainly by suppressing the PKA/CREB, PKC-β, and MAPK pathways. Once inactivated, it decreased the expression of MITF, tyrosinase, TRP-1, TRP-2, and inhibited the tyrosinase activity, finally inhibiting melanogenesis. During in vivo experiments, FGIN-1-27 inhibited the body pigmentation of zebrafish and reduced UVB-induced hyperpigmentation in guinea pig skin, but not a reduction of numbers of melanocytes. Our findings indicated that FGIN-1-27 exhibited no cytotoxicity and inhibited melanogenesis in both in vitro and in vivo models. It may prove quite useful as a safer skin-whitening agent.

Anthropogenic disturbances may decrease as we take measures to control them. However, the patterns and mechanisms of post-disturbance ecosystem succession have rarely been studied. Here we reported that disturbance level determined the importance of stochastic relative to deterministic changes in ecosystem components (plant community composition, soil microbial community composition, and soil physicochemical indices), and thus predefined the pattern of post-disturbance ecosystem succession. We proposed a theoretical framework with five disturbance levels corresponding to distinct succession patterns. We conducted a nitrogen addition experiment in a temperate steppe, monitored these ecosystem components during “disturbance” treatment (2010–2014) and post-treatment “succession” (2014–2018). The disturbance level experienced by each component in each treatment was inferred by fitting the observed succession patterns into the theoretical framework. The mean disturbance level of these components was found to increase quadratically with nitrogen addition rate. This was because increasing nitrogen addition reduced the importance of stochastic relative to deterministic changes in these components, and these changes had a quadratic relationship with disturbance level. Overall, our results suggested that by monitoring the importance of stochastic relative to deterministic changes in an ecosystem, we can estimate disturbance levels and predict succession patterns, as well as propose disturbance-level-dependent strategies for post-disturbance restoration.

The present study aimed to investigate the mechanisms of anti-VEGF treatment prior to eye surgery to reduce intraoperative bleeding. A total of 30 patients with proliferative vitreoretinopathy after clinical diagnosis were enrolled in the present study as the surgical group. Furthermore, 30 patients underwent intravitreal injection of the anti-VEGF drug conbercept and were considered the drug pretreatment group. The aqueous and vitreous humors from the eyes of patients in the surgical group were drawn during pars plana vitrectomy surgery. The aqueous humor in the eyes of patients in the drug pretreatment group was drawn prior to conbercept treatment and seven days after conbercept treatment immediately prior to surgery. The vitreous humor in this group was only taken during surgery. Furthermore, ELISA was used to detect the levels of VEGF-A and -B in the aqueous and vitreous humors. Semi-quantitative determination of VEGF-A and VEGF-B levels in fibrovascular proliferative membranes was performed using immunohistochemical staining. The results indicated that in the drug group, the levels of VEGF-A in the aqueous humor of patients prior to and after conbercept injection were 197.66±48.00 and 3.39±2.54 pg/ml, respectively. The levels of VEGF-A in the vitreous humor of patients in the surgical and drug groups were 267.53±179.60 and 21.43±5.81 pg/ml after injection, respectively. The levels of VEGF-B in the aqueous humor of patients prior to and after conbercept injection were 13.66±3.30 (before injection) and 2.17±0.94 pg/ml (after injection), respectively. The levels of VEGF-B in the vitreous humor of patients in the surgical and drug groups were 127.36±16.72 and 18.56±9.82 pg/ml after injection, respectively (P

Background To describe the clinical characteristics and analyze the predictive factors associated with improved visual acuity of 359 patients with infectious endophthalmitis. Methods This study retrospectively analyzed 359 eyes of 359 patients with infectious endophthalmitis from January 2014 to December 2018. The findings summarized some epidemiological characteristics of these patients, including age, sex, occupation, patient visit time, etiology, causative organisms, therapy, and best-corrected visual acuity. Multivariate logistic regression was performed to predict the relative factors of improved visual acuity (VA). Results Overall, 283 (78.83%) patients were male. The mean age was 48.0 ± 18.27 years. Ocular trauma, especially open globe injuries (246, 68.5%) was the most common etiology of infectious endophthalmitis in this study. The etiologies of infectious endophthalmitis were open globe injuries (68.5%), intraocular surgery (22.6%), and corneal ulcer-associated (6.7%) and endogenous causes (2.2%). In the etiology classification and visual acuity improvement group, had statistically significant differences in factors such as age, sex, patient visit time, pre-therapy visual acuity, etc. The average Logarithm of the Minimum Angle of Resolution (logMAR) best-corrected visual acuity on pre-therapy was 2.28 ± 0.60, and it had significantly improved to 1.67 ± 0.83 post-therapy (P 7 day (P = 0.034, OR = 0.522, 95% CI: 0.286–0.953), pre-therapy VA ≦logMAR 2.3 (P = 0.032, OR = 1.809, 95% CI: 1.052–3.110), post-surgical (vs. posttraumatic; P = 0.023, OR = 2.100, 95% CI: 1.109–3.974), and corneal ulcer-associated etiologies (vs. posttraumatic; P = 0.005, OR = 0.202, 95%CI: 0.066–0.621) were significantly associated with improved visual acuity after adjusting for possible confounding factors. Conclusions Among the patients with infectious endophthalmitis, middle-aged male, especially farmers and workers, accounted for a large proportion. Open globe injuries were the main cause and the gram-positive bacteria were the major causative organisms. The final visual outcomes seemed to vary according to the type of endophthalmitis, but early treatment and good initial visual acuity were important factors for visual acuity improvement.

Oxidative stress and inflammation are regarded as prime reasons for the progression and development of diabetic retinopathy. Currently, nuclear factor erythroid-2-related factor 2 (Nrf2), thioredoxin interacting protein (TXNIP) and NLRP3 inflammasome pathways are under increasing focus in research on oxidative stress and inflammation-related diseases. On the other hand, tilianin (TN) has received much attention because of its various pharmacological properties. Based on results of these studies, this investigation was performed to inspect the therapeutic efficiency of TN on the retina in diabetic rats. Rats were arbitrarily assigned to three groups: control group, diabetic group, and diabetic plus TN (20 mg/ kg body weight for 42 days, orally) group. TN supplementation in diabetic rats, their food intake, fasting blood glucose status, glycosylated hemoglobin (HbA1c) levels were drastically reduced, and there was a marked augmentation in serum insulin status. TN treatment of diabetic rats increased mRNA expression of Nrf2 and its target gene, HO-1, and noticeably decreased the malondialdehyde status. Activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidases (GPX) were increased relative to diabetic rats. Furthermore, administering TN to the diabetic rats resulted in decreased expression of TXNIP, NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, and IL-1β proteins and decreased distribution of TXNIP, NLRP3, ASC, and caspase-1 proteins in retinas. In addition, TN treatment ameliorated morphological and morphometric changes in the retinas of diabetic rats. Together, all of these findings provide clear evidence that TN treatment of diabetic rats attenuated diabetic retinal changes through its hypoglycemic, antioxidant, and anti-inflammatory properties. The antioxidant and anti-inflammatory effects in diabetic retinas occur at least in part through the modulation of Nrf2/TXNIP/NLRP3 inflammasome pathways, which may have remedial benefits in the healing of diabetic retinopathy.

The increased incidence of systemic lupus erythematosus (SLE) in recent decades might be related to changes in modern dietary habits. Since sodium chloride (NaCl) promotes pathogenic T cell responses, we hypothesize that excessive salt intake contributes to the increased incidence of autoimmune diseases, including SLE. Given the importance of dendritic cells (DCs) in the pathogenesis of SLE, we explored the influence of an excessive sodium chloride diet on DCs in a murine SLE model. We used an induced lupus model in which bone marrow-derived dendritic cells (BMDCs) were incubated with activated lymphocyte-derived DNA (ALD-DNA) and transferred into C57BL/6 recipient mice. We observed that a high-salt diet (HSD) markedly exacerbated lupus progression, which was accompanied by increased DC activation. NaCl treatment also stimulated the maturation, activation and antigen-presenting ability of DCs in vitro. Pretreatment of BMDCs with NaCl also exacerbated BMDC-ALD-DNA-induced lupus. These mice had increased production of autoantibodies and proinflammatory cytokines, more pronounced splenomegaly and lymphadenopathy, and enhanced pathological renal lesions. The p38 MAPK–STAT1 pathway played an important role in NaCl-induced DC immune activities. Taken together, our results demonstrate that HSD intake promotes immune activation of DCs through the p38 MAPK–STAT1 signaling pathway and exacerbates the features of SLE. Thus, changes in diet may provide a novel strategy for the prevention or amelioration of lupus or other autoimmune diseases.

Regulatory T cells (Treg) are an important immune cell population, playing a crucial role in regulating immune tolerance and preventing autoimmune diseases. These cells consist of various cell sub-populations and generally have an immunoregulatory or suppressive role against immune responses. They also have a different cell heterogeneity and each populations has own biological characteristics. Treg deficiency, reduction, instability, reduced vitality and dysfunction all account for multiple autoimmune diseases. In this review, we have systemically reviewed Treg classification, phenotypic features, regulation of Foxp3 expression, plasticity and stability of Treg as well as their relationship with several important autoimmune diseases. We particularly focus on why and how inflammatory and diet environments affect the functional capacity and underlying mechanisms of Treg cell populations. We also summarize new advances in technologies which help to analyze and dissect these cells in molecular levels in-depth. We also clarify the possible clinical relevance on application of these cells in patients with autoimmune diseases. The advantages and weaknesses have been carefully discussed as well. We also propose the possible approaches to overcome these weaknesses of Treg cells in complicate environments. Thus, we have displayed the updated knowledge of Treg cells, which provides an overall insight into the role and mechanisms of Treg cells in autoimmune diseases.

As a member of the histone lysine-specific demethylase family, KDM1A plays a pivotal role in biological processes including signal transduction, chromatin reprogramming, embryo development, hematopoiesis, glucose and lipid metabolism. Recently, increasing studies and clinical evidences suggest that the expression of KDM1A is related to initiation and development of tumors and plays a key role in regulating of initiation and development of tumors, such as prostate cancer, breast cancer, lung cancer and liver cancer. KDM1A binds to distinct complexes and mediates different downstream signaling pathways. However, KDM1A often plays an oncogenic role in the initiation and development of tumors. Based on the current literatures, we describe the latest research of KDM1A in the initiation and progression of various tumors, and summarize its mechanism of actions, to provide clues for cancer therapy.组蛋白赖氨酸特异性去甲基化酶 1A (Histone lysine-specific demethylase 1A，KDM1A) 作为组蛋白赖氨酸特异性去甲基化酶 (Histone lysine-specific demethylase) 家族的一员，在信号传导、染色体重构、胚胎发育、造血和糖脂代谢等生物学过程中起着重要的作用。近年来的研究及临床证据表明，KDM1A 的表达与肿瘤的发生发展密不可分，通过与不同的复合物结合并介导不同的下游信号通路，对多种肿瘤的生长增殖起着关键的调节作用，例如前列腺癌、乳腺癌、肺癌和肝癌等。在大多数情况下，KDM1A 在肿瘤的发生发展中扮演着促癌基因角色。文中结合近年来有关文献，阐述了KDM1A 在多种肿瘤发生及发展中的研究进展，总结了其作用机制，并对以KDM1A 为靶点的抑癌治疗的应用前景进行了展望。.

Impaired insulin sensitivity of insulin-sensitive tissues plays a major role in the pathogenesis of type 2 diabetes, salvianolic acid B (SalB), a natural antioxidant usually treated various cardiovascular diseases was also reported potential utility on diabetes and dyslipidemia. Based on these, we aimed to explored whether the antioxidant effect of SalB play a pivotal role in the molecular mechanisms leading to insulin resistance. We found that SalB improved glucose tolerance and insulin sensitivity, decreased serum ALT, AST and ALP levels of ob/ob mice. Also, transcription of Bip and CHOP, phosphorylation of PERK and IRE1 for endoplasmic reticulum stress (ER) and phosphorylation of IRS-1 for insulin sensitivity in the liver of ob/ob mice were relieved by SalB. Further, SalB decreased phosphorylation of PERK, IRE1 and IRS1 and transcription of Bip and CHOP stimulated by palmitate of hepatic cells HL7702, but did not reversed phosphorylation of JNK and IRS1 and transcription of Bip and CHOP when ER stress was stimulated by tunicamycin. These data shows that SalB improved insulin resistance of ob/ob mice through suppression of hepatic ER stress.

Understanding species responsiveness to anthropogenic environmental changes benefits the guide to manage biodiversity. Microbes are traditionally thought to be more sensitive to environmental changes than plants. However, this hypothesis is supported by little empirical evidence. We compared plant and microbial responses to 13 types of simulated environmental changes (mowing (M), adding nitrogen (N), adding phosphorus (P), watering (W), warming (T) and combinations of these) in a steppe ecosystem. Contrary to our hypothesis, the microbial responses were generally smaller than the plant responses to different types of environmental changes, both at the community-abundance level and species/operational taxonomic unit (OTU)/gene level. This might be ascribed to the soil buffering capacity to environmental changes, and the rapid evolutionary adaptation for microbial communities. Furthermore, the responses at the community-abundance level were larger than at the species/OTU/gene level to 13 types of environmental changes, both in plant and microbial communities. Given that the community abundance representing the total number of all individuals of the organism within the community, the responses to environmental changes at the community-abundance level is likely to be larger than at the species/OTU/gene level. Plant biomass was more responsive to N addition, particularly in such N- limiting grassland ecosystem. Our findings highlight that plant communities are more responsive to environmental changes than microbial communities, contrary to the traditional viewpoint. Therefore, plant communities could be used as ecological indicators of anthropogenic environmental changes in grasslands. Keywords: Plant community, Microbial community, Anthropogenic environmental changes, Grassland, Abundance, Species/OTU/Gene number

Aberrant number and/or dysfunction of CD4+Foxp3+ Regulatory T cells (Tregs) are associated with the pathogenesis of rheumatoid arthritis (RA). A previous study has demonstrated that thymus-derived, natural Tregs (nTregs) prefer to accumulate in inflamed joints and transdifferentiate to TH17 cells under the stimulation of inflamed synovial fibroblasts (SFs). In this study, we made a head-to-head comparison of both Treg subsets and demonstrated that induced Tregs (iTregs), but not nTregs, retained Foxp3 expression and regulatory function on T effector cells (Teffs) after being primed with inflamed SFs. In addition, iTregs inhibited proliferation, inflammatory cytokine production, migration, and invasion ability of collagen-induced arthritis (CIA)–SFs in vitro and in vivo. Moreover, we noted that iTregs directly targeted inflamed SFs to treat autoimmune arthritis, while nTregs failed to do this. Thus, manipulation of the iTreg subset may have a greater potential for prevention or treatment of patients with RA.

Different environmental changes may have some consistent effects on soil microbial community, which remains largely unexplored. Here, we report a novel and general pattern that different environmental changes consistently selected for the sub-dominant soil bacterial phyla. We mimicked 16 types of environmental changes relevant to the Eurasian steppe ecosystem, including removing different number of plant functional groups, mowing, nitrogen adding, phosphorus adding, watering, warming, and some of their combinations. While the absolute abundance of each of the four dominant bacteria phyla (Acidobacteria, Actinobacteria, Chloroflexi, and Proteobacteria) did not show a consistent response to these treatments, that of the five sub-dominant phyla (Bacteroidetes, Firmicutes, Gemmatimonadetes, Nitrospirae, and Planctomycetes) showed a consistent increase. The dominant phyla had high abundances of genes responsible for energy production/conversion and transcription, exhibiting oligotrophic traits; in contrast, the sub-dominant phyla had high abundance of 16S rDNA sequences, which could be due to greater rRNA copy number or smaller genomes, showing large growth/propagation potential and copiotrophic trait. Stochastic processes (e.g., random birth, death, colonization) played more important roles in structuring the sub-dominant than dominant phyla, and the treatments promoted the stochastic processes. The copiotrophy and stochasticity of sub-dominant phyla led to their positive responses to the treatments.

Our results demonstrated increased ecosystem nitrogen and water content as the primary drivers of the core and accessory components of soil microbial community functional diversity, respectively. Our findings suggested that more attention should be paid to certain components of community functional diversity under specific global change conditions. Our findings also indicated that microbial communities have adapted to nitrogen addition by strengthening the function of ammonia oxidization to deplete the excess nitrogen, thus maintaining ecosystem homeostasis. Because community gene richness is primarily determined by the presence/absence of accessory community genes, our findings further implied that strategies such as maintaining the amount of soil organic matter could be adopted to effectively improve the functional gene diversity of soil microbial communities subject to global change factors., It is a central ecological goal to explore the effects of global change factors on soil microbial communities. The vast functional gene repertoire of soil microbial communities is composed of both core and accessory genes, which may be governed by distinct drivers. This intuitive hypothesis, however, remains largely unexplored. We conducted a 5-year nitrogen and water addition experiment in the Eurasian steppe and quantified microbial gene diversity via shotgun metagenomics. Nitrogen addition led to an 11-fold increase in the abundance (based on quantitative PCR [qPCR]) of ammonia-oxidizing bacteria, which have mainly core community genes and few accessory community genes. Thus, nitrogen addition substantially increased the relative abundance of many core genes at the whole-community level. Water addition stimulated both plant diversity and microbial respiration; however, increased carbon/energy resources from plants did not counteract increased respiration, so soil carbon/energy resources became more limited. Thus, water addition selected for microorganisms with genes responsible for degrading recalcitrant soil organic matter. Accordingly, many other microorganisms without these genes (but likely with other accessory community genes due to relatively stable average microbial genome size) were selected against, leading to the decrease in the diversity of accessory community genes. In summary, nitrogen addition primarily affected core community genes through nitrogen-cycling processes, and water addition primarily regulated accessory community genes through carbon-cycling processes. Although both gene components may significantly respond as the intensity of nitrogen/water addition increases, our results demonstrated how these common global change factors distinctly impact each component. IMPORTANCE Our results demonstrated increased ecosystem nitrogen and water content as the primary drivers of the core and accessory components of soil microbial community functional diversity, respectively. Our findings suggested that more attention should be paid to certain components of community functional diversity under specific global change conditions. Our findings also indicated that microbial communities have adapted to nitrogen addition by strengthening the function of ammonia oxidization to deplete the excess nitrogen, thus maintaining ecosystem homeostasis. Because community gene richness is primarily determined by the presence/absence of accessory community genes, our findings further implied that strategies such as maintaining the amount of soil organic matter could be adopted to effectively improve the functional gene diversity of soil microbial communities subject to global change factors.

Objective This study aimed to investigate the physical relation and mechanism of bactericidal activity on pathogenic E. coli by ultrasonic field with whey protein isolate (WPI). Methods Ultrasound treatment was performed under the conditions of intensity at 65 W/cm2, pulse duty ratio at 0.5 for 0–15 min with WPI concentration ranged from 0 to 10%. Viscosity, granularity, surface hydrophobicity, free radical scavenging activity, and thermal denaturation were assessed by rotational viscometer, Malvern Mastersizer 2000 particle size analyzer, fluorescent probe ANS method, DPPH method, and differential scanning calorimetry, respectively. Results The thermal denaturation of WPI was not altered by ultrasound field, but the viscosity of WPI was increased upon 10 min treatment. Additionally, its ability to scavenge free radicals and hydrophobicity were increased. The result also showed that the bacteria viability was improved by WPI during ultrasound treatment. However, the WPI protection was decreased by the prolonged treatment. Conclusion Ultrasound treatment resulted in the increasing of the viscosity, free radicals scavenging activity and hydrophobicity of WPI which led to reduced bactericidal activity on E. coil, while WPI protection was disintegrated by prolonged treatment.

It is a central goal of current community ecology to explore the pattern and mechanism of community response to anthropogenic disturbances. Most researches focus on the response of community composition, which is based on the presence/absence or relative abundances of different species. However, the response of species-identity-independent community structure, such as the rank-abundance distribution, remains relatively understudied. We conducted a ten-year nitrogen addition experiment in a temperate steppe, with nine nitrogen rates under fencing (un-mowed) or mowing conditions. Mowing and nitrogen addition significantly altered both the composition and structure of plant communities. While the relative importance of stochastic change in community composition under mowing was not significantly different from that under fencing, the relative importance of stochastic change in community structure under mowing was significantly larger than that under fencing. Overall, our results demonstrated that mowing led to different drivers for the community composition and structure, meaning that mowing promoted the stochastic allocation of material and energy in primary producers in the grassland ecosystem.

Zhenzhen Yin, Ximei Zhang, Youyou Wang, Peiguo Wang, Zhiyong Yuan Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China Background: The purpose of this study is to assess the role of locoregional radiotherapy (RT) when used in combination with systemic chemotherapy, for patients with newly diagnosed metastatic nasopharyngeal carcinoma (NPC), in a non-endemic region of northern China. Methods: In total, 611 patients with NPCs were newly diagnosed between June 2011 and June2016 following visits to our hospital; of these, 32 patients presented with metastasis at initial diagnosis. Among these 32 patients, 29 had single-organ metastasis and 3 had multiple-organ metastasis. All patients were treated with RT for local and regional disease. Results: The median follow-up for all patients was 20 months (range 9–59 months), and median survival was not achieved (some patients had succumbed) at the time of the last follow-up. The 2-year overall survival (OS) rate was 75.2%, and 3-year OS rate was 50.1%. There was a significant difference between patients with single- and multiple-organ metastasis: 2-year OS was 67.5% for single- vs 0% for multiple-organ metastasis (p=0.039). Patients treated with intensity-modulated RT had a better prognosis than patients treated by conventional RT: 2-year OS was 76.6% for single- vs 44.4% for multiple-organ metastasis (no significant difference was found between the 2 groups, p=0.297). For patients with progression (all were with distant disease progression), the median progression time was 8 months (6–22 months), and the median survival after disease progression was 6 months (2–14 months). Conclusion: For patients with newly diagnosed metastatic NPCs, especially with single-organ metastasis, the addition of RT to systemic chemotherapy improved survival and disease control compared with historical cohort. Keywords: nasopharyngeal carcinoma, metastatic, radiotherapy, chemotherapy, advanced disease

Increasing atmospheric nitrogen (N) deposition causes profound changes in the plant community, significantly threatening the terrestrial ecosystem function and stability worldwide. Random migration is a primary determinant of plant community assembly in the neutral model. However, whether its role is affected by N deposition is obscure. Therefore, the effects of eight N application rates (0, 1, 2, 3, 5, 10, 15, and 20 g N m−2 yr−1) on the estimated migration rate of plant community were examined in a long-term field study in a semiarid steppe. Our results indicated that N addition significantly impacted the estimated migration rate (F = 4.89, P

Lipotoxicity induced by saturated fatty acids (SFAs) plays a central role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD); however, the exact mechanisms remain to be fully elucidated. Sirtuin 3 (SIRT3) is a nicotinamide adenine dinucleotide–dependent deacetylase located primarily inside mitochondria. In this study, we demonstrated that an SFA-rich high-fat diet (HFD) was more detrimental to the liver than an isocaloric unsaturated HFD rich in fatty acids. Unexpectedly, SIRT3 expression and activity were significantly elevated in the livers of mice exposed to the SFA-rich HFD. Using cultured HepG2 and AML-12 hepatocytes, we demonstrated that unlike monounsaturated fatty acids, SFAs up-regulate SIRT3 expression and activity. SIRT3 overexpression renders both the liver and hepatocytes susceptible to palmitate-induced cell death, which can be alleviated by SIRT3 small interfering RNA (siRNA) transfection. In contrast, SIRT3 suppression protects hepatocytes from palmitate cytotoxicity. Further studies revealed that SIRT3 acts as a negative regulator of autophagy, thereby enhancing the susceptibility of hepatocytes to SFA-induced cytotoxicity. Mechanistic investigations revealed that SIRT3 overexpression causes manganese superoxide dismutase deacetylation and activation, which depleted intracellular superoxide contents, leading to adenosine monophosphate–activated protein kinase (AMPK) inhibition and mammalian target of rapamycin C1 activation, resulting in autophagy suppression. In contrast, SIRT3 siRNA gene silencing enhanced autophagy flux. A similar result was observed in the liver tissue of SIRT3 knockout mice. Conclusion: Our data indicate that SIRT3 is a negative regulator of autophagy whose activation by SFAs contributes to lipotoxicity in hepatocytes and suggest that restraining SIRT3 overactivation can be a potential therapeutic choice for the treatment of NAFLD as well as other metabolic disorders, with lipotoxicity being the principal pathomechanism. (Hepatology 2017;66:936–952).

Long non-coding RNAs (lncRNA) have been reported as key regulators in the progression and metastasis of breast cancer. In this study, we found that the lncRNA myocardial infarction associated transcript (MIAT) expression was upregulated in breast cancer in The Cancer Genome Atlas (TCGA) data sets. We validated that MIAT was higher in breast cancer cell lines and advanced breast tumors than in normal controls. And MIAT overexpression associated with TNM stage and lymphnode metastasis. Knockdown MIAT inhibited breast cancer cell proliferation and promoted apoptosis. Also MIAT downregulation suppressed epithelial-mesenchymal transition (EMT) and decreased migration and invasion in MDA-MB-231 and MCF-7 breast cancer cell lines. More importantly, knockdown MIAT inhibited tumor growth in vivo. Our results suggested that MIAT acted as a competing endogenous RNA (ceRNA) to regulate the expression of dual specificity phosphatase 7 (DUSP7) by taking up miR-155-5p in breast cancer. There were positive correlation between MIAT and DUSP7 expression in breast cancer patients. We conclude that MIAT promotes breast cancer progression and functions as ceRNA to regulate DUSP7 expression by sponging miR-155-5p in breast cancer.

Anthropogenic environmental changes are accelerating the rate of biodiversity loss on Earth. Plant diversity loss is predicted to reduce soil microbial diversity primarily due to the decreased variety of carbon/energy resources. However, this intuitive hypothesis is supported by sparse empirical evidence, and most underlying mechanisms remain underexplored or obscure altogether. We constructed four diversity gradients (0-3) in a five-year plant functional group removal experiment in a steppe ecosystem in Inner Mongolia, China, and quantified microbial taxonomic and functional diversity with shotgun metagenome sequencing. The treatments had little effect on microbial taxonomic diversity, but were found to decrease functional gene diversity. However, the observed decrease in functional gene diversity was more attributable to a loss in plant productivity, rather than to the loss of any individual plant functional group per se. Reduced productivity limited fresh plant resources supplied to microorganisms, and thus, intensified the pressure of ecological filtering, favoring genes responsible for energy production/conversion, material transport/metabolism and amino acid recycling, and accordingly disfavored many genes with other functions. Furthermore, microbial respiration was correlated with the variation in functional composition but not taxonomic composition. Overall, the amount of carbon/energy resources driving microbial gene diversity was identified to be the critical linkage between above- and belowground communities, contrary to the traditional framework of linking plant clade/taxonomic diversity to microbial taxonomic diversity.

Human gingiva-derived mesenchymal stem cells (GMSCs) have been considered to be a better source of MSCs for cell therapy in some immunological diseases. We describe a protocol for isolation and culture of mesenchymal stem cells (MSCs) from human gingival tissue in detail, which provides a methodology to help clinical researches and clinical trial. GMSCs are generally isolated from a remnant or discarded tissue following a routine dental procedure, then cultured in complete culture medium at 37°C in a humidified tissue culture incubator with 5% CO(2) and 95% O(2). Non-adherent cells are removed after 48~72 h and the fresh medium is replaced. When primary cultures become 80%~90% confluent, the plastic-adherent cells are treated with 0.25% trypsin-EDTA and subcultured. A purified population of GMSCs can be obtained 2-3 weeks after the initiation of culture.

Background The aim of this study was to investigate the role of long non-coding RNA (lncRNA) H19 in gastric cancer (GC) with Helicobacter pylori (H. pylori). Methods H19 expression in peripheral blood from H. pylori+/− GC patients and healthy donors (control) as well as in GC tissues and cells were detected by qRT-PCR. Cell proliferation was evaluated by CCK-8 assay. Cell migration and invasion were evaluated by Transwell assay. The levels of pro-inflammatory cytokines were determined by ELISA. The protein levels of IκBα, p-IκBα and p65 were determined by western blotting. Results H19 expression was upregulated in H. pylori-infected GC tissues and cells. Furthermore, H. pylori promoted GC cell viability, migration, invasion and inflammatory response. Moreover, H19 overexpression promoted the proliferation, migration and invasion of H. pylori-infected GC cells via enhancing NF-κB-induced inflammation. Conclusions LncRNA H19 promotes H. pylori-induced GC cell growth via enhancing NF-κB-induced inflammation.

Background Mounting evidence has shown that a novel subset of mesenchymal stem cells (MSCs) derived from human gingiva referred to as gingival mesenchymal stem cells (GMSCs) displays a greater immunotherapeutic potential and regenerative repair expression than MSCs obtained from other tissues. However, the safety of the use of transplanted GMSCs in humans remains unclear. Methods In this study, we evaluated the safety of GMSCs transplanted into mouse, rat, rabbit, beagle dog, and monkey as well as two animal models of autoimmune diseases. Results In short- and long-term toxicity tests, infused GMSCs had no remarkable adverse effects on hematologic and biochemical indexes, particularly on the major organs such as heart, liver, spleen, and kidney in recipient animals. It was also shown that GMSCs were well tolerated in other assays including hemolysis, vascular, and muscular stimulation, as well as systemic anaphylaxis and passive skin Arthus reaction in animal models. GSMC infusion did not cause any notable side effects on animal models of either autoimmune arthritis or lupus. Significantly, GMSCs most likely play no role in genotoxicity and tumorigenesis. The biological features remained stable for an extended period after cell transfer. Conclusions GMSCs are safe in various animal models of autoimmunity, even during active disease episodes, especially in monkeys. This study paves a solid road for future clinical trials of GMSCs in patients with autoimmune and inflammatory diseases. Electronic supplementary material The online version of this article (10.1186/s13287-019-1262-5) contains supplementary material, which is available to authorized users.

BACKGROUND: Bone destruction is one of many severe complications that occurs in patients with rheumatoid arthritis (RA) and current therapies are unable to cure this manifestation. This study here aims to determine whether GMSC can directly inhibit osteoclast formation and eventually attenuate osteoclastogenesis and bone erosion in an inflammatory milieu. METHOD: GMSC were co-cultured with osteoclast precursors with or without CD39 inhibitor, CD73 inhibitor or adenosine receptors inhibitors pretreatment and osteoclast formation were evaluated in vitro. 2×10^6 GMSC per mouse were transferred to CIA mice and pathology scores, the frequency of osteoclasts, bone erosion in joints were assessed in vivo. FINDING: GMSC but not control cells, markedly suppressed human or mice osteoclastogenesis in vitro. GMSC treatment also resulted in a dramatically decreased level of NF-κB p65/p50 in osteoclasts in vitro. Infusion of GMSC to CIA significantly attenuated the severity of arthritis, pathology scores, frequency of osteoclasts, particularly bone erosion, as well as a decreased expression of RANKL in synovial tissues in vivo. Blockade of CD39/CD73 or adenosine receptors has significantly abrogated the suppressive ability of GMSC in vitro and therapeutic effect of GMSC on bone erosion during CIA in vivo. INTERPRETATION: GMSC inhibit osteoclast formation in vitro and in vivo partially via CD39-CD73-adenosine signals. Manipulation of GMSC may have a therapeutic implication on rheumatoid arthritis and other bone erosion related diseases. FUND: This study was supported by grants from the National Key R&D Program of China (2017YFA0105801 to F.H); the Zhujiang Innovative and Entrepreneurial Talent Team Award of Guangdong Province (2016 ZT 06S 252 to F·H) and National Institutes of Health (R01 AR059103, R61 AR073409 and NIH Star Award to S.G.Z).

Hypoxia associated with the high metabolic demand of rods has been implicated in the pathology of age-related macular degeneration (AMD), the most common cause of adult blindness in the developed world. The majority of AMD-associated severe vision loss cases are due to exudative AMD, characterized by neovascularization. To further investigate the causes and histopathology of exudative AMD, we conditionally induced hypoxia in a novel preclinical AMD model (Pde6gcreERT2/+;Vhl−/−) by targeting Vhl and used multimodal imaging and immunohistochemistry to track the development of hypoxia-induced neovascularization. In addition to developing a preclinical model that phenocopies exudative AMD, our studies revealed that the photoreceptor hypoxic response initiates and drives type 3 neovascularization, mainly in the outer retina. Activation of the VHL-HIF1a-VEGF-EPO pathway in the adult retina led to long-term neovascularization, retinal hemorrhages and compromised retinal layers. Our novel preclinical model would accelerate the testing of therapies that use metabolomic approaches to ameliorate AMD.

Supplementary figures and legends. Figure S1. The changes of histamine in both low and high dose of GMSC-treated beagle dog groups. Figure S2. GMSCs have no side effects in the coagulation system and organs of rats. Figure S3. GMSCs have no notable side effects and toxicity in autoimmune disease models. Figure S4. GMSCs were recovered from mice. Figure S5. GMSCs did not affect short-term toxicity in rhesus monkeys. Figure S6. GMSCs have no side effects in the coagulation system and organs of monkeys. (DOCX 3891 kb)

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Fencing facility has been widely employed in steppes. However, the effects of fencing facility on plant species and soil organic carbon (SOC) have been rarely understood in steppes. Using soil sampling and plant quadrat clipping methods, in this study, we investigated the effects of fencing facility on the distributions of plant species and SOC in the temperate steppes of the Inner Mongolia. Plant biomass significantly increased with approaching fencing facility and was obviously higher in the leeward (south) than windward (north) sides. Perennial grasses accounted for approximately 68%–76% of the total aboveground biomass in both sides of fencing facility. SOC content also significantly increased with approaching fencing facility in the 0–10 soil layer but slightly increased in the 10–30 cm soil layer. Wind erosion and dust storm did markedly neither change the fractions of soil texture nor cause the difference in SOC content between the windward and leeward sides. Fencing facility increased SOC storage by 16.5% and 9.1% at 0.1 and 0.5 m locations relative to at 3 m location in the 0–10 cm soil layer, respectively. Edge effect is suggested as a potential mechanism driving the variations of plant species and SOC in both sides of fencing facility.

Nicotinamide (NAM) is the amide of nicotinic acid and a predominant precursor for NAD(+) biosynthesis via the salvage pathway. Sirt1 is a NAD(+)-dependent deacetylase, playing an important role in regulating cellular functions. Although hepatoprotective effect of NAM has been reported, the underlying mechanism remains elusive. ER stress, induced by saturated fatty acids, in specific palmitate, plays a pathological role in the development of nonalcoholic fatty liver disease. This study aims to determine the effect of NAM on palmitate-induced ER stress in hepatocytes and to elucidate molecular mechanisms behind. Both HepG2 cells and primary mouse hepatocytes were exposed to palmitate (conjugated to BSA at a 2:1 M ratio), NAM, or their combination for different durations. Cellular NAD(+) level, Sirt1 expression/activity, ER stress, as well as cAMP/PKA/CREB pathway activation were determined. NAM increased Sirt1 expression and enzymatic activity, which contributes to the ameliorative effect of NAM on palmitate-triggered ER stress. NAM increased intracellular NAD(+) level in hepatocytes, however, blocking the salvage pathway, a pathway for NAD(+) synthesis from NAM, only partially prevented NAM-induced Sirt1 upregulation while completely prevented NAD+ increase in response to NAM. Further mechanistic investigations revealed that NAM elevated intracellular cAMP level via suppressing PDE activity, leading to downstream PKA and CREB activation. Importantly, cAMP/PKA/CREB pathway blockade abolished not only NAM-induced Sirt1 upregulation, but also its protective effect against ER stress. Our results demonstrate that NAM protects hepatocytes against palmitate-induced ER stress in hepatocytes via upregulating Sirt1. Activation of the cAMP/PKA/CREB pathway plays a key role in NAM-induced Sirt1 upregulation.

Rheumatoid arthritis (RA) is a systemic-autoimmune-mediated disease characterized by synovial hyperplasia and progressive destruction of joint. The aim of this study is to evaluate whether human gingiva derived MSCs (GMSCs) can alleviate rheumatoid arthritis through directly targeting of rheumatoid arthritis synovial fibroblasts (RA-SF) and underlying mechanism(s). GMSCs or Primary Dermal Fibroblast (PDF) were co-cultured with LPS-stimulated RA-SF. The proliferation, migration and invasion abilities of RA-SF or GMSCs treated RA-SF were examined for determining the suppressive effects of GMSCs on RA-SF. To learn whether GMSCs suppress RA-SF migration and invasion in vivo, GMSCs were subcutaneously co-transplanted with RA-SF and health cartilage into SCID mice to develop a humanized synovitis model, H&E or immunofluorescence staining were employed to determine the effects. Moreover, GMSCs were transferred into collagen induced arthritis model (CIA), proliferation, migration and invasion capacities of synovial fibroblasts from model mice or GMSCs treated mice were compared. We found that the proliferation, migration and invasion capacities of GMSCs treated RA SF were significantly declined. Importantly, the expression of IL-6, IL-8, MMP1, MMP2, MMP3 and MMP13 were dramatically reduced in GMSCs treated RA-SF (qPCR results). Administration of GMSCs was therapeutic in collagen induced arthritis synovial fibroblasts pathology (proliferation, migration and invasion). Furthermore, GMSCs directly suppress RA-SF invasion in a humanized synovitis model. We conclude that the manipulation of GMSCs can ameliorate rheumatoid arthritis (RA) through directly targeting of rheumatoid arthritis synovial fibroblasts.