ABSTRACT
BACKGROUND: Introduced in 1992, intracytoplasmic sperm injection (ICSI) was initially indicated for severe male infertility; however, its use has since been expanded to non-severe male infertility. We aimed to compare the efficacy and safety of ICSI versus conventional in-vitro fertilisation (IVF) in couples with infertility with non-severe male factor. METHODS: We conducted an investigator-initiated, multicentre, open-label, randomised controlled trial in ten reproductive medicine centres across China. Couples with infertility with non-severe male factor without a history of poor fertilisation were randomly assigned (1:1) to undergo either ICSI or conventional IVF. The primary outcome was live birth after first embryo transfer. We performed the primary analysis in the intention-to-treat population using log-binomial regression models for categorical outcomes or linear regression models for continuous outcomes, adjusting for centre. This trial is registered with Clinicaltrials.gov, NCT03298633, and is completed. FINDINGS: Between April 4, 2018, and Nov 15, 2021, 3879 couples were screened, of whom 2387 (61·5%) couples were randomly assigned (1184 [49·6%] to the ICSI group and 1203 [50·4%] to the conventional IVF group). After excluding couples who were ineligible, randomised twice, or withdrew consent, 1154 (97·5%) in the ICSI group and 1175 (97·7%) in the conventional IVF group were included in the primary analysis. Live birth after first embryo transfer occurred in 390 (33·8%) couples in the ICSI group and in 430 (36·6%) couples in the conventional IVF group (adjusted risk ratio [RR] 0·92 [95% CI 0·83-1·03]; p=0·16). Two (0·2%) neonatal deaths were reported in the ICSI group and one (0·1%) in the conventional IVF group. INTERPRETATION: In couples with infertility with non-severe male factor, ICSI did not improve live birth rate compared with conventional IVF. Given that ICSI is an invasive procedure associated with additional costs and potential increased risks to offspring health, routine use is not recommended in this population. FUNDING: National Natural Science Foundation of China, National Key Research and Development Program, Beijing Municipal Science & Technology Commission, and Peking University Third Hospital.
Subject(s)
Infertility, Male , Sperm Injections, Intracytoplasmic , Pregnancy , Female , Infant, Newborn , Male , Humans , Sperm Injections, Intracytoplasmic/methods , Semen , Fertilization in Vitro/methods , Infertility, Male/therapy , Fertilization , Pregnancy RateABSTRACT
We present the performances of a broadband optical parametric chirped pulse amplification (OPCPA) using partially deuterated potassium dihydrogen phosphate (DKDP) crystals with deuteration levels of 70% and 98%. When pumped by a Nd:glass double frequency laser, the OPCPA system using the 98% deuterated DKDP crystal achieves a broad bandwidth of 189â nm (full width at 1/e2 maximum) from 836â nm to 1025â nm. For the DKDP crystal with length of 43 mm, the pump-to-signal conversion efficiency reaches 28.4% and the compressed pulse duration is 13.7 fs. For a 70% deuterated DKDP crystal with a length of 30 mm, the amplified spectrum ranges from 846-1021â nm, the compressed pulse duration is 15.7 fs, and the conversion efficiency is 25.5%. These results demonstrate the potential of DKDP crystals with higher deuteration as promising nonlinear crystals for use as final amplifiers in 100 Petawatt (PW) laser systems, supporting compression pulse duration shorter than 15 fs.
ABSTRACT
We report on the investigation of continuous-wave (CW) and SEmiconductor Saturable Absorber Mirror (SESAM) mode-locked operation of a Yb:GdScO3 laser. Using a single-transverse-mode, fiber-coupled InGaAs laser diode at 976â nm as a pump source, the Yb:GdScO3 laser delivers 343â mW output power at 1062â nm in the CW regime, which corresponds to a slope efficiency of 52%. Continuous tuning is possible across a wavelength range of 84â nm (1027-1111â nm). Using a commercial SESAM to initiate mode-locking and stabilize soliton-type pulse shaping, the Yb:GdScO3 laser produces pulses as short as 42 fs at 1065.9â nm, with an average output power of 40â mW at 66.89â MHz. To the best of our knowledge, this is the first demonstration of passively mode-locking with Yb:GdScO3 crystal.
ABSTRACT
We demonstrate a gas-filled multipass cell (MPC) that cleaned the spatial mode of a spatial-filter-free 250â W, 100â kHz, 445â fs driven source based on an Innoslab amplifier and compressed the pulse duration to 41â fs simultaneously. The multipass cell acted as a spatial filter and benefited from its discrete waveguide nature, in which the input beam quality factor M2 was improved from 1.53 to a near-diffraction-limited value of 1.21 at 96% transmission.
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BACKGROUND AND PURPOSE: Emerging evidence has linked impaired kidney function with dementia in older adults, but the neuropathological pathways underlying their association remain poorly understood. We sought to examine the relationships of kidney function with dementia and plasma biomarkers in a Chinese rural population. METHODS: This population-based study used data from the baseline examination of the Multimodal Interventions to Delay Dementia and Disability in rural China (MIND-China) cohort (March-September 2018; n = 5715). Kidney function was assessed using estimated glomerular filtration rate (eGFR) based on serum creatinine level. Dementia, Alzheimer's disease (AD) and vascular dementia (VaD) were diagnosed according to the international criteria. Plasma biomarkers were measured using the SIMOA platform in a subsample (n = 1446). Data were analyzed using logistic, general linear, and mediation models. RESULTS: Of the 5715 participants, 306 were diagnosed with dementia, including 195 with AD and 100 with VaD. Impaired kidney function (eGFR <60 vs. ≥90 mL/min/1.73 m2) was associated with multivariable-adjusted odds ratios of 2.24 (95% confidence interval [CI] 1.44-3.46) for all-cause dementia, 1.85 (1.07-3.18) for AD, and 2.49 (1.16-5.22) for VaD. In the biomarker subsample, impaired kidney function was significantly associated with higher plasma amyloid-ß (Aß)40 (ß-coefficient = 54.36, 95% CI 43.34-65.39), Aß42 (ß-coefficient = 3.14, 95% CI 2.42-3.86), neurofilament light chain (ß-coefficient = 10.62, 95% CI 5.62-15.62), and total tau (ß-coefficient = 0.68, 95% CI 0.44-0.91), and a lower Aß42/Aß40 ratio (ß-coefficient = -4.11, 95% CI -8.08 to -0.14). The mediation analysis showed that plasma total tau significantly mediated 21.76% of the association between impaired kidney function and AD (p < 0.05). CONCLUSION: Impaired kidney function is associated with dementia and plasma biomarkers among rural-dwelling older Chinese adults, and the association with AD is partly mediated by plasma biomarkers for neurodegeneration.
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BACKGROUND: Socioeconomic status (SES) is associated with both depression and activities of daily living (ADL and IADL). However, the role of ADL as a biological mechanism in the relationship between SES and late-life depression, examined through longitudinal data, remains understudied. This study explored the longitudinal mediation effects of basic ADL or IADL on the SES-depression link in older adults. METHODS: Data from the China Health and Retirement Longitudinal Study (N = 4104) were utilized. Mediation analysis was performed using parallel process latent growth curve modeling. RESULTS: The average age of participants was 57.76 years, and 55.7% being females. Significant linear growth over time was observed in ADL, IADL, and depression. Adjusting for covariates, SES was positively linked to the initial levels (intercepts) of ADL (ßiADL=-0.100[-0.143, -0.057]), IADL (ßiIADL=-0.140[-0.185, -0.095]), and depression (ßiDEP=-0.103[-0.158, -0.048]). However, SES showed no significant correlation with the rate of change (slopes) in ADL, IADL, or depression (P > 0.05). The intercepts of ADL (ßiDEP = 0.566[0.503, 0.629]) and IADL (ßiDEP = 0.607[0.544, 0.670]) were positively correlated with the depression intercept but negatively with the depression slope. Conversely, the slopes of ADL and IADL were positively associated with the depression slope. These results suggest a negative indirect relationship between SES and the initial level of depression, but a positive indirect relationship with the rate of increase in depression through ADL (or IADL) intercept. CONCLUSIONS: Higher SES is associated with a lower initial risk of depression and ADL difficulties. However, this same higher SES may relate to a faster increase in ADL difficulties and depression among middle-aged and older adults. The findings underscore the need for increased governmental healthcare funding and improved healthcare accessibility. Additionally, maintaining adequate sleep and physical activity can help prevent disability and reduce depression risk later in life, particularly among older adults with lower SES.
Subject(s)
Activities of Daily Living , Depression , Social Class , Humans , Activities of Daily Living/psychology , Female , Male , Longitudinal Studies , Middle Aged , Depression/psychology , China/epidemiology , Aged , Mediation AnalysisABSTRACT
BACKGROUND: With the increasing incidence of obesity and the childbearing-age delay among women, a debate over obesity's impacts on pregnancy and neonatal outcomes becomes hot. The potential negative effects of obesity and aging on fertility lead to an idea, whether an obese female pursuing IVF treatment can benefit from an ideal BMI achieved over a long-time weight loss process at the cost of aging? We aimed to assess the association between body mass index (BMI) and clinical or neonatal outcomes in patients undergoing in vitro fertilization (IVF) treatment, for answering whether it is necessary to lose weight first for obese patients, particularly those at advanced age. METHODS: A retrospective cohort study was performed using multicentered data from China. The women were stratified into 5 groups in terms of pre-gravid BMI (kg/m2) with the WHO obesity standard (group 1: BMI < 18.5; group 2: 18.5 ≤ BMI < 23.0; group 3: 23.0 ≤ BMI < 25.0; group 4: 25.0 ≤ BMI < 30.0; group 5: BMI ≥ 30.0). The primary outcome was cumulative live birth rate (CLBR), and other clinical and neonatal outcomes were weighed as secondary outcomes. Multivariate logistic regression analyses were carried to evaluate the association between BMI and the CLBR, or between BMI and some neonatal outcomes. Furthermore, we implemented a machine-learning algorithm to predict the CLBR based on age and BMI. RESULTS: A total of 115,287 women who underwent first IVF cycles with autologous oocytes from January 2013 to December 2017 were included in our study. The difference in the CLBR among the five groups was statistically significant (P < 0.001). The multivariate logistic regression analysis showed that BMI had no significant impact on the CLBR, while women's age associated with the CLBR negatively. Further, the calculation of the CLBR in different age stratifications among the five groups revealed that the CLBR lowered with age increasing, quantitatively, it decreased by approximately 2% for each one-year increment after 35 years old, while little difference observed in the CLBR corresponding to the five groups at the same age stratification. The machine-learning algorithm derived model showed that BMI's effect on the CLBR in each age stratification was negligible, but age's impact on the CLBR was overwhelming. The multivariate logistic regression analysis showed that BMI did not affect preterm birth, low birth weight infant, small for gestational age (SGA) and large for gestational age (LGA), while BMI was an independent risk factor for fetal macrosomia, which was positively associated with BMI. CONCLUSIONS: Maternal pre-gravid BMI had no association with the CLBR and neonatal outcomes, except for fetal macrosomia. While the CLBR was lowered with age increasing. For the IVF-pursuing women with obesity plus advanced age, rather than losing weight first, the sooner the treatment starts, the better. A multicentered prospective study with a large size of samples is needed to confirm this conclusion in the future.
Subject(s)
Body Mass Index , Fertilization in Vitro , Obesity , Humans , Female , Retrospective Studies , Fertilization in Vitro/methods , Pregnancy , Adult , China/epidemiology , Obesity/therapy , Obesity/epidemiology , Live Birth/epidemiology , Pregnancy Outcome/epidemiology , Birth Rate , Infant, Newborn , Pregnancy RateABSTRACT
Aflatoxin G1 (AFG1) is a mycotoxin commonly found in agricultural products, including dried fruits, meat, and milk products. Oral AFG1 administration induced tumor necrosis factor (TNF)-α-dependent chronic pulmonary inflammation, promoting AFG1-induced damage in alveolar epithelial cell, which is associated with lung adenocarcinoma. Pulmonary macrophages may be divided into tissue-resident alveolar macrophages (TRAMs) and monocyte-derived macrophages (MoMs), which involve in chronic lung inflammation. However, whether these macrophages contribute to AFG1-induced chronic pulmonary inflammation remains unknown. In this study, we found oral AFG1 administration disrupted the balance between TRAMs and MoMs, increasing MoMs infiltration and decreasing the number of TRAMs. AFG1 upregulated TNF-α expression in MoMs, but downregulated sialic acid binding Ig-like lectin F (Siglec-F) expression in TRAMs. Inhibition of TNF-α-dependent inflammation rescued the imbalance between TRAMs and MoMs in AFG1-treated lung tissues. Additionally, AFG1 stimulated MoMs differentiation to the proinflammatory M1 phenotype in vitro. Using a specific in vitro TRAM model, AFG1 downregulated Siglec-F and the M2 phenotypic markers arginase 1 and YM1, and upregulated the M1 phenotypic markers IL-6, iNOS and TNF-α, altering the TRAMs phenotype to the pro-inflammatory M1 phenotype in vitro. Additionally, mouse maternal dietary exposure to AFG1 caused an imbalance in pulmonary macrophages, decreasing TRAMs and increasing MoMs population in offspring, which was associated with proliferative lesions in the alveolar septa. Thus, dietary AFG1 exposure triggered an imbalance in pulmonary macrophages in both mother and offspring mice, and induced pro-inflammatory phenotypic alterations, which contributed to AFG1-induced chronic lung inflammation. These results provide clues to how AFG1-induced immunotoxicity and genotoxicity in humans might be prevented.
Subject(s)
Aflatoxins , Macrophages, Alveolar , Animals , Mice , Macrophages, Alveolar/drug effects , Female , Aflatoxins/toxicity , Lung/drug effects , Lung/pathology , Pregnancy , Dietary Exposure/adverse effects , Macrophages/drug effects , Tumor Necrosis Factor-alpha/metabolism , Mice, Inbred C57BLABSTRACT
PURPOSE: This study aimed to evaluate the effectiveness of a random forest (RF) model in predicting clinical pregnancy outcomes from intrauterine insemination (IUI) and identifying significant factors affecting IUI pregnancy in a large Chinese population. METHODS: RESULTS: A total of 11 variables, including eight from female (age, body mass index, duration of infertility, prior miscarriage, and spontaneous abortion), hormone levels (anti-Müllerian hormone, follicle-stimulating hormone, luteinizing hormone), and three from male (smoking, semen volume, and sperm concentration), were identified as the significant variables associated with IUI clinical pregnancy in our Chinese dataset. The RF-based prediction model presents an area under the receiver operating characteristic curve (AUC) of 0.716 (95% confidence interval, 0.6914-0.7406), an accuracy rate of 0.6081, a sensitivity rate of 0.7113, and a specificity rate of 0.505. Importance analysis indicated that semen volume was the most vital variable in predicting IUI clinical pregnancy. CONCLUSIONS: The machine learning-based IUI clinical pregnancy prediction model showed a promising predictive efficacy that could provide a potent tool to guide selecting targeted infertile couples beneficial from IUI treatment, and also identify which parameters are most relevant in IUI clinical pregnancy.
Subject(s)
Insemination, Artificial , Machine Learning , Humans , Female , Pregnancy , Male , Adult , Insemination, Artificial/methods , Pregnancy Rate , China/epidemiology , Pregnancy Outcome , Luteinizing Hormone/blood , Follicle Stimulating Hormone/blood , Infertility/therapy , Anti-Mullerian Hormone/blood , ROC Curve , East Asian PeopleABSTRACT
AIMS: Drawing on the conservation of resources theory, this study examines the underlying process through which servant leadership is associated with nurses' in-role performance. Specifically, we test the indirect effect of servant leadership on in-role performance via a sequential mediating mechanism of job autonomy and emotional exhaustion. DESIGN: A time-lagged design was implemented using data gathered from two-wave online surveys (1 week apart) of registered nurses from Jiangsu Province, China. METHODS: Between September 2022 and February 2023, we used Wenjuanxing and Credma, which are two powerful and user-friendly data collection platforms, to distribute online surveys to potential participants. We received a total of 220 usable responses and employed the PROCESS Model 4 and Model 6 to assess our proposed hypotheses. RESULTS: Our proposed model was supported. Servant leadership has a positive indirect effect on nurses' in-role performance through job autonomy and emotional exhaustion. Job autonomy has a negative effect on emotional exhaustion. Additionally, job autonomy mediates the negative relationship between servant leadership and emotional exhaustion. CONCLUSION: The present research extends existing nursing studies by unravelling the complex mechanisms underlying the relationship between servant leadership and nurses' in-role performance. Our study also identifies the underlying mechanism of how servant leadership mitigates emotional exhaustion by supporting nurses' job autonomy. IMPACT: The sequential mediation results provide us with a more fine-grained understanding of the relationship between servant leadership and nurses' in-role performance. It further promotes job autonomy and decreases emotional exhaustion, which supports the UN Sustainable Development Goal #3 (Good Health and Well-being). PATIENT OR PUBLIC CONTRIBUTION: This study addresses the UN Sustainable Development Goal #3: 'To ensure healthy lives and promote well-being for all at all ages' and the healthcare providers will benefit from our study. Therefore, the study contributes to a more sustainable organization and society.
Subject(s)
Nurses , Nursing Staff, Hospital , Humans , Emotional Exhaustion , Leadership , Cross-Sectional Studies , Nursing Staff, Hospital/psychology , Surveys and Questionnaires , Job SatisfactionABSTRACT
INTRODUCTION: We examined the associations of polygenic risk score (PRS) with Alzheimer's disease (AD) and plasma biomarkers in the Chinese population. METHODS: This population-based study used baseline data from MIND-China (2018; n = 4873) and follow-up data from dementia-free individuals (2014-2018; n = 2117). We measured AD-related plasma biomarkers in a subsample (n = 1256). Data were analyzed using logistic and Cox regression models. RESULTS: We developed PRS with (PRSAPOE) and without (PRSnon- APOE) apolipoprotein E (APOE) gene. In the longitudinal analysis, PRSAPOE was associated with a multivariable-adjusted hazards ratio of 1.91 (95% CI = 1.13-3.23) for AD. PRSAPOE in combination with demographics yielded discriminative (area under the curve [AUC]) and predictive(C-statistic) accuracy of 0.80 (95% confidence interval [CI] = 0.77-0.84) and 0.80 (0.77-0.82), respectively. PRSnon- APOE showed an association with AD risk similar to PRSAPOE. PRSAPOE, but not PRSnon- APOE, was associated with reduced plasma Aß42/Aß40 ratio and increased Neurofilament light chain (NfL) (p < 0.05). DISCUSSION: The PRS with and without APOE gene, in combination with demographics, shows good discriminative and predictive ability for AD. The AD-related pathologies underlie AD risk associated with PRSAPOE. HIGHLIGHTS: The PRSAPOE and PRSnon- APOE were associated with AD risk in the Chinese population. The PRSAPOE and PRSnon- APOE, in combination with demographics, showed good discriminative and predictive ability for AD. The AD-related pathologies underlie the AD risk associated with PRSAPOE but not PRSnon- APOE.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Apolipoproteins E , Biomarkers , Multifactorial Inheritance , Humans , Alzheimer Disease/genetics , Alzheimer Disease/blood , Male , Female , Biomarkers/blood , Aged , China , Multifactorial Inheritance/genetics , Apolipoproteins E/genetics , Apolipoproteins E/blood , Amyloid beta-Peptides/blood , Asian People/genetics , Longitudinal Studies , Genetic Predisposition to Disease/genetics , Risk Factors , Neurofilament Proteins/blood , Neurofilament Proteins/genetics , Genetic Risk Score , East Asian PeopleABSTRACT
INTRODUCTION: Evidence has emerged that cardiometabolic multimorbidity (CMM) is associated with dementia, but the underlying mechanisms are poorly understood. METHODS: This population-based study included 5704 older adults. Of these, data were available in 1439 persons for plasma amyloid-ß (Aß), total tau, and neurofilament light chain (NfL) and in 1809 persons for serum cytokines. We defined CMM following two common definitions used in previous studies. Data were analyzed using general linear, logistic, and mediation models. RESULTS: The presence of CMM was significantly associated with an increased likelihood of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) (p < 0.05). CMM was significantly associated with increased plasma Aß40, Aß42, and NfL, whereas CMM that included visceral obesity was associated with increased serum cytokines. The mediation analysis suggested that plasma NfL significantly mediated the association of CMM with AD. DISCUSSION: CMM is associated with dementia, AD, and VaD in older adults. The neurodegenerative pathway is involved in the association of CMM with AD. HIGHLIGHTS: The presence of CMM was associated with increased likelihoods of dementia, AD, and VaD in older adults. CMM was associated with increased AD-related plasma biomarkers and serum inflammatory cytokines. Neurodegenerative pathway was partly involved in the association of CMM with AD.
Subject(s)
Amyloid beta-Peptides , Biomarkers , Dementia , Multimorbidity , Humans , Female , Male , Biomarkers/blood , Aged , China/epidemiology , Amyloid beta-Peptides/blood , Dementia/epidemiology , Dementia/blood , Rural Population/statistics & numerical data , tau Proteins/blood , Cytokines/blood , Neurofilament Proteins/blood , Alzheimer Disease/blood , Alzheimer Disease/epidemiology , Aged, 80 and overABSTRACT
Excess soil salinity affects large regions of land and is a major hindrance to crop production worldwide. Therefore, understanding the molecular mechanisms of plant salt tolerance has scientific importance and practical significance. In recent decades, studies have characterized hundreds of genes associated with plant responses to salt stress in different plant species. These studies have substantially advanced our molecular and genetic understanding of salt tolerance in plants and have introduced an era of molecular design breeding of salt-tolerant crops. This review summarizes our current knowledge of plant salt tolerance, emphasizing advances in elucidating the molecular mechanisms of osmotic stress tolerance, salt-ion transport and compartmentalization, oxidative stress tolerance, alkaline stress tolerance, and the trade-off between growth and salt tolerance. We also examine recent advances in understanding natural variation in the salt tolerance of crops and discuss possible strategies and challenges for designing salt stress-resilient crops. We focus on the model plant Arabidopsis (Arabidopsis thaliana) and the four most-studied crops: rice (Oryza sativa), wheat (Triticum aestivum), maize (Zea mays), and soybean (Glycine max).
Subject(s)
Arabidopsis , Crops, Agricultural , Crops, Agricultural/genetics , Arabidopsis/physiology , Glycine max , Salt Tolerance/genetics , SalinityABSTRACT
Lung adenocarcinoma is the most common type of lung cancer. We recently reported that inflammation-driven lung adenocarcinoma (IDLA) originates from alveolar type (AT)-II cells, which depend on major histocompatibility complex (MHC) class II to promote the expansion of regulatory T cells. The MHC class II-associated invariant chain (CD74) binds to the macrophage migration inhibitory factor (MIF), which is associated with promoting tumor growth and invasion. However, the role of MIF-CD74 in the progression of lung adenocarcinoma and the underlying mechanisms remain unclear. We aimed to explore the role of MIF-CD74 in the progression of lung adenocarcinoma and elucidate the mechanisms by which tumor necrosis (TNF)-α-mediated inflammation regulates CD74 and MIF expression in IDLA. In human lung adenocarcinoma, CD74 was upregulated on the surface of tumor cells originating from AT-II cells, which correlated positively with lymph node metastasis, tumor origin/nodal involvement/metastasis stage, and TNF-α expression. MIF interaction with CD74 promoted the proliferation and migration of A549 and H1299 cells in vitro. Using a urethane-induced IDLA mouse model, we observed that CD74 was upregulated in tumor cells and macrophages. MIF expression was upregulated in macrophages in IDLA. Blocking TNF-α-dependent inflammation downregulated CD74 expression in tumor cells and CD74 and MIF expression in macrophages in IDLA. Conditioned medium from A549 cells or activated mouse AT-II cells upregulated MIF in macrophages by secreting TNF-α. TNF-α-dependent lung inflammation contributes to the progression of lung adenocarcinoma by upregulating CD74 and MIF expression, and AT-II cells upregulate MIF expression in macrophages by secreting TNF-α. This study provides novel insights into the function of CD74 in the progression of IDLA.
Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Macrophage Migration-Inhibitory Factors , Pneumonia , Animals , Humans , Mice , Histocompatibility Antigens Class II/metabolism , Inflammation/metabolism , Intramolecular Oxidoreductases , Lung Neoplasms/metabolism , Macrophage Migration-Inhibitory Factors/metabolism , Pneumonia/chemically induced , Pneumonia/metabolism , Tumor Necrosis Factor-alphaABSTRACT
BACKGROUND AND AIMS: Genomic alterations that encourage stem cell activity and hinder proper maturation are central to the development of colorectal cancer (CRC). Key molecular mediators that promote these malignant properties require further elucidation to galvanize translational advances. We therefore aimed to characterize a key factor that blocks intestinal differentiation, define its transcriptional and epigenetic program, and provide preclinical evidence for therapeutic targeting in CRC. METHODS: Intestinal tissue from transgenic mice and patients were analyzed by means of histopathology and immunostaining. Human CRC cells and neoplastic murine organoids were genetically manipulated for functional studies. Gene expression profiling was obtained through RNA sequencing. Histone modifications and transcription factor binding were determined with the use of chromatin immunoprecipitation sequencing. RESULTS: We demonstrate that SRY-box transcription factor 9 (SOX9) promotes CRC by activating a stem cell-like program that hinders intestinal differentiation. Intestinal adenomas and colorectal adenocarcinomas from mouse models and patients demonstrate ectopic and elevated expression of SOX9. Functional experiments indicate a requirement for SOX9 in human CRC cell lines and engineered neoplastic organoids. Disrupting SOX9 activity impairs primary CRC tumor growth by inducing intestinal differentiation. By binding to genome wide enhancers, SOX9 directly activates genes associated with Paneth and stem cell activity, including prominin 1 (PROM1). SOX9 up-regulates PROM1 via a Wnt-responsive intronic enhancer. A pentaspan transmembrane protein, PROM1 uses its first intracellular domain to support stem cell signaling, at least in part through SOX9, reinforcing a PROM1-SOX9 positive feedback loop. CONCLUSIONS: These studies establish SOX9 as a central regulator of an enhancer-driven stem cell-like program and carry important implications for developing therapeutics directed at overcoming differentiation defects in CRC.
Subject(s)
Cell Differentiation , Colorectal Neoplasms/metabolism , Enhancer Elements, Genetic , Neoplastic Stem Cells/metabolism , SOX9 Transcription Factor/metabolism , AC133 Antigen/genetics , AC133 Antigen/metabolism , Animals , Cell Proliferation , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Genes, APC , HT29 Cells , Humans , Mice, Transgenic , Neoplastic Stem Cells/pathology , SOX9 Transcription Factor/genetics , Tumor Burden , Tumor Cells, Cultured , Wnt Signaling PathwayABSTRACT
The sodium cation (Na+ ) is the predominant cation with deleterious effects on crops in salt-affected agricultural areas. Salt tolerance of crop can be improved by increasing shoot Na+ exclusion. Therefore, it is crucial to identify and use genetic variants of various crops that promote shoot Na+ exclusion. Here, we show that a HKT1 family gene ZmNC3 (Zea mays L. Na+ Content 3; designated ZmHKT1;2) confers natural variability in shoot-Na+ accumulation and salt tolerance in maize. ZmHKT1;2 encodes a Na+ -preferential transporter localized in the plasma membrane, which mediates shoot Na+ exclusion, likely by withdrawing Na+ from the root xylem flow. A naturally occurring nonsynonymous SNP (SNP947-G) increases the Na+ transport activity of ZmHKT1;2, promoting shoot Na+ exclusion and salt tolerance in maize. SNP947-G first occurred in the wild grass teosinte (at a allele frequency of 43%) and has become a minor allele in the maize population (allele frequency 6.1%), suggesting that SNP947-G is derived from teosinte and that the genomic region flanking SNP947 likely has undergone selection during domestication or post-domestication dispersal of maize. Moreover, we demonstrate that introgression of the SNP947-G ZmHKT1;2 allele into elite maize germplasms reduces shoot Na+ content by up to 80% and promotes salt tolerance. Taken together, ZmNC3/ZmHKT1;2 was identified as an important QTL promoting shoot Na+ exclusion, and its favourable allele provides an effective tool for developing salt-tolerant maize varieties.
Subject(s)
Salt Tolerance , Zea mays , Salt Tolerance/genetics , Zea mays/genetics , Zea mays/metabolism , Plant Proteins/genetics , Plant Proteins/metabolism , Sodium/metabolism , Alleles , Membrane Transport Proteins/metabolismABSTRACT
The focusing spatiotemporal property of a femtosecond laser pulse is presented under tight focusing conditions by using the frequency-resolved incident electric field and vector diffraction formulas with the wavefront correction term. In the ideal case, the focused laser intensity reaches its maximum at the F-number of â¼0.35 due to the strong diffraction effect under extremely tight focusing conditions. In spatio-temporal coupling distortion cases, their spatiotemporal Strehl ratios show a trend of improvement as the F-number decreases and this phenomenon is mainly concentrated along the y-direction. Based on the numerical calculation method used in this work, the precise information of tightly focused ultra-intense femtosecond laser fields can be obtained, which is crucial for assessing a focused intensity and describing the motion of charged particles under an extremely strong electric field. Moreover, the evolution law of focal fields with spatiotemporal distortions found in this paper can offer some theoretical guidance for realizing ultrahigh laser intensity in the near future.
ABSTRACT
We demonstrated a TEM00 mode orthogonal dual-slab Yb:KG(WO4)2(Yb:KGW) laser oscillator with high average power. Polarization anisotropy of thermal lenses was investigated and alleviating the astigmatism based on orthogonal dual-slab. In addition, the laser polarization was directly controlled by adjusting the net gain of the two crystals. The maximum output power was highly enhanced compared with single crystal due to effective thermal distribution. For an absorbed pump power of 52.4 W, this oscillator delivered an average power of 26.5 W, corresponding to an optical-to-optical conversion efficiency of 50.6%. Meanwhile, the ellipticity of the output laser was optimized to 0.940. Nearly diffraction-limited beam quality was measured to be M x2 = 1.19 and M y2=1.18.
ABSTRACT
We demonstrate a 417â W, 175â kHz Innoslab chirped pulse amplification laser compressible to short and clean 406â fs pulse duration. A spectral bandwidth (full width at half maximum, FWHM) of â¼3â nm was maintained at full pump power, and the pulses exhibited good pulse quality in a wide tunable pulse energy range from 1.7â mJ to a maximum of 2.38â mJ. At the maximum output power, the compressed pulses were nearly pedestal free. The comprehensive effects of residual high-order dispersion from the front end, the gain shaping effects of the amplifier, and the slight mismatch of third-order dispersion (TOD) between the stretcher (CFBG) and the gating compressor, along with the small nonlinear phase shift accumulated in the amplifier, could have facilitated the high pulse quality. To the best of our knowledge, this is the shortest pulse duration from the Innoslab amplifiers at hundreds of watts average power in the millijoule energy regime.
ABSTRACT
A high-power regenerative amplifier (RA) based on dual-slab Yb:KGd(WO4)2 (Yb:KGW) was demonstrated, which provided a maximum average power of 33.7â W at a repetition rate of 75-200â kHz before compression with a central wavelength of 1039â nm, corresponding to an optical-to-optical conversion efficiency of 51.4%. To the best of our knowledge, this is the highest average power from the Yb:KGW solid-state RA. The compressed pulse duration of 205â fs was realized under the maximum output power. By adjusting the gain of the crystals, respectively, the spectral shaping can be achieved. A combination spectrum with root-mean-square (RMS) bandwidth of 4.5â nm was generated with a central wavelength of 1035â nm at an output power of 20â W, the compressed pulse duration was 159â fs. Meanwhile, effective mitigation of thermal effects by dual-slab configuration guaranteed the nearly diffraction-limited beam quality: M x2 = 1.17 and M y2 = 1.20.