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Kindlin-2 Regulates the Oncogenic Activities of Integrins and TGF-β In Triple Negative Breast Cancer Progression and Metastasis Kindlin-2 在三阴性乳腺癌进展和转移过程中调控整合素和 TGF-β 的致癌活性
Pub Date : 2024-02-05 DOI: 10.21203/rs.3.rs-3914650/v1
Neelum Aziz Yousafzai, Lamyae El Khalki, Wei Wang, Justin Szpendyk, K. Sossey-Alaoui
Abstract Background Kindlin-2, an adaptor protein, is dysregulated in various human cancers, including triple negative breast cancer (TNBC), where it drives tumor progression and metastasis by influencing several cancer hallmarks. One well-established role of Kindlin-2 involves the regulation of integrin signaling, achieved by directly binding to the cytoplasmic tail of the integrin β subunit. In this study, we present novel insights into Kindlin-2's involvement in stabilizing the β1-Integrin:TGF-β type 1 receptor (TβRI) complexes, acting as a physical bridge that links β1-Integrin to TβRI. The loss of Kindlin-2 results in the degradation of this protein complex, leading to the inhibition of downstream oncogenic pathways. Methods Our methodology encompassed a diverse range of in vitro assays, including CRISPR/Cas9 gene editing, cell migration, 3D tumorsphere formation and invasion, solid binding, co-immunoprecipitation, cell adhesion and spreading assays, as well as western blot and flow cytometry analyses, utilizing MDA-MB-231 and 4T1 TNBC cell lines. Additionally, preclinical in vivo mouse models of TNBC tumor progression and metastasis were employed to substantiate our findings. Results The investigation revealed that the direct interaction between Kindlin-2 and β1-Integrin is mediated through the C-terminal F3 domain of Kindlin-2, while the interaction between Kindlin-2 and TβRI is facilitated through the F2 domain of Kindlin-2. Disruption of this bridge, achieved via CRISPR/Cas9-mediated knockout of Kindlin-2, led to the degradation of β1-Integrin and TβRI, resulting in the inhibition of oncogenic pathways downstream of both proteins, subsequently hindering tumor growth and metastasis. Treatment of Kindlin-2-deficient cells with the proteasome inhibitor MG-132 restored the expression of both β1-Integrin and TβRI. Furthermore, the rescue of Kindlin-2 expression reinstated their oncogenic activities both in vitro and in vivo. Conclusions This study identifies a novel function of Kindlin-2 in stabilizing the β1-Integrin:TβR1 complexes and regulating their downstream oncogenic signaling. The translational implications of these findings are substantial, potentially unveiling new therapeutically targeted pathways crucial for the treatment of TNBC tumors.
摘要 背景 Kindlin-2是一种适配蛋白,在包括三阴性乳腺癌(TNBC)在内的多种人类癌症中出现失调。Kindlin-2 的一个公认作用是通过直接与整合素 β 亚基的胞质部结合来调节整合素信号转导。在这项研究中,我们对 Kindlin-2 参与稳定 β1-Integrin:TGF-β 1 型受体(TβRI)复合物,充当连接 β1-Integrin 和 TβRI 的物理桥梁提出了新的见解。Kindlin-2 的缺失会导致该蛋白复合物降解,从而抑制下游致癌途径。研究方法 我们的研究方法涵盖了多种体外检测,包括利用 MDA-MB-231 和 4T1 TNBC 细胞系进行 CRISPR/Cas9 基因编辑、细胞迁移、三维瘤球形成和侵袭、固体结合、共免疫沉淀、细胞粘附和扩散检测,以及 Western 印迹和流式细胞术分析。此外,还采用了 TNBC 肿瘤进展和转移的临床前体内小鼠模型来证实我们的研究结果。研究结果表明,Kindlin-2 和 β1-Integrin 之间的直接相互作用是通过 Kindlin-2 的 C 端 F3 结构域介导的,而 Kindlin-2 和 TβRI 之间的相互作用是通过 Kindlin-2 的 F2 结构域促进的。通过CRISPR/Cas9介导的Kindlin-2基因敲除实现了对这一桥梁的破坏,导致了β1-Integrin和TβRI的降解,从而抑制了这两种蛋白下游的致癌通路,继而阻碍了肿瘤的生长和转移。用蛋白酶体抑制剂MG-132处理Kindlin-2缺陷细胞可恢复β1-Integrin和TβRI的表达。此外,Kindlin-2 的表达得到挽救后,它们在体外和体内的致癌活性都得到了恢复。结论 本研究发现了 Kindlin-2 在稳定 β1-Integrin:TβR1 复合物和调节其下游致癌信号转导方面的新功能。这些发现的转化意义重大,有可能揭示治疗 TNBC 肿瘤的新靶向途径。
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引用次数: 0
Somatic growth outcomes in response to an individualized neonatal sodium supplementation protocol 个体化新生儿钠补充方案的体格生长结果
Pub Date : 2024-02-05 DOI: 10.21203/rs.3.rs-3911085/v1
Lyndsay Harshman, Elliot Stalter, Silvia Verhofste, John Dagle, Emily Steinbach, P. Eyck, Linder Wendt, Jeffrey Segar
Abstract Objective Evaluate the impact of a sodium (Na) supplementation protocol based upon urine Na concentration on growth parameters and morbidities. Study Design Retrospective cohort study of infants 26 0/7 -33 6/7 weeks gestational age (GA) cared for before (2012-15, n = 225) and after (2016-20, n = 157) implementation of the protocol. Within- and between-group changes over time were assessed using repeated measures generalized linear models. Results For infants 26 0/7 -29 6/7 weeks GA, utilization of the protocol was associated with increased mean body weight z-score at 8-weeks postnatal age, increased mean head circumference z-score at 16-weeks postnatal age, and decreased time on mechanical ventilation (all p < 0.02). No impact on growth was identified for infants 30–33 6/7 weeks GA. Incidences of hypertension, hypernatremia, bronchopulmonary dysplasia, and culture positive sepsis were unaffected by the protocol. Conclusion Protocolized Na supplementation results in improved growth and reduced time on invasive mechanical ventilation in extremely preterm infants without increasing incidence of morbidities.
摘要 目的 评估基于尿液钠浓度的钠(Na)补充方案对生长参数和发病率的影响。研究设计 对该方案实施前(2012-15 年,n = 225)和实施后(2016-20 年,n = 157)孕龄为 26 0/7 -33 6/7 周的婴儿进行回顾性队列研究。使用重复测量广义线性模型评估组内和组间随时间的变化。结果 对于出生后 26 0/7 -29 6/7 周的婴儿,使用该方案与出生后 8 周平均体重 Z 值的增加、出生后 16 周平均头围 Z 值的增加以及机械通气时间的减少有关(均 p < 0.02)。对于出生后 30-33 6/7 周的婴儿,未发现对生长有任何影响。该方案对高血压、高钠血症、支气管肺发育不良和败血症培养阳性的发生率没有影响。结论 对极度早产儿按方案补充钠可改善其生长发育并缩短其接受有创机械通气的时间,同时不会增加发病率。
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引用次数: 0
Comparing methods for risk prediction of multicategory outcomes: dichotomized logistic regression vs. multinomial logit regression 多类别结果风险预测方法比较:二分法逻辑回归与多项式逻辑回归
Pub Date : 2024-02-05 DOI: 10.21203/rs.3.rs-3911212/v1
lei li, Matthew A. Rysavy, G. Bobashev, Abhik Das
Abstract Background Medical outcomes of interest to clinicians may have multiple categories. Researchers face several options for risk prediction of such outcomes, including dichotomized logistic regression and multinomial logit regression modeling. We aimed to compare these methods and provide practical guidance needed. Methods We described dichotomized logistic regression and competing risks regression, and an alternative to standard multinomial logit regression, continuation-ratio logit regression for ordinal outcomes. We then applied these methods to develop prediction models of survival and growth outcomes based on the NICHD Extremely Preterm Birth Outcome Tool model. The statistical and practical advantages and flaws of these methods were examined and both discrimination and calibration of the estimated models were assessed. Results The dichotomized logistic models and multinomial continuation-ratio logit model had similar discrimination and calibration in predicting death and survival without neurodevelopmental impairment. But the continuation-ratio logit model had better discrimination and calibration in predicting probabilities of neurodevelopmental impairment. The sum of predicted probabilities of outcome categories from the logistic models did not equal 100% for about half of the study infants, ranging from 87.7% to 124.0%, and the logistic model of neurodevelopmental impairment greatly overpredicted the risk among low-risk infants and underpredicted among high-risk infants. Conclusions Estimating multiple logistic regression models of dichotomized outcomes may result in poorly calibrated predictions. For an outcome with multiple ordinal categories, continuation-ratio logit regression is a useful alternative to standard multinomial logit regression. It produces better calibrated predictions and has the advantages of simplicity in model interpretation and flexibility to include outcome category-specific predictors and random-effect terms for patient heterogeneity by hospital.
摘要 背景 临床医生感兴趣的医疗结果可能有多个类别。研究人员面临着对此类结果进行风险预测的几种选择,包括二分法逻辑回归和多项式逻辑回归模型。我们旨在对这些方法进行比较,并提供所需的实用指导。方法 我们介绍了二分法 logistic 回归和竞争风险回归,以及标准多叉 logit 回归的替代方法,即用于序数结果的延续比 logit 回归。然后,我们应用这些方法开发了基于 NICHD 极早产儿结局工具模型的生存和生长结局预测模型。我们考察了这些方法在统计学和实用性方面的优势和缺陷,并对估计模型的区分度和校准进行了评估。结果 在预测无神经发育障碍的死亡和存活率方面,二分法逻辑模型和多项式连续比对数模型具有相似的区分度和校准性。但连续比对数模型在预测神经发育障碍概率方面具有更好的区分度和校准性。在约一半的研究婴儿中,逻辑模型预测的结果类别概率之和不等于100%,从87.7%到124.0%不等,神经发育障碍的逻辑模型大大高估了低风险婴儿的风险,而低估了高风险婴儿的风险。结论 对二分法结果的多重逻辑回归模型进行估计可能会导致预测校准不良。对于具有多个序数类别的结果,延续比率 logit 回归是标准多二项 logit 回归的有效替代方法。它能得出更好的校准预测结果,而且具有模型解释简单、灵活性强等优点,可纳入结果类别特异性预测因子和随机效应项,以反映各医院患者的异质性。
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引用次数: 0
Repurposing mebendazole against triple-negative breast cancer leptomeningeal disease 将甲苯咪唑重新用于治疗三阴性乳腺癌脑膜疾病
Pub Date : 2024-02-05 DOI: 10.21203/rs.3.rs-3915392/v1
Adrian Rodrigues, Sophia B. Chernikova, Yuelong Wang, Thy T. H. Trinh, D. Solow-Cordero, Ludmila Alexandrova, Kerriann M. Casey, Elizabeth Alli, Abhishek Aggarwal, Tyler Quill, Ashley Koegel, Brian J. Feldman, James M. Ford, M. Hayden-Gephart
Abstract Purpose Triple-negative breast cancer (TNBC) is an aggressive subtype that often metastasizes to the brain. Leptomeningeal disease (LMD), a devastating brain metastasis common in TNBC, has limited treatment options. We sought to test whether the common anti-helminthic drug mebendazole (MBZ) may be effective against murine TNBC LMD. Methods A small-molecule screen involving TNBC cell lines identified benzimidazoles as potential therapeutic agents for further study. In vitro migration assays were used to evaluate cell migration capacity and the effect of MBZ. For in vivo testing, LMD was introduced into BALB/c athymic nude mice through internal carotid artery injections of brain-tropic MDA-MB-231-BR or MCF7-BR cells. Tumor growth and spread was monitored by bioluminescence imaging. MBZ was given orally at 50 and 100 mg/kg doses. MBZ bioavailability was assayed by mass spectrometry. Results Bioinformatic analysis and migration assays revealed higher migratory capacity of TNBC compared to other breast cancer subtypes. MBZ effectively slowed down migration of TNBC cell line MDA-MB-231 and its brain tropic derivative MDA-MB-231-BR. In animal studies, MBZ reduced tumor growth and extended survival in the LMD model produced by MDA-MB-231-BR cells. MBZ did not have an effect in the non-migratory MCF7-BR model. Conclusions We demonstrated that MBZ is a safe and effective oral agent in an animal model of TNBC LMD. Our findings are concordant with previous efforts involving MBZ and central nervous system pathology and further support the drug’s potential utility as an alternative therapeutic for TNBC LMD.
摘要 目的 三阴性乳腺癌(TNBC)是一种侵袭性很强的亚型癌症,经常转移到脑部。脑转移瘤(LMD)是 TNBC 常见的一种破坏性脑转移瘤,但其治疗方案有限。我们试图测试常见的抗蠕虫药物甲苯咪唑(MBZ)是否对小鼠 TNBC LMD 有效。方法 通过对 TNBC 细胞系进行小分子筛选,发现苯并咪唑类药物具有进一步研究的潜力。体外迁移试验用于评估细胞迁移能力和 MBZ 的作用。在体内测试中,通过颈内动脉注射致脑MDA-MB-231-BR或MCF7-BR细胞,将LMD引入BALB/c无胸腺裸鼠体内。通过生物发光成像监测肿瘤的生长和扩散。口服 MBZ 的剂量为 50 和 100 毫克/千克。通过质谱法检测 MBZ 的生物利用度。结果 生物信息分析和迁移试验显示,与其他乳腺癌亚型相比,TNBC 的迁移能力更强。MBZ 能有效减缓 TNBC 细胞系 MDA-MB-231 及其脑滋养衍生物 MDA-MB-231-BR 的迁移。在动物实验中,MBZ 在 MDA-MB-231-BR 细胞产生的 LMD 模型中减少了肿瘤生长,延长了存活时间。MBZ 对非迁移性 MCF7-BR 模型没有影响。结论 我们证明,在 TNBC LMD 动物模型中,MBZ 是一种安全有效的口服药物。我们的研究结果与之前涉及 MBZ 和中枢神经系统病理学的研究结果一致,并进一步支持了该药物作为 TNBC LMD 替代疗法的潜在用途。
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引用次数: 0
Epidemiology of unintentional injuries among 15-24-year-old vocational school youth from Peshawar Pakistan: A cross-sectional survey. 巴基斯坦白沙瓦青年(15-24岁)自我报告的意外伤害:对在职业学院工作的青年的横断面调查。
Pub Date : 2024-01-31 DOI: 10.21203/rs.3.rs-2603081/v1
Sarwat Masud, Adnan A Hyder, Uzma Rahim Khan, Nadeem Ullah Khan, Ahmed Raheem, Pammla Petrucka

Background: The burden of unintentional injuries among youth (15-24 years) is high. There is paucity of data on unintentional injuries in youth working in Vocational Training Institutes.

Objective: To determine the incidence, characteristics, and risk factors of unintentional injuries among youth.

Methods: Design:: A retrospective cross-sectional survey was conducted among select vocational school youth in Peshawar, Pakistan between February 2022 to October 2022.Participants:: A total of 547 study participants participated in the survey, 356 were males while 191 were females. Data were collected on using the World Health Organization community survey guide for injuries and violence. Multilevel Negative Binomial Regression model was used to report incidence rate ratios of all unitentional injuries.

Results: A total of 503 injuries were reported by the youth, with road traffic injuries being the most common (n=197, 39%), followed by burns (n=89, 18%), falls (n=79, 16%) and poisonings (n=15, 3%), drownings (n=23, 7.1%). Occupational injuries reported during vocational training were (n=95, 18%). Males had a higher incidence rates of RTI 3.24[2.35-5.3], falls 1.30 [0.74-2.27], poisonings 2.14 [0.57-7.58] and drownings 2.46(0.84-7.21), while females had a higher incidence rate of burns 2.19 [1.785-3.46].Lack of education 4.6 [1.12 -18.91] (p=0.034), smoking 1.25 [1.05 -2.69] (p=0.049), lack of fathers education 4.71 [2.12 -10.49] (p=<0.001), carrying a gun 6.59 [2.54 -17.11] (p=<0.001), crowded families 3.59 [3.11 -5.07] (p=<0.001), lower family income 2.04 [1.04 -4.02](p=0.039*), lack of helmet use 4.54 [2.12 -9.76] (p=<0.001) and lack of seat belt use 1.3 [1.14 -1.69] (p= <0.001) were significant risk factors for unintentional injuries in youth.

Conclusion added value of the study: This study is one of the first research studies conducted in vocational school youth in Pakistan. It provides the recent rate of unintentional injuries among the youth of Pakistan. High occupational injuries among vocational school youth were reported which needs further research.

背景:15-24岁青年的意外伤害负担很高。关于职业培训机构工作的青少年意外伤害的数据很少。目的:确定青少年自我报告的非致命性意外伤害的发生率、特征和危险因素。方法:设计:这是一项对2022年2月至2022年10月期间从巴基斯坦白沙瓦职业培训中心招募的年轻人的回顾性横断面调查。参与者:共有547名研究参与者,其中356名男性,191名女性。使用世界卫生组织伤害和暴力工具收集了过去12个月内自我报告的意外伤害数据[1]。使用多水平负二项回归模型对总伤害作为结果和社会人口统计学风险因素进行分析,并根据年龄和性别进行调整。结果:我们总共记录了503起伤害,其中道路交通伤害最常见(n=197,39%),其次是烧伤(n=89,18%)和跌倒(n=79,16%)。中毒(n=13%)和溺水(n=23,7.1%)是最不常见的伤害。在训练中报告的职业伤害为(n=95.18%)。女性的烧伤发生率比男性高2.19[1.785-3.46],而男性的RTI发生率更高3.24[2.35-5.3],跌倒1.30[0.74-2.27],中毒2.14[0.57-7.58],溺水2.46(0.84-7.21)。缺乏教育4.6[1.12-18.91](p=0.034),缺乏头盔4.54[2.12-9.76](p=0.049),缺乏父亲教育4.71[2.12-10.49](p=0.039*)是青少年意外伤害的重要危险因素。结论本研究的附加值:本研究提供了巴基斯坦白沙瓦青年意外伤害的最新统计和发生率。它还提供了经性别调整后的青少年意外伤害类型的最新趋势。令人关切的领域仍然是,男性和女性的RTI数量都在增加,女性的烧伤率高于男性,年轻人的烧伤率下降。据报告,职业青年在培训中职业伤害的发生率很高。
{"title":"Epidemiology of unintentional injuries among 15-24-year-old vocational school youth from Peshawar Pakistan: A cross-sectional survey.","authors":"Sarwat Masud, Adnan A Hyder, Uzma Rahim Khan, Nadeem Ullah Khan, Ahmed Raheem, Pammla Petrucka","doi":"10.21203/rs.3.rs-2603081/v1","DOIUrl":"10.21203/rs.3.rs-2603081/v1","url":null,"abstract":"<p><strong>Background: </strong>The burden of unintentional injuries among youth (15-24 years) is high. There is paucity of data on unintentional injuries in youth working in Vocational Training Institutes.</p><p><strong>Objective: </strong>To determine the incidence, characteristics, and risk factors of unintentional injuries among youth.</p><p><strong>Methods: </strong><b>Design::</b> <b>A</b> retrospective cross-sectional survey was conducted among select vocational school youth in Peshawar, Pakistan between February 2022 to October 2022.<b>Participants::</b> A total of 547 study participants participated in the survey, 356 were males while 191 were females. Data were collected on using the World Health Organization community survey guide for injuries and violence. Multilevel Negative Binomial Regression model was used to report incidence rate ratios of all unitentional injuries.</p><p><strong>Results: </strong><b>A</b> total of 503 injuries were reported by the youth, with road traffic injuries being the most common (n=197, 39%), followed by burns (n=89, 18%), falls (n=79, 16%) and poisonings (n=15, 3%), drownings (n=23, 7.1%). Occupational injuries reported during vocational training were (n=95, 18%). Males had a higher incidence rates of RTI 3.24[2.35-5.3], falls 1.30 [0.74-2.27], poisonings 2.14 [0.57-7.58] and drownings 2.46(0.84-7.21), while females had a higher incidence rate of burns 2.19 [1.785-3.46].Lack of education 4.6 [1.12 -18.91] (<i>p</i>=0.034), smoking 1.25 [1.05 -2.69] (<i>p</i>=0.049), lack of fathers education 4.71 [2.12 -10.49] (<i>p</i>=<0.001), carrying a gun 6.59 [2.54 -17.11] (<i>p</i>=<0.001), crowded families 3.59 [3.11 -5.07] (<i>p</i>=<0.001), lower family income 2.04 [1.04 -4.02](<i>p</i>=0.039*), lack of helmet use 4.54 [2.12 -9.76] (<i>p</i>=<0.001) and lack of seat belt use 1.3 [1.14 -1.69] <i>(p=</i> <0.001) were significant risk factors for unintentional injuries in youth.</p><p><strong>Conclusion added value of the study: </strong>This study is one of the first research studies conducted in vocational school youth in Pakistan. It provides the recent rate of unintentional injuries among the youth of Pakistan. High occupational injuries among vocational school youth were reported which needs further research.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10029088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9186958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Migrate3D: Software for simplified post-tracking analysis of 3D and 2D cell migration data. Migrate3D:用于简化三维和二维细胞迁移数据跟踪后分析的软件。
Pub Date : 2024-01-18 DOI: 10.21203/rs.3.rs-2451513/v1
Emily R Mynar, Matthew W Kinahan, Markus Thali, Menelaos Symeonides

Migrate3D is a cell migration analysis tool whose purpose is to computationally process positional cell tracking data generated via other image acquisition/analysis software and generate biologically meaningful results. The functionalities of Migrate3D include step-based calculations of each cell track, single-cell-level summary statistics, mean squared displacement analysis, and machine learning-based evaluation of the entire dataset and subpopulations of cells found within it. The parameters calculated within Migrate3D have been previously developed and validated by other groups, and were selected to facilitate extraction of the maximum depth of information possible from input datasets. Variables are user-adjustable to enable customized analyses of diverse motility patterns and cell types, both in three-and two-dimensional timelapse data. Independent of any particular upstream image analysis or cell tracking software, Migrate3D only needs positional data over time to execute the suite of calculations. This presents a unique opportunity to standardize and streamline cell migration analysis.

Migrate3D是一种细胞迁移分析工具,其目的是计算处理通过其他图像采集/分析软件生成的位置细胞跟踪数据,并生成具有生物学意义的结果。Migrate3D的功能包括对每个细胞轨迹进行基于步长的计算、单细胞水平的汇总统计、均方位移分析,以及对整个数据集和其中发现的细胞亚群进行基于机器学习的评估。Migrate3D中计算的参数先前已由其他小组开发和验证,并且被选择以便于从输入数据集中提取可能的最大信息深度。变量是用户可调节的,可以在三维和二维延时数据中对不同的运动模式和细胞类型进行定制分析。与任何特定的上游图像分析或细胞跟踪软件无关,Migrate3D只需要随时间推移的位置数据即可执行一套计算。这为标准化和简化细胞迁移分析提供了一个独特的机会。
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引用次数: 0
[WITHDRAWN] Serum biomarkers of liver fibrosis identify changes in striatal metabolite levels. 肝纤维化的血清生物标志物可识别纹状体代谢物水平的变化。
Pub Date : 2024-01-15 DOI: 10.21203/rs.3.rs-2729490/v1

The full text of this preprint has been withdrawn by the authors due to author disagreement with the posting of the preprint. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.

在肝硬化中进行的1H磁共振波谱(MRS)显示出一致的CNS变化,例如谷氨酸(Glu)+谷氨酰胺(Gln)的组合共振(Glx)的高水平以及相对于总肌酸(tCr)的含胆碱化合物(Cho)和肌肌醇(mI)的低水平。然而,丙型肝炎病毒(HCV)感染的研究发现,tCr、Cho和mI的水平高于对照组。在这里,评估了肝纤维化的血清标志物,以确定它们是否会区分纹状体、小脑和脑桥中的神经代谢产物。天冬氨酸氨基转移酶与血小板比值指数(APRI)>0.7在9.0%(n=13)的队列中发现肝纤维化;纤维化评分(FIB4)>1.5在32.4%(n=34)的人群中确定了肝纤维化。APRI>0.7的患者纹状体tCr(p=0.001)和Cho(p=0.003)水平较高。同样,FIB>1.5的患者纹状体Cho水平较高(p=0.01)。包括变量APRI>0.7HCV在内的多元回归解释了16.5%的纹状体Cho方差,并由APRI驱动。同样地,FIB4相对于HCV解释了纹状体Cho的更多变化。较高的纹状体Cho水平与苍白球信号强度呈正相关(r=.18,p=.04)。此外,较高的苍白球T1信号与闭眼时更大的站立平衡不稳定性有关(r=-22,p=.008),这些结果表明,纹状体Cho和基底节T1信号强度的升高与肝纤维化的存在和功能后果有关。
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引用次数: 0
A week in the life of the human brain: stable states punctuated by chaotic transitions. 人类大脑生命中的一周:稳定的状态被混乱的过渡所打断。
Pub Date : 2024-01-15 DOI: 10.21203/rs.3.rs-2752903/v1
Maxwell Wang, Max G'Sell, James F Castellano, R Mark Richardson, Avniel Ghuman

Many important neurocognitive states, such as performing natural activities and fluctuations of arousal, shift over minutes-to-hours in the real-world. We harnessed 3-12 days of continuous multi-electrode intracranial recordings in twenty humans during natural behavior (socializing, using digital devices, sleeping, etc.) to study real-world neurodynamics. Applying deep learning with dynamical systems approaches revealed that brain networks formed consistent stable states that predicted behavior and physiology. Changes in behavior were associated with bursts of rapid neural fluctuations where brain networks chaotically explored many configurations before settling into new states. These trajectories traversed an hourglass-shaped structure anchored around a set of networks that slowly tracked levels of outward awareness related to wake-sleep stages, and a central attractor corresponding to default mode network activation. These findings indicate ways our brains use rapid, chaotic transitions that coalesce into neurocognitive states slowly fluctuating around a stabilizing central equilibrium to balance flexibility and stability during real-world behavior.

在现实世界中,许多重要的神经认知状态,如与进行自然活动和觉醒波动有关的状态,会在几分钟到几天内发生变化。我们分析了20名参与者3-12天的连续颅内记录,这些参与者自由社交、使用数字设备、睡觉等,以了解神经动力学是如何随着行为形成和变化的。大脑网络形成了稳定的状态,可以预测行为和生理。行为变化与神经的快速波动有关,在进入新状态之前,大脑网络混乱地探索了许多配置。这些轨迹穿过沙漏状结构,清醒和睡眠处于相反的两端,中间是由默认模式网络激活表示的吸引子状态。这些发现说明了我们的大脑如何平衡稳定性和灵活性来产生真实世界的行为。
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引用次数: 0
The Planetary Child Health & Enterics Observatory (Plan-EO): a protocol for an interdisciplinary research initiative and web-based dashboard for mapping enteric infectious diseases and their risk factors and interventions in LMICs. 行星儿童健康和肠道观察站(Plan EO):低收入和中等收入国家肠道传染病及其风险因素和干预措施的跨学科研究倡议和基于网络的气候知情图谱的协议。
Pub Date : 2024-01-10 DOI: 10.21203/rs.3.rs-2640564/v3
Josh M Colston, Pavel Chernyavskiy, Lauren Gardner, Malena Nong, Bin Fang, Eric Houpt, Samarth Swarup, Hamada Badr, Benjamin Zaitchik, Venkataraman Lakshmi, Margaret Kosek

Background: Diarrhea remains a leading cause of childhood illness throughout the world that is increasing due to climate change and is caused by various species of ecologically sensitive pathogens. The emerging Planetary Health movement emphasizes the interdependence of human health with natural systems, and much of its focus has been on infectious diseases and their interactions with environmental and human processes. Meanwhile, the era of big data has engendered a public appetite for interactive web-based dashboards for infectious diseases. However, enteric infectious diseases have been largely overlooked by these developments.

Methods: The Planetary Child Health and Enterics Observatory (Plan-EO) is a new initiative that builds on existing partnerships between epidemiologists, climatologists, bioinformaticians, and hydrologists as well as investigators in numerous low- and middle-income countries. Its objective is to provide the research and stakeholder community with an evidence base for the geographical targeting of enteropathogen-specific child health interventions such as novel vaccines. The initiative will produce, curate, and disseminate spatial data products relating to the distribution of enteric pathogens and their environmental and sociodemographic determinants.

Discussion: As climate change accelerates there is an urgent need for etiology-specific estimates of diarrheal disease burden at high spatiotemporal resolution. Plan-EO aims to address key challenges and knowledge gaps by making rigorously obtained, generalizable disease burden estimates freely available and accessible to the research and stakeholder communities. Pre-processed environmental and EO-derived spatial data products will be housed, continually updated, and made publicly available to the research and stakeholder communities both within the webpage itself and for download. These inputs can then be used to identify and target priority populations living in transmission hotspots and for decision-making, scenario-planning, and disease burden projection.

Study registration: PROSPERO protocol #CRD42023384709.

背景:腹泻仍然是世界各地儿童疾病的主要原因,由各种生态敏感病原体引起。新兴的行星健康运动强调人类健康与自然系统的相互依存性,其重点一直放在传染病及其与环境和人类过程的相互作用上。与此同时,大数据时代激发了公众对传染病交互式网络仪表盘的兴趣。然而,肠道传染病在很大程度上被这些发展所忽视。方法:行星儿童健康和娱乐观察站(Plan EO)是一项新举措,建立在许多中低收入国家的流行病学家、气候学家、生物信息学家、水文学家以及研究人员之间现有的伙伴关系基础上。其目的是为研究和利益相关者群体提供一个证据基础,以确定肠道病原体特异性儿童健康干预措施(如新型疫苗)的地理目标。该倡议将制作、策划和传播与肠道病原体分布及其环境和社会人口决定因素有关的空间数据产品。讨论:随着气候变化的加速,迫切需要以高时空分辨率对腹泻疾病负担进行病因特异性估计。EO计划旨在通过向研究和利益相关者社区免费提供严格获得的、可推广的疾病负担估计,来解决关键挑战和知识差距。预处理的环境和地球观测衍生的空间数据产品将被容纳、不断更新,并在网页内和下载时向研究和利益相关者社区公开。然后,这些输入可用于识别和针对生活在传播热点地区的优先人群,并用于决策、情景规划和疾病负担预测。研究注册:PROSPERO方案编号CRD42023384709。
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引用次数: 0
FAK loss reduces BRAFV600E-induced ERK phosphorylation to promote intestinal stemness and cecal tumor formation. FAK缺失可减少BRAFV600E诱导的ERK磷酸化,从而促进肠道干性和盲肠肿瘤的形成。
Pub Date : 2024-01-05 DOI: 10.21203/rs.3.rs-2531119/v2
Chenxi Gao, Huaibin Ge, Shih-Fan Kuan, Chunhui Cai, Xinghua Lu, Farzad Esni, Robert Schoen, Jing Wang, Edward Chu, Jing Hu

BRAF V600E mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAFV600E drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a "just-right" level optimal for tumorigenesis remains undetermined. In this study, we found that FAK (Focal adhesion kinase) expression was reduced in BRAFV600E-mutant adenomas/polyps in mice and patients. In Vill-Cre;BRAFV600E/+;Fakfl/fl mice, Fak deletion maximized BRAFV600E's oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAFV600E-induced ERK pathway transcriptional output, reduced EGFR (epidermal growth factor receptor)-dependent ERK phosphorylation. Reduction in ERK phosphorylation increased the level of Lgr4, promoting intestinal stemness and cecal tumor formation. Our findings show that a "just-right" ERK signaling optimal for BRAFV600E-induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation.

BRAF V600E 突变是导致结直肠癌的锯齿状通路中的驱动突变。BRAF V600E通过构成性下游细胞外信号调节激酶(ERK)激活驱动肿瘤发生,但高强度的ERK激活也会引发肿瘤抑制。致癌ERK信号是否以及如何在本质上调整到 "恰到好处 "的最适合肿瘤发生的水平仍未确定。在这项研究中,我们发现在小鼠和患者的 BRAF V600E 突变腺瘤/息肉中,FAK(病灶粘附激酶)的表达减少。在Vill-Cre ; BRAF V600E/+ ; Fak fl/fl小鼠中,Fak缺失可最大限度地提高BRAF V600E的致癌活性,并使盲肠肿瘤发病率上升至100%。从机理上讲,我们的研究结果表明,Fak缺失在不损害BRAF V600E诱导的ERK通路转录输出的情况下,降低了表皮生长因子受体(EGFR)依赖的ERK磷酸化。ERK磷酸化的降低提高了Lgr4的水平,促进了肠道干性和盲肠肿瘤的形成。我们的研究结果表明,通过Fak缺失介导的ERK磷酸化下调,可以为BRAF V600E诱导的盲肠肿瘤形成提供 "恰到好处 "的最佳ERK信号。
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