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Hypothetical Earlier Dating for The Passionate Pilgrim and First Folio

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Journal of Literature and Art Studies 2014年第11期4卷 916-940页

作者： W. Ron Hess johns hopkins university graduate extension center

Did part or all of Shakespeare＇s The Passionate Pilgrim （TPP） actually predate 1593 Venus ＆ Adonis （V＆A） and 1594 Rape ofLuereee （RofL）？ Oddly enough, that may be the case, because the sole extant copy of its first edition has no title page, thus no date. Copies of its second edition do have a title page and are clearly dated 1599, plus a 1612 augmented project was marked ＂third edition＂. Thus, it should be significant that some of TPP＇s poetry have been found in manuscript or early publications back to the early 1590s, and in one case perhaps as early as 1585. But TPP may be a relic of a much larger anthology of poetry which possibly existed in manuscript circa 1589-94, was revised circa 1610-12 to accompany an intended publication of all of Shakespeare＇s works （poetry and drama）, but was not fully published until nearly three decades later. It is also notable that the 1640 anthology attributed to Shakespeare contained TPP plus lengthy poetic paraphrases from Ovid in much the same mold as V＆A and RofL. Moreover, the 1640 anthology may hold a key to radically earlier dating of the 1623 First Folio （F1）. We will briefly delve into the murky world of the Elizabethan publishing world of the 1580s and beyond, wherein the 17th Earl of Oxford＇s former servant, Anthony Munday, may have had an important role in the disposition of each ＂Shake-speare＂ work.

关键词： Shakespeare Passionate Pilgrim First Folio 1640 Poems Thomas Heywood William JaggardLeonard Digges Anthony Munday

A literature review of genetics and epigenetics of HCV-related hepatocellular carcinoma: translational impact

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Hepatobiliary Surgery and Nutrition 2024年第4期13卷 650-661页

作者： Ziyan Pan Wai-Kay Seto Chun-Jen Liu Yilei Mao Saleh A.Alqahtani Mohammed Eslam Storr Liver Centre Westmead Institute for Medical ResearchWestmead Hospital and University of SydneySydneyNSWAustralia Department of Medicine The University of Hong KongHong KongChina State Key Laboratory of Liver Research The University of Hong KongHong KongChina Department of Internal Medicine National Taiwan University HospitalTaipei Hepatitis Research center National Taiwan University HospitalTaipei graduate Institute of Clinical Medicine National Taiwan University College of MedicineTaipei Department of Liver Surgery Peking Union Medical College(PUMC)HospitalPUMC&Chinese Academy of Medical SciencesBeijingChina Organ Transplant center of Excellence King Faisal Specialist Hospital&Research CenterRiyadhSaudi Arabia Division of Gastroenterology&Hepatology Johns Hopkins UniversityBaltimoreMDUSA

Background and Objective:Hepatocellular carcinoma(HCC)poses a significant global health burden and ranks as the fifth most prevalent cancer on a global *** C virus(HCV)infection remains one of the major risk factors for HCC *** is a heterogeneous disease,and the development of HCC caused by HCV is intricate and involves various factors,including genetic susceptibility,viral factors,immune response due to chronic inflammation,alcohol abuse,and metabolic dysfunction associated with fatty liver *** this review,we provide a comprehensive and updated review of research on the genetics and epigenetic mechanisms implicated in developing HCC associated with HCV *** also discuss the potential translational implications,including novel biomarkers and drugs for ***:A comprehensive literature search was conducted in June 2023 in PubMed and Embase *** Content and Findings:Recent findings indicate that a variety of genetic and epigenetic processes are involved in the pathogenesis and continue to exist even after the complete elimination of *** deregulation of the epigenome has been identified as a significant factor in the deletrious effects of liver disease,especially during the initial stages when genetic alterations are *** enduring“epigenetic memory”of gene expression is believed to be regulated by epigenetic mechanisms,indicating that alterations caused by HCV infection continue to exist and are linked to the risk of development of liver cancer even after successful *** biology analytical methods will be required to delineate the magnitude and significance of both genetic and epigenomic alterations in tumor ***:By facilitating a more profound understanding of these aspects,this will ultimately foster the advancement of novel therapies and ultimately improve outcomes for patients.

关键词： Epigenetics genetics hepatitis C virus-related hepatocellular carcinoma(HCV-related HCC) translational implications

Pancreatic cancer cells render tumor-associated macrophages metabolically reprogrammed by a GARP and DNA methylation-mediated mechanism

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Signal Transduction and Targeted Therapy 2021年第11期6卷 3348-3365页

作者： Mengwen Zhang Xingyi Pan Kenji Fujiwara Noelle Jurcak Stephen Muth Jiaojiao Zhou Qian Xiao Anqi Li Xu Che Zihai Li Lei Zheng Department of Oncology Johns Hopkins University School of MedicineBaltimoreMD21287USA The Sidney Kimmel Cancer center Johns Hopkins University School of MedicineBaltimoreMD21287USA The Pancreatic Cancer Precision Medicine center of Excellence Program Johns Hopkins University School of MedicineBaltimoreMD21287USA The Cellular and Molecular Medicine graduate Program Johns Hopkins University School of MedicineBaltimoreMD21287USA Pelotonia Institute for Immune-Oncology The Ohio State University Comprehensive Cancer CenterColumbusOH43210USA Department of Surgery Johns Hopkins University School of MedicineBaltimoreMD21287USA The Second Affiliated Hospital Zhejiang University School of MedicineHangzhouChina Department of Surgery Sada HospitalFukuokaJapan Cancer Hospital Chinese Academy of Medical SciencesShenzhenChina

How tumor-associated macrophages transit from a predominant antitumor M1-like phenotype to a protumoral M2-like phenotype during the development of pancreatic ductal adenocarcinoma (PDA) remains to be elucidated. We thus conducted a study by employing a PDA-macrophage co-culture system, an “orthotopic” PDA syngeneic mouse model, and human PDA specimens, together with macrophages derived from GARP knockout mice and multiple analytic tools including whole-genome RNA sequencing, DNA methylation arrays, multiplex immunohistochemistry, metabolism measurement, and invasion/metastasis assessment. Our study showed that PDA tumor cells, through direct cell–cell contact, induce DNA methylation and downregulation of a panel of glucose metabolism and OXPHOS genes selectively in M1-like macrophages, leading to a suppressed glucose metabolic status in M1-like but not in M2-like macrophages. Following the interaction with PDA tumor cells, M1-like macrophages are reprogrammed phenotypically to M2-like macrophages. The interaction between M1-like macrophages and PDA cells is mediated by GARP and integrin αV/β8, respectively. Blocking either GARP or integrin would suppress tumor-induced DNA methylation in Nqo-1 gene and the reprogramming of M1-like macrophages. Glucose-response genes such as Il-10 are subsequently activated in tumor-educated M1-like macrophages. Partly through Il-10 and its receptor Il-10R on tumor cells, M1-like macrophages functionally acquire a pro-cancerous capability. Both exogenous M1-like and M2-like macrophages promote metastasis in a mouse model of PDA while such a role of M1-like macrophages is dependent on DNA methylation. Our results suggest that PDA cells are able to reprogram M1-like macrophages metabolically and functionally through a GARP-dependent and DNA methylation-mediated mechanism to adopt a pro-cancerous fate.

关键词： metabolism metastasis mediated

Differences in clinicopathological characteristics between lipohypertrophy and localized insulin-derived amyloidosis:A scoping review

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Chronic Diseases and Translational Medicine 2024年第1期10卷 22-30页

作者： Kanae Mukai Hiromasa Tanno Junko Sugama Toshihiko Yanagita Emi Kanno Department of Clinical Nursing Faculty ofHealth SciencesInstitute of MedicalPharmaceutical and Health SciencesKanazawa UniversityKanazawaJapan Department of Translational Science forNursing Tohoku University Graduate School ofMedicineSendaiJapan Research center for Implementation NursingScience Initiative School of Health SciencesFujita Health UniversityToyoakeJapan Department of Clinical Pharmacology Schoolof NursingUniversity of MiyazakiMiyazakiJapan

Insulin is used as a therapeutic agent in patients with diabetes,and cutaneous lipohypertrophy(LH)and localized insulin-derived amyloidosis(LIDA)are well-known adverse effects associated with insulin *** clinical implications,management,assessment methods,and pathological differentiation of LH and LIDA have been recently *** review was to update our knowledge of the pathological differentiation,effects of insulin absorption,hypoglycemic events,and recent assessment methods for LH and LIDA.A scoping review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses extension for Scoping Reviews *** studies and case reports in English were also *** and Scopus databases were searched for keywords to identify papers published up to January 2022.A total of 113 studies were identified through a database search,and 31 were eligible for inclusion in this scoping *** the 31 studies included in this review,patients with type 2 diabetes had high frequencies of LH and *** outcome parameters were assessed using pathological findings and *** is mainly determined by pathological methods,such as hematoxylin and eosin and Congo red *** in vitro and in vivo LIDA models of LIDA have been *** results suggest that pathological analysis is required to identify LH and *** is important to consider LIDA,as it likely influences insulin adsorption and glycemic *** several studies have evaluated the LIDA process,little is known about the mechanisms underlying the development of adverse effects associated with insulin injections.

关键词： diabetes mellitus insulin injection lipohypertrophy localized insulin-derived amyloidosis

Genetic and epigenetic dependencies in colorectal cancer development

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Gastroenterology Report 2022年第1期10卷 115-131页

作者： Sehej Parmar Hariharan Easwaran Cancer Genetics and Epigenetics OncologySidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreMDUSA

Recent studies have mapped key genetic changes in colorectal cancer(CRC)that impact important pathways contributing to the multistep models for CRC initiation and *** parallel with genetic changes,normal and cancer tissues harbor epigenetic alterations impacting regulation of critical genes that have been shown to play profound roles in the tumor ***,these molecular changes are only loosely associated with heterogenous transcriptional programs,reflecting the heterogeneity in the various CRC molecular subtypes and the paths to CRC *** from mapping molecular alterations in early CRC lesions and use of experimental models suggest that the intricate dependencies of various genetic and epigenetic hits shape the early development of CRC via different pathways and its manifestation into various CRC *** highlight the dependency of epigenetic and genetic changes in driving CRC development and discuss factors affecting epigenetic alterations over time and,by extension,risk for cancer.

关键词： colorectal cancer epigenetics aging classification subtyping DNA methylation consensus molecular subtypes

Testing the rate isomorphy hypothesis using five statistical methods

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Insect Science 2012年第1期19卷 121-128页

作者： Xian-Ju Kuang Megha N.Parajulee Pei-Jian Shi Feng Ge Fang-Sen Xue Institute of Entomology Jiangxi Agricultural UniversityNanchangChina Texas A&M AgriLife Research and extension center Lubbock TexasUSA Institute of Zoology Chinese Academy of SciencesBeijing graduate university of Chinese Academy of Sciences Beijing China

Organisms are said to be in developmental rate isomorphy when the pro- portions of developmental stage durations are unaffected by temperature. Comprehensive stage-specific developmental data were generated on the cabbage beetle, Colaphellus bowringi Baly （Coleoptera： Chrysomelidae）, at eight temperatures ranging from 16℃ to 30℃ （in 2℃ increments） and five analytical methods were used to test the rate isomor- phy hypothesis, including：（i） direct comparison of lower developmental thresholds with standard errors based on the traditional linear equation describing developmental rate as the linear function of temperature; （ii） analysis of covariance to compare the lower devel- opmental thresholds of different stages based on the Ikemoto-Takai linear equation; （iii） testing the significance of the slope item in the regression line of arcsin（√p） versus tem- perature, where p is the ratio of the developmental duration of a particular developmental stage to the entire pre-imaginal developmental duration for one insect or mite species; （iv） analysis of variance to test for significant differences between the ratios of developmental stage durations to that ofpre-imaginal development; and （v） checking whether there is an element less than a given level of significance in the p-value matrix of rotating regres- sion line. The results revealed no significant difference among the lower developmental thresholds or among the aforementioned ratios, and thus convincingly confirmed the rate isomorphy hypothesis.

关键词： analysis ofcovariance lower developmental threshold rate isomorphy sum of effective temperatures temperature

Mechanically induced Ca^(2+) oscillations in osteocytes release extracellular vesicles and enhance bone formation

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Bone Research 2018年第1期6卷 72-82页

作者： Andrea E.Morrell Genevieve N.Brown Samuel T.Robinson Rachel L.Sattler Andrew D.Baik Gehua Zhen Xu Cao Lynda F.Bonewald Weiyang Jin Lance C.Kam X.Edward Guo Bone Bioengineering Laboratory Department of Biomedical Engineering Columbia University center for Musculoskeletal Research Department of Orthopaedic Surgery Johns Hopkins University Indiana center for Musculoskeletal Health Indiana University School of Medicine Microscale Biocomplexity Laboratory Department of Biomedical Engineering Columbia University

The vast osteocytic network is believed to orchestrate bone metabolic activity in response to mechanical stimuli through production of sclerostin, RANKL, and osteoprotegerin(OPG). However, the mechanisms of osteocyte mechanotransduction remain poorly understood. We've previously shown that osteocyte mechanosensitivity is encoded through unique intracellular calcium (Ca^(2+) ) dynamics. Here, by simultaneously monitoring Ca^(2+) and actin dynamics in single cells exposed to fluid shear flow, we detected actin network contractions immediately upon onset of flow-induced Ca^(2+) transients, which were facilitated by smooth muscle myosin and further confirmed in native osteocytes ex vivo. Actomyosin contractions have been linked to the secretion of extracellular vesicles(EVs), and our studies demonstrate that mechanical stimulation upregulates EV production in osteocytes through immunostaining for the secretory vesicle marker Lysosomal-associated membrane protein 1(LAMP1) and quantifying EV release in conditioned medium, both of which are blunted when Ca^(2+) signaling was inhibited by neomycin. Axial tibia compression was used to induce anabolic bone formation responses in mice, revealing upregulated LAMP1 and expected downregulation of sclerostin in vivo. This load-related increase in LAMP1 expression was inhibited in neomycin-injected mice compared to ***-computed tomography revealed significant load-related increases in both trabecular bone volume fraction and cortical thickness after two weeks of loading, which were blunted by neomycin treatment. In summary, we found mechanical stimulation of osteocytes activates Ca^(2+) -dependent contractions and enhances the production and release of EVs containing bone regulatory proteins. Further, blocking Ca^(2+) signaling significantly attenuates adaptation to mechanical loading in vivo, suggesting a critical role for Ca^(2+) -mediated signaling in bone adaptation.

关键词： OPG conditioned medium Ca2+-dependent

The NLRP4-DTX4 axis： a key suppressor of TBK1 and innate antiviral signaling

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Cellular & Molecular Immunology 2012年第6期9卷 431-433页

作者： Soratree Charoenthongtrakul Linlin Gao Edward W Harhaj Department of Microbiology and Immunology The University of Miami Miller School of Medicine Miami FL 33136 USA graduate Program in Cancer Biology Sylvester Comprehensive Cancer Center The University of Miami Miller School of Medicine Miami FL 33136 USA Department of Oncology Johns Hopkins School of Medicine Sidney Kimmel Comprehensive Cancer Center. Baltimore MD 21287. USA

Cellular ＆ Molecular Immunology （2012） 9, 431-433; do i= 10.1038/c m i. 2012.49; published on li ne 15 October 2012 The innate immune system provides the first line of defense for protectionagainst pathogenic bacteria or viruses. The host ＇senses＇ pathogen infection by re- cognition of pathogen-associated molecular patterns via germ-line-encoded pattern- recognition receptors including Toll-like receptors, RIG-I-like receptors （RLRs）,

关键词： innate immune system NLRP4-DTX4 TBK1

Measurement of J/ψ decays into Λ■ π^+π^-

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Chinese Physics C 2012年第11期36卷 1031-1039页

作者：阿布里克木.麦迪娜白景芝白羽班勇蔡啸陈宏芳陈和生陈江川陈进陈元柏陈初萍戴又善邓子艳杜书先方建傅成栋高原宁顾运厅郭子敬 F.A.Huarris 何康林何瑁衡月昆胡海明 T.Hussain 胡涛黄光顺黄性涛黄燕萍季晓斌江晓山焦健斌金大鹏金山李刚李海波李金李蕾李仁英李卫东李卫国李晓玲李小男李学潜梁勇飞刘北江刘春秀刘芳刘峰刘宏邦刘怀民刘觉平刘倩刘荣光刘振安吕峰鲁公儒吕军光罗成林马凤才马海龙马秋海 M.Q.A.Malik 毛泽普莫晓虎聂晶 S.L.Olsen 平荣刚邱进发荣刚阮向东单连友尚雷沈成平沈肖雁盛华义孙海生孙胜森孙永昭孙志嘉唐晓田俊平 G.S.Varner 万霞王岚王亮亮王灵淑王平王佩良王贻芳王铮王至勇魏诚林魏代会吴宁许国发俆新平俆晔阎沐霖杨洪勋杨明杨永栩叶铭汉叶云秀喻纯旭苑长征袁野曾云张丙新张炳云张长春张达华张华桥章红宇张家文张建勇张学尧张一云张子平赵京伟赵明刚赵平平赵政国郑波郑海青郑建平郑志鹏钟彬周莉朱科军朱启明朱兴旺朱永生朱自安邹冰松 Institute of High Energy Physics Peking university university of Science and Technology of China Zhejiang university Zhengzhou university Tsinghua university Guangxi university university of Hawaii Honolulu johns hopkins university Shandong university Centre for High Energy Physics University of the Punjab Nankai university Sichuan university Huazhong Normal university Wuhan university graduate university of Chinese Academy of Sciences Henan Normal university Nanjing Normal university Liaoning university Seoul National university Nagoya university Guangxi Normal university Soochow university China center of Advanced Science and Technology Hunan university

Based on 58 million J/ψ events collected by the BESⅡ detector at the BEPC, J/ψ→ΛΛ π＋π- is observed for the first time. The branching fraction is measured to be Br（J/ψ→ΛΛ π＋π-）=（4.30±0.13±0.99）×10-3, excluding the decays to intermediate states, namely J/ψ→Ξ-Ξ＋, J/ψ→Σ（1385）-Σ（1385）＋, and J/ψ→Σ（1385）＋Σ（1385）-. The branching fractions for these intermediate resonance channels are measured to be：Br（J/ψ→Ξ-Ξ＋）=（0.90±0.03±0.18）×10-3, Br（J/ψ→Σ（1385）-Σ（1385）＋）=（1.23±0.07±0.30）×10-3,and Br（J/ψ→Σ（1385）＋Σ（1385）-）=（1.50±0.08±0.38）×10-3, respectively. The angular distribution is of the form dN/d（cosθ）α（1＋αcos2θ） with α=（0.35±0.29±0.06） for J/ψ→Ξ-Ξ＋, α=（-0.54±0.22±0.10） for J/ψ→Σ（1385）-Σ（1385）＋, and α=（-0.35±0.29±0.06） for J/ψ→Σ（1385）＋Σ（1385）-.

关键词： baryonic decays branching fraction alpha distribution