Circulating NK cells are known to convert to a type 1 innate lymphoid cell (ILC1)-like phenotype in response to TGF-β exposure. However, the precise cellular changes defining this process as well as the downstream signaling pathways guiding it remain poorly defined, particularly in humans. We used mass cytometry by time-of-flight (CyTOF) to model this phenotypic shift in vitro and identify a synergistic activity of TGF-β and IL-15 in this cellular conversion. CyTOF profiling identified substantial heterogeneity in the propensity of NK cells to adopt an ILC1-like phenotype in culture, characterized by the step-wise acquisition of various markers, including CD69, CD9, CD103, and CD49a. Activating and inhibitory receptors, including NKG2A, NKG2D, KIR2DL1, KIR3DL1, NKp30, NKp44, and NKp46, were all found to be upregulated exclusively on the cellular subsets that converted most readily in response to TGF-β. An assessment of downstream TGF-β signaling identified TAK1-mediated activation of p38 MAPK as the critical pathway driving conversion. IL-15 enhanced TGF-β-mediated conversion through Ras:RAC1 signaling as well as via the activation of MEK/ERK. Interestingly, the adoption of an ILC1-like phenotype was independent of the effect of IL-15 or TGF-β on mTOR, as the culture of NK cells in the presence of mTOR inhibitors, such as rapamycin or torin1, had minimal impact on the degree of conversion. In conclusion, we have used in vitro human culture systems and CyTOF to define the conversion of circulating NK cells to an ILC1-like phenotype and have clarified the pathways responsible for this process.
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Angiotensin-converting enzyme 2 (ACE2) is a homolog of ACE, which is not blocked by ACE inhibitors. High amounts of ACE2 are present in the proximal tubule, and ACE2 catalyzes generation of angiotensin 1-7 (Ang-(1-7)) by this segment. Ang-(1-7) binds to a receptor distinct from the AT1 or AT2 Ang II receptor, identified as the mas receptor. We studied the effects of Ang-(1-7) on Ang II-mediated cell signaling pathways in proximal tubule. In primary cultures of rat proximal tubular cells, activation of mitogen-activated protein kinases (MAPK) was detected by immunoblotting, in the presence or absence of agonists/antagonists. Transforming growth factor-beta1 (TGF-beta1) was measured by enzyme-linked immunosorbent assay. Ang II (5 min, 10(-7) M) stimulated phosphorylation of the three MAPK (p38, extracellular signal-related kinase (ERK 1/2), and c-Jun N-terminal kinase (JNK)). While incubation of proximal tubular cells with Ang-(1-7) alone did not significantly affect MAPK phosphorylation, Ang-(1-7) (10(-7) M) completely inhibited Ang II-stimulated phosphorylation of p38, ERK 1/2, and JNK. This inhibitory effect was reversed by the Ang-(1-7) receptor antagonist, D-Ala7-Ang-(1-7). Ang II significantly increased production of TGF-beta1 in proximal tubular cells, an effect that was partly inhibited by Ang-(1-7). Ang-(1-7) had no significant effect on cyclic 3',5'-adenosine monophosphate production in these cells. In summary, Ang-(1-7) inhibits Ang II-stimulated MAPK phosphorylation in proximal tubular cells. Generation of Ang-(1-7) by proximal tubular ACE2 could thereby serve a protective role by counteracting the effects of locally generated Ang II.
Value converters are a cross between Type Converters and Value Resolvers. Type converters are globally scoped, so that any time you map from type Foo to type Bar in any mapping, the type converter will be used. Value converters are scoped to a single map, and receive the source and destination objects to resolve to a value to map to the destination member. Optionally value converters can receive the source member as well.
The Chinese historical sources on Majapahit mainly acquired from the chronicles of the Yuan and following Ming dynasty. The Chinese accounts on Majapahit are mainly owed to the Ming admiral Zheng He's reports during the his visit to Majapahit between 1405 and 1432. Zheng He's translator Ma Huan wrote a detailed description of Majapahit and where the king of Java lived.[19] The report was composed and collected in Yingya Shenglan, which provides valuable insight on the culture, customs, and also various social and economic aspects of Chao-Wa (Java) during Majapahit period.[20]
This Ming dynasty voyages are extremely important for Majapahit historiography, since Zheng He's translator Ma Huan wrote Yingya Shenglan, a detailed description of Majapahit,[19] which provides valuable insight on the culture, customs, and also various social and economic aspects of Java during Majapahit period.[20]
In later period near the fall of Majapahit, the art and architecture of Majapahit witnessed the revival of indigenous native Austronesian megalithic architectural elements, such as Sukuh and Cetho temples on western slopes of Mount Lawu. Unlike previous Majapahit temples that demonstrate typical Hindu architecture of high-rise towering structure, the shape of these temples are step pyramid, quite similar to Mesoamerican pyramids. The stepped pyramid structure called Punden Berundak (stepped mounds) is a common megalithic structure during Indonesian prehistoric era before the adoption of Hindu-Buddhist culture.
The vivid, rich and festive Balinese culture is considered one of Majapahit's legacy. The Javanese Hindu civilisation since the era of Airlangga to the era of Majapahit kings has profoundly influenced and shaped the Balinese culture and history.[151] The ancient links and Majapahit legacy is observable in many ways; architecture, literature, religious rituals, dance-drama and artforms. The aesthetics and style of bas-reliefs in Majapahit East Javanese temples were preserved and copied in Balinese temples. It is also because, after the fall of the empire, many Majapahit nobles, artisans and priests had taken refuge either in the interior mountainous region of East Java or across the narrow strait to Bali. Indeed, in some ways, the Kingdom of Bali was the successor of Majapahit. Large numbers of Majapahit manuscripts, such as Nagarakretagama, Sutasoma, Pararaton and Tantu Pagelaran, were being well-kept in royal libraries of Bali and Lombok and provides the glimpse and valuable historical records on Majapahit. The Majapahit Hindu-Javanese culture has shaped the culture of Bali, that led to popular expression; "without Java, there is no Bali". Yet in return, Bali is credited as the last stronghold to safeguard and preserve the ancient Hindu Javanese civilisation.
Celebrated as 'the golden era of the archipelago', the Majapahit empire has inspired many writers and artists (and continues to do so) to create their works based on this era or to describe and mention it. The impact of the Majapahit theme on popular culture can be seen in the following:
Students become published authors by creating a narrative collaborative Story(e)book designed for younger children. Taking a story from Paul Salopek's journey or answering one of the essential questions of this unit (ex. In what ways can migration improve the lives of human beings?), students write a simple script and illustrate their story. Students use a Word processing program like Microsoft Word (PC) or Pages (mac) or any of the book creator apps on the iPad, such as Book Creator or Scribble Press to design their book. If necessary, especially with Microsoft Word, export story into an eBook format with an ePub converter. Class disseminates eBook for younger students to read and learn about Paul Salopek's journey or human migration. Students should keep their audience of younger students in mind and adjust their vocabulary and word usage to fit that younger audience. Teacher produced or collaboratively (student and teacher) produced rubric should be created to provide guidance of what quality of the e-book should look like.
By the same token, the valley centers of wet-rice cultivation may profitably be seen as constituting a hill effect in the following ways. The valley states are, of course, new structures historically speaking, dating back to roughly the middle of the first millennium CE. They were formed from an earlier ingathering of diverse peoples, some of whom may have adopted fixed-field agriculture, but who were, by definition, not previously part of an established state.[57] The very earliest mandala states were less engines of military conquest than cultural spaces available to all those who wished to conform to their religious, linguistic, and cultural formats, whatever their origin.[58] Perhaps because such identities were newly confected from many cultural shards, the resulting valley self-representations were at pains to distinguish their culture from populations outside the state. Thus if hill society could be termed a state effect, valley culture could be seen as a hill effect.
In the early nineteenth century, as in the classical mainland states, Sir Stamford Raffles, quoted above, understood that the precondition of colonial rule was the concentration of population and sedentary agriculture. He required a nonfugitive people whose labor and production were legible and hence appropriable by the state. We turn our attention next, then, to an understanding of the logic and dynamics behind the creation of state spaces in mainland Southeast Asia.
Here again the distinction between gross domestic product and state-accessible product is at work. As a general rule, the agriculture organized by and for states and enterprises with appropriation, above all, in mind, is likely to bear the marks of legibility and monocropping. Monoculture plantations, the now defunct collective farms of the socialist bloc, cotton share-cropping in the postbellum U.S. South, not to mention the coercive agricultural landscapes created by counterinsurgency campaigns in Vietnam or Malaya, are cases in point. They are rarely models of efficient or sustainable agriculture, but they are, and they are intended to be, models of legibility and appropriation.[169] 2ff7e9595c
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