200 research outputs found
STRATEGI PENGEMBANGAN RUMAH MAKAN MANG YEYE DALAM UPAYA MENINGKATKAN VOLUME
No full textTingginya tingkat kunjungan pariwisata di Indonesia berdampak terhadap sarana prasana pendukung seperti rumah makan yang semakin menjamur. Banyak nya rumah makan menimbulkan persaingan yang semakin luas sehingga diperlukan strategi pengembangan bisnis, Penelitian ini ditujukan untuk memberikan strategi bersaing yang tepat untuk diterapkan di Rumah Makan Mang Yeye. Tujuan dari penelitian (1) untuk mengetahui faktor internal (kekuatan & kelemahan) Rumah Makan Mang Yeye (2) untuk mengetahui faktor Eksternal (Peluang & Ancaman) (3) Bagaimana strategi yang paling tepat untuk Rumah Makan Mang Yeye tersebut kemudian dijadikan sebagai acuan untuk penetapan alternatif strategi pengembangan bisnis Rumah Makan Mang Yeye. Metode yang digunakan adalah metode deskriptif. Populasi pada penelitian ini diambil dari jumlah konsumen selama 1 minggu. Sampel pada penelitian ini adalah konsumen Rumah Makan Mang Yeye sebanyak 85 orang. Sebagai acuan untuk menetapkan strategi pengembangan bisnis Rumah Makan Mang Yeye, penelitian ini menggunakan metode analisis SWOT. Analisis SWOT terdiri dari matriks IFE, matriks EFE, matriks IE, matriks SWOT, dan QSPM. Berdasarkan analisis data menggunakan matriks diagram analisis SWOT , Rumah Makan Mang Yeye berada dalam kuadran I. Posisi tersebut merupakan situasi dimana Perusahaan tersebut memiliki peluang dan kekuatan sehingga dapat memanfaatkan peluang yang ada. Berdasarkan hasil olahan data terdapat 8 alternatif strategi untuk pengembangan usaha Rumah Makan Mang Yeye. melalui pengolahan data menggunakan QSPM, dapat diketahui bahwa alternatif strategi pengembangan usaha yang menjadi prioritas adalah Pengembangan manajemen operasional untuk mewujudkan pelayanan yang maksimal terhadap konsumen.
The high level of tourism visits in Indonesia has an impact on supporting infrastructure facilities such as restaurants that are increasingly mushrooming. Many restaurants create increasingly widespread competition so that a business development strategy is needed, this research is intended to provide the right competitive strategy to be applied at Mang Yeye Restaurant. The purpose of the study (1) to find out internal factors (strengths & weaknesses) of Mang Yeye Restaurant (2) to find out External factors (Opportunities & Threats) (3) How the most appropriate strategy for Mang Yeye Restaurant is then used as a reference for alternative determination of the business development strategy of Mang Yeye Restaurant. The method used is descriptive method. The population in this study was taken from the number of consumers for 1 week. The sample in this study were 85 consumers of Mang Yeye Restaurant. Data collection techniques by distributing questionnaires (google form) and interview methods for owners and employees Internal factors use assessments regarding human resource management, marketing, finance, and production or operations. External factors use assessments regarding the macro environment and industrial environment. As a reference for determining the business development strategy of Rumah Makan Mang Yeye, this study uses the SWOT analysis method. SWOT analysis consists of IFE matrix, EFE matrix, IE matrix, SWOT matrix, and QSPM. Based on data analysis using SWOT analysis matrix diagram, Mang Yeye Restaurant is in quadrant I. This position is a situation where the company has the opportunity and strength so that it can take advantage of opportunities. With this, the author recommends alternative strategies that maximize the power of Rumah Makan Mang Yeye in utilizing opportunities. Based on the results of processed data there are 8 alternative strategies for developing the business of Mang Yeye Restaurant. through processing data using QSPM, it can be seen that the alternative business development strategy that becomes a priority is operational management development to realize maximum service to consumers
On the Supporters of the Wang Mang Government Regime as Seen from its Relationships with Scholars
No full textIt has been said that the policies of the Han Period Wang Mang 王莽 regime were unrealistic and meaningless; nevertheless, within the process in which he came to power, Wang Mang received support and was able to implement his policies and assumed the throne. Wang Mang's policies were also praised by his contemporaries. This article takes up the subject of exactly who were the supporters of Wang Mang and examines the background to their support, in an attempt to grasp the meaning of the Wang Mang regime for contemporary Han Period society.
While it is a fact that the frequent popular movements praising Wang Mang during the reign of Former Han Emperor Ping Di 平帝 were staged by the supporters of Wang Mang, these performances did reflect the participants' evaluation of Wang's policies and their expectations concerning his leadership abilities. Who were these supporters and why did they invest their hopes in the Wang Mang regime? To answer these questions, the author investigates the relatively large amount of source materials concerning the scholars (zhusheng 諸生) active at the time.
During that time, there was a great deal of interest in politics on the part of the zhusheng residing in the capital of Chang'an; and it was Wang Mang's intention to grant them favors and act as their patron. Within this context, Wang Mang planned to utilize zhusheng, by having them participate in ceremonies, so to dramatize the superior spirit and mentality of Confucianism. In this manner, zhusheng placed their hopes in the leadership of Wang Mang, participated in popular movements of s upport and thus became an important part of his regime.
Turning to the question of why zhusheng attached themselves to Wang Mang, the author examines the historical background of scholars active in the capital from the last decades of the Fom1er Han Dynasty on into the era of Wang Mang's Xin Dynasty. The nominal purpose of all zhusheng for being in the capital was to become high level bureaucrats in the central govemment, but in reality, only a very few could ever accomplish that dream. For the majority, the actual purpose of studying in the capital became efforts at personal refinement or developing advantageous personal connections. As far as the Wang Mang regime was concerned, it was an excellent opportunity for the sons of powerful families to experience the influential power of the government and take back to their homes stories of Chang'an's power and splendor. In other words, zhusheng became the means by which stable relations could be established between the central government and powerful leaders in the provinces, and those zhusheng and powerful families who welcomed such relations formed the backbone of the Wang Mang regime.journal articl
TINDAK TUTUR DIREKTIF PADA RUBRIK LAPORAN MANG SRIPO: SUARA PEMBACA SURAT KABAR SRIWIJAYA POST
No full textThis study aims to find out the forms of directive speech acts that exist in the reader\u27s voice in the Mang Sripo Report rubric of the Sriwijaya Post newspaper. Data analysis was carried out in research since the data collection process. From the results of the analysis, it was found that the form of directive speech acts contained in the Mang Sripo Report Rubric: the voices of readers of the Sriwijaya Post newspaper which the author found had twelve data consisting of the form of asking for seven utterances; ask as many as four utterances, and prohibit as many as one utterances; Of the three forms that have been found, the form that is most commonly found in the form of asking
Fujita-Kato theorem for the 3-D inhomogeneous Navier-Stokes equations
No full textIn this paper, we prove the global existence and uniqueness of the solution with discontinuous density for the 3-D inhomogeneous Navier Stokes equations if the initial data (rho(0), u(0)) is an element of L-infinity (R-3) x H-s (R-3) with s > 1/2 satisfies 0 < c(0) <= rho(0) <= C-0 < +infinity, parallel to u(0)parallel to((H) over dot1/2) <= epsilon for some small epsilon > 0 depending only on c(0), C-0. Furthermore, we introduce the dual method to show that if u(0) is an element of L-P (R-3) for p is an element of[6/5, 2], the velocity satisfies the decay estimate parallel to del(k)u(t)parallel to(L2) <= C(1 + t)(-k/2-alpha(p)) for t >= 1, k = 0, 1, with alpha(p) = 3/2 (1/p - 1/2). (C) 2016 Elsevier Inc. All rights reserved.NSFC [11371039, 11421101, 11571306]SCI(E)[email protected]; [email protected]; [email protected]
ULIKAN STRUKTURAL JEUNG AJÉN ÉTNOPÉDAGOGIK DINA RUMPAKA TEMBANG CIANJURAN WANDA PANAMBIH KARYA MANG BAKANG PIKEUN BAHAN PANGAJARAN SASTRA DI SMA
No full textIeu panalungtikan dikasangtukangan ku kurangna pangaweruh masarakat kana rumpaka tembang Cianjuran, hususna wanda panambih karya Mang Bakang. Tujuan panalungtikanna nyaéta maluruh perkara rumpaka panambih karya Mang Bakang, struktur jeung ajén étnopédagogikna, sarta pikeun bahan pangajaran sastra di SMA. Ieu panalungtikan ngagunakeun métodeu déskriptif-analitik. Data dikumpulkeun ngagunakeun téhnik studi pustaka jeung wawancara. Hasil panalungtikan manggihan tilu puluh tilu rumpaka panambih karya Mang Bakang anu diulik tina jihat struktur jeung ajén atikan karakter. Tina kajian struktur kapaluruh 10 rumpaka nu dianggit dina wangun pupuh, 18 rumpaka anu diangggit dina wangun sajak bébas, jeung 5 rumpaka anu dianggit dina wangun sisindiran. Kapaluruh ogé imaji anu nyampak nyaéta lolobana imaji taktil, téma anu nyampak lolobana ngeunaan kamanusaan, nada nu nyampak lolobana pangarang ngadidik, ngélingan nu maca. Basa figuratif anu nyampak lolobana ngagunakeun gaya basa ébréhan (peripraseu). Tina jihat étnopédagogik kapaluruh aya 71 karakter. Éta hal téh nyoko kana ajén atikan karakter budaya jeung bangsa nurutkeun pusat kurikulum. Satuluyna, éta hal téh bisa dipakébahan pangajaran sastra di SMA. Ieu panalungtikan bisa nambahan pangaweruh ngeunaan tembang jeung sastra sarta ayana rasa reueus ti masarakat kana tembang Cianjuran. Saran dina ieu panalungtikan téh ditujulkeun ka mahasiswa, guru, pamaréntah, jeung masarakat.;---Penelitian ini dilatarbelakangi oleh kurangnya pengetahuan masarakat terhadap lirik tembang Cianjuran, khususnya dalam wanda panambih karya Mang Bakang. Oleh sebab itu, penelitian ini bertujuan untuk mengetahui rumpaka panambih karya Mang Bakang, struktur dan pendidikan karakter berdasarkan nilai etnopedagogi, serta bahan ajar yang dibuat untuk pembelajaran sastra di SMA. Penelitian ini menggunakan metode deskriptif-analitik. Data dikumpulkan melalui tekhnik studi pustaka dan wawancara. Hasil penelitian ditemukan 33 lirik tembang Cianjuran wanda panambih karya Mang Bakang yang dikaji dari segi struktur dan nilai pendidikan karakter. Dari segi struktur ditemukan 10 lirik dalam bentuk pupuh, 18 lirik dalam bentuk puisi bebas, dan 5 lirik dalam bentuk sisindiran.Di dalam rumpaka tersebut, kebanyakan ditemukan imaji rasa, tema yang paling dominan yaitu kemanusiaan, nada yang paling dominan yaitu mendidik, mengingatkan pembaca. Basa figuratif yang paling dominan yaitu gaya basa Periprase. Dari segiétnopédagogik ditemukan 71 karakter. Hal tersebut merujuk pada nilai pendidikan karakter budaya dan bangsa yang berdasar pada pusat kurikulum. Selanjutnya, hal tersebut dijadikan sebagai bahan pembelajaran sastra di SMA. Penelitian ini bisa menambah wawasan tentang tembang dan sastra serta timbulnya rasa bangga dari masyarakat terhadap tembang Cianjuran. Saran dalam penelitian ini ditujukan kepada mahasiswa, guru, pemerintah, dan masyarakat.;---This research is motivated by the lack of people knowledge about Cianjuran lyrics, especially in Wanda Panambih by Mang Bakang. Because of that, this research aims to determine about Rumpaka Panambih by Mang Bakang, structural and character education based on the etnopedagogik, and the material prepared for learning literature in Senior High School. The study analyzed uses the descriptive-analytic methode. Data collected through literature study technique and interview.The results of the researchwerefound 33 lyrics of Cianjuran wanda panambih by Mang Bakang examined in terms of the structure and the character of education. In terms of structure 10 lyrics was found in form of pupuh, 18 lyrics in form of free poems, and 5 lyrics in form of sisindiran. Inside of rumpaka was found the imagination, as follows feeling imagination, sight imagination and hearing imagination, the themes most dominant of religious, the tone most dominant about author remind the readers. Figurative language most dominant of parallelism or purwakanti. In terms of etnopedagogik was found 71 characters. It refers to the value of education culture and character of the nation based on the center of the curriculum. Furthermore, it is used as the basis of literature in high school. This research will be able to add perspectives concerning tembang and literature and also the incurrence proud of the community for tembang sunda cianjuran. The recommendations for this research aims to students, teachers, the government, and the society
Chimera: An efficient design space exploration tool for FPGA high-level synthesis
No full textIn recent years, hardware accelerators based on field-programmable gate array (FPGA) started to be widely applied in large data centers, thanks to FPGA's extraordinary flexibility and power efficiency. However, with the high flexibility comes the difficulty in design and optimizations. Conventionally, the FPGA designs are written in low-level hardware descriptive languages, which means creating larger designs with complex behavior is extremely difficult. Therefore, high-level synthesis (HLS) tools have been created to close the gap between the design and compute capability. The HLS tools enable the user to create hardware designs using high-level languages and provide various optimization directives to help to improve the performance of the synthesized hardware. However, applying these optimizations to achieve high performance requires expert knowledge and abundant experience in HLS, which calls for an automated tuning tool to reduce the human efforts needed.
In the light of this trend, we develop an efficient automated design space exploration (DSE) tool for applying HLS optimization directives, called Chimera. This tool can significantly reduce the human effort needed by automatically and efficiently exploring the design space of optimizations. Moreover, it is based on a multi-objective optimization method, which means that it can explore a Pareto curve consisting of design points that represent the best trade-offs between resource and latency. These points provide the designer with more choices that also facilitate system integration. In terms of efficiency, Chimera combines statistical learning, Bayesian optimization, and evolutionary algorithms to reduce the number of design points needed to be evaluated, such that the number of time-consuming HLS syntheses is minimized. In the experiments, it reaches the same or superior performance compared to highly optimized hand-tuned designs from the Rosetta benchmark suite.Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2023-05-01The student, Mang Yu, accepted the attached license on 2021-04-30 at 11:46.The student, Mang Yu, submitted this Thesis for approval on 2021-04-30 at 11:53.This Thesis was approved for publication on 2021-04-30 at 13:31.DSpace SAF Submission Ingestion Package generated from Vireo submission #16624 on 2021-09-16 at 17:06:58Made available in DSpace on 2021-09-17T02:34:51Z (GMT). No. of bitstreams: 2
YU-THESIS-2021.pdf: 650661 bytes, checksum: 13c627aacf964080ec4817239cae434c (MD5)
LICENSE.txt: 4204 bytes, checksum: 9d56a0cdd8a765115bcececc3c132d01 (MD5)
Previous issue date: 2021-04-30Embargo set by: Seth Robbins for item 118601
Lift date: 2023-09-17T02:34:57Z
Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD systemAuthor requested U of Illinois access only (OA after 2yrs) in Vireo ETD systemU of I Onl
Mga reyna ng jukebox: Isang maikling kasaysayan ng mga jukebox hits at sa mga mang-aawit nito
No full textSa risert na ito, tinalakay ang panahon ng Jukebox kung saan sinuri ang tatlong Reyna ng Jukebox na sina Eva Eugenio, Claire De La Fuente, at Imelda Papin at ang kanilang signature songs na \u27Tukso\u27, \u27Sayang\u27, at \u27Bakit\u27. Hinagad ng tesis na ito masagot kung bakit nanatili sa kamalayan ng mga tao noong dekada 70 hanggang sa kasalukuyan ang mga signature songs ng binanggit na mang-aawit. Kasabay nito, sinagot din ng tesis na ito ang mga sumusunod na tanong. 1. Ano ang pangkalahatang politikal, ekonomik, kultural, at panlipunang sitwasyon noong Dekada 70, 80, 90, 2000 na nakakaapekto sa kalagayan ng musika ng Pilipinas. 2.Kaugnay sa unang tanong, ano ang naging lugar ng mga kanta nina Eva Eugenio, Claire De La Fuente, at Imelda Papin sa bawat dekada? Paano sila pumusisyon sa bawat panahon bilang mang-aawit? 3. Ano ang pormal na katangian ng mga awit nina Eva Eugenio, Claire De La Fuente at Imelda Papin? Paano naapektuhan ng kanilang mga estilo ang kanilang pananatili sa industriya ng musika?
Ang papel na ito ay isang dayakronik at sinkronik na pag-aaral, kung saan sinuri ang mga dekada 60, 70, 80, 90, at 2000 upang masagot at mapaliwanag kung ano ang mga ibat-ibang salik na humuhubog sa pananatili ng mga kanta ng mga Jukebox sa bawat dekada. Sa estilong ito mapapakita kung ano ang mga posisyon ng mga mang-aawit at ng kanilang kanta sa bawat panahon kung saan makikita ang mga rason kung bakit nanatili pa rin ang mga kanta ng mga Jukebox sa puso ng mga Pilipino. Karagdagan dito sisilipin din ang estilo, tipo at tema ng mga kanta ng mga Jukebox upang mapakita naman kung ano ang posisyon ng mga kanta sa buhay ng mga Pilipino.
Sa risert na ito, natuklasan na ang pinakamalakas na salik sa pagsikat at pagtagal ng mga kanta ng mga Jukebox sa industriya ng musika ay ang tamang panahon na pagpasok noong dekada 70. Ito ay dahil noong dekada 70, nagsisimula pa lamang ang pag-usbong nang industriya ng musika sa Pilipinas. Ito ang taon kung saan talagang natuto nang gumawa ng musika ang mga Pilipino na puwede na nilang tawagin sa kanila. Karagdagan dito, masasabi rin na naging isang inpluensiya ang gobyerno dahil sinuportahan nito ang musikang Pilipino.
Sa kabilang dako naman noong Dekada 80, marami pa rin mga kantang Pilipino ang sumikat. Ngunit, hindi masyadong napagtuunan ng pansin ang mga musikang Pilipino. Karamihan kasi ng mga kanta na pinapatugtug sa radyo ay mga kanta galing sa kanluran. Pagdating naman nang dekada 90, muling sumikat ang mga tugtug na galing sa dekada 70. Dito napansin ang mga kanta ng mga Jukebox Queens, kung saan nagkaroon ng isang revival ang isang kanta ng Reyna ng Jukebox. Samantala, noong dekada 2000, muling nanatili pa rin sa kamalayan ng mga Pilipino ang mga kantang Jukebox kung saan ang kanilang kanta ay pinapatugtog pa rin sa radyo. Dahil dito binansagan na sila ng titlong mga OPM legends ng Viva Records dahil sa kanilang kakaibang estilo na talagang naging impluensiya ng Pilipino.
Karagdagan dito, hindi lamang ang oras ang naging isang bagay na tumulong sa pagsikat ng mga kantang Jukebox, pero pati ang kanilang estilo sa pagdating sa titik.
Sa pag-aaral na ito, hinahangad nito makapagdagdag impormasyon sa kasaysayan ng musika. Ito ay dahil sa karamihan sa mga libro at artikulo hinggil sa musikang Pilipino ay nakakaligtaan ang panahon at musika ng Jukebox. Itong risert na ito ay magsisilbing dagdag impormasyon sa panahon at musikang Jukebox. Karagdagan dito, hinahangad din ng risert na ito makatulong at makadagdag datos sa mga ibat-ibang larawan ng midya, musika at Aralin Pilipino
The efficacy of assertiveness levels of African male graduate students on their self-concepts, educational objectives and career decision making, 1984
No full textExtracorporeal life support in COVID‐19‐related acute respiratory distress syndrome: A EuroELSO international survey
No full textÜber Kalziumsignale und Zytotoxizität menschlicher natürlicher Killerzellen : Calcium signaling and cytotoxicity of human natural killer cells
No full textCalcium signaling is an essential component of immune cell function. Immunocompetent
cells employ calcium ions as a second messenger to regulate proliferation, migration
and maturation. In addition, intracellular calcium signals are necessary for cytotoxic
lymphocytes (CLs) such as CD8+ T-cells and natural killer cells (NK cells) to eliminate
target cells. For several decades, the doctrine used to be that this elimination is mainly
achieved by forcing a target cell into apoptosis. In recent years, several groups reported
that there is at least one further way of target cell killing. Given the right circumstances,
CLs are also able to kill by a direct lysis of the target cell’s membrane, a process referred
to as ’necrosis’.
Our research group, the Department of Biophysics at Saarland University, directed by
Prof. Dr. Markus Hoth, investigates the Ca2+ dependence of signaling processes in immune
cells. We found that calcium ion influx into killer cells is not only necessary for a
successful attack on pathogens and tumor cells, but that extracellular calcium supply can
influence a killer cell’s global killing efficiency.
The aim of this doctoral thesis was to study influx kinetics of Ca2+ ions in active NK
cells at a single-cell level using fluorescence microscopy. The conducted experiments led
to two main conclusions:
I) Not only do NK cells employ both necrosis and apoptosis when killing certain target
cells, but the frequency distributions of both killing types depend highly on the extracellular
Ca2+ concentration ([Ca2+]ext). Low concentrations favor the occurrence
of apoptosis, while an increase in [Ca2+]ext shifts the balance towards necrotic killing.
This shift occurs even after raising Ca2+ ion levels beyond the amount necessary for
necrosis induction.
II) The shape of Ca2+ influx differs, regarding necrotic and apoptotic killing. Necrosis
induction depends on high sustained rises in [Ca2+]int, while NK cells causing
apoptosis tend to show low and oscillatory Ca2+ signals.
Further experiments were conducted in attempt to reveal the responsible molecular mechanisms.
Artificially releasing high amounts of Ca2+ ions into the cytosol of killing NK
cells, using a photolabile Ca2+ chelator, suggests that high cytosolic Ca2+ concentrations
are necessary but not sufficient for necrosis induction by NK cells.
The presented results have contributed to shedding light on the Ca2+ dependence of
NK cell function. In his doctoral thesis published in 2016, Christian Backes from our
research group demonstrated that the balance of necrosis to apoptosis induced by NK
cells greatly affects their total killing competence. The observation that global killing efficiency of CD8+ T-lymphocytes and NK cells depends on [Ca2+]ext can now in parts
be explained by the likelihood of necrotic and apoptotic killing processes shifting.
Although different Ca2+ influx patterns in active NK cells were previously described
by other groups, no exact quantification of these signals has yet been provided. In addition
to giving such a quantification, this thesis can provide evidence that these different
signal types are clearly linked to distinct outcomes regarding NK cell cytotoxicity in vitro.
NK cells play a pivotal role in tumor surveillance and - in case of already developed
cancer - keeping malignant cell clones in check. Apoptosis and lysis of target cells may
both help achieve a shared aim but will differently affect the anti-tumor immune response.
Hence, different Ca2+ signals in tumor-killing NK cells as well as their likelihood of inducing
apoptosis or necrosis may also affect tumor development, progression as well as
the efficacy of immune therapy and adoptive cell transfer. Many recent studies suggest
that tumor cells benefit from necrosis by taking advantage of the resulting microenvironment.
If we can deepen our understanding of how different calcium signal types in CLs
come about, we could try to modulate killing behaviour to shape a more desirable cellular
immune response to malignancies.Kalziumsignale spielen eine Schlüsselrolle in der Funktion unserer Immunabwehr. Immunzellen
verwenden diese Signale, um komplexe Prozesse wie Proliferation, Migration
und Reifung zu regulieren. Darüber hinaus benötigen Killerzellen wie CD8+-T-Zellen und
natürliche Killerzellen (NK-Zellen) hohe zytosolische Kalziumspiegel, um Zielzellen abzutöten.
Die Doktrin der letzten Jahrzehnte war, dass dieses Abtöten im Wesentlichen
auf einem einzigen Mechanismus basiert: der Aktivierung des programmierten Zelltodes,
der Apoptose der Zielzelle. Seit einiger Zeit mehren sich jedoch die Hinweise, dass es noch
mindestens einen weiteren Mechanismus gibt. Unter gewissen Voraussetzungen können
Killerzellen ihre Opfer auch durch eine direkte Lyse der Zellmembran töten. Dieser Prozess
wird gemeinhin als "Nekrose" bezeichnet.
Unter der Leitung von Prof. Dr. Markus Hoth erforscht unsere biophysikalische Arbeitsgruppe
seit Jahren die Bedeutung von Kalziumsignalen für eine Vielzahl von Immunzellen.
Wissenschaftler unserer Abteilung fanden heraus, dass ein Kalziumeinstrom in Killerzellen
nicht nur notwendig für das Abtöten von Bakterien und Tumorzellen ist, sondern dass das
extrazelluläre Kalziumionenangebot auch einen Einfluss auf die absolute Killingeffizienz
ausübt.
Das Ziel der vorliegenden Doktorarbeit war, die Kinetik dieser Kalziumströme in aktiven
NK-Zellen mittels Fluoreszenzmikroskopie auf Einzelzellebene zu erforschen. Die in
diesem Rahmen durchgeführten Experimente lieferten zwei wichtige Erkenntnisse:
I) Zusätzlich zur Bestätigung, dass NK-Zellen sowohl Apoptose als auch Nekrose in
geeigneten Zielzellen induzieren, stellte sich heraus, dass die statistische Verteilung
beider Killingtypen stark vom extrazellulären Kalziumangebot abhängt. Niedrige
Konzentrationen an Kalziumionen begünstigen das Auftreten von Apoptosen, während
steigende Kalziumspiegel zu mehr und mehr Nekrosen führen. Dieser Einfluss
zeigt sich auch noch bei extrazellulären Kalziumkonzentrationen, die weit über dem
für Nekrose notwendigen Maß liegen.
II) NK-Zellen zeigen verschiedene Arten von Kalziumsignalen, je nachdem, welchen Typ
Zytotoxizität (i.e. Nekrose oder Apoptose) sie in ihrer Zielzelle induzieren. Die Lyse
der Zelle bedurfte dabei stets eines hohen und anhaltenden Einstroms von Kalziumionen,
während Killerzellen, die Apoptose hervorriefen, niedrigere und oszillierende
Kalziumströme zeigten.
Weitere Experimente zielten darauf ab, die molekularen Mechanismen für diese Unterschiede
in den Signalen aufzudecken. Indem große Mengen an Kalziumionen mittels eines
photolabilen Chelators künstlich in Killerzellen freigesetzt wurden, konnte gezeigt werden,
dass hohe Kalziumeinströme zwar notwendig, aber sehr wahrscheinlich nicht hinreichend für das nekrosebasierte Abtöten sind.
Die vorliegenden Ergebnisse haben dazu beigetragen, die Kalziumabhängigkeit der Funktion
von NK-Zellen besser zu verstehen. In seiner 2016 publizierten Doktorarbeit konnte
Christian Backes aus unserer Arbeitsgruppe zeigen, dass die Balance von Nekrose- zu
Apoptoseinduktion einen starken Einfluss auf das globale Killingpotential von NK-Zellen
ausübt. Mit Hilfe der hier gewonnenen Erkenntnis, dass diese Balance vom extrazellulären
Kalziumangebot abhängt, kann die Beeinflussung der Effizienz natürlicher Killerzellen
durch die Verfügbarkeit von Kalziumionen nun in Teilen erklärt werden.
Verschiedenartige Muster von Kalziumströmen in aktiven NK-Zellen wurden in der Vergangenheit
bereits von anderen Arbeitsgruppen postuliert, jedoch nicht exakt quantifiziert.
Neben einer solchen Quantifizierung kann die vorliegende Arbeit erstmals beweisen,
dass diese Signalmuster deutlich mit den verschiedenen Killingarten assoziiert sind, zu
denen NK-Zellen fähig sind.
Natürliche Killerzellen zählen zu den wichtigsten Effektoren der Tumorüberwachung.
Auch im Falle von bereits entstandenen Tumoren tragen sie essenziell dazu bei, den Tumor
in Schach zu halten. Unmittelbar führen Apoptoseinduktion und Lyse zwar zum
gleichen Ergebnis - dem Tod der Tumorzelle -, beide Prozesse beinflussen jedoch die gegen
den Tumor gerichtete folgende Immunantwort auf stark unterschiedliche Weise. Es ist
anzunehmen, dass die Frage, wie NK-Zellen Tumorzellen eliminieren und welche Kalziumsignale
sie dabei präsentieren, auch einen Einfluss auf die Wirksamkeit von Chemotherapien,
immunmodulierenden Therapien und adoptivem Zelltransfer haben könnte. Viele
aktuelle Studien legen nahe, dass Tumorzellen von einem bestimmten immunologischen
Mikromilieu profitieren. Ein solches Milieu scheint insbesondere durch nekrotische Zellen
begünstigt zu werden. Ein tiefer gehendes Verständnis davon, wie verschiedene Kalziumsignale
in NK-Zellen zustande kommen, könnte es erlauben, sie pharmakologisch zu
beeinflussen, um das Tötungsverhalten von NK-Zellen zu modifizieren. Auf diese Weise
könnte ein immunologisches Mikromilieu im Tumorgewebe erreicht werden, das bösartige
Zellen schädigt, ohne gleichzeitig die Vermehrung benachbarter Tumorzellen zu stimuliere
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