Miracle-dz/UniFAR-FTUs huggingface dataset:
Peak-valley-peak pattern of histone modifications delineates active regulatory elements and their directionality

Formation of nucleosome free region (NFR) accompanied by specific histone modifications at flanking nucleosomes is an important prerequisite for enhancer and promoter activity. Due to this process, active regulatory elements often exhibit a distinct shape of histone signal in the form of a peak-valley-peak (PVP) pattern. However, different features of PVP patterns and their robustness in predicting active regulatory elements have never been systematically analyzed. Here, we present PARE, a novel computational method that systematically analyzes the H3K4me1 or H3K4me3 PVP patterns to predict NFRs. We show that NFRs predicted by H3K4me1 and me3 patterns are associated with active enhancers and promoters, respectively. Furthermore, asymmetry in the height of peaks flanking the central valley can predict the directionality of stable transcription at promoters. Using PARE on ChIP-seq histone modifications from four ENCODE cell lines and four hematopoietic differentiation stages, we identified several enhancers whose regulatory activity is stage specific and correlates positively with the expression of proximal genes in a particular stage. In conclusion, our results demonstrate that PVP patterns delineate both the histone modification landscape and the transcriptional activities governed by active enhancers and promoters, and therefore can be used for their prediction. PARE is freely available at http://servers.binf. ku.dk/pare.
Bile acids repress E‐cadherin through the induction of Snail and increase cancer invasiveness in human hepatobiliary carcinoma

Although some kinds of bile acids have been implicated in colorectal cancer development, the mechanism of cancer progression remains unexplored in hepatobiliary cancer. From our personal results using complementary DNA microarray, we found that chenodeoxycholic acid (CDCA) induced Snail expression in human carcinoma cell lines derived from hepatocellular carcinoma and cholangiocarcinoma. Snail expression plays an important role in the regulation of E‐cadherin and in the acquisition of invasive potential in many types of human cancers including hepatocellular carcinoma. We found that CDCA and lithocholic acid (LCA) induced Snail expression in a concentration‐dependent manner and down‐regulated E‐cadherin expression in hepatocellular carcinoma and cholangiocarcinoma cell lines. Moreover, Snail short interference RNA (siRNA) treatment reduced the down‐regulation of E‐cadherin by CDCA or LCA. Luciferase analysis demonstrated that the promoter region from –111 to –24 relative to the transcriptional start site was necessary for this induction and, at least in part, nuclear factor Y (NF‐Y) and stimulating protein 1 (Sp1) might be an inducer of Snail expression in response to bile acids. In addition, using an in vitro wound healing assay and invasion assay, we observed that CDCA and LCA induced cell migration and invasion. These results suggest that bile acids repress E‐cadherin through the induction of transcription factor Snail and increase cancer invasiveness in human hepatocellular carcinoma and cholangiocarcinoma. Inhibition of this bile acid‐stimulated pathway may prove useful as an adjuvant in the therapy of hepatocellular carcinoma. (Cancer Sci 2008; 99: 1785–1792)
Economic potential for clinically significant in vitro diagnostics

In recent years, significant advances have been made in the realm of in vitro diagnostics with the development of novel tests which are able to meaningfully impact the course of a patients' disease management. This transformation has strained the traditional in vitro diagnostic business model and raised questions as to whether the economics support the commercial development of these tests. The goal of this study is to evaluate the economics of in vitro diagnostics from development to commercialization, with a focus on a specific a class of novel and complex tests called In Vitro Diagnostic Multivariate Index Assays (IVDMIA). My hypothesis is that the current dynamics of the market can only sustain a small number of such novel tests. To evaluate this hypothesis, I construct an economic model of the development of a hypothetical new in vitro diagnostics which focuses on both the cost of development and commercialization together with market potential and adoption. The analysis reviews specific break-even scenarios to determine the parameters which would allow for an economically viable complex in vitro diagnostic. The conclusion I reach based on this analysis is that only a very small number of medical conditions could economically support the development of a novel in vitro diagnostic. The medical conditions which could support the development of a novel test are governed by complexity, severity and prevalence of the disease. Given the dramatic impact these new tests may have on disease management, incentives may be required to offset the risks associated with expanding novel diagnostics into smaller but medically significant disease areas. Thesis Advisor: Ernst Berndt, Ph.D Title: Louis E. Seley Professor in Applied Economics Thesis Advisor: Mark Trusheim Title: Executive in Residence and Visiting Scientist Acknowledgements Over the past three years I have had the fortune and privilege to be guided by an outstanding group of mentors from across MIT, Harvard and the Biomedical Enterprise Program. Their experiences and insights, which they have generously been willing to share with me, have given me an amazing foundation to address the challenges I face as both a student and a professional. I would like to express my special gratitude and appreciation to Prof. Ernst Berndt and Mark Trusheim for their support and advice in the development of my thesis. Their incredible generosity, knowledge and drive to address the challenges of the complex healthcare industry inspired me to expand my own thinking in the field. Thank you to the faculty, staff and fellow students at MIT, Harvard Medical School and the Biomedical Enterprise Program. My fellow students in the Biomedical Enterprise Program provided an amazing foundation of experiences and interests which continues to motivate me academically, professionally and personally. I would also like to give a special acknowledgement to Teo Dagi and Stan Lapidus, who provided a window into the world of healthcare entrepreneurship along with guidance for how that world might influence both my thesis and professional goals.
Regional differences in population‐based cancer survival between six prefectures in Japan: Application of relative survival models with funnel plots

We used new methods to examine differences in population‐based cancer survival between six prefectures in Japan, after adjustment for age and stage at diagnosis. We applied regression models for relative survival to data from population‐based cancer registries covering each prefecture for patients diagnosed with stomach, lung, or breast cancer during 1993–1996. Funnel plots were used to display the excess hazard ratio (EHR) for each prefecture, defined as the excess hazard of death from each cancer within 5 years of diagnosis relative to the mean excess hazard (in excess of national background mortality by age and sex) in all six prefectures combined. The contribution of age and stage to the EHR in each prefecture was assessed from differences in deviance‐based R2 between the various models. No significant differences were seen between prefectures in 5‐year survival from breast cancer. For cancers of the stomach and lung, EHR in Osaka prefecture were above the upper 95% control limits. For stomach cancer, the age‐ and stage‐adjusted EHR in Osaka were 1.29 for men and 1.43 for women, compared with Fukui and Yamagata. Differences in the stage at diagnosis of stomach cancer appeared to explain most of this excess hazard (61.3% for men, 56.8% for women), whereas differences in age at diagnosis explained very little (0.8%, 1.3%). This approach offers the potential to quantify the impact of differences in stage at diagnosis on time trends and regional differences in cancer survival. It underlines the utility of population‐based cancer registries for improving cancer control. (Cancer Sci 2009; 100: 1306–1311)
Structural Characterization of Multi‐Quantum Wells in Electroabsorption‐Modulated Lasers by using Synchrotron Radiation Micrometer‐Beams

Advanced optoelectronic devices, the backbone of modern communication technology, require the monolithic integration of different functions at chip level. An example of devices fulfilling this requirement are multi-quantum well (MQW) electroabsorption-modulated lasers (EMLs) employed in long-distance, high-frequency optical fiber communications technology. Such devices are realized by using the selective area growth (SAG) technique. Optimization of the growth parameters is carried out by empirical approaches as direct structural characterization of the MQW is not possible with laboratory X-ray sources, owing to the micrometer-variation of composition and thickness inherent to the SAG technique. Micrometer-resolved X-ray (m-X-ray) beam available at third generation synchrotron radiation sources, such as the ID22 at the European Synchrotron Radiation Facility (ESRF), allowed us to directly measure the determinant structural parameters of MQW EML structures such as well and barrier widths and mismatches with a 2 mm spatial resolution. In more detail, optoelectronic devices, widely used in the generation and detection of optical signal for telecom and datacom applications, consist of different III-V semiconductors alloys deposited on suitable substrates. The deposition can be performed by different techniques that are based on the crystal rebuilding of a semiconductor used as substrate, such as metal
Localisation and endocrine control of hyaluronan synthase (HAS) 2, HAS3 and CD44 expression in sheep granulosa cells.

The aim of the present study was to investigate the hormonal regulation of hyaluronan (HA) components in sheep granulosa cells. HA components are present in the reproductive tract and have a range of physical and signalling properties related to reproductive function in several species. First, abattoir-derived ovaries of sheep were used to determine the localisation of HA synthase (HAS) 1-3 and CD44 proteins in antral follicles. Staining for HAS1-3 and CD44 proteins was most intense in the granulosa layer. Accordingly, the expression of HAS2, HAS3 and CD44 mRNA was measured in cultured granulosa cells exposed to 0-50ngmL(-1) of 17β-oestradiol and different combinations of oestradiol, gonadotropins, insulin-like growth factor (IGF)-1 and insulin for 48-96h (1ngmL(-1) FSH, 10ngmL(-1) insulin, 10ngmL(-1) IGF-1, 40ngmL(-1) E2 and 25ngmL(-1) LH. ). mRNA expression was quantified by real-time polymerase chain reaction using a fold induction method. The results revealed that the hormones tested generally stimulated mRNA expression of the genes of interest in cultured granulosa cells. Specifically, oestradiol, when combined with IGF-1, insulin and FSH, stimulated HAS2 mRNA expression. Oestradiol and LH had synergistic effects in increasing HAS3 mRNA expression. In conclusion, we suggest that the hormones studied differentially regulate HAS2, HAS3 and CD44 in ovine granulosa cells in vitro. Further work is needed to address the signalling pathways involved.
The morphological and functional development of the stria vascularis in miniature pigs.

The purpose of this study was to examine the morphological and functional development of the lateral wall of the scala media of the cochlea in miniature pigs; light and transmission electron microscopy and electrophysiology were used for this purpose. We showed that the lateral wall of the scala media of the cochlea appears at embryonic Day 21 (E21) when the cochlear duct begins to form. From E28 to E49, the lateral wall can be distinguished according to its position along the cochlea. At E56, cells in the lateral wall begin to differentiate into three different types. At E70, three cell types, marginal, intermediate and basal, can be clearly distinguished. At E91, the stria vascularis is adult-like and the organ of Corti is also morphologically mature. The average endocochlear potential measured from the second turn of the cochlea (at E98, postnatal Day 1 (P1), P13 and P30) was 71.4 ± 2.5 (n = 7), 78.8 ± 1.5 (n = 10), 77.3 ± 2.3 (n = 10) and 78.0 ± 2.1 mV (n = 10), respectively. Our results suggest that in miniature pigs the stria vascularis develops during the embryonic period, concurrent with maturation of the organ of Corti. The magnitude of the endocochlear potential reached its mature level when the stria vascularis was morphologically adult-like at E98. These findings provide a morphological and functional basis for future animal studies using the miniature pig model concerning the pathogenesis of various inner-ear diseases.
Liquid Crystalline Elastomers as Actuators and Sensors

This review collects recent developments in the field of liquid crystalline elastomers (LCEs) with an emphasis on their use for actuator and sensor applications. Several synthetic pathways leading to crosslinked liquid crystalline polymers are discussed and how these materials can be oriented into liquid crystalline monodomains are described. By comparing the actuating properties of different systems, general structure–property relationships for LCEs are obtained. In the final section, how these materials can be turned into usable devices using different interdisciplinary techniques are described.
Photoswitches: From Molecules to Materials

Small organic molecules, capable of undergoing efficient and reversible photochemical reactions to switch them between (at least) two (meta)stable isomers associated with markedly different properties, continue to impact the materials world. Such photoswitches are being implemented in a variety of materials for applications ranging from optical devices to “smart” polymers. All approaches exploit the photoswitching molecular entities as gates, which translate an incoming light stimulus to trigger macroscopic property changes of the materials. In this progress report, the most promising recent examples in this field are highlighted and put in perspective. Moving from supramolecular systems in solution to surfaces and finally to bulk materials, important design concepts are discussed, emphasizing both the challenges as well as the great promise of such truly advanced materials.
Expression of platelet‐derived growth factor (PDGF)‐B and PDGF‐receptor β is associated with lymphatic metastasis in human gastric carcinoma

Recent study of murine fibrosarcoma has revealed that platelet‐derived growth factor (PDGF) plays a direct role in promoting lymphangiogenesis and metastatic spread to lymph nodes. Thus, we investigated the relation between PDGF and PDGF receptor (PDGF‐R) expression and lymphatic metastasis in human gastric carcinoma. We examined PDGF‐B and PDGF‐Rβ expression in four human gastric carcinoma cell lines (TMK‐1, MKN‐1, MKN‐45, and KKLS) and in 38 surgical specimens of gastric carcinoma. PDGF‐B and PDGF‐Rβ expression was examined by immunofluorescence in surgical specimens and in human gastric carcinoma cells (TMK‐1) implanted orthotopically in nude mice. Groups of mice (n = 10, each) received saline (control) or PDGF‐R tyrosine kinase inhibitor imatinib. PDGF‐B and PDGF‐Rβ mRNA expression was significantly higher in patients with lymph node metastasis than in those without and was also significantly higher in diffuse‐type carcinoma than in intestinal‐type carcinoma. In surgical specimens, tumor cells expressed PDGF‐B, but PDGF‐Rβ was expressed predominantly by stromal cells. Under culture conditions, expression of PDGF‐B mRNA was found in all of the gastric cell lines, albeit at different levels. In orthotopic TMK‐1 tumors, cancer cells expressed PDGF‐B but not PDGF‐Rβ. PDGF‐Rβ was expressed by stromal cells, including lymphatic endothelial cells. Four weeks of treatment with imatinib significantly decreased the area of lymphatic vessels. Our data indicate that secretion of PDGF‐B by gastric carcinoma cells and expression of PDGF‐Rβ by tumor‐associated stromal cells are associated with lymphatic metastasis. Blockade of PDGF‐R signaling pathways may inhibit lymph node metastasis of gastric carcinoma. (Cancer Sci 2010)
Probe‐Based 3‐D Nanolithography Using Self‐Amplified Depolymerization Polymers

Scanning probes are capable of addressing and modifying surface structures on the atomic scale, [ 1 ] a capability that has been exploited to create molecular logic devices. [ 2 ] However, in realworld applications, the production of nanoscale patterns and devices requires substantial throughput capabilities in combination with suffi cient tip endurance to address areas on the order of 0.1–1 mm 2 at high resolution. At a typical pixel pitch of 10 nm, this translates to 10 8 –10 10 pixels being written with a single tip. Therefore a highly sensitive patterning approach that is gentle on the tip would be indispensable. Besides the well-established method of local anodic oxidation, [ 3 – 5 ] recent developments in this direction are the fi eld-induced deposition of materials [ 6 , 7 ] and the tip-induced modifi cation or removal of thermomechanically responsive organic materials. [ 8 – 12 ] In addition, it has been shown that on polymeric substrates the wear on a sliding silicon tip can be virtually eliminated, [ 13 ] which is a prerequisite for high-resolution patterning on technologically viable scales. Other stimuli have been used to structure polymers locally using atomic force microscopy (AFM) tips, e.g., mechanical forces in plowing [ 14 ] and ultrasonic patterning [ 15 ] or electron irradiation using fi eld emission from the tip. [ 16 ] In this paper, we describe the fabrication of twoand threedimensional structures based on the local removal of a resist polymer using heated tips. Previous experiments have shown that suffi cient energy is provided by heated tips to break the chemical bonds of a Diels–Alder material, [ 11 ] which subsequently decomposes into volatile monomer units. However, the overall patterning effi ciency is low. The effi ciency can be dramatically enhanced by using self-amplifi ed depolymerization (SAD) polymers. Here, the breaking of a single bond induces the spontaneous depolymerization of the entire polymer chain, [ 17 , 18 ] a concept that was fi rst demonstrated in the early 80’s as a dry lithography approach. Recently it was discovered that using phthalaldehyde SAD polymers two-dimensional
Curving Nanostructures Using Extrinsic Stress

Many thin films develop high residual stress during deposition. These stresses develop due to grain boundaries, dislocations, voids, and impurities within the film itself, or interfacial factors such as a lattice mismatch, difference in thermal expansion, or adsorption. [1–4] It is known that these intrinsic stresses can cause the spontaneous curving of substrates on which they are deposited. [5] If the substrate is much thicker than the stressed thin film, the substrate curves with a large radius of curvature. [6] In contrast, when the stressed thin film is deposited atop or below another thin film and the films are released from the substrate, it will spontaneously curve with a micro or nanoscale radii of curvature. [7–13] However, it is challenging to get the high intrinsic stress magnitudes needed to enable assembly with small nanoscale radii of curvature; typically, heteroepitaxial deposition at elevated temperatures is required, [11–13] which limits the types of devices and structures that can be assembled.
Tympanoplasty, Mastoidectomy, and Stapes Surgery

Tympanoplasty General Considerations - Definitions - Aims of Tympanoplasty - Preoperative Care - Postoperative Care - Anesthesia - Facial Nerve Monitoring - Instrumentation - Rules and Hints Chapter 2 Myringoplasty General Considerations - Definitions - Surgical Approaches - Selection of Surgical Approach - Grafting Technique Specific Surgical Techniques - Transcanal Approach - Endaural Approach - Retroauricular Approach - Antrotomy - Complications of Myringoplasty - Results - Rules and Hints Chapter 3 Ossiculoplasty General Considerations - Basic Situations in Ossiculoplasty Specific Surgical Techniques - Factors that Improve the Results of Ossicular Reconstruction - Results of Ossiculoplasty - Rules and Hints Chapter 4 Special Applications with Tympanoplasty - Transcanal Myringotomy with Ventilating Tube - Temporary Round Window Electrode - Canalplasty for Exostosis - Canalplasty for Otitis Externa Obliterans - Congenital Aural Atresia - Rules and Hints Chapter 5 Mastoidectomy General Considerations - Definitions - Cholesteatoma - Classification of Cholesteatoma - Surgical Treatment of Acquired Cholesteatoma Specific Surgical Techniques for Cholesteatoma Removal - Wound Closure and Packing - Results of Surgery for Cholesteatoma - Rules and Hints Chapter 6 Special Applications of Mastoidectomy - Reconstruction of Open Cavity - Cochlear Implant - Results - Rules and Hints Chapter 7 Stapes Surgery General Considerations - Stapedotomy versus Stapedectomy Specific Surgical Techniques - Results - Rules and Hints Chapter 8 Special Applications of Stapes Surgery Appendix: Instrumentation, Manufacturers, and Suppliers of Microsurgical Equipment Index
Biomimetic Nanopatterns as Enabling Tools for Analysis and Control of Live Cells

It is becoming increasingly evident that cell biology research can be considerably advanced through the use of bioengineered tools enabled by nanoscale technologies. Recent advances in nanopatterning techniques pave the way for engineering biomaterial surfaces that control cellular interactions from the nano‐ to the microscale, allowing more precise quantitative experimentation capturing multi‐scale aspects of complex tissue physiology in vitro. The spatially and temporally controlled display of extracellular signaling cues on nanopatterned surfaces (e. g., cues in the form of chemical ligands, controlled stiffness, texture, etc.) that can now be achieved on biologically relevant length scales is particularly attractive enabling experimental platform for investigating fundamental mechanisms of adhesion‐mediated cell signaling. Here, we present an overview of bio‐nanopatterning methods, with the particular focus on the recent advances on the use of nanofabrication techniques as enabling tools for studying the effects of cell adhesion and signaling on cell function. We also highlight the impact of nanoscale engineering in controlling cell‐material interfaces, which can have profound implications for future development of tissue engineering and regenerative medicine.