Discovery Today Research Articles

A Rusyn-American Life in Books: George Sabo in New York and Florida

ABSTRACT As the Soviet Union and its challenge to the West recede, we still have much to learn about the Slavic book trade and about the rise of the great Russian, East European, and Eurasian area studies collections in academic libraries in 20th-century North America. Who were the book dealers behind these collections, which still inform so much discovery and knowledge-making today? What can we learn about these personalities and their work? One such book dealer was George Sabo (1896–1983), who followed two brothers to Pittsburgh in 1913 but made his career in New York after 1920, first with a “steamship agency” for fellow immigrants. As a Carpatho-Rusyn from the Kingdom of Hungary, Sabo took his outlook and cultural capital from an ethno-religious group at the very center of the Slavic world and in remarkable symbiosis with nearly all its peoples, languages, identities, and states. Sabo’s native village (Orechová) became part of Czechoslovakia after World War I and his wife’s (Haidosh) part of the Soviet Union after World War II. Sabo’s Carpatho-Rusyn-ness equipped him well as a Slavic-American book dealer and enterprising New Yorker, and we can illuminate much of his life, family, network, surroundings, and career in the city and beyond from many kinds of sources.

The effects of nanotechnology investments on costs

With the revolutions in the dimension of the science, human needs are steadily changing. The developments, discoveries and inventions, which could not be imagined by those having lived in the previous centuries, are still seen as insufficient in the technology era we live in. That’s why new technologies are being researched. The fundamental one of these new technologies is described as nanotechnology introduced as the new discovery of today. Nanotechnology is considered a fertile farm for the enterprises; therefore they focus on this technology for investment. In order to capture the market, maximize the value and profit and gain economic and politic power, both states and enterprises are trying to obtain this technology via their accomplished R&D investments as soon as possible. Therefore, the very essential effects of nanotechnology investments on costs are researched. In addition, several financial and econometrical analyses are applied on some enterprises that are registered in Borsa Istanbul (Istanbul Stock Exchange), and that carry out nanotechnology investments. As a result of the analyses, it is stated that the costs of the products obtained by nanotechnology operations are decreased, that there is a negative relation between investments and costs of sales, and that there are increases in selling capacity of the enterprises through this kind of investments.

A Unifying Ontology to Integrate Histological and Clinical Observations for Drug-Induced Liver Injury

Drug-induced liver injury (DILI) may present any morphologic characteristic of acute or chronic liver disease with no standardized terminology in place. Defining lexemes of DILI histopathology would allow the development of advanced knowledge discovery and data mining tools for across comparisons of publicly available information. For these purposes, a DILI ontology (DILIo) was developed by using the Unified Medical Language System tool and the standardized terminology of the Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT). The DILIo was entrained on findings of 114 US Food and Drug Administration-approved drugs by extracting all clinically DILI-related histopathologic descriptions for 1082 liver biopsy samples, which were then analyzed using the Unified Medical Language System MetaMap and subsequently mapped to the SNOMED CT. The DILIo provides a standard means to describe and organize liver injury induced by drugs, enabling comparative analysis of drugs within and across histopathologic terms. The analysis showed that flutamide, troglitazone, diclofenac, isoniazid, and tamoxifen were reported to have the most diverse histopathologic observations in liver biopsy. Necrosis, cholestasis, fatty degeneration, fibrosis, infiltrate, and hepatic necrosis were the most frequent terms used as descriptors of histopathologic features of DILI. In conclusion, DILIo entrains different algorithms for an efficient meta-analysis of published findings for an improved understanding of mechanisms and clinical characteristics of DILI.

The Immune-Modulating Cytokine and Endogenous Alarmin Interleukin-33 Is Upregulated in Skin Exposed to Inflammatory UVB Radiation

The cellular and molecular mechanisms by which UV radiation modulates inflammation and immunity while simultaneously maintaining skin homeostasis is complex and not completely understood. Similar to the effects of UV, IL-33 has potent immune-modulating properties that are mediated by the downstream induction of cytokines and chemokines. We have discovered that exposure of mice in vivo or human skin samples ex vivo to inflammatory doses of UVB induced IL-33 expression within the epidermal and dermal skin layers. Using a combination of murine cell lines and primary human cells, we demonstrate that both UV and the oxidized lipid platelet activating factor induce IL-33 expression in keratinocytes and dermal fibroblasts. Highlighting the significance of these results, we found that administering IL-33 to mice in vivo suppressed the induction of Th1-mediated contact hypersensitivity responses. This may have consequences for skin cancer growth because UV-induced squamous cell carcinomas that evade immunological destruction were found to express significantly higher levels of IL-33. Finally, we demonstrate that dermal mast cells and skin-infiltrating neutrophils closely associate with UV-induced IL-33-expressing fibroblasts. Our results therefore identify and support a role for IL-33 as an important early danger signal produced in response to inflammation-inducing UV radiation.

Linking molecules to mood: new insight into the biology of depression.

Major depressive disorder is a heritable psychiatric syndrome that appears to be associated with subtle cellular and molecular alterations in a complex neural network. The affected brain regions display dynamic neuroplastic adaptations to endocrine and immunologic stimuli arising from within and outside the CNS. Depression's clinical and etiological heterogeneity adds a third level of complexity, implicating different pathophysiological mechanisms in different patients with the same DSM diagnosis. Current pharmacological antidepressant treatments improve depressive symptoms through complex mechanisms that are themselves incompletely understood. This review summarizes the current knowledge of the neurobiology of depression by combining insights from human clinical studies and molecular explanations from animal models. The authors provide recommendations for future research, with a focus on translating today's discoveries into improved diagnostic tests and treatments.

The biomarker revolution: a step toward personalized medicine.

Any drug-based treatment, be it prophylactic or therapeutic, is bound to suffer from two limitations. The fi rst one is that the drug will never be active in 100% of individuals. In fact, even in classes of drugs such as prophylactic vaccines, which exhibit very high levels of effi cacy, a full effi cacy rate is very rarely obtained. In the case of small chemical drugs, the range of effi cacy is approximately 50‐70% and overall, 30% of patients do not benefi t from current medicines. The second limitation of any drug is its safety profi le. An ‘active’ drug is likely to induce side effects that will vary in severity from one individual to another. It is noteworthy in this context that the number of reported serious adverse

Discovering Antibiotic Efficacy Biomarkers

As current antibiotic therapy is increasingly challenged by emerging drug-resistant bacteria, new technologies are required to identify and develop novel classes of antibiotics. A major bottleneck in today's discovery efforts, however, is a lack of an efficient and standardized method for assaying the efficacy of a drug candidate. We propose a new high content screening approach for identifying efficacious molecules suitable for development of antibiotics. Key to our approach is a new microarray-based efficacy biomarker discovery strategy. We first produced a large dataset of transcriptional responses of Bacillus subtilis to numerous structurally diverse antibacterial drugs. Second we evaluated different protocols to optimize drug concentration and exposure time selection for profiling compounds of unknown mechanism. Finally we identified a surprisingly low number of gene transcripts (approximately 130) that were sufficient for identifying the mechanism of novel substances with reasonable accuracy (approximately 90%). We show that the statistics-based approach reveals a physiologically meaningful set of biomarkers that can be related to major bacterial defense mechanisms against antibiotics. We provide statistical evidence that a parallel measurement of the expression of the biomarkers guarantees optimal performance when using expression systems for screening libraries of novel substances. The general approach is also applicable to drug discovery for medical indications other than infectious diseases.

The 7 TM G‐Protein‐Coupled Receptor Target Family

Chemical biology approaches have a long history in the exploration of the G-protein-coupled receptor (GPCR) family, which represents the largest and most important group of targets for therapeutics. The analysis of the human genome revealed a significant number of new members with unknown physiological function which are today the focus of many reverse pharmacology drug-discovery programs. As the seven hydrophobic transmembrane segments are a defining common structural feature of these receptors, and as signaling through heterotrimeric G proteins is not demonstrated in all cases, these proteins are also referred to as seven transmembrane (7 TM) or serpentine receptors. This review summarizes important historic milestones of GPCR research, from the beginning, when pharmacology was mainly descriptive, to the age of modern molecular biology, with the cloning of the first receptor and now the availability of the entire human GPCR repertoire at the sequence and protein level. It shows how GPCR-directed drug discovery was initially based on the careful testing of a few specifically made chemical compounds and is today pursued with modern drug-discovery approaches, including combinatorial library design, structural biology, molecular informatics, and advanced screening technologies for the identification of new compounds that activate or inhibit GPCRs specifically. Such compounds, in conjunction with other new technologies, allow us to study the role of receptors in physiology and medicine, and will hopefully result in novel therapies. We also outline how basic research on the signaling and regulatory mechanisms of GPCRs is advancing, leading to the discovery of new GPCR-interacting proteins and thus opening new perspectives for drug development. Practical examples from GPCR expression studies, HTS (high-throughput screening), and the design of monoamine-related GPCR-focused combinatorial libraries illustrate ongoing GPCR chemical biology research. Finally, we outline future progress that may relate today's discoveries to the development of new medicines.

Genomics: Offering hope for oncology care

HAT AN amazing time to be an oncology nurse! After almost 30 years as an oncology nurse, I can honestly say that the discoveries of today are (thankfully) moving at a faster pace than I’ve ever seen before. This is fantastic news– especially for those personally affected by cancer. It is challenging news–for those health care providers trying to explain what was seen in the headlines or found on the internet by today’s clinic patient. It is a challenge not only because of the pace of the emerging news, but also because the advances are based on genetic discoveries. Because most nurses today have not had genetics as a foundation to their scientific basis of knowledge, many of us are at a disadvantage to be able to explain options for cancer care accurately and clearly. Insight into what drives cancer at the molecular or cellular level is changing the whole view of the lifelong cancer continuum of care. These insights are also inspiring hope for patients and their families of new options that will make a difference in their personal experience of living with the threat of cancer, the diagnosis of cancer, or dying from cancer. Maintaining hope in these patients, while creating realistic expectations for individuals and

Schizophrenia, IX: Cognition in schizophrenia--the MATRICS initiative.

Symptoms of schizophrenia cluster into distinct domains: positive symptoms (hallucinations, delusions, thought disorder), negative symptoms (anhedonia, thought paucity, alogia), and cognitive dysfunction (attention, working memory, and executive dysfunction). The pharmacologic strategies, genetics, and disease courses associated with these domains differ from one another. Therefore, it has been hypothesized that they are distinct disease entities or at least have distinct pathophysiologies. For this reason, a useful strategy for treatment development may be to investigate these different symptom domains individually for distinct and optimal treatments. Existing antipsychotic drugs act by blocking dopamine and serotonin receptors, primarily targeting positive symptoms. Cognitive dysfunction remains a distinct and potentially important clinical target. The National Institute of Mental Health took the lead in organizing a government/academic/industry cooperative initiative called Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) to isolate distinct cognitive disruptions, identify putative molecular targets active in modulating cognition, find actual drug candidates for those targets, and promote the development of a new treatments for schizophrenia (see Figure). It is known that cognitive dysfunction in outpatient schizophrenia populations accounts for a great part of the residual psychosocial impairment standing in the way of these individuals finding homes, social networks, and employment. A treatment for cognitive dysfunction in these populations has great potential for a reduction of not only symptoms but also illness burden. So far, the MATRICS Initiative has identified 1) the areas of cognition that are specifically impaired in schizophrenia, 2) the most likely molecular targets involved, and 3) a cognitive battery that is sensitive and specific enough for broad use. As a next step, the NIMH will organize a cognitive testing network in clinical research settings to rigorously test new drugs for treatment of cognitive dysfunction. The goal is to find medications that will supplement current antipsychotic drugs by improving cognition in general or in specific subtypes and that can achieve recognition by the Food and Drug Administration (FDA) as indicated medications for this condition. While FDA recognition has not yet been fully realized, a road map to this goal is emerging. This road map may be a template for other innovative treatment development efforts.

Decade of the brain: neurological advances.

In the last half century, neurological developments have been phenomenal and have escalated in this decade of the brain. Many infective disorders have been conquered, but AIDS has posed new challenges. Neuropharmacology has transformed the management of parkinsonism and epilepsy. New imaging techniques such as CT, NMR, PET and ultrasonic scanning have presented us with remarkable images of the nervous system in health and disease. Steroids control many autoimmune disorders; beta-interferon and other new drugs have begun to influence multiple sclerosis. Intensive care has saved many of those with head injury or acute neurological disorders, and we have greatly improved methods of rehabilitation. There are still many incurable neurological disorders but none are untreatable. Today's discovery in basic science brings tomorrow's improvement in patient care, as is clearly shown by molecular genetics. Some neurological and neuromuscular diseases in which the causal gene or genes have been located and characterised and in which the missing or abnormal gene product has been identified will be mentioned, as well as the prospects of carrier detection, antenatal diagnosis and gene therapy.

Allograft survival prolongation after microsurgical lymphatic reconstruction in a short-term immunosuppressed rat small bowel transplantation model

“It is clear, however, that today's discovery by bacteriologists, immunologists, biochemists, pathologists and other specialists have their origin in the questions raised by early surgical pioneers, whose primary concern was adequate wound coverage and healing.” This quotation by Felix T. Rapaport and plastic surgeon John Marquis Converse represents the early history of transplantation. “It remains there to this day and did him lasting good in many ways.” This statement by Sir Winston Churchill of his donation of a skin allograft to a brother officer in 1899 illustrates an example of allogeneic grafting without immunosuppression. “Their vasculature is established by direct end-to-end anastomosis of some at least of vessels in the graft with the vessels of the bed.” A quotation from Sir Peter Medawar's classic Harvey Lecture of March 21, 1957, describes the importance of vessel connections between the graft and the host to prevent rejection of allografts described by others. “Nature presents us with her protests against removing lymphatics, with her protests against any lymphatic malfunctioning.” Leo Clodius, who spent his career studying lymphatics, opened with these words a congress on lymphology in 1987. He referred later to the clinical lymphedema treatment by plastic and microsurgical operations. These four quotations demonstrate that (1) grafts can be transplanted allogeneically without immunosuppression; (2) they will not be rejected if no connection to the vascular system of the host take place, like in the brain; (3) but will be rejected if vessels of the host shoot up to the allograft; and (4) lymphatics also belong to a vascular system that transports immunological circulating cells. Interestingly, the possibility of microsurgical reconstructions of the lymphatic system is not seen to be necessary in transplantation today. It is unclear why the actual state of the art of microneurolymphovascular transplantation in plastic surgery is not considered in today's transplantation research.

Reservoir Development Using Offset VSP Techniques in the Denver-Julesburg Basin

Multioffset vertical seismic profiles (VSP's) have been used successfully to delineate and develop a Sand D field in the Denver-Julesburg basin. Sand D production in Wattenberg field was established by the Sierra Energy and Berge Exploration Well 34-3. Subsequently, three successive wells failed to find the Sand D channel. A stratigraphic model study suggested that offset VSP techniques could be used to determine the extent of the Sand D reservoir accurately and to identify potential offset drilling locations. On the basis of this study, a five-offset VSP was conducted in the discovery well. Interpretation of the data produced an accurate map of the reservoir limits and identified two additional drilling locations. The first of these locations was drilled and completed in Sand D. Subsequently, a VSP was run in this well to complete the delineation of the reservoir and to reconfirm the second offset location.

Superconductors: Past, Present, and Future

Abstract The exciting discoveries of the past few years along with the key participants in the superconducting field are examined in this report. The current and possible future uses of superconductors are shown to be imaginative and very important. The past, present, and future of superconductors is studied in a technical and historical context. From the beginning back in 1911 to the exciting discoveries of today, superconductors are quite a phenomenon. The conventional theory of superconductors does not explain the newly discovered “ high” temperature superconductors. The structure of the superconducting ceramics are very similar and their current densities are directly related to alignment of grain boundaries. The manufacturing process is rather straightforward but care must be exercised to insure reaching the superconducting phase. Many current industrial processes use superconductors. Long distance superconducting power transmission lines are not economically feasible at the present time

Where Are the Great Physicians of America?

Most physicians are familiar with the achievements of such medical luminaries as Sir William Osler, Harvey Cushing, and Oliver Wendell Holmes, and we are continually informed about the discoveries of today's medical researchers and academicians. Yet in this, as in all eras of US medicine, the great physicians of America are not widely known. The great physicians of America are practitioners. They are respected by their colleagues and patients and esteemed in their communities. Their lives are bound to the unique heritage and role of the physician: the care of the patient. A physician may be a great medical thinker, a great medical writer, even a great medical scientist, and still not be a great physician. This issue marks the first appearance of a new JAMA department (p 1261), PRACTITIONERS, which will be published occasionally and will present the thoughts and experiences of outstanding practicing physicians. It is our goal

The growing shortage of dentists in the United States.

THE STORY of the United States since the end of World War II is a story of great growth and change and technical advance. Our cities are bigger, our buildings are taller, and our children are more numerous-and harder to control. Dishpan hands have been cured by the automatic dishwasher and our cars are now so long we cannot park them. Even Jello has added a couple of new delicious flavors-and perpetual motion has been discovered carrying a guitar. In short, we live in an exciting age. Today's discovery makes yesterday's miracle a commonplace-and who is to say what tomorrow will bring. But what tomorrow will bring is a question we today would be wise to ask, and we should not ask it lightly as a tribute to our own inventiveness, but seriously, as a question basic to human welfare. More children require more schools. More cars require more highways. A new technology means a need for new technicians. Growth means change, and stimulating though it is, change can become chaos unless we are prepared for it. This is true in education. It is true in transportation and in industry. It is even more true in public health. For surely, preparation and planning in a field as -vital to our welfare as health services cannot wait until tomorrow. It must begin today. In the area of dental manpower resources today is none too soon. The fact that we have been losing ground steadily in our effort to supply needed services to our people is not new. The supply of dentists in this country has been lagging behind the growth of the population for more than a quarter of a century. Ironically enough, this decline began as a result of a successful and muchneeded effort by the dental profession to raise the educational standards of our dental schools. This occurred in the 1920's, and the subsequent closing of unaccredited and substandard schools meant a sharp decrease in dental school enrollments. Enrollments continued to fall off during the depression years and by the time World War II began we were not graduating enough dentists to replace those who died or retired. The war ended over a decade ago. We have added new schools and increased classroom space in the old ones until today the schools are graduating nearly twice as many students as they were in the last year before the war began. And yet, the shortage has grown