Pioneering studies of the "morning-after" pill

Yale School of Medicine produced the first proof-of-concept study on the viability of a "morning-after" pill for human use. This study was a result of a fruitful collaboration between a pair of Yale scientists, Drs. John M. Morris and Gertrude van Wagenen, who sought a non-abortion, post-coital contraceptive. They tested a variety of hormones, hormone-based synthetic drugs, and other compounds in monkeys in an effort to uncover a compound that was non-toxic but highly effective. Unfortunately, although they were unable to identify such a drug, their initial studies inspired other scientists to further pursue the concept of a "morning-after" pill, leading to the development of Food and Drug Administration (FDA)-approved emergency contraceptives.     

Exploration of the central dogma at the interface of chemistry and biology: 2010 Yale Chemical Biology Symposium

Ever since the term "central dogma" was coined in 1958, researchers have sought to control information flow from nucleic acids to proteins. Talks delivered by Drs. Anna Pyle and Hiroaki Suga at this year's Chemical Biology Symposium at Yale in May 2010 applauded recent advances in this area, at the interface between chemistry and biology.     

Reducing the harm of stress: medications to rescue the prefrontal cortex and overcome bad habits: the science of stress: focus on the brain, breaking bad habits, and chronic disease

Our brain is sensitive to stress. Both acute and chronic stress cause cognitive deficits and induce chronic disorders such as drug addiction. In a June 2011 conference at Yale entitled "The Science of Stress: Focus on the Brain, Breaking Bad Habits, and Chronic Disease," Drs. Amy Arnsten and Sherry Mckee discussed the roles of prefrontal cortex in the treatment of stress impairments and addiction. Medications to strengthen the prefrontal function, such as prazosin and guanfacine, may reduce the harm of stress and help overcome smoking and alcohol abuse.     

The early years of coeducation at the Yale University School of Medicine.

The Yale School of Medicine began accepting women as candidates for the degree of medicine in the fall of 1916. This decision was consistent with the trend in medical education at the time. While Yale was not the first prestigious Eastern medical school to admit women, joining Johns Hopkins (1893) and the University of Pennsylvania (1914), it was not one of the last. Columbia University College of Physicians and Surgeons admitted women a year later, but Harvard Medical School held out until 1945. The years 1916--1920 saw the number of women enrolled in medical school almost double. Yale''s decision to admit women seems to have been made with little resistance from the faculty. The final decision was made through the encouragement and financial help of Henry Farnam, a professor of economics at Yale, who agreed to pay for the women''s bathrooms. His daughter, Louise, was in the first class of women. At graduation she was awarded the highest scholastic honors, the Campbell Gold Prize. From Yale she travelled to the Yale-sponsored medical school in Changsha, China, where she became the first female faculty member, a position she held for twelve years. The impressions of Ella Clay Wakeman Calhoun, the only woman to graduate in the second class of women, are presented here. Since 1916 the Yale School of Medicine has undergone extensive physical and philosophical changes, developments in which women have participated.     

Putting together the pieces of polio: how Dorothy Horstmann helped solve the puzzle

Dr. Dorothy Horstmann, epidemiologist, virologist, clinician, and educator, was the first woman appointed as a professor at the Yale School of Medicine. Horstmann made significant contributions to the fields of public health and virology, her most notable being the demonstration that poliovirus reached the central nervous system via the bloodstream, upsetting conventional wisdom and paving the way for polio vaccines. In 1961, she was appointed a professor at Yale School of Medicine, and in 1969, she became the first woman at Yale to receive an endowed chair, which was named in honor of her mentor, Dr. John Rodman Paul. In this review, the major scientific contributions of Dr. Dorothy Horstmann will be highlighted from her more than 50-year tenure at Yale School of Medicine.     

Trapping tunnel design incorporating behavioural preferences of stoats

Abstract

Stoats (Mustela erminea) are introduced pests in New Zealand, and there is an urgent need for effective trapping systems that kill the animal in a humane manner. A treadle trap was designed, the Dominus trap, that utilised an earlier‐proven humane killing system enhanced by the addition of a treadle plate trigger. This system enabled the trap to be classified as a Class A trap under the National Animal Welfare Advisory Committee (NAWAC) guidelines for animal kill traps, by successfully rendering 10/10 animals unconscious within 30 s. The Dominus trap mimics a tunnel, which by its very shape entices the animal to enter, but weighs only 600 g. Atrial at Flea Bay, on Banks Peninsula, used 35 Dominus traps placed alternately between 35 Fenn Mk VI traps set over 3150 trap nights (TN). The trial was conducted from March to May 2007 and was repeated for a further 7740 trap nights from January to March 2008, using 20 Dominus traps. The Dominus trap caught stoats consistently at the rate of 0.22 stoats/100 TN in both years, compared with 0 and 0.14/100 TN in Fenn traps, so potentially provides a humane alternative to the Fenn.     

Detection of Mycobacterium avium spp. paratuberculosis (Map) in samples of sheep paratuberculosis (Johne's disease or JD) and human Crohn's disease (CD) using liquid phase RT-PCR,in situ RT-PCR and immunohistochemistry

The association between the human Crohn's disease (CD) and Mycobacterium avium ssp. paratuberculosis (Map), the etiological agent of the sheep paratuberculosis (Johne's disease or JD), has been controversial because of technical limits to detection of the microorganism. Intestinal samples from 10 sheep naturally affected with JD (5 paucibacillary and 5 multibacillary infections), 8 humans with CD and 1 sheep experimentally infected with a reference strain (ATCC 43015) of Map isolated from a patient with CD were collected. A procedure for the extraction of RNA from formalin-fixed, paraffin embedded tissues was optimized. Archived tissue samples from cases of JD and CD were examined by light microscopy using Haematoxyline and Eosin and Ziehl–Neelsen stains. Liquid phase RT-PCR, in situ RT-PCR and immunohistochemistry were also performed on the same samples. In situ RT-PCR targets were the IS900 sequence and the gene locus F57. The effectiveness of the primer–probes was demonstrated using Dot-Blot testing. A diffuse granulomatous enteritis was present in samples from all sheep with JD; lesions were categorized as subtypes 3b and 3c (Perez classification). Human CD samples appeared very similar to the lymphocytic paucimicrobial form of JD (subtype 3c) and the experimentally infected sheep had an enteritis with lesions compatible with Perez type 2. Liquid phase RT-PCR and Dot-Blot test were positive for Map in all sheep with JD and negative in all samples from CD patients as well as the experimentally infected sheep. In situ RT-PCR was positive for the presence of Map both in JD and CD infected samples. Immunohistochemistry confirmed the in situ RT-PCR results in all JD and CD samples, with the exception of the experimentally infected sheep, which resulted negative. This study demonstrated the effectiveness of the in situ RT-PCR technique in the contribution to establish Map as the etiological agent of CD.     

Digitization of the Nissen–Riesen chimpanzee radiological growth series

Longitudinal morphological growth data of apes are incredibly difficult to obtain. Long life histories, combined with practical and ethical issues of obtaining such long‐term data have resulted in few longitudinal data sets in chimpanzees of known chronological ages. One classic, long‐term growth study of chimpanzees was that of Drs Nissen and Riesen initiated at the Yale Laboratories of Primate Biology in 1939. Through that study, whole‐body radiological images were taken on a regular basis from a “normative” group of chimpanzees from birth to adulthood. Here we have digitized the known remaining radiographs from that growth study, many of which are deteriorating, and uploaded the data set to the free, online database MorphoSource. The database comprises 3,568 X‐ray images of 15 of the 16 chimpanzee subjects in the normative group and 1 individual from an experimental group. Herein, we briefly review the historical context of this study and specific details of the data set.     

Systems biology: new institute and applications

The Yale Systems Biology Institute (YSBI) sponsored its first symposium at the university's West Campus in October 2010. The symposium served to provide Yale's scientific community with a glimpse into the wide range of research at the forefront of this interdisciplinary field. YSBI was conceived less than a year ago, and the event was the perfect forum for its debut, both at Yale and in the U.S. scientific community. This article includes a brief overview of the different topics presented at the symposium, followed by a discussion of the advantages and challenges of practical application of systems biology.     

Origins of cancer therapy

This is a brief overview of the development of cancer therapy with a focus on systemic therapy. The modern era of chemotherapy developed at Yale University Medical School during World War II, a fact that has been generally unrecognized until recently. The observations preceding and involved in the discovery of effective drugs for cancer seem particularly pertinent for this anniversary year.     

"C.-E.A. Winslow and the early years of public health at Yale, 1915-1925"

C.-E.A. Winslow was the first chairman of the Department of Public Health at the Yale University School of Medicine. This paper considers the development and changing agenda of his department, the structure of Yale University, and the maturation of public health as a discipline. Winslow's successes and failures are discussed as they relate to Yale and external societal influences.     

Abraham Flexner and the development of the Yale School of Medicine. 1999

Abraham Flexner first toured the Yale University School of Medicine in preparation for his report of 1910, but it was just the beginning of his relationship with the school. While his review of Yale in his report was generally favorable, he mentioned several shortfalls that needed to be improved to make the school acceptable. Throughout the next twenty-five years, Flexner worked with Deans George Blumer and Milton C. Winternitz to improve the school's finances, infrastructure, and quality of education through his work with the Carnegie Foundation and General Education Board. Flexner has been given great accolades for his work on medical education for the country, but little mention is made of him at Yale, even though he was one of the most influential figures in the development of Yale in the last century.     

Abraham Flexner and the development of the Yale School of Medicine

Abraham Flexner first toured the Yale University School of Medicine in preparation for his report of 1910, but it was just the beginning of his relationship with the school. While his review of Yale in his report was generally favorable, he mentioned several shortfalls that needed to be improved to make the school acceptable. Throughout the next twenty-five years, Flexner worked with Deans George Blumer and Milton C. Winternitz to improve the school's finances, infrastructure, and quality of education through his work with the Carnegie Foundation and General Education Board Flexner has been given great accolades for his work on medical education for the country, but little mention is made of him at Yale, even though he was one of the most influential figures in the development of Yale in the last century.     

黑腹果蝇抗真菌肽Drosomycin同系物的免疫原性和抗真菌活性

通过黑腹果蝇 Drosophila melanogaster抗真菌肽Drosomycin（Drs）及其同系物Drs-lC和Drs-lE的抗体制备及Western blotting 结果,分析了Drs同系物的免疫原性与其抗真菌活性的关系。研究采用了2种技术路线,分别将Drs、Drs-lC和Drs-lE 基因构建成与细胞生长因子基因 afgf 融合的重组表达质粒 pET-afgf-Drs、pET-afgf-C和pET-afgf-E,以及通过基因同向串连获得重组表达质粒 pRSET-2Drs、4Drs、6Drs 和 pRSET-2E、4E、6E,并将这些重组表达质粒转化到BL21（DE3）plysS受体菌进行诱导表达。分离纯化后的融合蛋白afgf-Drs、afgf-C和afgf-E 以及串连蛋白 4 Drs、4 Drs-lE分别免疫小白鼠获得相应的抗血清。Western blotting免疫原性检测结果表明,Drs及其同系物与各自的抗血清具有强的免疫反应,同时相互间也有交叉免疫反应,提示它们具有相似的主要抗原决定簇,这些抗原决定簇可能与抗真菌活性无关。同系物之间抗真菌活性的差异可能来源于某些细微结构上的差异。     

Reflections of a member of the bicentennial class on the Bicentennial Symposium

This perspective piece explores what it means to be a first-year medical student at Yale School of Medicine during its bicentennial year. At first, it seemed like a hefty burden to bear. However, upon listening to Dr. Eric Kandel speak at the Bicentennial Symposium at Yale on April 28, 2011, it became clear what it means to be a part of the future of science and medicine at Yale.     

Auto-inhibition of Drs2p,a Yeast Phospholipid Flippase,by Its Carboxyl-terminal Tail

Drs2p, a yeast type IV P-type ATPase (P4-ATPase), or flippase, couples ATP hydrolysis to phosphatidylserine translocation and the establishment of membrane asymmetry. A previous study has shown that affinity-purified Drs2p, possessing an N-terminal tandem affinity purification tag (TAP_N-Drs2), retains ATPase and translocase activity, but Drs2p purified using a C-terminal tag (Drs2-TAP_C) was inactive. In this study, we show that the ATPase activity of N-terminally purified Drs2p associates primarily with a proteolyzed form of Drs2p lacking the C-terminal cytosolic tail. Truncation of most of the Drs2p C-terminal tail sequence activates its ATPase activity by ∼4-fold. These observations are consistent with the hypothesis that the C-terminal tail of Drs2p is auto-inhibitory to Drs2p activity. Phosphatidylinositol 4-phosphate (PI(4)P) has been shown to positively regulate Drs2p activity in isolated Golgi membranes through interaction with the C-terminal tail. In proteoliposomes reconstituted with purified, N-terminally TAP-tagged Drs2p, both ATPase and flippase activity were significantly higher in the presence of PI(4)P. In contrast, PI(4)P had no significant effect on the activity of a truncated form of Drs2p, which lacked the C-terminal tail. This work provides the first direct evidence, in a purified system, that a phospholipid flippase is subject to auto-inhibition by its C-terminal tail, which can be relieved by a phosphoinositide to stimulate flippase activity.     

How ultrasound first came to new England

Diagnostic ultrasound came to Yale in the 1960s and was first developed in Glasgow and London. This story tells us that ultrasound was well-established in the Department of Obstetrics and Gynecology at Yale University School of Medicine in the Yale-New Haven Hospital by 1970. By then it had caught up with the pioneers in New York, Denver, and even Glasgow.     

Phosphatidylserine stimulation of Drs2p·Cdc50p lipid translocase dephosphorylation is controlled by phosphatidylinositol-4-phosphate

Here, Drs2p, a yeast lipid translocase that belongs to the family of P(4)-type ATPases, was overexpressed in the yeast Saccharomyces cerevisiae together with Cdc50p, its glycosylated partner, as a result of the design of a novel co-expression vector. The resulting high yield allowed us, using crude membranes or detergent-solubilized membranes, to measure the formation from [γ-(32)P]ATP of a (32)P-labeled transient phosphoenzyme at the catalytic site of Drs2p. Formation of this phosphoenzyme could be detected only if Cdc50p was co-expressed with Drs2p but was not dependent on full glycosylation of Cdc50p. It was inhibited by orthovanadate and fluoride compounds. In crude membranes, the phosphoenzyme formed at steady state at 4 °C displayed ADP-insensitive but temperature-sensitive decay. Solubilizing concentrations of dodecyl maltoside left this decay rate almost unaltered, whereas several other detergents accelerated it. Unexpectedly, the dephosphorylation rate for the solubilized Drs2p·Cdc50p complex was inhibited by the addition of phosphatidylserine. Phosphatidylserine exerted its anticipated accelerating effect on the dephosphorylation of Drs2p·Cdc50p complex only in the additional presence of phosphatidylinositol-4-phosphate. These results explain why phosphatidylinositol-4-phosphate tightly controls Drs2p-catalyzed lipid transport and establish the functional relevance of the Drs2p·Cdc50p complex overexpressed here.     

Identification of esg, a genetic locus involved in cell-cell signaling during Myxococcus xanthus development.

JD258, a Tn5 insertion mutant of Myxococcus xanthus, was shown to have major defects in three development-associated properties: expression of the developmentally regulated tps gene, spore formation, and production of multicellular fruiting bodies. The defects in tps gene expression and sporulation could be substantially corrected, at the phenotypic level, by mixing JD258 with wild-type cells (extracellular complementation). By this criterion, JD258 appeared to be a new member of a group of conditional developmental mutants that were previously characterized and placed in four extracellular complementation groups (A to D) based on the ability of mutants in one group to stimulate development in mutants belonging to a different group (D. C. Hagen, A. P. Bretscher, and D. Kaiser, Dev. Biol. 64:284-296, 1978). Mutants from groups A, B, C, and D all displayed extracellular complementation activity when mixed with JD258. These results, and other aspects of the phenotype of JD258, indicate that this mutant defines a fifth extracellular complementation group, group E. The M. xanthus esg locus identified by the Tn5 insertion in JD258 was cloned in Escherichia coli and used for further genetic analysis of the locus. These studies indicated that the esg locus resides within a 2.5-kb region of the M. xanthus chromosome and that the locus contains at least two genetic complementation groups. Our results are consistent with a model in which the esg locus controls the production of a previously unrecognized extracellular signal that must be transmitted between cells for the completion of M. xanthus development.     

The Organization for Flora Neotropica

The Organization for Flora Neotropica (OFN) is a UNESCO Category B organization with the mission of, among other things, providing published information about the plants and fungi of the New World tropics (Neotropics). OFN was established in 1964, largely through the efforts of Drs. José Cuatrecasas and F. Raymond Fosberg. Beginning with the first Flora Neotropica monograph (a treatment ofSwartzia by R. S. Cowan in 1968), 67 volumes treating 905 species of fungi, 18 species of lichens, 228 species of bryophytes, and 5971 species of flowering plants have been published. Despite this impressive record of accomplishment, it is apparent that the rate of monograph production is neither sufficient to supply the need for information about the plants of the Neotropics nor fast enough to keep ahead of the rapid destruction of Neotropical habitats. Recommendations are made for improving the productivity of OFN.