Expression of Cytosolic Peroxiredoxins in Plasmodium Berghei Ookinetes is Regulated by Environmental Factors in the Mosquito bloodmeal

The Plasmodium ookinete develops over several hours in the bloodmeal of its mosquito vector where it is exposed to exogenous stresses, including cytotoxic reactive oxygen species (ROS). How the parasite adapts to these challenging conditions is not well understood. We have systematically investigated the expression of three cytosolic antioxidant proteins, thioredoxin-1 (Trx-1), peroxiredoxin-1 (TPx-1), and 1-Cys peroxiredoxin (1-Cys Prx), in developing ookinetes of the rodent parasite Plasmodium berghei under various growth conditions. Transcriptional profiling showed that tpx-1 and 1-cys prx but not trx-1 are more strongly upregulated in ookinetes developing in the mosquito bloodmeal when compared to ookinetes growing under culture conditions. Confocal immunofluorescence imaging revealed comparable expression patterns on the corresponding proteins. 1-Cys Prx in particular exhibited strong expression in mosquito-derived ookinetes but was not detectable in cultured ookinetes. Furthermore, ookinetes growing in culture upregulated tpx-1 and 1-cys prx when challenged with exogenous ROS in a dose-dependent fashion. This suggests that environmental factors in the mosquito bloodmeal induce upregulation of cytosolic antioxidant proteins in Plasmodium ookinetes. We found that in a parasite line lacking TPx-1 (TPx-1KO), expression of 1-Cys Prx occurred significantly earlier in mosquito-derived TPx-1KO ookinetes when compared to wild type (WT) ookinetes. The protein was also readily detectable in cultured TPx-1KO ookinetes, indicating that 1-Cys Prx at least in part compensates for the loss of TPx-1 in vivo. We hypothesize that this dynamic expression of the cytosolic peroxiredoxins reflects the capacity of the developing Plasmodium ookinete to rapidly adapt to the changing conditions in the mosquito bloodmeal. This would significantly increase its chances of survival, maturation and subsequent escape. Our results also emphasize that environmental conditions must be taken into account when investigating Plasmodium-mosquito interactions

A Mechanism Misregulating p27 in Tumors Discovered in a Functional Genomic Screen

The cyclin-dependent kinase inhibitor p27KIP1 is a tumor suppressor gene in mice, and loss of p27 protein is a negative prognostic indicator in human cancers. Unlike other tumor suppressors, the p27 gene is rarely mutated in tumors. Therefore misregulation of p27, rather than loss of the gene, is responsible for tumor-associated decreases in p27 protein levels. We performed a functional genomic screen in p27+/− mice to identify genes that regulate p27 during lymphomagenesis. This study demonstrated that decreased p27 expression in tumors resulted from altered transcription of the p27 gene, and the retroviral tagging strategy enabled us to pinpoint relevant transcription factors. inhibitor of DNA binding 3 (Id3) was isolated and validated as a transcriptional repressor of p27. We further demonstrated that p27 was a downstream target of Id3 in src-family kinase Lck-driven thymic lymphomagenesis and that p27 was an essential regulator of Lck-dependent thymic maturation during normal T-cell development. Thus, we have identified and characterized transcriptional repression of p27 by Id3 as a new mechanism decreasing p27 protein in tumors

The life and scientific work of William R. Evitt (1923-2009)

Occasionally (and fortunately), circumstances and timing combine to allow an individual, almost singlehandedly, to generate a paradigm shift in his or her chosen field of inquiry. William R. (‘Bill’) Evitt (1923-2009) was such a person. During his career as a palaeontologist, Bill Evitt made lasting and profound contributions to the study of both dinoflagellates and trilobites. He had a distinguished, long and varied career, researching first trilobites and techniques in palaeontology before moving on to marine palynomorphs. Bill is undoubtedly best known for his work on dinoflagellates, especially their resting cysts. He worked at three major US universities and spent a highly significant period in the oil industry. Bill's early profound interest in the natural sciences was actively encouraged both by his parents and at school. His alma mater was Johns Hopkins University where, commencing in 1940, he studied chemistry and geology as an undergraduate. He quickly developed a strong vocation in the earth sciences, and became fascinated by the fossiliferous Lower Palaeozoic strata of the northwestern United States. Bill commenced a PhD project on silicified Middle Ordovician trilobites from Virginia in 1943. His doctoral research was interrupted by military service during World War II; Bill served as an aerial photograph interpreter in China in 1944 and 1945, and received the Bronze Star for his excellent work. Upon demobilisation from the US Army Air Force, he resumed work on his PhD and was given significant teaching duties at Johns Hopkins, which he thoroughly enjoyed. He accepted his first professional position, as an instructor in sedimentary geology, at the University of Rochester in late 1948. Here Bill supervised his first two graduate students, and shared a great cameraderie with a highly motivated student body which largely comprised World War II veterans. At Rochester, Bill continued his trilobite research, and was the editor of the Journal of Paleontology between 1953 and 1956. Seeking a new challenge, he joined the Carter Oil Company in Tulsa, Oklahoma, during 1956. This brought about an irrevocable realignment of his research interests from trilobites to marine palynology. He undertook basic research on aquatic palynomorphs in a very well-resourced laboratory under the direction of one of his most influential mentors, William S. ‘Bill’ Hoffmeister. Bill Evitt visited the influential European palynologists Georges Deflandre and Alfred Eisenack during late 1959 and, while in Tulsa, first developed several groundbreaking hypotheses. He soon realised that the distinctive morphology of certain fossil dinoflagellates, notably the archaeopyle, meant that they represent the resting cyst stage of the life cycle. The archaeopyle clearly allows the excystment of the cell contents, and comprises one or more plate areas. Bill also concluded that spine-bearing palynomorphs, then called hystrichospheres, could be divided into two groups. The largely Palaeozoic spine-bearing palynomorphs are of uncertain biological affinity, and these were termed acritarchs. Moreover, he determined that unequivocal dinoflagellate cysts are all Mesozoic or younger, and that the fossil record of dinoflagellates is highly selective. Bill was always an academic at heart and he joined Stanford University in 1962, where he remained until retiring in 1988. Bill enjoyed getting back into teaching after his six years in industry. During his 26-year tenure at Stanford, Bill continued to revolutionise our understanding of dinoflagellate cysts. He produced many highly influential papers and two major textbooks. The highlights include defining the acritarchs and comprehensively documenting the archaeopyle, together with highly detailed work on the morphology of Nannoceratopsis and Palaeoperidinium pyrophorum using the scanning electron microscope. Bill supervised 11 graduate students while at Stanford University. He organised the Penrose Conference on Modern and Fossil Dinoflagellates in 1978, which was so successful that similar meetings have been held about every four years since that inaugural symposium. Bill also taught many short courses on dinoflagellate cysts aimed at the professional community. Unlike many eminent geologists, Bill actually retired from actively working in the earth sciences. His full retirement was in 1988; after this he worked on only a small number of dinoflagellate cyst projects, including an extensive paper on the genus Palaeoperidinium

Clinical Manifestations of Subjects With the Non-Specific Pulmonary Function Test Pattern

Introduction: Non-specific pattern (NSP) is a subgroup of preserved ratio impaired spirometry (PRISm) that requires a normal total lung capacity measurement. NSP has been historically classified as being an obstructive lung disease pattern. There has been heightened interest and investigation into PRISm recently as it has been associated with an increased likelihood of developing chronic obstructive pulmonary disease (COPD). Given the inherent challenges of understanding the clinical significance of the NSP, the aim of this study was to further explore the clinical characteristics of patients with this pulmonary function test pattern. Material and methods: We identified 111 and 79 subjects using pre-bronchodilator (pre-BD) and post-bronchodilator (post-BD) values, respectively, that met criteria for NSP. The outpatient medical records were retrospectively reviewed for associated diagnoses that were then clustered into ‘obstructive’ or ‘non-obstructive’ groups based on the treating physician's primary pulmonary clinical diagnosis. Results: Within this NSP cohort, cough, wheezing and sputum production were documented more frequently in those with an obstructive lung disease diagnosis. Whether identified using pre-BD or post-BD spirometric values, those with NSP and a positive BD response were more likely to carry an obstructive lung disease diagnosis. Conclusion: Approximately one third of patients with NSP in this study were not given an obstructive lung disease diagnosis by their clinician, which supports the classification of NSP as not an exclusively obstructive lung disease pattern. However, the presence of supporting clinical symptoms, such as cough with sputum production and wheeze, and/or a positive BD response on PFT, support a diagnosis of obstruction in patients with NSP. Resumen: Introducción: El patrón inespecífico constituye un subgrupo de alteraciones de la espirometría con conservación de la relación (PRISm, siglas en inglés) que precisa de una medición de la capacidad pulmonar total normal; históricamente se ha clasificado como un patrón de neumopatía obstructiva. En épocas recientes se ha intensificado el interés en las PRISm y su investigación, ya que se ha asociado a un aumento de la probabilidad de aparición de una enfermedad pulmonar obstructiva crónica (EPOC). Dadas las dificultades inherentes que conlleva interpretar la importancia clínica del patrón inespecífico, el objetivo de este estudio consistió en explorar con más detalle las características clínicas de los pacientes con dicho patrón en las pruebas de la función pulmonar. Material y métodos: Se identificaron 111 y 79 sujetos empleando valores prebroncodilatador y posbroncodilatador, respectivamente, que cumplieron los criterios de patrón inespecífico. Se revisaron retrospectivamente las historias clínicas ambulatorias para detectar diagnósticos asociados que después se agregaron en grupos «obstructivos» o «no obstructivos» en función del diagnóstico clínico pulmonar primario del médico. Resultados: En esta cohorte de pacientes con patrones inespecíficos, se documentó una mayor incidencia de tos, sibilancias y producción de esputo entre los que tenían un diagnóstico de neumopatía obstructiva. Los pacientes con patrón inespecífico y una respuesta positiva al broncodilatador, que hubiesen sido identificados con valores pre o posbroncodilatador, tenían más probabilidades de haber recibido un diagnóstico de neumopatía obstructiva. Conclusión: Aproximadamente un tercio de los pacientes con patrón inespecífico de este estudio no habían recibido un diagnóstico de neumopatía obstructiva, dato que avala no clasificar los patrones inespecíficos exclusivamente en las neumopatías obstructivas. Sin embargo, la presencia de síntomas clínicos indicativos, como tos productiva y sibilancias, o una respuesta positiva al broncodilatador en las pruebas de la función pulmonar, sustenta un diagnóstico de obstrucción en los pacientes con patrón inespecífico