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The majority of experiments investigating the immune response to gastrointestinal helminth infection use a single bolus infection. However, in situ individuals are repeatedly infected with low doses. Therefore, to model natural infection, mice were repeatedly infected (trickle infection) with low doses of Trichuris muris. Trickle infection resulted in the slow acquisition of immunity reflected by a gradual increase in worm burden followed by partial expulsion. Flow cytometry revealed that the CD4+ T cell response shifted from Th1 dominated to Th2 dominated, which coincided with an increase in Type 2 cytokines. The development of resistance following trickle infection was associated with increased worm expulsion effector mechanisms including goblet cell hyperplasia, Muc5ac production and increased epithelial cell turn over. Depletion of CD4+ T cells reversed resistance confirming their importance in protective immunity following trickle infection. In contrast, depletion of group 2 innate lymphoid cells did not alter protective immunity. T. muris trickle infection resulted in a dysbiotic mircrobiota which began to recover alpha diversity following the development of resistance. These data establish trickle infection as a robust and informative model for analysis of immunity to chronic intestinal helminth infection more akin to that observed under natural infection conditions and confirms the importance of CD4+ T cell adaptive immunity in host protection.

Chimeric antigen receptor (CAR) T cell therapy has achieved unrivalled success in the treatment of B cell and plasma cell malignancies, with five CAR T cell products now approved by the US Food and Drug Administration (FDA). However, CAR T cell therapies for solid tumours have not been nearly as successful, owing to several additional challenges. Here, we discuss mechanisms of tumour resistance in CAR T cell therapy and the emerging strategies that are under development to engineer CAR T cells to overcome resistance.

Trichuris trichiura is a gastrointestinal helminth infection causing global morbidity and economic burden. The mouse species Trichuris muris is a well established laboratory model to study infection and immunity. Studies investigating the immune response to T. muris revealed that resistance is dependent on CD4+ Th2 cells and the production of IL-13 that mediates worm expulsion mechanisms. The majority of experimental studies follow infection and immunity after a single dose infection, however individuals are naturally infected with repeated low doses resulting in the slow development of partial immunity. Therefore to replicate a more natural infection regime in the laboratory, mice were infected repeatedly with low doses of T. muris, so called trickle infection and the developing immune response was investigated.Trickle infection of C57BL/6 mice resulted in the slow build up of worm burden followed by a significant decrease in adult worms and early larval stages, thus partial immunity was established. Flow cytometry revealed that a reduction in worm burden was associated with an increase in CD4+ Th2 cell populations that coincided with an increase in IL-13 and worm expulsion mechanisms, including goblet cell hyperplasia, Muc5ac production and increased epithelial cell turnover. Depletion of CD4+ T cells confirmed their importance in the development of resistance following trickle infection. Challenge experiments confirmed that resistance developed following trickle infection was long lasting. Additionally, trickle infection resulted in a microbiome dysbiosis that recovered following the development of resistance.Group 2 innate lymphoid cells (ILC2s) have been shown to be essential for resistance following N. brasiliensis infection, therefore ILC responses were investigated during T. muris infection. Analysis of ILC populations by flow cytometry during single dose and trickle T. muris infection suggested there was no significant response during infection. Depletion of ILC2s in ICOS-T mice confirmed they were not essential for the development of resistance following a single high dose T. muris infection or a T. muris trickle infection.Together the data presented here demonstrates the need for natural infection regimes to be used in the laboratory for animal helminth models to become more applicable to human infections.

This study was designed to examine the knowledge of women's collegiate gymnastics, cheerleading, swimming, cross country, track & field, tennis and volleyball coaches on the etiology, identifying signs, symptoms, risk factors, prevention, education, management and treatment of eating disorders, the confidence of the coaches in response correctness, and measure their self perceived coaching leader behaviors. A secondary purpose was to determine what role the athletic departments play in the education of coaches regarding eating disorders. The subjects included 125 Division I coaches and a non-experimental, correlation, survey design was utilized. The coaches were given a two part questionnaire. First, the Five Domains of Eating Disorders: A Survey for Collegiate Coaches, designed by Turk (1995) measured knowledge on eating disorders and confidence in responses and the second section of the instrument measured the coach's perception of his or her own leader behavior (Chelladurai & Saleh, 1980). Content validity was established through a panel of experts and reliability was previously determined. Descriptive statistics were used to analyze research questions 1, 2 and 4 regarding knowledge on the etiology, identifying signs, symptoms, risk factors, prevention, education, management and treatment of eating disorders, confidence in correct responses and the role the athletic departments play in the education of eating disorders. A Pearson Correlation was used to determine the correlation between the domains of leader behaviors, knowledge of eating disorder factors and confidence in correctness. Lastly, a Multiple Regression was used to determine the correlation between knowledge scores and level of academic preparation, age, gender and number of years coaching. Results indicated that coaches had a high level of knowledge on the domains of eating disorders with 86% scoring higher than 70%. The coaches were most knowledgeable about the risk factors of eating disorders and most confident in the correctness of their responses to prevention and education of eating disorders, however, that domain had the lowest accuracy level. Over one-third of the coaches attended an education program sponsored by their athletic department and literature was the most widely provided educational resource. Coaches who had a Bachelor's or Master's degree scored higher overall on the knowledge instrument. Coaches who perceived themselves to exhibit autocratic behaviors displayed a lower level of knowledge on the risk factors associated with eating disorders. The higher the frequency of training and instruction behaviors, the less confident the coaches were of their correct responses to statements on signs and symptoms of eating disorders.

The majority of experiments investigating the immune response to gastrointestinal helminth infection use a single bolus infection. However, in situ individuals are repeatedly infected with low doses. Therefore, to model natural infection, mice were repeatedly infected (trickle infection) with low doses of Trichuris muris. Trickle infection resulted in the slow acquisition of immunity reflected by a gradual increase in worm burden followed by a partial expulsion. Flow cytometry revealed that the CD4+ T cell response shifted from Th1 dominated to Th2 dominated, which coincided with an increase in Type 2 cytokines. The development of resistance following trickle infection was associated with increased worm expulsion effector mechanisms including goblet cell hyperplasia, Muc5ac production and increased epithelial cell turn over. Depletion of CD4+ T cells reversed resistance confirming their importance in protective immunity following trickle infection. In contrast, depletion of group 2 innate lymphoid cells did not alter protective immunity. T. muris trickle infection resulted in a dysbiotic mircrobiota which began to recover alpha diversity following the development of resistance. These data support trickle infection as a robust and informative model for analysis of immunity to chronic intestinal helminth infection more akin to that observed under natural infection conditions and confirms the importance of CD4+ T cell adaptive immunity in host protection.

The circumsporozoite protein (CSP) builds up the surface coat of sporozoites and is the leading malaria pre-erythrocytic-stage vaccine candidate. CSP has been shown to induce robust CD8+ T cell responses that are capable of eliminating developing parasites in hepatocytes resulting in protective immunity. In this study, we characterised the importance of the immunodominant CSP-derived epitope, SYIPSAEKI, of Plasmodium berghei in both sporozoite- and vaccine-induced protection in murine infection models. In BALB/c mice, where SYIPSAEKI is efficiently presented in the context of the major histocompatibility complex class I (MHC-I) molecule H-2-Kd, we established that epitope-specific CD8+ T cell responses contribute to parasite killing following sporozoite immunisation. Yet, sterile protection was achieved in the absence of this epitope substantiating the concept that other antigens can be sufficient for parasite-induced protective immunity. Furthermore, we demonstrated that SYIPSAEKI-specific CD8+ T cell responses elicited by viral-vectored CSP-expressing vaccines effectively targeted parasites in hepatocytes. The resulting sterile protection strictly relied on the expression of SYIPSAEKI. In C57BL/6 mice, which are unable to present the immunodominant epitope, CSP-based vaccines did not confer complete protection, despite the induction of high levels of CSP-specific antibodies. These findings underscore the significance of CSP in protection against malaria pre-erythrocytic stages and demonstrate that a significant proportion of the protection against the parasite is mediated by CD8+ T cells specific for the immunodominant CSP-derived epitope.

Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency. We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM. Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies. This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L'Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).

Gianni Versace Reaction on the beach. With a backdrop of a [Andrew Cunanan] wanted poster, [Arturo], a restaurant manager, says Thursday he is relieved Gianni Versace's suspected killer is dead. URSULA E. SEEMANN/SUN SENTINEL Search for clues. Investigators gather evidence on the 2nd floor of the houseboat. KRT BOX: Many questions, few answers Unanswered questions about suspected serial killer Andrew Cunanan: Why did he kill himself? Cunanan left no suicide note, but investigators said he was simply trapped and experts on serial killers theorized he may have finished what he set out to do. Why did he target his victims? Some victims were specifically targeted for revenge and others were opportunity killings. Police have said they do not know why Gianni Versace was targeted. Had Cunanan altered his appearance to elude capture? Cunanan may have altered his appearance on numerous occasions and police said he may have dressed as a woman after the slaying of Versace. But no information was released on his appearance when he died. Did he break into the houseboat or did he have a key? Police said they found no signs of forced entry to the houseboat and the caretaker found only one of the door's two locks fastened. How did he elude police for a week when he was only 2 1/2 miles from the the mansion where Versace was shot? The FBI said he kept a much lower profile after the Versace slaying and may have altered his appearance and used the empty houseboat where he died as a base of operations. How did the red pickup stolen from a New Jersey victim go unnoticed in the Miami Beach garage for weeks? ''That's a good question,'' said FBI Deputy Director William Esposito. - ASSOCIATED PRESS