The Acquisition of Human B Cell Memory in Response to Plasmodium Falciparum Malaria

Immunity to Plasmodium falciparum (Pf), the most deadly agent of malaria, is only acquired after years of repeated infections and appears to wane rapidly without ongoing exposure. Antibodies (Abs) are central to malaria immunity, yet little is known about the B‐cell biology that underlies Pf‐specific humoral immunity. To address this gap in our knowledge we carried out a year‐long prospective study of the acquisition and maintenance of long‐lived plasma cells (LLPCs) and memory B cells (MBCs) in 225 individuals aged two to twenty‐five years in Mali, in an area of intense seasonal transmission. Using protein microarrays containing approximately 25% of the Pf proteome we determined that Pf‐specific Abs were acquired only gradually, in a stepwise fashion over years of Pf exposure. Pf‐specific Ab levels were significantly boosted each year during the transmission season but the majority of these Abs were short lived and were lost over the subsequent six month period of no transmission. Thus, we observed only a small incremental increase in stable Ab levels each year, presumably reflecting the slow acquisition LLPCs. The acquisition Pf‐specific MBCs mirrored the slow step‐wise acquisition of LLPCs. This slow acquisition of Pf‐specific LLPCs and MBCs was in sharp contrast to that of tetanus toxoid (TT)‐specific LLPCs and MBCs that were vi vi rapidly acquired and stably maintained following a single vaccination in individuals in this cohort. In addition to the development of normal MBCs we observed an expansion of atypical MBCs that are phenotypically similar to hyporesponsive FCRL4+ cells described in HIV‐infected individuals. Atypical MBC expansion correlated with cumulative exposure to Pf, and with persistent asymptomatic Pf‐infection in children, suggesting that the parasite may play a role in driving the expansion of atypical MBCs. Collectively, these observations provide a rare glimpse into the process of the acquisition of human B cell memory in response to infection and provide evidence for a selective deficit in the generation of Pf‐specific LLPCs and MBCs during malaria. Future studies will address the mechanisms underlying the slow acquisition of LLPCs and MBCs and the generation and function of atypical MBCs

The format in which uncertainty information is presented affects decision biases

ABSTRACT-We examined how the format in which uncertainty information is presented affects two biases in humans' choice behavior. In a computer task, participants were given four common-ratio effect and four commonconsequence effect problems in each of four different formats. In these problems, uncertainty information was described, as percentages (e.g., 80%) or as frequencies (e.g., 16/20), or was experienced, either serially (20 outcomes shown one at a time) or simultaneously (20 outcomes all shown at once). Presenting information as percentages attenuated the common-ratio effect and augmented the common-consequence effect, which suggests that these biases have different underlying mechanisms. Participants' percentage estimates of outcome likelihoods did not differ according to the format in which the information was presented; however, participants' nonverbal estimates of outcome likelihoods differed across formats. The results suggest that uncertainty information presented as percentages is processed differently than the same uncertainty information presented in other formats. The world is predictable, but only probabilistically so. Choices rarely lead to certain outcomes, and an important part of an organism's life involves assessing an option when multiple outcomes are possible. Foraging animals must allocate time across locations, even though there is no guarantee that any one location will provide sustenance at any given time. People must choose which route is likely to be fastest, which course of action is most likely to provide relief from back pain, and which job will provide the best balance of money, security, and enjoyment. In all these choices, there is an element of uncertainty as to which particular outcome will occur, and how this uncertainty is represented and processed determines the choices organisms make. In studies of decision making under uncertainty in humans, people receive information about the value of an outcome and its likelihood of occurrence before being asked to make a decision based on that information. Typically, information is given in a summarized form that includes probabilities and payouts (e.g., ''Lottery A pays 5 with a probability of .75''), and less frequently information is presented as frequencies or in graphical form (E.U. Weber, Humans exhibit decision-making biases in which their choices are inconsistent with normative principles. One might wonder whether such decision biases reflect the functioning of core cognitive mechanisms that are likely present across species or rather result from the use of the more recently developed and uniquely human capacity to represent probabilistic information in symbolic form. This article focuses on how two decisionmaking biases, the common-ratio effect and the common-consequence effect, are influenced by the format in which uncertainty information is presented. Consider the following choice: Low-risk, high-probability option: 100% chance of 3,000 High-risk, high-probability option: 80% chance of $4,00

Obesity Accelerates Acute Promyelocytic Leukemia in Mice and Reduces Sex Differences in Latency and Penetrance

Objective: Obesity has emerged as a prominent risk factor for multiple serious disease states, including a variety of cancers, and is increasingly recognized as a primary contributor to preventable cancer risk. However, few studies of leukemia have been conducted in animal models of obesity. This study sought to characterize the impact of obesity, diet, and sex in a murine model of acute promyelocytic leukemia (APL). Methods: Male and female C57BL/6J.mCG+/PR mice, genetically predisposed to sporadic APL development, and C57BL/6J (wild type) mice were placed on either a high-fat diet (HFD) or a low-fat diet (LFD) for up to 500 days. Results: Relative to LFD-fed mice, HFD-fed animals displayed increased disease penetrance and shortened disease latency as indicated by accelerated disease onset. In addition, a diet-responsive sex difference in APL penetrance and incidence was identified, with LFD-fed male animals displaying increased penetrance and shortened latency relative to female counterparts. In contrast, both HFD-fed male and female mice displayed 100% disease penetrance and insignificant differences in disease latency, indicating that the sexual dimorphism was reduced through HFD feeding. Conclusions: Obesity and obesogenic diet promote the development of APL in vivo, reducing sexual dimorphisms in disease latency and penetrance

Treaties in Collision: The Biosafety Protocol and the World Trade Organization Agreements

In the event of a conflict between the requirements of the Biosafety Protocol, a multilateral agreement governing the trade in genetically modified organisms, and the requirements of the General Agreement on Tariffs and Trade and associated agreements (collectively WTO Agreements), which treaty\u27s requirements prevail? This question lies as the legal heart of the perceived conflict between trade globalization and environmental protection. This issue is particularly timely given the present trade dispute between the United States and European Union over the European Union’s restrictions on the importation of genetically modified agricultural commodities. In this piece, I analyze the relationship between these agreements. I conclude that while the “savings clause” language ultimately included in the Biosafety Protocol preserves countries’ rights and obligations under the WTO Agreements, the Protocol and the WTO Agreements are less on a collision course than some may fear

The Grizzly, November 24, 1992

Demas\u27s Furious Presentation • Possibility of AIDS Quilt at Ursinus • Lewis Receives the Muhlenberg Award • Share the Season • Clergy Assembly Held At U.C. • Senior Profile: Rick Naratil • Concert Band and Jazz Ensemble Perform Fall Concert • Messiah Tickets • Denis Leary\u27s No Cure For Cancer Breath of Fresh Air • Libo Speaks on Voyages to Freedom Exhibit • The Pointlessness of Political Correctness • Letters: Clark Responds to Christ on Campus ; Handicapped Accessibility: A Response From Someone Who Knows • Bears Basketball Buckles Under • Cross-Country Finishes Unbeaten Seasonhttps://digitalcommons.ursinus.edu/grizzlynews/1306/thumbnail.jp

Conservation of birds in fragmented landscapes requires protected areas

For successful conservation of biodiversity, it is vital to know whether protected areas in increasingly fragmented landscapes effectively safeguard species. However, how large habitat fragments must be, and what level of protection is required to sustain species, remains poorly known. We compiled a global dataset on almost 2000 bird species in 741 forest fragments varying in size and protection status, and show that protection is associated with higher bird occurrence, especially for threatened species. Protection becomes increasingly effective with increasing size of forest fragments. For forest fragments >50 ha our results show that strict protection (International Union for Conservation of Nature [IUCN] categories I–IV) is strongly associated with higher bird occurrence, whereas fragments had to be at least 175 ha for moderate protection (IUCN categories V and VI) to have a positive effect. This meta-analysis quantifies the importance of fragment size, protection status, and their interaction for the conservation of bird species communities, and stresses that protection should not be limited to large pristine areas

Parasite fate and involvement of infected cells in the induction of CD4+ and CD8+ T cell responses to Toxoplasma gondii

During infection with the intracellular parasite Toxoplasma gondii, the presentation of parasite-derived antigens to CD4+ and CD8+ T cells is essential for long-term resistance to this pathogen. Fundamental questions remain regarding the roles of phagocytosis and active invasion in the events that lead to the processing and presentation of parasite antigens. To understand the most proximal events in this process, an attenuated non-replicating strain of T. gondii (the cpsII strain) was combined with a cytometry-based approach to distinguish active invasion from phagocytic uptake. In vivo studies revealed that T. gondii disproportionately infected dendritic cells and macrophages, and that infected dendritic cells and macrophages displayed an activated phenotype characterized by enhanced levels of CD86 compared to cells that had phagocytosed the parasite, thus suggesting a role for these cells in priming naïve T cells. Indeed, dendritic cells were required for optimal CD4+ and CD8+ T cell responses, and the phagocytosis of heat-killed or invasion-blocked parasites was not sufficient to induce T cell responses. Rather, the selective transfer of cpsII-infected dendritic cells or macrophages (but not those that had phagocytosed the parasite) to naïve mice potently induced CD4+ and CD8+ T cell responses, and conferred protection against challenge with virulent T. gondii. Collectively, these results point toward a critical role for actively infected host cells in initiating T. gondii-specific CD4+ and CD8+ T cell responses

Isolation and Mutagenesis of a Capsule-Like Complex (CLC) from Francisella tularensis, and Contribution of the CLC to F. tularensis Virulence in Mice

BACKGROUND: Francisella tularensis is a category-A select agent and is responsible for tularemia in humans and animals. The surface components of F. tularensis that contribute to virulence are not well characterized. An electron-dense capsule has been postulated to be present around F. tularensis based primarily on electron microscopy, but this specific antigen has not been isolated or characterized. METHODS AND FINDINGS: A capsule-like complex (CLC) was effectively extracted from the cell surface of an F. tularensis live vaccine strain (LVS) lacking O-antigen with 0.5% phenol after 10 passages in defined medium broth and growth on defined medium agar for 5 days at 32°C in 7% CO₂. The large molecular size CLC was extracted by enzyme digestion, ethanol precipitation, and ultracentrifugation, and consisted of glucose, galactose, mannose, and Proteinase K-resistant protein. Quantitative reverse transcriptase PCR showed that expression of genes in a putative polysaccharide locus in the LVS genome (FTL_1432 through FTL_1421) was upregulated when CLC expression was enhanced. Open reading frames FTL_1423 and FLT_1422, which have homology to genes encoding for glycosyl transferases, were deleted by allelic exchange, and the resulting mutant after passage in broth (LVSΔ1423/1422_P10) lacked most or all of the CLC, as determined by electron microscopy, and CLC isolation and analysis. Complementation of LVSΔ1423/1422 and subsequent passage in broth restored CLC expression. LVSΔ1423/1422_P10 was attenuated in BALB/c mice inoculated intranasally (IN) and intraperitoneally with greater than 80 times and 270 times the LVS LD₅₀, respectively. Following immunization, mice challenged IN with over 700 times the LD₅₀ of LVS remained healthy and asymptomatic. CONCLUSIONS: Our results indicated that the CLC may be a glycoprotein, FTL_1422 and -FTL_1423 were involved in CLC biosynthesis, the CLC contributed to the virulence of F. tularensis LVS, and a CLC-deficient mutant of LVS can protect mice against challenge with the parent strain