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This article examines some of the assumptions and implications associated with the Belmont era context in which the concept of therapeutic misconception was forged. We argue that the justification of therapeutic misconception should be reconsidered based on less paternalistic and more participatory models of research. Finally, we identify conceptual and practical approaches that might better reflect contemporary research practice.

Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide.

Background: Improvements in oocyte cryopreservation techniques and establishment of cryopreserved donor oocyte banks have led to improved access to and lower cost of donor oocytes, upending the traditional practice of fresh oocyte donation. The objective of this study was to examine national trends in utilization and live birth rates with fresh versus cryopreserved donor oocytes. Methods: A retrospective analysis of 2013 through 2015 aggregate U.S. national data reported by the Society for Assisted Reproductive Technology which included 30,160 IVF cycles with either fresh or cryopreserved donor oocytes was performed. Results: During the study period utilization of fresh oocyte donations rapidly declined by 32.9%, while cryopreserved oocyte donation increased by 44.4%. Fresh donor oocytes produced significantly higher live birth rates per recipient cycle start than cryopreserved donor oocytes (51.1% vs. 39.7%). Over the three-year study period fresh donor oocytes produced stable live birth rates per recipient cycle start while those with cryopreserved oocytes significantly declined year-by-year. Conclusion: Despite rising popularity of cryopreserved donor oocytes, prospective patients should be counselled that fresh donor oocytes still represent standard of care due to higher live birth rates.

A fundamental question in human susceptibility to bacterial infections is to what extent variability is a function of differences in the pathogen species or in individual humans. To focus on the pathogen species, we compared in the same individual the human adaptive T and B cell immune response to multiple strains of two major human pathogens, Staphylococcus aureus and Streptococcus pyogenes. We found wide variability in the acute adaptive immune response induced by various strains of a species, with a unique combination of activation within the two arms of the adaptive response. Further, this was also accompanied by a dramatic difference in the intensity of the specific protective T helper (Th) response. Importantly, the same immune response differences induced by the individual strains were maintained across multiple healthy human donors. A comparison of isogenic phage KO strains, demonstrated that of the pangenome, prophages were the major contributor to inter-strain immune heterogeneity, as the T cell response to the remaining "core genome" was noticeably blunted. Therefore, these findings extend and modify the notion of an adaptive response to a pathogenic bacterium, by implying that the adaptive immune response signature of a bacterial species should be defined either per strain or alternatively to the species' 'core genome', common to all of its strains. Further, our results demonstrate that the acquired immune response variation is as wide among different strains within a single pathogenic species as it is among different humans, and therefore may explain in part the clinical heterogeneity observed in patients infected with the same species.

Long-lived, donor-reactive memory B cells (Bmems) can produce alloantibodies that mediate transplant injury. Autophagy, an intrinsic mechanism of cell organelle/component recycling, is required for Bmem survival in infectious and model antigen systems, but whether autophagy affects alloreactive Bmem is unknown. We studied mice with an inducible yellow fluorescent protein (YFP) reporter expressed under the activation-induced cytidine deaminase (AID) promoter active in B cells undergoing germinal center reactions. Up to 12months after allogeneic sensitization, splenic YFP+ B cells were predominantly IgD(-)IgM(-)IgG(+) and expressed CD73, CD80, and PD-L2, consistent with Bmems. Labeled cells contained significantly more cells with autophagosomes and more autophagosomes per cell than unlabeled, naive B cells. To test for a functional link, we quantified alloantibody formation in mice with B cells conditionally deficient in the requisite autophagy gene ATG7. These experiments revealed absent B cell ATG7 (1) prevented B cell autophagy, (2) inhibited secondary alloantibody responses without altering primary alloantibody formation, and (3) diminished frequencies of alloreactive Bmems. Pharmacological autophagy inhibition with 3-methyladenine had similar effects on wild-type mice. Together with new documentation of increased autophagosomes within human Bmems, our data indicate that targeting autophagy has potential for eliminating donor-reactive Bmems in transplant recipients.

While the cell-intrinsic pathways governing beige adipocyte development and phenotype have been increasingly delineated, comparatively little is known about how beige adipocytes interact with other cell types in fat. Here, we introduce a whole-tissue clearing method for adipose that permits immunolabeling and three-dimensional profiling of structures including thermogenic adipocytes and sympathetic innervation. We found that tissue architecture and sympathetic innervation differ significantly between subcutaneous and visceral depots. Subcutaneous fat demonstrates prominent regional variation in beige fat biogenesis with localization of UCP1(+) beige adipocytes to areas with dense sympathetic neurites. We present evidence that the density of sympathetic projections is dependent on PRDM16 in adipocytes, providing another potential mechanism underlying the metabolic benefits mediated by PRDM16. This powerful imaging tool highlights the interaction of tissue components during beige fat biogenesis and reveals a previously undescribed mode of regulation of the sympathetic nervous system by adipocytes.

Vaccination with radiation-attenuated sporozoites has been shown to induce CD8+ T cell-mediated protection against pre-erythrocytic stages of malaria. Empirical evidence suggests that successive inoculations often improve the efficacy of this type of vaccines. An initial dose (prime) triggers a specific cellular response, and subsequent inoculations (boost) amplify this response to create a robust CD8+ T cell memory. In this work we propose a model to analyze the effect of T cell dynamics on the performance of prime-boost vaccines. This model suggests that boost doses and timings should be selected according to the T cell response elicited by priming. Specifically, boosting during late stages of clonal contraction would maximize T cell memory production for vaccines using lower doses of irradiated sporozoites. In contrast, single-dose inoculations would be indicated for higher vaccine doses. Experimental data have been obtained that support theoretical predictions of the model.

Amyloid fibrils are highly ordered protein aggregates associated with more than 40 human diseases. The exact conditions under which the fibrils are grown determine many types of reported fibril polymorphism, including different twist patterns. Twist-based polymorphs display unique mechanical properties in vitro, and the relevance of twist polymorphism in amyloid diseases has been suggested. We present transmission electron microscopy images of A beta 42-derived (amyloid beta) fibrils, which are associated with Alzheimer's disease, demonstrating the presence of twist variability even within a single long fibril. To better understand the molecular underpinnings of twist polymorphism, we present a structural and thermodynamics analysis of molecular dynamics simulations of the twisting of beta-sheet protofilaments of a well-characterized cross-beta model: the GNNQQNY peptide from the yeast prion Sup35. The results show that a protofilament model of GNNQQNY is able to adopt twist angles from -11 degrees on the left-hand side to +8 degrees on the right-hand side in response to various external conditions, keeping an unchanged peptide structure. The potential of mean force (PMF) of this cross-beta structure upon twisting revealed that only similar to 2k(B)T per peptide are needed to stabilize a straight conformation with respect to the left-handed free-energy minimum. The PMF also shows that the canonical structural core of beta-sheets, i.e., the hydrogen-bonded backbone beta-strands, favors the straight conformation. However, the concerted effects of the side chains contribute to twisting, which provides a rationale to correlate polypeptide sequence, environmental growth conditions and number of protofilaments in a fibril with twist polymorphisms.

Retroviruses incorporate specific host cell RNAs into virions. In particular, the host noncoding 7SL RNA is highly abundant in all examined retroviruses compared with its cellular levels or relative to common mRNAs such as actin. Using live cell imaging techniques, we have determined that the 7SL RNA does not arrive with the HIV-1 RNA genome. Instead, it is recruited contemporaneously with assembly of the protein HIV-1 Gag at the plasma membrane. Further, we demonstrate that complexes of 7SL RNA and Gag can be immunoprecipitated from both cytosolic and plasma membrane fractions. This indicates that 7SL RNAs likely interact with Gag prior to high-order Gag multimerization at the plasma membrane. Thus, the interactions between Gag and the host RNA 7SL occur independent of the interactions between Gag and the host endosomal sorting complex required for transport (ESCRT) proteins, which are recruited temporarily at late stages of assembly. The interactions of 7SL and Gag are also independent of interactions of Gag and the HIV-1 genome which are seen on the plasma membrane prior to assembly of Gag.

Manganese superoxide dismutase (MnSOD) is a key enzyme in the protection of cells from oxidative stress. A tandem duplication of the MnSOD gene (NbMnSOD1 and NbMnSOD2) in the genome of Nosema bombycis, a parasite of the silkworm Bombyx mori, was previously identified. Here, we compare the protein structures of NbMnSOD1 and NbMnSOD2 and characterize these two proteins in terms of cellular localization, timing of transcription, protein structure, and enzyme activity. Despite a similarity in the primary sequence of NbMnSOD1 and NbMnSOD2, the latter shows a remarkable degree of amino acid sequence difference on the protein's surface and in the active site, where there is a substitution of a phenylalanine for a histidine in NbMnSOD2. Immuno-electron microscopy demonstrates that NbMnSOD1 is present in the cytosol of mature spores, whereas NbMnSOD2 is localized on the polar tube and the spore wall. Immunofluorescence confirms the localization of NbMnSOD2 on the polar tube of the germinated spore. Quantitative measurement of gene expression (qRT-PCR) demonstrates production of both alleles during the first day of infection followed by a dramatic decrease during the second to fourth day of infection. From the fifth day onward, the two alleles show a complementary pattern of expression. The qRT-PCR of the host manganese superoxide dismutase (BmMnSOD) shows a notable increase in transcription upon infection, leading to a three-fold spike by the first day of infection, followed by a decrease in transcription. Measurement of overall MnSOD activity shows a similar peak at day 1 followed by a decrease to a constant rate of enzyme activity. The differences in cellular localization and pattern of gene expression of NbMnSOD2 compared to NbMnSOD1, as well as the differences in protein structure seen for NbMnSOD2 compared to other microsporidial MnSODs, strongly suggest a unique, recently evolved role for NbMnSOD2.