Ambient Pyrite in Precambrian Chert: New Evidence and a Theory

Ambient pyrites of two distinct types were described from middle Precambrian rocks of the Lake Superior area. A new class of this phenomenon is here described from middle Precambrian chert from western Australia. The newly found ambient pyrites are quite minute and characteristically occur in groups forming a "starburst" pattern. All three types of ambient pyrite may be explained in terms of pressure solution initiated by gas evolution from organic material attached to the pyrite. Thermal degradation of the kerogen produces the gases which, due to the impermeability of the encompassing chert, build up the pressures necessary to initiate solution. Pyrite appendages bear a striking resemblance to micro-organisms and, thus, constitute the smallest pseudofossils known.Organismic and Evolutionary Biolog

Did sulfate availability facilitate the evolutionary expansion of chlorophyll a+c phytoplankton in the oceans?

During the Mesozoic Era, dinoflagellates, coccolithophorids and diatoms became prominent primary producers in the oceans, succeeding an earlier biota in which green algae and cyanobacteria had been proportionally more abundant. This transition occurred during an interval marked by increased sulfate concentration in seawater. To test whether increasing sulfate availability facilitated the evolutionary transition in marine phytoplankton, the cyanobacterium Synechococcus sp., the green alga Tetraselmis suecica and three algae containing chlorophyll a+c (the diatom Thalassiosira weissflogii, the dinoflagellate Protoceratium reticulatum and the coccolithophorid Emiliania huxleyi) were grown in media containing 1, 5, 10, 20, or 30 mm SO42−. The cyanobacterium and the green alga showed no growth response to varying [SO42−]. By contrast, the three chlorophyll a+c algae showed improved growth with higher [SO42−], but only up to 10 mm. The chlorophyll a+c algae, but not the green alga or cyanobacterium, also showed lower C:S with higher [SO42−]. When the same experiment was repeated in the presence of a ciliate predator (Euplotes sp.), T. suecica and T. weissflogii increased their specific growth rate in most treatments, whereas the growth rate of Synechococcus sp. was not affected or decreased in the presence of grazers. In a third experiment, T. suecica, T. weissflogii, P. reticulatum and Synechococcus sp. were grown in conditions approximating modern, earlier Paleozoic and Proterozoic seawater. In these treatments, sulfate availability, nitrogen source, metal availability and Pco2 varied. Monospecific cultures exhibited their highest growth rates in the Proterozoic treatment. In mixed culture, T. weissflogii outgrew other species in modern seawater and T. suecica outgrew the others in Paleozoic water. Synechococcus sp. grew best in Proterozoic seawater, but did not outgrow eukaryotic species in any treatment. Collectively, our results suggest that secular increase in seawater [SO42−] may have facilitated the evolutionary expansion of chlorophyll a+c phytoplankton, but probably not to the exclusion of other biological and environmental factors.Earth and Planetary Science

Microbiota Restoration Therapies for Recurrent Clostridioides difficile Infection Reach an Important New Milestone

Microbiota restoration therapy has become a standard treatment for recurrent Clostridioides difficile infection (rCDI). In this article, we review the studies supporting the licensure of two live biotherapeutic products (LBPs) designed to prevent rCDI and to provide clinicians with a perspective on their differences. PubMed was reviewed on 1 October 2023, for all papers published concerning the current Food and Drug Administration allowance of the use of fecal microbiota transplantation (FMT) and the studies that led to the licensure of RBX2660 (REBYOTA™), generic name, fecal microbiota, live-jslm, and SER-109 (VOWST™), generic name, fecal microbiota spores, live-brpk. OpenBiome continues to produce fecal products for patients with rCDI at their treatment sites, and the American Gastroenterology Association has a National Registry focused on long-term safety of administering fecal microbiota products. The science behind the licensing of fecal microbiota, live-jslm, a consortium of fecal anaerobes found in stool augmented with strains of Bacteroidetes and fecal microbiota spores, live-brpk, a mixture of 50 species of purified Firmicutes spores is reviewed. Both products appear to be safe in clinical trials and effective in reducing rCDI episodes by mechanisms established for FMT, including normalization of α- and β-diversity of the microbiome and by increasing fecal secondary bile acids. The different makeup of the two LBPs suggests that rCDI responds to a variety of engrafting microbiota which explains why nearly all donors in FMT of rCDI are generally effective. Fecal microbiota, live-jslm has also been shown to successfully treat rCDI in elderly patients with advanced comorbidities. With the licensure of two novel LBPs, we are entering a new phase of microbiota replacement therapy. Having standardized manufacturing and proper monitoring of products, harnessing the microbiome to control and prevent disease has a new beginning

Incorporation of membrane-bound, mammalian-derived immunomodulatory proteins into influenza whole virus vaccines boosts immunogenicity and protection against lethal challenge

<p>Abstract</p> <p>Background</p> <p>Influenza epidemics continue to cause morbidity and mortality within the human population despite widespread vaccination efforts. This, along with the ominous threat of an avian influenza pandemic (H5N1), demonstrates the need for a much improved, more sophisticated influenza vaccine. We have developed an in vitro model system for producing a membrane-bound Cytokine-bearing Influenza Vaccine (CYT-IVAC). Numerous cytokines are involved in directing both innate and adaptive immunity and it is our goal to utilize the properties of individual cytokines and other immunomodulatory proteins to create a more immunogenic vaccine.</p> <p>Results</p> <p>We have evaluated the immunogenicity of inactivated cytokine-bearing influenza vaccines using a mouse model of lethal influenza virus challenge. CYT-IVACs were produced by stably transfecting MDCK cell lines with mouse-derived cytokines (GM-CSF, IL-2 and IL-4) fused to the membrane-anchoring domain of the viral hemagglutinin. Influenza virus replication in these cell lines resulted in the uptake of the bioactive membrane-bound cytokines during virus budding and release. <it>In vivo </it>efficacy studies revealed that a single low dose of IL-2 or IL-4-bearing CYT-IVAC is superior at providing protection against lethal influenza challenge in a mouse model and provides a more balanced Th₁/Th₂humoral immune response, similar to live virus infections.</p> <p>Conclusion</p> <p>We have validated the protective efficacy of CYT-IVACs in a mammalian model of influenza virus infection. This technology has broad applications in current influenza virus vaccine development and may prove particularly useful in boosting immune responses in the elderly, where current vaccines are minimally effective.</p

Age and emotional salience of stimuli alter the expression of visual recognition memory

Il y a reconnaissance visuelle quand dans une tâche de comparaison visuelle par paires  des enfants en bas âge préfèrent regarder un stimulus nouveau plutôt qu’un stimulus auquel ils viennent d’être familiarisés. Les événements qui se produisent pendant la période de familiarisation peuvent toutefois modifier l’expression de la préférence visuelle au détriment de la nouveauté et en faveur de la familiarité. Notre recherche  avait  pour but d’examiner l’effet de stimuli familiers à forte saillance émotionnelle sur l’expression de la reconnaissance visuelle. 80 jeunes enfants de 6 à 24 mois ont été familiarisés à une marionnette manuelle interactive. Le test de reconnaissance a été effectué tout de suite après la phase de familiarisation au moyen d’images inanimées représentant la marionnette familière ou  une nouvelle. Les enfants  de 6, 9 et 12 mois ne présentent pas de préférence significative en faveur du nouveau alors que les enfants de 18 et 24 mois présentent une préférence pour le stimulus familier. La préférence en faveur du familier s’avère être donc un moyen de mesure important de la reconnaissance visuelle, laquelle évolue en fonction de l’age et de la compétence sociale au cours de la première enfance.Recognition memory is typically demonstrated in the Visual Paired Comparison (VPC) task when infants display a preference for looking at a novel stimulus compared to a stimulus which they have been recently habituated. Events occurring during the habituation period may, however, alter the expression of a visual preference from novelty to familiarity. The present study examined the effect of emotionally salient habituation stimuli on the expression of recognition memory. Eighty infants aged between 6- and 24-months were habituated to an interactive glove puppet. Visual recognition memory was tested immediately with static pictures of the familiar and a novel puppet. The expected novelty preference was notably absent in 6-, 9- and 12-month-old infants. Eighteen- and 24-month-old infants exhibited a visual preference for the familiar stimulus. Familiarity preferences appear to be an important measure of recognition memory that evolve with age and social competence across the infancy period

Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells

Li-Fraumeni syndrome (LFS) patients harbor germ line mutations in the TP53 gene and are at increased risk of hormone receptor-positive breast cancers. Recently, elevated levels of aromatase, the rate-limiting enzyme for estrogen biosynthesis, were found in the breast tissue of LFS patients. Although p53 down-regulates aromatase expression, the underlying mechanisms are incompletely understood. In the present study, we found that LFS stromal cells expressed higher levels of Hsp90 ATPase activity and aromatase compared with wild-type stromal cells. Inhibition of Hsp90 ATPase suppressed aromatase expression. Silencing Aha1 (activator of Hsp90 ATPase 1), a co-chaperone of Hsp90 required for its ATPase activity, led to both inhibition of Hsp90 ATPase activity and reduced aromatase expression. In comparison with wild-type stromal cells, increased levels of the Hsp90 client proteins, HIF-1α, and PKM2 were found in LFS stromal cells. A complex comprised of HIF-1α and PKM2 was recruited to the aromatase promoter II in LFS stromal cells. Silencing either HIF-1α or PKM2 suppressed aromatase expression in LFS stromal cells. CP-31398, a p53 rescue compound, suppressed levels of Aha1, Hsp90 ATPase activity, levels of PKM2 and HIF-1α, and aromatase expression in LFS stromal cells. Consistent with these in vitro findings, levels of Hsp90 ATPase activity, Aha1, HIF-1α, PKM2, and aromatase were increased in the mammary glands of p53 null versus wild-type mice. PKM2 and HIF-1α were shown to co-localize in the nucleus of stromal cells of LFS breast tissue. Taken together, our results show that the Aha1-Hsp90-PKM2/HIF-1α axis mediates the induction of aromatase in LFS

Structural basis for complement factor H-linked age-related macular degeneration

This is the final version of the article. Available from the publisher via the DOI in this record.Nearly 50 million people worldwide suffer from age-related macular degeneration (AMD), which causes severe loss of central vision. A single-nucleotide polymorphism in the gene for the complement regulator factor H (FH), which causes a Tyr-to-His substitution at position 402, is linked to approximately 50% of attributable risks for AMD. We present the crystal structure of the region of FH containing the polymorphic amino acid His402 in complex with an analogue of the glycosaminoglycans (GAGs) that localize the complement regulator on the cell surface. The structure demonstrates direct coordination of ligand by the disease-associated polymorphic residue, providing a molecular explanation of the genetic observation. This glycan-binding site occupies the center of an extended interaction groove on the regulator's surface, implying multivalent binding of sulfated GAGs. This finding is confirmed by structure-based site-directed mutagenesis, nuclear magnetic resonance-monitored binding experiments performed for both H402 and Y402 variants with this and another model GAG, and analysis of an extended GAG-FH complex.B. Prosser is funded by the Wellcome Trust Structural Biology Training Program (075415/Z/04/Z). S. Johnson and P. Roversi were funded by grants to S.M. Lea from the Medical Research Council (MRC) of the United Kingdom (grants G0400389 and G0400775). D. Uhrin and P.N. Barlow were funded by the Wellcome Trust (078780/ Z/05/Z). S.J. Clark was funded by an MRC Doctoral Training Account (G78/7925), and R.B. Sim and A.J. Day were funded by MRC core funding to the MRC Immunochemistry Unit

Niemann-Pick C1 (NPC1)/NPC1-like1 Chimeras Define Sequences Critical for NPC1’s Function as a Filovirus Entry Receptor

We recently demonstrated that Niemann-Pick C1 (NPC1), a ubiquitous 13-pass cellular membrane protein involved in lysosomal cholesterol transport, is a critical entry receptor for filoviruses. Here we show that Niemann-Pick C1-like1 (NPC1L1), an NPC1 paralog and hepatitis C virus entry factor, lacks filovirus receptor activity. We exploited the structural similarity between NPC1 and NPC1L1 to construct and analyze a panel of chimeras in which NPC1L1 sequences were replaced with cognate sequences from NPC1. Only one chimera, NPC1L1 containing the second luminal domain (C) of NPC1 in place of its own, bound to the viral glycoprotein, GP. This engineered protein mediated authentic filovirus infection nearly as well as wild-type NPC1, and more efficiently than did a minimal NPC1 domain C-based receptor recently described by us. A reciprocal chimera, NPC1 containing NPC1L1’s domain C, was completely inactive. Remarkably, an intra-domain NPC1L1-NPC1 chimera bearing only a ~130-amino acid N–terminal region of NPC1 domain C could confer substantial viral receptor activity on NPC1L1. Taken together, these findings account for the failure of NPC1L1 to serve as a filovirus receptor, highlight the central role of the luminal domain C of NPC1 in filovirus entry, and reveal the direct involvement of N–terminal domain C sequences in NPC1’s function as a filovirus receptor