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Abstract Commercial scale decarbonization through carbon capture and storage may likely involve many CO2 storage projects located in close proximity. The close proximity could raise concerns over caprock integrity associated with reservoir pressure buildup and interference among adjacent projects. Commercial-scale injection will also require large prospective CO2 storage resource and high injectivity in the targeted storage formations. To accommodate the need for both large resource and high injectivity, project operators could consider injecting CO2 into a stacked sequence of formations. This analysis investigates the benefits of injecting CO2 into a vertically stacked sequence of saline formations, over injecting the same amount of CO2 into a single saline formation, in addressing these challenges. Our analysis shows that injecting into the stacked sequence mitigates the extent of pressure buildup among the stacked formations, while still achieving the same or greater target CO2 storage volumes. Among cases modeled, the resulting pressure buildup front is most reduced when each storage site distributes injection volumes over several wells, each of which injects a portion of the total CO2 mass across the stacked sequence. This favorable case not only results in the smallest CO2 aerial footprint, but also shows the largest reduction in the pressure buildup at the top of perforation at the injection wells (upwards of approximately 46% compared to the single-formation storage), the result of which is crucial to maintain caprock integrity. This analysis provides insights into required decision-making when considering multi-project deployment in a shared basin.

Background and aims – The forests of the Congo Basin contain high levels of biodiversity, and are globally important for carbon storage. In order to design effective conservation strategies, and to accurately model carbon stocks, a fine-scale understanding of the different forest types that make up this forest block is needed. Monodominant Gilbertiodendron dewevrei forest covers large areas of the Congo Basin, but it is currently unclear whether it is sufficiently distinct from adjacent mixed terre firme forest to warrant separate treatment for conservation planning and carbon calculations. This study aimed to compare the structure and diversity of monodominant and mixed forest, and ask whether there is a unique vascular plant community associated with G. dewevrei forest. Material and methods – We utilised a combination of plot data and herbarium specimens collected in the Sangha Trinational (a network of protect areas in Cameroon, Central African Republic, and the Republic of Congo). Plot inventories were used to compare G. dewevrei forest and mixed forest for stem density, basal area, above ground biomass, stem size distribution, species diversity, and species composition. In addition, a database of 3,557 herbarium specimens was used to identify species of vascular plant that are associated with G. dewevrei forest. Key results – Gilbertiodendron dewevrei forest is distinct in both structure and species composition from mixed forest. Gilbertiodendron dewevrei forest has a lower stem number (of trees ≥ 10 cm), but a greater proportion of larger trees (> 70 cm), suggesting higher carbon stocks. The species composition is distinct from mixed forest, with 56 species of vascular plant significantly associated with G. dewevrei forest. Conclusion – Monodominant G. dewevrei forest in the Sangha Trinational is both compositionally and structurally distinct from mixed forest. We therefore recommend this forest type be considered separately from mixed forest for conservation planning and carbon stock calculations.

IntroductionThe field of Medicines Development faces a continuous need for educational evolution to match the interdisciplinary and global nature of the pharmaceutical industry. This paper discusses the outcomes of a 7-year collaboration between King’s College London and the Global Medicines Development Professionals (GMDP) Academy, which aimed to address this need through a blended e-learning program.MethodsThe collaboration developed a comprehensive curriculum based on the PharmaTrain syllabus, delivered through a combination of asynchronous and synchronous e-learning methods. The program targeted a diverse range of professionals serving in areas related to Medical Affairs.ResultsOver seven annual cohorts, 682 participants from eighty-six countries were enrolled in the program. The program’s effectiveness was assessed using Kirkpatrick’s model, showing elevated levels of satisfaction (over 4.0 on a five-point scale), suggesting significant gains in competence at the cognitive level and leveraged performance. Notably, 70% of responding alumni reported significant improvement in their functions, corroborated by 30% of their supervisors. The further long-term impact of the program on their respective organization has not been established.DiscussionThe GMDP Academy’s program has significantly contributed to life-long learning in Medicines Development, addressing educational gaps and fostering interdisciplinary collaboration. Its success highlights the importance of continuous education in keeping pace with the industry’s evolving demands and underscores the potential of blended learning in achieving educational objectives in pharmaceutical medicine.

It is often assumed in X-ray Photoelectron Spectroscopy that binding energy shifts are synonymous with changes in the chemical state of an atom and the chemical state can be described in terms of oxidation state and stoichiometry of the elements in a material that correlates with photoemission peaks. However, when an atom is bonded into a crystal lattice, the shapes and binding energy of photoemission may not match the expected stoichiometry when measured by XPS, even though shifts in binding energy suggest new oxidation states. In this work, a set of experiments is presented, in which Ar+ and He+ ions of different energies modify the native oxide on a titanium foil which yields XPS spectra that are not easily open to analysis by conventional peak models. In the course of analyzing these complex photoemission data by linear algebraic methods, the prospect emerged that XPS is suggesting that sputtering a native oxide may be providing insight into structural perturbation in addition to the stoichiometry-type changes to the native oxide.

Abstract INTRODUCTION Alzheimer's disease (AD) is a progressive neurodegenerative disease in which extracellular aggregates of the amyloid beta (Aβ) peptide precede widespread intracellular inclusions of the microtubule‐associated protein tau. The autosomal dominant form of AD requires mutations that increase production or aggregation of the Aβ peptide. This has led to the hypothesis that amyloid deposition initiates downstream responses that lead to the hyperphosphorylation and aggregation of tau. METHODS Here we use a novel approach, somatic gene transfer via intravenous adeno‐associated virus (AAV), to further explore the effects of pre‐existing amyloid deposits on tauopathy. APP+PS1 mice, which develop amyloid deposits at 3 to 6 months of age, and non‐transgenic littermates were injected at 8 months of age intravenously with AAV‐PHP.eB encoding P301L human tau. Tissue was collected at 13 months and tauopathy was assessed. RESULTS Total human tau expression was observed to be relatively uniform throughout the brain, reflecting the vascular route of AAV administration. Phospho‐tau deposition was not equal across brain regions and significantly increased in APP+PS1 mice compared to non‐transgenic controls. Interestingly, the rank order of phospho‐tau deposition of affected brain regions in both genotypes paralleled the rank order of amyloid plaque deposits in APP+PS1 mice. We also observed significantly increased MAPT RNA expression in APP+PS1 mice compared to non‐transgenic despite equal AAV transduction efficiency between groups. DISCUSSION This model has advantages over prior approaches with widespread uniform human tau expression throughout the brain and the ability to specify the stage of amyloidosis when the tau pathology is initiated. These data add further support to the amyloid cascade hypothesis and suggest RNA metabolism as a potential mechanism for amyloid‐induced tauopathy.

Carbon dioxide (CO2) capture and storage (CCS) is frequently identified as a potential component to achieving a decarbonized power system at least cost; however, power system models frequently lack detailed representation of CO2 transportation, injection, and storage (CTS) infrastructure. In this paper, we present a novel approach to explicitly represent CO2 storage potential and CTS infrastructure costs and constraints within a continental-scale power system capacity expansion model. In addition, we evaluate the sensitivity of the results to assumptions about the future costs and performance of CTS components and carbon capture technologies. We find that the quantity of CO2 captured within the power sector is relatively insensitive to the range of CTS costs explored, suggesting that the cost of CO2 capture retrofits is a more important driver of CCS implementation than the costs of transportation and storage. Finally, we demonstrate that storage and injection costs account for the predominant share of total costs associated with CTS investment and operation, suggesting that pipeline infrastructure costs have limited influence on the competitiveness of CCS.

Abstract Conservation funding is currently limited; cost‐effective conservation solutions are essential. We suggest that the thousands of field stations worldwide can play key roles at the frontline of biodiversity conservation and have high intrinsic value. We assessed field stations’ conservation return on investment and explored the impact of COVID‐19. We surveyed leaders of field stations across tropical regions that host primate research; 157 field stations in 56 countries responded. Respondents reported improved habitat quality and reduced hunting rates at over 80% of field stations and lower operational costs per km2 than protected areas, yet half of those surveyed have less funding now than in 2019. Spatial analyses support field station presence as reducing deforestation. These “earth observatories” provide a high return on investment; we advocate for increased support of field station programs and for governments to support their vital conservation efforts by investing accordingly.

Abstract The N-acylsulfonamide derivative, I942, represents the first non-cyclic nucleotide partial agonist of EPAC1. This was soon followed by the identification of the I942 analogues, PW0381, PW0521 and PWO577 and a series of benzofuran oxoacetic acid EPAC1 activators, SY006, SY007 and SY009. Protein interaction, cytotoxicity and EPAC1 activation assays applied here identify PWO577 and SY007 as being effective EPAC1 binders that are well tolerated in HUVECs at concentrations greater than 100 μM and up to 48 h incubation and are effective activators of transfected EPAC1 in U2OS cells. Using RNAseq in HUVECs we show that PWO577 and SY007 regulate approximately 11,000 shared genes, with only few differential gene changes being “off-target”. The genes significantly regulated by both PWO577 and SY007 included a subset of genes normally associated with endothelial activation, including ICAM1, MMP1 and CCL2. Of these, only the expression of MMP1 was markedly increased at the protein level, as determined by LC–MS-based proteomics. Both PWO577 and SY007 suppressed IL-6-induced STAT3 activation and associated downstream gene expression, including inhibition of SOCS3, STAT3, IL6ST and JAK3 genes. Together these results demonstrate the utility of structurally distinct, specific and non-toxic EPAC1 activators. Future modifications will be aimed at eliminating the few noted off-target effects.

Summary: Background: This phase 1b/2 PCYC-1123-CA study evaluated efficacy and safety of the combination of ibrutinib, lenalidomide, and rituximab (iR2 regimen) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) ineligible for stem cell transplantation. Methods: In phase 2, patients with relapsed/refractory non-germinal centre B-cell–like DLBCL received oral ibrutinib 560 mg once daily and oral lenalidomide 20 mg or 25 mg once daily on Days 1–21 of each 28-day cycle until disease progression or unacceptable toxicity and intravenous rituximab 375 mg/m2 on Day 1 of Cycles 1–6. The primary endpoint was overall response rate (ORR) in the response-evaluable population (received any study treatment and had ≥1 post-baseline disease assessment). The study was done at 24 academic and community hospitals in Belgium, Germany, United Kingdom, and USA. This study was registered with ClinicalTrials.gov, NCT02077166. Findings: Between March 13, 2014 and October 2, 2018, 89 patients were enrolled with a median time on study of 35.0 months. Best ORR in the response-evaluable population (n = 85) was 49% (95% confidence interval [CI], 38–61) across dose cohorts and 53% (95% CI, 39–67) and 44% (95% CI, 26–62) in the 20 mg and 25 mg lenalidomide cohorts, respectively, with complete responses in 24/85 (28%), 17/53 (32%), and 7/32 (22%) patients, respectively. Grade 3/4 adverse events (AEs) occurred in 81/89 patients (91%), most frequently neutropenia (36/89; 40%), maculopapular rash (16/89; 18%), anaemia (12/89; 13%), and diarrhoea (9/89; 10%). Serious adverse events occurred in 57/89 patients (64%). Fatal AEs occurred in 12/89 patients (13%); causes of death were worsening of DLBCL (n = 7), pneumonia (n = 3), sepsis (n = 1), and cardiac arrest (n = 1). Interpretation: The most frequent AEs (diarrhoea, neutropenia, fatigue, cough, anaemia, peripheral oedema, and maculopapular rash) were consistent with known safety profiles of the individual drugs. The iR2 regimen demonstrated antitumour activity with durable responses in patients with relapsed/refractory DLBCL. Funding: Pharmacyclics LLC, an AbbVie Company.

Background: We catalog and summarize evidence of the analytical performance of portable quantitative and semi-quantitative devices for the assessment of vitamin A status and vitamin A deficiency (VAD) in various biological samples—including whole blood, plasma, serum, and milk—in addition to VAD determination by functional indicators such as pupillary response. Methods: We searched the literature for published research articles, patents, and information from manufacturers of mobile devices, particularly those appropriate for low-resource settings. The included devices were required to be portable (lightweight and ideally not needing a power outlet) and to measure vitamin A as well as define VAD. Eligible studies compared a portable device to a reference standard of high-performance liquid chromatography for blood and milk, or a Goldmann-Weekers dark adaptometer for eyes/vision. Where available, identified devices were compared with reference methods across several performance criteria. When possible, we compared the device’s performance reported in published studies against the stated performance criteria from the manufacturers’ websites. Results: We catalogued 25 portable devices for measuring vitamin A and/or VAD via biological samples. We also identified 18 comparison studies (plus associated reports) assessing nine methods: the iCheck Fluoro, iCheck Carotene, CRAFTi, Tidbit with or without the HYPER filtration system, custom field-friendly immunoassays, and microfluidic assays for blood; the iCheck Fluoro and iCheck Carotene for milk; and the Scotopic Sensitivity Tester-1 for eye function. Conclusions: The iCheck Fluoro and iCheck Carotene are commercially available for use and are acceptable for measuring vitamin A in blood and milk samples, according to the available validation data. Many of the other identified devices, including other portable fluorometers, photometers, immunoassays, microfluidics-based devices, and dark adaptometers, were proofs of concept and not yet commercially available. Furthermore, none of these other devices included manufacturer-described device performance criteria to compare with descriptions from experimental studies. Several gaps remain, including studies comparing the other portable devices against a reference standard, particularly for functional indicators of vitamin A status/deficiency; available manufacturer-reported device performance criteria against which to compare future results of investigations; and more comprehensive reporting of validation metrics including sensitivity, specificity, precision, and Bland-Altman analysis.

Summary: Knowledge on the population history of endangered species is critical for conservation, but whole-genome data on chimpanzees (Pan troglodytes) is geographically sparse. Here, we produced the first non-invasive geolocalized catalog of genomic diversity by capturing chromosome 21 from 828 non-invasive samples collected at 48 sampling sites across Africa. The four recognized subspecies show clear genetic differentiation correlating with known barriers, while previously undescribed genetic exchange suggests that these have been permeable on a local scale. We obtained a detailed reconstruction of population stratification and fine-scale patterns of isolation, migration, and connectivity, including a comprehensive picture of admixture with bonobos (Pan paniscus). Unlike humans, chimpanzees did not experience extended episodes of long-distance migrations, which might have limited cultural transmission. Finally, based on local rare variation, we implement a fine-grained geolocalization approach demonstrating improved precision in determining the origin of confiscated chimpanzees.

In October 2021, 59 scientists from 14 countries and 13 U.S. states collaborated virtually in the Third Annual Baylor College of Medicine & DNANexus Structural Variation hackathon. The goal of the hackathon was to advance research on structural variants (SVs) by prototyping and iterating on open-source software. This led to nine hackathon projects focused on diverse genomics research interests, including various SV discovery and genotyping methods, SV sequence reconstruction, and clinically relevant structural variation, including SARS-CoV-2 variants. Repositories for the projects that participated in the hackathon are available at https://github.com/collaborativebioinformatics.

Lester and colleagues use faecal samples and genetic analyses to investigate the genetic connectivity across chimpanzees. Their results indicate that the global pattern of genetic diversity in chimpanzees is largely characterized by a pattern of isolation by distance with several isolated populations exhibiting strong local differentiation.

Abstract Background Circulating autoantibodies and sex-dependent discrepancy in prevalence are unexplained phenomena of Alzheimer’s disease (AD). Using the 3xTg-AD mouse model, we reported that adult males show early manifestations of systemic autoimmunity, increased emotional reactivity, enhanced expression of the histone variant macroH2A1 in the cerebral cortex, and loss of plaque/tangle pathology. Conversely, adult females display less severe autoimmunity and retain their AD-like phenotype. This study examines the link between immunity and other traits of the current 3xTg-AD model. Methods Young 3xTg-AD and wild-type mice drank a sucrose-laced 0.4 mg/ml solution of the immunosuppressant cyclophosphamide on weekends for 5 months. After behavioral phenotyping at 2 and 6 months of age, we assessed organ mass, serologic markers of autoimmunity, molecular markers of early AD pathology, and expression of genes associated with neurodegeneration. Results Chronic immunosuppression prevented hematocrit drop and reduced soluble Aβ in 3xTg-AD males while normalizing the expression of histone variant macroH2A1 in 3xTg-AD females. This treatment also reduced hepatosplenomegaly, lowered autoantibody levels, and increased the effector T cell population while decreasing the proportion of regulatory T cells in both sexes. Exposure to cyclophosphamide, however, neither prevented reduced brain mass and BDNF expression nor normalized increased tau and anxiety-related behaviors. Conclusion The results suggest that systemic autoimmunity increases soluble Aβ production and affects transcriptional regulation of macroH2A1 in a sex-related manner. Despite the complexity of multisystem interactions, 3xTg-AD mice can be a useful in vivo model for exploring the regulatory role of autoimmunity in the etiology of AD-like neurodegenerative disorders.

Environmental variability is one potential driver of behavioural and cultural diversity in humans and other animals. Here, the authors show that chimpanzee behavioural diversity is higher in habitats that are more seasonal and historically unstable, and in savannah woodland relative to forested sites.

Prolonged intermittent renal replacement therapy (PIRRT) is an emerging form of renal replacement therapy in critically ill patients, but dosing data for antibiotics such as amoxicillin and cefepime are scarce and limited. This case report describes the effect of PIRRT on the plasma pharmacokinetics of amoxicillin and cefepime in a 69-year-old, critically ill patient with a polymicrobial intra-abdominal infection. Blood samples taken over 2 days, including a 7-hour PIRRT session, were analysed and a two-compartment model was used to describe cefepime and amoxicillin clearance and dosing requirements during PIRRT and off-PIRRT in this patient. Based on these data, an off-PIRRT dose of 1 g amoxicillin 12-hourly and cefepime 2 g daily with an on-PIRRT dose of 1 g amoxicillin 8-hourly and cefepime 2 g 12-hourly was deemed appropriate.

Pd–Zn/TiO2 catalysts containing 1 wt% total metal loading, but with different Pd to Zn ratios, were prepared using a modified impregnation method and tested in the solvent-free aerobic oxidation of benzyl alcohol. The catalyst with the higher Pd content exhibited an enhanced activity for benzyl alcohol oxidation. However, the selectivity to benzaldehyde was significantly improved with increasing presence of Zn. The effect of reduction temperature on catalyst activity was investigated for the catalyst having a Pd to Zn metal molar ratio of 9:1. It was found that lower reduction temperature leads to the formation of PdZn nanoparticles with a wide particle size distribution. In contrast, smaller PdZn particles were formed upon catalyst reduction at higher temperatures. Computational studies were performed to compare the adsorption energies of benzyl alcohol and the reaction products (benzaldehyde and toluene) on PdZn surfaces to understand the oxidation mechanism and further explain the correlation between the catalyst composition and its activity.

Widespread transduction of the CNS with a single, non-invasive systemic injection of adeno-associated virus is now possible due to the creation of blood-brain barrier-permeable capsids. However, as these capsids are mutants of AAV9, they do not have specific neuronal tropism. Therefore, it is necessary to use genetic tools to restrict expression of the transgene to neuronal tissues. Here we compare the strength and specificity of two neuron-specific promoters, human synapsin 1 and mouse calmodulin/calcium dependent kinase II, to the ubiquitous CAG promoter. Administration of a high titer of virus is necessary for widespread CNS transduction. We observed the neuron-specific promoters drive comparable overall expression in the brain to the CAG promoter. Furthermore, the neuron-specific promoters confer significantly less transgene expression in peripheral tissues compared with the CAG promoter. Future experiments will utilize these delivery platforms to over-express the Alzheimer-associated pathological proteins amyloid-beta and tau to create mouse models without transgenesis.

Gut microbial communities are drivers of primate physiology and health, but the factors that influence the gut microbiome in wild primate populations remain largely undetermined. We report data from a continent-wide survey of wild chimpanzee gut microbiota and highlight the effects of genetics, vegetation, and potentially even tool use at different spatial scales on the chimpanzee gut microbiome, including bacteria, archaea, and eukaryotic parasites.

In an era of environmental change leading to rising sea levels and increased storminess, there is a need to quantify the volume of beach sediment on the coast of Britain in order to assess the vulnerability to erosion using cheap, easy-to-deploy and non-invasive methods. Horizontal-to-vertical spectral ratio (HVSR) is a technique that uses the natural background seismic ‘noise’ in order to determine the depth of underlying geological interfaces that have contrasting physical properties. In this study, the HVSR technique was deployed at a number of settings on the coast of England that represented a range of different compositions, geomorphology, and underlying bedrock. We verified the results by comparison to other survey techniques, such as ground-penetrating RADAR, multichannel analysis of surface waves (MASW), and cone penetration tests. At locations where there was sufficient contrast in physical properties of the beach material compared to the underlying bedrock, the beach thickness (and therefore the volume of erodible material) was successfully determined, showing that HVSR is a useful tool to use in these settings.

THC has been used as a promising treatment approach for neurological disorders, but the highly psychoactive effects have largely warned off many scientists from pursuing it further. We conducted an intranasal treatment using low-dose THC on 12-month-old APP/PS1 mice daily for 3 months to overcome any potential psychoactive response induced by the systemic delivery. Our results demonstrate that the THC nasal treatment at 0.002 and 0.02 mg/kg significantly slowed the memory decline compared to that in the vehicle-treated transgenic mouse control group. An enzyme-linked immunosorbent assay showed that the Aβ1–40 and 1–42 peptides decreased in the THC-treated groups. The Western blot data indicate that long-term low-dose THC intranasal administration promoted p-tau level reduction and mitochondrial function marker redistribution. The blood biochemical parameter data demonstrate some insignificant changes in cytokine, immunoglobulin, and immune cell profiles during intranasal THC treatment. Intranasal delivery is a non-invasive and convenient method that rapidly targets therapeutics to the brain, minimizing systemic exposure to avoid unwanted adverse effects. Our study provides new insights into the role of low-dose THC intranasal treatment as a pharmacological strategy to counteract alterations in Alzheimer’s disease-related cognitive performance.

Studies on the effective and safe therapeutic dosage of delta-9-tetrahydrocannabinol (THC) for the treatment of Alzheimer’s disease (AD) have been sparse due to the concern about THC’s psychotropic activity. The present study focused on demonstrating the beneficial effect of low-dose THC treatment in preclinical AD models. The effect of THC on amyloid-β (Aβ) production was examined in N2a/AβPPswe cells. An in vivo study was conducted in aged APP/PS1 transgenic mice that received an intraperitoneal injection of THC at 0.02 and 0.2 mg/kg every other day for three months. The in vitro study showed that THC inhibited Aβ aggregation within a safe dose range. Results of the radial arm water maze (RAWM) test demonstrated that treatment with 0.02 and 0.2 mg/kg of THC for three months significantly improved the spatial learning performance of aged APP/PS1 mice in a dose-dependent manner. Results of protein analyses revealed that low-dose THC treatment significantly decreased the expression of Aβ oligomers, phospho-tau and total tau, and increased the expression of Aβ monomers and phospho-GSK-3β (Ser9) in the THC-treated brain tissues. In conclusion, treatment with THC at 0.2 and 0.02 mg/kg improved the spatial learning of aged APP/PS1 mice, suggesting low-dose THC is a safe and effective treatment for AD.

Qualitative researchers face unique opportunities and challenges as a result of the disruption of COVID-19. Although the pandemic represents a unique opportunity to study the crisis itself, social distancing mandates are restricting traditional face-to-face investigations of all kinds. In this article, we describe options and resources for researchers who find themselves needing to alter their study designs from face-to-face qualitative data collection to a “socially distant” method. Although technologies are constantly changing, we review the latest videoconferencing services available to researchers and provide guidance on what services might best suit a project’s needs. We describe options for various platforms and applications including information about enhanced security applications for researchers collecting sensitive patient health information. Concerns about these technologies including security of the platform and logistical needs such as computer equipment are also discussed. Special attention is given to ethical issues when transitioning research efforts to online venues.

Although the Parmenidean poem (late 6th-early 5th centuries BCE) is in epic meter and teems with vivid imagery, it has been translated into the domain of philosophy since its earliest reception. Within this domain it has traditionally been interpreted as the first "explicit and self-conscious argumentation" of western philosophy (Gallop 1984, 3). Yet, the poem aims at persuasion and affect rather than logical demonstration (Smith 2003, 269-75). Working primarily with a sense of translation as critical reception, this paper articulates the history of a translational protocol that excises conceptual matter from linguistic form (Cassin 2010, 19; Batchelor 2010, 49-50), reducing the semantic range of the Parmenidean poem. Beginning with Zeno and Melissus (early 5th c BCE), a series of translations reduces the Parmenidean poem into a vehicle for a separable and fully translatable doctrine, stabilizing and homogenizing a thinking that otherwise persists as polyvalent and heterogeneous.

Infants are more likely to develop lethal disseminated forms of tuberculosis compared with older children and adults. The reasons for this are currently unknown. In this study we test the hypothesis that antimycobacterial function is impaired in infant alveolar macrophages (AMϕs) compared with those of adults. We develop a method of obtaining AMϕs from healthy infants using rigid bronchoscopy and incubate the AMϕs with live virulent Mycobacterium tuberculosis (Mtb). Infant AMϕs are less able to restrict Mtb replication compared with adult AMϕs, despite having similar phagocytic capacity and immunophenotype. RNA-Seq showed that infant AMϕs exhibit lower expression of genes involved in mycobactericidal activity and IFNγ-induction pathways. Infant AMϕs also exhibit lower expression of genes encoding mononuclear cell chemokines such as CXCL9. Our data indicates that failure of AMϕs to contain Mtb and recruit additional mononuclear cells to the site of infection helps to explain the more fulminant course of tuberculosis in early life.

Abstract Introduction The quest to identify an effective therapeutic strategy for neurodegenerative diseases, such as mild congitive impairment (MCI) and Alzheimer's disease (AD), suffers from the lack of good human‐based models. Animals represent the most common models used in basic research and drug discovery studies. However, safe and effective compounds identified in animal studies often translate poorly to humans, yielding unsuccessful clinical trials. Methods A functional in vitro assay based on long‐term potentiation (LTP) was used to demonstrate that exposure to amyloid beta (Aβ42) and tau oligomers, or brain extracts from AD transgenic mice led to prominent changes in human induced pluripotent stem cells (hiPSC)‐derived cortical neurons, notably, without cell death. Results Impaired information processing was demonstrated by treatment of neuron‐MEA (microelectrode array) systems with the oligomers and brain extracts by reducing the effects of LTP induction. These data confirm the neurotoxicity of molecules linked to AD pathology and indicate the utility of this human‐based system to model aspects of AD in vitro and study LTP deficits without loss of viability; a phenotype that more closely models the preclinical or early stage of AD. Discussion In this study, by combining multiple relevant and important molecular and technical aspects of neuroscience research, we generated a new, fully human in vitro system to model and study AD at the preclinical stage. This system can serve as a novel drug discovery platform to identify compounds that rescue or alleviate the initial neuronal deficits caused by Aβ42 and/or tau oligomers, a main focus of clinical trials.

Devotional piety broadly depends on events that are not accessible for direct observation and commonly offer very little, if anything, in the way of historical documentation. Sometimes the experiences to which devotion is directed in the veneration of saints is based on visionary experience for which reports are contradictory. This essay explores ways in which word and image are brought together to anchor evanescent or ephemeral, or entirely uncertain, origins and provide devotion with stable objects. I develop the view that word and image are generatively entangled, meaning that their ambiguous connections with one another are able to produce a medium in which devotion finds a footing. The discussion focuses on two case studies: Our Lady of Fátima and Saint Jude. Fátima is based on a series of apparitions to young children in 1917 and Jude is a historically shadowy figure whose cult underwent a modern revival, in part assisted by new iconographic developments that allowed devotees to link their saint to very old traditions. Lore and imagery work together as forms of saying and seeing that bring elusive origins into focus.