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Ninety students were randomly selected from students enrolled in a college general biology course and assigned randomly to two groups working in audio-tutorial laboratories. The "direct" group was taught by audio-taped lectures, laboratory exercises, and guide sheets that were primarily expository and descriptive; the "indirect" group received similar materials which involved periods of question and answer activities. Each group was administered tests to determine their mastery of facts, concepts, and principles concerning heredity, their critical thinking skills, and their attitudes toward biology, genetics, and audio-tutorial instruction at the beginning and end of the 8-week course. A fact retention test was given 10 weeks later. The pretest scores indicated that the groups were initially comparable. No significant differences were found between the two groups in total achievement, critical thinking abilities, retention, or attitude. Both groups showed a significant positive change in attitude toward audio-tutorials as a teaching method. There was a significant difference in favor of the indirect group with respect to problem solving abilities. (Author/AL)

Aims/hypothesis Beta cells control glucose homeostasis via regulated production and secretion of insulin. This function arises from a highly specialised gene expression programme that is established during development and then sustained, with limited flexibility, in terminally differentiated cells. Dysregulation of this programme is seen in type 2 diabetes but mechanisms that preserve gene expression or underlie its dysregulation in mature cells are not well resolved. This study investigated whether methylation of histone H3 lysine 4 (H3K4), a marker of gene promoters with unresolved functional importance, is necessary for the maintenance of mature beta cell function. Methods Beta cell function, gene expression and chromatin modifications were analysed in conditional Dpy30 knockout mice, in which H3K4 methyltransferase activity is impaired, and in a mouse model of diabetes. Results H3K4 methylation maintains expression of genes that are important for insulin biosynthesis and glucose responsiveness. Deficient methylation of H3K4 leads to a less active and more repressed epigenome profile that locally correlates with gene expression deficits but does not globally reduce gene expression. Instead, developmentally regulated genes and genes in weakly active or suppressed states particularly rely on H3K4 methylation. We further show that H3K4 trimethylation (H3K4me3) is reorganised in islets from the Leprdb/db mouse model of diabetes in favour of weakly active and disallowed genes at the expense of terminal beta cell markers with broad H3K4me3 peaks. Conclusions/interpretation Sustained methylation of H3K4 is critical for the maintenance of beta cell function. Redistribution of H3K4me3 is linked to gene expression changes that are implicated in diabetes pathology. Graphical abstract

The 9th biennial conference titled “Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases” was hosted virtually, due to the ongoing COVID-19 pandemic, in collaboration with the University of Vermont Larner College of Medicine, the National Heart, Lung, and Blood Institute, the Alpha-1 Foundation, the Cystic Fibrosis Foundation, and the International Society for Cell & Gene Therapy. The event was held from July 12th through 15th, 2021 with a pre-conference workshop held on July 9th. As in previous years, the objectives remained to review and discuss the status of active research areas involving stem cells (SCs), cellular therapeutics, and bioengineering as they relate to the human lung. Topics included 1) technological advancements in the in situ analysis of lung tissues, 2) new insights into stem cell signaling and plasticity in lung remodeling and regeneration, 3) the impact of extracellular matrix in stem cell regulation and airway engineering in lung regeneration, 4) differentiating and delivering stem cell therapeutics to the lung, 5) regeneration in response to viral infection, and 6) ethical development of cell-based treatments for lung diseases. This selection of topics represents some of the most dynamic and current research areas in lung biology. The virtual workshop included active discussion on state-of-the-art methods relating to the core features of the 2021 conference, including in situ proteomics, lung-on-chip, induced pluripotent stem cell (iPSC)-airway differentiation, and light sheet microscopy. The conference concluded with an open discussion to suggest funding priorities and recommendations for future research directions in basic and translational lung biology.

The demand for animal-based protein sources is increasing rapidly. The rearing of insects on bioproducts and their subsequent use as feedstock for animals has been receiving a lot of attention lately. Hermetia illucens, black soldier flies are highly investigated insects owing to their ability to reduce and transform different types of wastes, such as agricultural, household, municipal wastes, and human sludge. The nutritional composition and amino acid profile of black soldier fly larvae (BSFL) raised on these organic wastes is similar to that of several feed constituents making it a suitable material for feed. However, the commercialisation of BSFL is limited due to prevailing unclear legislative requirements regarding their use as feed. In this paper, the legislative landscape involved in using BSFL as feed in different regions is addressed. European Union, Australia, Canada and USA specifically allow the trade and manufacture of BSFL as feed under specific conditions. Interestingly, most countries where entomophagy is a tradition, lack specific regulations concerning their use as feed and are currently drafting regulatory frameworks. Understanding the legislative layout is essential for harmonising the industrial upscaling of BSFL as animal feed.

The treatment landscape for advanced urothelial cancer has changed dramatically owing to the US Food and Drug Administration approval and introduction of antibody-drug conjugates (ADCs), including enfortumab vedotin and sacituzumab govitecan. Efforts have begun to use these therapies in earlier disease states, specifically bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). We assessed gene expression associated with these newly approved therapies in a novel cohort of treatment-naïve NMIBC tumors before and after BCG therapy. Multiple genes, including Nectin-4, Trop-2, and Her-2, exhibited increased expression after BCG therapy compared to baseline. However, few of the tumors with increased expression of ADC targets also exhibited increased PD-L1/PD-1 expression. Taken together, these data demonstrate the heterogeneous genomic landscape of BCG-exposed NMIBC, and provide evidence supporting the evaluation of ADCs in NMIBC. PATIENT SUMMARY: We evaluated the potential role of targeted therapies that have been approved in the USA for advanced non-muscle-invasive bladder cancer (NMIBC) that has recurred after treatment with bacillus Calmette-Guérin (BCG). By assessing levels of specific genes and proteins linked to the targeted therapies, we demonstrate that there is rationale for further evaluation of these therapies in NMIBC.

Contains fulltext : 248576.pdf (Publisher’s version ) (Open Access) Single-cell antigen-receptor gene amplification and sequencing platforms have been used to characterize T cell receptor (TCR) repertoires but typically fail to generate paired full-length gene products for direct expression cloning and do not enable linking this data to cell phenotype information. To overcome these limitations, we established a high-throughput platform for the quantitative and qualitative analysis of human TCR repertoires that provides insights into the clonal and functional composition of human CD4(+) and CD8(+) αβ T cells at the molecular and cellular level. The strategy is a powerful tool to qualitatively assess differences between antigen receptors of phenotypically defined αβ T cell subsets, e.g. in immune responses to cancer, vaccination, or infection, and in autoimmune diseases.

Background Diurnal rhythms in gene expression have been detected in the human brain. Previous studies found that males and females exhibit 24-hour rhythms in known circadian genes, with earlier peak expression in females. Whether there are sex differences in large-scale transcriptional rhythms in the cortex that align with observed sex differences in physiological and behavioral rhythms is currently unknown. Methods Diurnal rhythmicity of gene expression was determined for males and females using RNA sequencing data from human postmortem dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). Sex differences among rhythmic genes were determined using significance cutoffs, threshold-free analyses, and R2 difference. Phase concordance was assessed across the DLPFC and ACC for males and females. Pathway and transcription factor analyses were also conducted on significantly rhythmic genes. Results Canonical circadian genes had diurnal rhythms in both sexes with similar amplitude and phase. When analyses were expanded to the entire transcriptome, significant sex differences in transcriptional rhythms emerged. There were nearly twice as many rhythmic transcripts in the DLPFC in males and nearly 4 times as many rhythmic transcripts in the ACC in females. Results suggest a diurnal rhythm in synaptic transmission specific to the ACC in females (e.g., GABAergic [gamma-aminobutyric acidergic] and cholinergic neurotransmission). For males, there was phase concordance between the DLPFC and ACC, while phase asynchrony was found in females. Conclusions There are robust sex differences in molecular rhythms of genes in the DLPFC and ACC, providing potential mechanistic insights into how neurotransmission and synaptic function are modulated in a circadian-dependent and sex-specific manner.

The biostimulant BC204 is a commercially available biostimulant based on an extract from Citrus aurantium, comprising a mixture of bioflavonoids, other plant extracts and organic acids. In this study, the potential of BC204 to cause positive effects on plant growth and overall plant health by altering the rhizosphere microbial community of Solanum lycopersicum L. was investigated. Mycorrhizal colonization of plant roots was analysed by trypan blue-staining and light microscopy, followed by polymerase chain reaction (PCR) amplification of a region of the 18S rRNA gene conserved among arbuscular mycorrhizal fungi. No difference in mycorrhizal colonization of roots was observed between control and treated plants. The structural and functional diversity of rhizosphere bacteria between different treatment groups was assessed using 16S rRNA gene restriction fragment length polymorphism (RFLP) analysis and community-level physiological profiling (CLPP), respectively. Nearest sequence matches for three isolates from the rhizosphere of plants treated with BC204 as a soil drench in soil supplemented with Mycoroot™ revealed bacterial genera which play a role in promoting plant growth. Furthermore, the microbial community from this treatment group showed increased richness of substrate utilization on Biolog EcoPlates™. These results indicate some form of interaction between BC204 and Mycoroot™ which causes a shift in the structural and functional diversity of the rhizosphere bacterial community.

Myxococcus xanthus is a common soil bacterium with a complex life cycle, which is known for production of secondary metabolites. However, little is known about the effects of nutrient availability on M. xanthus metabolite production. In this study, we utilize confocal Raman microscopy (CRM) to examine the spatiotemporal distribution of chemical signatures secreted by M. xanthus and their response to varied nutrient availability. Ten distinct spectral features are observed by CRM from M. xanthus grown on nutrient-rich medium. However, when M. xanthus is constrained to grow under nutrient-limited conditions, by starving it of casitone, it develops fruiting bodies, and the accompanying Raman microspectra are dramatically altered. The reduced metabolic state engendered by the absence of casitone in the medium is associated with reduced, or completely eliminated, features at 1140 cm-1, 1560 cm-1, and 1648 cm-1. In their place, a feature at 1537 cm-1 is observed, this feature being tentatively assigned to a transitional phase important for cellular adaptation to varying environmental conditions. In addition, correlating principal component analysis heat maps with optical images illustrates how fruiting bodies in the center co-exist with motile cells at the colony edge. While the metabolites responsible for these Raman features are not completely identified, three M. xanthus peaks at 1004, 1151, and 1510 cm-1 are consistent with the production of lycopene. Thus, a combination of CRM imaging and PCA enables the spatial mapping of spectral signatures of secreted factors from M. xanthus and their correlation with metabolic conditions.

Colonization factor antigen I (CFA/I) fimbria, an adhesin from enterotoxigenic Escherichia coli, confers protection in murine autoimmune models for type 1 diabetes (T1D), multiple sclerosis, and rheumatoid arthritis. Although CFA/I fimbriae's initial mode of action is in a bystander or in an antigen (Ag)-independent fashion, protection is ultimately dependent upon the induction and/or activation of auto-Ag-specific regulatory T cells (Tregs). However, little is known about how protection transitions from bystander suppression to Ag-specific Tregs. Since dendritic cells (DCs) play an integral role in fate decisions for T cells becoming inflammatory or tolerogenic, the described study tests the hypothesis that Lactococcus lactis expressing CFA/I (LL-CFA/I) stimulates DCs to establish a regulatory microenvironment. To this end, bone marrow-derived dendritic cells (BMDCs) were infected in vitro with LL-CFA/I. Results revealed increased production of IL-10, TGF-β, and indoleamine 2,3-deoxygenase (IDO). Although co-culture of LL-CFA/I infected BMDCs with naive T cells did not promote Foxp3 expression, TNF-α and IFN-γ production was suppressed. NOD mice orally dosed with LL-CFA/I showed an increase in regulatory plasmacytoid DCs (pDCs) expressing IDO and TGF-β in pancreatic lymph nodes (PaLNs) and spleen three days post-treatment. However, Tregs did not appear in the mucosal inductive sites until much later. These findings show that LL-CFA/I influences specific DC populations to establish tolerance.

Food acquisition is an important modulator of animal behavior and habitat selection that can affect fitness. Optimal foraging theory predicts that predators should select habitat patches to maximize their foraging success and net energy gain, likely achieved by targeting areas with high prey availability. However, it is debated whether prey availability drives fine‐scale habitat selection for predators. We assessed whether an ambush predator, the timber rattlesnake (Crotalus horridus), exhibits optimal foraging site selection based on the spatial distribution and availability of prey. We used passive infrared camera trap detections of potential small mammal prey (Peromyscus spp., Tamias striatus, and Sciurus spp.) to generate variables of prey availability across the study area and used whether a snake was observed in a foraging location or not to model optimal foraging in timber rattlesnakes. Our models of small mammal spatial distributions broadly predicted that prey availability was greatest in mature deciduous forests, but T. striatus and Sciurus spp. exhibited greater spatial heterogeneity compared with Peromyscus spp. We found the spatial distribution of cumulative small mammal encounters (i.e., overall prey availability), rather than the distribution of any one species, to be highly predictive of snake foraging. Timber rattlesnakes appear to forage where the probability of encountering prey is greatest. Our study provides evidence for fine‐scale optimal foraging in a low‐energy, ambush predator and offers new insights into drivers of snake foraging and habitat selection., We assessed whether the spatial distribution and availability of potential prey influence foraging site selection in a low‐energy ambush predator, the timber rattlesnake. We found the spatial distribution of cumulative small mammal encounters (i.e. overall prey availability), rather than the distribution of any one prey species, to be highly predictive of snake foraging. We demonstrate that optimal foraging theory may be applicable to the habitat selection of low‐energy ambush predators.

Idiopathic pulmonary fibrosis (IPF) is a severe fibrotic lung disease, in which inflammation is thought to only play a secondary role. Several factors associated with acute exacerbations of IPF (AE-IPF) have been identified, including infections. This study investigated whether humoral immunodeficiency or increased inflammatory markers at diagnosis were associated with AE-IPF and survival. Four-hundred-and-nine patients diagnosed with IPF between 2011 and 2017 were retrospectively included. Immune status investigations at diagnosis included measurement of serum immunoglobulins (available in 38%), leukocyte and lymphocyte subsets in blood and bronchoalveolar lavage (BAL) fluid (available in 58%), as well as response to pneumococcal vaccination (available in 64%). Serum immunoglobulins or IgG subclass levels were below the lower limit of normal in 6%. The response to pneumococcal vaccination was severely impaired in 1%. Thirteen percent of patients developed an AE-IPF (4.7% per year). AE-IPF were associated with elevated lymphocytes in BAL fluid at diagnosis (p = 0.03). Higher serum IgA and IgG at diagnosis were associated with worse survival (p = 0.01; and p = 0.04), as were an increased BAL lymphocyte percentage (p = 0.005), and higher blood leukocytes and neutrophils (p = 0.01; and p = 0.0005). In a multivariate model, only BAL lymphocyte count retained statistical significance (p = 0.007). The prevalence of humoral immunodeficiencies was low in patients with IPF and not associated with AE-IPF or survival. Elevated lymphocytes in BAL were associated with the development of AE-IPF and worse survival. Higher serum immunoglobulins and immune cells in blood were also associated with worse survival. The local immune response in the lungs may be a target for future therapies.

Assessing relative performance of different sampling methods used for early detection monitoring (EDM) is a critical step in understanding the likelihood of detecting new non-indigenous species (NIS) in an environment of interest. EDM performance metrics are typically based on the probability of detecting established NIS or rare indigenous species; however, detection probability estimates for these proxies may not accurately reflect survey effectiveness for newly introduced NIS. We used data from three different EDM survey approaches that varied by targeted life-stage (adult–juvenile versus ichthyoplankton), media (physical fish versus environmental DNA), and taxonomic method (morphology-based versus DNA-based taxonomy) to explore relative detection sensitivity for recently introduced white bass (Morone chrysops) and gizzard shad (Dorosoma cepedianum) in the Port of Duluth-Superior, a NIS introduction hot spot within the Laurentian Great Lakes. Detection efficiency, measured by the effort (number of samples) required to achieve 95% probability of detection, differed by EDM approach and species. Also, the relative sensitivity (detection rate) of each survey approach differed by species. For both species, detection in surveys using DNA-based taxonomy was generally as good or better than the adult–juvenile survey using morphology-based taxonomy. While both species appear to have been detected at early stages of invasion, white bass were likely present up to 5 years prior to initial detection, whereas gizzard shad may have been detected in the first year of introduction. We conclude that using complimentary sampling methods can help to balance the strengths and weaknesses of each approach and provide more reliable early detection of new invaders.

Lipid anchors are common post-translational modifications for proteins engaged in signaling and vesicular transport in eukaryotic cells. Rab proteins are geranylgeranylated at their C-termini, a modification which is important for their stable binding to lipid bilayers. The Rab escort protein (REP) is an accessory protein of the Rab geranylgeranyl transferase (RGT) complex and it is obligatory for Rab prenylation. While REP-Rab interactions have been studied by biochemical, structural, and genetic methods in animals and yeast, data on the plant RGT complex are still limited. Here we use hydrogen-deuterium exchange mass spectrometry (HDX-MS) to describe the structural basis of plant REP-Rab binding. The obtained results show that the interaction of REP with Rabs is highly dynamic and involves specific structural changes in both partners. In some cases the Rab and REP regions involved in the interaction are molecule-specific, and in other cases they are common for a subset of Rabs. In particular, the C-terminus of REP is not involved in binding of unprenylated Rab proteins in plants, in contrast to mammalian REP. In line with this, a C-terminal REP truncation does not have pronounced phenotypic effects in planta. On the contrary, a complete lack of functional REP leads to male sterility in Arabidopsis: pollen grains develop in the anthers, but they do not germinate efficiently and hence are unable to transmit the mutated allele. The presented data show that the mechanism of action of REP in the process of Rab geranylgeranylation is different in plants than in animals or yeast.

Previous economic estimates of infection with Toxoplasma gondii and chronic sequelae following infection lack sufficient data to establish the true burden of disease and its chronic sequelae. This ...

Background/aim Primary osteosarcoma of the breast is an exceedingly-rare malignant tumor that shares histological characteristics with osteosarcoma of the bone. Since effective therapies have not yet been established, standard therapy for osteosarcoma of the bone was examined in the present study for efficacy against primary osteosarcoma of the breast in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Materials and methods The PDOX mouse models were established by surgical implantation of the primary osteosarcoma of the breast specimen into the mammary gland of nude mice. Mice with tumors were randomized into four groups, each n=4: control group; cisplatinum (CDDP)-treatment group; doxorubicin (DOX)-treatment group; and CDDP/DOX-combination-treatment group. Mice were treated for twenty-one days, three weeks after implantation. Tumor size and body weight were measured during three weeks of treatment. Results Significant tumor growth inhibition was observed, compared to the control, in the CDDP-treatment group, the DOX-treatment group, and the combination-treatment-group. Only the combination treatment regressed the tumor. Conclusion CDDP and DOX which are standard first-line therapies for osteosarcoma, may be clinically effective against primary osteosarcoma of the breast, and in particular, their combination.

Prior to initiation of DNA replication, the eukaryotic helicase, Mcm2-7, must be activated to unwind DNA at replication start sites in early S phase. To study helicase activation within origin chromatin, we constructed a conditional mutant of the polymerase α subunit Cdc17 (or Pol1) to prevent priming and block replication. Recovery of these cells at permissive conditions resulted in the generation of unreplicated gaps at origins, likely due to helicase activation prior to replication initiation. We used micrococcal nuclease (MNase)-based chromatin occupancy profiling under restrictive conditions to study chromatin dynamics associated with helicase activation. Helicase activation in the absence of DNA replication resulted in the disruption and disorganization of chromatin, which extends up to 1 kb from early, efficient replication origins. The CMG holohelicase complex also moves the same distance out from the origin, producing single-stranded DNA that activates the intra-S-phase checkpoint. Loss of the checkpoint did not regulate the progression and stalling of the CMG complex but rather resulted in the disruption of chromatin at both early and late origins. Finally, we found that the local sequence context regulates helicase progression in the absence of DNA replication, suggesting that the helicase is intrinsically less processive when uncoupled from replication.

In nature, methane is oxidized to methanol by two enzymes, the iron-dependent soluble methane monooxygenase (sMMO) and the copper-dependent particulate MMO (pMMO). While sMMO's diiron metal active site is spectroscopically and structurally well-characterized, pMMO's copper sites are not. Recent EPR and ENDOR studies have established the presence of two monocopper sites, but the coordination environment of only one has been determined, that within the PmoB subunit and denoted CuB. Moreover, this recent work only focused on a type I methanotrophic pMMO, while previous observations of the type II enzyme were interpreted in terms of the presence of a dicopper site. First, this report shows that the type II Methylocystis species strain Rockwell pMMO, like the type I pMMOs, contains two monocopper sites and that its CuB site has a coordination environment identical to that of type I enzymes. As such, for the full range of pMMOs this report completes the refutation of prior and ongoing suggestions of multicopper sites. Second, and of primary importance, EPR/ENDOR measurements (a) for the first time establish the coordination environment of the spectroscopically observed site, provisionally denoted CuC, in both types of pMMO, thereby (b) establishing the assignment of this site observed by EPR to the crystallographically observed metal-binding site in the PmoC subunit. Finally, these results further indicate that CuC is the likely site of biological methane oxidation by pMMO, a conclusion that will serve as a foundation for proposals regarding the mechanism of this reaction.

Transcriptional regulation, a pivotal biological process by which cells adapt to environmental fluctuations, is achieved by the binding of transcription factors to target sequences in a sequence-specific manner. However, how transcription factors recognize the correct target from amongst the numerous candidates in a genome has not been fully elucidated. We here show that, in the fission-yeast fbp1 gene, when transcription factors bind to target sequences in close proximity, their binding is reciprocally stabilized, thereby integrating distinct signal transduction pathways. The fbp1 gene is massively induced upon glucose starvation by the activation of two transcription factors, Atf1 and Rst2, mediated via distinct signal transduction pathways. Atf1 and Rst2 bind to the upstream-activating sequence 1 region, carrying two binding sites located 45 bp apart. Their binding is reciprocally stabilized due to the close proximity of the two target sites, which destabilizes the independent binding of Atf1 or Rst2. Tup11/12 (Tup-family co-repressors) suppress independent binding. These data demonstrate a previously unappreciated mechanism by which two transcription-factor binding sites, in close proximity, integrate two independent-signal pathways, thereby behaving as a hub for signal integration.

Purpose Evaluate changes in early adolescent substance use during the coronavirus disease 2019 (COVID-19) pandemic using a prospective, longitudinal, nationwide cohort. Methods Participants were enrolled in the Adolescent Brain Cognitive Development Study. A total of 7,842 youth (mean age = 12.4 years, range = 10.5–14.6) at 21 study sites across the U.S. completed a three-wave assessment of substance use between May and August 2020. Youth reported whether they had used alcohol, nicotine, cannabis, or other substances in the past 30 days. Data were linked to prepandemic surveys that the same youth had completed in the years 2018–2020, before the advent of the COVID-19 pandemic. Results Past-30-day substance use remained stable in the 6 months since stay-at-home orders were first issued in U.S. states/counties; was primarily episodic (1–2 days in the past month); and was typically limited to a single substance. Using pretest/posttest and age-period designs, we found that compared to before the pandemic, fewer youth were using alcohol and more youth were using nicotine or misusing prescription drugs. During the pandemic, youth were more likely to use substances when they were more stressed by pandemic-related uncertainty; their family experienced material hardship; their parents used alcohol or drugs; or they experienced greater depression or anxiety. Neither engagement in social distancing nor worry about COVID-19 infection was associated with substance use. Several risk factors were stronger among older (vs. younger) adolescents. Conclusions Among youth in early adolescence, advent of the COVID-19 pandemic was associated with decreased use of alcohol and increased use of nicotine and misuse of prescription drugs.

The radiation-attenuated Plasmodium falciparum sporozoite (PfSPZ) vaccine provides protection against P. falciparum infection in malaria-naive adults. Preclinical studies show that T cell-mediated immunity is required for protection and is readily induced in humans after vaccination. However, previous malaria exposure can limit immune responses and vaccine efficacy (VE) in adults. We hypothesized that infants with less previous exposure to malaria would have improved immunity and protection. We conducted a multi-arm, randomized, double-blind, placebo-controlled trial in 336 infants aged 5–12 months to determine the safety, tolerability, immunogenicity and efficacy of the PfSPZ Vaccine in infants in a high-transmission malaria setting in western Kenya ( NCT02687373 ). Groups of 84 infants each received 4.5 × 105, 9.0 × 105 or 1.8 × 106 PfSPZ Vaccine or saline three times at 8-week intervals. The vaccine was well tolerated; 52 (20.6%) children in the vaccine groups and 20 (23.8%) in the placebo group experienced related solicited adverse events (AEs) within 28 d postvaccination and most were mild. There was 1 grade 3-related solicited AE in the vaccine group (0.4%) and 2 in the placebo group (2.4%). Seizures were more common in the highest-dose group (14.3%) compared to 6.0% of controls, with most being attributed to malaria. There was no significant protection against P. falciparum infection in any dose group at 6 months (VE in the 9.0 × 105 dose group = −6.5%, P = 0.598, the primary statistical end point of the study). VE against clinical malaria 3 months after the last dose in the highest-dose group was 45.8% (P = 0.027), an exploratory end point. There was a dose-dependent increase in antibody responses that correlated with VE at 6 months in the lowest- and highest-dose groups. T cell responses were undetectable across all dose groups. Detection of Vδ2+Vγ9+ T cells, which have been correlated with induction of PfSPZ Vaccine T cell immunity and protection in adults, were infrequent. These data suggest that PfSPZ Vaccine-induced T cell immunity is age-dependent and may be influenced by Vδ2+Vγ9+ T cell frequency. Since there was no significant VE at 6 months in these infants, these vaccine regimens will likely not be pursued further in this age group. The PfSPZ Vaccine does not protect infants from infection with Plasmodium falciparum, the major cause of malaria.

Despite over a decade of cystic fibrosis (CF) microbiome research, much remains to be learned about the overall composition, metabolic activities, and pathogenicity of the microbes in CF airways, limiting our understanding of the respiratory microbiome's relation to disease. Systems-level integration and modeling of host-microbiome interactions may allow us to better define the relationships between microbiological characteristics, disease status, and treatment response. In this way, modeling could pave the way for microbiome-based development of predictive models, individualized treatment plans, and novel therapeutic approaches, potentially serving as a paradigm for approaching other chronic infections. In this review, we describe the challenges facing this effort and propose research priorities for a systems biology approach to CF lung disease.

This plain language summary describes some results of a study called ATTR-ACT. This was the first large study to include people with wild-type and hereditary transthyretin amyloid cardiomyopathy (ATTR-CM for short). ATTR-CM is a type of heart disease that happens when abnormal clumps of protein build up in the heart. This build-up prevents the heart from working properly, causing a condition called heart failure. Wild-type ATTR-CM happens for unknown reasons in some people as they get older. Hereditary ATTR-CM can happen because of changes in people's genes (known as gene variants or mutations).In this study, 441 people with ATTR-CM took either a medicine called tafamidis or a placebo (a capsule that looked like tafamidis but didn't contain any active medicine) by mouth for 30 months, once a day. The researchers' main aim was to find out how tafamidis treatment affected the risk of people dying or being admitted to the hospital for heart problems. They found that tafamidis lowered these risks by about one-third compared with placebo.As described in this summary, after ATTR-ACT was completed, researchers looked back at the results from people who took placebo to learn how ATTR-CM progressed without treatment. The researchers found that about 4 in 10 people with wild-type ATTR-CM who took placebo died and 6 in 10 were admitted to the hospital because of heart problems over 30 months. People who took placebo also could not walk as far at the end of the study as they did at the start because their heart function worsened over time.By showing how ATTR-CM affects people's health when they do not take treatment, these results highlight the benefits of early diagnosis and treatment of ATTR-CM. ClinicalTrials.gov NCT number: NCT01994889.

Microbial co-culture fermentations can improve chemical production from complex biosynthetic pathways over monocultures by distributing enzymes across multiple strains, thereby reducing metabolic burden, overcoming endogenous regulatory mechanisms, or exploiting natural traits of different microbial species. However, stabilizing and optimizing microbial subpopulations for maximal chemical production remains a major obstacle in the field. In this study, we demonstrate that optogenetics is an effective strategy to dynamically control populations in microbial co-cultures. Using a new optogenetic circuit we call OptoTA, we regulate an endogenous toxin-antitoxin system, enabling tunability of Escherichia coli growth using only blue light. With this system we can control the population composition of co-cultures of E. coli and Saccharomyces cerevisiae. When introducing in each strain different metabolic modules of biosynthetic pathways for isobutyl acetate or naringenin, we found that the productivity of co-cultures increases by adjusting the population ratios with specific light duty cycles. This study shows the feasibility of using optogenetics to control microbial consortia populations and the advantages of using light to control their chemical production.

PREMISE Nearly 200 araceous leaves and two spadices have been identified among Paleocene fossils from the Blindman River locality near Blackfalds, Alberta, Canada. Although not found in attachment, these probably represent parts of the same extinct plant species. METHODS Specimens were studied using light microscopy. Phylogenetic analyses using a morphological matrix of living and fossil Araceae were performed using TNT version 1.5 to help establish relationships of the fossil leaves and spadices within Araceae and to each other. RESULTS Leaves are simple with a broad petiole, entire margin, and elliptic to ovate or oblong blade with an acute to slightly rounded apex. A multi-veined midrib extends into the basal region of the blade. Parallelodromous primary veins of two orders diverge at acute angles, converging with a submarginal vein or at the apex. Transverse veins are opposite percurrent, producing rectangular to polygonal areoles. Higher-order veins are mixed opposite/alternate. Spadices are cylindrical, with helically arranged, bisexual, perigoniate flowers, each with six free tepals and a protruding style. Fruits are trilocular, with axile placentation and one seed per locule. CONCLUSIONS Leaves are assignable to the fossil genus Orontiophyllum J. Kvacek & S.Y. Sm. as O. grandifolium comb. nov. Spadices are described as Bognerospadix speirsiae gen. et sp. nov. Leaves and spadices each conform to an early-diverging lineage of Araceae, increasing the known diversity of Proto-Araceae (viz., subfamilies Gymnostachydoideae and Orontioideae). Together, they provide strong evidence for extinct Proto-Araceae with novel combinations of characters shortly after the Cretaceous-Paleogene floral transition.

Plasmacytoid dendritic cells (pDC), a highly specialized class of innate immune cells that serve as rapid sensors of danger signals in circulation or in lymphoid tissue are well studied. However, there remains knowledge gaps about age-dependent changes of pDC function in the intestinal mucosa. Here, we report that under homeostatic conditions, the proportion of pDC expressing C-C chemokine receptor 9 (CCR9) in the intestinal intraepithelial cell (iIEC) population is comparable between young (2-4 months) and aged (18-24 months) mice, but the absolute numbers of iIEC and pDC are significantly lower in aged mice. Employing the classic model of acute endotoxemia induced by lipopolysaccharide (LPS), we found a decrease in the proportion and absolute number of intraepithelial pDC in both young and aged mice despite the LPS-induced increased expression of the chemokine C-C ligand 25 (CCL25), the ligand of CCR9, in the intestinal mucosa of young mice. In adoptive transfer experiments, a significantly lower number of pDC was retained into the intestinal layer of aged host mice after LPS administration. This was associated with recoverable pDC numbers in the intestinal lumen. Furthermore, co-adoptive transfer of young and aged pDC into young hosts also showed significantly lower retention of aged pDC in the epithelial layer compared to the co-transferred young pDC. Collectively, these data show age-associated changes in mucosal CCL25 gene expression and in pDC number. These may underlie the reported inadequate responses to gastrointestinal pathogens during chronologic aging.

Background A specific 3-dimensional intrachromosomal architecture of core stem cell factor genes is required to reprogram a somatic cell into pluripotency. As little is known about the epigenetic readers that orchestrate this architectural remodeling, we used a novel chromatin RNA in situ reverse transcription sequencing (CRIST-seq) approach to profile long noncoding RNAs (lncRNAs) in the Oct4 promoter. Results We identify Platr10 as an Oct4 - Sox2 binding lncRNA that is activated in somatic cell reprogramming. Platr10 is essential for the maintenance of pluripotency, and lack of this lncRNA causes stem cells to exit from pluripotency. In fibroblasts, ectopically expressed Platr10 functions in trans to activate core stem cell factor genes and enhance pluripotent reprogramming. Using RNA reverse transcription-associated trap sequencing (RAT-seq), we show that Platr10 interacts with multiple pluripotency-associated genes, including Oct4, Sox2, Klf4, and c-Myc, which have been extensively used to reprogram somatic cells. Mechanistically, we demonstrate that Platr10 helps orchestrate intrachromosomal promoter-enhancer looping and recruits TET1, the enzyme that actively induces DNA demethylation for the initiation of pluripotency. We further show that Platr10 contains an Oct4 binding element that interacts with the Oct4 promoter and a TET1-binding element that recruits TET1. Mutation of either of these two elements abolishes Platr10 activity. Conclusion These data suggest that Platr10 functions as a novel chromatin RNA molecule to control pluripotency in trans by modulating chromatin architecture and regulating DNA methylation in the core stem cell factor network.

This consensus statement is an update of the 1987 American College of Sports Medicine (ACSM) position stand on the use of anabolic-androgenic steroids (AAS). Substantial data have been collected since the previous position stand, and AAS use patterns have changed significantly. The ACSM acknowledges that lawful and ethical therapeutic use of AAS is now an accepted mainstream treatment for several clinical disorders; however, there is increased recognition that AAS are commonly used illicitly to enhance performance and appearance in several segments of the population, including competitive athletes. The illicit use of AAS by competitive athletes is contrary to the rules and ethics of many sport governing bodies. Thus, the ACSM deplores the illicit use of AAS for athletic and recreational purposes. This consensus statement provides a brief history of AAS use, an update on the science of how we now understand AAS to be working metabolically/biochemically, potential side effects, the prevalence of use among athletes, and the use of AAS in clinical scenarios.

Background Obesity is associated with restrictive ventilatory defects and a faster rate of decline in FVC. This association is not exclusively mediated by mechanical factors and may reflect direct pulmonary injury by adipose-derived mediators. Research Question Is adipose tissue involved in the pathogenesis of interstitial lung disease (ILD)? Study Design and Methods We evaluated the association of CT measures of pericardial, abdominal visceral, and abdominal subcutaneous adipose tissue with high-attenuation areas (HAAs) and interstitial lung abnormalities (ILAs) in a large multicenter cohort study of community-dwelling adults, using multivariable-adjusted models. We secondarily evaluated the association of adipose depot size with FVC and biomarkers of obesity and inflammation. Results In fully adjusted models, every doubling in pericardial adipose tissue volume was associated with a 63.4-unit increase in HAA (95% CI, 55.5-71.3), 20% increased odds of ILA (95% CI, –2% to 50%), and a 5.5% decrease in percent predicted FVC (95% CI, –6.8% to –4.3%). IL-6 levels accounted for 8% of the association between pericardial adipose tissue and HAA. Every doubling in visceral adipose tissue area was associated with a 41.5-unit increase in HAA (95% CI, 28.3-54.7), 30% increased odds of ILA (95% CI, –10% to 80%), and a 5.4% decrease in percent predicted FVC (95% CI, –6.6% to –4.3%). IL-6 and leptin accounted for 17% and 18%, respectively, of the association between visceral adipose tissue and HAA. Interpretation Greater amounts of pericardial and abdominal visceral adipose tissue were associated with CT measures of early lung injury and lower FVC in a cohort of community-dwelling adults. Adipose tissue may represent a modifiable risk factor for ILD.

Background It is difficult to distinguish between a tumor and its liver segment with traditional use of indocyanine green (ICG) alone. In the present study, a method was used to limit ICG to the liver segment adjacent to a tumor. A spectrally-distinct fluorescently-labeled tumor-specific antibody against human carcinoembryonic antigen-related cell-adhesion molecules was used to label the metastatic tumor in a patient-derived orthotopic xenograft mouse model to enable color-coded visualization and distinction of a colon-cancer liver metastases and its adjacent liver segment. Materials and Methods Nude mice received surgical orthotopic implantation in the liver of colon-cancer liver metastases derived from two patients. An anti- carcinoembryonic antigen-related cell-adhesion molecules monoclonal antibody (mAb 6G5j) was conjugated to a near-infrared dye IR700DX (6G5j-IR700DX). After three weeks, mice received 6G5j-IR700DX via tail-vein injection 48 hours before surgery. ICG was intravenously injected after ligation of the left or left lateral Glissonean pedicle resulting in labeling of the segment with preserved blood-flow in the liver. Imaging was performed with the Pearl Trilogy and FLARE Imaging Systems. Results The metastatic liver tumor had a clear fluorescence signal due to selective tumor targeting by 6G5j-IR700DX, which was imaged on the 700 nm channel. The adjacent liver segment, with preserved blood-flow in the liver, had a clear fluorescence ICG 800 nm signal, while the left or left lateral segment had no fluorescence signal. Overlay of the images showed clear color-coded differentiation between the tumor fluorescing at 700 nm and the adjacent liver segment fluorescing at 800 nm. Conclusions Color-coding of a liver tumor and uninvolved liver segment has the potential for improved liver resection.

Arguably, the most important discovery in the biology of aging to date was that simply reducing food intake extended life and improved many aspects of health in a diversity of animal species. The conventional wisdom that emerged from first 50 years of rodent food restriction studies included (1) that the longevity impact of restriction was greater the longer restriction was imposed, and (2) that restricting calories rather than any specific macronutrient was critical to its health and longevity benefits. However these assumptions began to crumble as more and more restriction research was performed on other species besides laboratory rodents. Recent investigations of flies, rodents, monkeys, and increasingly humans, has begun to parse how calorie restriction, protein restriction, intermittent fasting, and the temporal pattern of eating all impact the health benefits of food restriction. Fly research continues to inform, as it has repeatedly shown that genotype, age, sex, duration, and tempo restriction all affect the health impact. Ultimately, optimizing human diets will require a personalized approach using omics approaches.

There are few studies that have investigated the evolutionary history of large vertebrates on islands off the Caribbean coast of South America. Here we use the spectacled caiman (Caiman crocodilus) to investigate among- and within-population patterns of genetic diversity to understand connectivity between island and mainland populations. The spectacled caiman is naturally distributed across Central and South America including the islands of Trinidad and Tobago, which are considered to have the only natural insular populations of the species. Because of this apparent isolation, we sought to determine whether caimans on Trinidad and Tobago comprise a unique lineage and have reduced genetic diversity compared to mainland caimans. We test these hypotheses by using mitochondrial DNA variation to assess the phylogenetic and phylogeographical relationships of the C. crocodilus populations inhabiting these islands within the evolutionary context of the entire spectacled caiman complex. Phylogenetic analyses placed the Trinidad and Tobago samples together with samples from Colombia, Venezuela and Brazil into one well-supported clade, which corresponds to the defined Orinoco/upper Negro lineage. Interestingly, the majority of sequences from Trinidad and Tobago are similar or identical to haplotypes reported from Venezuela and Colombia, supporting the idea of a dispersal process from the Orinoco River to these islands. We discuss the implications of our findings for systematics and the conservation of the species and how these dispersal movements could shape the current phylogeographical structure depicted for C. crocodilus.

Previous studies have suggested the involvement of serum insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in the regulation of the female reproductive system. Little is known of these peptides in the seminal plasma (SP) of men and their potential effects on fertility. We assessed SP levels of these peptides in infertile men with low sperm motility (asthenozoospermic; AZ) and low sperm counts (oligozoospermic; OZ), its effects on in vivo sperm motility, and whether there is a correlation with aging. Twenty-eight infertile men (AZ; n = 18 and OZ; n = 10) and 20 fertile normozoospermic (NZ) men were studied. Seminal plasma IGF-I, IGF-II, IGFBP-2, IGFBP-3, and prostate-specific antigen (PSA) levels were measured, and spermatozoa mRNA transcript patterns were examined. Asthenozoospermic men had higher SP IGF-I, IGF-II, IGFBP-2, and PSA levels than NZ and OZ men, whereas SP IGFBP-3 levels were similar between the three groups. Sperm count positively correlated with SP IGF-I, IGF-II, and IGFBP-2; sperm motility negatively correlated with SP IGF-II and IGFBP-2; and age correlated positively with SP IGF-II. The expression of IGF-I and IGF-II mRNA and mRNA receptors was detectable, but no variations in transcript levels were noted. Decreased sperm motility, but not sperm count, in infertile AZ men is associated with increased SP IGF-I, IGF-II, IGFBP-2, and PSA levels. Changes in SP IGFs and their interactions with IGFBPs and IGF receptors, and PSA levels suggest a role of these SP peptides in modulating sperm motility and possibly prostate disease development in aging men.

Limited data exist on the spatial distribution of the colonic bacteria in humans. We collected the colonic biopsies from five segments of 27 polyp-free adults and collected feces from 13 of them. We sequenced the V4 region of the bacterial 16S rRNA gene using the MiSeq platform. The sequencing data were assigned to the amplicon sequence variant (ASV) using SILVA. Biodiversity and the relative abundance of the ASV were compared across the colonic segments and between the rectal and fecal samples. Bacterial functional capacity was assessed using Tax4fun. Each individual had a unique bacterial community composition (Weighted Bray–Curtis P value = 0.001). There were no significant differences in richness, evenness, community composition, and the taxonomic structure across the colon segments in all the samples. Firmicutes (47%), Bacteroidetes (39%), and Proteobacteria (6%) were the major phyla in all segments, followed by Verrucomicrobia, Fusobacteria, Desulfobacterota, and Actinobacteria. There were 15 genera with relative abundance > 1%, including Bacteroides, Faecalibacterium, Escherichia/Shigella, Sutterella, Akkermansia, Parabacteroides, Prevotella, Lachnoclostridium, Alistipes, Fusobacterium, Erysipelatoclostridium, and four Lachnospiraceae family members. Intra-individually, the community compositional dissimilarity was the greatest between the cecum and the rectum. There were significant differences in biodiversity and the taxonomic structure between the rectal and fecal bacteria. The bacterial community composition and structure were homogeneous across the large intestine in adults. The inter-individual variability of the bacteria was greater than inter-segment variability. The rectal and fecal bacteria differed in the community composition and structure.

We examined the association between the colonic adherent microbiota and nocturnal sleep duration in humans. In a cross-sectional study, 63 polyp-free adults underwent a colonoscopy and donated 206 mucosal biopsies. The gut microbiota was profiled using the 16S rRNA gene sequencing targeting the V4 region. The sequence reads were processed using UPARSE and DADA2, respectively. Lifestyle factors, including sleep habits, were obtained using an interviewer-administered questionnaire. We categorized the participants into short sleepers (n = 16) and normal sleepers (6–8 h per night; n = 47) based on self-reported data. Differences in bacterial biodiversity and the taxonomic relative abundance were compared between short vs. normal sleepers, followed by multivariable analysis. A false discovery rate-adjusted p value (q value) < 0.05 indicated statistical significance. The bacterial community composition differed in short and normal sleepers. The relative abundance of Sutterella was significantly lower (0.38% vs. 1.25%) and that of Pseudomonas was significantly higher (0.14% vs. 0.08%) in short sleepers than in normal sleepers (q values < 0.01). The difference was confirmed in the multivariable analysis. Nocturnal sleep duration was associated with the bacterial community composition and structure in the colonic gut microbiota in adults.

Background Extensive malaria control measures have been implemented on Bioko Island, Equatorial Guinea over the past 16 years, reducing parasite prevalence and malaria-related morbidity and mortality, but without achieving elimination. Malaria vaccines offer hope for reducing the burden to zero. Three phase 1/2 studies have been conducted successfully on Bioko Island to evaluate the safety and efficacy of whole Plasmodium falciparum (Pf) sporozoite (SPZ) malaria vaccines. A large, pivotal trial of the safety and efficacy of the radiation-attenuated Sanaria® PfSPZ Vaccine against P. falciparum is planned for 2022. This study assessed the incidence of malaria at the phase 3 study site and characterized the influence of socio-demographic factors on the burden of malaria to guide trial design. Methods A cohort of 240 randomly selected individuals aged 6 months to 45 years from selected areas of North Bioko Province, Bioko Island, was followed for 24 weeks after clearance of parasitaemia. Assessment of clinical presentation consistent with malaria and thick blood smears were performed every 2 weeks. Incidence of first and multiple malaria infections per person-time of follow-up was estimated, compared between age groups, and examined for associated socio-demographic risk factors. Results There were 58 malaria infection episodes observed during the follow up period, including 47 first and 11 repeat infections. The incidence of malaria was 0.25 [95% CI (0.19, 0.32)] and of first malaria was 0.23 [95% CI (0.17, 0.30)] per person per 24 weeks (0.22 in 6–59-month-olds, 0.26 in 5–17-year-olds, 0.20 in 18–45-year-olds). Incidence of first malaria with symptoms was 0.13 [95% CI (0.09, 0.19)] per person per 24 weeks (0.16 in 6–59-month-olds, 0.10 in 5–17-year-olds, 0.11 in 18–45-year-olds). Multivariate assessment showed that study area, gender, malaria positivity at screening, and household socioeconomic status independently predicted the observed incidence of malaria. Conclusion Despite intensive malaria control efforts on Bioko Island, local transmission remains and is spread evenly throughout age groups. These incidence rates indicate moderate malaria transmission which may be sufficient to support future larger trials of PfSPZ Vaccine. The long-term goal is to conduct mass vaccination programmes to halt transmission and eliminate P. falciparum malaria.

For DNA metabarcoding to attain its potential as a community assessment tool, we need to better understand its performance versus traditional morphological identification and work to address any remaining performance gaps in incorporating DNA metabarcoding into community assessments. Using fragments of the 18S nuclear and 16S mitochondrial rRNA genes and two fragments of the mitochondrial COI marker, we examined the use of DNA metabarcoding and traditional morphological identification for understanding the diversity and composition of crustacean zooplankton at 42 sites across western Lake Superior. We identified 51 zooplankton taxa (genus or species, depending on the finest resolution of the taxon across all identification methods), of which 17 were identified using only morphological traits, 13 using only DNA and 21 using both methods. The taxa found using only DNA metabarcoding included four species and one genus-level identification not previously known to occur in Lake Superior, the presence of which still needs to be confirmed. A substantial portion of taxa that were identified to genus or species by morphological identification, but not identified using DNA metabarcoding, had zero (“no record”) or < 2 (“underrepresented records”) reference barcodes in the BOLD or NCBI databases (63% for COI, 80% for 16S, 74% for 18S). The two COI marker fragments identified the most genus- and species-level taxa, whereas 18S was the only marker whose family-level percent sequence abundance patterns showed high correlation to composition patterns from morphological identification, based on a NMDS analysis of Bray-Curtis similarities. Multiple replicates were collected at a subset of sites and an occupancy analysis was performed, which indicated that rare taxa were more likely to be detected using DNA metabarcoding than traditional morphology. Our results support that DNA metabarcoding can augment morphological identification for estimating zooplankton diversity and composition of zooplankton over space and time, but may require use of multiple markers. Further addition of taxa to reference DNA databases will improve our ability to use DNA metabarcoding to identify zooplankton and other invertebrates in aquatic surveys.

Anthropogenic disturbances associated with urban ecosystems can create favorable conditions for populations of some invasive plant species. Light pollution is one of these disturbances, but how it affects the growth and establishment of invasive plant populations is unknown. Cheatgrass (Bromus tectorum) is a problematic invasive species where it has displaced native grassland communities in the United States, but to our knowledge, there have been no studies of the ecological factors that affect cheatgrass presence in urban ecosystems. We conducted field surveys in urban alleys in Denver, Colorado, to compare the presence of cheatgrass at sites with and without artificial light at night (hereafter artificial light) from streetlights. These streetlights are mounted on utility poles, which cause ground disturbance when installed in alleys; we were able to test the independent effect of poles on cheatgrass establishment because not all poles have streetlights on them. We found that cheatgrass was positively associated with the presence of streetlights and to a lesser extent poles. In addition to cheatgrass, we also found that other plants were positively associated with the presence of both poles and streetlights. Our results suggest that artificial light may benefit the occurrence of cheatgrass and other plant species in urban settings. While invasive populations of cheatgrass in wild habitats attract the most attention from managers, we suggest more consideration for this grass in urban environments where its growth and establishment benefit from anthropogenic changes., We have found that light pollution facilitates an invasive plant species, cheatgrass. Ours is the first study to document the effect of this global change driver, artificial light at night, on this important invasive plant species.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike pseudotyped virus (PSV) assays are widely used to measure neutralization titers of sera and of isolated neutralizing Abs (nAbs). PSV neutralization assays are safer than live virus neutralization assays and do not require access to biosafety level 3 laboratories. However, many PSV assays are nevertheless somewhat challenging and require at least 2 d to carry out. In this study, we report a rapid (

The global decline in malaria has stalled1, emphasizing the need for vaccines that induce durable sterilizing immunity. Here we optimized regimens for chemoprophylaxis vaccination (CVac), for which aseptic, purified, cryopreserved, infectious Plasmodium falciparum sporozoites (PfSPZ) were inoculated under prophylactic cover with pyrimethamine (PYR) (Sanaria PfSPZ-CVac(PYR)) or chloroquine (CQ) (PfSPZ-CVac(CQ))—which kill liver-stage and blood-stage parasites, respectively—and we assessed vaccine efficacy against homologous (that is, the same strain as the vaccine) and heterologous (a different strain) controlled human malaria infection (CHMI) three months after immunization ( https://clinicaltrials.gov/ , NCT02511054 and NCT03083847). We report that a fourfold increase in the dose of PfSPZ-CVac(PYR) from 5.12 × 104 to 2 × 105 PfSPZs transformed a minimal vaccine efficacy (low dose, two out of nine (22.2%) participants protected against homologous CHMI), to a high-level vaccine efficacy with seven out of eight (87.5%) individuals protected against homologous and seven out of nine (77.8%) protected against heterologous CHMI. Increased protection was associated with Vδ2 γδ T cell and antibody responses. At the higher dose, PfSPZ-CVac(CQ) protected six out of six (100%) participants against heterologous CHMI three months after immunization. All homologous (four out of four) and heterologous (eight out of eight) infectivity control participants showed parasitaemia. PfSPZ-CVac(CQ) and PfSPZ-CVac(PYR) induced a durable, sterile vaccine efficacy against a heterologous South American strain of P. falciparum, which has a genome and predicted CD8 T cell immunome that differs more strongly from the African vaccine strain than other analysed African P. falciparum strains. Two malaria vaccines comprising Plasmodium falciparum sporozoites and treatment with either pyrimethamine or chloroquine induced durable protective responses against both the African vaccine strain and a heterologous South American strain of P. falciparum.