Myosin-I's motor and actin assembly activation activities are modular and separable in budding yeast clathrin-mediated endocytosis.

The myosin-Is, Myo3 and Myo5 in budding yeast, are implicated in force generation and actin assembly during clathrin-mediated endocytosis (CME). The myosin-Is have motor activity, bind the plasma membrane, and activate the Arp2/3 complex to promote branched actin assembly. We reveal that Myo5 's force-generating motor activity and nucleation-promoting factor (NPF) activity each must be coupled to membrane binding for successful CME. However, the motor and NPF activities are modular and separable, showing that these activities function independently rather than in an obligatorily integrated manner to provide myosin-I's essential functions in actin network assembly and force generation during budding yeast CME.

HEX17(Neumifil): An intranasal respiratory biotherapeutic with broad-acting antiviral activity.

Broad-acting antiviral strategies to prevent respiratory tract infections are urgently required. Emerging or re-emerging viral diseases caused by new or genetic variants of viruses such as influenza viruses (IFVs), respiratory syncytial viruses (RSVs), human rhinoviruses (HRVs), parainfluenza viruses (PIVs) or coronaviruses (CoVs), pose a severe threat to human health, particularly in the very young or old, or in those with pre-existing respiratory conditions such as asthma or chronic obstructive pulmonary disease (COPD). Although vaccines remain a key component in controlling and preventing viral infections, they are unable to provide broad-spectrum protection against recurring seasonal infections or newly emerging threats. HEX17 (aka Neumifil), is a first-in-class protein-based antiviral prophylactic for respiratory viral infections. HEX17 consists of a hexavalent carbohydrate-binding module (CBM) with high affinity to sialic acids, which are typically present on terminating branches of glycans on viral cellular receptors. This allows HEX17 to block virus engagement of host receptors and inhibit infection of a wide range of viral pathogens and their variants with reduced risk of antiviral resistance. As described herein, HEX17 has demonstrated broad-spectrum efficacy against respiratory viral pathogens including IFV, RSV, CoV and HRV in multiple in vivo and in vitro studies. In addition, HEX17 can be easily administered via an intranasal spray and is currently undergoing clinical trials.

Evaluating the Efficacy of Cervical Tactile Ultrasound Technique as a Predictive Tool for Spontaneous Preterm Birth.

Background: Premature cervical softening and shortening may be considered an early mechanical failure that predispose to preterm birth. Purpose: This study aims to explore the applicability of an innovative cervical tactile ultrasound approach for predicting spontaneous preterm birth (sPTB). Materials and Methods: Eligible participants were women with low-risk singleton pregnancies in their second trimester, enrolled in this prospective observational study. A Cervix Monitor (CM) device was designed with a vaginal probe comprising four tactile sensors and a single ultrasound transducer operating at 5 MHz. The probe enabled the application of controllable pressure to the external cervical surface, facilitating the acquisition of stress-strain data from both anterior and posterior cervical sectors. Gestational age at delivery was recorded and compared against cervical elasticity. Results: CM examination data were analyzed for 127 women at 240/7 - 286/7 gestational weeks. sPTB was observed in 6.3% of the cases. The preterm group exhibited a lower average cervical stress-to-strain ratio (elasticity) of 0.70 ± 0.26 kPa/mm compared to the term group's 1.63 ± 0.65 kPa/mm with a p-value of 1.1 × 10-4. Diagnostic accuracy for predicting spontaneous preterm birth based solely on cervical elasticity data was found to be 95.0% (95% CI, 88.5 - 100.0). Conclusion: These findings suggest that measuring cervical elasticity with the designed tactile ultrasound probe has the potential to predict spontaneous preterm birth in a cost-effective manner.

Naringin: Cardioprotective properties and safety profile in diabetes treatment.

Flavonoids derived from plants offer a broad spectrum of therapeutic potential for addressing metabolic syndrome, particularly diabetes mellitus (DM), a prevalent non-communicable disease. Hyperglycemia in DM is a known risk factor for cardiovascular diseases (CVDs), which substantially impact global mortality rates. This review examines the potential effects of naringin, a citrus flavonoid, on both DM and its associated cardiovascular complications, including conditions like diabetic cardiomyopathy. The safety profile of naringin is summarized based on various pre-clinical studies. The data for this review was gathered from diverse electronic databases, including Medline, PubMed, ScienceDirect, SpringerLink, Google Scholar, and Emerald Insight. Multiple pre-clinical studies have demonstrated that naringin exerts hypoglycemic and cardioprotective effects by targeting various vascular mechanisms. Specifically, research indicates that naringin down-regulates the renin-angiotensin and oxidative stress systems while concurrently upregulating ß-cell and immune system functions. Clinical trial outcomes also support the therapeutic potential of naringin in managing hyperglycemic states and associated cardiovascular issues. Moreover, toxicity studies have confirmed the safety of naringin in animal models, suggesting its potential for safe administration in humans. In conclusion, naringin emerges as a promising natural candidate for both antidiabetic and cardioprotective purposes, offering potential improvements in health outcomes. While naringin presents a new avenue for therapies targeting DM and CVDs, additional controlled and long-term clinical trials are necessary to validate its efficacy and safety for human use.

Evaluation of Lag of Accommodation with Full-Field Diffusion Optics Technology™ (DOT) Contrast Management Spectacle Lenses in Emmetropic Children.

Purpose: To evaluate the impact on the lag of accommodation (LOA) in emmetropic children after short-term wear of full-field Diffusion Optics TechnologyTM (DOT) spectacle lenses, designed to modulate retinal contrast to control myopia progression. Patients and Methods: This was a single-visit, prospective, randomized, subject-masked study of emmetropes (ametropes ±1.00D or less in each meridian) with no history of myopia control treatment. Unaided logMAR visual acuity was measured, and ocular dominance was determined using the sighting method. In a randomized order, participants wore plano full-field contrast management (DOT) spectacles (no clear central aperture) or control spectacles (standard single vision spectacle lenses). Each participant was given 5 minutes for adaptation to the respective lenses before open field autorefraction measurements were taken at 6 meters and 40 cm. Ten measurements were taken for each eye. Data were evaluated from the right eye and the dominant eye separately. Results: A total of 30 participants (20 females and 10 males) with a mean age of 10.4 ± 2.8 (7 to 17) years completed the study. There was no significant difference in right eye mean LOA with contrast management spectacles 0.57 ± 0.39D versus control spectacles 0.62 ± 0.34D; Wilcoxon test, p = 0.37. For dominant eyes, LOA values were 0.60 ± 0.40D and 0.68 ± 0.33D with contrast management spectacles and control spectacles, respectively (p = 0.14). Additionally, no significant difference was observed in mean LOA between males and females or between age groups (7-11 years vs 12-17 years) for either right or dominant eyes with contrast management or control spectacles (all p > 0.05). Conclusion: Full-field contrast management spectacle lenses had no significant effect on LOA compared to standard single vision spectacle lenses, indicating no differential impact on accommodative response over the short period of lens wear tested.

"Deeper cuts": A 55-word story.

Health professionals spend their careers in the expert care of patients experiencing difficult and chronic illnesses. However, there is no equivalent in professional training for personal, lived experiences as patients or loved ones of patients, both of which can serve as unforgettably humanizing teachers for building empathy, compassion, and perspective-taking skills. This 55-word story is a reflection on a memorable moment in one such experience. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A Role for Cross-linking Proteins in Actin Filament Network Organization and Force Generation.

The high turgor pressure across the plasma membrane of yeasts creates a requirement for substantial force production by actin polymerization and myosin motor activity for clathrin-mediated endocytosis (CME). Endocytic internalization is severely impeded in the absence of fimbrin, an actin filament crosslinking protein called Sac6 in budding yeast. Here, we combine live-cell imaging and mathematical modeling to gain new insights into the role of actin filament crosslinking proteins in force generation. Genetic manipulation showed that CME sites with more crosslinking proteins are more effective at internalization under high load. Simulations of an experimentally constrained, agent-based mathematical model recapitulate the result that endocytic networks with more double-bound fimbrin molecules internalize the plasma membrane against elevated turgor pressure more effectively. Networks with large numbers of crosslinks also have more growing actin filament barbed ends at the plasma membrane, where the addition of new actin monomers contributes to force generation and vesicle internalization. Our results provide a richer understanding of the crucial role played by actin filament crosslinking proteins during actin network force generation, highlighting the contribution of these proteins to the self-organization of the actin filament network and force generation under increased load.

Obesity Differs from Diabetes Mellitus in Antibody and T Cell Responses Post COVID-19 Recovery.

Obesity and type 2 diabetes (DM) are risk factors for severe COVID-19 outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors with obesity and DM in Bangladesh. In this cross-sectional study, SARS-CoV-2-specific antibody and T cell responses were investigated in 63 healthy and 75 PCR-confirmed COVID-19 recovered individuals in Bangladesh, during the pre-vaccination first wave of the COVID-19 pandemic in 2020. In COVID-19 survivors, SARS-CoV-2 infection induced robust antibody and T cell responses, which correlated with disease severity. After adjusting for age, sex, DM status, disease severity, and time since onset of symptoms, obesity was associated with decreased neutralising antibody titers, and increased SARS-CoV-2 spike-specific IFN-γ response along with increased proliferation and IL-2 production by CD8+ T cells. In contrast, DM was not associated with SARS-CoV-2-specific antibody and T cell responses after adjustment for obesity and other confounders. Obesity is associated with lower neutralising antibody levels and higher T cell responses to SARS-CoV-2 post COVID-19 recovery, while antibody or T cell responses remain unaltered in DM.

The proteome of the blood-brain barrier in rat and mouse: highly specific identification of proteins on the luminal surface of brain microvessels by in vivo glycocapture.

BACKGROUND: The active transport of molecules into the brain from blood is regulated by receptors, transporters, and other cell surface proteins that are present on the luminal surface of endothelial cells at the blood-brain barrier (BBB). However, proteomic profiling of proteins present on the luminal endothelial cell surface of the BBB has proven challenging due to difficulty in labelling these proteins in a way that allows efficient purification of these relatively low abundance cell surface proteins. METHODS: Here we describe a novel perfusion-based labelling workflow: in vivo glycocapture. This workflow relies on the oxidation of glycans present on the luminal vessel surface via perfusion of a mild oxidizing agent, followed by subsequent isolation of glycoproteins by covalent linkage of their oxidized glycans to hydrazide beads. Mass spectrometry-based identification of the isolated proteins enables high-confidence identification of endothelial cell surface proteins in rats and mice. RESULTS: Using the developed workflow, 347 proteins were identified from the BBB in rat and 224 proteins in mouse, for a total of 395 proteins in both species combined. These proteins included many proteins with transporter activity (73 proteins), cell adhesion proteins (47 proteins), and transmembrane signal receptors (31 proteins). To identify proteins that are enriched in vessels relative to the entire brain, we established a vessel-enrichment score and showed that proteins with a high vessel-enrichment score are involved in vascular development functions, binding to integrins, and cell adhesion. Using publicly-available single-cell RNAseq data, we show that the proteins identified by in vivo glycocapture were more likely to be detected by scRNAseq in endothelial cells than in any other cell type. Furthermore, nearly 50% of the genes encoding cell-surface proteins that were detected by scRNAseq in endothelial cells were also identified by in vivo glycocapture. CONCLUSIONS: The proteins identified by in vivo glycocapture in this work represent the most complete and specific profiling of proteins on the luminal BBB surface to date. The identified proteins reflect possible targets for the development of antibodies to improve the crossing of therapeutic proteins into the brain and will contribute to our further understanding of BBB transport mechanisms.

Comparing online versus laboratory measures of speech perception in older children and adolescents.

Given the increasing prevalence of online data collection, it is important to know how behavioral data obtained online compare to samples collected in the laboratory. This study compares online and in-person measurement of speech perception in older children and adolescents. Speech perception is important for assessment and treatment planning in speech-language pathology; we focus on the American English /ɹ/ sound because of its frequency as a clinical target. Two speech perception tasks were adapted for web presentation using Gorilla: identification of items along a synthetic continuum from rake to wake, and category goodness judgment of English /ɹ/ sounds in words produced by various talkers with and without speech sound disorder. Fifty typical children aged 9-15 completed these tasks online using a standard headset. These data were compared to a previous sample of 98 typical children aged 9-15 who completed the same tasks in the lab setting. For the identification task, participants exhibited smaller boundary widths (suggestive of more acute perception) in the in-person setting relative to the online setting. For the category goodness judgment task, there was no statistically significant effect of modality. The correlation between scores on the two tasks was significant in the online setting but not in the in-person setting, but the difference in correlation strength was not statistically significant. Overall, our findings agree with previous research in suggesting that online and in-person data collection do not yield identical results, but the two contexts tend to support the same broad conclusions. In addition, these results suggest that online data collection can make it easier for researchers connect with a more representative sample of participants.

Pursuing Scholarship: Creating Effective Conference Submissions.

Medical educators are expected to disseminate peer-reviewed scholarly work for academic promotion and tenure. However, developing submissions for presentations at national meetings can be confusing and sometimes overwhelming. Awareness and use of some best practices can demystify the process and maximize opportunities for acceptance for a variety of potential submission categories. This article outlines logistical steps and best practices for each stage of the conference submission process that faculty should consider when preparing submissions. These include topic choice, team composition, consideration of different submission types, and strategies for effectively engaging participants.

The impact of the cost-of-living crisis on population health in the UK: rapid evidence review.

BACKGROUND: In the UK, unique and unforeseen factors, including COVID-19, Brexit, and Ukraine-Russia war, have resulted in an unprecedented cost of living crisis, creating a second health emergency. We present, one of the first rapid reviews with the aim of examining the impact of this current crisis, at a population level. We reviewed published literature, as well as grey literature, examining a broad range of physical and mental impacts on health in the short, mid, and long term, identifying those most at risk, impacts on system partners, including emergency services and the third sector, as well as mitigation strategies. METHODS: We conducted a rapid review by searching PubMed, Embase, MEDLINE, and HMIC (2020 to 2023). We searched for grey literature on Google and hand-searched the reports of relevant public health organisations. We included interventional and observational studies that reported outcomes of interventions aimed at mitigating against the impacts of cost of living at a population level. RESULTS: We found that the strongest evidence was for the impact of cold and mouldy homes on respiratory-related infections and respiratory conditions. Those at an increased risk were young children (0-4 years), the elderly (aged 75 and over), as well as those already vulnerable, including those with long-term multimorbidity. Further short-term impacts include an increased risk of physical pain including musculoskeletal and chest pain, and increased risk of enteric infections and malnutrition. In the mid-term, we could see increases in hypertension, transient ischaemic attacks, and myocardial infarctions, and respiratory illnesses. In the long term we could see an increase in mortality and morbidity rates from respiratory and cardiovascular disease, as well as increase rates of suicide and self-harm and infectious disease outcomes. Changes in behaviour are likely particularly around changes in food buying patterns and the ability to heat a home. System partners are also impacted, with voluntary sectors seeing fewer volunteers, an increase in petty crime and theft, alternative heating appliances causing fires, and an increase in burns and burn-related admissions. To mitigate against these impacts, support should be provided, to the most vulnerable, to help increase disposable income, reduce energy bills, and encourage home improvements linked with energy efficiency. Stronger links to bridge voluntary, community, charity and faith groups are needed to help provide additional aid and support. CONCLUSION: Although the CoL crisis affects the entire population, the impacts are exacerbated in those that are most vulnerable, particularly young children, single parents, multigenerational families. More can be done at a community and societal level to support the most vulnerable, and those living with long-term multimorbidity. This review consolidates the current evidence on the impacts of the cost of living crisis and may enable decision makers to target limited resources more effectively.

Benzimidazole Derivative (N-{4-[2-(4-Methoxyphenyl)-1H-Benzimidazole-1-Sulfonyl] Phenyl} Acetamide) Ameliorates Methotrexate-Induced Intestinal Mucositis by Suppressing Oxidative Stress and Inflammatory Markers in Mice.

Methotrexate (MTX)-induced intestinal mucositis (IM) is a common side effect in cancer treatment that impairs the immune system and gut microbes, resulting in loss of mucosal integrity and gut barrier dysfunction. The quality of life and outcomes of treatment are compromised by IM. The present study was designed to investigate the mucoprotective potential of the benzimidazole derivative N-{4-[2-(4-methoxyphenyl)-1H-benzimidazole-1-sulfonyl] phenyl} acetamide (B8) on MTX-induced IM in mice. IM was induced by a single dose of MTX in mice and assessed by physical manifestations as well as biochemical, oxidative, histological, and inflammatory parameters. B8 (1, 3, 9 mg/kg) significantly reduced diarrhea score, mitigated weight loss, increased feed intake and, survival rate in a dose-dependent manner. Notably, B8 exhibited a mucoprotective effect evident through the mitigation of villus atrophy, crypt hypoplasia, diminished crypt mitotic figures, mucin depletion, and oxidative stress markers (GSH, SOD, MDA, and catalase concentration). Gene expression analysis revealed that B8 downregulated the mRNA expression of tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), IL-1ß, and nuclear factor-κB (NF-κB) and concurrently upregulated IL-10 expression in contrast to the MTX group. Further, B8 significantly improved the luminal microflora profile by augmenting the growth of Lactobacillus spp. and reducing the number of pathogenic bacteria (E. coli). Additionally, the enzyme-linked immunoassay showed that B8 decreased the levels of pro-inflammatory cytokines. Our findings suggest that B8 had mucoprotective effects against MTX-induced IM and could be used as an adjunct in chemotherapy to deter this side effect.

Adverse Childhood Experiences and Depression among Homeless Young Adults: A Social Determinants of Health Perspective.

Homelessness is a pervasive issue in the United States that presents significant challenges to public health. Homeless young adults (HYAs) are at particular risk for increased incidence and severity of depression. Using primary survey data (n = 205) collected in the Phoenix Metropolitan Area, Arizona, from June to August 2022, this study aims to examine the relationship between adverse childhood experiences (ACEs) and depression among HYAs. We adopted the ACEs 10-item scale to measure childhood traumatic experiences, whereas depression was measured by using a PHQ-4 depression scale and diagnosed depression. Regression models were conducted to test the relationships between ACEs and depression outcomes while controlling for the covariates at the individual, interpersonal, and socioeconomic/living environment levels. The average PHQ-4 score was 5.01 (SD = 3.59), and 59.69% of HYAs reported being diagnosed previously with depression. The mean ACEs score was 5.22 out of 10. Other things being equal, for every one unit increase in ACEs scores, the odds of being diagnosed with depression increased by 11.5%, yet it was not statistically significant, while the PHQ-4 score increased by 0.445 (p < 0.001). Overall, HYAs were disproportionately affected by depression. This study elucidates the complex relationship between ACEs and depression among HYAs.

Metabolic control of puberty: 60 years in the footsteps of Kennedy and Mitra's seminal work.

An individual's nutritional status has a powerful effect on sexual maturation. Puberty onset is delayed in response to chronic energy insufficiency and is advanced under energy abundance. The consequences of altered pubertal timing for human health are profound. Late puberty increases the chances of cardiometabolic, musculoskeletal and neurocognitive disorders, whereas early puberty is associated with increased risks of adult obesity, type 2 diabetes mellitus, cardiovascular diseases and various cancers, such as breast, endometrial and prostate cancer. Kennedy and Mitra's trailblazing studies, published in 1963 and using experimental models, were the first to demonstrate that nutrition is a key factor in puberty onset. Building on this work, the field has advanced substantially in the past decade, which is largely due to the impressive development of molecular tools for experimentation and population genetics. In this Review, we discuss the latest advances in basic and translational sciences underlying the nutritional and metabolic control of pubertal development, with a focus on perspectives and future directions.

Circadian neurogenetics and its implications in neurophysiology, behavior, and chronomedicine.

The circadian rhythm affects multiple physiological processes, and disruption of the circadian system can be involved in a range of disease-related pathways. The genetic underpinnings of the circadian rhythm have been well-studied in model organisms. Significant progress has been made in understanding how clock genes affect the physiological functions of the nervous system. In addition, circadian timing is becoming a key factor in improving drug efficacy and reducing drug toxicity. The circadian biology of the target cell determines how the organ responds to the drug at a specific time of day, thus regulating pharmacodynamics. The current review brings together recent advances that have begun to unravel the molecular mechanisms of how the circadian clock affects neurophysiological and behavioral processes associated with human brain diseases. We start with a brief description of how the ubiquitous circadian rhythms are regulated at the genetic, cellular, and neural circuit levels, based on knowledge derived from extensive research on model organisms. We then summarize the latest findings from genetic studies of human brain disorders, focusing on the role of human clock gene variants in these diseases. Lastly, we discuss the impact of common dietary factors and medications on human circadian rhythms and advocate for a broader application of the concept of chronomedicine.

Writing an External Letter of Review for Promotion.

Academic promotion, representing achievement of a level of distinction in one's body of work, is an honorable accomplishment in a faculty member's career. External letters of review written by faculty at higher ranks are a critical component of the promotion portfolio. We discuss key considerations for writing external letters. These considerations can be used to mentor this skill for less experienced letter writers. We also highlight how professional societies can aid faculty in developing and strengthening writing and mentoring capabilities for this vital task.

Melioidosis Vaccines (MeVa): Attitudes to vaccines, melioidosis and clinical trials in key stakeholders in Ubon Ratchathani, Thailand.

Background: Melioidosis is a bacterial infection which kills an estimated 89,000 people per year in tropical and sub-tropical regions, chiefly affecting the poorest. Diabetes is the primary risk factor, conferring a 12-fold increase in risk. Despite limited funding compared to other neglected tropical diseases, melioidosis vaccine development has generated several candidates for clinical development. CPS-CRM 197/Hcp1 is a promising vaccine candidate developed at the University of Nevada, Reno which is due to enter a Phase I clinical trial in Oxford, UK in 2024. As we move closer to the possibility of field trials of a melioidosis vaccine, it is critical to work in parallel to understand perceptions toward a vaccine among those living where melioidosis rates are high. Reasons for vaccine acceptance versus hesitancy are complex, and include perceived risk of the target disease, concern about side effects, and above all trust in government, scientists, the pharmaceutical industry and other authorities. Methods: We will carry out a qualitative study in Ubon Ratchathani, Thailand, an endemic region for melioidosis, as groundwork for a potential future melioidosis vaccine efficacy study, and in the longer-term vaccine introduction. This study seeks to explore knowledge and attitudes in three main areas; 1) melioidosis disease, 2) vaccines, and 3) participation in clinical vaccine trials. In-depth interviews and focus group discussions will take place in five participant groups of different risks and exposure to melioidosis. Purposive, convenience sampling will be used, also snowball sampling to reach some participant groups. Sample size will be based on participant's experience, to inform the line of enquiries of study, or until data saturation, expecting 66-90 participants across all groups. Discussion: The findings of this study will be written up and published in an open access journal, and will be valuable to inform future design of clinical trials as well as engagement and communications associated with future vaccine rollout.

Cell surface profiling of cultured cells by direct hydrazide capture of oxidized glycoproteins.

Glycoproteins are a particularly interesting subset of the cellular proteome as a high proportion of proteins present on the extracellular cell surface are glycosylated. These cell surface proteins are ideal targets for biologic drug therapies or for diagnostics tests. Here, we describe a modification of the well-described Cell Surface Capture (CSC) method for the selective isolation and identification of cell surface glycoproteins that contain N-linked carbohydrates. This modification, which we refer to as Direct Cell Surface Capture (D-CSC), is based on oxidation of cell surface glycans on intact cells, followed by direct conjugation of the oxidized oligosaccharides to a solid support using hydrazide chemistry, with no biotinylation step. As a proof-of-principle, we applied D-CSC to the analysis of cell surface membrane proteins of three adherent cancer cell lines (A549, OVCAR3, and U87MG) and compared our results to those published using the well-established Cell Surface Capture (CSC) method, demonstrating comparable selectivity for cell surface proteins. •A method enabling the identification of cell surface proteins from cells in culture is described.•Application of this method to profile the cell surface on three different cancer cell lines is included.

Early transcriptional responses to human enteric fever challenge.

Enteric fever, caused by oral infection with typhoidal Salmonella serovars, presents as a non-specific febrile illness preceded by an incubation period of 5 days or more. The enteric fever human challenge model provides a unique opportunity to investigate the innate immune response during this incubation period, and how this response is altered by vaccination with the Vi polysaccharide or conjugate vaccine. We find that on the same day as ingestion of typhoidal Salmonella, there is already evidence of an immune response, with 199 genes upregulated in the peripheral blood transcriptome 12 hours post-challenge (false discovery rate <0.05). Gene sets relating to neutrophils, monocytes, and innate immunity were over-represented (false discovery rate <0.05). Estimating cell proportions from gene expression data suggested a possible increase in activated monocytes 12 hours post-challenge (P = 0.036, paired Wilcoxon signed-rank test). Furthermore, plasma TNF-α rose following exposure (P = 0.011, paired Wilcoxon signed-rank test). There were no significant differences in gene expression (false discovery rate <0.05) in the 12 hours response between those who did and did not subsequently develop clinical or blood culture confirmed enteric fever or between vaccination groups. Together, these results demonstrate early perturbation of the peripheral blood transcriptome after enteric fever challenge and provide initial insight into early mechanisms of protection.