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Two lineages of Salmonella enterica serovar Typhimurium (S. Typhimurium) of multi-locus sequence type ST313 have been linked with the emergence of invasive Salmonella disease across sub-Saharan Africa. The expansion of these lineages has a temporal association with the HIV pandemic and antibiotic usage. We analysed the whole genome sequence of 129 ST313 isolates representative of the two lineages and found evidence of lineage-specific genome degradation, with some similarities to that observed in S. Typhi. Individual ST313 S. Typhimurium isolates exhibit a distinct metabolic signature and modified enteropathogenesis in both a murine and cattle model of colitis, compared to S. Typhimurium outside of the ST313 lineages. These data define phenotypes that distinguish ST313 isolates from other S. Typhimurium and may represent adaptation to a distinct pathogenesis and lifestyle linked to an-immuno-compromised human population.

In order to control and eradicate epidemic cholera, we need to understand how epidemics begin, how they spread, and how they decline and eventually end. This requires extensive sampling of epidemic disease over time, alongside the background of endemic disease that may exist concurrently with the epidemic. The unique circumstances surrounding the Argentinian cholera epidemic of 1992–1998 presented an opportunity to do this. Here, we use 490 Argentinian V. cholerae genome sequences to characterise the variation within, and between, epidemic and endemic V. cholerae . We show that, during the 1992–1998 cholera epidemic, the invariant epidemic clone co-existed alongside highly diverse members of the Vibrio cholerae species in Argentina, and we contrast the clonality of epidemic V. cholerae with the background diversity of local endemic bacteria. Our findings refine and add nuance to our genomic definitions of epidemic and endemic cholera, and are of direct relevance to controlling current and future cholera epidemics. Pandemic cholera was reintroduced to Argentina in 1992, leading to epidemic spread. Here, the authors use whole genome sequencing to show how, over 6 years, epidemic cholera was caused by invariant 7PET lineage Vibrio cholerae , against a background of sporadic disease caused by diverse local strains.

The co-stimulatory molecule CD28 is essential for activation of helper T cells. Despite this critical role, it is not known whether CD28 has functions in maintaining T cell responses following activation. To determine the role for CD28 after T cell priming, we generated a strain of mice where CD28 is removed from CD4+ T cells after priming. We show that continued CD28 expression is important for effector CD4+ T cells following infection; maintained CD28 is required for the expansion of T helper type 1 cells, and for the differentiation and maintenance of T follicular helper cells during viral infection. Persistent CD28 is also required for clearance of the bacterium Citrobacter rodentium from the gastrointestinal tract. Together, this study demonstrates that CD28 persistence is required for helper T cell polarization in response to infection, describing a novel function for CD28 that is distinct from its role in T cell priming. Invasion by a bacterium or virus typically activates a mammalian host's immune system to eliminate the pathogen. The cells of the so-called ‘innate immune system’ are the body's first line of defense against infection, and these cells patrol the organs and tissues in an effort to locate and eliminate pathogens quickly. The innate immune response is rapid and non-specific, but often cannot completely clear an infection. When necessary, innate immune cells will escalate the immune response by activating the second branch of the immune system, called the ‘adaptive immune system’. This specifically targets and eradicates an invading pathogen. T cells are essential components of the adaptive immune system, and these cells can be readily distinguished from other types of cell by proteins called T cell receptors (or TCRs) found on their surface. There are also different types of T cell, each with a specific function. T helper cells, for example, help other adaptive immune cells to mature and activate, which involves these immune cells proliferating and developing into more specialized cells. For a T cell to activate, two events must occur at the same time. First, the TCR must recognize and bind to a fragment of the pathogen that is presented to it by an innate immune cell. And second, ‘co-stimulatory molecules’ present on the surfaces of both the T cell and the same innate immune cell must interact. Using these two signals to activate a T cell helps to ensure the adaptive immune response is not ‘unleashed‘ unnecessarily. Co-stimulatory molecules have become popular targets for therapies aimed at treating autoimmune disorders—where the immune system attacks and destroys the body's own tissues. One of the most well studied co-stimulatory molecules expressed by T cells is called CD28; however, it remained unknown whether CD28 is involved in any processes after T cell activation. Now, Linterman et al. reveal that the CD28 co-stimulatory molecule plays a number of roles in addition to T cell activation. For example, a newly developed mouse model showed that CD28 must remain on the surface of T helper cells after they have been activated for these cells to effectively specialize. Linterman et al. also discovered that CD28 helps different T helper cell subtypes to develop. Linterman et al. demonstrate that CD28 is critical throughout a host's response to infection, and suggest that if CD28 is lost on activated T cells (which happens during aging, HIV infection and autoimmune diseases) the responses of T helper cells become limited. Furthermore, these findings reveal that treatments that target the CD28 co-stimulatory molecule will also affect on-going immune responses.

The interferon-inducible transmembrane (IFITM) family of proteins has been shown to restrict a broad range of viruses in vitro and in vivo by halting progress through the late endosomal pathway. Further, single nucleotide polymorphisms (SNPs) in its sequence have been linked with risk of developing severe influenza virus infections in humans. The number of viruses restricted by this host protein has continued to grow since it was first demonstrated as playing an antiviral role; all of which enter cells via the endosomal pathway. We therefore sought to test the limits of antimicrobial restriction by Ifitm3 using a knockout mouse model. We showed that Ifitm3 does not impact on the restriction or pathogenesis of bacterial (Salmonella typhimurium, Citrobacter rodentium, Mycobacterium tuberculosis) or protozoan (Plasmodium berghei) pathogens, despite in vitro evidence. However, Ifitm3 is capable of restricting respiratory syncytial virus (RSV) in vivo either through directly restricting RSV cell infection, or by exerting a previously uncharacterised function controlling disease pathogenesis. This represents the first demonstration of a virus that enters directly through the plasma membrane, without the need for the endosomal pathway, being restricted by the IFITM family; therefore further defining the role of these antiviral proteins.

Interferon lambda (IFNλ) is a group of cytokines that belong to the IL-10 family. They exhibit antiviral activities against certain viruses during infection of the liver and mucosal tissues. Here we report that IFNλ restricts in vitro replication of the β-herpesvirus murine cytomegalovirus (mCMV). However, IFNλR1-deficient (Ifnλr1-/-) mice were not preferentially susceptible to mCMV infection in vivo during acute infection after systemic or mucosal challenge, or during virus persistence in the mucosa. Instead, our studies revealed that IFNλ influences NK cell responses during mCMV infection. Ifnλr1-/- mice exhibited defective development of conventional interferon-gamma (IFNγ)-expressing NK cells in the spleen during mCMV infection whereas accumulation of granzyme B-expressing NK cells was unaltered. In vitro, development of splenic IFNγ+ NK cells following stimulation with IL-12 or, to a lesser extent, IL-18 was abrogated by IFNλR1-deficiency. Thus, IFNλ regulates NK cell responses during mCMV infection and restricts virus replication in vitro but is redundant in the control of acute and persistent mCMV replication within mucosal and non-mucosal tissues.

Clinical models of sexual response link anxiety to the etiology of sexual dysfunction. Furthermore, some cognitive behavioral therapies (CBTs) for sexual dysfunction have included strategies targeting anxiety reduction. This review examines the experimental literature on the effects of manipulating aspects of the anxiety response (e.g., anxious sensations, thoughts, attentional focus) on genital and self-reported sexual arousal. An additional aim was to use this literature to elucidate potential mechanisms that may be useful for CBT for sexual dysfunction. Our review suggested that anxiety sometimes facilitates, inhibits, or has no effect on sexual arousal. These findings suggest that caution is warranted incorporating anxiety-focused interventions in the treatment of sexual dysfunctions. Importantly, little experimental research has utilized precise manipulations of anxiety (e.g., manipulating fear of penetration) that are related to current CBT interventions. To better understand the relationship between anxiety and sexual dysfunction, future research should explore the question of why and how anxiety exerts a variable effect on sexual arousal rather than simply if anxiety exerts an effect on sexual arousal. Importantly, experimental research examining individual differences in beliefs about anxiety and sex may be helpful in answering this important question and help advance and improve CBT interventions for sexual dysfunctions.

USP21 is a ubiquitin specific protease that catalyzes protein deubiquitination, however the identification of its physiological substrates remains challenging. USP21 is known to deubiquitinate transcription factor GATA3 and death-domain kinase RIPK1 in vitro, however the in vivo settings where this regulation plays a biologically significant role remain unknown. In order to determine whether USP21 is an essential and non-redundant regulator of GATA3 or RIPK1 activity in vivo, we characterized Usp21-deficient mice, focusing on mouse viability and development, hematopoietic stem cell function, and lymphocyte differentiation. The Usp21-knockout mice were found to be viable and fertile, with no significant dysmorphology, in contrast to the GATA3 and RIPK1 knockout lines that exhibit embryonic or perinatal lethality. Loss of USP21 also had no effect on hematopoietic stem cell function, lymphocyte development, or the responses of antigen presenting cells to TLR and TNFR stimulation. GATA3 levels in hematopoietic stem cells or T lymphocytes remained unchanged. We observed that aged Usp21-knockout mice exhibited spontaneous T cell activation, however this was not linked to altered GATA3 levels in the affected cells. The contrast in the phenotype of the Usp21-knockout line with the previously characterized GATA3 and RIPK1 knockout mice strongly indicates that USP21 is redundant for the regulation of GATA3 and RIPK1 activity during mouse development, in hematopoietic stem cells, and in lymphocyte differentiation. The Usp21-deficient mouse line characterized in this study may serve as a useful tool for the future characterization of USP21 physiological functions.

FBXO7 encodes an F box containing protein that interacts with multiple partners to facilitate numerous cellular processes and has a canonical role as part of an SCF E3 ubiquitin ligase complex. Mutation of FBXO7 is responsible for an early onset Parkinsonian pyramidal syndrome and genome-wide association studies have linked variants in FBXO7 to erythroid traits. A putative orthologue in Drosophila, nutcracker, has been shown to regulate the proteasome, and deficiency of nutcracker results in male infertility. Therefore, we reasoned that modulating Fbxo7 levels in a murine model could provide insights into the role of this protein in mammals. We used a targeted gene trap model which retained 4-16% residual gene expression and assessed the sensitivity of phenotypic traits to gene dosage. Fbxo7 hypomorphs showed regenerative anaemia associated with a shorter erythrocyte half-life, and male mice were infertile. Alterations to T cell phenotypes were also observed, which intriguingly were both T cell intrinsic and extrinsic. Hypomorphic mice were also sensitive to infection with Salmonella, succumbing to a normally sublethal challenge. Despite these phenotypes, Fbxo7 hypomorphs were produced at a normal Mendelian ratio with a normal lifespan and no evidence of neurological symptoms. These data suggest that erythrocyte survival, T cell development and spermatogenesis are particularly sensitive to Fbxo7 gene dosage.

Traditional convenience sampling methods relying solely on student participants have raised concerns about the external validity of psychology research findings. Crowdsourced participant sampling methods, like Qualtrics online panels, may offer a viable alternative by minimizing barriers to external validity. However, our understanding of the reliability and external validity of data from these sources is limited. Utilizing secondary data from a larger study conducted in Canada, the present study sought to explore differences between a Qualtrics-recruited sample (n = 295) and a sample recruited via a university participant pool (n = 270) on sociodemographic characteristics, participant response characteristics, and mental health variables. Differences were found between sample source on sociodemographic characteristics such as participant age, racial background, marital status, and occupational status. The samples differed on participant response characteristics, with the Qualtrics sample demonstrating a higher failure rate on the total attention check measure and shorter survey completion time compared to the student sample. The sample sources also differed on mental health, with a higher prevalence of self-reported mental disorder diagnosis and higher levels of depression, anxiety, stress, and social anxiety symptoms in the Qualtrics sample compared to the student sample. Findings suggest that although Qualtrics panel data may be of lower quality than that of student pool samples with regard to attentive responding, it may still provide a useful recruitment source for clinical and occupational psychology researchers. When deciding on a recruitment method, researchers in psychology should aim to balance convenient access to representative samples with data quality. Les méthodes traditionnelles d'échantillonnage de commodité reposant uniquement sur des participants étudiants ont soulevé des inquiétudes quant à la validité externe des résultats de la recherche en psychologie. Les méthodes d'échantillonnage par participation, comme les panels en ligne Qualtrics, peuvent offrir une alternative viable en minimisant les obstacles à la validité externe. Cependant, notre compréhension de la fiabilité et de la validité externe des données provenant de ces sources est limitée. En utilisant les données secondaires d'une étude plus large menée au Canada, la présente étude visait à explorer les différences entre un échantillon recruté par Qualtrics (n = 295) et un échantillon recruté via un pool de participants universitaires (n = 270) sur les caractéristiques sociodémographiques, les caractéristiques de réponse des participants et les variables de santé mentale. Des différences ont été constatées entre les sources d'échantillons en ce qui a trait aux caractéristiques sociodémographiques telles que l'âge, l'origine raciale, l'état matrimonial et la situation professionnelle des participants. Les échantillons présentaient des différences au niveau des caractéristiques de réponse des participants, l'échantillon Qualtrics présentant un taux d'échec plus élevé sur la mesure de contrôle de l'attention totale et un temps de réponse à l'enquête plus court que l'échantillon d'étudiants. Les échantillons différaient également sur le plan de la santé mentale, avec une prévalence supérieure de diagnostics de troubles mentaux autodéclarés et des degrés plus élevés de dépression, d'anxiété, de stress et de symptômes d'anxiété sociale dans l'échantillon Qualtrics par rapport à l'échantillon d'étudiants. Les résultats suggèrent que, bien que les données du panel Qualtrics soient de moins bonne qualité que celles des échantillons d'étudiants en ce qui concerne les réponses attentives, elles peuvent néanmoins constituer une source de recrutement utile pour les chercheurs en psychologie clinique et en psychologie du travail. Lorsqu'ils choisissent une méthode de recrutement, les chercheurs en psychologie devraient s'efforcer de trouver un équilibre entre l'accès pratique à des échantillons représentatifs et la qualité des données. Public Significance Statement This study compared two different methods of recruiting participants for psychological research-university students versus an online panel recruited from Qualtrics. Results revealed key differences between the two samples on the sociodemographic characteristics, attentive responding, survey completion time, as well as mental health of participants. The observed differences between the two recruitment methods imply that the suitability of each approach may vary depending on the researchers' area of focus and their preference for data quality.