Publisher Correction: Clonal analysis of Salmonella-specific effector T cells reveals serovar-specific and cross-reactive T cell responses.

In the version of this article initially published, the first affiliation lacked 'MRC'; the correct name of the institution is 'MRC Weatherall Institute of Molecular Medicine'. Two designations (SP110Y and ST110H) were incorrect in the legend to Fig. 6f,h,i. The correct text is as follows: for panel f, "...loaded with either the CdtB(105-125)SP110Y (DRB4*SP110Y) or the CdtB(105-125)ST110H (DRB4*ST110H) peptide variants..."; for panel h, "...decorated by the DRB4*SP110Y tetramer (lower-right quadrant), the DRB4*ST110H (upper-left quadrant)..."; and for panel i, "...stained ex vivo with DRB4*SP110Y, DRB4*ST110H...". In Fig. 8e, the final six residues (LTEAFF) of the sequence in the far right column of the third row of the table were missing; the correct sequence is 'CASSYRRTPPLTEAFF'. In the legend to Fig. 8d, a designation (HLyE) was incorrect; the correct text is as follows: "(HlyE?)." Portions of the Acknowledgements section were incorrect; the correct text is as follows: "This work was supported by the UK Medical Research Council (MRC) (MR/K021222/1) (G.N., M.A.G., A.S., V.C., A.J.P.),...the Oxford Biomedical Research Centre (A.J.P., V.C.),...and core funding from the Singapore Immunology Network (SIgN) (E.W.N.) and the SIgN immunomonitoring platform (E.W.N.)." Finally, a parenthetical element was phrased incorrectly in the final paragraph of the Methods subsection "T cell cloning and live fluorescence barcoding"; the correct phrasing is as follows: "...(which in all cases included HlyE, CdtB, Ty21a, Quailes, NVGH308, and LT2 strains and in volunteers T5 and T6 included PhoN)...". Also, in Figs. 3c and 4a, the right outlines of the plots were not visible; in the legend to Fig. 3, panel letter 'f' was not bold; and in Fig. 8f, 'ND' should be aligned directly beneath DRB4 in the key and 'ND' should be removed from the diagram at right, and the legend should be revised accordingly as follows: "...colors indicate the HLA class II restriction (gray indicates clones for which restriction was not determined (ND)). Clonotypes are grouped on the basis of pathogen selectivity (continuous line), protein specificity (dashed line) and epitope specificity; for ten HlyE-specific clones (pixilated squares), the epitope specificity was not determined...". The errors have been corrected in the HTML and PDF versions of the article.

Clonal analysis of Salmonella-specific effector T cells reveals serovar-specific and cross-reactive T cell responses.

To tackle the complexity of cross-reactive and pathogen-specific T cell responses against related Salmonella serovars, we used mass cytometry, unbiased single-cell cloning, live fluorescence barcoding, and T cell-receptor sequencing to reconstruct the Salmonella-specific repertoire of circulating effector CD4+ T cells, isolated from volunteers challenged with Salmonella enterica serovar Typhi (S. Typhi) or Salmonella Paratyphi A (S. Paratyphi). We describe the expansion of cross-reactive responses against distantly related Salmonella serovars and of clonotypes recognizing immunodominant antigens uniquely expressed by S. Typhi or S. Paratyphi A. In addition, single-amino acid variations in two immunodominant proteins, CdtB and PhoN, lead to the accumulation of T cells that do not cross-react against the different serovars, thus demonstrating how minor sequence variations in a complex microorganism shape the pathogen-specific T cell repertoire. Our results identify immune-dominant, serovar-specific, and cross-reactive T cell antigens, which should aid in the design of T cell-vaccination strategies against Salmonella.

Blood and immune development in human fetal bone marrow and Down syndrome.

Haematopoiesis in the bone marrow (BM) maintains blood and immune cell production throughout postnatal life. Haematopoiesis first emerges in human BM at 11-12 weeks after conception1,2, yet almost nothing is known about how fetal BM (FBM) evolves to meet the highly specialized needs of the fetus and newborn. Here we detail the development of FBM, including stroma, using multi-omic assessment of mRNA and multiplexed protein epitope expression. We find that the full blood and immune cell repertoire is established in FBM in a short time window of 6-7 weeks early in the second trimester. FBM promotes rapid and extensive diversification of myeloid cells, with granulocytes, eosinophils and dendritic cell subsets emerging for the first time. The substantial expansion of B lymphocytes in FBM contrasts with fetal liver at the same gestational age. Haematopoietic progenitors from fetal liver, FBM and cord blood exhibit transcriptional and functional differences that contribute to tissue-specific identity and cellular diversification. Endothelial cell types form distinct vascular structures that we show are regionally compartmentalized within FBM. Finally, we reveal selective disruption of B lymphocyte, erythroid and myeloid development owing to a cell-intrinsic differentiation bias as well as extrinsic regulation through an altered microenvironment in Down syndrome (trisomy 21).

Spatial and molecular profiling of the mononuclear phagocyte network in classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL) has a rich immune infiltrate, which is an intrinsic component of the neoplastic process. Malignant Hodgkin Reed-Sternberg cells (HRSCs) create an immunosuppressive microenvironment by the expression of regulatory molecules, preventing T-cell activation. It has also been demonstrated that mononuclear phagocytes (MNPs) in the vicinity of HRSCs express similar regulatory mechanisms in parallel, and their presence in tissue is associated with inferior patient outcomes. MNPs in cHL have hitherto been identified by a small number of canonical markers and are usually described as tumor-associated macrophages. The organization of MNP networks and interactions with HRSCs remains unexplored at high resolution. Here, we defined the global immune-cell composition of cHL and nonlymphoma lymph nodes, integrating data across single-cell RNA sequencing, spatial transcriptomics, and multiplexed immunofluorescence. We observed that MNPs comprise multiple subsets of monocytes, macrophages, and dendritic cells (DCs). Classical monocytes, macrophages and conventional DC2s were enriched in the vicinity of HRSCs, but plasmacytoid DCs and activated DCs were excluded. Unexpectedly, cDCs and monocytes expressed immunoregulatory checkpoints PD-L1, TIM-3, and the tryptophan-catabolizing protein IDO, at the same level as macrophages. Expression of these molecules increased with age. We also found that classical monocytes are important signaling hubs, potentially controlling the retention of cDC2 and ThExh via CCR1-, CCR4-, CCR5-, and CXCR3-dependent signaling. Enrichment of the cDC2-monocyte-macrophage network in diagnostic biopsies is associated with early treatment failure. These results reveal unanticipated complexity and spatial polarization within the MNP compartment, further demonstrating their potential roles in immune evasion by cHL.

Dual DAT and sigma receptor inhibitors attenuate cocaine effects on nucleus accumbens dopamine dynamics in rats.

Psychostimulant use disorders (PSUD) are prevalent; however, no FDA-approved medications have been made available for treatment. Previous studies have shown that dual inhibitors of the dopamine transporter (DAT) and sigma receptors significantly reduce the behavioral/reinforcing effects of cocaine, which have been associated with stimulation of extracellular dopamine (DA) levels resulting from DAT inhibition. Here, we employ microdialysis and fast scan cyclic voltammetry (FSCV) procedures to investigate the effects of dual inhibitors of DAT and sigma receptors in combination with cocaine on nucleus accumbens shell (NAS) DA dynamics in naïve male Sprague Dawley rats. In microdialysis studies, administration of rimcazole (3, 10 mg/kg; i.p.) or its structural analog SH 3-24 (1, 3 mg/kg; i.p.), compounds that are dual inhibitors of DAT and sigma receptors, significantly reduced NAS DA efflux stimulated by increasing doses of cocaine (0.1, 0.3, 1.0 mg/kg; i.v.). Using the same experimental conditions, in FSCV tests, we show that rimcazole pretreatments attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Under the same conditions, JJC8-091, a modafinil analog and dual inhibitor of DAT and sigma receptors, similarly attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Our results provide the neurochemical groundwork towards understanding actions of dual inhibitors of DAT and sigma receptors on DA dynamics that likely mediate the behavioral effects of psychostimulants like cocaine.

Validation of epidermal AMBRA1 and loricrin (AMBLor) as a prognostic biomarker for nonulcerated American Joint Committee on Cancer stage I/II cutaneous melanoma.

BACKGROUND: Combined expression of the autophagy-regulatory protein AMBRA1 (activating molecule in Beclin1-regulated autophagy) and the terminal differentiation marker loricrin in the peritumoral epidermis of stage I melanomas can identify tumour subsets at low risk of -metastasis. OBJECTIVES: To validate the combined expression of peritumoral AMBRA1 and loricrin (AMBLor) as a prognostic biomarker able to identify both stage I and II melanomas at low risk of tumour recurrence. METHODS: Automated immunohistochemistry was used to analyse peritumoral AMBRA1 and loricrin expression in geographically distinct discovery (n = 540) and validation (n = 300) cohorts of nonulcerated American Joint Committee on Cancer (AJCC) stage I and II melanomas. AMBLor status was correlated with clinical outcomes in the discovery and validation cohorts separately and combined. RESULTS: Analysis of AMBLor in the discovery cohort revealed a recurrence-free survival (RFS) rate of 95.5% in the AMBLor low-risk group vs. 81.7% in the AMBLor at-risk group (multivariate log-rank, P < 0.001) and a negative predictive value (NPV) of 96.0%. In the validation cohort, AMBLor analysis revealed a RFS rate of 97.6% in the AMBLor low-risk group vs. 78.3% in the at-risk group (multivariate log-rank, P < 0.001) and a NPV of 97.6%. In a multivariate model considering AMBLor, Breslow thickness, age and sex, analysis of the combined discovery and validation cohorts showed that the estimated effect of AMBLor was statistically significant, with a hazard ratio of 3.469 (95% confidence interval 1.403-8.580, P = 0.007) and an overall NPV of 96.5%. CONCLUSIONS: These data provide further evidence validating AMBLor as a prognostic biomarker to identify nonulcerated AJCC stage I and II melanoma tumours at low risk of disease recurrence.

Building Healthy Babies: A Mixed-Methods Needs Assessment for a Pre-Conception Program in Ontario.

OBJECTIVES: The objective of this study was to gather Ontario clinicians' and public members' views on the design of a pre-conception patient education program. METHODS: In this mixed-methods study, online surveys comprised of rank order, multiple choice, and short answer questions were completed by clinicians and public members. Semi-structured focus groups consisting of 2-6 participants each were then held via videoconference. Demographic variables and survey responses were analyzed quantitatively using descriptive and summary statistics. Descriptive thematic qualitative analysis using the constant comparative method of grounded theory was completed on each transcript to generate themes. RESULTS: A total of 168 public members and 43 clinicians in Ontario completed surveys, while 11 clinicians and 11 public members participated in the focus groups. A pre-conception program in Ontario was felt to be important. An individual appointment with a primary care provider was the favoured program format per survey responses, whereas a virtual format with an interactive component was preferred among focus group participants. Important topics to include were pre-conception health (infertility, genetic screening, folic acid), prenatal and postpartum counselling (diet, activity, substance use, prenatal care, postpartum course), and medical optimization in pregnancy (high-risk medical conditions, medications, mental health). Both groups emphasized the need to consider accommodations for marginalized populations and various cultures and languages. CONCLUSION: A standardized pre-conception patient education program is felt to be of high value by Ontario clinicians and public members. A pre-conception program may help improve obstetrical outcomes and decrease rates of major congenital anomalies in Ontario.

Conspiracy theory beliefs in the adolescent population: A systematic review.

INTRODUCTION: While the study of conspiracy theory beliefs is a relatively new research area, there has been a rise in academic interest in recent years. The literature provides evidence of relationships between conspiracy theory beliefs and a range of factors, but the vast majority of studies are limited to adult samples, and it is unclear how such beliefs present in adolescence. METHODS: The systematic review was conducted according to the PRISMA-S format. Relevant databases were searched up to February 23, 2023, for quantitative studies related to adolescent conspiracy theory beliefs. RESULTS: The six included articles show that conspiracy theory beliefs are present from the start of adolescence, and stable from age 14 upwards, with correlations reported for mistrust and paranoid thinking. Negative relationships were reported for cognitive factors such as ontological confusion, cognitive ability, and actively open-minded thinking. Health-related beliefs correlated with adverse childhood experiences, peer problems, conduct, and sociodemographic factors. Right-wing authoritarianism and anxiety positively correlated with intergroup conspiracy theory beliefs. CONCLUSION: While some factors from adult studies are replicated in the review, there are differences between age groups. The age at which conspiracy theory beliefs begin to form indicate developmental aspects of adolescence, and possibly childhood, that require further examination. Cognitive factors show promise for interventions and should be explored further. However, the lack of studies using adolescent populations is an issue that must be resolved for a greater understanding of conspiracy theory beliefs and a move toward effective interventions.

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.

Regulation and Role of αE Integrin and Gut Homing Integrins in Migration and Retention of Intestinal Lymphocytes during Inflammatory Bowel Disease.

Targeting interactions between α4ß7 integrin and endothelial adhesion molecule MAdCAM-1 to inhibit lymphocyte migration to the gastrointestinal tract is an effective therapy in inflammatory bowel disease (IBD). Following lymphocyte entry into the mucosa, a subset of these cells expresses αEß7 integrin, which is expressed on proinflammatory lymphocytes, to increase cell retention. The factors governing lymphocyte migration into the intestinal mucosa and αE integrin expression in healthy subjects and IBD patients remain incompletely understood. We evaluated changes in factors involved in lymphocyte migration and differentiation within tissues. Both ileal and colonic tissue from active IBD patients showed upregulation of ICAM-1, VCAM-1, and MAdCAM-1 at the gene and protein levels compared with healthy subjects and/or inactive IBD patients. ß1 and ß7 integrin expression on circulating lymphocytes was similar across groups. TGF-ß1 treatment induced expression of αE on both ß7+ and ß7- T cells, suggesting that cells entering the mucosa independently of MAdCAM-1/α4ß7 can become αEß7+ ITGAE gene polymorphisms did not alter protein induction following TGF-ß1 stimulation. Increased phospho-SMAD3, which is directly downstream of TGF-ß, and increased TGF-ß-responsive gene expression were observed in the colonic mucosa of IBD patients. Finally, in vitro stimulation experiments showed that baseline ß7 expression had little effect on cytokine, chemokine, transcription factor, and effector molecule gene expression in αE+ and αE- T cells. These findings suggest cell migration to the gut mucosa may be altered in IBD and α4ß7-, and α4ß7+ T cells may upregulate αEß7 in response to TGF-ß once within the gut mucosa.

Patients' and providers' perspectives on non-urgent egg freezing decision-making: a thematic analysis.

BACKGROUND: The decision to undergo non-urgent egg freezing (EF) is complex for patients and providers supporting them. Though prior studies have explored patient perspectives, no study has also included the separate perspectives of providers. METHODS: This qualitative study involved semi-structured individual interviews exploring the decision to undergo EF. Participants included patients considering EF at one academic fertility clinic and providers who counsel patients about EF from across Canada. Data analysis was accomplished using thematic analysis. Data saturation was met after interviewing 13 providers and 12 patients. FINDINGS: Four themes were identified and explored, illuminating ways in which patients and providers navigate decision-making around EF: (1) patients viewed EF as a 'back-up plan' for delaying the decision about whether to have children, while providers were hesitant to present EF in this way given the uncertainty of success; (2) providers viewed ovarian reserve testing as essential while patients believed it unnecessarily complicated the decision; (3) patients and providers cited a need for change in broader societal attitudes regarding EF since social stigma was a significant barrier to decision-making; and (4) commonality and peer support were desired by patients to assist in their decision, although some providers were hesitant to recommend this to patients. CONCLUSIONS: In conclusion, the decision to undergo EF is complex and individual patient values play a significant role. In some areas, there is disconnect between providers and patients in their views on how to navigate EF decision-making, and these should be addressed in discussions between providers and patients to improve shared decision-making.

Patients' and providers' perspectives on the decision to undergo non-urgent egg freezing: a needs assessment.

BACKGROUND: Previous research has demonstrated that patients have difficulty with the decision to undergo non-urgent egg freezing (EF). This study aimed to investigate the decisional difficulties and possible decisional support mechanisms for patients considering EF, and for their providers. METHODS: This qualitative study involved a needs assessment via individual interviews. Participants included patients considering EF at one academic fertility clinic and providers from across Canada who counsel patients considering EF. 25 participants were included (13 providers and 12 patients). The interview guide was developed according to the Ottawa Decision Support Framework. Interviews were transcribed, and transcripts analyzed for themes and concepts using NVIVO 12. FINDINGS: Multiple factors contributing to decisional difficulty were identified, including: (1) multiple reproductive options available with differing views from patients/providers regarding their importance; (2) a decision typically made under the pressure of reproductive aging; (3) uncertainty surrounding the technology/inadequate outcome data; (4) the financial burden of EF; (5) inherent uncertainty relating to potential decision regret; and (6) differing perceptions between patients/providers regarding the role providers should play in the decision. Additionally, potential sources of decisional support were identified, including provision of basic information before and/or during initial consultation, followed by an opportunity during or after initial consultation for clarifying information and helping with value judgements. Individualized counselling based on patient values, adequate follow-up, psychosocial counselling, and peer support were also emphasized. CONCLUSIONS: More decisional support for women considering EF is needed. Suggestions include a patient decision aid in conjunction with modified healthcare provider counselling, support and follow up.

Exploring the views and experiences of people recovering from a stroke about a new text message intervention to promote physical activity after rehabilitation-Keeping Active with Texting After Stroke: A qualitative study.

BACKGROUND: Participating in exercise following a stroke is essential for recovery. When community-based rehabilitation services end, some people struggle to remain active. We codesigned Keeping Active with Texting After Stroke (KATS), a text message intervention to support home-based, self-directed plans to continue exercising. KATS delivers a series of automated text messages over a 12-week period from the point of discharge from National Health Service-funded therapy. The aim of this study was to explore the views and experiences of the first cohort of participants to complete the KATS intervention about the meaning, engagement, workability and worth of the intervention. METHODS: We undertook a qualitative study, theoretically informed by Normalisation Process Theory. We conducted semi-structured telephone interviews with people with stroke from two Health Boards in Scotland. Data collection took place over two phases, with each participant being interviewed twice: first, halfway through intervention delivery (Week 6) and then again at the end of the intervention (Week 12). All interviews were audio-recorded, transcribed and analysed thematically. RESULTS: A total of 24 interviews were conducted with 12 participants. Our findings were organised around four overarching analytical themes: (1) making sense of KATS: timing and complementarity in the rehabilitation journey; (2) engaging with KATS: connection and identification with others; (3) making KATS work: flexibility and tailorable guidance; (4) appraising the worth of KATS: encouragement and friendliness. Participants differentiated KATS from current rehabilitation practice, finding it relevant, fitting and worthwhile. Variations were reported in engagement with behaviour change techniques, but participants were able to tailor KATS use, making it work for them in different ways. CONCLUSIONS: Perceived benefits went beyond promoting physical activity, including feeling supported and connected. Future research will test the effectiveness of KATS in promoting physical activity and explore any associations with relevant social and emotional secondary outcomes. PATIENT OR PUBLIC CONTRIBUTION: A research funding proposal was developed in collaboration with five people with stroke and three spouses. After securing funding, six people with stroke were invited to join the project's Collaborative Working Group, alongside health professionals and stroke rehabilitation experts, to codevelop the intervention and support the feasibility study.

An open source pipeline for quantitative immunohistochemistry image analysis of inflammatory skin disease using artificial intelligence.

BACKGROUND: The application of artificial intelligence (AI) to whole slide images has the potential to improve research reliability and ultimately diagnostic efficiency and service capacity. Image annotation plays a key role in AI and digital pathology. However, the work-streams required for tissue-specific (skin) and immunostain-specific annotation has not been extensively studied compared with the development of AI algorithms. OBJECTIVES: The objective of this study is to develop a common workflow for annotating whole slide images of biopsies from inflammatory skin disease immunostained with a variety of epidermal and dermal markers prior to the development of the AI-assisted analysis pipeline. METHODS: A total of 45 slides containing 3-5 sections each were scanned using Aperio AT2 slide scanner (Leica Biosystems). These slides were annotated by hand using a commonly used image analysis tool which resulted in more than 4000 images blocks. We used deep learning (DL) methodology to first sequentially segment (epidermis and upper dermis), with the exclusion of common artefacts and second to quantify the immunostained signal in those two compartments of skin biopsies and the ratio of positive cells. RESULTS: We validated two DL models using 10-fold validation runs and by comparing to ground truth manually annotated data. The models achieved an average (global) accuracy of 95.0% for the segmentation of epidermis and dermis and 86.1% for the segmentation of positive/negative cells. CONCLUSIONS: The application of two DL models in sequence facilitates accurate segmentation of epidermal and dermal structures, exclusion of common artefacts and enables the quantitative analysis of the immunostained signal. However, inaccurate annotation of the slides for training the DL model can decrease the accuracy of the output. Our open source code will facilitate further external validation across different immunostaining platforms and slide scanners.

The impact of continuing bonds following bereavement: A systematic review.

Following bereavement, continuing bonds (CBs) include engaging with memories, illusions, sensory and quasi-sensory perceptions, hallucinations, communication, actions, and belief that evoke an inner relationship with the deceased. To date, the literature has been unable to confirm whether retaining, rather than relinquishing, bonds is helpful. A mixed studies systematic literature search explored how CBs affect grief. Studies on the effect or experience of CBs on adjustment following bereavement were eligible for inclusion. Six computerized databases were searched. A total of 79 of 319 screened studies were included. Three themes were derived from the thematic analysis: (1) comfort and distress, (2) ongoing bonds and relational identity, and (3) uncertainty, conceptualizing, and spirituality. Themes describe the role of CBs for the accommodation of the death story, transformation of the relationship, meaning reconstruction, identity processes, and affirmation of spiritual belief. Results shed light on the adaptive potentials for CBs.

A latent profile analysis of COVID-19 conspiracy beliefs: Associations with thinking styles, mistrust, socio-political control, need for closure and verbal intelligence.

Throughout the COVID-19 pandemic, attention has been drawn to conspiracy theories. To date, research has largely examined commonalities in conspiracy theory belief, however it is important to identify where there may be notable differences. The aim of the present research was first to distinguish between typologies of COVID-19 conspiracy belief and explore demographic, social cognitive factors associated with these beliefs. Secondly, we aimed to examine the effects of such beliefs on adherence to government health guidelines. Participants (N = 319) rated well known COVID-19 conspiracy theories, completing measures of thinking style, socio-political control, mistrust, verbal intelligence, need for closure and demographic information. Participants also rated the extent to which they followed government health guidelines. Latent profile analysis suggests three profiles of COVID-19 conspiracy beliefs with low, moderate, and high COVID conspiracy belief profiles and successively stronger endorsement on all but one of the COVID-19 conspiracy theories. Those holding stronger COVID-19 conspiracy theory beliefs are more likely to reason emotively, feel less socio-political control, mistrust others, have lower verbal ability and adhere less to COVID-19 guidelines. The social and health implications of these findings are discussed.

Are There Prevalent Sex Differences in Psychostimulant Use Disorder? A Focus on the Potential Therapeutic Efficacy of Atypical Dopamine Uptake Inhibitors.

Psychostimulant use disorders (PSUD) affect a growing number of men and women and exert sizable public health and economic burdens on our global society. Notably, there are some sex differences in the onset of dependence, relapse rates, and treatment success with PSUD observed in preclinical and clinical studies. The subtle sex differences observed in the behavioral aspects of PSUD may be associated with differences in the neurochemistry of the dopaminergic system between sexes. Preclinically, psychostimulants have been shown to increase synaptic dopamine (DA) levels and may downregulate the dopamine transporter (DAT). This effect is greatest in females during the high estradiol phase of the estrous cycle. Interestingly, women have been shown to be more likely to begin drug use at younger ages and report higher levels of desire to use cocaine than males. Even though there is currently no FDA-approved medication, modafinil, a DAT inhibitor approved for use in the treatment of narcolepsy and sleep disorders, has shown promise in the treatment of PSUD among specific populations of affected individuals. In this review, we highlight the therapeutic potential of modafinil and other atypical DAT inhibitors focusing on the lack of sex differences in the actions of these agents.

Electrochemically-Switched 2nd Order Non-Linear Optical Response in an Arylimido-Polyoxometalate with High Contrast and Cyclability.

Electrochemically switched 2nd order non-linear optical responses have been demonstrated for the first time in polyoxometalates (POMs), with an arylimido-derivative showing a leading combination of high on/off contrast (94 %), high visible transparency, and cyclability. Spectro-electrochemical and TD-DFT studies indicate that the switch-off results from weakened charge transfer (CT) character of the electronic transitions in the reduced state. This represents the first study of an imido-POM reduced state, and demonstrates the potential of POM hybrids as electrochemically activated molecular switches.

Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers.

Infections with Salmonella enterica serovars Typhi and Paratyphi A cause an estimated 14 million cases of enteric fever annually. Here, the controlled nature of challenge studies is exploited to identify genetic variants associated with enteric fever susceptibility. Human challenge participants were genotyped by Illumina OmniExpress-24 BeadChip array (n = 176) and/or transcriptionally profiled by RNA sequencing (n = 174). While the study was underpowered to detect any single nucleotide polymorphisms (SNPs) significant at the whole-genome level, two SNPs within CAPN14 and MIATNB were identified with P < 10-5 for association with development of symptoms or bacteremia following oral S. Typhi or S. Paratyphi A challenge. Imputation of classical human leukocyte antigen (HLA) types from genomic and transcriptomic data identified HLA-B*27:05, previously associated with nontyphoidal Salmonella-induced reactive arthritis, as the HLA type most strongly associated with enteric fever susceptibility (P = 0.011). Gene sets relating to the unfolded protein response/heat shock and endoplasmic reticulum-associated protein degradation were overrepresented in HLA-B*27:05+ participants following challenge. Furthermore, intracellular replication of S. Typhi is higher in C1R cells transfected with HLA-B*27:05 (P = 0.02). These data suggest that activation of the unfolded protein response by HLA-B*27:05 misfolding may create an intracellular environment conducive to S. Typhi replication, increasing susceptibility to enteric fever.

Center of mass and anatomical coordinate system definition for sheep head kinematics, with application to ovine models of traumatic brain injury.

Pathological outcomes of traumatic brain injury (TBI), including diffuse axonal injury, are influenced by the direction, magnitude, and duration of head acceleration during the injury exposure. Ovine models have been used to study injury mechanics and pathological outcomes of TBI. To accurately describe the kinematics of the head during an injury exposure, and better facilitate comparison with human head kinematics, anatomical coordinate systems (ACS) with an origin at the head or brain center of mass (CoM), and axes that align with the ovine Frankfort plane equivalent, are required. The aim of this study was to determine the mass properties of the sheep head and brain, and define an ACSvirtual for the head and brain, using anatomical landmarks on the skull with the aforementioned origins and orientation. Three-dimensional models of 10 merino sheep heads were constructed from computed tomography images, and the coordinates of the head and brain CoMs, relative to a previously reported sheep head coordinate system (ACSphysical ), were determined using the Hounsfield unit-mass density relationship. The ACSphysical origin was 34.8 ± 3.1 mm posterosuperior of the head CoM and 43.7 ± 1.7 anteroinferior of the brain CoM. Prominent internal anatomical landmarks were then used to define a new ACS (ACSvirtual ) with axes aligned with the Frankfort plane equivalent and an origin 10.4 ± 3.2 mm from the head CoM. The CoM and ACSvirtual defined in this study will increase the potential for comparison of head kinematics between ovine models and humans, in the context of TBI.