Reverse vaccinology-based identification of a novel surface lipoprotein that is an effective vaccine antigen against bovine infections caused by Pasteurella multocida.

Pasteurella multocida can infect a multitude of wild and domesticated animals, with infections in cattle resulting in hemorrhagic septicemia (HS) or contributing to bovine respiratory disease (BRD) complex. Current cattle vaccines against P. multocida consist of inactivated bacteria, which only offer limited and serogroup specific protection. Here, we describe a newly identified surface lipoprotein, PmSLP, that is present in nearly all annotated P. multocida strains isolated from cattle. Bovine associated variants span three of the four identified phylogenetic clusters, with PmSLP-1 and PmSLP-2 being restricted to BRD associated isolates and PmSLP-3 being restricted to isolates associated with HS. Recombinantly expressed, soluble PmSLP-1 (BRD-PmSLP) and PmSLP-3 (HS-PmSLP) vaccines were both able to provide full protection in a mouse sepsis model against the matched P. multocida strain, however no cross-protection and minimal serum IgG cross-reactivity was identified. Full protection against both challenge strains was achieved with a bivalent vaccine containing both BRD-PmSLP and HS-PmSLP, with serum IgG from immunized mice being highly reactive to both variants. Year-long stability studies with lyophilized antigen stored under various temperatures show no appreciable difference in biophysical properties or loss of efficacy in the mouse challenge model. PmSLP-1 and PmSLP-3 vaccines were each evaluated for immunogenicity in two independent cattle trials involving animals of different age ranges and breeds. In all four trials, vaccination with PmSLP resulted in an increase in antigen specific serum IgG over baseline. In a blinded cattle challenge study with a recently isolated HS strain, the matched HS-PmSLP vaccine showed strong efficacy (75-87.5% survival compared to 0% in the control group). Together, these data suggest that cattle vaccines composed of PmSLP antigens can be a practical and effective solution for preventing HS and BRD related P. multocida infections.

Prevalence of Slam-dependent hemophilins in Gram-negative bacteria.

Iron acquisition systems are crucial for pathogen growth and survival in iron-limiting host environments. To overcome nutritional immunity, bacterial pathogens evolved to use diverse mechanisms to acquire iron. Here, we examine a heme acquisition system that utilizes hemophores called hemophilins which are also referred to as HphAs in several Gram-negative bacteria. In this study, we report three new HphA structures from Stenotrophomonas maltophilia, Vibrio harveyi, and Haemophilus parainfluenzae. Structural determination of HphAs revealed an N-terminal clamp-like domain that binds heme and a C-terminal eight-stranded ß-barrel domain that shares the same architecture as the Slam-dependent Neisserial surface lipoproteins. The genetic organization of HphAs consists of genes encoding a Slam homolog and a TonB-dependent receptor (TBDR). We investigated the Slam-HphA system in the native organism or the reconstituted system in Escherichia coli cells and found that the efficient secretion of HphA depends on Slam. The TBDR also played an important role in heme uptake and conferred specificity for its cognate HphA. Furthermore, bioinformatic analysis of HphA homologs revealed that HphAs are conserved in the alpha, beta, and gammaproteobacteria. Together, these results show that the Slam-dependent HphA-type hemophores are prevalent in Gram-negative bacteria and further expand the role of Slams in transporting soluble proteins. IMPORTANCE: This paper describes the structure and function of a family of Slam (Type IX secretion System) secreted hemophores that bacteria use to uptake heme (iron) while establishing an infection. Using structure-based bioinformatics analysis to define the diversity and prevalence of this heme acquisition pathway, we discovered that a large portion of gammaproteobacterial harbors this system. As organisms, including Acinetobacter baumannii, utilize this system to facilitate survival during host invasion, the identification of this heme acquisition system in bacteria species is valuable information and may represent a target for antimicrobials.

Contributing factors to secondary traumatic stress and vicarious posttraumatic growth in therapists.

Alongside the recognized potential negative repercussions of working as a psychological therapist, there is growing interest in the potential positive impacts of engaging in such work. The current study used a cross-sectional online survey design to explore the impact of a range of demographic, work-related, and compassion-related factors on levels of secondary traumatic stress (STS) and vicarious posttraumatic growth (VPTG) in an international sample of 359 psychological therapists. Hierarchical multiple regressions demonstrated that burnout, lower levels of self-compassion, having a personal trauma history, reporting a higher percentage of working time with a trauma focus, and being female were the statistically significant contributors to STS scores, explaining 40.8% of the variance, F(9, 304) = 23.2, p <.001. For VPTG, higher compassion satisfaction, higher self-compassion, higher STS, a higher percentage of working time with a trauma focus, fewer years qualified, being male, and having a personal trauma history were all statistically significant contributors, explaining 27.3% of the variance, F (10, 304) = 11.37, p <.001. The findings illustrate the potential risk and protective factors for developing STS and clarify factors that may increase the likelihood of experiencing VPTG. Implications for psychological therapists and the organizations and institutions for which they work are considered along with potential directions for future research in the discussion.

Actinobacillus utilizes a binding protein-dependent ABC transporter to acquire the active form of vitamin B6.

Bacteria require high-efficiency uptake systems to survive and proliferate in nutrient-limiting environments, such as those found in host organisms. ABC transporters in the bacterial plasma membrane provide a mechanism for transport of many substrates. In this study, we examine an operon containing a periplasmic binding protein in Actinobacillus for its potential role in nutrient acquisition. The electron density map of 1.76 Å resolution obtained from the crystal structure of the periplasmic binding protein was best fit with a molecular model containing a pyridoxal-5'-phosphate (P5P/pyridoxal phosphate/the active form of vitamin B6) ligand within the protein's binding site. The identity of the P5P bound to this periplasmic binding protein was verified by isothermal titration calorimetry, microscale thermophoresis, and mass spectrometry, leading us to name the protein P5PA and the operon P5PAB. To illustrate the functional utility of this uptake system, we introduced the P5PAB operon from Actinobacillus pleuropneumoniae into an Escherichia coli K-12 strain that was devoid of a key enzyme required for P5P synthesis. The growth of this strain at low levels of P5P supports the functional role of this operon in P5P uptake. This is the first report of a dedicated P5P bacterial uptake system, but through bioinformatics, we discovered homologs mainly within pathogenic representatives of the Pasteurellaceae family, suggesting that this operon exists more widely outside the Actinobacillus genus.

A meta-analysis of executive functions among survivors of subarachnoid haemorrhage.

Subarachnoid Haemorrhage (SAH) is a type of stroke which is suggested to result in Executive Functioning (EF) deficits. Within the SAH research, EF is typically assessed as a unitary cognitive construct. Therefore, the nature and extent to which the different components of EF are impacted post SAH remain unclear. In this meta-analysis, 10 studies met selection criteria including 248 SAH participants, treated by endovascular coiling. Participants were assessed by EF measures and compared with 230 controls. Searches were conducted in November 2018 including Medline, PsychINFO, Web of Science, Scopus and CINAHL databases. EF measures were assigned to categories including Cognitive Flexibility, Working Memory, Inhibitory Control and Planning/Problem Solving [Diamond, 2013. Executive functions. Annual Review of Psychology, 64(1), 135-168. https://doi.org/10.1146/annurev-psych-113011-143750]. A statistically significant effect was found for overall EF. Cognitive Flexibility (G = -0.76) and Inhibitory Control (G = -0.51) generated moderate effect sizes, while Working Memory and Planning/Problem Solving found a small effect size (G = -0.45 and G = -0.49, respectively). The I2 statistic suggested small to moderate heterogeneity between studies, hypothesized to relate to different cognitive tools. Underlying components of EF appear to be differentially impacted post SAH, with Cognitive flexibility demonstrating the largest degree of deficit. Recommendations for a standardized and uniform assessment of EF post SAH are outlined.

A meta-analytic review of the relationship between attachment styles and posttraumatic growth.

OBJECTIVE: The present review aimed to examine the relationship between attachment styles and posttraumatic growth in adults exposed to traumatizing events. METHOD: A systematic literature search resulted in the inclusion of 14 studies in the review. Four correlational meta-analyses of the relationship between the attachment styles of secure, dismissive, preoccupied, and fearful, and posttraumatic growth, were conducted. RESULTS: These revealed a significant small positive relationship between secure attachment and posttraumatic growth (r = 0.21, p < 0.001); a significant small negative relationship between dismissive attachment and posttraumatic growth (r = -0.12, p < 0.001), and a weak relationship between preoccupied attachment and posttraumatic growth (r = -0.04, p = 0.235), and fearful attachment and posttraumatic growth (r = 0.08, p = 0.248). CONCLUSIONS: The relationship between attachment styles and posttraumatic growth is modest and may be better explained by other variables. Nonetheless, findings provide useful information for clinicians regarding the potential small impact of attachment style following traumatizing exposure. Implications for future research are highlighted with respect to methodological rigor and the role of other potentially influential variables.

A Meta-Analytic Review of the Association Between Alienation Appraisals and Posttraumatic Stress Disorder Symptoms in Trauma-Exposed Adults.

Ehlers and Clark's (2000) cognitive model of posttraumatic stress disorder (PTSD) highlights the importance of negative appraisals in maintaining posttraumatic stress. Recent research suggests that alienation appraisals, defined as feeling disconnected from the self and others, mediate the association between traumatic experiences and subsequent PTSD symptoms. To our knowledge, no systematic review has yet explored the relation between alienation appraisals and PTSD symptoms in trauma-exposed adults, despite the important clinical implications posed by this association. A systematic search of the SCOPUS, Web of Science, PsycInfo, MEDLINE, CINAHL Plus, and PILOTS databases resulted in 470 studies, nine of which met full inclusion criteria. Studies were quality-assessed for risk of bias using the Quality Assessment Tool for Studies with Diverse Designs (QATSDD) quality assessment tool. A random-effects meta-analysis for the association between alienation appraisals and PTSD symptoms showed a large total effect size, r = .57, 95% CI [.46, .66], z = 8.41, p < .001. This large effect suggests that as alienation appraisals increase, PTSD symptoms increase. Although a strong positive association was found between alienation and PTSD symptoms, the mechanism of this association remains unclear. Limitations of the research included significant heterogeneity across studies and the fact that data were correlational. Future research to explore why alienation appraisals are significant in posttraumatic stress may further help to inform therapeutic approaches to targeting alienation appraisals in trauma survivors. Recommendations are made for the clinical assessment of alienation appraisals when exploring the impact of the traumatic experience on the survivor.

A Meta-Analysis of the Association Between Appraisals of Trauma and Posttraumatic Stress in Children and Adolescents.

Cognitive models of posttraumatic stress disorder (PTSD) place an emphasis on the role of negative appraisals of traumatic events. It is suggested that the way in which the event is appraised determines the extent to which posttraumatic stress symptoms will be experienced. Therefore, a strong relationship between trauma appraisals and symptoms of PTSD might be expected. However, this relationship is not as firmly established in the child and adolescent literature. A systematic literature review of this relationship returned 467 publications, of which 11 met full eligibility criteria. A random effects meta-analysis revealed a large effect size for the relationship between appraisals and PTSD symptoms in children and adolescents, r = .63, 95% CI [.58, .68], Z = 17.32, p < .001, with significant heterogeneity present. A sensitivity analysis suggested that this relationship was not contingent on 1 specific measure of appraisals. Results were consistent with the cognitive behavioral theory of PTSD, demonstrating that appraisals of trauma are strongly related to posttraumatic stress in children and adolescents. However, this relationship was not observed in a sample of 4- to 6-year-olds, indicating that further research is required to explicate cognitive processing of trauma in very young children.

Shame, Dissociation, and Complex PTSD Symptoms in Traumatized Psychiatric and Control Groups: Direct and Indirect Associations With Relationship Distress.

OBJECTIVES: Elevated shame and dissociation are common in dissociative identity disorder (DID) and chronic posttraumatic stress disorder (PTSD) and are part of the constellation of symptoms defined as complex PTSD. Previous work examined the relationship between shame, dissociation, and complex PTSD and whether they are associated with intimate relationship anxiety, relationship depression, and fear of relationships. This study investigated these variables in traumatized clinical samples and a nonclinical community group. METHOD: Participants were drawn from the DID (n = 20), conflict-related chronic PTSD (n = 65), and nonclinical (n = 125) populations and completed questionnaires assessing the variables of interest. A model examining the direct impact of shame and dissociation on relationship functioning, and their indirect effect via complex PTSD symptoms, was tested through path analysis. RESULTS: The DID sample reported significantly higher dissociation, shame, complex PTSD symptom severity, relationship anxiety, relationship depression, and fear of relationships than the other two samples. Support was found for the proposed model, with shame directly affecting relationship anxiety and fear of relationships, and pathological dissociation directly affecting relationship anxiety and relationship depression. The indirect effect of shame and dissociation via complex PTSD symptom severity was evident on all relationship variables. CONCLUSION: Shame and pathological dissociation are important for not only the effect they have on the development of other complex PTSD symptoms, but also their direct and indirect effects on distress associated with relationships.

Expanding the view on the evolution of the nematode dauer signalling pathways: refinement through gene gain and pathway co-option.

BACKGROUND: Signalling pathways underlie development, behaviour and pathology. To understand patterns in the evolution of signalling pathways, we undertook a comprehensive investigation of the pathways that control the switch between growth and developmentally quiescent dauer in 24 species of nematodes spanning the phylum. RESULTS: Our analysis of 47 genes across these species indicates that the pathways and their interactions are not conserved throughout the Nematoda. For example, the TGF-ß pathway was co-opted into dauer control relatively late in a lineage that led to the model species Caenorhabditis elegans. We show molecular adaptations described in C. elegans that are restricted to its genus or even just to the species. Similarly, our analyses both identify species where particular genes have been lost and situations where apparently incorrect orthologues have been identified. CONCLUSIONS: Our analysis also highlights the difficulties of working with genome sequences from non-model species as reliance on the published gene models would have significantly restricted our understanding of how signalling pathways evolve. Our approach therefore offers a robust standard operating procedure for genomic comparisons.

Figmop: a profile HMM to identify genes and bypass troublesome gene models in draft genomes.

MOTIVATION: Gene models from draft genome assemblies of metazoan species are often incorrect, missing exons or entire genes, particularly for large gene families. Consequently, labour-intensive manual curation is often necessary. We present Figmop (Finding Genes using Motif Patterns) to help with the manual curation of gene families in draft genome assemblies. The program uses a pattern of short sequence motifs to identify putative genes directly from the genome sequence. Using a large gene family as a test case, Figmop was found to be more sensitive and specific than a BLAST-based approach. The visualization used allows the validation of potential genes to be carried out quickly and easily, saving hours if not days from an analysis. AVAILABILITY AND IMPLEMENTATION: Source code of Figmop is freely available for download at https://github.com/dave-the-scientist, implemented in C and Python and is supported on Linux, Unix and MacOSX. CONTACT: curran.dave.m@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Survey on the attitudes of hospital doctors towards the terms 'acopia' and 'social admission' in clinical practice.

Letters not directly related to articles published in Clinical Medicine and presenting unpublished original data should be submitted for publication in this section. Clinical and scientific letters should not exceed 500 words and may include one table and up to five references.

Neurocognitive functioning among children and young people with Duchenne Muscular Dystrophy: A systematic review and meta-analysis.

Objective: The neurocognitive aspects of DMD have received less attention than the physiological sequalae. This study conducted a systematic review and meta-analysis of available literature on the neurocognitive profile of children and young people with DMD. Method: Five databases (EMBASE, Medline, PsycInfo, Scopus and Web of Science) and the grey literature was searched on 27th January 2023. Eligible articles were available in English and reported neurocognitive outcomes. Neurocognitive domains reported in a comparable way across a minimum of three studies were included. The neurocognitive domains of Full-Scale IQ (FSIQ), Verbal IQ (VIQ), Performance IQ (PIQ) and Working memory (WMI) derived from Wechsler scales and receptive vocabulary ability derived from the Peabody Picture Verbal Test (PPVT) were included. A single mean meta-analysis was completed. Results: Relevant data was extracted and presented for 38 eligible studies; 2 of which are from grey literature. Results suggest children with DMD perform around 1SD below non-clinical norms for FSIQ, PIQ, VIQ and WMI. Unlike VIQ, scores derived from the PPVT were within the non-clinical norms. Studies were of moderate - high quality, there was significant heterogeneity and no publication bias. Conclusion: A systematic review of working memory has not previously been completed, it appears that children with DMD perform around 1SD below the mean, like FSIQ, PIQVIQ and WMI. The PPVT is a measure of receptive verbal ability and caution is recommended around the interchangeability of PPVT scores and the wider construct of verbal intelligence.

Short palate, lung, and nasal epithelial clone-1 is a tightly regulated airway sensor in innate and adaptive immunity.

Short palate, lung, and nasal epithelial clone-1 (SPLUNC1) is a protein abundantly expressed by the respiratory epithelium of the proximal lower respiratory tract, a site of great environmental exposure. Previous studies showed that SPLUNC1 exerts antimicrobial effects, regulates airway surface liquid and mucociliary clearance, and suppresses allergic airway inflammation. We studied SPLUNC1 to gain insights into its role in host defense. In the lower respiratory tract, concentrations of SPLUNC1 are high under basal conditions. In models of pneumonia caused by common respiratory pathogens, and in Th1-induced and Th2-induced airway inflammation, SPLUNC1 secretion is markedly reduced. Pathogen-associated molecular patterns and IFN-γ act directly on airway epithelial cells to inhibit SPLUNC1 mRNA expression. Thus, SPLUNC1 is quickly suppressed during infection, in response to an insult on the epithelial surface. These experiments highlight the finely tuned fluctuations of SPLUNC1 in response to exposures in the respiratory tract, and suggest that the loss of SPLUNC1 is a crucial feature of host defense across air-breathing animal species.

Eosinophil recruitment to nasal nerves after allergen challenge in allergic rhinitis.

In allergen challenged animal models, eosinophils localize to airway nerves leading to vagally-mediated hyperreactivity. We hypothesized that in allergic rhinitis eosinophils recruited to nasal nerves resulted in neural hyperreactivity. Patients with persistent allergic rhinitis (n=12), seasonal allergic rhinitis (n=7) and controls (n=10) were studied. Inferior nasal turbinate biopsies were obtained before, 8 and 48h after allergen challenge. Eight hours after allergen challenge eosinophils localized to nerves in both rhinitis groups; this was sustained through 48h. Bradykinin challenge, with secretion collection on the contralateral side, was performed to demonstrate nasal nerve reflexes. Twenty fourhours after allergen challenge, bradykinin induced a significant increase in secretions, indicating nasal hyperreactivity. Histological studies showed that nasal nerves expressed both vascular cell adhesion molecule-1 (VCAM-1) and chemokine (C-C motif) ligand 26 (CCL-26). Hence, after allergen challenge eosinophils are recruited and retained at nerves and so may be a mechanism for neural hyperreactivity.

The impact of shame on the therapeutic alliance and intimate relationships.

OBJECTIVES: This study examined the role of shame coping styles and state shame in predicting the therapeutic alliance and intimate relationship functioning in individuals with mental health problems. METHOD: A sample of 50 treatment-receiving adults aged 21 to 67 years with a mix of common mental health difficulties was recruited from a clinical psychology service. Participants were given questionnaire measures of shame states, shame coping styles, intimate relationship functioning, and the therapeutic alliance. RESULTS: Regression analyses indicated that the shame coping strategy of physical and psychological withdrawal was the primary risk factor for development of a less effective therapeutic alliance. Both withdrawal and attack self coping styles were significant predictors of impaired intimate relationship functioning. CONCLUSIONS: These findings have implications for the theoretical role of shame in mental health presentations as well as the potential for internalizing shame coping styles (i.e., withdrawal, attack self) to act as a barrier to successful therapy and interpersonal relationships. The inclusion of shame-focused assessments and interventions in the initial stages of treatment with clients exhibiting these strategies could improve prognosis.

A systematic review of quality of life and health-related quality of life as outcomes in substance and behavioural addictions.

ISSUES: Consideration of an individual's quality of life (QoL) can benefit assessment and treatment of addictive disorders, however, uncertainty remains over operationalisation of the construct as an outcome and the appropriateness of existing measures for these populations. This systematic review aimed to identify and evaluate QoL and health-related QoL outcome instruments used in addiction-related risk and harm research and map their conceptualised domains. APPROACH: Three electronic databases and a specialised assessment library were searched on 1 February 2022 for QoL or health-related QoL outcome instruments used with addiction-related risk and harm populations. PRISMA reporting guidance was followed and included outcome instruments were appraised using mixed methods. Psychometric evidence supporting their use was summarised. The COSMIN risk of bias tool was used to assess validation studies. KEY FINDINGS: A total of 298 articles (330 studies) used 53 outcome instruments and 41 unique domains of QoL. Eleven instruments' psychometric properties were evaluated. No instrument was assessed for any parameter in at least five studies for meta-analytic pooling. Cronbach's alpha (α) internal consistency was the most widely assessed parameter with the AQoLS, WHOQOL-BREF, ALQoL-9, Q-LES-Q-SF, SF-12, DUQoL, QLI and SF-36 displaying promising statistics (α > 0.70). IMPLICATIONS AND CONCLUSION: Many instruments have been utilised. However, a significant proportion of studies applied a small number of instruments with minimal high-quality validation evidence supporting their use within addiction-related risk and harm. Promising instruments are recommended, however, the paucity of supporting evidence limits confidence in the reliability and validity of QoL measurement in these populations.