Expanding understanding of adolescent neural sensitivity to peers: Using social information processing theory to generate new lines of research.

Adolescence is a period of normative heightened sensitivity to peer influence. Individual differences in susceptibility to peers is related to individual differences in neural sensitivity, particularly in brain regions that support an increasingly greater orientation toward peers. Despite these empirically-established patterns, the more specific psychosocial and socio-cognitive factors associated with individual differences in neural sensitivity to peer influence are just beginning to gain research attention. Specific features of the factors that contribute to how adolescents process social information can inform understanding of the psychological and neurobiological processes involved in what renders adolescents to be more or less susceptible to peer influences. In this paper, we (1) review the literature about peer, family, and broader contextual influences on sensitivity to peers' positive and negative behaviors, (2) outline components of social information processing theories, and (3) discuss features of these models from the perspectives and social cognitive development and social neuroscience. We identify gaps in the current literature that need to be addressed in order to gain a more comprehensive view of adolescent neural sensitivity to peer influence. We conclude by suggesting how future neuroimaging studies can adopt components of this social information processing model to generate new lines of research.

Biochemical characterization of Escherichia coli DnaC variants that alter DnaB helicase loading onto DNA.

DNA replication in Escherichia coli starts with loading of the replicative helicase, DnaB, onto DNA. This reaction requires the DnaC loader protein, which forms a 6:6 complex with DnaB and opens a channel in the DnaB hexamer through which single-stranded DNA is thought to pass. During replication, replisomes frequently encounter DNA damage and nucleoprotein complexes that can lead to replication fork collapse. Such events require DnaB re-loading onto DNA to allow replication to continue. Replication restart proteins mediate this process by recruiting DnaB6/DnaC6 to abandoned DNA replication forks. Several dnaC mutations that bypass the requirement for replication restart proteins or that block replication restart have been identified in E. coli. To better understand how these DnaC variants function, we have purified and characterized the protein products of several such alleles. Unlike wild-type DnaC, three of the variants (DnaC 809, DnaC 809,820, and DnaC 811) can load DnaB onto replication forks bound by single-stranded DNA-binding protein. DnaC 809 can also load DnaB onto double-stranded DNA. These results suggest that structural changes in the variant DnaB6/DnaC6 complexes expand the range of DNA substrates that can be used for DnaB loading, obviating the need for the existing replication restart pathways. The protein product of dnaC1331, which phenocopies deletion of the priB replication restart gene, blocks loading through the major restart pathway in vitro. Overall, the results of our study highlight the utility of bacterial DnaC variants as tools for probing the regulatory mechanisms that govern replicative helicase loading.

Replication fork binding triggers structural changes in the PriA helicase that govern DNA replication restart in E. coli.

Bacterial replisomes often dissociate from replication forks before chromosomal replication is complete. To avoid the lethal consequences of such situations, bacteria have evolved replication restart pathways that reload replisomes onto prematurely terminated replication forks. To understand how the primary replication restart pathway in E. coli (PriA-PriB) selectively acts on replication forks, we determined the cryogenic-electron microscopy structure of a PriA/PriB/replication fork complex. Replication fork specificity arises from extensive PriA interactions with each arm of the branched DNA. These interactions reshape the PriA protein to create a pore encircling single-stranded lagging-strand DNA while also exposing a surface of PriA onto which PriB docks. Together with supporting biochemical and genetic studies, the structure reveals a switch-like mechanism for replication restart initiation in which restructuring of PriA directly couples replication fork recognition to PriA/PriB complex formation to ensure robust and high-fidelity replication re-initiation.

A secondary function of trehalose-6-phosphate synthase is required for resistance to oxidative and desiccation stress in Fusarium verticillioides.

The disaccharide trehalose has long been recognized for its role as a stress solute, but in recent years some of the protective effects previously ascribed to trehalose have been suggested to arise from a function of the trehalose biosynthesis enzyme trehalose-6-phosphate (T6P) synthase that is distinct from its catalytic activity. In this study, we use the maize pathogenic fungus Fusarium verticillioides as a model to explore the relative contributions of trehalose itself and a putative secondary function of T6P synthase in protection against stress as well as to understand why, as shown in a previous study, deletion of the TPS1 gene coding for T6P synthase reduces pathogenicity against maize. We report that a TPS1-deletion mutant of F. verticillioides is compromised in its ability to withstand exposure to oxidative stress meant to simulate the oxidative burst phase of maize defense and experiences more ROS-induced lipid damage than the wild-type strain. Eliminating T6P synthase expression also reduces resistance to desiccation, but not resistance to phenolic acids. Expression of catalytically-inactive T6P synthase in the TPS1-deletion mutant leads to a partial rescue of the oxidative and desiccation stress-sensitive phenotypes, suggesting the importance of a T6P synthase function that is independent of its role in trehalose synthesis.

Multi-institutional retrospective study of canine foot pad malignant melanomas: 20 cases.

Melanomas arising from the foot pad are a rare clinical entity in dogs. The biologic behaviour of foot pad malignant melanoma is not well understood, and these tumours are infrequently described. The objective of this study was to evaluate the clinical characteristics of primary canine foot pad melanoma in a larger cohort of patients. Eligible cases were solicited from the American College of Veterinary Internal Medicine (ACVIM) Oncology listserv for retrospective review. Included dogs had a cytologic and/or histologic diagnosis of foot pad melanoma evaluated by a board-certified clinical or anatomic pathologist. Dogs with cutaneous, oral, digital, subungual or interdigital melanomas were excluded. A total of 20 cases were included. Eleven dogs received various adjuvant therapies including chemotherapy, radiation therapy, and/or the ONCEPT canine melanoma vaccine following surgery. At diagnosis, regional lymph node metastasis was observed in four dogs (20%). Seven dogs developed subsequent regional and/or distant metastasis for an overall metastatic rate of 55%. The progression-free interval (PFI) was 101 days (range, 20-960 days). The median survival time (MST) was 240 days (range, 25-479 days). For dogs receiving adjuvant therapy, the MST was 159 days (range, 25-387 days). Canine foot pad melanoma is a rare neoplasm that can exhibit an aggressive behaviour.

G-quadruplexes in bacteria: insights into the regulatory roles and interacting proteins of non-canonical nucleic acid structures.

G-quadruplexes (G4s) are highly stable, non-canonical DNA or RNA structures that can form in guanine-rich stretches of nucleic acids. G4-forming sequences have been found in all domains of life, and proteins that bind and/or resolve G4s have been discovered in both bacterial and eukaryotic organisms. G4s regulate a variety of cellular processes through inhibitory or stimulatory roles that depend upon their positions within genomes or transcripts. These include potential roles as impediments to genome replication, transcription, and translation or, in other contexts, as activators of genome stability, transcription, and recombination. This duality suggests that G4 sequences can aid cellular processes but that their presence can also be problematic. Despite their documented importance in bacterial species, G4s remain understudied in bacteria relative to eukaryotes. In this review, we highlight the roles of bacterial G4s by discussing their prevalence in bacterial genomes, the proteins that bind and unwind G4s in bacteria, and the processes regulated by bacterial G4s. We identify limitations in our current understanding of the functions of G4s in bacteria and describe new avenues for studying these remarkable nucleic acid structures.

Outcome in dogs with curative-intent treatment of localized primary pulmonary histiocytic sarcoma.

Primary pulmonary histiocytic sarcoma (PHS) is a rare form of dendritic cell or macrophage neoplasia originating within the pulmonary parenchyma. There is limited literature describing prognosis in dogs with PHS receiving curative-intent treatment consisting of surgical excision and adjuvant chemotherapy. The primary objective of this study was to report outcomes in dogs with localized PHS treated with standardized local and systemic therapy. A secondary objective was to identify prognostic factors in this population. A multi-institutional retrospective study was performed and medical records including all surgical and histopathologic reports were retrospectively reviewed. For inclusion, dogs were required to have confirmed localized PHS and they must have undergone curative-intent surgery with resection of all gross primary tumour and enlarged tracheobronchial lymph nodes; additionally, they must have received curative-intent treatment with adjuvant single-agent CCNU chemotherapy. Twenty-seven dogs from six veterinary teaching hospitals and five private practices treated from 2008-2019 were included. The overall median survival time was 432 days. Higher CCNU dose was demonstrated to have a negative impact on survival on univariate, but not multivariable, analysis. Factors that were not found to be associated with survival on univariate analysis included body weight, breed, clinical signs at the time of diagnosis, hypoalbuminaemia, tumour size, lung lobe affected, lymph node metastasis, surgical margins and CCNU dose reductions. This study supports a favourable prognosis for dogs diagnosed with localized PHS treated with curative-intent surgery in addition to adjuvant CCNU chemotherapy and suggests that multimodal treatment may be advisable to attempt to prolong survival.

The molecular coupling between substrate recognition and ATP turnover in a AAA+ hexameric helicase loader.

In many bacteria and eukaryotes, replication fork establishment requires the controlled loading of hexameric, ring-shaped helicases around DNA by AAA+(ATPases Associated with various cellular Activities) ATPases. How loading factors use ATP to control helicase deposition is poorly understood. Here, we dissect how specific ATPase elements of Escherichia coli DnaC, an archetypal loader for the bacterial DnaB helicase, play distinct roles in helicase loading and the activation of DNA unwinding. We have identified a new element, the arginine-coupler, which regulates the switch-like behavior of DnaC to prevent futile ATPase cycling and maintains loader responsiveness to replication restart systems. Our data help explain how the ATPase cycle of a AAA+-family helicase loader is channeled into productive action on its target; comparative studies indicate that elements analogous to the Arg-coupler are present in related, switch-like AAA+ proteins that control replicative helicase loading in eukaryotes, as well as in polymerase clamp loading and certain classes of DNA transposases.

Building Capacity in Health Professionals to Conduct Quality Improvement: Evaluation From a Collaborative Interorganizational Program.

BACKGROUND: The Toronto Academic Health Sciences Network Health Professions Innovation Fellowship Program began in 2014 as a pilot initiative among 4 academic teaching hospitals in Toronto, Ontario. The purpose of the Program was to cultivate applied leadership, interprofessional collaboration, and quality improvement capacity among health professionals. PURPOSE: This article reports on the evaluation findings from the initial year as well as an update on current program status and sustainability. METHODS: A formative evaluation was conducted focused on the impact on clinical practice, participant skill development, participant experience, and cross-organizational partnerships. Data were collected through a focus group, interviews, and pre- and postsurveys. RESULTS: Data from the initial pilot showed increases in leadership practices, project management, and quality improvement knowledge, with changes in leadership practices being significant. Positive changes in clinical practice at both the individual and unit/team levels and capacity for building relationships were also reported. Since the pilot, more than 160 participants from 15 health professions and 9 organizations have participated. Several graduates have taken on leadership roles since their participation in the Program. CONCLUSIONS: Health care organizations wishing to advance academic practice may benefit from implementing a similar collaborative program to reap benefits beyond organizational silos.

Impact of cancer-associated mutations in Hsh155/SF3b1 HEAT repeats 9-12 on pre-mRNA splicing in Saccharomyces cerevisiae.

Mutations in the splicing machinery have been implicated in a number of human diseases. Most notably, the U2 small nuclear ribonucleoprotein (snRNP) component SF3b1 has been found to be frequently mutated in blood cancers such as myelodysplastic syndromes (MDS). SF3b1 is a highly conserved HEAT repeat (HR)-containing protein and most of these blood cancer mutations cluster in a hot spot located in HR4-8. Recently, a second mutational hotspot has been identified in SF3b1 located in HR9-12 and is associated with acute myeloid leukemias, bladder urothelial carcinomas, and uterine corpus endometrial carcinomas. The consequences of these mutations on SF3b1 functions during splicing have not yet been tested. We incorporated the corresponding mutations into the yeast homolog of SF3b1 and tested their impact on splicing. We find that all of these HR9-12 mutations can support splicing in yeast, and this suggests that none of them are loss of function alleles in humans. The Hsh155V502F mutation alters splicing of several pre-mRNA reporters containing weak branch sites as well as a genetic interaction with Prp2 and physical interactions with Prp5 and Prp3. The ability of a single allele of Hsh155 to perturb interactions with multiple factors functioning at different stages of the splicing reaction suggests that some SF3b1-mutant disease phenotypes may have a complex origin on the spliceosome.

Patient involvement in health professionals' education: a meta-narrative review.

More than 100 years ago, Osler inspired educators to consider health professions education (HPE) as intricately reliant on patients. Since that time, patient involvement in HPE has taken on many different meanings. The result is a disparate body of literature that is challenging to search, making it difficult to determine how to continue to build knowledge in the field. To address this problem, we conducted a review of the literature on patient involvement in HPE using a meta-narrative approach. The aim of the review was to synthesize how questions of patient involvement in HPE have been considered across various research traditions and over time. In this paper, we focus on three scholarly communities concerned with various interpretations of patient involvement in HPE-patient as teachers, real patients as standardized patients, and bedside learning. Focus on these three research communities served as a way to draw out various meta-narratives in which patients are thought of in particular ways, specific rationales for involvement are offered, and different research traditions are put to use in the field. Attending to the intersections between these meta-narratives, we focus on the potentially incommensurate ways in which "active" patient engagement is considered within the broader field and the possible implications. We end by reflecting on these tensions and what they might mean for the future of patient involvement, specifically patient involvement as part of future iterations of competency based education.

Post-surgical outcome and prognostic factors in canine malignant melanomas of the haired skin: 87 cases (2003-2015).

The medical records of 87 dogs treated with surgery for cutaneous malignant melanoma (CMM) of the haired skin were retrospectively reviewed for overall survival time (OST), progression-free survival time (PFS), and prognostic factors. The post-surgery median PFS and median OST were 1282 days and 1363 days, respectively. The post-surgery metastatic rate was 21.8% with a local recurrence rate of 8%. Increasing mitotic index (MI) was predictive of a significantly decreased OST and PFS on multivariable analysis [hazard ratio (HR): 1.05, 95% confidence interval (CI): 1.02 to 1.07 and HR: 1.04, 95% CI: 1.02 to 1.06, respectively]. Increasing age was likewise predictive of a significantly decreased OST and PFS on multivariable analysis (HR: 1.39, 95% CI: 1.17 to 1.65 and HR: 1.33, 95% CI: 1.14 to 1.54, respectively). These results confirm clinical impressions that long survival times are likely in dogs diagnosed with malignant melanoma of the haired skin when treated with surgery alone.

Résultat post-chirurgical et facteurs de pronostic pour les mélanomes malins canins de la peau poilue : 87 cas (2003­2015). Les dossiers médicaux de 87 chiens traités à l'aide d'une chirurgie pour le mélanome malin cutané (MMC) de la peau poilue ont été évalués rétrospectivement pour le temps de survie global (TSG), le temps de survie sans progression (TSSP) et les facteurs de pronostic. Le TSSP médian après la chirurgie et le TSG médian étaient de 1282 jours et de 1363 jours, respectivement. Le taux métastasique après la chirurgie était de 21,8 % avec un taux de récurrence local de 8 %. L'augmentation de l'indice mitotique (IM) était prédictive d'un TSG et d'un TSSP réduits à l'analyse multivariable (ratio de risque [RR] : 1,05, intervalle de confiance [IC] de 95 % : 1,02 à 1,07 et RR : 1,04, IC de 95 % : 1,02 à 1,06, respectivement). La progression de l'âge était aussi prédictive d'une réduction importante du TSG et du TSSP à l'analyse multivariable (RR : 1,39, IC de 95 % : 1,17 à 1,65 et RR : 1,33, IC de 95 % : 1,14 à 1,54, respectivement). Ces résultats confirment les impressions cliniques que des longs délais de survie sont probables chez les chiens diagnostiqués avec le mélanome malin de la peau poilue lorsqu'ils sont uniquement traités à l'aide d'une chirurgie.(Traduit par Isabelle Vallières).

What is "the patient perspective" in patient engagement programs? Implicit logics and parallels to feminist theories.

Public and patient involvement (PPI) in health care may refer to many different processes, ranging from participating in decision-making about one's own care to participating in health services research, health policy development, or organizational reforms. Across these many forms of public and patient involvement, the conceptual and theoretical underpinnings remain poorly articulated. Instead, most public and patient involvement programs rely on policy initiatives as their conceptual frameworks. This lack of conceptual clarity participates in dilemmas of program design, implementation, and evaluation. This study contributes to the development of theoretical understandings of public and patient involvement. In particular, we focus on the deployment of patient engagement programs within health service organizations. To develop a deeper understanding of the conceptual underpinnings of these programs, we examined the concept of "the patient perspective" as used by patient engagement practitioners and participants. Specifically, we focused on the way this phrase was used in the singular: "the" patient perspective or "the" patient voice. From qualitative analysis of interviews with 20 patient advisers and 6 staff members within a large urban health network in Canada, we argue that "the patient perspective" is referred to as a particular kind of situated knowledge, specifically an embodied knowledge of vulnerability. We draw parallels between this logic of patient perspective and the logic of early feminist theory, including the concepts of standpoint theory and strong objectivity. We suggest that champions of patient engagement may learn much from the way feminist theorists have constructed their arguments and addressed critique.

Patient and family involvement in adult critical and intensive care settings: a scoping review.

BACKGROUND: Despite international bodies calling for increased patient and family involvement, these concepts remain poorly defined within literature on critical and intensive care settings. OBJECTIVE: This scoping review investigates the extent and range of literature on patient and family involvement in critical and intensive care settings. Methodological and empirical gaps are identified, and a future agenda for research into optimizing patient and family involvement is outlined. METHODS: Searches of MEDLINE, CINAHL, Social Work Abstracts and PsycINFO were conducted. English-language articles published between 2003 and 2014 were retrieved. Articles were included if the studies were undertaken in an intensive care or critical care setting, addressed the topic of patient and family involvement, included a sample of adult critical care patients, their families and/or critical care providers. Two reviewers extracted and charted data and analysed findings using qualitative content analysis. FINDINGS: A total of 892 articles were screened, 124 were eligible for analysis, including 61 quantitative, 61 qualitative and 2 mixed-methods studies. There was a significant gap in research on patient involvement in the intensive care unit. The analysis identified five different components of family and patient involvement: (i) presence, (ii) having needs met/being supported, (iii) communication, (iv) decision making and (v) contributing to care. CONCLUSION: Three research gaps were identified that require addressing: (i) the scope, extent and nature of patient involvement in intensive care settings; (ii) the broader socio-cultural processes that shape patient and family involvement; and (iii) the bidirectional implications between patient/family involvement and interprofessional teamwork.

Cystatin F Ensures Eosinophil Survival by Regulating Granule Biogenesis.

Eosinophils are now recognized as multifunctional leukocytes that provide critical homeostatic signals to maintain other immune cells and aid tissue repair. Paradoxically, eosinophils also express an armory of granule-localized toxins and hydrolases believed to contribute to pathology in inflammatory disease. How eosinophils deliver their supporting functions while avoiding self-inflicted injury is poorly understood. We have demonstrated that cystatin F (CF) is a critical survival factor for eosinophils. Eosinophils from CF null mice had reduced lifespan, reduced granularity, and disturbed granule morphology. In vitro, cysteine protease inhibitors restored granularity, demonstrating that control of cysteine protease activity by CF is critical for normal eosinophil development. CF null mice showed reduced pulmonary pathology in a model of allergic lung inflammation but also reduced ability to combat infection by the nematode Brugia malayi. These data identify CF as a "cytoprotectant" that promotes eosinophil survival and function by ensuring granule integrity. VIDEO ABSTRACT.

Rapid response systems and collective (in)competence: An exploratory analysis of intraprofessional and interprofessional activation factors.

The rapid response system (RRS) is a patient safety initiative instituted to enable healthcare professionals to promptly access help when a patient's status deteriorates. Despite patients meeting the criteria, up to one-third of the RRS cases that should be activated are not called, constituting a "missed RRS call". Using a case study approach, 10 focus groups of senior and junior nurses and physicians across four hospitals in Australia were conducted to gain greater insight into the social, professional and cultural factors that mediate the usage of the RRS. Participants' experiences with the RRS were explored from an interprofessional and collective competence perspective. Health professionals' reasons for not activating the RRS included: distinct intraprofessional clinical decision-making pathways; a highly hierarchical pathway in nursing, and a more autonomous pathway in medicine; and interprofessional communication barriers between nursing and medicine when deciding to make and actually making a RRS call. Participants also characterized the RRS as a work-around tool that is utilized when health professionals encounter problematic interprofessional communication. The results can be conceptualized as a form of collective incompetence that have important implications for the design and implementation of interprofessional patient safety initiatives, such as the RRS.

Interprofessional collaboration and family member involvement in intensive care units: emerging themes from a multi-sited ethnography.

This article presents emerging findings from the first year of a two-year study, which employed ethnographic methods to explore the culture of interprofessional collaboration (IPC) and family member involvement in eight North American intensive care units (ICUs). The study utilized a comparative ethnographic approach - gathering observation, interview and documentary data relating to the behaviors and attitudes of healthcare providers and family members across several sites. In total, 504 hours of ICU-based observational data were gathered over a 12-month period in four ICUs based in two US cities. In addition, 56 semi-structured interviews were undertaken with a range of ICU staff (e.g. nurses, doctors and pharmacists) and family members. Documentary data (e.g. clinical guidelines and unit policies) were also collected to help develop an insight into how the different sites engaged organizationally with IPC and family member involvement. Directed content analysis enabled the identification and categorization of major themes within the data. An interprofessional conceptual framework was utilized to help frame the coding for the analysis. The preliminary findings presented in this paper illuminate a number of issues related to the nature of IPC and family member involvement within an ICU context. These findings are discussed in relation to the wider interprofessional and health services literature.

A crucial role for ß2 integrins in podosome formation, dynamics and Toll-like-receptor-signaled disassembly in dendritic cells.

The dynamic properties of podosomes, their ability to degrade the underlying matrix and their modulation by Toll-like receptor (TLR) signaling in dendritic cells (DCs) suggests they have an important role in migration. Integrins are thought to participate in formation and dynamics of podosomes but the multiplicity of integrins in podosomes has made this difficult to assess. We report that murine DCs that lack ß2 integrins fail to form podosomes. Re-expression of ß2 integrins restored podosomes but not when the membrane proximal or distal NPxF motifs, or when an intervening triplet of threonine residues were mutated. We show that ß2 integrins are remarkably long-lived in podosome clusters and form a persistent framework that hosts multiple actin-core-formation events at the same or adjacent sites. When ß2 integrin amino acid residues 745 or 756 were mutated from Ser to Ala, podosomes became resistant to dissolution mediated through TLR signaling. TLR signaling did not detectably modulate phosphorylation at these sites but mutation of either residue to phospho-mimetic Asp increased ß2 integrin turnover in podosomes, indicating that phosphorylation at one or both sites establishes permissive conditions for TLR-signaled podosome disassembly.

Siglec-E promotes ß2-integrin-dependent NADPH oxidase activation to suppress neutrophil recruitment to the lung.

Siglec-E is a sialic acid-binding Ig-like lectin expressed on murine myeloid cells. It has recently been shown to function as a negative regulator of ß2-integrin-dependent neutrophil recruitment to the lung following exposure to lipopolysaccharide (LPS). Here, we demonstrate that siglec-E promoted neutrophil production of reactive oxygen species (ROS) following CD11b ß2-integrin ligation with fibrinogen in a sialic acid-dependent manner, but it had no effect on ROS triggered by a variety of other stimulants. Siglec-E promotion of ROS was likely mediated via Akt activation, because siglec-E-deficient neutrophils plated on fibrinogen exhibited reduced phosphorylation of Akt, and the Akt inhibitor, MK2206, blocked fibrinogen-induced ROS. In vivo imaging showed that siglec-E also promoted ROS in acutely inflamed lungs following exposure of mice to LPS. Importantly, siglec-E-promoted ROS were required for its inhibitory function, as the NADPH oxidase inhibitor, apocynin, reversed the siglec-E-mediated suppression of neutrophil recruitment and blocked neutrophil ROS production in vitro. Taken together, these results demonstrate that siglec-E functions as an inhibitory receptor of neutrophils via positive regulation of NADPH oxidase activation and ROS production. Our findings have implications for the inhibitory role of siglec-9 on human neutrophils in sepsis and acute lung injury.