PTP1B mediates the inhibitory effect of MFGE8 on insulin signaling through the ß5 integrin.

Integrins are cell adhesion receptors that dimerize to mediate cell-cell interactions and regulate processes, including proliferation, inflammation, and tissue repair. The role of integrins in regulating insulin signaling is incompletely understood. We have previously shown that binding of the integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) to the αvß5 integrin promotes termination of insulin receptor signaling in mice. Upon ligation of MFGE8, integrin ß5 complexes with the insulin receptor beta (IRß) in skeletal muscle, resulting in dephosphorylation of IRß and reduction of insulin-stimulated glucose uptake. Here, we investigate the mechanism by which the interaction between ß5 and IRß impacts IRß phosphorylation status. We show in in vitro and in vivo in skeletal muscle in mice that antibody-mediated blockade of the ß5 integrin inhibits and recombinant MFGE8 promotes PTP1B binding to and dephosphorylation of IRß resulting in increased or reduced insulin-stimulated glucose uptake, respectively. The ß5-PTP1B complex is recruited by MFGE8 to IRß leading to termination of canonical insulin signaling. ß5 blockade enhances insulin-stimulated glucose uptake in wildtype but not Ptp1b KO mice indicating that PTP1B functions downstream of MFGE8 in modulating insulin receptor signaling. Furthermore, in a human cohort, we report serum MFGE8 levels correlate with indices of insulin resistance. These data provide mechanistic insights into the role of MFGE8 and ß5 in regulating insulin signaling.

"Roses have thorns for a reason": The promises and perils of critical youth participatory research with system-impacted girls of Color.

Scholarship on girlhood-especially for girls of Color-is often relegated to studying risk and emphasizing individual deficits over humanizing girls and centering their voices. This approach to generating scholarship renders oppressive systems and processes invisible from inquiry and unaddressed by practice, with particularly insidious consequences for youth in the legal system. Critical youth participatory action research (YPAR) is acknowledged as an antidote to these conceptualizations because it resists deficit-oriented narratives circling systems-impacted youth by inviting them to the knowledge-generating table. In this paper, we present an empirical analysis of the promises and perils that emerged as we conducted a year-long critical YPAR project alongside five system-impacted girls of Color. Our thematic analysis of process notes (30 meetings, 120 h) documents the stories posited by girls, in a democratized space, about the injustices of interconnected institutions, and unearths a complicated tension for both youth and adult coresearchers around the promises and perils of engaging in YPAR within the academy. These findings underscore the importance of using intersectional, collaborative research to challenge perceptions around how we legitimize knowledge. We describe lessons learned in conducting YPAR in academic settings and highlight recommendations to grow youth-adult partnerships within oppressive systems to share power.

Association of lipoprotein subfractions with incidence of type 2 diabetes among five U.S. Race and Ethnic groups: The Mediators of Atherosclerosis in South Asians Living in America (MASALA) and Multi-Ethnic study of Atherosclerosis (MESA).

AIMS: We examined associations between lipoprotein subfractions and prevalent and incident T2D in two race/ethnically diverse cohort studies. METHODS: Adults self-identifying as White, Black, Chinese, Hispanic and South Asian-American without cardiovascular disease, with fasting serum, demographic, and clinical data at enrollment and after 5 years of follow-up were included. Lipoprotein subfractions were measured at enrollment using NMR spectrometry. LASSO regularized logistic regression models adjusted for age, sex, race/ethnicity, lipid-lowering agent use, and waist circumference assessed odds of incident T2D in pooled analyses. RESULTS: There were 4474 participants with lipoprotein subfraction data at enrollment and 3839 participants without prevalent diabetes, mean age 62 years, 51 % women, with 234 incident T2D cases at 5 years. Triglycerides in small, dense LDL-5 [OR 1.26 (95 % CI 1.11,1.43)], VLDL triglycerides 1.30** [1.16,1.46] and phospholipids in VLDL-1 [OR 1.31 (1.17,1.47)] were associated with higher odds of incident T2D, while free cholesterol in large HDL-1 [OR 0.75 (95 % CI 0.63,0.89)] was inversely associated. The results were similar for prevalent diabetes and did not vary by race/ethnic group. CONCLUSIONS: Composition of lipoprotein subfractions is differentially associated with prevalent and incident T2D without difference by race/ethnic group. Assessment of lipoprotein composition may enhance targeted risk reduction for T2D.

MFGE8 inhibits insulin signaling through PTP1B.

The role of integrins in regulating insulin signaling is incompletely understood. We have previously shown that binding of the integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) to the αvß5 integrin promotes termination of insulin receptor signaling in mice. Upon ligation of MFGE8, ß5 complexes with the insulin receptor beta (IRß) in skeletal muscle resulting in dephosphorylation of IRß and reduction of insulin-stimulated glucose uptake. Here we investigate the mechanism by which the interaction between ß5 and IRß impacts IRß phosphorylation status. We show that ß5 blockade inhibits and MFGE8 promotes PTP1B binding to and dephosphorylation of IRß resulting in reduced or increased insulin-stimulated myotube glucose uptake respectively. The ß5-PTP1B complex is recruited by MFGE8 to IRß leading to termination of canonical insulin signaling. ß5 blockade enhances insulin-stimulated glucose uptake in wild type but not Ptp1b KO mice indicating that PTP1B functions downstream of MFGE8 in modulating insulin receptor signaling. Furthermore, in a human cohort, we report serum MFGE8 levels correlate with indices of insulin resistance. These data provide mechanistic insights into the role of MFGE8 and ß5 in regulating insulin signaling.

Persistent Paternalism: The Instantiation of Gendered Attributions in the System Response to Girls.

Prior research suggests that the juvenile legal system does too little to address the sources and underlying reasons for girls' court referrals. Drawing on attribution theories, the current study examined perspectives that characterize the response of the system to girls' behaviors. Data from this study were derived from a multimethod, qualitative study on system-involved girls. We find that court actors hold gendered attributions of girls' delinquency, in turn informing their decision-making about how to treat and sanction girls. Paternalism remains a persistent feature in how the system locates, defines, and responds to girls through varying gendered attributions. The findings lend further support to attribution perspectives that suggest implicit gender-biases influence court actor decision-making, exacerbating the challenges girls face in and out of the juvenile legal system. By extension, this study offers concrete policy and practice implications for systems change and improving its response to girls.

Identification of Risk Factors in the Development of Heterotopic Ossification After Primary Total Hip Arthroplasty.

PURPOSE: Heterotopic ossification (HO) is a process by which bone forms abnormally in soft tissues. Known risk factors for developing HO include male sex, spinal cord injury, trauma, and surgery. We investigated additional risk factors in the development of HO after hip arthroplasty. METHODS: We performed a retrospective review of electronic medical records of 4070 individuals who underwent hip arthroplasty from September 2010 to October 2019 at the University of California, San Francisco Hospital. Demographics, anthropometrics, medications, and comorbid conditions were used in logistic regression analysis to identify factors associated with the development of HO. RESULTS: A total of 2541 patients underwent primary hip arthroplasty in the analyzed timeframe (46.04% men, mean age at procedure: 62.13 ±â€…13.29 years). The incidence of postsurgical HO was 3% (n = 80). A larger proportion of individuals who developed HO had underlying osteoporosis (P < 0.001), vitamin D deficiency (P < 0.001), spine disease (P < 0.001), type 1 or 2 diabetes (P < 0.001), amenorrhea (P = 0.037), postmenopausal status (P < 0.001), parathyroid disorders (P = 0.011), and history of pathologic fracture (P = 0.005). Significant predictors for HO development were Black/African American race [odds ratio (OR) 2.97, P = 0.005], preexisting osteoporosis (OR 2.72, P = 0.001), spine disease (OR 2.04, P = 0.036), and low estrogen states (OR 1.99, P = 0.025). In the overall group, 75.64% received perioperative nonsteroidal anti-inflammatory drugs (NSAIDs), which negatively correlated with HO formation (OR 0.39, P = 0.001). CONCLUSIONS: We identified new factors potentially associated with an increased risk of developing HO after primary hip arthroplasty, including African American race, osteoporosis, and low estrogen states. These patients may benefit from HO prophylaxis, such as perioperative NSAIDs.

When Diversity is Not Enough: An Intersectional Examination of How Juvenile Legal System Actors of Color Experience the System's Welfare Mandate for Girls of Color.

System actors of color are considered a key intervention to reduce disparities in the juvenile legal system precisely because they share intersectional experiences of oppression similar to those experienced by system-involved youth. In this study, we interrogate the assumption that diversifying the workforce can remedy intersectional disparities in youth outcomes. Grounded in intersectionality, we analyzed semi-structured interviews with 17 (12 women, five men) actors of color-eight at the frontline, five at the mid-level, and four at the top level. Specifically, we examined their narratives of lived oppressions, juxtaposed these narratives with their articulations of how well the system meets its welfare mandate, and examined actors' sense of their ability to contribute to girls' welfare, attending especially to how these experiences vary by their positions in the system's hierarchy. Our findings suggest that actors of color indeed share experiences of oppression as system-involved youth, particularly along axes of race and gender. Further, across all levels of institutional positionality, actors articulate a disjunction, revealing the system's accountability to bureaucratic and funding structures rather than girls; they respond to this disjunction through resistant actions-with different degrees of effectiveness-anchored in accountability to girls, and by envisioning how, given their roles and relative power, the system can meet its social welfare mandate.

Coronavirus Disease 2019 and Cold Agglutinin Syndrome: An Interesting Case.

The coronavirus disease 2019 (COVID-19) pandemic has caused significant morbidity and mortality worldwide. While patients with COVID-19 most frequently present with pneumonia, respiratory failure and acute respiratory distress syndrome, increasing cases of immune-mediated disorders such as autoimmune thrombocytopenia, haemolytic anaemia and antiphospholipid syndrome have been reported. In this article we describe a rare case of cold agglutinin syndrome (CAS) in a patient with COVID-19. The patient was a 77-year-old man with a history of glucose-6-phosphate dehydrogenase (G6PD) deficiency who presented with COVID-19 infection and acute respiratory failure. Initially he was started on intravenous steroids, antibiotics and hydroxychloroquine. Laboratory analysis revealed haemolytic anaemia with a positive direct anti-globulin test (DAT) and high titres of cold agglutinins. Hydroxychloroquine was stopped due to suspicion of haemolysis due to G6PD deficiency but the haemolysis persisted. Unfortunately, the respiratory failure progressed and the patient died. In summary, this article describes a rare case of CAS associated with COVID-19. CAS is a heterogenous group of cold autoimmune haemolytic anaemias occurring secondary to infections or malignancies. No definite treatment for CAS in COVID-19 patients has been approved so far. LEARNING POINTS: Autoimmune haemolytic anaemia has been reported in COVID-19 patients.Cold agglutinin syndrome (CAS) can occur in patients with COVID-19.Efforts to determine the optimal management of CAS in COVID-19 patients must continue.

Tetraspanin18 regulates angiogenesis through VEGFR2 and Notch pathways.

The VEGF pathway is critically required for vasculogenesis, the formation of the primary vascular network. It is also required for angiogenesis resulting in sprouting and pruning of vessels to generate mature arborizing structures. The Notch pathway is essential for arterial-venous specification and the maturation of nascent vessels. We have determined that Tspan18, a member of the Tetraspanin family, is expressed in developing vessels but not in mature vasculature in zebrafish and mouse wound healing. Moreover, reduction at Tspan18 level resulted in aberrant vascular patterning, impaired vessel stability and defective arterial-venous specification. Tspan18 deficiency reduced VEGF, VEGFR2, Notch3 and EphrinB2, and increased EphB4, VEGFR3, Semaphorin3, Neuropilin and PlexinD1 expression. Furthermore, vascular defects of Tspan18 deficiency could be rescued by ectopic expression of VEGFR2 and Notch, but not by knockdown of Semaphorin or Plexin. Functional studies showed that knockdown of Tspan18 led to reduced endothelial cell migration, invasion and tube formation. Tspan18 has dynamic expression, regulates vascular development and maturation in the embryo with re-expression in adult life in wound healing.

Traumatic Incidents and Experiences of Racism and Sexism: Examining Associations with Components of Critical Consciousness for System-Involved Girls of Color.

Scholarship identifies critical consciousness as a key developmental asset in promoting the well-being of adolescents experiencing multiple socio-structural axes of oppression. Girls of color at acute risk for legal system involvement or re-involvement are absent from this literature. They are a critical population in which to examine this construct given their experiences of oppression and the myriad benefits of critical consciousness. The current study addresses this gap by examining traumatic incidents and experiences of racism and sexism as correlates of critical reflection and action among a sample of girls (N = 220; Mean age = 14.5 years; SD = 1.3 years). Using path analysis and multigroup modeling, we examine direct associations between these three manifestations of structural oppression and critical consciousness and explore the interplay of traumatic incidents, and racism and sexism in girls' critical consciousness development. Findings suggest that experiences of sexism and racism, uniquely and positively predict critical action, but not critical reflection. Surprisingly, girls' experiences of traumatic incidents do not predict reflection or action. Finally, multigroup analyses show no evidence that these associations vary by the interplay of traumatic incidents, racism, and sexism. Implications for community psychology values and juvenile legal system practice and policy are discussed.

Factor structure of the critical consciousness scale in juvenile legal system-involved boys and girls.

The Critical Consciousness Scale (CCS) is a recently developed and validated measure for use with low-income, diverse adolescents. However, research on the psychometric properties of this scale with juvenile legal system-involved youth is lacking. This study examines the psychometric properties of the critical reflection subscales of the CCS in a cross-sectional sample of 206 youth (48% girls) involved in the juvenile legal system to investigate (a) the factor structure of the critical reflection subscales of the CCS compared to existing adolescent samples, and (b) the extent to which critical reflection demonstrates measurement equivalence between boys and girls. Findings indicate (a) congruence with the previous literature on critical reflection but for system-involved girls, and (b) a difference in the structural relationships between perceived inequality and egalitarianism by gender. This study contributes to the nascent, psychometric literature on measures of critical consciousness in an underrepresented and unique adolescent population.

Surgical management of bilateral hip fractures in a patient with fibrodysplasia ossificans progressiva treated with the RAR-γ agonist palovarotene: a case report.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder marked by painful, recurrent flare-ups and heterotopic ossification (HO) in soft and connective tissues, which can be idiopathic or provoked by trauma, illness, inflammation, or surgery. There are currently no effective treatments for FOP, or for patients with FOP who must undergo surgery. Palovarotene, an investigational retinoic acid receptor-γ agonist, offers a potential avenue to prevent HO formation. CASE PRESENTATION: The patient is a 32 year-old male, who at age 29 enrolled in a study evaluating palovarotene to prevent HO formation in FOP. One year after starting palovarotene, he fell resulting in a left intertrochanteric fracture. He underwent intramedullary nailing of the femur shaft with screw placement at the distal femur. After surgery, he received palovarotene at 20 mg/day for 4 weeks, then 10 mg/day for 8 weeks. Imaging 12 weeks after surgery showed new bridging HO at the site of intramedullary rod insertion and distal screw. Nine months after the left hip fracture, the patient had a second fall resulting in a subdural hematoma, left parietal bone fracture, and right intertrochanteric fracture. He underwent intramedullary nailing of the right hip, in a modified procedure which did not require distal screw placement. Palovarotene 20 mg/day was started at fracture occurrence and continued for 4 weeks, then reduced to 10 mg/day for 8 weeks. HO also formed near the insertion site of the intramedullary rod. No HO developed at the right distal intramedullary rod. After each fracture, the patient had prolonged recurrent flare-ups around the hips. CONCLUSION: Surgery is only rarely considered in FOP due to the high risks of procedural complications and potential for inducing HO. This case emphasizes the risks of increased flare activity and HO formation from injury and surgery in patients with FOP. The efficacy of HO prevention by palovarotene could not be assessed; however, our observation that palovarotene can be administered in an individual with FOP following surgery with no negative impact on clinical fracture healing, osteointegration, or skin healing will help facilitate future trials testing the role of palovarotene as a therapy for HO.

"This is probably the reason why she resorted to that kind of action": A qualitative analysis of juvenile justice workers attributions for girls' offending.

A large body of evidence suggests that within the juvenile justice system, girls fare worse than boys on several measures, including number of arrests, length of stay, and mental health outcomes while in the system. Scholarship suggests a myriad of gendered social factors that precipitate girls' involvement in the juvenile justice system; however, less is known about how stakeholders within the juvenile justice system perceive the girls they work with or interpret their experiences. The current paper examines the attributions that juvenile justice system workers make about the reasons girls offend. In line with previous research, we identify both internal (personality, character traits) and external (situational) explanations for girls' involvement in the juvenile justice system that correspond to gender stereotypes and expectations of girls. Furthermore, we identify structural attributions as a special subset of external attributions that take into account how larger social, economic, and historical factors shape girls' situations and experiences and contribute to their criminal behavior. These structural attributions have implications for practitioners' views of justice and the role of the juvenile justice system in the lives of girls. We conclude with a set of implications for practice and policy.

The Praxis of Decoloniality in Researcher Training and Community-Based Data Collection.

In this paper, we detail our praxis of decoloniality in the context of a community-based study that employs a quantitative experimental methodology to evaluate an intervention for girls involved in the juvenile legal system. We resist the essentializing of methodology that positions quantitative paradigms as impermeable to reflexivity and decoloniality, and describe a model for training and supervising researchers engaged in an experimental randomized controlled trial of an advocacy program for girls, most of whom are girls of color and about half of whom identify as LGBT. In this way, we consider researcher training as a critical teaching context and describe the ways in which our training, community-based data collection, and supervision structure are anchored in de/anti/post colonial and indigenous scholarships. Specifically, our praxis is centered on conducting research as a site of resistance to hegemony, and practicing a critical compassion rooted in remembering complex personhoods. We further discuss the boundaries and limitations of our own epistemic power in relation to two central questions: how can researchers influence how knowledge is produced? How can researchers influence how knowledge producers are themselves produced?

Negotiating Ethical Paradoxes in Conducting a Randomized Controlled Trial: Aligning Intervention Science with Participatory Values.

In this article, we describe ethical tensions we have faced in the context of our work as intervention scientists, where we aim to promote social justice and change systems that impact girls involved in the juvenile legal system. These ethical tensions are, at their core, about resisting collusion with systems of control while simultaneously collaborating with them. Over the course of designing and implementing a randomized controlled trial (RCT) of an ecological advocacy intervention for girls, called ROSES, ethical paradoxes crystalized and prompted us to engage in critical reflection and action toward the aim of moving away from conducting research on legal-system-involved girls and moving toward a more democratic, participatory process of inquiry with girls. Our experience revealed two intertwined paradoxes that ultimately served generative purposes. First, in collaborating with legal system stakeholders, we observed a single story of girls' pathology narrated for girls, without girls, and ultimately internalized by girls. Second, in reflecting critically on the ethical implications of our study design, it became clear that the design was grounded in a medical model of inquiry although the intervention we sought to evaluate was based, in part, on resistance to the medical model. We describe emergent ethical tensions and the solutions we sought, which center on creating counternarratives and counterspaces that leverage, extend, and disrupt our existing RCT. We detail these solutions, focusing on how we restructured our research team to enhance structural competence, shifted the subject of inquiry to include the systems in which youth are embedded, and created new opportunities for former research participants to become co-researchers through formal roles on an advisory board.

The effect of E-glass fibers and acrylic resin thickness on fracture load in a simulated implant-supported overdenture prosthesis.

STATEMENT OF PROBLEM: Implant overdenture prostheses are prone to acrylic resin fracture because of space limitations around the implant overdenture components. PURPOSE: The purpose of this study was to evaluate the influence of E-glass fibers and acrylic resin thickness in resisting acrylic resin fracture around a simulated overdenture abutment. MATERIAL AND METHODS: A model was developed to simulate the clinical situation of an implant overdenture abutment with varying acrylic resin thickness (1.5 or 3.0 mm) with or without E-glass fiber reinforcement. Forty-eight specimens with an underlying simulated abutment were divided into 4 groups (n=12): 1.5 mm acrylic resin without E-glass fibers identified as thin with no E-glass fiber mesh (TN-N); 1.5 mm acrylic resin with E-glass fibers identified as thin with E-glass fiber mesh (TN-F); 3.0 mm acrylic resin without E-glass fibers identified as thick without E-glass fiber mesh (TK-N); and 3.0 mm acrylic resin with E-glass fibers identified as thick with E-glass fiber mesh (TK-F). All specimens were submitted to a 3-point bending test and fracture loads (N) were analyzed with a 2-way ANOVA and Tukey's post hoc test (α=.05). RESULTS: The results revealed significant differences in fracture load among the 4 groups, with significant effects from both thickness (P<.001) and inclusion of the mesh (P<.001). Results demonstrated no interaction between mesh and thickness (P=.690). The TN-N: 39 ±5 N; TN-F: 50 ±6.9 N; TK-N: 162 ±13 N; and TK-F: 193 ±21 N groups were all statistically different (P<.001). CONCLUSIONS: The fracture load of a processed, acrylic resin implant-supported overdenture can be significantly increased by the addition of E-glass fibers even when using thin acrylic resin sections. On a relative basis, the increase in fracture load was similar when adding E-glass fibers or increasing acrylic resin thickness.

Caries risk assessment and management for the prosthodontic patient.

Prosthodontic patients are often at a high risk for caries, and assessing that risk prior to treatment is important. Historically, the nature of dental education and clinical practice has oriented clinicians toward recognizing and correcting the damaging effects of caries, rather than actively assessing and managing caries risk potential. New developments have led to better diagnostics and protocols for caries management, although one adapted to the specific needs of the prosthodontic patient has not been proposed. Our purpose is to outline caries risk assessment and management for the prosthodontic patient.

Self-assembly and potassium ion triggered disruption of peptide-based soft structures.

This report describes formation of soft vesicular structures by a tetrapeptide and its disruption triggered by potassium ions.