A Conserved Local Structural Motif Controls the Kinetics of PTP1B Catalysis.

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin and leptin signaling pathways, making it a highly attractive target for the treatment of type II diabetes. For PTP1B to perform its enzymatic function, a loop referred to as the "WPD loop" must transition between open (catalytically incompetent) and closed (catalytically competent) conformations, which have both been resolved by X-ray crystallography. Although prior studies have established this transition as the rate-limiting step for catalysis, the transition mechanism for PTP1B and other PTPs has been unclear. Here we present an atomically detailed model of WPD loop transitions in PTP1B based on unbiased, long-timescale molecular dynamics simulations and weighted ensemble simulations. We found that a specific WPD loop region─the PDFG motif─acted as the key conformational switch, with structural changes to the motif being necessary and sufficient for transitions between long-lived open and closed states of the loop. Simulations starting from the closed state repeatedly visited open states of the loop that quickly closed again unless the infrequent conformational switching of the motif stabilized the open state. The functional importance of the PDFG motif is supported by the fact that it is well conserved across PTPs. Bioinformatic analysis shows that the PDFG motif is also conserved, and adopts two distinct conformations, in deiminases, and the related DFG motif is known to function as a conformational switch in many kinases, suggesting that PDFG-like motifs may control transitions between structurally distinct, long-lived conformational states in multiple protein families.

Discovery and Validation of the Binding Poses of Allosteric Fragment Hits to Protein Tyrosine Phosphatase 1b: From Molecular Dynamics Simulations to X-ray Crystallography.

Fragment-based drug discovery has led to six approved drugs, but the small sizes of the chemical fragments used in such methods typically result in only weak interactions between the fragment and its target molecule, which makes it challenging to experimentally determine the three-dimensional poses fragments assume in the bound state. One computational approach that could help address this difficulty is long-timescale molecular dynamics (MD) simulations, which have been used in retrospective studies to recover experimentally known binding poses of fragments. Here, we present the results of long-timescale MD simulations that we used to prospectively discover binding poses for two series of fragments in allosteric pockets on a difficult and important pharmaceutical target, protein tyrosine phosphatase 1b (PTP1b). Our simulations reversibly sampled the fragment association and dissociation process. One of the binding pockets found in the simulations has not to our knowledge been previously observed with a bound fragment, and the other pocket adopted a very rare conformation. We subsequently obtained high-resolution crystal structures of members of each fragment series bound to PTP1b, and the experimentally observed poses confirmed the simulation results. To the best of our knowledge, our findings provide the first demonstration that MD simulations can be used prospectively to determine fragment binding poses to previously unidentified pockets.

Reconstructing codependent cellular cross-talk in lung adenocarcinoma using REMI.

Cellular cross-talk in tissue microenvironments is fundamental to normal and pathological biological processes. Global assessment of cell-cell interactions (CCIs) is not yet technically feasible, but computational efforts to reconstruct these interactions have been proposed. Current computational approaches that identify CCI often make the simplifying assumption that pairwise interactions are independent of one another, which can lead to reduced accuracy. We present REMI (REgularized Microenvironment Interactome), a graph-based algorithm that predicts ligand-receptor (LR) interactions by accounting for LR dependencies on high-dimensional, small-sample size datasets. We apply REMI to reconstruct the human lung adenocarcinoma (LUAD) interactome from a bulk flow-sorted RNA sequencing dataset, then leverage single-cell transcriptomics data to increase the cell type resolution and identify LR prognostic signatures among tumor-stroma-immune subpopulations. We experimentally confirmed colocalization of CTGF:LRP6 among malignant cell subtypes as an interaction predicted to be associated with LUAD progression. Our work presents a computational approach to reconstruct interactomes and identify clinically relevant CCIs.

Exploring Black adolescent males' experiences with racism and internalized racial oppression.

We explore Black male high school students' perceptions of racial oppression, their internalization of racial oppression, and the impact of these experiences on their academic lives. Using constructivist grounded theory, 10 semi-structured interviews were conducted with Black adolescent boys. Results identified five core categories: (a) racial socialization, (b) understandings of and experiences with racism, (c) emotional and behavioral responses to racism, (d) internalization of racial oppression, and (e) school resistance and support needed. Based on these categories, we developed an ecological model of Black male students' experiences with racism and internalized racial oppression to elucidate existing interactional dynamics within students' ecological contexts. We discuss how schools and counselors can better support Black adolescent boys' positive development and ability to cope with racism and internalized racial oppression. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Optimism and distress tolerance in the social adjustment of nurses: examining resilience as a mediator and gender as a moderator.

BACKGROUND: As nursing is recognised as one of the most stressful occupations in healthcare organisations, nurses are vulnerable to adjustment challenges. AIMS: The authors examine the association between optimism, distress tolerance and social adjustment through the mediating role of resilience and the moderating role of gender among Iranian nurses. METHODS: The sample consisted of 183 nurses working in six private hospitals in Iran. The authors employed structural equation modelling to test a moderation-mediation model of social adjustment. RESULTS: Findings reveal that: (a) resilience partially mediates the association between distress tolerance and social adjustment and the link between optimism and social adjustment - nurses with high levels of optimism and distress tolerance are significantly more likely to report greater resilience and subsequently report higher social adjustment; and (b) gender plays a moderating role in the model - women reported higher levels of optimism and lower levels of both resilience and distress tolerance than men. However, men reported higher levels of both distress tolerance and resilience as well as better social adjustment in comparison to female nurses. CONCLUSIONS: The promotion of resilience may contribute to increased social adjustment, optimism and distress tolerance at work.

What types of racial messages protect Asian American adolescents from discrimination? A latent interaction model.

In this brief report, the authors investigate how different types of parental racial-ethnic socialization messages (i.e., cultural socialization/pluralism, promotion of mistrust, and preparation for racial bias) moderate the relationship between racial discrimination and psychological distress in a sample of 187 Asian American adolescents. Results indicated a significant positive relationship between racial discrimination and psychological distress. Cultural socialization/pluralism and promotion of mistrust also moderated the racial discrimination and psychological distress link. Specifically, for adolescents reporting low frequencies of cultural socialization/pluralism messages, discrimination was positively associated with psychological distress, suggesting cultural socialization/pluralism messages may be a protective factor. Discrimination was also positively associated with psychological distress for adolescents reporting high frequencies of promotion of mistrust, suggesting that promotion of mistrust may be a risk factor. Overall, the findings emphasize the important role that racial-ethnic socialization messages can have on psychological distress among Asian American adolescents who experience racial discrimination. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Renal Saturation and Acute Kidney Injury in Neonates with Hypoxic Ischemic Encephalopathy Undergoing Therapeutic Hypothermia.

OBJECTIVE: To investigate the range of renal near-infrared spectroscopy (NIRS) measures in neonates undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE) and to determine the association between renal NIRS measures and the development of acute kidney injury (AKI). STUDY DESIGN: A retrospective chart review was conducted of neonates with moderate to severe HIE who received therapeutic hypothermia at a tertiary care center from 2014 to 2016. Neonates had routine continuous NIRS monitoring of cerebral and renal saturation (Rsat) as part of their clinical care for 72 hours of cooling and until 24 hours after rewarming. The outcome of AKI was defined by an abnormal rate of decline of serum creatinine over the first 5 days of life. Mixed effects models determined the association between renal NIRS measures and AKI over time. RESULTS: Of 38 neonates with HIE undergoing cooling, 15 (39%) developed AKI. Rsat was lower than cerebral saturation during cooling (P < .01), but Rsat increased over time after rewarming, while renal oxygen extraction levels decreased (P < .0001). Neonates with AKI had higher Rsat levels (P < .01) compared with those without AKI after 24 hours of life. Using receiver operating characteristic curves, Rsat >75% by 24-48 hours predicted AKI with a sensitivity of 79% and specificity of 82% (area under the receiver operating characteristic curve = 0.76). CONCLUSIONS: Throughout cooling, neonates with AKI had higher Rsat measures than those without AKI. These differences may reflect lower oxygen extraction by the injured kidney. NIRS monitoring of Rsat may identify neonates with HIE at risk of developing AKI.

Integrative Personal Omics Profiles during Periods of Weight Gain and Loss.

Advances in omics technologies now allow an unprecedented level of phenotyping for human diseases, including obesity, in which individual responses to excess weight are heterogeneous and unpredictable. To aid the development of better understanding of these phenotypes, we performed a controlled longitudinal weight perturbation study combining multiple omics strategies (genomics, transcriptomics, multiple proteomics assays, metabolomics, and microbiomics) during periods of weight gain and loss in humans. Results demonstrated that: (1) weight gain is associated with the activation of strong inflammatory and hypertrophic cardiomyopathy signatures in blood; (2) although weight loss reverses some changes, a number of signatures persist, indicative of long-term physiologic changes; (3) we observed omics signatures associated with insulin resistance that may serve as novel diagnostics; (4) specific biomolecules were highly individualized and stable in response to perturbations, potentially representing stable personalized markers. Most data are available open access and serve as a valuable resource for the community.

Vitamin D supplementation decreases serum 27-hydroxycholesterol in a pilot breast cancer trial.

PURPOSE: 27-hydroxycholesterol (27HC), an endogenous selective estrogen receptor modulator (SERM), drives the growth of estrogen receptor-positive (ER+) breast cancer. 1,25-dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D, is known to inhibit expression of CYP27B1, which is very similar in structure and function to CYP27A1, the synthesizing enzyme of 27HC. Therefore, we hypothesized that 1,25(OH)2D may also inhibit expression of CYP27A1, thereby reducing 27HC concentrations in the blood and tissues that express CYP27A1, including breast cancer tissue. METHODS: 27HC, 25-hydroxyvitamin D (25OHD), and 1,25(OH)2D were measured in sera from 29 breast cancer patients before and after supplementation with low-dose (400 IU/day) or high-dose (10,000 IU/day) vitamin D in the interval between biopsy and surgery. RESULTS: A significant increase (p = 4.3E-5) in 25OHD and a decrease (p = 1.7E-1) in 27HC was observed in high-dose versus low-dose vitamin D subjects. Excluding two statistical outliers, 25OHD and 27HC levels were inversely correlated (p = 7.0E-3). CONCLUSIONS: Vitamin D supplementation can decrease circulating 27HC of breast cancer patients, likely by CYP27A1 inhibition. This suggests a new and additional modality by which vitamin D can inhibit ER+ breast cancer growth, though a larger study is needed for verification.

Assessing biological and technological variability in protein levels measured in pre-diagnostic plasma samples of women with breast cancer.

BACKGROUND: Quantitative proteomics allows for the discovery and functional investigation of blood-based pre-diagnostic biomarkers for early cancer detection. However, a major limitation of proteomic investigations in biomarker studies remains the biological and technical variability in the analysis of complex clinical samples. Moreover, unlike 'omics analogues such as genomics and transcriptomics, proteomics has yet to achieve reproducibility and long-term stability on a unified technological platform. Few studies have thoroughly investigated protein variability in pre-diagnostic samples of cancer patients across multiple platforms. METHODS: We obtained ten blood plasma "case" samples collected up to 2 years prior to breast cancer diagnosis. Each case sample was paired with a matched control plasma from a full biological sister without breast cancer. We measured protein levels using both mass-spectrometry and antibody-based technologies to: (1) assess the technical considerations in different protein assays when analyzing limited clinical samples, and (2) evaluate the statistical power of potential diagnostic analytes. RESULTS: Although we found inherent technical variation in the three assays used, we detected protein dependent biological signal from the limited samples. The three assay types yielded 32 proteins with statistically significantly (p < 1E-01) altered expression levels between cases and controls, with no proteins retaining statistical significance after false discovery correction. CONCLUSIONS: Technical, practical, and study design considerations are essential to maximize information obtained in limited pre-diagnostic samples of cancer patients. This study provides a framework that estimates biological effect sizes critical for consideration in designing studies for pre-diagnostic blood-based biomarker detection.

Mentoring ethnic minority counseling and clinical psychology students: A multicultural, ecological, and relational model.

The aim of the current study was to understand the role of race and culture in successful mentoring relationships in graduate school. We examined the practices of 9 faculty mentors working with 15 ethnic minority doctoral students in counseling and clinical psychology. Grounded theory was used to discern unifying patterns and to formulate a theory of multicultural mentoring. Five overall themes significant to multicultural mentoring emerged: (a) career support and guidance tailored for ethnic minorities, (b) relationality between mentors and protégés, (c) significance of contexts, (d) interconnections across contexts, and (e) multidirectionality of interactions between contexts. The 5 themes combined to form a multicultural, ecological, and relational model of mentoring. Our findings suggest that mentoring ethnic minority students can be successful, productive, and satisfying for both mentors and protégés when mentors possess the necessary skills, time, commitment, and multicultural competencies. Implications for doctoral programs in counseling and clinical psychology are discussed, along with recommendations for future research directions.

Clinical recovery from surgery correlates with single-cell immune signatures.

Delayed recovery from surgery causes personal suffering and substantial societal and economic costs. Whether immune mechanisms determine recovery after surgical trauma remains ill-defined. Single-cell mass cytometry was applied to serial whole-blood samples from 32 patients undergoing hip replacement to comprehensively characterize the phenotypic and functional immune response to surgical trauma. The simultaneous analysis of 14,000 phosphorylation events in precisely phenotyped immune cell subsets revealed uniform signaling responses among patients, demarcating a surgical immune signature. When regressed against clinical parameters of surgical recovery, including functional impairment and pain, strong correlations were found with STAT3 (signal transducer and activator of transcription), CREB (adenosine 3',5'-monophosphate response element-binding protein), and NF-κB (nuclear factor κB) signaling responses in subsets of CD14(+) monocytes (R = 0.7 to 0.8, false discovery rate <0.01). These sentinel results demonstrate the capacity of mass cytometry to survey the human immune system in a relevant clinical context. The mechanistically derived immune correlates point to diagnostic signatures, and potential therapeutic targets, that could postoperatively improve patient recovery.

Family support, self-esteem, and perceived racial discrimination among Asian American male college students.

This study was conducted to examine under what situation (i.e., when individuals used more or less family support) and for whom (i.e., those with high or low self-esteem) perceived racial discrimination would or would not have a significant positive association with psychological distress. A total of 95 Asian American male college students completed an online survey. A hierarchical regression analysis indicated a significant 3-way interaction of family support, self-esteem, and perceived racial discrimination in predicting psychological distress after controlling for perceived general stress. A simple effect analysis was used to explore the nature of the interaction. When Asian American male college students used more family support to cope with racial discrimination, the association between perceived racial discrimination and psychological distress was not significant for those with high or low self-esteem. The result from the simple interaction indicated that, when more family support was used, the 2 slopes for high and low self-esteem were not significantly different from each other. Conversely, when they used less family support, the association between perceived racial discrimination and psychological distress was not significant for those with high self-esteem, but was significantly positive for those with low self-esteem. The result from the simple interaction indicated that, when less family support was used, the slopes for high and low self-esteem were significantly different. The result suggested that low use of family support may put these male students with low self-esteem at risk for psychological distress. Limitations, future research directions, and clinical implications were discussed.

Payment for obesity services: examples and recommendations for stage 3 comprehensive multidisciplinary intervention programs for children and adolescents.

OBJECTIVE: The Reimbursement and Payment Subcommittee of the National Association of Children's Hospitals and Related Institutions FOCUS on a Fitter Future group sought to guide medical providers, patients, and payers to better serve obese children and adolescents to enable optimum health. Recommendations are provided for the essential components of a stage 3 comprehensive multidisciplinary intervention program as defined by the 2007 Expert Committee recommendations. In addition, suggestions are offered for a stepwise approach to implement these recommendations. METHODS: In 2009, key informant interviews were conducted with 15 children's hospitals participating in FOCUS on a Fitter Future and 1 nonparticipating hospital. Interview transcripts identified 5 financially sustainable stage 3 programs, each funded differently. RESULTS: The stage 3 programs interviewed ranged from being nascent to 21 years old (27%, <2 years; 47%, 2-6 years; 27%, >6 years). All of them had multidisciplinary teams that delivered services through 1 of 3 institutional structures: 60% freestanding; 7% specialty; and 33% hospital within a hospital. One-third of them had 1 to 2 funding sources, and 67% had ≥ 3 sources. CONCLUSIONS: The stage 3 programs in this review shared some common strategies for achieving financial stability. All of them followed key strategies of the chronic care model, the details of which led to the following recommendation: stage 3 programs should include a health care team with a medical provider, registered dietitian, physical activity specialist, mental health specialist, and coordinator who, as a team, provide service to overweight and obese children at no less than moderate intensity (26-75 hours).

Evaluation of a school-based internship program for Chinese immigrant adolescents in the United States.

The experiences of five Chinese immigrant adolescents who became participatory action researchers (PAR) (Fine et al,, 2002) through a school-based internship program in the United States are analyzed and presented. Evaluation of the project was conducted using content analysis of student researchers' journal entries. Discovery Oriented Approach analysis (Mahrer & Boulet, 1999; Mahrer 1988) was implemented and revealed the following main domains: Learning and Growth, Program Evaluation, Adjustment and Coping, Identity Development and Social Role, Pride, Social Support, Empathy, and Group Process. Implications for conducting PAR with ethnic minority populations are discussed in the context of the participants' experiences with cultural adjustment.

Chinese immigrant high school students' cultural interactions, acculturation, family obligations, language use, and social support.

When immigrant youth come to the United States, they must learn to interact with dominant and cultural groups as part of the adjustment process. The current study investigated whether the association between Chinese immigrant high school students' (N = 286) English fluency, academic and career/ college help-seeking, multidimensional acculturation, family responsibilities, and social support, predicted their intercultural competence concerns (their interactions across dominant and cultural groups). Results indicate that this was the case. Implications for research and practice with immigrant youth in a high school context are discussed.

Suicide among Asian Americans: what do we know? What do we need to know?

The current review begins with an acknowledgment of the diversity within the Asian American population as well as the scarcity of information on suicide among this particular racial/ethnic minority group. In analyzing what is known and what still needs to be learned about suicide among Asian Americans, the current article provides a critical review of significant factors such as age, gender, religious and spirituality issues, acculturation, social support, familial dynamics, social integration as well as gay/lesbian/bisexual orientations. In examining these factors, recommendations related to interventions and the existing research gaps are also discussed.

Development of a mentoring program for Chinese immigrant adolescents' cultural adjustment.

The development and evaluation of a peer mentoring program for Chinese immigrant adolescents' cultural adjustment is described. Twenty-three high school students who recently immigrated from Mainland China participated in the year-long program and 4 high school students served as their peer mentors. Data analyses revealed that the students who participated in the mentoring program had significantly higher peer attachment-trust and need for closeness scores at post-test than at pre-test. Implications for working with adolescent immigrants are discussed.

Asian American families' collectivistic coping strategies in response to 9/11.

Our study investigated the use of individualistic and collectivistic coping strategies among Asian American family members of victims of the World Trade Center (WTC) attacks on September 11th, 2001. Interviews were conducted with 11 Asian Americans who had lost a member of their family in the WTC attacks. Using the Discovery-Oriented Research analysis (Mahrer, 1988), results indicated that Asian Americans utilized the following collectivistic coping methods to deal with their losses: individualistic coping, familial coping, intracultural coping, relational universality, forbearance, fatalism/ spirituality, and indigenous healing methods. Additionally, our research found that cultural stigmata, privacy issues, and lack of culturally responsive counselors were factors in participants not utilizing available mental health services. Implications for culturally appropriate services, counseling, and research are discussed.

Outcomes of surgical fundoplication in children.

BACKGROUND & AIMS: Surgical fundoplication has been recommended for children with persistent GERD. The purpose of this study was to determine the frequency of postoperative symptoms requiring medical evaluation and/or treatment after fundoplication in children with or without associated medical disorders. METHODS: In a retrospective cohort study, we reviewed the medical records of all children who underwent fundoplication during 1996-1999. Data were collected to analyze the following: (1) postoperative complications, (2) postoperative symptoms, (3) procedures performed to evaluate postoperative symptoms, (4) medical treatment, and (5) repeat surgery. RESULTS: A total of 198 children underwent fundoplication, and 176 (89%) came for follow-up evaluation within 2 months after surgery. The median age at the time of surgery was 2.1 y (range, 6 mo-18 y) and the median duration of follow-up was 2.0 y (range, 1.2-4.8 y). A total of 130 (74%) children had one or more associated medical disorders including neurodevelopmental delay (70%), cystic fibrosis (8%), tracheoesophageal anomalies (8%), bronchopulmonary dysplasia (8%), and reactive airway disease (35%). Postoperatively, children with associated medical disorders had a higher frequency of lung infections (52% vs. 22%, P = .03) and dumping syndrome (2% vs. 0%, P = .05). Most children (63%) received evaluation and treatment for symptoms suggestive of recurrent reflux despite fundoplication. CONCLUSIONS: Nearly two thirds of children who received fundoplication and were followed-up within 2 months after surgery either have symptoms or receive medical therapy for reflux. Fundoplication for the control of GERD in children needs further evaluation.