Dual role of the peptide-loading complex as proofreader and limiter of MHC-I presentation.

Antigen presentation via major histocompatibility complex class I (MHC-I) molecules is essential for surveillance by the adaptive immune system. Central to this process is the peptide-loading complex (PLC), which translocates peptides from the cytosol to the endoplasmic reticulum and catalyzes peptide loading and proofreading of peptide-MHC-I (pMHC-I) complexes. Despite its importance, the impact of individual PLC components on the presented pMHC-I complexes is still insufficiently understood. Here, we used stoichiometrically defined antibody-nanobody complexes and engineered soluble T cell receptors (sTCRs) to quantify different MHC-I allomorphs and defined pMHC-I complexes, respectively. Thereby, we uncovered distinct effects of individual PLC components on the pMHC-I surface pool. Knockouts of components of the PLC editing modules, namely tapasin, ERp57, or calreticulin, changed the MHC-I surface composition to a reduced proportion of HLA-A*02:01 presentation compensated by a higher ratio of HLA-B*40:01 molecules. Intriguingly, these knockouts not only increased the presentation of suboptimally loaded HLA-A*02:01 complexes but also elevated the presentation of high-affinity peptides overexpressed in the cytosol. Our findings suggest that the components of the PLC editing module serve a dual role, acting not only as peptide proofreaders but also as limiters for abundant peptides. This dual function ensures the presentation of a broad spectrum of antigenic peptides.

Chemical cousins with contrasting behavioural profiles: MDMA users and methamphetamine users differ in social-cognitive functions and aggression.

Methamphetamine (METH, "Crystal Meth") and 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") share structural-chemical similarities but have distinct psychotropic profiles due to specific neurochemical actions. Previous research has suggested that their impact on social cognitive functions and social behaviour may differ significantly, however, direct comparisons of METH and MDMA users regarding social cognition and interaction are lacking. Performances in cognitive and emotional empathy (Multifaceted Empathy Test) and emotion sensitivity (Face Morphing Task), as well as aggressive social behaviour (Competitive Reaction Time Task) were assessed in samples of n = 40 chronic METH users, n = 39 chronic MDMA users and n = 86 stimulant-naïve controls (total N = 165). Self-reports and hair samples were used to obtain subjective and objective estimates of substance use patterns. METH users displayed diminished cognitive and emotional empathy towards positive stimuli, elevated punitive social behaviour regardless of provocation, and self-reported heightened trait anger relative to controls. MDMA users diverged from the control group only by exhibiting a distinct rise in punitive behaviour when faced with provocation. Correlation analyses indicated that both higher hair concentrations of MDMA and METH may be associated with reduced cognitive empathy. Moreover, greater lifetime MDMA use correlated with increased punitive behaviour among MDMA users. Our findings confirm elevated aggression and empathy deficits in chronic METH users, while chronic MDMA users only displayed more impulsive aggression. Dose-response correlations indicate that some of these deficits might be a consequence of use. Specifically, the dopaminergic mechanism of METH might be responsible for social-cognitive deficits.

Dynamic Multiplexed Control and Modeling of Optogenetic Systems Using the High-Throughput Optogenetic Platform, Lustro.

The ability to control cellular processes using optogenetics is inducer-limited, with most optogenetic systems responding to blue light. To address this limitation, we leverage an integrated framework combining Lustro, a powerful high-throughput optogenetics platform, and machine learning tools to enable multiplexed control over blue light-sensitive optogenetic systems. Specifically, we identify light induction conditions for sequential activation as well as preferential activation and switching between pairs of light-sensitive split transcription factors in the budding yeast, Saccharomyces cerevisiae. We use the high-throughput data generated from Lustro to build a Bayesian optimization framework that incorporates data-driven learning, uncertainty quantification, and experimental design to enable the prediction of system behavior and the identification of optimal conditions for multiplexed control. This work lays the foundation for designing more advanced synthetic biological circuits incorporating optogenetics, where multiple circuit components can be controlled using designer light induction programs, with broad implications for biotechnology and bioengineering.

G protein-coupled receptor (GPCR) gene variants and human genetic disease.

Genetic variations in the genes encoding G protein-coupled receptors (GPCRs) can disrupt receptor structure and function, which can result in human genetic diseases. Disease-causing mutations have been reported in at least 55 GPCRs for more than 66 monogenic diseases in humans. The spectrum of pathogenic and likely pathogenic variants includes loss of function variants that decrease receptor signaling on one extreme and gain of function that may result in biased signaling or constitutive activity, originally modeled on prototypical rhodopsin GPCR variants identified in retinitis pigmentosa, on the other. GPCR variants disrupt ligand binding, G protein coupling, accessory protein function, receptor desensitization and receptor recycling. Next generation sequencing has made it possible to identify variants of uncertain significance (VUS). We discuss variants in receptors known to result in disease and in silico strategies for disambiguation of VUS such as sorting intolerant from tolerant and polymorphism phenotyping. Modeling of variants has contributed to drug development and precision medicine, including drugs that target the melanocortin receptor in obesity and interventions that reverse loss of gonadotropin-releasing hormone receptor from the cell surface in idiopathic hypogonadotropic hypogonadism. Activating and inactivating variants of the calcium sensing receptor (CaSR) gene that are pathogenic in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia have enabled the development of calcimimetics and calcilytics. Next generation sequencing has continued to identify variants in GPCR genes, including orphan receptors, that contribute to human phenotypes and may have therapeutic potential. Variants of the CaSR gene, some encoding an arginine-rich region that promotes receptor phosphorylation and intracellular retention, have been linked to an idiopathic epilepsy syndrome. Agnostic strategies have identified variants of the pyroglutamylated RF amide peptide receptor gene in intellectual disability and G protein-coupled receptor 39 identified in psoriatic arthropathy. Coding variants of the G protein-coupled receptor L1 (GPR37L1) orphan receptor gene have been identified in a rare familial progressive myoclonus epilepsy. The study of the role of GPCR variants in monogenic, Mendelian phenotypes has provided the basis of modeling the significance of more common variants of pharmacogenetic significance.

Conflict monitoring and emotional processing in 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine users - A comparative neurophysiological study.

In stimulant use and addiction, conflict control processes are crucial for regulating substance use and sustaining abstinence, which can be particularly challenging in social-affective situations. Users of methamphetamine (METH, "Ice") and 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") both experience impulse control deficits, but display different social-affective and addictive profiles. We thus aimed to compare the effects of chronic use of the substituted amphetamines METH and MDMA on conflict control processes in different social-affective contexts (i.e., anger and happiness) and investigate their underlying neurophysiological mechanisms. For this purpose, chronic but recently abstinent users of METH (n = 38) and MDMA (n = 42), as well as amphetamine-naïve healthy controls (n = 83) performed an emotional face-word Stroop paradigm, while event-related potentials (ERPs) were recorded. Instead of substance-specific differences, both MDMA and METH users showed smaller behavioral effects of cognitive-emotional conflict processing (independently of emotional valence) and selective deficits in emotional processing of anger content. Both effects were underpinned by stronger P3 ERP modulations suggesting that users of substituted amphetamines employ altered stimulus-response mapping and decision-making. Given that these processes are modulated by noradrenaline and that both MDMA and METH use may be associated with noradrenergic dysfunctions, the noradrenaline system may underlie the observed substance-related similarities. Better understanding the functional relevance of this currently still under-researched neurotransmitter and its functional changes in chronic users of substituted amphetamines is thus an important avenue for future research.

Linking a latent variable trait-state-occasion model of emotion regulation to cognitive control.

Emotion dysregulation (ED) is a vulnerability factor for affective disorders that may originate from deficits in cognitive control (CC). Although measures of ED are often designed to assess trait-like tendencies, the extent to which such measures capture a time-varying (TV) or state-like construct versus a time-invariant (TI) or trait-like personality characteristic is unclear. The link between the TV and TI components of ED and CC is also unclear. In a 6-wave, 5-month longitudinal study, community participants (n = 1281) completed the Difficulties in Emotion Regulation Scale (DERS-16), a commonly used measure of ED and measures of CC. A latent variable (trait-state-occasion) model showed that the proportion of TI factor variance (.80) was greater than the TV factor variance (.19). Although TV factor stability was significant, the coefficients were small in magnitude. Furthermore, regression weights for the ED TI factor (average ß = -.62) were significant and larger than those for the TV factor (average ß = -.10) in predicting latent CC at each of the six-time points. These findings suggest that ED, as assessed by the DERS-16, is largely TI and this TI component is more strongly linked to CC than the TV component.

Intolerance of Uncertainty and Worry Prospectively Predict COVID-19 Anxiety and Distress: A 4-Year Longitudinal Study.

The COVID-19 pandemic precipitated an uptick in poor mental health outcomes, including coronavirus-related anxiety and distress. Preliminary research has shown that intolerance of uncertainty (IU) and worry proneness, two transdiagnostic risk factors for anxiety and related disorders, are associated cross-sectionally with pandemic-related fear and distress. However, the extent to which IU and worry proneness prospectively predict coronavirus-related anxiety and distress is unclear. Whether IU and worry may also interact in prospectively predicting coronavirus-related anxiety and distress is also unknown. To address this knowledge gap, the present study examined IU and trait worry as prospective predictors of the level and trajectory of coronavirus anxiety and COVID stress syndrome over time, as well as the extent to which worry moderated the relation between IU and pandemic-related outcomes. Participants (n = 310) who completed self-report measures of IU and trait worry in 2016 were contacted following the onset of COVID-19 in 2020 and completed biweekly measures of coronavirus anxiety and COVID stress syndrome for 30 weeks. Multilevel models revealed that IU assessed in 2016 significantly predicted the severity of both coronavirus anxiety and COVID stress syndrome throughout the study period in 2020. Worry also moderated the link between IU and coronavirus anxiety, such that individuals with high levels of trait worry and high IU in 2016 experienced the most coronavirus anxiety in 2020. Results suggest that IU and worry functioned as independent and interactive vulnerability factors for subsequent adverse psychological reactions to COVID-19. Clinical implications and future directions are discussed.

Urinary Vitamin D Binding Protein: A Marker of Kidney Tubular Dysfunction in Patients at Risk for Type 2 Diabetes.

Context: Recent studies have reported elevated urinary vitamin D binding protein (uVDBP) concentrations in patients with diabetic kidney disease, although the utility of uVDBP to predict deterioration of kidney function over time has not been examined. Objective: Our objective was to assess the association of uVDBP with longitudinal changes in kidney function. Methods: Adults at-risk for type 2 diabetes from the Prospective Metabolism and Islet Cell Evaluation (PROMISE) study had 3 assessments over 6 years (n = 727). Urinary albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were used as measures of kidney function. Measurements of uVDBP were performed with enzyme-linked immunosorbent assay and normalized to urine creatinine (uVDBP:cr). Generalized estimating equations (GEEs) evaluated longitudinal associations of uVDBP and uVDBP:cr with measures of kidney function, adjusting for covariates. Results: Renal uVDBP loss increased with ACR severity at baseline. Individuals with normoalbuminuria, microalbuminuria, and macroalbuminuria had median log uVDBP:cr concentrations of 1.62 µg/mmol, 2.63 µg/mmol, and 2.48 µg/mmol, respectively, and ACR positively correlated with uVDBP concentrations (r = 0.37; P < .001). There was no significant association between uVDBP and eGFR at baseline. Adjusted longitudinal GEE models indicated that each SD increase both in baseline and longitudinal uVDBP:cr was significantly associated with higher ACR over 6 years (ß = 30.67 and ß = 32.91, respectively). Conversely, neither baseline nor longitudinal uVDBP:cr measures showed a significant association with changes in eGFR over time. These results suggest that loss of uVDBP:cr over time may be a useful marker for predicting renal tubular damage in individuals at risk for diabetes.

Neonatal Birth Weight With Daily Compared With Every-Other-Day Glucose Monitoring in Gestational Diabetes Mellitus: A Randomized Controlled Trial.

OBJECTIVE: To assess whether universal use of every-other-day glucose monitoring in patients with gestational diabetes mellitus (GDM) resulted in similar birth weights and medication use and was preferred by the patient compared with traditional daily glucose monitoring. METHODS: This was a noninferiority randomized controlled trial conducted at a single New York City hospital between April 2021 and May 2022. Patients with singleton pregnancies who were diagnosed with GDM after 20 weeks of gestation and had a minimum of 7 days of previous daily blood glucose testing were randomly assigned to test blood glucose values daily or every other day. The primary outcome was neonatal birth weight. We calculated a total sample size of 196 participants needed for noninferiority to be tested, assuming the mean birth weight in the every-other-day group, compared with the daily group, was no higher than the predefined noninferiority margin of 200 g (80% power and one-sided alpha of 0.05). Postrandomization characteristics, including blood glucose values and medication initiation and timing, were recorded. Satisfaction with treatment group was assessed using the validated Oxford Maternity Diabetes Treatment Satisfaction Questionnaire. RESULTS: A total of 197 patients were randomized: 98 in the daily group and 99 in the every-other-day group. Baseline characteristics were similar between groups. The mean neonatal birth weight was similar between groups (mean±SD 3,090±418 g among newborns in the daily group compared with 3,181±482 g among newborns in the every-other-day group). For the primary outcome, the every-other-day group was found to be noninferior to the daily group with an upper confidence limit for the mean difference in mean birth weight of 197 g, which was below the noninferiority margin of 200 g (P=.046). Postrandomization, there were no significant differences in the number of patients who required medication, the gestational age at which medication was started, or the type of medication used. Average fasting and postprandial glucose values were similar between groups. There was an increase in adherence to treatment group in those randomized to every-other-day blood sugars, but no difference in patient satisfaction. CONCLUSION: In patients with GDM, testing blood glucose values every other day was as effective as testing daily, without apparent effects on birth weight, medication initiation, or glucose control. Reduced frequency of blood glucose monitoring might help decrease the emotional, physical, and financial burden experienced by patients with GDM. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04857073.

The anti-proliferative effects of a frankincense extract in a window of opportunity phase ia clinical trial for patients with breast cancer.

PURPOSE: Boswellic acids, active components of frankincense, suppress tumor proliferation in vitro with a strong clinical trial safety profile in patients with inflammatory diseases. We performed a Phase Ia window of opportunity trial of Boswellia serrata (B. serrata) in patients with breast cancer to evaluate its biologic activity and safety. METHODS: Patients with invasive breast cancer were treated pre-operatively with B. Serrata (2400 mg/day PO) until the night before surgery for a median of 11 days (SD 6 days; range: 5-23 days). Paraffin-embedded sections from pretreatment diagnostic core biopsies and post-treatment surgical excisions were evaluated using a tunnel assay and immunohistochemistry staining with Ki-67 antibodies. A non-intervention retrospective control arm consisting of core and surgical tissue specimens from untreated patients was used to compare patients treated with B. Serrata. The change in proliferation and apoptosis between diagnostic core specimens and surgical specimens was compared between the control and treatment groups using a two-tailed paired t-test. RESULTS: Twenty-two patients were enrolled, of which 20 received treatment, and 18 had sufficient tissue for IHC. There was an increase in percent change in proliferation from core biopsy to surgical excision in the control group (n = 18) of 54.6 ± 21.4%. In the B. serrata-treated group there was a reduction in proliferation between core biopsy and excision (n = 18) of 13.8 ± 11.7%. This difference was statistically significant between the control and B. serrata-treated groups (p = 0.008). There was no difference in change in apoptosis. There were no serious adverse events related to the drug. CONCLUSION: Boswellia serrata inhibited breast cancer proliferation and was well-tolerated in a Phase Ia window of opportunity trial.

Tuning the potency and selectivity of ImmTAC molecules by affinity modulation.

T-cell-engaging bispecifics have great clinical potential for the treatment of cancer and infectious diseases. The binding affinity and kinetics of a bispecific molecule for both target and T-cell CD3 have substantial effects on potency and specificity, but the rules governing these relationships are not fully understood. Using immune mobilizing monoclonal TCRs against cancer (ImmTAC) molecules as a model, we explored the impact of altering affinity for target and CD3 on the potency and specificity of the redirected T-cell response. This class of bispecifics binds specific target peptides presented by human leukocyte antigen on the cell surface via an affinity-enhanced T-cell receptor and can redirect T-cell activation with an anti-CD3 effector moiety. The data reveal that combining a strong affinity TCR with an intermediate affinity anti-CD3 results in optimal T-cell activation, while strong affinity of both targeting and effector domains significantly reduces maximum cytokine release. Moreover, by optimizing the affinity of both parts of the molecule, it is possible to improve the selectivity. These results could be effectively modelled based on kinetic proofreading with limited signalling. This model explained the experimental observation that strong binding at both ends of the molecules leads to reduced activity, through very stable target-bispecific-effector complexes leading to CD3 entering a non-signalling dark state. These findings have important implications for the design of anti-CD3-based bispecifics with optimal biophysical parameters for both activity and specificity.

BackWards - Unveiling the brain's topographic organization of paraspinal sensory input.

Cortical reorganization and its potential pathological significance are being increasingly studied in musculoskeletal disorders such as chronic low back pain (CLBP) patients. However, detailed sensory-topographic maps of the human back are lacking, and a baseline characterization of such representations, reflecting the somatosensory organization of the healthy back, is needed before exploring potential sensory map reorganization. To this end, a novel pneumatic vibrotactile stimulation method was used to stimulate paraspinal sensory afferents, while studying their cortical representations in unprecedented detail. In 41 young healthy participants, vibrotactile stimulations at 20 Hz and 80 Hz were applied bilaterally at nine locations along the thoracolumbar axis while functional magnetic resonance imaging (fMRI) was performed. Model-based whole-brain searchlight representational similarity analysis (RSA) was used to investigate the organizational structure of brain activity patterns evoked by thoracolumbar sensory inputs. A model based on segmental distances best explained the similarity structure of brain activity patterns that were located in different areas of sensorimotor cortices, including the primary somatosensory and motor cortices and parts of the superior parietal cortex, suggesting that these brain areas process sensory input from the back in a "dermatomal" manner. The current findings provide a sound basis for testing the "cortical map reorganization theory" and its pathological relevance in CLBP.

Understanding the Aggregation of Model Island and Archipelago Asphaltene Molecules near Kaolinite Surfaces using Molecular Dynamics.

The solubility of asphaltenes in hydrocarbons changes with pressure, composition, and temperature, leading to precipitation and deposition, thereby causing one of the crucial problems that negatively affects oil production, transportation, and processing. Because, in some circumstances, it might be advantageous to promote asphaltene agglomeration into small colloidal particles, molecular dynamics simulations were conducted here to understand the impacts of a chemical additive inspired by cyclohexane on the mechanism of aggregation of model island and archipelago asphaltene molecules in toluene. We compared the results in the presence and absence of a kaolinite surface at 300 and 400 K. Cluster size analyses, radial distribution functions, angles between asphaltenes, radius of gyration, and entropic and energetic calculations were used to provide insights on the behavior of these systems. The results show that the hypothetical additive inspired by cyclohexane promoted the aggregation of both asphaltenes. Structural differences were observed among the aggregates obtained in our simulations. These differences are attributed to the number of aromatic cores and side chains on the asphaltene molecules as well as to that of heteroatoms. For the island structure, aggregation in the bulk phase was less pronounced than that in the proximity of the kaolinite surface, whereas the opposite was observed for the archipelago structure. In both cases, the additive promoted stacking of asphaltenes, yielding more compact aggregates. The results provided insights into the complex nature of asphaltene aggregation, although computational approaches that can access longer time and larger size scales should be chosen for quantifying emergent meso- and macroscale properties of systems containing asphaltenes in larger numbers than those that can currently be sampled via atomistic simulations.

Physiology and emotions: Within individual associations during caregiver-adolescent conflict.

Concordance between physiological and emotional responses is central to models of emotion and has been shown to correspond to effective responses and well-being in adults. A deeper understanding of physiological-emotional concordance during ecologically relevant scenarios is essential to then determine if these associations predict mental health problems or can serve as a helpful biomarker of risk or resilience in adults and youth. The present study assessed the minute-to-minute associations between sympathetic (i.e., skin conductance level [SCL]) and parasympathetic (i.e., respiratory sinus arrhythmia [RSA]) nervous system activity and self-reported emotions, assessed via video-mediated recall procedures, during a parent-adolescent conflict discussion task. Associations between emotion ratings and physiological activity were assessed in adolescents (N = 97; ages 10-15) and their adult caregivers (N = 97). Utilizing a multilevel modeling approach, findings demonstrated a significant positive association between SCL and emotion ratings for youth, suggesting that increased engagement and alertness contributed to more positive emotion. RSA was unrelated to emotion ratings. The presence of significant variability in associations indicated the presence of potential moderators. This could include clinically relevant processes (e.g., emotion regulation, relationship quality, and mental health). Future research should continue to build on findings to determine if, when, and for whom, physiological-emotional concordance occurs, and whether the degree of concordance predicts risk for mental and physical health problems.

The functional connectome of 3,4-methyldioxymethamphetamine-related declarative memory impairments.

The chronic intake of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") bears a strong risk for sustained declarative memory impairments. Although such memory deficits have been repeatedly reported, their neurofunctional origin remains elusive. Therefore, we here investigate the neuronal basis of altered declarative memory in recurrent MDMA users at the level of brain connectivity. We examined a group of 44 chronic MDMA users and 41 demographically matched controls. Declarative memory performance was assessed by the Rey Auditory Verbal Learning Test and a visual associative learning test. To uncover alterations in the whole brain connectome between groups, we employed a data-driven multi-voxel pattern analysis (MVPA) approach on participants' resting-state functional magnetic resonance imaging data. Recent MDMA use was confirmed by hair analyses. MDMA users showed lower performance in delayed recall across tasks compared to well-matched controls with moderate-to-strong effect sizes. MVPA revealed a large cluster located in the left postcentral gyrus of global connectivity differences between groups. Post hoc seed-based connectivity analyses with this cluster unraveled hypoconnectivity to temporal areas belonging to the auditory network and hyperconnectivity to dorsal parietal regions belonging to the dorsal attention network in MDMA users. Seed-based connectivity strength was associated with verbal memory performance in the whole sample as well as with MDMA intake patterns in the user group. Our findings suggest that functional underpinnings of MDMA-related memory impairments encompass altered patterns of multimodal sensory integration within auditory processing regions to a functional heteromodal connector hub, the left postcentral gyrus. In addition, hyperconnectivity in regions of a cognitive control network might indicate compensation for degraded sensory processing.

Empathy deficits, callous-unemotional traits and structural underpinnings in autism spectrum disorder and conduct disorder youth.

Distinct empathy deficits are often described in patients with conduct disorder (CD) and autism spectrum disorder (ASD) yet their neural underpinnings and the influence of comorbid Callous-Unemotional (CU) traits are unclear. This study compares the cognitive (CE) and affective empathy (AE) abilities of youth with CD and ASD, their potential neuroanatomical correlates, and the influence of CU traits on empathy. Adolescents and parents/caregivers completed empathy questionnaires (N = 148 adolescents, mean age = 15.16 years) and T1 weighted images were obtained from a subsample (N = 130). Group differences in empathy and the influence of CU traits were investigated using Bayesian analyses and Voxel-Based Morphometry with Threshold-Free Cluster Enhancement focusing on regions involved in AE (insula, amygdala, inferior frontal gyrus and cingulate cortex) and CE processes (ventromedial prefrontal cortex, temporoparietal junction, superior temporal gyrus, and precuneus). The ASD group showed lower parent-reported AE and CE scores and lower self-reported CE scores while the CD group showed lower parent-reported CE scores than controls. When accounting for the influence of CU traits no AE deficits in ASD and CE deficits in CD were found, but CE deficits in ASD remained. Across all participants, CU traits were negatively associated with gray matter volumes in anterior cingulate which extends into the mid cingulate, ventromedial prefrontal cortex, and precuneus. Thus, although co-occurring CU traits have been linked to global empathy deficits in reports and underlying brain structures, its influence on empathy aspects might be disorder-specific. Investigating the subdimensions of empathy may therefore help to identify disorder-specific empathy deficits.

The impact of nurse navigation on timeliness to treatment for benign high-risk breast pathology.

PURPOSE: High-risk breast pathology is a breast cancer risk factor for which timely treatment is crucial. Nurse navigation programs have been implemented to minimize delays in patient care. This study evaluated nurse navigation in terms of timeliness to surgery for patients with high-risk breast pathology. METHODS: This was a single-institution, retrospective review of patients with identified high-risk breast pathology undergoing lumpectomy between January 2017 and June 2019. Patients were stratified into cohorts based on periods with and without nurse navigation. Preoperative and postoperative time to care as well as demographic and tumor characteristics were compared using univariate and multivariate analysis. RESULTS: 100 patients had assigned nurse navigators and 29 patients did not. Nurse navigation was associated with reduced time from referral to date of surgery (DOS) by 16.9 days (p = 0.003). Patients > 75 years had a shorter time to first appointment (p = 0.03), and patients with Medicare insurance had a reduced time from referral to DOS (p = 0.005). 20% of all patients were upstaged to cancer on final surgical pathology. CONCLUSION: Nurse navigation was significantly associated with decreased time to care for patients with high-risk breast pathology undergoing lumpectomy. We recommend nurse navigation programs as part of a comprehensive approach for patients with high-risk breast pathology.

The relation of depressive symptoms to theory of mind in adults.

BACKGROUND: Theory of mind (ToM) is the ability to understand thoughts and feelings of others. Significant heterogeneity exists for the strength of the association between depression and ToM performance. METHODS: To clarify these relations, two studies of depressed and nondepressed adults investigate cross-sectional associations of four latent depression factors (i.e., somatic symptoms, depressed affect, positive affect, and interpersonal problems) to two aspects of ToM (reasoning vs. decoding). Study 1 investigated associations between depression factors and reasoning ToM (N = 258), and Study 2 investigated associations between depression factors and decoding ToM (N = 219). RESULTS: In Study 1, the interpersonal problems factor was negatively related to reasoning ToM, though in Study 2, no consistent associations emerged between depression and decoding ToM. Study 2 also replicated a novel approach to assessing valence with the Reading the Mind in the Eyes Test. LIMITATIONS: This investigation was primarily limited by cross-sectional designs, self-report, and online delivery of measures. CONCLUSIONS: Findings emphasize the heterogeneity of ToM as a construct and identify targets for clinical intervention, with specific focus on bolstering reasoning ToM skills.

Targeting of multiple tumor-associated antigens by individual T cell receptors during successful cancer immunotherapy.

The T cells of the immune system can target tumors and clear solid cancers following tumor-infiltrating lymphocyte (TIL) therapy. We used combinatorial peptide libraries and a proteomic database to reveal the antigen specificities of persistent cancer-specific T cell receptors (TCRs) following successful TIL therapy for stage IV malignant melanoma. Remarkably, individual TCRs could target multiple different tumor types via the HLA A∗02:01-restricted epitopes EAAGIGILTV, LLLGIGILVL, and NLSALGIFST from Melan A, BST2, and IMP2, respectively. Atomic structures of a TCR bound to all three antigens revealed the importance of the shared x-x-x-A/G-I/L-G-I-x-x-x recognition motif. Multi-epitope targeting allows individual T cells to attack cancer in several ways simultaneously. Such "multipronged" T cells exhibited superior recognition of cancer cells compared with conventional T cell recognition of individual epitopes, making them attractive candidates for the development of future immunotherapies.

Genetic variants in the vitamin D pathway and their association with vitamin D metabolite levels: Detailed studies of an inner-city pediatric population suggest a modest but significant effect in early childhood.

OBJECTIVES: In a large cohort of healthy infants and toddlers 6-36 months of age (n = 776), we have been exploring the potential role of genetic variation in predisposition to vitamin D insufficiency. The genes encoding the key cytochrome P450 hydroxylases (CYP2R1, CYP24A1, and CYP27B1) harbour recurrent mutations of uncertain effect. This study was undertaken to look for biochemically relevant associations of these variants with inter-individual differences in vitamin D metabolism in an at-risk pediatric population. METHODS: Genotyping for CYP2R1-CT (c.-1127 C>T, rs10741657), CYP24A1-AG (c.-686A>G, rs111622401), and CYP27B1-CA (c.-1261 C>A, rs10877012) mutations were performed using SNaPshot assay, followed by Sanger sequencing confirmation. Vitamin D metabolites and vitamin D binding protein (DBP) were measured by established methods. RESULTS: In a multivariate regression model, with corrections for co-variates, subjects with the homozygous CYP2R1-TT variant had significantly higher concentrations of 25(OH)D, free 25(OH)D, and 24,25(OH)2D levels. In subjects with the CYP24A1-AG mutation, concentrations of 25(OH)D were significantly higher. CONCLUSIONS: The CYP2R1-TT and CYP24A1-AG variants have measurable effects on the vitamin D pathway. It seems unlikely that they will be clinically relevant in isolation, but they may be members of the large pool of infrequent mutations contributing to different risks for the vitamin D deficiency phenotype.