Exploring the physicochemical and antiproliferative properties of biaryl-linked [13]-macrodilactones.

A macrocyclic motif fosters productive protein-small molecule interactions. There are numerous examples of both natural product and designed, synthetic macrocycles that modulate the immune system, slow microbial infection, or kill eukaryotic cells. Reported here are the synthesis, physicochemical characterization, and antiproliferative activity of a group of [13]-macrodilactones decorated with a pendant biaryl moiety. Biaryl analogs were prepared by Suzuki reactions conducted on a common intermediate that contained a bromophenyl unit alpha to one of the carbonyls of the [13]-macrodilactone. Principal component analysis placed the new compounds in physicochemical context relative to a variety of pharmaceuticals and natural products. Modest inhibition of proliferation was observed in ASZ cells, a murine basal cell carcinoma line. This work underscores the value of an approach toward the identification of bioactive compounds that places the evaluation of physicochemical parameters early in the search process.

Trajectories of Perceived Parental Psychological Control across Adolescence and Implications for the Development of Depressive and Anxiety Symptoms.

Theory and research indicate considerable changes in parental control across adolescence (e.g., declining behavioral control), but the developmental course and significance of psychological control remains largely unknown. This study examined trajectories of adolescents' reports of mothers' and fathers' psychological control from ages 12 to 19, predictors of occupying distinct trajectories, and the developmental significance of these trajectories for adolescents' development of depressive and anxiety symptoms. It used eight waves of survey data on 500 adolescents (Mage = 11.83, SD = 1.03; 52% female; 67% White, 12% African American) and their parents from the Pacific Northwest United States. Most adolescents (about 90%) reported low but increasing levels of parental psychological control over time, with a small but significant subset (about 10%) perceiving perpetually elevated levels. Mothers' (but not fathers') depressive symptoms, reported at the age 12 assessment, predicted adolescents' membership in the elevated psychological control trajectory. Adolescents occupying these elevated trajectories showed more problematic growth in depressive and anxiety symptoms across adolescence. Taken together, the findings suggest that many adolescents experience increased parental psychological control as they age, and that variability in these trends indicates individual differences in their development of depressive and anxiety symptoms over time.

Lymphoblastoid cell lines do not recapitulate physiological circulating B cell subtypes.

Lymphoblastoid cell lines (LCLs) are immortalised peripheral B lymphocytes, transformed via infection with Epstein Barr virus (EBV). The use of LCLs to study B cell function remains controversial and core markers to define physiological B cell populations are not consistent between studies of physiological B cells and LCLs. A consensus on the nature of these commonly used cell lines has not been reached. Recently, a core set of markers to subtype peripheral B cells was proposed, addressing the lack of agreed markers for B cell characterisation. In this present study, the consensus panel was applied to describe the B cell subtypes in LCLs. We found that LCLs were generally not physiologically representative of B cells, with most cells harbouring marker combinations absent on peripheral B cells. Some B cell subtyping markers were fundamentally altered during EBV transformation to LCLs (e.g. CD19, CD21). Notably, most LCLs secreted IgG but the associated marker combinations were predominantly only present in vitro following EBV transformation. This study therefore informs interpretation of past investigations, and planning of future studies using LCLs, as these cells are unlikely to behave like their pre-transformed B cell subtype.

Autoantibodies against acetylcholine receptors are increased in archived serum samples from patients with schizophrenia.

Previous studies have demonstrated that the levels of IgG against neurotransmitter receptors are increased in patients with schizophrenia. Genome-wide association (GWA) studies of schizophrenia confirmed that 108 loci harbouring over 300 genes were associated with schizophrenia. Although the functional implications of genetic variants are unclear, theoretical functional alterations of these genes could be replicated by the presence of autoantibodies. This study examined the levels of plasma IgG antibodies against four neurotransmitter receptors, CHRM4, GRM3, CHRNA4 and CHRNA5, using an in-house ELISA in 247 patients with schizophrenia and 344 non-psychiatric controls. Four peptides were designed based on in silico analysis with computational prediction of HLA-DRB1 restricted and B-cell epitopes. The relationship between plasma IgG levels and psychiatric symptoms, as defined by the Operational Criteria Checklist for Psychotic Illness and Affective Illness (OPCRIT), were examined. The results showed that the levels of plasma IgG against peptides derived from CHRM4 and CHRNA4 were significantly increased in patients with schizophrenia compared with control subjects, but there was no significant association of plasma IgG levels with any symptom domain or any specific symptoms. These preliminary results suggest that CHRM4 and CHRNA4 may be novel targets for autoantibody responses in schizophrenia, although the pathogenic relationship between increased serum autoantibody levels and schizophrenia symptoms remains unclear.

A multi-institutional meningioma MRI dataset for automated multi-sequence image segmentation.

Meningiomas are the most common primary intracranial tumors and can be associated with significant morbidity and mortality. Radiologists, neurosurgeons, neuro-oncologists, and radiation oncologists rely on brain MRI for diagnosis, treatment planning, and longitudinal treatment monitoring. However, automated, objective, and quantitative tools for non-invasive assessment of meningiomas on multi-sequence MR images are not available. Here we present the BraTS Pre-operative Meningioma Dataset, as the largest multi-institutional expert annotated multilabel meningioma multi-sequence MR image dataset to date. This dataset includes 1,141 multi-sequence MR images from six sites, each with four structural MRI sequences (T2-, T2/FLAIR-, pre-contrast T1-, and post-contrast T1-weighted) accompanied by expert manually refined segmentations of three distinct meningioma sub-compartments: enhancing tumor, non-enhancing tumor, and surrounding non-enhancing T2/FLAIR hyperintensity. Basic demographic data are provided including age at time of initial imaging, sex, and CNS WHO grade. The goal of releasing this dataset is to facilitate the development of automated computational methods for meningioma segmentation and expedite their incorporation into clinical practice, ultimately targeting improvement in the care of meningioma patients.

An examination of plasma autoantibodies against voltage gated calcium channels in schizophrenia.

Autoantibodies targeting the central nervous system have been shown to induce psychiatric symptoms resembling schizophrenia. Concurrently, genetic studies have characterised a number of risk variants associated with schizophrenia although their functional implications are largely unknown. Any biological effects of functional variants on protein function may potentially be replicated by the presence of autoantibodies against such proteins. Recent research has demonstrated that the R1346H variant in the CACNA1I gene coding for the Cav 3.3 protein results in a synaptic reduction of Cav3.3 voltage gated calcium channels and, consequently, sleep spindles, which have been shown to correlate with several symptom domains in patients with schizophrenia. The present study measured plasma levels of IgG against two peptides derived from CACNA1I and CACNA1C, respectively, in patients with schizophrenia and healthy controls. The results demonstrated that increased anti-CACNA1I IgG levels were associated with schizophrenia but not associated with any symptom domain related to the reduction of sleep spindles. In contrast to previously published work indicating that inflammation may be a marker for a depressive phenotype, plasma levels of IgG against either CACNA1I or CACNA1C peptides were not associated with depressive symptoms, suggesting that anti-Cav3.3 autoantibodies may function independently of pro-inflammatory processes.

The ASNR-MICCAI Brain Tumor Segmentation (BraTS) Challenge 2023: Intracranial Meningioma.

Meningiomas are the most common primary intracranial tumor in adults and can be associated with significant morbidity and mortality. Radiologists, neurosurgeons, neuro-oncologists, and radiation oncologists rely on multiparametric MRI (mpMRI) for diagnosis, treatment planning, and longitudinal treatment monitoring; yet automated, objective, and quantitative tools for non-invasive assessment of meningiomas on mpMRI are lacking. The BraTS meningioma 2023 challenge will provide a community standard and benchmark for state-of-the-art automated intracranial meningioma segmentation models based on the largest expert annotated multilabel meningioma mpMRI dataset to date. Challenge competitors will develop automated segmentation models to predict three distinct meningioma sub-regions on MRI including enhancing tumor, non-enhancing tumor core, and surrounding nonenhancing T2/FLAIR hyperintensity. Models will be evaluated on separate validation and held-out test datasets using standardized metrics utilized across the BraTS 2023 series of challenges including the Dice similarity coefficient and Hausdorff distance. The models developed during the course of this challenge will aid in incorporation of automated meningioma MRI segmentation into clinical practice, which will ultimately improve care of patients with meningioma.

A B-cell or a key player? The different roles of B-cells and antibodies in melanoma.

The B-cell system plays an important role in the melanoma immune response; however, consensus has yet to be reached in many facets. Here, we comprehensively review human studies only, due to fundamental differences in the humoral response with animal models. Tumour-infiltrating B-cells are associated with contradictory prognostic values, reflecting a lack of agreement between studies on cell subset classification and differences in the markers used, particularly the common use of a single marker not differentiating multiple subsets. Tertiary lymphoid structures (TLS) organise T-cells and B-cells within tumours to generate a local anti-tumour response and TLS presence associates with improved survival in response to immune checkpoint blockade, in late-stage disease. Autoantibody production is increased in melanoma patients and has been proposed as biomarkers for diagnosis, prognosis and treatment/toxicity response; however, no consistent targets are yet identified. The function of antibodies in an anti-tumour response is determined by its isotype and subclass; IgG4 is immune-suppressive and robustly correlate with poor patient survival in melanoma. We conclude that the current B-cell literature needs careful interpretation based on the methods used and that we need a consensus of markers to define B-cells and associated lymphoid organs. Furthermore, future studies need to not only examine antibody targets, but also isotypes when considering functional roles.

Correlation of Patient Reported Satisfaction With Adverse Events Following Elective Posterior Lumbar Fusion Surgery: A Single Institution Analysis.

Background: With increasing emphasis on patient satisfaction metrics, such as the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey, hospital reputations and reimbursements are being affected by their results. The purpose of the current study is to determine if post-operative self-reported patient satisfaction differed among patients who experienced any adverse event (AAE) following elective posterior lumbar fusion (PLF) surgery compared to those who did not. Methods: Patients who underwent elective PLF surgery performed at a single institution between February 2013 and May 2020 and returned an HCAHPS survey following discharge were included in the retrospective cohort analysis. Demographic, comorbidity, and HCAHPS survey data were compared between patients who did and did not experience any adverse event (AAE) in the 30-days postoperatively. Results: Of 5,117 PLF patients, the HCAHPS survey was returned by 1,071 patients, of which 30-day AAE was experienced by 40 (3.73%). Of those that experienced AAE, the survey response rate was significantly lower (13.94% versus 21.35%, p=0.003). Those responding reported lower scores pertaining to if medication side-effects were adequately explained (22.22% versus 52.56%, p=0.002) and if post-discharge care was adequately explained (79.17% versus 93.76%, p=0.005), as well as overall top-box responses (67.62% versus 75.93% survey average, p<0.001). Conclusions: Patients experiencing AAE after elective PLF surgery are less likely to respond to surveys about their hospital experience. For those who did respond, they report less satisfaction with multiple aspects of their hospital care measured by the HCAHPS survey. Understanding how postoperative adverse events impact patients' perception of healthcare quality provides insight into what patients value and has implications for optimizing their care.

Admission NarxCare Narcotic Scores Are Associated With Increased Odds of Readmission and Prolonged Length of Hospital Stay After Primary Elective Total Knee Arthroplasty.

INTRODUCTION: The association of preoperative narcotic use with postoperative outcomes after primary elective total knee arthroplasty (TKA) has remained poorly characterized. The NarxCare platform analyzes patients' state Prescription Drug Monitoring Program records to assign numerical scores that approximate a patient's overall opioid usage. The present study investigated the utility of admission NarxCare narcotic scores in predicting the odds of adverse events (AEs) after primary elective TKA. METHODS: Elective primary TKA patients performed at a single institution between October 2017 and May 2020 were evaluated. NarxCare narcotic scores at the time of admission, patient characteristics, 30-day AEs, readmissions, revision surgeries, and mortality were abstracted. Elective TKA patients were binned based on admission NarxCare narcotic scores. The odds of experiencing adverse outcomes were compared. RESULTS: In total, 1136 patients met the criteria for inclusion in the study (Narx Score 0: n = 293 [25.8%], 1 to 99: n = 253 [22.3%], 100 to 299: n = 368 [32.4%], 300 to 499: n = 161 [14.2%], and 500+: n = 61 [5.37%]). By logistic regression, patients with higher admission narcotic scores tended to have a dose-dependent increase in the odds of prolonged length of hospital stay, readmission within 30 days, and aggregated AEs. DISCUSSION: Admission narcotic scores may be used to predict readmission and to stratify TKA patients by risk of AEs.

How Do Parents Teach "No Means No"? An Exploration of How Sexual Consent Beliefs Are Socialized During Adolescence.

Research on sexual consent has increased in recent years, but we know almost nothing about how beliefs about consent are socialized during adolescence, which likely has important implications for behaviors related to obtaining sexual consent. The current study explored the frequency of parent-adolescent consent communication, as well as demographic, adolescent, and parent predictors of adolescents' beliefs about the importance of consent and the frequency of parent-adolescent consent communication. Two national samples were used, one consisting of 2,044 adolescents, ages 13 to 18 (M age = 16.19, SD = 1.71; 50% female), and a second sample of 2,081 nonrelated individuals, ages 28 to 81, who were parents of teens ages 13-18 (M age = 15.25, SD = 1.56). Findings suggested that parents did not talk about sexual consent any more than they did about other sexual topics (e.g., reproduction). We also found that maternal warmth was positively associated with adolescents' importance of consent beliefs and that adolescents' uninhibited temperament and parents' self-efficacy and sexual beliefs were associated with parent-adolescent consent communication. The discussion focuses on the need to educate parents so they feel more confident talking to adolescents about the importance of giving and receiving sexual consent.

Is There More Than One Way to Talk About Sex? A Longitudinal Growth Mixture Model of Parent-Adolescent Sex Communication.

PURPOSE: Parents can be effective and consistent sex educators of their children, but research suggests that most parents only engage in a one-time talk about sex with their children. That being said, we know little about the potential variability in trajectories of parent-child sex communication over time. Thus, the present study took a person-centered approach to parent-child sex communication about sexual risk and explored predictors and outcomes of varying trajectories. METHODS: Participants included 468 adolescents and their parents who took part in a longitudinal study every year from ages 14-18 years (52% female, 67% white, and 33% single parents). RESULTS: Growth mixture modeling suggested four different trajectories of parent-child sex communication using child reports and two different trajectories using mother and father reports, with the majority of parents displaying low and stable levels of communication over time. Predictors and outcomes suggested that varying trajectories were in part a function of child behaviors (i.e., early sexual debut and externalizing behaviors), and mothers who reported trajectories of moderate-stable levels of communication had children who reported safer sex practices at age 21 years. CONCLUSIONS: The discussion focused on the benefits of longitudinal, person-centered approaches at identifying variability in parenting and the implications of findings for those concerned about the need for parental education on the importance of sex communication across adolescence.

No correlation between HLA-DQ 2.5, DQ 8.1 and DQ 6.2 and circulating levels of antibodies against gliadins in schizophrenia.

It has been suggested that gluten consumption is linked to schizophrenia, with this link strengthened through the presence of circulating anti-native gliadin antibodies (AGAs). The human leukocyte antigen (HLA) system is crucial for antigen presentation and antibody secretion but no study has examined the relationship between HLA-II variants and circulating antibodies against gliadin peptides. In this study, HLA-II variants were genotyped in patients with schizophrenia and the relationship between these variants and plasma AGA levels was examined. Although there was no association found, HLA-AGA associations could potentially serve as a marker of gluten sensitivity in patients with schizophrenia.

PPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma.

Pediatric high-grade gliomas are among the deadliest of childhood cancers due to limited knowledge of early driving events in their gliomagenesis and the lack of effective therapies available. In this study, we investigate the oncogenic role of PPM1D, a protein phosphatase often found truncated in pediatric gliomas such as DIPG, and uncover a synthetic lethal interaction between PPM1D mutations and nicotinamide phosphoribosyltransferase (NAMPT) inhibition. Specifically, we show that mutant PPM1D drives hypermethylation of CpG islands throughout the genome and promotes epigenetic silencing of nicotinic acid phosphoribosyltransferase (NAPRT), a key gene involved in NAD biosynthesis. Notably, PPM1D mutant cells are shown to be sensitive to NAMPT inhibitors in vitro and in vivo, within both engineered isogenic astrocytes and primary patient-derived model systems, suggesting the possible application of NAMPT inhibitors for the treatment of pediatric gliomas. Overall, our results reveal a promising approach for the targeting of PPM1D mutant tumors, and define a critical link between oncogenic driver mutations and NAD metabolism, which can be exploited for tumor-specific cell killing.

Detection of Campylobacter jejuni in Lizard Faeces from Central Australia Using Quantitative PCR.

Worldwide, Campylobacter is a significant cause of gastrointestinal illness. It is predominately considered a foodborne pathogen, with human exposure via non-food transmission routes generally overlooked. Current literature has been exploring environmental reservoirs of campylobacteriosis including potential wildlife reservoirs. Given the close proximity between lizards and human habitats in Central Australia, this study examined the presence of Campylobacter jejuni from lizard faeces collected from this region. Of the 51 samples collected, 17 (33%) (this included 14/46 (30%) wild and 3/5 (60%) captive lizard samples) were positive for C. jejuni using quantitative PCR (qPCR). This was the first study to investigate the presence of C. jejuni in Australian lizards. This has public health implications regarding the risk of campylobacteriosis from handling of pet reptiles and through cross-contamination or contact with wild lizard faeces. Additionally this has implication for horizontal transmission via lizards of C. jejuni to food production farms. Further research is needed on this environmental reservoir and potential transmission routes to reduce the risk to public health.