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Background: Humanized mice transplanted with CD34+ hematopoietic cells (HPCs) are broadly used to study human immune responses and infections in vivo and for testing therapies pre-clinically. However, until now, it was not clear whether interactions between the mouse major histocompatibility complexes (MHCs) and/or the human leukocyte antigens (HLAs) were necessary for human T-cell development and immune reactivity. Methods: We evaluated the long-term (20-week) human hematopoiesis and human T-cell development in NOD Scid Gamma (NSG) mice lacking the expression of MHC class I and II (NSG-DKO). Triplicate experiments were performed with HPCs obtained from three donors, and humanization was confirmed in the reference strain NOD Rag Gamma (NRG). Further, we tested whether humanized NSG-DKO mice would respond to a lentiviral vector (LV) systemic delivery of HLA-A*02:01, HLA-DRB1*04:01, human GM-CSF/IFN-α, and the human cytomegalovirus gB antigen. Results: Human immune reconstitution was detectable in peripheral blood from 8 to 20 weeks after the transplantation of NSG-DKO. Human single positive CD4+ and CD8+ T-cells were detectable in lymphatic tissues (thymus, bone marrow, and spleen). LV delivery harnessed the detection of lymphocyte subsets in bone marrow (αβ and γδ T-cells and NK cells) and the expression of HLA-DR. Furthermore, RNA sequencing showed that LV delivery increased the expression of different human reactome pathways, such as defense responses to other organisms and viruses. Conclusions: Human T-cell development and reactivity are independent of the expression of murine MHCs in humanized mice. Therefore, humanized NSG-DKO is a promising new model for studying human immune responses, as it abrogates the xenograft mouse MHC interference. [ABSTRACT FROM AUTHOR]

Simple Summary: Diffuse large B cell lymphoma (DLBCL) is the most diagnosed, aggressive non-Hodgkin lymphoma, a type of blood cancer. In this study, we developed new DLBCL cell-derived xenograft mouse models. We found that our models show consistent tumor burden with unformal disease progression and organ-specific infiltration. Diffuse large B cell lymphoma (DLBCL) is the most diagnosed, aggressive non-Hodgkin lymphoma, with ~40% of patients experiencing refractory or relapsed disease. Given the low response rates to current therapy, alternative treatment strategies are necessary to improve patient outcomes. Here, we sought to develop an easily accessible new xenograft mouse model that better recapitulates the human disease for preclinical studies. We generated two Luciferase (Luc)-EGFP-expressing human DLBCL cell lines representing the different DLBCL cell-of-origin subtypes. After intravenous injection of these cells into humanized NSG mice, we monitored the tumor growth and evaluated the organ-specific engraftment/progression period. Our results showed that human IL6-expressing NSG (NSG-IL6) mice were highly permissive for DLBCL cell growth. In NSG-IL6 mice, systemic engraftments of both U2932 activated B cell-like- and VAL germinal B cell-like-DLBCL (engraftment rate; 75% and 82%, respectively) were detected within 2nd-week post-injection. In the organ-specific ex vivo evaluation, both U2932-Luc and VAL-Luc cells were initially engrafted and expanded in the spleen, liver, and lung and subsequently in the skeleton, ovary, and brain. Consistent with the dual BCL2/MYC translocation association with poor patient outcomes, VAL cells showed heightened proliferation in human IL6-conditioned media and caused rapid tumor expansion and early death in the engrafted mice. We concluded that the U2932 and VAL cell-derived human IL6-expressing mouse models reproduced the clinical features of an aggressive DLBCL with a highly consistent pattern of tumor development. Based on these findings, NSG mice expressing human IL6 have the potential to serve as a new tool to develop DLBCL xenograft models to overcome the limitations of standard subcutaneous DLBCL xenografts. [ABSTRACT FROM AUTHOR]

Comorbid externalizing and internalizing disorders are common in offspring of a parent with bipolar I or II disorder. In some cases, the symptoms are harbingers of future bipolar spectrum disorder. Even when they are not, they are likely to be impairing to the child. Clinicians need to be better informed about how the history leading up to mania/hypomania unfolds, and what comorbid disorders are impairing in and of themselves. More information is needed about the parents' psychopathology, course of illness and response to treatment. Until we have data on how to prevent bipolar disorder, the best course of action is to treat the child's current impairing symptoms and render the parent as asymptomatic as possible. [ABSTRACT FROM AUTHOR]

Background: Offspring of parents with bipolar disorder (BD‐I/II) are at increased risk to develop the disorder. Previous work indicates that bipolar spectrum disorder (BPSD) is often preceded by mood/anxiety symptoms. In school‐age offspring of parents with BD, we previously built a risk calculator to predict BPSD onset, which generates person‐level risk scores. Here, we test whether preschool symptoms predict school‐age BPSD risk. Methods: We assessed 113 offspring of parents with BD 1–3 times during preschool years (2–5 years old) and then approximately every 2 years for a mean of 10.6 years. We used penalized (lasso) regression with linear mixed models to assess relationships between preschool mood, anxiety, and behavioral symptoms (parent‐reported) and school‐age predictors of BPSD onset (i.e., risk score, subthreshold manic symptoms, and mood lability), adjusting for demographics and parental symptomatology. Finally, we conducted survival analyses to assess associations between preschool symptoms and school‐age onset of BPSD and mood disorder. Results: Of 113 preschool offspring, 33 developed new‐onset mood disorder, including 19 with new‐onset BPSD. Preschool irritability, sleep problems, and parental factors were lasso‐selected predictors of school‐age risk scores. After accounting for demographic and parental factors, preschool symptoms were no longer significant. Lasso regressions to predict mood lability and subthreshold manic symptoms yielded similar predictors (irritability, sleep problems, and parental affective lability), but preschool symptoms remained predictive even after adjusting for parental factors (ps <.005). Exploratory analyses indicated that preschool irritability univariately predicted new‐onset BPSD (p =.02) and mood disorder (p =.02). Conclusions: These results provide initial prospective evidence that, as early as preschool, youth who will develop elevated risk scores, mood lability, and subthreshold manic symptoms are already showing symptomatology; these preschool symptoms also predict new‐onset BPSD. While replication of findings in larger samples is warranted, results point to the need for earlier assessment of risk and development of early interventions. [ABSTRACT FROM AUTHOR]

Diabetic patients are more affected by depression than non-diabetics, and this is related to greater treatment resistance and associated with poorer outcomes. This increase in the prevalence of depression in diabetics is also related to hyperglycemia and hypercortisolism. In diabetics, the hyperactivity of the HPA axis occurs in parallel to gut dysbiosis, weakness of the intestinal permeability barrier, and high bacterial-product translocation into the bloodstream. Diabetes also induces an increase in the permeability of the blood–brain barrier (BBB) and Toll-like receptor 4 (TLR4) expression in the hippocampus. Furthermore, lipopolysaccharide (LPS)-induced depression behaviors and neuroinflammation are exacerbated in diabetic mice. In this context, we propose here that hypercortisolism, in association with gut dysbiosis, leads to an exacerbation of hippocampal neuroinflammation, glutamatergic transmission, and neuronal apoptosis, leading to the development and aggravation of depression and to resistance to treatment of this mood disorder in diabetic patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Patient-derived xenografts (PDX) are valuable models in preclinical oncology drug development. However, they are not well suited for testing immune-based therapies. In contrast, when humanized mice are developed by xenotransplantation of irradiated mice with human CD34+ stem cells to allow for the growth of human tumor tissue in the context of a humanized immune system, it is possible to evaluate the response to both targeted therapy and immune therapy. Unfortunately, humanized mice transplanted with human PDX tissue frequently develop graft-versus-host disease (GVHD). Here, we optimized a protocol for generating humanized PDX mouse models with considerably reduced development of GVHD, making preclinical trials with immune checkpoint inhibitors possible. Current methodologies for developing PDX in humanized mice in preclinical trials with immune-based therapies are limited by GVHD. Here, we compared two approaches for establishing PDX tumors in humanized mice: (1) PDX are first established in immune-deficient mice; or (2) PDX are initially established in humanized mice; then established PDX are transplanted to a larger cohort of humanized mice for preclinical trials. With the first approach, there was rapid wasting of PDX-bearing humanized mice with high levels of activated T cells in the circulation and organs, indicating immune-mediated toxicity. In contrast, with the second approach, toxicity was less of an issue and long-term human melanoma tumor growth and maintenance of human chimerism was achieved. Preclinical trials from the second approach revealed that rigosertib, but not anti-PD-1, increased CD8/CD4 T cell ratios in spleen and blood and inhibited PDX tumor growth. Resistance to anti-PD-1 was associated with PDX tumors established from tumors with limited CD8+ T cell content. Our findings suggest that it is essential to carefully manage immune editing by first establishing PDX tumors in humanized mice before expanding PDX tumors into a larger cohort of humanized mice to evaluate therapy response. [ABSTRACT FROM AUTHOR]

Background: Attention‐deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with onset as early as preschool and impairment across the lifespan. Temperament factors, specifically those that theoretically map onto ADHD symptoms, may be early markers of risk for developing later childhood ADHD that could be identifiable in infancy or toddlerhood. This meta‐analysis examined the associations between these early temperamental factors and later symptoms and diagnosis of ADHD and mapped early temperament constructs onto the three ADHD symptom dimensions. Methods: A systemic review of the literature was conducted to identify prospective longitudinal studies that included theoretically relevant temperament constructs (sustained attention, activity level, inhibition, and negative emotionality) examined from birth to 36 months old and ADHD (symptoms or diagnosis) in preschool or childhood. The association between each temperament construct and ADHD outcomes was examined using pooled standardized estimates in meta‐analyses. Results: Forty‐eight articles (n = 112,716 infants/toddlers) prospectively examined temperament and the relation to childhood ADHD symptoms or diagnosis. Activity level (k = 18) in infancy and toddlerhood was moderately associated with childhood ADHD (r =.39, CI = 0.27, 0.51, p <.001). Moderate effect sizes were also observed for sustained attention (k = 9; r = −.28, CI = −0.42, −0.12, p <.001) and negative emotionality (k = 33; r =.25, CI = 0.16, 0.34, p <.001) with ADHD. The specificity of each temperament construct for later ADHD symptom dimensions was such that activity level and negative emotionality were predictive of all three symptom dimensions (i.e., inattention, hyperactivity/impulsivity, and combined), whereas sustained attention was only associated with combined symptoms. Conclusions: Infant and toddler temperament is an early risk factor for the development of childhood ADHD that could be utilized for early intervention identification. Yet, this systematic review found that relatively few prospective longitudinal studies have examined sustained attention (k = 9) and inhibition (k = 15) in infancy and toddlerhood in relation to later ADHD highlighting the need for further research. [ABSTRACT FROM AUTHOR]

Electroconvulsive therapy (ECT) is a long-standing treatment choice for disorders such as depression when pharmacological treatments have failed. However, a major drawback of ECT is its cognitive side effects. While numerous studies have investigated the therapeutic effects of ECT and its mechanism, much less research has been conducted regarding the mechanism behind the cognitive side effects of ECT. As both clinical remission and cognitive deficits occur after ECT, it is possible that both may share a common mechanism. This review highlights studies related to ECT as well as those investigating the mechanism of its outcomes. The process underlying these effects may lie within BDNF and NMDA signaling. Edema in the astrocytes may also be responsible for the adverse cognitive effects and is mediated by metabotropic glutamate receptor 5 and the protein Homer1a. [ABSTRACT FROM AUTHOR]

This is the first study that examined and compared the survival, LC50, and RR50 estimates of Megacopta cribraria F. (Hemiptera: Plataspidae) nymphs and adults that were exposed to two native Beauveria bassiana isolates (Previously codified as NI8 and KUDSC strains) at four concentrations. The greatest reduction in survival and mortality was observed primarily on or after 10 d post-exposure to B. bassiana isolates. Survival of early instars (2nd, 3rd) were not affected by either strains or concentration at 3 d and 5 d post-exposure. Survival of later instars (5th) and adults was significantly reduced when exposed to the KUDSC strain at all concentrations. Comparison of dose–mortality values (LC50) using resistance ratios (RR50) were significantly different between life stages of the kudzu bug for both strains of B. bassiana. The LC50 values showed that kudzu bug adults are more susceptible than any other life stage when exposed to either strain. The KUDSC strain was more pathogenic than NI8 10 d after exposure, but NI8 exhibited significantly higher pathogenicity than KUDSC 20 d after exposure. Our results suggest potential field application of B. bassiana for kudzu bug control and their integration into pest management strategies to suppress them before they cause economic damage to soybean crops. [ABSTRACT FROM AUTHOR]

The anticoagulant response to warfarin, a narrow therapeutic index drug, increases with age, which may make older patients susceptible to adverse outcomes resulting from small differences in bioavailability between generic and brand products. Using US Medicare claims linked to electronic medical records from two large hospitals in Boston, we designed a cohort study of ≥ 65‐year‐old patients. Patients were followed for a composite effectiveness outcome of ischemic stroke or venous thromboembolism, a composite safety outcome, including major hemorrhage, and a 1‐year all‐cause mortality outcome. After propensity score fine‐stratification and weighting to account for > 90 confounders, hazard ratios comparing brand vs. generic warfarin initiators (95% confidence intervals) for the effectiveness, safety, and all‐cause mortality outcomes, were 0.97 (0.65–1.46), 0.94 (0.65–1.35), and 0.84 (0.62–1.13), respectively. Results from subgroup analyses of patients with atrial fibrillation, CHADS‐VASc score ≥ 3, and HAS‐BLED score ≥ 3 were consistent with the primary analysis. [ABSTRACT FROM AUTHOR]

Toosendanin (TSN) is a triterpenoid purified from the medicinal herb Melia toosendan Sieb. et Zucc and has been used as an insecticide for decades. Recent studies have attracted increasing interest of TSN due to its novel anti-cancer effect in diverse cancer models. The broad spectrum anti-cancer activity suggests that TSN inhibits multiple pathways/targets that are critical for cancer cell survival and proliferation. Our recent study indicated that TSN has anti-cancer effect in glioblastoma through induction of estrogen receptor β (ERβ) and p53. This review highlights the anti-cancer efficacy of TSN and provides proof-of-principle insight into the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Both illusion and disillusion play an important role in development, fostering processes of going-on-being and separation (Winnicott 1960). The capacity to bear disillusionment is both a developmental necessity and an ongoing challenge. Disillusionment penetrates the sphere of illusion and invites the individual into an expanded encounter with shared realities. But when disillusionment becomes chronic and pervasive or is accompanied by severe psychic pain, then suicide is felt by some to be an urgent option for refusing or escaping this pain. Contextualized within a review of psychoanalytic developmental theories of disillusion, vignettes from a research study of participants who have survived a near lethal suicide attempt illuminate the phenomenon of suicide as an illusory solution to what feels like unbearable disillusionment. [ABSTRACT FROM AUTHOR]

The intrinsic capacity of human hematopoietic stem cells (hHSCs) to reconstitute myeloid and lymphoid lineages combined with their self-renewal capacity hold enormous promises for gene therapy as a viable treatment option for a number of immune-mediated diseases, most prominently for inborn errors of immunity (IEI). The current development of such therapies relies on disease models, both in vitro and in vivo, which allow the study of human pathophysiology in great detail. Here, we discuss the current challenges with regards to developmental origin, heterogeneity and the subsequent implications for disease modeling. We review models based on induced pluripotent stem cell technology and those relaying on use of adult hHSCs. We critically review the advantages and limitations of current models for IEI both in vitro and in vivo. We conclude that existing and future stem cell-based models are necessary tools for developing next generation therapies for IEI. [ABSTRACT FROM AUTHOR]