Factor Structure of Repetitive Behaviors Across Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder

Journal of Autism and Developmental Disorders - Restricted interests and repetitive behaviors (RRBs) are core symptoms of autism spectrum disorder (ASD), and commonly occur in...     

Mapping default mode connectivity alterations following a single season of subconcussive impact exposure in youth football

Repetitive head impact (RHI) exposure in collision sports may contribute to adverse neurological outcomes in former players. In contrast to a concussion, or mild traumatic brain injury, “subconcussive” RHIs represent a more frequent and asymptomatic form of exposure. The neural network‐level signatures characterizing subconcussive RHIs in youth collision‐sport cohorts such as American Football are not known. Here, we used resting‐state functional MRI to examine default mode network (DMN) functional connectivity (FC) following a single football season in youth players (n = 50, ages 8–14) without concussion. Football players demonstrated reduced FC across widespread DMN regions compared with non‐collision sport controls at postseason but not preseason. In a subsample from the original cohort (n = 17), players revealed a negative change in FC between preseason and postseason and a positive and compensatory change in FC during the offseason across the majority of DMN regions. Lastly, significant FC changes, including between preseason and postseason and between in‐ and off‐season, were specific to players at the upper end of the head impact frequency distribution. These findings represent initial evidence of network‐level FC abnormalities following repetitive, non‐concussive RHIs in youth football. Furthermore, the number of subconcussive RHIs proved to be a key factor influencing DMN FC.     

Lymphatic Vessel Memory Stimulated by Recurrent Inflammation

Inflammation stimulates new lymphatic vessel growth (inflammatory lymphangiogenesis). One key question is how recurrent inflammation, a common clinical condition, regulates lymphatic vessel remodeling. We show here that recurrent inflammation accelerated the development a functional lymphatic vessel network. This observation suggests a novel program of lymphangiogenesis and identifies a property of lymphatic vessel memory in response to recurrent inflammation. A brief episode of initial inflammation regressed lymphatic vessels, and a significant increase in CD11b⁺ macrophages were associated with the development of lymphatic vessel memory. These vessels had major differences in the structure and the spatial distribution of specialized lymphatic vessel features. Surprisingly, we found that the lymphatic vessel memory response did not depend on the vascular endothelial growth factor C or A pathway, indicating that different molecular pathways regulate inflammatory lymphangiogenesis and lymphatic vessel memory. These findings uncover a priming mechanism to facilitate a rapid lymphatic vessel memory response: a potential important component of peripheral host defense.The lymphatic vasculature is one component of the inflammatory response that is remarkably understudied. The lymphatic system can be broadly classified into the lymphoid tissue (tonsils, lymph nodes, and spleen) and the conduit system or lymphatic vasculature. The focus of these studies is the lymphatic capillaries which literally are the most peripheral extension of the immune system and reside intimately in the diseased tissue. Aside from the classic functions of the lymphatic vasculature described many years ago (transport of extracellular fluid, cells, antigens, and lipid), surprisingly little is known about the normal physiology of this system and how it regulates inflammation and wound recovery. Multiple lines of evidence have shown that the lymphatic vasculature proliferates in response to inflammatory conditions, suggesting an active, perhaps essential, role during the inflammatory response.^1–6 Inflammatory lymphangiogenesis is thought to be a physiological mechanism that develops to meet the increased demands of fluid, antigen, and cellular transport during an inflammatory response. New lymphatic vessel growth has been associated with beneficial effects in several different preclinical models of acute or chronic inflammatory disease.^3,7–9 It is well recognized that vascular endothelial growth factor (VEGF)-C-VEGF receptor (VEGFR)-3 and VEGF-A-VEGFR-2 pathways are important in inflammatory lymphangiogenesis.¹⁰ The most accepted model of inflammatory lymphangiogenesis is that vessels sprout and elongate from pre-existing lymphatic vessels. In contrast, is some evidence is available that circulating endothelial progenitors or macrophages differentiate into lymphatic endothelial cells to comprise newly synthesized lymphatic vessels.^11,12Clinically, two general outcomes occur after an initial episode of inflammatory disease: wound recovery or recurrent inflammation. We developed a mouse model of wound recovery and recurrent inflammation to simulate these clinical outcomes and to study the lymphatic vasculature during these conditions. We recently demonstrated that lymphatic vessel regression developed during wound recovery in the cornea.¹³ Fragmented lymphatic vessels that persisted over time were visualized in wound recovery conditions.In contrast to wound recovery, recurrent inflammation is a common clinical outcome after an initial episode of inflammation. We studied the effects of recurrent inflammation in corneal tissue recovered from an initial inflammatory response. This approach is different from earlier studies in that it features wound recovery followed by recurrent inflammation rather than an acute or chronic unrelenting pathogen or tumor-based inflammatory stimuli.^3,4,7,14 We induced recurrent inflammation in recovered corneal tissue by placing a subsequent suture in the cornea (re-suturing). Here, we show that one feature of recurrent inflammation was the accelerated localized development of a functional lymphatic vessel network. The rapid kinetics and memory response were reminiscent of an immunological memory response; for this reason we describe this process as lymphatic vessel memory. This response appeared to stimulate the anastomosis of fragmented lymphatic vessels. Unlike inflammatory lymphangiogenesis induced by initial inflammation, we showed that lymphatic vessel memory was independent of the VEGF-C and VEGF-A pathways. Thus, these studies reveal a novel program of lymphatic vessel memory.     

Positive selection of protective variants for type 2 diabetes from the Neolithic onward: a case study in Central Asia

The high prevalence of type 2 diabetes and its uneven distribution among human populations is both a major public health concern and a puzzle in evolutionary biology. Why is this deleterious disease so common, while the associated genetic variants should be removed by natural selection? The ‘thrifty genotype'' hypothesis proposed that the causal genetic variants were advantageous and selected for during the majority of human evolution. It remains, however, unclear whether genetic data support this scenario. In this study, we characterized patterns of selection at 10 variants associated with type 2 diabetes, contrasting one herder and one farmer population from Central Asia. We aimed at identifying which alleles (risk or protective) are under selection, dating the timing of selective events, and investigating the effect of lifestyle on selective patterns. We did not find any evidence of selection on risk variants, as predicted by the thrifty genotype hypothesis. Instead, we identified clear signatures of selection on protective variants, in both populations, dating from the beginning of the Neolithic, which suggests that this major transition was accompanied by a selective advantage for non-thrifty variants. Combining our results with worldwide data further suggests that East Asia was particularly prone to such recent selection of protective haplotypes. As much effort has been devoted so far to searching for thrifty variants, we argue that more attention should be paid to the evolution of non-thrifty variants.     

Creation of a High‐fidelity,Low‐cost Pediatric Skull Fracture Ultrasound Phantom

Over the past decade, point‐of‐care ultrasound has become a common tool used for both procedures and diagnosis. Developing high‐fidelity phantoms is critical for training in new and novel point‐of‐care ultrasound applications. Detecting skull fractures on ultrasound imaging in the younger‐than‐2‐year‐old patient is an emerging area of point‐of‐care ultrasound research. Identifying a skull fracture on ultrasound imaging in this age group requires knowledge of the appearance and location of sutures to distinguish them from fractures. There are currently no commercially available pediatric skull fracture models. We outline a novel approach to building a cost‐effective, simple, high‐fidelity pediatric skull fracture phantom to meet a unique training requirement.     

Colony-Stimulating Factor-1: A Potential Biomarker for Lupus Nephritis

A noninvasive means to predict the onset and recurrence of lupus nephritis (LN) before overt renal injury is needed to optimize and individualize treatment. Colony-stimulating factor-1 (CSF-1) is expressed by kidney tubules at the onset of LN, increases with disease progression, and spills into the circulation in lupus-prone mice. We tested the hypothesis that amplified expression of CSF-1 detected in the serum or urine correlates with intrarenal CSF-1 expression and histopathology (increased macrophage accumulation, activity indices) and clinical kidney disease activity and predicts the onset and recurrence of nephritis in patients with systemic lupus erythematosus (SLE). We found increased serum or urine CSF-1 levels in patients with cutaneous, serositis, and musculoskeletal disease; however, the increase in CSF-1 levels was far greater in LN. Moreover, an elevation in serum or urine CSF-1 levels correlated with increasing intrarenal CSF-1 expression and histopathology. By longitudinally tracking patients, we found that elevated serum CSF-1 heralded the initial onset of disease, and a rise in serum or urine CSF-1 predicted recurrences of LN before clinical evidence of glomerular dysfunction and conventional serologic measures, even in patients with other manifestations of SLE. These findings indicate that serial monitoring for a rise in serum or urine CSF-1 levels in patients with SLE reflects kidney histopathology and may predict renal disease activity and the onset and recurrence of LN more accurately than conventional laboratory measures.     

Sphingolipids Mediate Differential Echinocandin Susceptibility in Candida albicans and Aspergillus nidulans

The cell wall synthesis-inhibiting echinocandins, including caspofungin and micafungin, play important roles in the treatment of candidiasis and aspergillosis. Previous studies revealed that, in the haploid yeast Candida glabrata, sphingolipid biosynthesis pathway mutations confer caspofungin reduced susceptibility (CRS) but micafungin increased susceptibility (MIS). Here, we describe one Candida albicans strain (of 10 tested) that similarly yields CRS-MIS mutants at relatively high frequency. Mutants demonstrated increased levels of long-chain bases (sphingolipid pathway intermediates) and, unique to this strain, loss of His104/Pro104 heterozygosity in the TSC13-encoded enoyl reductase. CRS-MIS was similarly observed in a C. albicans homozygous fen1Δ fen12Δ laboratory strain and in diverse wild-type strains following exogenous long-chain-base treatment. Analogous to these results, CRS-MIS was demonstrated in an Aspergillus nidulans basA mutant encoding defective sphingolipid C₄-hydroxylase and in its wild-type parent exposed to long-chain bases. Sphingolipids likely modulate echinocandin interaction with their Fks membrane target in all susceptible fungi, with potential implications for optimizing therapy with existing antifungals and the development of novel agents.