Abstract Concussion is among the least understood neurologic injuries. The impact of concussion on the adolescent brain remains largely unknown. This study sought to establish short-term changes in ...white-matter integrity after sports-related concussion in adolescents, and examine the association between changes in white-matter integrity and a clinical measure of concussion. Twelve adolescents, aged 14-17 years with a sports-related concussion within 2 months, and 10 age-matched adolescents with no history of concussion were evaluated with the Sports Concussion Assessment Tool 2 and diffusion tensor imaging. Two measures compared the two groups: fractional anisotropy and mean diffusivity. Whole-brain fractional anisotropy values significantly increased (F(1,40) = 6.29, P = 0.010), and mean diffusivity values decreased (F(1,40) = 4.75, P = 0.036), in concussed athletes compared with control participants. Total scores on the Sports Concussion Assessment Tool 2 were associated with whole-brain fractional anisotropy. Mean diffusivity values with lower scores were associated with higher fractional anisotropy (R2 = 0.25, P = 0.017) and lower mean diffusivity (R2 = 0.20, P = 0.038). We provide evidence of structural changes in the integrity of white matter in adolescent athletes after sports-related concussion.
Prostratin is a unique phorbol ester that stimulates protein kinase C activity but is nontumor promoting. Remarkably, prostratin is also able to inhibit de novo human immunodeficiency virus type 1 ...(HIV-1) infection yet up-regulate viral expression from latent proviruses. Prostratin's lack of tumor promotion, coupled with its ability to block viral spread yet induce latent proviral expression, prompted studies to determine whether this compound could serve as an inductive adjuvant therapy for patients treated with highly active antiretroviral therapy (HAART). The current experiments indicate that prostratin is a potent mitogen for mononuclear phagocytes possessing many of the activities of phorbol myristate acetate (PMA) with notable functional differences. Prostratin, like PMA, accelerates differentiation of the myeloid cell-lines, HL-60 and THP-1, as well as mononuclear phagocytes from bone marrow and peripheral blood. Enzyme-linked immunosorbent assay and gene array analyses indicate significant changes in the expression of proteins and messenger RNA after treatment of cells with prostratin, consistent with phagocyte activation and differentiation. Prostratin blocks HIV-1 infection relating to down-regulation of CD4 receptor expression. The array analysis indicates a similar down-regulation of the HIV-1 coreceptors, CXCR4 and CCR5, and this may also reduce viral infectivity of treated host cells. Finally, prostratin is capable of up-regulating HIV-1 expression from CD8+ T lymphocyte–depleted peripheral blood mononuclear cells of patients undergoing HAART. This novel observation suggests the agent may be an excellent candidate to augment HAART by inducing expression of latent HIV-1 with the ultimate goal of eliminating persistent viral reservoirs in certain individuals infected with HIV-1.
Garlic-derived polysulfides (e.g., diallyl trisulfide, DATS) act as potent donors of the cell-signalling mediator H2S when exposed to endogenous thiols. Inspired by this chemistry, we incorporated a ...trisulfide linkage into a conjugate comprising an mPEG tail and a cholesteryl head via thiol-mediated fragmentation chemistry. The synthesized conjugate releases H2S upon exposure to thiol even at intracellular levels.
Targeting of human cancer stem cells (CSCs) requires the identification of vulnerabilities unique to CSCs versus healthy resident stem cells (SCs). Unfortunately, dysregulated pathways that support ...transformed CSCs, such as Wnt/β-catenin signaling, are also critical regulators of healthy SCs. Using the ICG-001 and CWP family of small molecules, we reveal Sam68 as a previously unappreciated modulator of Wnt/β-catenin signaling within CSCs. Disruption of CBP-β-catenin interaction via ICG-001/CWP induces the formation of a Sam68-CBP complex in CSCs that alters Wnt signaling toward apoptosis and differentiation induction. Our study identifies Sam68 as a regulator of human CSC vulnerability.
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•CWP selectively reduces self-renewal of patient-derived LSCs over healthy HSCs•ICG/CWP molecules induce Sam68/CBP complex formation that inhibits Wnt/β-catenin•Sam68 is specifically overexpressed in breast, blood, and colon CSCs•Sam68/CBP complexes uniquely form in CSCs to facilitate selectivity
Benoit et al. provide a framework to understand the selective targeting of cancer stem cells by the ICG-001/CWP family of molecules. Their findings highlight Sam68 as an unappreciated regulator of unique responses of cancer stem cells versus normal healthy stem cells.
Toll-like receptor (TLR) signaling regulates macrophage activation and effector cytokine propagation in the constrained environment of a tissue. In macrophage populations, TLR4 stimulates the ...dose-dependent transcription of nuclear factor κB (NF-κB) target genes. However, using single-RNA counting, we found that individual cells exhibited a wide range (three orders of magnitude) of expression of the gene encoding the proinflammatory cytokine tumor necrosis factor-α (TNF-α). The TLR4-induced
transcriptional response correlated with the extent of NF-κB signaling in the cells and their size. We compared the rates of TNF-α production and uptake in macrophages and mouse embryonic fibroblasts and generated a mathematical model to explore the heterogeneity in the response of macrophages to TLR4 stimulation and the propagation of the TNF-α signal in the tissue. The model predicts that the local propagation of the TLR4-dependent TNF-α response and cellular NF-κB signaling are limited to small distances of a few cell diameters between neighboring tissue-resident macrophages. In our predictive model, TNF-α propagation was constrained by competitive uptake of TNF-α from the environment, rather than by heterogeneous production of the cytokine. We propose that the highly constrained architecture of tissues enables effective localized propagation of inflammatory cues while avoiding out-of-context responses at longer distances.
The neurophysiological mechanism of interhemispheric inhibition (IHI) between the human primary sensory cortices (S1s) is poorly understood. Here we used a paired median nerve somatosensory evoked ...potential protocol to observe S1-S1 IHI from the dominant to the nondominant hemisphere with electroencephalography. In 10 healthy, right-handed individuals, we compared mean peak-to-peak amplitudes of five somatosensory evoked potential components (P14/N20, N20/P25, P25/N30, N30/P40, and P40/N60) recorded over the right S1 after synchronous versus asynchronous stimulation of the right and left median nerves. Asynchronous conditioning + test stimuli (CS+TS) were delivered at interstimulus intervals of 15, 20, 25, 30, and 35 ms. We found that, in relation to synchronous stimulation, when a CS to the left S1 preceded a TS to the right S1 at the short intervals (15 and 20 ms) the amplitude of the cortical N20/P25 complex was significantly depressed, whereas at the longer intervals (25, 30, and 35 ms) significant inhibition was observed for the thalamocortical P14/N20 as well as the cortical N20/P25 components. We conclude that the magnitude of S1 IHI appears to depend on the temporal asynchrony of bilateral inputs and the specific timing is likely reflective of a direct transcallosal mechanism. Employing a method that enables direct S1 IHI to be reliably quantified may provide a novel tool to assess potential IHI imbalances in individuals with neurological damage, such as stroke.
Multidrug-resistant
Salmonella enterica serovar Typhimurium phage type DT104, resistant to ampicillin, chloramphenicol/florfenicol, streptomycin, sulfonamides, and tetracycline, has disseminated ...worldwide. The resistance genes reside on the 43-kb
Salmonella genomic island 1 (SGI1), which is transferable. Drug-resistant variants of SGI1 have been identified in numerous serotypes. Strains harboring SGI1 may be more virulent and have a tendency to rapidly disseminate.
Many insects host facultative, bacterial symbionts that confer conditional fitness benefits to their hosts. Hamiltonella defensa is a common facultative symbiont of aphids that provides protection ...against parasitoid wasps. Protection levels vary among strains of H. defensa that are also differentially infected by bacteriophages named APSEs. However, little is known about trait variation among strains because only one isolate has been fully sequenced. Generating complete genomes for facultative symbionts is hindered by relatively large genome sizes but low abundances in hosts like aphids that are very small. Here, we took advantage of methods for culturing H. defensa outside of aphids to generate complete genomes and transcriptome data for four strains of H. defensa from the pea aphid Acyrthosiphon pisum. Chosen strains also spanned the breadth of the H. defensa phylogeny and differed in strength of protection conferred against parasitoids. Results indicated that strains shared most genes with roles in nutrient acquisition, metabolism, and essential housekeeping functions. In contrast, the inventory of mobile genetic elements varied substantially, which generated strain specific differences in gene content and genome architecture. In some cases, specific traits correlated with differences in protection against parasitoids, but in others high variation between strains obscured identification of traits with likely roles in defense. Transcriptome data generated continuous distributions to genome assemblies with some genes that were highly expressed and others that were not. Single molecule real-time sequencing further identified differences in DNA methylation patterns and restriction modification systems that provide defense against phage infection.
Integrity of the corticospinal tract (CST) is an important biomarker for upper limb motor function following stroke. However, when structurally compromised, other tracts may become relevant for ...compensation or recovery of function.
We used the ENIGMA Stroke Recovery data set, a multicenter, retrospective, and cross-sectional collection of patients with upper limb impairment during the chronic phase of stroke to test the relevance of tracts in individuals with less and more severe (laterality index of CST fractional anisotropy ≥0.25) CST damage in an observational study design. White matter integrity was quantified using fractional anisotropy for the CST, the superior longitudinal fascicle, and the callosal fibers interconnecting the primary motor cortices between hemispheres. Optic radiations served as a control tract as they have no a priori relevance for the motor system. Pearson correlation was used for testing correlation with upper limb motor function (Fugl-Meyer upper extremity).
From 1235 available data sets, 166 were selected (by imaging, Fugl-Meyer upper extremity, covariates, stroke location, and stage) for analyses. Only individuals with severe CST damage showed a positive association of fractional anisotropy in both callosal fibers interconnecting the primary motor cortices (
21=0.49;
0.025) and superior longitudinal fascicle (
21=0.51;
.018) with Fugl-Meyer upper extremity.
Our data support the notion that individuals with more severe damage of the CST depend on residual pathways for achieving better upper limb outcome than those with less affected CST.
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