Biology subjects

Kim, S. H.

Publications and source records attributed to Kim, S. H..

At least 109 records · Page 6Linked to original sources

bioRxiv2021

The responsiveness of gait and balance outcomes to disease progression in Friedreich ataxia

ObjectiveTo identify gait and balance measures that are responsive to change during the timeline of a clinical trial in Friedreich ataxia (FRDA) we administered a battery of potential measures three times over a 12-month period. MethodsSixty-one ambulant individuals with FRDA underwent assessment of gait and balance at baseline, six months and 12 months. Outcomes included: GAITRite(R) spatiotemporal gait parameters; Biodex Balance System Postural Stability Test (PST) and Limits of Stability; Berg Balance Scale (BBS); Timed 25 Foot Walk Test; Dynamic Gait Index (DGI); SenseWear MF Armband step and energy activity; and the Friedreich Ataxia Rating Scale Upright Stability Subscale (FARS USS). The standardised response mean (SRM) or correlation coefficients were reported as effect size indices for comparison of internal responsiveness. Internal responsiveness was also analysed in subgroups. ResultsSenseWear Armband daily step count had the largest effect size of all the variables over six months (SRM=-0.615), while the PST medial-lateral index had the largest effect size (SRM=0.829) over 12 months. The FARS USS (SRM=0.824) and BBS (SRM=-0.720) were the only outcomes able to detect change over 12 months in all subgroups. The DGI was the most responsive outcome in children, detecting a mean change of -2.59 (95% CI -3.52 to -1.66, p<0.001, SRM=-1.429). ConclusionsThe FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.

neuroscience↗

bioRxiv2021

Robust T1 MRI cortical surface pipeline for neonatal brain and systematic evaluation using multi-site MRI datasets

The human brain grows the most dramatically during the perinatal and early postnatal periods, during which preterm birth or perinatal injury that may alter brain structure and lead to developmental anomalies. Thus, characterizing cortical thickness of developing brains remains an important goal. However, this task is often complicated by inaccurate cortical surface extraction due to small-size brains. Here, we propose a novel complex framework for the reconstruction of neonatal WM and pial surfaces, accounting for large partial volumes due to small-size brains. The proposed approach relies only on T1-weighted images unlike previous T2-weighted image-based approaches while only T1-weighted images are sometimes available under the different clinical/research setting. Deep neural networks are first introduced to the neonatal MRI pipeline to address the mis-segmentation of brain tissues. Furthermore, this pipeline enhances cortical boundary delineation using combined models of the CSF/GM boundary detection with edge gradient information and a new skeletonization of sulcal folding where no CSF voxels are seen due to the limited resolution. We also proposed a systematic evaluation using three independent datasets comprising 736 preterm and 97 term neonates. Qualitative assessment for reconstructed cortical surfaces shows that 86.9% are rated as accurate across the three site datasets. In addition, our landmark-based evaluation shows that the mean displacement of the cortical surfaces from the true boundaries was less than a voxel size (0.532{+/-}0.035mm). Evaluating the proposed pipeline (namely NEOCIVET 2.0) shows the robustness and reproducibility across different sites and different age-groups. The mean cortical thickness measured positively correlated with postmenstrual age (PMA) at scan (p<0.0001); Cingulate cortical areas grew the most rapidly whereas the inferior temporal cortex grew the least rapidly. The range of the cortical thickness measured was biologically congruent (1.3mm at 28 weeks of PMA to 1.8mm at term equivalent). Cortical thickness measured on T1 MRI using NEOCIVET 2.0 was compared with that on T2 using the established dHCP pipeline. It was difficult to conclude that either T1 or T2 imaging is more ideal to construct cortical surfaces. NEOCIVET 2.0 has been open to the public through CBRAIN (https://mcin-cnim.ca/technology/cbrain/), a web-based platform for processing brain imaging data.

bioinformatics↗

bioRxiv2020

Atypical Mediofrontal Theta Oscillations Underlying Cognitive Control in Kindergarteners with Autism Spectrum Disorder

BackgroundChildren with autism spectrum disorder (ASD) often exhibit deficits in cognitive control. Neuroimaging approaches have implicated disruptions to medio-frontal cortex (MFC) structure and function. However, prior work has not directly tested whether young children with ASD exhibit disruptions to task-related theta oscillations thought to arise from the MFC. MethodsForty-three children with ASD and 24 age- and gender-matched typically developing (TD) peers performed a child-friendly Go/No-go task while 64-channel electroencephalography (EEG) was recorded at kindergarten-entry. Time-frequency approaches were employed to assess the magnitude of mediofrontal theta oscillations immediately following error (vs. correct) responses ("early theta"), as well as later emerging theta oscillations ("late theta"). We tested whether error-related mediofrontal theta oscillations differed as a function of diagnosis (ASD/typical) and timing (early/late theta). Additionally, links to social and academic outcomes were tested. ResultsOverall, children showed increased theta power following error vs. correct responses. Compared to TD children, children with ASD exhibited a selective reduction in error-related mediofrontal theta power during the late theta time window. There were no significant group differences for early theta power. Moreover, reduced error-related theta power during the late, but not early, time window significantly predicted poorer academic and social skills. ConclusionsKindergarteners with ASD demonstrated a selective reduction in error-related mediofrontal theta power during a relatively late time window, which is consistent with impairments in specific cognitive processes that recruit top-down control. Targeting these particular cognitive control processes via intervention prior to school-entry may promote more successful functional outcomes for children with ASD.

neuroscience↗

bioRxiv2020

Encoding multiple virtual signals in DNA barcodes with single-molecule FRET

DNA barcoding provides a way to label a huge number of different biological molecules using the extreme programmability in DNA sequence synthesis. Fluorescence imaging is an easy-to-access method to detect individual DNA barcodes, which can be scaled up to a massively high-throughput format. Large overlaps between emission spectra of fluorescence dyes, however, severely limit the numbers of DNA barcodes-and thus its signal space-that can be detected in a simultaneous manner. We here demonstrate the use of single-molecule fluorescence resonance energy transfer (FRET) to encode virtual signals in DNA barcodes using conventional two-color fluorescence microscopy. By optimizing imaging and biochemistry conditions for weak hybridization events for DNA barcodes, we markedly enhanced accuracy in our determination of the efficiency by which single-molecule FRET occurred. This allowed us to unambiguously differentiate six DNA barcodes exhibiting different FRET values without involving probe sequence exchanges. Our method can be directly incorporated with previous DNA barcode techniques, and may thus be widely adopted to expand the signal space of the DNA barcode techniques.

biophysics↗

bioRxiv2020

TRAF6 and TAK1 contribute to SAMHD1-mediated negative regulation of NF-kB signaling

Sterile alpha motif and HD-domain-containing protein 1 (SAMHD1) restricts HIV-1 replication by limiting the intracellular dNTP pool. SAMHD1 also suppresses the activation of NF-{kappa}B in response to viral infections and inflammatory stimuli. However, the mechanisms by which SAMHD1 negatively regulates this pathway remain unclear. Here we show that SAMHD1-mediated suppression of NF-{kappa}B activation is modulated by two key mediators of NF-{kappa}B signaling, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and transforming growth factor-{beta}-activated kinase-1 (TAK1). We compared NF-{kappa}B activation stimulated by interleukin (IL)-1{beta} in monocytic THP-1 control and SAMHD1 knockout (KO) cells with and without partial TRAF6 knockdown (KD), or in cells treated with TAK1 inhibitors. Relative to control cells, IL-1{beta}-treated SAMHD1 KO cells showed increased phosphorylation of the inhibitor of NF-{kappa}B (I{kappa}B), an indication of pathway activation, and elevated levels of TNF- mRNA. Moreover, SAMHD1 KO combined with TRAF6 KD or pharmacological TAK1 inhibition reduced I{kappa}B phosphorylation and TNF- mRNA to the level of control cells. SAMHD1 KO cells infected with single-cycle HIV-1 showed elevated infection and TNF- mRNA levels compared to control cells, and the effects were significantly reduced by TRAF6 KD or TAK1 inhibition. We further demonstrated that overexpressed SAMHD1 inhibited TRAF6-stimulated NF-{kappa}B reporter activity in HEK293T cells in a dose-dependent manner. SAMHD1 contains a nuclear localization signal (NLS), but an NLS-defective SAMHD1 exhibited a suppressive effect similar to the wild-type protein. Our data suggest that the TRAF6-TAK1 axis contributes to SAMHD1-mediated suppression of NF-{kappa}B activation and HIV-1 infection. ImportanceCells respond to pathogen infection by activating a complex innate immune signaling pathway, which culminates in the activation of transcription factors and secretion of a family of functionally and genetically related cytokines. However, excessive immune activation may cause tissue damage and detrimental effects on the host. Therefore, in order to maintain host homeostasis, the innate immune response is tightly regulated during viral infection. We have reported SAMHD1 as a novel negative regulator of the innate immune response. Here, we provide new insights into SAMHD1-mediated negative regulation of the NF-{kappa}B pathway at the TRAF6-TAK1 checkpoint. We show that SAMHD1 inhibits TAK1 activation and TRAF6 signaling in response to proinflammatory stimuli. Interestingly, TRAF6 knockdown in SAMHD1-deficient cells significantly inhibited HIV-1 infection and activation of NF-{kappa}B induced by virus infection. Our research reveals a new negative regulatory mechanism by which SAMHD1 participates in the maintenance of cellular homeostasis during HIV-1 infection and inflammation.

microbiology↗

bioRxiv2020

High-Resolution Single-Molecule FRET via DNA eXchange (FRET X)

Single-molecule FRET is a versatile tool to study nucleic acids and proteins at the nanometer scale. However, currently, only a couple of FRET pairs can be reliably measured on a single object. The limited number of available FRET pair fluorophores and complicated data analysis makes it challenging to apply single-molecule FRET for structural analysis of biomolecules. Currently, only a couple of FRET pairs can be reliably measured on a single object. Here we present an approach that allows for the determination of multiple distances between FRET pairs in a single object. We use programmable, transient binding between short DNA strands to resolve the FRET efficiency of multiple fluorophore pairs. By allowing only a single FRET pair to be formed at a time, we can determine the FRET efficiency and pair distance with sub-nanometer resolution. We determine the distance between other pairs by sequentially exchanging DNA strands. We name this multiplexing approach FRET X for FRET via DNA eXchange. We envision that our FRET X technology will be a tool for the high-resolution structural analysis of biomolecules and other nano-structures.

biophysics↗

bioRxiv2020

MFG-E8 Signaling Promotes Elastolysis and Calcification in the Aging Aortic Wall

Milk fat globule-EGF factor 8 (MFG-E8) protein increases with age and is mainly secreted by vascular smooth muscle cells in the arterial wall. Here, we investigated the role of MFG-E8 signaling during proinflammation, elastolysis, fibrosis, and calcification within the aging arterial wall. In vivo studies indicated that (1) Elastic lamina breaks collagen deposition and calcium-phosphorus products were markedly increased in the aging arterial wall of rats; (2) MFG-E8 protein abundance was markedly increased while intact tropoelastin (TPELN), an element of repair of the elastic fibers, was markedly decreased in the aging arterial wall of rats; (3) The absence of MFG-E8 markedly alleviated age-associated increases in elastic lamina breaks, collagen deposition and calcium-phosphorus products in mice; and (4) MFG-E8 deficiency significantly decreased age-associated increases in matrix metalloproteinase type II (MMP-2) activation, alkaline phosphatase, and runt-related transcription factor 1 (Runx1) expression in the aortic walls of mice. The in vitro studies demonstrated that (1) treating either young or old rat VSMCs with recombinant human MFG-E8 protein (rhMFG-E8) significantly reduced TPELN levels while MFG-E8 gene silencing significantly increased TPELN levels; (2) rhMFG-E8 treatment activated MMP-2 levels in both young and old VSMCs; and (3) MMP-2 bound to and cleaved TPELN secreted from VSMCs. Thus, these findings suggest that MFG-E8 signaling promotes age-associated adverse structural remodeling, including elastolysis, fibrosis, and calcification; however, MFG-E8 deficiency markedly mitigates these adverse effects in mice.

pathology↗

bioRxiv2020

FRETboard: semi-supervised classification of FRET traces

AO_SCPLOWBSTRACTC_SCPLOWForster resonance energy transfer (FRET) is a useful phenomenon in biomolecular investigations, as it can be leveraged for nano-scale measurements. The optical signals produced by such experiments can be analyzed by fitting a statistical model. Several software tools exist to fit such models in an unsupervised manner, but their operating system-dependent installation requirements and lack of flexibility impede wide-spread adoption. Here we propose to fit such models more efficiently and intuitively by adopting a semi-supervised approach, in which the user interactively guides the model to fit a given dataset, and introduce FRETboard, a web tool that allows users to provide such guidance. We show that our approach is able to closely reproduce ground truth FRET statistics in a wide range of simulated single-molecule scenarios, and correctly estimate parameters for up to eleven states. On in vitro data we retrieve parameters identical to those obtained by laborious manual classification in a fraction of the required time. Moreover, we designed FRETboard to be easily extendable to other models, allowing it to adapt to future developments in FRET measurement and analysis. Availabilitysource code is available at https://github.com/cvdelannoy/FRETboard. The FRETboard classification tool is also available as a browser application at https://www.bioinformatics.nl/FRETboard.

biophysics↗

bioRxiv2020

Dual-Mechanism Estrogen Receptor Inhibitors Reveal an Ensemble of Binding Modes for Robust Breast Cancer Antagonism

Efforts to improve estrogen receptor-a (ER)-targeted therapies in breast cancer have relied upon a single mechanism, with ligands having a single side chain on the ligand core that extends outward to determine antagonism of breast cancer growth. Here, we describe inhibitors with two ER-targeting moieties, one of which uses an alternate structural mechanism to generate full antagonism, freeing the side chain to independently determine other critical properties of the ligands. By combining two molecular targeting approaches into a single ER ligand, we have generated antiestrogens that function through new mechanisms and structural paradigms to achieve antagonism. These dual-mechanism ER inhibitors (DMERIs) cause alternate, non-canonical structural perturbations of the receptor ligand-binding domain (LBD) to drive antagonism of proliferation in ER-positive breast cancer cells and in allele-specific resistance models. Solution structural and coregulator peptide binding analyses with DMERIs highlight marked differences from current standard-of-care, single-mechanism antiestrogens. These findings uncover an enhanced flexibility of the ER LBD through which it can access non-consensus conformational modes in response to DMERI binding, broadly and effectively suppressing ER activity. Significance StatementTo address the unmet clinical need for effectively suppressing estrogen receptor (ER) activity with both de novo resistance and in advanced ER-positive breast cancers that are resistant to standard-of-care antiestrogens, we have developed dual-mechanism ER inhibitors (DMERIs) that employ two distinct ER targeting moieties. These DMERI elicited non-canonical structural perturbations of the receptor ligand-binding domain and stabilized multiple antagonist sub-states within the dimer to generate highly efficacious antagonism of proliferation in ER-positive breast cancer cells and in allele-specific resistance models. This work reveals new conformational modes by which the activity of ER can be effectively suppressed to block breast cancer proliferation.

cancer biology↗

bioRxiv2020

LFA-1 signals to promote actin polymerization and upstream migration in T cells

T cell entry into inflamed tissue requires firm adhesion, cell spreading, and migration along and through the endothelial wall. These events require the T cell integrins LFA-1 and VLA-4 and their endothelial ligands ICAM-1 and VCAM-1, respectively. T cells migrate against the direction of shear flow on ICAM-1 and with the direction of shear flow on VCAM-1, suggesting that these two ligands trigger distinct cellular responses. However, the contribution of specific signaling events downstream of LFA-1 and VLA-4 has not been explored. Using primary mouse T cells, we found that engagement of LFA-1, but not VLA-4, induces cell shape changes associated with rapid 2D migration. Moreover, LFA-1 ligation results in activation of the PI3K and ERK pathways, and phosphorylation of multiple kinases and adaptor proteins, while VLA-4 ligation triggers only a subset of these signaling events. Importantly, T cells lacking Crk adaptor proteins, key LFA-1 signaling intermediates, or the ubiquitin ligase cCbl, failed to migrate against the direction of shear flow on ICAM-1. These studies identify novel signaling differences downstream of LFA-1 and VLA-4 that drive T cell migratory behavior. Summary StatementInflammatory responses require leukocyte migration along the vascular wall. We show that signaling from {beta}2, but not {beta}1, integrins induces cytoskeletal changes needed for upstream migration under shear flow.

cell biology↗

bioRxiv2020

Fused in sarcoma regulates DNA replication timing and progression

Fused in sarcoma (FUS) encodes a low complexity RNA-binding protein with diverse roles in transcriptional activation and RNA processing. While oncogenic fusions of FUS and transcription factor DNA-binding domains are associated with soft tissue sarcomas, dominant mutations in FUS cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). FUS has also been implicated in DNA double-strand break repair (DSBR) and genome maintenance. However, the underlying mechanisms are unknown. Here we employed quantitative proteomics, transcriptomics, and DNA copy number analysis (Sort-Seq), in conjunction with FUS-/- cells to ascertain roles of FUS in genome protection. FUS-/- cells exhibited alterations in the recruitment and retention of DSBR factors BRCA1 and 53BP1 but were not overtly sensitive to genotoxins. By contrast, FUS-deficient cells had reduced proliferative potential that correlated with reduced replication fork speed, diminished loading of pre-replication complexes, and attenuated expression of S-phase associated genes. FUS interacted with lagging strand DNA synthesis factors and other replisome components, but did not translocate with active replication forks. Using a Sort-Seq workflow, we show that FUS contributes to genome-wide control of DNA replication timing and is essential for the early replication of transcriptionally active DNA. These findings illuminate new roles for FUS in DNA replication initiation and timing that may contribute to genome instability and functional defects in cells harboring disease-associated FUS fusions.

genomics↗

bioRxiv2020

Successful Correction of ALD Patient-derived iPSCs Using CRISPR/Cas9

X-linked adrenoleukodystrophy (ALD) caused by the ABCD1 mutation, is the most common inherited peroxisomal disease. It is characterized by three phenotypes: inflammatory cerebral demyelination, progressive myelopathy, and adrenal insufficiency, but there is no genotype-phenotype correlation. Hematopoietic stem cell transplantation can only be used in a few patients in the early phase of cerebral inflammation; therefore, most affected patients have no curative option. Previously, we reported the generation of an ALD patient-derived iPSC model and its differentiation to oligodendrocytes. In this study, we have performed the first genome editing of ALD patient-derived iPSCs using homology-directed repair (HDR). The mutation site, c.1534G>A [GenBank: NM_000033.4], was corrected by introducing ssODN and the CRISPR/Cas9 system. The cell line exhibited normal ALD protein expression following genome editing. We differentiated the intermediate oligodendrocytes from mutation-corrected iPSCs and the metabolic derangement of ALD tended to correct but was not statistically significant. Mutation-corrected iPSCs from ALD patient can be used in research into the pathophysiology of and therapeutics for ALD.

neuroscience↗

bioRxiv2019

Metastatic function of METTL18 in breast cancer via actin methylation and Src

Recently, a SET domain containing 3 (SETD3) was identified as an actin histidine methyltransferase, functioning to control replication and pathogenesis in multiple mouse models for enterovirus infection as well as the regulation of smooth muscle contractility linked to primary dystocia. Here, in this study, we report another type of actin histidine methyltransferase, METTL18, that regulates the metastatic potential of breast cancer in human. Among methyltransferases, METTL18 was highly amplified in human breast cancer. In particular, poor prognosis was associated with high expression of METTL18 in HER2-negative breast cancer patients. This gene product was also found to be a critical component of metastatic responses. Loss of METTL18 expression significantly reduced metastatic responses of breast tumor cells both in vitro and in vivo. Mechanistically, it was observed that METTL18 increased actin polymerization, upregulated complex formation with HSP90AA1 and Src, enhanced the activity of an intermediate form of Src with tyrosine phosphorylation at both Y416 and Y527, and induced cellular metastatic responses, including morphological change, migration, and invasion of MDA-MB-231 cells in vitro and in mice. Methylated actin at His73 served as a critical site for interaction with HSP90AA1 and Src to activate p85/PI3K and STAT3. Our findings suggest that METTL18 plays critical roles in metastatic responses of HER2-negative breast cancer cells via actin polymerization and the generation of an intermediate form of Src.

cancer biology↗

bioRxiv2019

Glioma-induced alterations in neuronal activity and neurovascular coupling during disease progression

Diffusely infiltrating gliomas are known to cause alterations in cortical function, vascular disruption and seizures. These neurological complications present major clinical challenges, yet their underlying mechanisms and causal relationships to disease progression are poorly characterized. Here, we followed glioma progression in awake Thy1-GCaMP6f mice using in-vivo wide-field optical mapping to monitor alterations in both neuronal activity and functional hemodynamics. The bilateral synchrony of spontaneous neuronal activity in glioma-infiltrated cortex gradually decreased, while neurovascular coupling was also progressively disrupted compared to uninvolved cortex. Over time, mice developed diverse patterns of high amplitude discharges and eventually generalized seizures that begin at the infiltrative margin of the tumors. Interictal and seizure events exhibited positive neurovascular coupling in uninfiltrated cortex, however glioma-infiltrated regions exhibited inverted hemodynamic responses driving seizure-evoked hypoxia. These results reveal a landscape of complex physiological interactions occurring during glioma progression and present new opportunities for exploring new biomarkers and therapeutic targets.\n\nHighlights- Glioma disrupts neural synchrony between bilateral cortical regions.\n- WFOM reveals frequent interictal discharges and seizures during glioma progression.\n- Tumor development is accompanied by local changes in neurovascular coupling.\n- Altered neurovascular coupling drives hypoperfusion of the tumor during seizures.

neuroscience↗

bioRxiv2019

SEQUIN multiscale imaging of mammalian central synapses reveals loss of synaptic microconnectivity resulting from diffuse traumatic brain injury

The complex microconnectivity of the mammalian brain underlies its computational abilities, and its vulnerability to injury and disease. It has been challenging to illuminate the features of this synaptic network due in part to the small size and exceptionally dense packing of its elements. Here we describe a rapid and accessible super-resolution imaging and image analysis workflow--SEQUIN--that identifies, quantifies, and characterizes central synapses in animal models and in humans, enabling automated volumetric imaging of mesoscale synaptic networks without the laborious production of large histological arrays. Using SEQUIN, we identify delayed cortical synapse loss resulting from diffuse traumatic brain injury. Similar synapse loss is observed in an Alzheimer disease model, where SEQUIN mesoscale mapping of excitatory synapses across the hippocampus identifies region-specific synaptic vulnerability to neurodegeneration. These results establish a novel, easily implemented and robust nano-to-mesoscale synapse quantification and molecular characterization method. They furthermore identify a mechanistic link--synaptopathy--between Alzheimer neurodegeneration and its best-established epigenetic risk factor, brain trauma.

neuroscience↗

bioRxiv2019

Localized semi-nonnegative matrix factorization (LocaNMF) of widefield calcium imaging data

Widefield calcium imaging enables recording of large-scale neural activity across the mouse dorsal cortex. In order to examine the relationship of these neural signals to the resulting behavior, it is critical to demix the recordings into meaningful spatial and temporal components that can be mapped onto well-defined brain regions. However, no current tools satisfactorily extract the activity of the different brain regions in individual mice in a data-driven manner, while taking into account mouse-specific and preparation-specific differences. Here, we introduce Localized semi-Nonnegative Matrix Factorization (LocaNMF), a method that efficiently decomposes widefield video data and allows us to directly compare activity across multiple mice by outputting mouse-specific localized functional regions that are significantly more interpretable than more traditional decomposition techniques. Moreover, it provides a natural subspace to directly compare correlation maps and neural dynamics across different behaviors, mice, and experimental conditions, and enables identification of task- and movement-related brain regions.

neuroscience↗

bioRxiv2018

Neural Dynamics of Executive Function in Cognitively-able Kindergarteners with Autism Spectrum Disorders (ASD) as Predictors of Concurrent Academic Achievement: Preliminary Study

Although electrophysiological (EEG) measures of executive functions (EF) (e.g. error monitoring) have been used to predict academic achievement in typically developing (TD) children, work investigating a link between error monitoring, and academic skills in children with autism spectrum disorder (ASD) is limited. In the current study, we employed traditional electrophysiological and advanced time-frequency methods, combined with principal components analyses, to extract neural activity related to error monitoring, and tested their relations to academic achievement in cognitively-able kindergarteners with ASD. Thirty-five cognitively-able kindergarteners with ASD completed academic assessments and the child-friendly \"Zoo Game\" Go/No-go task at school entry. The Go/No-go task successfully elicited an error-related negativity (ERN) and error positivity (Pe) in children with ASD as young as 5 years at medio-frontal and posterior electrode sites, respectively. We also observed increased response-related theta power during errors relative to correct trials at medio-frontal sites. Both larger Pe and theta power significantly predicted concurrent academic achievement after controlling for behavioral performance on the Zoo Game and IQ. These results suggest that the use of time frequency EEG analyses, combined with traditional ERP measures, may provide new opportunities to investigate neurobiological mechanisms of EF and academic achievement in young children with ASD.

neuroscience↗

bioRxiv2018

Pasakbumin A controls the growth of Mycobacterium tuberculosis by enhancing the autophagy and production of antibacterial mediators in mouse macrophages

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb) and remains a major health problem worldwide. Thus, there is an urgent need to identify new and more effective drugs to treat emerging multidrug-resistant TB (MDR-TB) and to reduce the side effects of anti-TB drugs, such as liver toxicity and other detrimental changes. In this study, to develop a novel candidate drug for effective TB treatment with few side effects in the host, we selected pasakbumin A isolated from Eurycoma longifolia (E. longifolia) Jack, which protected host cells against Mtb infection-induced death. Pasakbumin A significantly inhibited intracellular Mtb growth by inducing autophagy via the ERK1/2-mediated signaling pathway in Mtb-infected macrophages. We further investigated whether pasakbumin A could be used as a potential adjuvant for TB treatment. Treatment with pasakbumin A and the anti-TB drug rifampicin (RMP) potently suppressed intracellular Mtb killing by promoting autophagy as well as TNF- production via the ERK1/2- and NF-{kappa}B-mediated signaling pathways in Mtb-infected cells. Our results suggest that pasakbumin A could be developed as a novel anti-TB drug or host-directed therapeutic (HDT) strategy to protect against host cell death and improve host defense mechanisms against Mtb infection in macrophages.

immunology↗