Neural substrates underlying effortful control deficit in autism spectrum disorder: a meta-analysis of fMRI studies.

Effortful control comprises attentional control, inhibitory control, and cognitive flexibility subprocesses. Effortful control is impaired in individuals with autism spectrum disorder, yet its neural underpinnings remain elusive. By conducting a coordinate-based meta-analysis, this study compared the brain activation patterns between autism and typically developing individuals and examined the effect of age on brain activation in each effortful control subprocesses. Meta-analytic results from 22 studies revealed that, individuals with autism showed hypoactivation in the default mode network for tasks tapping inhibitory control functioning (threshold-free cluster enhancement p < 0.001). When these individuals perform tasks tapping attentional control and cognitive flexibility, they exhibited aberrant activation in various brain networks including default mode network, dorsal attention, frontoparietal, visual and somatomotor networks (uncorrected ps < 0.005). Meta-regression analyses revealed that brain regions within the default mode network showed a significant decreasing trend in activation with increasing age (uncorrected p < 0.05). In summary, individuals with autism showed aberrant activation patterns across multiple brain functional networks during all cognitive tasks supporting effortful control, with some regions showing a decrease in activation with increasing age.

MG53 preserves mitochondrial integrity of cardiomyocytes during ischemia reperfusion-induced oxidative stress.

Ischemic injury to the heart induces mitochondrial dysfunction due to increasing oxidative stress. MG53, also known as TRIM72, is highly expressed in striated muscle, is secreted as a myokine after exercise, and is essential for repairing damaged plasma membrane of many tissues by interacting with the membrane lipid phosphatidylserine (PS). We hypothesized MG53 could preserve mitochondrial integrity after an ischemic event by binding to the mitochondrial-specific lipid, cardiolipin (CL), for mitochondria protection to prevent mitophagy. Fluorescent imaging and Western blotting experiments showed recombinant human MG53 (rhMG53) translocated to the mitochondria after ischemic injury in vivo and in vitro. Fluorescent imaging indicated rhMG53 treatment reduced superoxide generation in ex vivo and in vitro models. Lipid-binding assay indicated MG53 binds to CL. Transfecting cardiomyocytes with the mitochondria-targeted mt-mKeima showed inhibition of mitophagy after MG53 treatment. Overall, we show that rhMG53 treatment may preserve cardiac function by preserving mitochondria in cardiomyocytes. These findings suggest MG53's interactions with mitochondria could be an attractive avenue for developing MG53 as a targeted protein therapy for cardioprotection.

Abnormal Prefrontal Functional Connectivity Is Associated with Inflexible Information Processing in Patients with Autism Spectrum Disorder (ASD): An fNIRS Study.

Individuals with autism spectrum disorder (ASD) are characterized by impairments in flexibly acquiring and maintaining new information, as well as in applying learned information for problem solving. However, the neural mechanism underpinning such impairments remains unclear. This study investigated the flexibility in the acquisition and application of visual information in ASD (aged 14−21) when they performed the Wisconsin Card Sorting Test (WCST). Behavioral data including response accuracy and latency, and prefrontal hemodynamic data measured by functional near-infrared spectroscopy (fNIRS), were collected when individuals performed WCST. Canonical general linear model and functional connectivity analyses were performed to examine the prefrontal activation and synchronization patterns, respectively. Results showed that although ASD individuals (n = 29) achieved comparable accuracy rates when compared with age- and intelligence quotient (IQ)-matched typically developing (TD; n = 26) individuals (F1,53 = 3.15, p = 0.082), ASD individuals needed significantly more time to acquire and apply WCST card sorting rules (F1,53 = 17.92, p < 0.001). Moreover, ASD individuals showed significantly lower prefrontal functional connectivity than TD individuals during WCST (F1,42 = 9.99, p = 0.003). The hypoconnectivity in ASD individuals was highly significant in the right lateral PFC in the acquisition condition (p = 0.005) and in the bilateral lateral PFC in the application condition (ps = 0.006). Furthermore, slower WCST reaction time was correlated with lower bilateral lateral PFC functional connectivity only in the application condition (ps = 0.003) but not the acquisition condition. Impairment in information acquisition and application is evident in ASD individuals and is mediated by processing speed, which is associated with lower functional connectivity in the bilateral lateral PFC when these individuals apply learned rules to solve novel problems.

Neurophysiological and behavioral effects of multisession prefrontal tDCS and concurrent cognitive remediation training in patients with autism spectrum disorder (ASD): A double-blind, randomized controlled fNIRS study.

BACKGROUND: The clinical effects and neurophysiological mechanisms of prefrontal tDCS and concurrent cognitive remediation training in individuals with autism spectrum disorder (ASD) remain unclear. OBJECTIVE: This two-armed, double-blind, randomized, sham-controlled trial aimed to investigate the beneficial effects of tDCS combined with concurrent cognitive remediation training on adolescents and young adults with ASD. METHODS: Participants were randomly assigned to either active or sham tDCS groups and received 1.5 mA prefrontal tDCS with left dorsolateral prefrontal cortex (dlPFC) cathode placement and right supraorbital region anode placement for 20 minutes over two consecutive weeks. tDCS was delivered concurrently with a computerized cognitive remediation training program. Social functioning and its underlying cognitive processes, as well as prefrontal resting-state functional connectivity (rsFC), were measured. RESULTS: The results from 41 participants indicated that multisession prefrontal tDCS, compared to sham tDCS, significantly enhanced the social functioning of ASD individuals [F(1,39) = 4.75, p = .035, ηp2 = 0.11]. This improvement was associated with enhanced emotion recognition [F(1,39) = 8.34, p = .006, ηp2 = 0.18] and cognitive flexibility [F(1,39) = 4.91, p = .033, ηp2 = 0.11]. Specifically, this tDCS protocol optimized information processing efficiency [F(1,39) = 4.43, p = .042, ηp2 = 0.10], and the optimization showed a trend to be associated with enhanced rsFC in the right medial prefrontal cortex (ρ = 0.339, pFDR = .083). CONCLUSION: Multisession tDCS with left dlPFC cathode placement and right supraorbital region anode placement paired with concurrent cognitive remediation training promoted social functioning in individuals with ASD. This appeared to be associated with the enhancement of the functional connectivity of the right medial PFC, a major hub for flexible social information processing, allowing these individuals to process information more efficiently in response to different social situations. TRIAL REGISTRATION: ClinicalTrials.gov (ID: NCT03814083).

Effortful Control and Prefrontal Cortex Functioning in Children with Autism Spectrum Disorder: An fNIRS Study.

Effortful control (EC) is an important dimension of temperament, but is impaired in autism spectrum disorder (ASD). While EC is associated with the prefrontal cortex (PFC) functioning in typically developing (TD) children, it is unclear whether EC deficits are associated with PFC dysfunction in ASD. This study examines the relationship between EC and PFC activation and connectivity in children with high-functioning ASD. Thirty-nine right-handed children (ASD: n = 20; TD: n = 19) aged 8-12 years were recruited. The EC level was assessed with the Early Adolescent Temperament Questionnaire-Revised (EATQ-R), and PFC functioning, in terms of activation and connectivity during a frontal-sensitive (n-back) task, was assessed using functional near-infrared spectroscopy (fNIRS). Children with ASD showed a significant deficit in EC and its related constructs (i.e., executive, and socioemotional functions) compared to TD controls. They also showed significantly increased overall PFC activation and reduced right frontal connectivity during the n-back task. Among children with ASD, the EC level correlated significantly with neither PFC activation nor connectivity; it significantly correlated with social functioning only. This study demonstrated EC deficits and altered PFC functioning in children with ASD, but the exact neural basis of EC deficits remains to be determined.

Parents' perceptions of children's executive functions across different cities.

Culture is thought to strongly influence the development of executive functions (EF), such that ethnic groups with similar cultural origins are generally assumed to exhibit comparable levels of EF performance. However, other characteristics, such as urbanization and Westernization, may also affect EF performance in societies comprising different ethnic groups, even if the ethnic groups share a similar cultural origin. The present study aimed to compare the perceptions of parents in three cities [China-Shenzhen (ZH group), China-Hong Kong (HK group), and Singapore (SG group)] regarding the EF performances of their children, all of whom share the same genetic and cultural (i.e., Chinese) origin. The study recruited 95 children aged 5-6 years (ZH group = 32; HK group = 32; SG group = 31). Their parents were invited to complete the Behavior Rating Inventory of Executive Function (BRIEF). The ZH group had significantly lower BRIEF scores compared to both the HK and SG groups. However, the BRIEF scores of the HK and SG groups only differed significantly in terms of the Organization of Materials domain. The results suggest city-related differences in parents' perceptions of their children's EF performances, despite their similar genetic and cultural backgrounds. We additionally discuss further interpretations of our results and the limitations of this study.

Does Tai Chi improve balance and reduce falls incidence in neurological disorders? A systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of Tai Chi on balance and reducing falls incidence in neurological disorders. DATA SOURCES: AMED, Embase, Web of Science, SCOPUS, EBSCO and Medline from inception until February 2018. REVIEW METHOD: Randomized controlled trials of Tai Chi compared with active or no treatment control, measuring balance with the Berg Balance Scale or the Timed Up and Go Test and number of falls in neurological disorders were included. Methodological quality was assessed using PEDro and quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. RESULTS: A total of 10 studies involving 720 participants were reviewed. Seven studies were in Parkinson's disease and three in stroke. Seven studies were of high methodological quality and three were low. Meta-analyses of balance measured with the Timed Up and Go Test in Parkinson's disease revealed a statistically significant effect of Tai Chi compared to no treatment (weighted mean difference (WMD), -2.13; 95% confidence interval (CI), -3.26 to -1.00; P < 0.001) and was insignificant (WMD, -0.19; 95% CI, -1.74 to 1.35; P = 0.81) when compared with active treatment. Tai Chi significantly reduced falls incidence in Parkinson's disease (odds ratio (OR), 0.47; 95% CI, 0.29 to 0.77; P = 0.003) and stroke (OR, 0.21; 95% CI, 0.09 to 0.48; P < 0.001). Balance measured with the Timed Up and Go Test comparing Tai Chi and active treatment was insignificant (WMD, 0.45; 95% CI, -3.43 to 2.54; P = 0.77) in stroke. CONCLUSION: Tai Chi is effective in reducing falls incidence in Parkinson's disease and stroke. This systematic review did not find high-quality studies among other neurological disorders.

Francisella induced microparticulate caspase-1/gasdermin-D activation is regulated by NLRP3 independent of Pyrin.

Although the study of pathogen sensing by host defense systems continues to uncover a role for inflammasome components specific to particular pathogens, gaps remain in our knowledge. After internalization, Francisella escapes from the phagosome in mononuclear cells and is thought to be detected by intracellular pathogen-response-receptors pyrin and Aim2 in human and murine models, respectively. However, it remains controversial as to the role of pyrin in detecting Francisella. Our current work aims to study the contribution of inflammasome sensor, Pyrin in regulating microparticulate caspase-1/GSDM-D activation by Francisella. Our findings suggest that NLRP3 is central to the activation/release of active caspase-1/GSDM-D encapsulated in microparticles (MP) by Francisella. We also provide evidence that this regulation is independent of pyrin, implicated in sensing cytosolic Francisella in NLRP3-/- conditions where endogenous Pyrin is present. Absence of NLRP3 completely abrogated Francisella mediated MP caspase-1/GSDM-D activation and release both before and after internalization of the pathogen. However, deletion of pyrin not only enhanced both LPS and Francisella mediated MP active caspase-1/GSDM-D release, but pyrin overexpression resulted in a reduction of inflammasome activation and release; suggesting an inhibitory role of pyrin in LPS and Francisella mediated MP responses. This NLRP3 dependence and inhibitory effect of pyrin correlated with cytokine release as well. These observations also correlated with MPs ability to induce cell death; as LPS and Francisella-induced MPs from pyrin-deficient cells were more potent than wild-type monocytes whereas, NLRP3-/- MPs failed to induce cell death. Taken together, we report that NLPR3 not only mediates Francisella induced cytokine responses, but is also critical for cytokine-independent microparticle-induced inflammasome activation and endothelial cell injury independent of pyrin.

Heat shock factor-1 knockout enhances cholesterol 7α-hydroxylase (CYP7A1) and multidrug transporter (MDR1) gene expressions to attenuate atherosclerosis.

AIMS: Stress response, in terms of activation of stress factors, is known to cause obesity and coronary heart disease such as atherosclerosis in human. However, the underlying mechanism(s) of these pathways are not known. Here, we investigated the effect of heat shock factor-1 (HSF-1) on atherosclerosis. METHODS AND RESULTS: HSF-1 and low-density lipoprotein receptor (LDLr) double knockout (HSF-1(-/-)/LDLr(-/-)) and LDLr knockout (LDLr(-/-)) mice were fed with atherogenic western diet (WD) for 12 weeks. WD-induced weight gain and atherosclerotic lesion in aortic arch and carotid regions were reduced in HSF-1(-/-)/LDLr(-/-) mice, compared with LDLr(-/-) mice. Also, repression of PPAR-γ2 and AMPKα expression in adipose tissue, low hepatic steatosis, and lessened plasma adiponectins and lipoproteins were observed. In HSF-1(-/-)/LDLr(-/-) liver, higher cholesterol 7α-hydroxylase (CYP7A1) and multidrug transporter [MDR1/P-glycoprotein (P-gp)] gene expressions were observed, consistent with higher bile acid transport and larger hepatic bile ducts. Luciferase reporter gene assays with wild-type CYP7A1 and MDR1 promoters showed lesser luminescence than with mutant promoters (HSF-1 binding site deleted), indicating that HSF-1 binding is repressive of CYP7A1 and MDR1 gene expressions. CONCLUSION: HSF-1 ablation not only eliminates heat shock response, but it also transcriptionally up-regulates CYP7A1 and MDR1/P-gp axis in WD-diet fed HSF-1(-/-)/LDLr(-/-) mice to reduce atherosclerosis.

Rehabilitation Interventions for Poststroke Hand Oedema: A Systematic Review.

OBJECTIVE/BACKGROUND: To review the evidence of rehabilitation interventions for the management of poststroke hand oedema. METHODS: We conducted a systematic review of research articles in electronic databases published in English between 1999 and 2015. Two investigators working independently retrieved articles from the Cochrane Central Register of Controlled Trials, SCOPUS, Taylor & Francis Online, Wiley Online Library, CINAHL, Springer (MetaPress), ScienceDirect, PubMed, SAGE Journals Online, EBSCO, and Web of Science. Only controlled trials with outcome measures and interventions for poststroke hand oedema were included. Three investigators critically appraised the selected studies using the Physiotherapy Evidence Database Scale. RESULTS: Of the 189 articles identified, nine (5 randomized controlled trials, 3 nonrandomized controlled trials, and 1 crossover controlled trial) were selected. These studies are heterogeneous in terms of design and types of intervention for poststroke hand oedema. The interventions reducing hand oedema are Lycra pressure garments with glove splints, bilateral passive motion upper-limb exercises, laser therapy, and acupressure. However, due to these studies' short intervention periods and the fact that hand oedema is not their primary outcome measure, it is not possible to draw a firm conclusion on their clinical significance for managing poststroke hand oedema. CONCLUSION: Further study needs to focus solely on interventions for poststroke hand oedema and their long-term effects. No conclusion can be made on the most effective management of poststroke hand oedema until much more evidence is available.

Heat shock factor-1 knockout induces multidrug resistance gene, MDR1b, and enhances P-glycoprotein (ABCB1)-based drug extrusion in the heart.

Heat-shock factor 1 (HSF-1), a transcription factor for heat-shock proteins (HSPs), is known to interfere with the transcriptional activity of many oncogenic factors. In the present work, we have discovered that HSF-1 ablation induced the multidrug resistance gene, MDR1b, in the heart and increased the expression of P-glycoprotein (P-gp, ABCB1), an ATP binding cassette that is usually associated with multidrug-resistant cancer cells. The increase in P-gp enhanced the extrusion of doxorubicin (Dox) to alleviate Dox-induced heart failure and reduce mortality in mice. Dox-induced left ventricular (LV) dysfunction was significantly reduced in HSF-1(-/-) mice. DNA-binding activity of NF-κB was higher in HSF-1(-/-) mice. IκB, the NF-κB inhibitor, was depleted due to enhanced IκB kinase (IKK)-α activity. In parallel, MDR1b gene expression and a large increase in P-gp and lowering Dox loading were observed in HSF-1(-/-) mouse hearts. Moreover, application of the P-gp antagonist, verapamil, increased Dox loading in HSF-1(-/-) cardiomyocytes, deteriorated cardiac function in HSF-1(-/-) mice, and decreased survival. MDR1 promoter activity was higher in HSF-1(-/-) cardiomyocytes, whereas a mutant MDR1 promoter with heat-shock element (HSE) mutation showed increased activity only in HSF-1(+/+) cardiomyocytes. However, deletion of HSE and NF-κB binding sites diminished luminescence in both HSF-1(+/+) and HSF-1(-/-) cardiomyocytes, suggesting that HSF-1 inhibits MDR1 activity in the heart. Thus, because high levels of HSF-1 are attributed to poor prognosis of cancer, systemic down-regulation of HSF-1 before chemotherapy is a potential therapeutic approach to ameliorate the chemotherapy-induced cardiotoxicity and enhance cancer prognosis.

Heat shock protein 25-enriched plasma transfusion preconditions the heart against doxorubicin-induced dilated cardiomyopathy in mice.

Extracellular heat shock proteins (eHsps) in the circulation have recently been found to activate both apoptotic and protective signaling in the heart. However, the role of eHsps in doxorubicin (Dox)-induced heart failure has not yet been studied. The objective of the present study was to determine how Dox affects circulating eHsp25 in blood plasma and how eHsp25 affects Dox-induced dilated cardiomyopathy. Wild-type mice [HSF-1(+/+)] were pretreated with 100 µl of heterozygous heat shock factor-1 [HSF-1(+/-)] mouse plasma (which contained 4-fold higher eHsp25 compared with wild-type mice), HSF-1(+/+) plasma, or saline, before treatment with Dox (6 mg/kg). After 4 weeks of this treatment protocol, HSF-1(+/-) plasma-pretreated mice showed increased eHsp25 in plasma and improved cardiac function (percentage of fractional shortening 37.3 ± 2.1 versus 26.4 ± 4.0) and better life span (31 ± 2 versus 22 ± 3 days) compared with the HSF-1(+/+) plasma or saline-pretreated mice. Preincubation of isolated adult cardiomyocytes with HSF-1(+/-) plasma or recombinant human Hsp27 (rhHsp27) significantly reduced Dox-induced activation of nuclear factor-κB and cytokine release and delayed cardiomyocyte death. Moreover, when cardiomyocytes were incubated with fluorescence-tagged rhHsp27, a saturation in binding was observed, suggesting that eHsp25 can bind to surface receptors. Competitive assays with a Toll-like receptor 2 (TLR2) antibody reduced the rhHSP27 binding, indicating that Hsp25 interacts with TLR2. In conclusion, transfusion of Hsp25-enriched blood plasma protected the heart from Dox-induced cardiotoxicity. Hsp25 antagonized Dox binding to the TLR2 receptor on cardiomyocytes.

Forced expression of heat shock protein 27 (Hsp27) reverses P-glycoprotein (ABCB1)-mediated drug efflux and MDR1 gene expression in Adriamycin-resistant human breast cancer cells.

Mutant p53 accumulation has been shown to induce the multidrug resistance gene (MDR1) and ATP binding cassette (ABC)-based drug efflux in human breast cancer cells. In the present work, we have found that transcriptional activation of the oxidative stress-responsive heat shock factor 1 (HSF-1) and expression of heat shock proteins, including Hsp27, which is normally known to augment proteasomal p53 degradation, are inhibited in Adriamycin (doxorubicin)-resistant MCF-7 cells (MCF-7/adr). Such an endogenous inhibition of HSF-1 and Hsp27 in turn results in p53 mutation with gain of function in its transcriptional activity and accumulation in MCF-7/adr. Also, lack of HSF-1 enhances nuclear factor κB (NF-κB) DNA binding activity together with mutant p53 and induces MDR1 gene and P-glycoprotein (P-gp, ABCB1), resulting in a multidrug-resistant phenotype. Ectopic expression of Hsp27, however, significantly depleted both mutant p53 and NF-κB (p65), reversed the drug resistance by inhibiting MDR1/P-gp expression in MCF-7/adr cells, and induced cell death by increased G(2)/M population and apoptosis. We conclude from these results that HSF-1 inhibition and depletion of Hsp27 is a trigger, at least in part, for the accumulation of transcriptionally active mutant p53, which can either directly or NF-κB-dependently induce an MDR1/P-gp phenotype in MCF-7 cells. Upon Hsp27 overexpression, this pathway is abrogated, and the acquired multidrug resistance is significantly abolished so that MCF-7/adr cells are sensitized to Dox. Thus, clinical alteration in Hsp27 or NF-κB level will be a potential approach to circumvent drug resistance in breast cancer.