Functional brain network alterations in the co-occurrence of autism spectrum disorder and attention deficit hyperactivity disorder.

Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are two highly prevalent and commonly co-occurring neurodevelopmental disorders. The neural mechanisms underpinning the comorbidity of ASD and ADHD (ASD + ADHD) remain unclear. We focused on the topological organization and functional connectivity of brain networks in ASD + ADHD patients versus ASD patients without ADHD (ASD-only). Resting-state functional magnetic resonance imaging (rs-fMRI) data from 114 ASD and 161 typically developing (TD) individuals were obtained from the Autism Brain Imaging Data Exchange II. The ASD patients comprised 40 ASD + ADHD and 74 ASD-only individuals. We constructed functional brain networks for each group and performed graph-theory and network-based statistic (NBS) analyses. Group differences between ASD + ADHD and ASD-only were analyzed at three levels: nodal, global, and connectivity. At the nodal level, ASD + ADHD exhibited topological disorganization in the temporal and occipital regions, compared with ASD-only. At the global level, ASD + ADHD and ASD-only displayed no significant differences. At the connectivity level, the NBS analysis revealed that ASD + ADHD showed enhanced functional connectivity between the prefrontal and frontoparietal regions, as well as between the orbitofrontal and occipital regions, compared with ASD-only. The hippocampus was the shared region in aberrant functional connectivity patterns in ASD + ADHD and ASD-only compared with TD. These findings suggests that ASD + ADHD displays altered topology and functional connectivity in the brain regions that undertake social cognition, language processing, and sensory processing.

H2O2 and Phosphorylated Peptide Dual-Responsive Nanochannel Device.

Oxidation and protein phosphorylation are critical mechanisms involved in regulating various cellular activities. Increasing research has suggested that oxidative stress could affect the activities of specific kinases or phosphatases, leading to alterations in the phosphorylation status of certain proteins. Ultimately, these alterations can affect cellular signaling pathways and gene expression patterns. However, the relationship between oxidation and protein phosphorylation remains complex and not yet fully understood. Therefore, the development of effective sensors capable of detecting both oxidation and protein phosphorylation simultaneously presents an ongoing challenge. To address this need, we introduce a proof-of-concept nanochannel device that is dual-responsive to both H2O2 and phosphorylated peptide (PP). Specifically, we design a peptide GGGCEG(GPGGA)4CEGRRRR, which contains an H2O2-sensitive unit CEG, an elastic peptide fragment (GPGGA)4, and a phosphorylation site recognition fragment RRRR. When the peptides are immobilized on the inner walls of conical nanochannels in a polyethylene terephthalate membrane, this peptide-modified nanochannel device exhibits a sensitive response to both H2O2 and PPs. The peptide chains undergo a random coil-to-α-helix transition in response to H2O2, which leads to a close-to-open transition of the nanochannel, accompanied with a remarkable increase in the transmembrane ionic current. In contrast, binding of the peptides with PPs shields the positive charge of the RRRR fragments, causing a decrease of the transmembrane ionic current. These unique features enable the sensitive detection of reactive oxygen species released by 3T3-L1 cells stimulated by platelet-derived growth factor (PDGF) as well as PDGF-induced change in the PP level. Real-time kinase activity monitoring further confirms the device's potential utility for kinase inhibitor screening.

Robust Cellulose Nanocrystal-Based Self-Assembled Composite Membranes Doped with Polyvinyl Alcohol and Graphene Oxide for Osmotic Energy Harvesting.

Osmotic energy from the salinity gradients represents a promising energy resource with stable and sustainable characteristics. Nanofluidic membranes can be considered as powerful alternatives to the traditional low-performance ion exchange membrane to achieve high-efficiency osmotic energy harvesting. However, the development of a highly efficient and easily scalable core membrane component from low-cost raw materials remains challenging. Here, a composite membrane based on the self-assembly of cellulose nanocrystals (CNCs) with polyvinyl alcohol (PVA) and graphene oxide (GO) nanoflakes as additives is developed to provide a solution. The introduction of soft PVA polymer significantly improves the mechanical strength and water stability of the composite membrane by forming a nacre-like structure. Benefiting from the abundant negative charges of CNC nanorods and GO nanoflakes and the generated network nanochannels, the composite membrane demonstrates a good cation-selective transport capacity, thus contributing to an optimal osmotic energy conversion of 6.5 W m-2 under a 100-fold salinity gradient and an exemplary stability throughout 25 consecutive days of operation. This work provides an option for the development of nanofluidic membranes that can be easily produced on a large scale from well-resourced and sustainable biomass materials for high-efficiency osmotic energy conversion.

Uncovering neural distinctions and commodities between two creativity subsets: A meta-analysis of fMRI studies in divergent thinking and insight using activation likelihood estimation.

The dual-process theory that two different systems of thought coexist in creative thinking has attracted considerable attention. In the field of creative thinking, divergent thinking (DT) is the ability to produce multiple solutions to open-ended problems in a short time. It is mainly considered an associative and fast process. Meanwhile, insight, the new and unexpected comprehension of close-ended problems, is frequently marked as a deliberate and time-consuming thinking process requiring concentrated effort. Previous research has been dedicated to revealing their separate neural mechanisms, while few studies have compared their differences and similarities at the brain level. Therefore, the current study applied Activation Likelihood Estimation to decipher common and distinctive neural pathways that potentially underlie DT and insight. We selected 27 DT studies and 30 insight studies for retrospective meta-analyses. Initially, two single analyses with follow-up contrast and conjunction analyses were performed. The single analyses showed that DT mainly involved the inferior parietal lobe (IPL), cuneus, and middle frontal gyrus (MFG), while the precentral gyrus, inferior frontal gyrus (IFG), parahippocampal gyrus (PG), amygdala (AMG), and superior parietal lobe were engaged in insight. Compared to insight, DT mainly led to greater activation in the IPL, the crucial part of the default mode network. However, insight caused more significant activation in regions related to executive control functions and emotional responses, such as the IFG, MFG, PG, and AMG. Notably, the conjunction analysis detected no overlapped areas between DT and insight. These neural findings implicate that various neurocognitive circuits may support DT and insight.

Increased TIGIT expressing NK cells with dysfunctional phenotype in AML patients correlated with poor prognosis.

AML is the most common blood cancer in adults with a high relapse and an overall poor survival rate. NK cells have been demonstrated to have the capacity to eradicate AML blast, and an impaired NK cell function is involved in AML development and progression. Immune checkpoints are involved in immune escape in various cancers. Immune checkpoints blockade therapy mainly aimed to unleash CD8+T cells function, but NK cells have emerged as new target. However, immune checkpoints profile on NK cells has not been observed in AML patients. Here, we studied the immune checkpoints expression of NK cells from AML patients at initial diagnosis and found increased PD-1, TIGIT and TIM-3 expression compared to NK cells from healthy donors. Further analysis showed that TIGIT expressing NK cells from AML patients had a dysfunctional phenotype, as TIGIT+NK cells exhibit lower antileukemia effect, cytokine production and degranulation compared to TIGIT-NK cells. TIGIT blockade could significantly enhance the function of NK cells. Moreover, AML patients with high frequency of TIGIT+NK cells had higher frequency of poor prognosis risk. Further analysis found that IL-10 upregulated TIGIT expression on NK cells. Thus, TIGIT blockade alone or in combination with other therapy might be potential strategy to treat AML.

CD8+T cells expressing both PD-1 and TIGIT but not CD226 are dysfunctional in acute myeloid leukemia (AML) patients.

Acute myeloid leukemia (AML) is one of the most common types of leukemia among adults with an overall poor prognosis and very limited treatment management. Immune checkpoint blockade of PD-1 alone or combined with other immune checkpoint blockade has gained impressive results in murine AML models by improving anti-leukemia CD8+T cell function, which has greatly promoted the strategy to utilize combined immune checkpoint inhibitors to treat AML patients. However, the expression profiles of these immune checkpoint receptors, such as co-inhibitory receptors PD-1 and TIGIT and co-stimulatory receptor CD226, in T cells from AML patients have not been clearly defined. Here we have defined subsets of CD8+ and CD4+ T cells in the peripheral blood (PB) from newly diagnosed AML patients and healthy controls (HCs). We have observed increased frequencies of PD-1- and TIGIT- expressing CD8+ T cells but decreased occurrence of CD226-expressing CD8+T cells in AML patients. Further analysis of these CD8+ T cells revealed a unique CD8+ T cell subset that expressed PD-1 and TIGIT but displayed lower levels of CD226 was associated with failure to achieve remission after induction chemotherapy and FLT3-ITD mutations which predict poor clinical prognosis in AML patients. Importantly, these PD-1+TIGIT+CD226-CD8+T cells are dysfunctional with lower expression of intracellular IFN-γ and TNF-α than their counterparts in HCs. Therefore, our studies revealed that an increased frequency of a unique CD8+ T cell subset, PD-1+TIGIT+CD226-CD8+T cells, is associated with CD8+T cell dysfunction and poor clinical prognosis of AML patients, which may reveal critical diagnostic or prognostic biomarkers and direct more efficient therapeutic strategies.

Existence of Th22 in children and evaluation of IL-22 + CD4 + T, Th17, and other T cell effector subsets from healthy children compared to adults.

BACKGROUND: Children are prone to get infections, especially in the respiratory system and the gut mainly because their immune system is immature. T cells significantly contribute to the prevention of infections, and different helper T cell (Th) subsets play different anti-pathogen roles. Interleukin (IL)-22 producing by T-helper 22 cells (Th22) play an important role in host defense against Gram-negative bacterial organisms in gut and lung. T-helper 17 cells (Th17) protect against extracelluar bacteria and fungi especially at the epithelial surface. However, there is no report comparing IL-22 producing T cells and Th17 cells in healthy young children to adults. METHODS: Flow cytometry (FCM) was used to observe whether Th22 subset existed in the peripheral blood of healthy young children. Meanwhile, we determined the frequencies of Th subsets including Th17, Th1 and Th2, cytotoxic T (Tc)1 subset, CD4+ and CD8+ memory T cells in the peripheral blood of both young children and adults. RESULTS: In the present study, we demonstrated that Th22 subset existed in peripheral blood of children, with IL-22 mainly secreted by CD4 + CD45RO+ memory T cells. Moreover, we observed that IL-22 + CD4 + T cells and Th subsets including Th17, Th1, and Th2 frequencies of young children (1-6 years old) were significantly lower than adults. While the Th1 frequency from Group A (1-3 years old) was markedly lower than that from Group B (4-6 years old). No significant differences of Th17 or IL-22 + CD4 + T cells frequencies were observed between these two groups. In addition, Tc1 subset frequencies were also remarkably lower in young children than in adults. Furthermore, lower frequencies of CD45RO+ memory CD4+ and CD8+ T cells in young children than in adults, and significant correlation between CD45RO+ memory CD4 + T cells and IL-22 + CD4 + T cells, Th1, Th17 were observed. CONCLUSIONS: Th22 subset exists in the peripheral blood of young children. Compared with adults, there are lower frequencies of IL-22 + CD4 + T cells, as well as Th1, Th17, Th2 and Tc1 subsets in the peripheral blood of young children.

Altered cortical gyrification, sulcal depth, and fractal dimension in the autism spectrum disorder comorbid attention-deficit/hyperactivity disorder than the autism spectrum disorder.

Autism spectrum disorder (ASD) frequently occurs accompanied by attention-deficit/hyperactivity disorder (ADHD), which catches increasing attention. The comorbid diagnosis of ASD with ADHD (ASD + ADHD) is permitted in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V). However, compared to autism spectrum disorder without other symptoms (ASD-only), the special neural underpinnings in ASD+ADHD remain unclear. Therefore, this study aimed to uncover the differences in cortical complexity between ASD + ADHD and ASD-only patients. A total of 114 ASD participants (i.e. containing 40 ASD + ADHD and 74 ASD-only participants) with T1-weighted magnetic resonance images were collected from the Autism Brain Imaging Data Exchange II. Afterward, a surface-based morphometry method was carried out to compare the cortical complexity (i.e. gyrification index, fractal dimension, and sulcal depth) between the ASD + ADHD and ASD-only cohorts. Results showed the increased fractal dimension in the right fusiform gyrus of the ASD + ADHD cohort in comparison to the ASD-only cohort. Moreover, the ASD + ADHD cohort exhibited increased sulcal depth in the left middle temporal gyrus/inferior temporal gyrus and right middle temporal gyrus compared to the ASD-only cohort. Last but not least, the increased gyrification index in the insula/postcentral gyrus was observed in the ASD + ADHD cohort in comparison to the ASD-only cohort. Overall, the present study contributes to the delineation of particular structural abnormalities in ASD + ADHD than ASD-only, enriching the evidence of the combined phenotype of ASD + ADHD.

Altered functional brain network patterns in patients with migraine without aura after transcutaneous auricular vagus nerve stimulation.

Transcutaneous auricular vagus nerve stimulation (taVNS) shows excellent effects on relieving clinical symptoms in migraine patients. Nevertheless, the neurological mechanisms of taVNS for migraineurs remain unclear. In recent years, voxel-wise degree centrality (DC) and functional connectivity (FC) methods were extensively utilized for exploring alterations in patterns of FC in the resting-state brain. In the present study, thirty-five migraine patients without aura and thirty-eight healthy controls (HCs) were recruited for magnetic resonance imaging scans. Firstly, this study used voxel-wise DC analysis to explore brain regions where abnormalities were present in migraine patients. Secondly, for elucidating neurological mechanisms underlying taVNS in migraine, seed-based resting-state functional connectivity analysis was employed to the taVNS treatment group. Finally, correlation analysis was performed to explore the relationship between alterations in neurological mechanisms and clinical symptoms. Our findings indicated that migraineurs have lower DC values in the inferior temporal gyrus (ITG) and paracentral lobule than in healthy controls (HCs). In addition, migraineurs have higher DC values in the cerebellar lobule VIII and the fusiform gyrus than HCs. Moreover, after taVNS treatment (post-taVNS), patients displayed increased FC between the ITG with the inferior parietal lobule (IPL), orbitofrontal gyrus, angular gyrus, and posterior cingulate gyrus than before taVNS treatment (pre-taVNS). Besides, the post-taVNS patients showed decreased FC between the cerebellar lobule VIII with the supplementary motor area and postcentral gyrus compared with the pre-taVNS patients. The changed FC of ITG-IPL was significantly related to changes in headache intensity. Our study suggested that migraine patients without aura have altered brain connectivity patterns in several hub regions involving multisensory integration, pain perception, and cognitive function. More importantly, taVNS modulated the default mode network and the vestibular cortical network related to the dysfunctions in migraineurs. This paper provides a new perspective on the potential neurological mechanisms and therapeutic targets of taVNS for treating migraine.

SARS-CoV-2 virus-like-particles via liposomal reconstitution of spike glycoproteins.

The SARS-CoV-2 virus, implicated in the COVID-19 pandemic, recognizes and binds host cells using its spike glycoprotein through an angiotensin converting enzyme 2 (ACE-2) receptor-mediated pathway. Recent research suggests that spatial distributions of the spike protein may influence viral interactions with target cells and immune systems. The goal of this study has been to develop a liposome-based virus-like particle (VLP) by reconstituting the SARS-CoV-2 spike glycoprotein within a synthetic nanoparticle membrane, aiming to eventually establish tunability in spike protein presentation on the nanoparticle surface. Here we report on first steps to this goal, wherein liposomal SARS-CoV-2 VLPs were successfully produced via detergent mediated spike protein reconstitution. The resultant VLPs are shown to successfully co-localize in vitro with the ACE-2 receptor on lung epithelial cell surfaces, followed by internalization into these cells. These VLPs are the first step toward the overall goal of this research which is to form an understanding of the relationship between spike protein surface density and cell-level immune response, eventually toward creating better vaccines and anti-viral therapeutics.

Does End-Expiratory Occlusion Test Predict Fluid Responsiveness in Mechanically Ventilated Patients? A Systematic Review and Meta-Analysis.

BACKGROUND: We performed a systematic review and meta-analysis of studies investigating the end-expiratory occlusion (EEO) test induced changes in cardiac index (CI) and in arterial pressure as predictors of fluid responsiveness in adults receiving mechanical ventilation. METHODS: MEDLINE, EMBASE, Cochrane Database, and Chinese database were screened for relevant original and review articles. The meta-analysis determined the pooled sensitivity, specificity, diagnostic odds ratio, area under the receiver operating characteristic curve (AUROC), and threshold for the EEO test assessed with CI and arterial pressure. In addition, heterogeneity and subgroup analyses were performed. RESULTS: We included 13 studies involving 479 adult patients and 523 volume expansion. Statistically significant heterogeneity was identified, and meta-regression indicated that prone position was the major sources of heterogeneity. After removal of the study performed in prone position, heterogeneity became nonsignificant. EEO-induced changes in CI (or surrogate) are accurate for predicting fluid responsiveness in semirecumbent or supine patients, with excellent pooled sensitivity of 92% (95% CI, 0.88-0.95, I = 0.00%), specificity of 89% (95% CI, 0.83-0.93, I = 34.34%), and a summary AUROC of 0.95 (95% CI, 0.93-0.97). The mean threshold was an EEO-induced increase in CI (or surrogate) of more than 4.9 ± 1.5%. EEO test exhibited better diagnostic performance in semirecumbent or supine patients than prone patients, with higher AUROC (0.95 vs. 0.65; P < 0.001). In addition, EEO test exhibited higher specificity (0.93 vs. 0.83, P < 0.001) in patients ventilated with low tidal volume compared with normal or nearly normal tidal volume. However, EEO test was less accurate when its hemodynamic effects were detected on arterial pressure. EEO-induced changes in arterial pressure exhibited a lower sensitivity (0.88 vs. 0.92; P = 0.402), specificity (0.77 vs. 0.90; P = 0.019), and AUROC (0.87 vs. 0.96; P < 0.001) compared with EEO-induced changes in CI (or surrogate). CONCLUSIONS: EEO test is accurate to predict fluid responsiveness in semirecumbent or supine patients but not in prone patients. EEO test exhibited higher specificity in patients ventilated with low tidal volume, and its accuracy is better when its hemodynamic effects are assessed by direct measurement of CI than by the arterial pressure.