Association between the skin microbiome and lichen striatus hypopigmentation: Cutibacterium acnes as a potential cause.

BACKGROUND: Lichen striatus (LS) is an acquired skin disorder with a linear pattern along Blaschko's lines. It commonly occurs in childhood, and the lesions spontaneously regress within several months. OBJECTIVES: Although up to 50% of LS cases exhibit hypopigmentation that can persist for several months to years, it is unknown why LS is associated with such a high incidence of hypopigmentation compared to other inflammatory skin diseases. Therefore, this study aimed to analyse the differences in the skin microbiome between LS patients with and without hypopigmentation. METHODS: Differences in skin microbiome were analysed using whole genome sequencing of skin biopsies and subsequent bioinformatics analyses. RESULTS: Some microbes commonly found in hypopigmented skin disorders, including Cutibacterium acnes, were more abundant in patients with LS showing hypopigmentation than in those not showing hypopigmentation. CONCLUSIONS: The skin microbiota may be involved in the development of hypopigmentation in LS and may be considered a treatment target to reduce LS duration and hypopigmentation.

Change in the Usage of Complementary and Alternative Medicine in the Era of Biologics Among Korean Patients With Psoriasis.

BACKGROUND: Patients with long-standing psoriasis who are not treated with conventional medicine seek complementary and alternative medicine (CAM). The biological revolution in the field of psoriasis since the late 2000s has progressed, expecting clearance or almost clearance of the disease. The frequency and type of CAM usage may have changed after these advances. We aimed to investigate changes in CAM use in Korean patients with psoriasis before and after the prevalent use of biologics. METHODS: Patients with psoriasis who visited Pusan National University Hospitals (Busan and Yangsan) between March 2020 and June 2022 were made to complete a face-to-face structured questionnaire. These results were compared with our previous study conducted approximately 10 years ago. RESULTS: In total, 207 patients were included. Compared with the previous results, the frequency of CAM use (67.6%) increased (P < 0.001). Oriental medicine (67.1%) has most commonly been used, followed by health supplements and bath therapy. The biggest reason for using CAM was "to try all the potential treatments." Meanwhile, negative concerns about conventional medicine (13.5%) significantly decreased during the 10-year period (P < 0.001). CONCLUSION: Although treatment efficacy has increased with biologics development, CAM usage remains prevalent among Korean patients with psoriasis. Therefore, dermatologists need more efforts to improve patients' understanding of conventional medicine, including biologics.

Deficiency of Inositol Monophosphatase Activity Decreases Phosphoinositide Lipids and Enhances TRPV1 Function In Vivo.

Membrane remodeling by inflammatory mediators influences the function of sensory ion channels. The capsaicin- and heat-activated transient receptor potential vanilloid 1 (TRPV1) channel contributes to neurogenic inflammation and pain hypersensitivity, in part because of its potentiation downstream of phospholipase C-coupled receptors that regulate phosphoinositide lipid content. Here, we determined the effect of phosphoinositide lipids on TRPV1 function by combining genetic dissection, diet supplementation, and behavioral, biochemical, and functional analyses in Caenorhabditis elegans As capsaicin elicits heat and pain sensations in mammals, transgenic TRPV1 worms exhibit an aversive response to capsaicin. TRPV1 worms with low levels of phosphoinositide lipids display an enhanced response to capsaicin, whereas phosphoinositide lipid supplementation reduces TRPV1-mediated responses. A worm carrying a TRPV1 construct lacking the distal C-terminal domain features an enhanced response to capsaicin, independent of the phosphoinositide lipid content. Our results demonstrate that TRPV1 activity is enhanced when the phosphoinositide lipid content is reduced, and the C-terminal domain is key to determining agonist response in vivo.

Efficacy of Intravenous Mesenchymal Stem Cells for Motor Recovery After Ischemic Stroke: A Neuroimaging Study.

BACKGROUND AND PURPOSE: Stem cell-based therapy is a promising approach to repair brain damage after stroke. This study was conducted to investigate changes in neuroimaging measures using stem cell-based therapy in patients with ischemic stroke. METHODS: In this prospective, open-label, randomized controlled trial with blinded outcome evaluation, patients with severe middle cerebral artery territory infarct were assigned to the autologous mesenchymal stem cell (MSC) treatment or control group. Of 54 patients who completed the intervention, 31 for the MSC and 13 for the control groups were included in this neuroimaging analysis. Motor function was assessed before the intervention and 90 days after randomization using the Fugl-Meyer assessment scale. Neuroimaging measures included fractional anisotropy values of the corticospinal tract and posterior limb of the internal capsule from diffusion tensor magnetic resonance imaging and strength of connectivity, efficiency, and density of the motor network from resting-state functional magnetic resonance imaging. RESULTS: For motor function, the improvement ratio of the Fugl-Meyer assessment score was significantly higher in the MSC group compared with the control group. In neuroimaging, corticospinal tract and posterior limb of the internal capsule fractional anisotropy did not decrease in the MSC group but significantly decreased at 90 days after randomization in the control group. Interhemispheric connectivity and ipsilesional connectivity significantly increased in the MSC group. Change in interhemispheric connectivity showed a significant group difference. CONCLUSIONS: Stem cell-based therapy can protect corticospinal tract against degeneration and enhance positive changes in network reorganization to facilitate motor recovery after stroke. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01716481.

A phase 2 evaluation of pembrolizumab for recurrent Lynch-like versus sporadic endometrial cancers with microsatellite instability.

BACKGROUND: Microsatellite instability-high (MSI-H)/mismatch repair deficiency (dMMR) is a biomarker for responses to immune checkpoint inhibitors (ICIs). Whether mechanisms underlying microsatellite instability alter responses to ICIs is unclear. This article reports data from a prospective phase 2 pilot study of pembrolizumab in patients with recurrent MSI-H endometrial cancer (EC) analyzed by whole exome sequencing (WES) and potential mechanisms of primary/secondary ICI resistance (NCT02899793). METHODS: Patients with measurable MSI-H/dMMR EC confirmed by polymerase chain reaction/immunohistochemistry were evaluated by WES and received 200 mg of pembrolizumab every 3 weeks for ≤2 years. The primary end point was the objective response rate (ORR). Secondary end points included progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty-five patients (24 evaluable) were treated. Six patients (25%) harbored Lynch/Lynch-like tumors, whereas 18 (75%) had sporadic EC. The tumor mutation burden was higher in Lynch-like tumors (median, 2939 mutations/megabase [Mut/Mb]; interquartile range [IQR], 867-5108 Mut/Mb) than sporadic tumors (median, 604 Mut/Mb; IQR, 411-798 Mut/Mb; P = .0076). The ORR was 100% in Lynch/Lynch-like patients but only 44% in sporadic patients (P = .024). The 3-year PFS and OS proportions were 100% versus 30% (P = .017) and 100% versus 43% (P = .043), respectively. CONCLUSIONS: This study suggests prognostic significance of Lynch-like cancers versus sporadic MSI-H/dMMR ECs for ORR, PFS, and OS when patients are treated with pembrolizumab. Larger confirmatory studies in ECs and other MSI-H/dMMR tumors are necessary. Defective antigen processing/presentation and deranged induction in interferon responses serve as mechanisms of resistance in sporadic MSI-H ECs. Oligoprogression in MSI-H/dMMR patients appears salvageable with surgical resection and/or local treatment and the continuation of pembrolizumab off study. Clinical studies evaluating separate MSI-H/dMMR EC subtypes treated with ICIs are warranted.

Visual Development of Healthy Full-Term Infants under 24 Months of Age Using the Preverbal Visual Assessment Questionnaire.

As visual perception development proceeds rapidly after birth, early detection of developmental maturity is required. Healthy infants do not have many opportunities for visual perception evaluation, so a reliable evaluation method is necessary. This retrospective study included 276 healthy full-term infants <24 months of age using the Preverbal Visual Assessment (PreViAs) questionnaire, which measures scores of subdivided age-groups for the global scores and 4 domains: visual attention (VA), visual communication (VC), visual-motor coordination (VMC), and visual processing (VP). Through this study, reference values and cutoff scores of the PreViAs questionnaire were presented, reliability was secured, and potential influencing factors of the PreViAs scores were analyzed. Using Cronbach's α coefficient, the global scores were 0.938, 0.781 for VA, 0.660 for VC, 0.874 for VMC, and 0.942 for VP. The internal consistency of the questionnaire was high in the global scores and 3 domains (VA, VMC, and VP). In infants under 12 months, the global scores and the VA, VMC, and VP domains showed positive association with gestational age, whereas the VC domain correlated with sex: which was found to be greater for females (p < 0.05). In those 12 month and above, no clinical factors were significantly associated with the PreViAs scores in all domains. The PreViAs questionnaire is a useful tool for visual assessment of healthy full-term infants under 24 months of age, suggesting reference values and cutoff scores according to age, and estimating the maturation age for visual perception development of each domain.

The structural connectome and motor recovery after stroke: predicting natural recovery.

Stroke patients vary considerably in terms of outcomes: some patients present 'natural' recovery proportional to their initial impairment (fitters), while others do not (non-fitters). Thus, a key challenge in stroke rehabilitation is to identify individual recovery potential to make personalized decisions for neuro-rehabilitation, obviating the 'one-size-fits-all' approach. This goal requires (i) the prediction of individual courses of recovery in the acute stage; and (ii) an understanding of underlying neuronal network mechanisms. 'Natural' recovery is especially variable in severely impaired patients, underscoring the special clinical importance of prediction for this subgroup. Fractional anisotropy connectomes based on individual tractography of 92 patients were analysed 2 weeks after stroke (TA) and their changes to 3 months after stroke (TC - TA). Motor impairment was assessed using the Fugl-Meyer Upper Extremity (FMUE) scale. Support vector machine classifiers were trained to separate patients with natural recovery from patients without natural recovery based on their whole-brain structural connectomes and to define their respective underlying network patterns, focusing on severely impaired patients (FMUE < 20). Prediction accuracies were cross-validated internally, in one independent dataset and generalized in two independent datasets. The initial connectome 2 weeks after stroke was capable of segregating fitters from non-fitters, most importantly among severely impaired patients (TA: accuracy = 0.92, precision = 0.93). Secondary analyses studying recovery-relevant network characteristics based on the selected features revealed (i) relevant differences between networks contributing to recovery at 2 weeks and network changes over time (TC - TA); and (ii) network properties specific to severely impaired patients. Important features included the parietofrontal motor network including the intraparietal sulcus, premotor and primary motor cortices and beyond them also attentional, somatosensory or multimodal areas (e.g. the insula), strongly underscoring the importance of whole-brain connectome analyses for better predicting and understanding recovery from stroke. Computational approaches based on structural connectomes allowed the individual prediction of natural recovery 2 weeks after stroke onset, especially in the difficult to predict group of severely impaired patients, and identified the relevant underlying neuronal networks. This information will permit patients to be stratified into different recovery groups in clinical settings and will pave the way towards personalized precision neurorehabilitative treatment.

Isolation, screening and identification of key components having intense insect repellent activity against Plodia interpunctella from four different medicinal plant materials.

BACKGROUND: Global warming and the indiscriminate use of pesticides have increased the propagation of the stored-product insect pests, leading to enormous losses in the agriculture and food industries. The most used insect repellents are synthetic derivatives; however, these have an adverse effect on human health as well as on the environment. Therefore, we attempted to find materials with insect repellent activity in natural products. The present study aimed to identify the single chemical component with intense insect repellent activity in extracts from four different Oriental medicinal plant materials: (i) Anethum graveolens L. (dill) seeds; (ii) Artemisia capillaris Thunb. (capillary wormwood) leaves; (iii) smoked Prunus mume Siebold & Zucc. (mume) fruits; and (iv) Rhus javanica L. (galls). RESULTS: As a result of the bioassay-guided fractionation of each extract against the Plodia interpunctella, stored-product insect, the n-hexane fraction of dill seeds extract was confirmed as the optimal fraction between all of the fractions. In total, 32 chemical components were identified from the n-hexane fraction of dill seeds by gas chromatography-mass spectrometry analysis, and the two main components were dillapiole (47.51%) and carvone (26.76%). Of the two components, dillapiole was confirmed as the key component playing an essential role in insect repellent activity. CONCLUSION: Our study suggests that dillapiole has the potential to be used as a natural insect repellent for the control of P. interpunctella infestation in agricultural and food products during distribution and storage. © 2021 Society of Chemical Industry.

Disconnectomics of the Rich Club Impacts Motor Recovery After Stroke.

BACKGROUND AND PURPOSE: Structural brain networks possess a few hubs, which are not only highly connected to the rest of the brain but are also highly connected to each other. These hubs, which form a rich-club, play a central role in global brain organization. To investigate whether the concept of rich-club sheds new light on poststroke recovery, we applied a novel network-theoretical quantification of lesions to patients with stroke and compared the outcomes with what lesion size alone would indicate. METHODS: Whole-brain structural networks of 73 patients with ischemic stroke were reconstructed using diffusion-weighted imaging data. Disconnectomes, a new type of network analyses, were constructed using only those fibers that pass through the lesion. Fugl-Meyer upper extremity scores and their changes were used to determine whether the patients show natural recovery or not. RESULTS: Cluster analysis revealed 3 patient clusters: small-lesion-good-recovery, midsized-lesion-poor-recovery (MLPR), and large-lesion-poor-recovery (LLPR). The small-lesion-good-recovery consisted of subjects whose lesions were small, and whose prospects for recovery were relatively good. To explain the nondifference in recovery between the MLPR and LLPR clusters despite the difference (LLPR>MLPR) in lesion volume, we defined the [Formula: see text] metric to be the sum of the entries in the disconnectome and, more importantly, the [Formula: see text] to be the sum of all entries in the disconnectome corresponding to edges with at least one node in the rich-club. Unlike lesion volume and corticospinal tract damage (MLPRLLPR) or showed no difference for [Formula: see text]. CONCLUSIONS: Smaller lesions that focus on the rich-club can be just as devastating as much larger lesions that do not focus on the rich-club, pointing to the role of the rich-club as a backbone for functional communication within brain networks and for recovery from stroke.

Correlation between cardiopulmonary metabolic energy cost and lower-limb muscle activity during inclined treadmill gait in older adults.

BACKGROUND: Inclined walking requires more cardiopulmonary metabolic energy and muscle strength than flat-level walking. This study sought to investigate changes in lower-limb muscle activity and cardiopulmonary metabolic energy cost during treadmill walking with different inclination grades and to discern any correlation between these two measures in older adults. METHODS: Twenty-four healthy older adults (n = 11 males; mean age: 75.3 ± 4.0 years) participated. All participants walked on a treadmill that was randomly inclined at 0% (condition 1), 10% (condition 2), and 16% (condition 3) for five minutes each. Simultaneous measurements of lower-limb muscle activity and cardiopulmonary metabolic energy cost during inclined treadmill walking were collected. Measured muscles included the rectus abdominis (RA), erector spinae (ES), rectus femoris (RF), biceps femoris (BF), vastus medialis (VM), tibialis anterior (TA), medial head of the gastrocnemius (GCM), and soleus (SOL) muscles on the right side. RESULTS: As compared with 0% inclined treadmill gait, the 10% inclined treadmill gait increased the net cardiopulmonary metabolic energy cost by 22.9%, while the 16% inclined treadmill gait increased the net cardiopulmonary metabolic energy cost by 44.2%. In the stance phase, as the slope increased, activity was significantly increased in the RA, RF, VM, BF, GCM, and SOL muscles. In the swing phase, As the slope increased activity was significantly increased in the RA, RF, VM, BF, and TA muscles. SOL muscle activity was most relevant to the change in cardiopulmonary metabolic energy cost in the stance phase of inclined treadmill walking. The relationship between the increase in cardiopulmonary metabolic energy cost and changes in muscle activity was also significant in the VM, GCM, and RF. CONCLUSION: This study demonstrated that changes in SOL, VM, GCM, and RA muscle activity had a significant relationship with cardiopulmonary metabolic energy cost increment during inclined treadmill walking. These results can be used as basic data for various gait-training programs and as an indicator in the development of assistive algorithms of wearable walking robots for older adults. TRIAL REGISTRATION: Clinical trials registration information: ClinicalTrials.gov Identifier: NCT04614857 (05/11/2020).

Ordered Mesoporous Carbons with Graphitic Tubular Frameworks by Dual Templating for Efficient Electrocatalysis and Energy Storage.

Ordered mesoporous carbons (OMCs) have attracted considerable interest owing to their broad utility. OMCs reported to date comprise amorphous rod-like or tubular or graphitic rod-like frameworks, which exhibit tradeoffs between conductivity and surface area. Here we report ordered mesoporous carbons constructed with graphitic tubular frameworks (OMGCs) with tunable pore sizes and mesostructures via dual templating, using mesoporous silica and molybdenum carbide as exo- and endo-templates, respectively. OMGCs simultaneously realize high electrical conductivity and large surface area and pore volume. Benefitting from these features, Ru nanoparticles (NPs) supported on OMGC exhibit superior catalytic activity for alkaline hydrogen evolution reaction and single-cell performance for anion exchange membrane water electrolysis compared to Ru NPs on other OMCs and commercial catalysts. Further, the OMGC-based full-carbon symmetric cell demonstrates excellent performances for Li-ion capacitors.

Differential Relationship between Microstructural Integrity in White Matter Tracts and Motor Recovery following Stroke Based on Brain-Derived Neurotrophic Factor Genotype.

Objective: The relationship between white matter integrity and the brain-derived neurotrophic factor (BDNF) genotype and its effects on motor recovery after stroke are poorly understood. We investigated the values of fractional anisotropy (FA) in the corticospinal tract (CST), the intrahemispheric connection from the primary motor cortex to the ventral premotor cortex (M1PMv), and the interhemispheric connection via the corpus callosum (CC) in patients with the BDNF genotype from the acute to the subacute phase after stroke. Methods: The Fugl-Meyer assessment, upper extremity (FMA-UE), and tract-related FA were assessed at 2 weeks (T1) and 3 months (T2) after stroke using diffusion tensor imaging (DTI). Fifty-eight patients diagnosed with ischemic stroke were classified according to the BDNF genotype into a Val (valine homozygotes) or Met (methionine heterozygotes and homozygotes) group. Results: The Val group exhibited a larger reduction of FA values in the ipsilesional M1PMv than the Met group from T1 to T2. The FMA-UE at T2 was negatively correlated with FA of the contralesional M1PMv at T2 in the Val group but was positively correlated with FA of the ipsilesional CST and CC at T2 in the Met group. Conclusions: The integrity of the intra- and interhemispheric connections might be related to different processes of motor recovery dependent on the BDNF genotype. Thus, the BDNF genotype may need to be considered as a factor influencing neuroplasticity and functional recovery in patients with stroke. This trial is registered with http://www.clinicaltrials.gov: NCT03647787.

Comparison between DiaPlexQ™ STI6 and GeneFinder™ STD I/STD II multiplex Real-time PCR Kits in the detection of six sexually transmitted disease pathogens.

BACKGROUND: The DiaPlexQ™ STI6 Detection Kit (DiaPlexQ; Solgent Co., Ltd., Daejeon, South Korea) is a multiplex real-time PCR assay for the detection of the following sexually transmitted disease (STD) pathogens: Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma hominis, Trichomonas vaginalis, Ureaplasma urealyticum, and Mycoplasma genitalium. We compared the performance of the DiaPlexQ assay with the GeneFinder™ STD I (CT/NG/UU) and STD II (MG/MH/TV) Multiplex Real-time PCR Kits (GeneFinder; Infopia Co., Ltd., Anyang, South Korea). METHODS: We evaluated the performance of the DiaPlexQ assay in comparison to that of GeneFinder using 1106 clinical specimens (542 genital swabs and 564 urine samples). The analytical performance of the DiaPlexQ assay, including the limit of detection (LOD) and analytical specificity, was evaluated using reference strains. RESULTS: The positive percent agreement, negative percent agreement, and kappa value between the two assays were 96.6%-99.4%, 98.2%-99.8%, and 0.93%-0.99%, respectively. No cross-reactivity was observed in a collection of 41 different microorganisms and the LOD of the DiaPlexQ assay ranged from 1 to 10 copies/reaction for each microorganism. CONCLUSION: The DiaPlexQ assay showed comparable performance to that of the GeneFinder assay so that it can be used for the screening and diagnosis of non-viral curable STD pathogens.

Different Brain Connectivity between Responders and Nonresponders to Dual-Mode Noninvasive Brain Stimulation over Bilateral Primary Motor Cortices in Stroke Patients.

Noninvasive brain stimulation (NBS), such as repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS), has been used in stroke patients with motor impairment. NBS can help recovery from brain damage by modulating cortical excitability. However, the efficacy of NBS varies among individuals. To obtain insights of responsiveness to the efficacy of NBS, we investigated characteristic changes of the motor network in responders and nonresponders of NBS over the primary motor cortex (M1). A total of 21 patients with subacute stroke (13 males, mean age 59.6 ± 11.5 years) received NBS in the same manner: 1 Hz rTMS on the contralesional M1 and anodal tDCS on the ipsilesional M1. Participants were classified into responders and nonresponders based on the functional improvement of the affected upper extremity after applying NBS. Twelve age-matched healthy controls (8 males, mean age 56.1 ± 14.3 years) were also recruited. Motor networks were constructed using resting-state functional magnetic resonance imaging. M1 intrahemispheric connectivity, interhemispheric connectivity, and network efficiency were measured to investigate differences in network characteristics between groups. The motor network characteristics were found to differ between both groups. Specifically, M1 intrahemispheric connectivity in responders showed a noticeable imbalance between affected and unaffected hemispheres, which was markedly restored after NBS. The responders also showed greater interhemispheric connectivity and higher efficiency of the motor network than the nonresponders. These results may provide insight on patient-specific NBS treatment based on the brain network characteristics in neurorehabilitation of patients with stroke. This trial is registered with trial registration number NCT03390192.

Differences in motor network dynamics during recovery between supra- and infra-tentorial ischemic strokes.

Most previous stroke studies have been performed in heterogeneous patient populations. Moreover, the brain network might demonstrate different recovery dynamics according to lesion location. In this study, we investigated variation in motor network alterations according to lesion location. Forty patients with subcortical ischemic stroke were enrolled. Patients were divided into two groups: 21 patients with supratentorial stroke (STS) and 19 patients with infratentorial stroke (ITS). All patients underwent resting-state functional magnetic resonance imaging and behavioral assessment at 2 weeks and 3 months poststroke. Twenty-four healthy subjects participated as a control group. To compare altered connectivity between groups, measures used in previous studies to evaluate interhemispheric balance and global network reorganization were investigated and the relationship between network measures and motor functions were examined. Cortico-cerebellar connectivity was also extracted to investigate its relationship with interhemispheric connectivity. In the STS group, measures related to interhemispheric balance were disrupted compared to the control group 2 weeks poststroke, while this was not found in the ITS group. During recovery, measures related to global network reorganization in the STS group and measures related to interhemispheric balance in the ITS group demonstrated significant changes, respectively. Moreover, motor functions were correlated with altered network measures in both groups. There was an interactive relationship between cortico-cerebellar and interhemispheric cortical connectivity only in the ITS group. Different changes in the motor network were observed depending on the location of stroke lesions. These results might originate from differences in the interactions between cortico-cerebellar and interhemispheric connectivity.

Alteration and Role of Interhemispheric and Intrahemispheric Connectivity in Motor Network After Stroke.

This study investigated local and global changes in the motor network using longitudinal resting-state functional magnetic resonance imaging (rs-fMRI). Motor impairment was measured in 81 stroke patients using Fugl-Meyer assessment on the same day as rs-fMRI acquisition at both 2 weeks and 3 months post-stroke. The relationships between network measures and motor function scores were assessed. With regard to local connectivity, interhemispheric connectivity was noticeably altered at each time point. Interhemispheric connectivity was also related to residual motor function and improvement in motor function. The anterior intraparietal sulcus and other well-known primary and secondary motor-related regions played important roles in motor function. Changes in global connectivity according to stroke type and initial severity were investigated. In global connectivity, interhemispheric connectivity was disrupted at 2 weeks post-stroke regardless of stroke type and initial severity. During the recovery period, interhemispheric connectivity recovered well in patients with hemorrhagic stroke or low severity. In contrast, there were no significant between-group and within-group alterations in intrahemispheric connectivity. Intrahemispheric connectivity of the inferior frontal cortex (IFC) exhibited opposite alterations compared to other connections. There were no differences between groups in IFC connectivity alterations; however, decreasing ipsilesional IFC connectivity and contralesional IFC during recovery were noticeable in patients with mild to moderate impairments and patients with severe impairments, respectively. These results may be helpful in understanding the network changes that occur after stroke and could have important implications for treatment strategy development in future studies.

Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function.

Autism spectrum disorder (ASD) is a group of conditions characterized by impaired social interaction and communication, and restricted and repetitive behaviours. ASD is a highly heritable disorder involving various genetic determinants. Shank2 (also known as ProSAP1) is a multi-domain scaffolding protein and signalling adaptor enriched at excitatory neuronal synapses, and mutations in the human SHANK2 gene have recently been associated with ASD and intellectual disability. Although ASD-associated genes are being increasingly identified and studied using various approaches, including mouse genetics, further efforts are required to delineate important causal mechanisms with the potential for therapeutic application. Here we show that Shank2-mutant (Shank2(-/-)) mice carrying a mutation identical to the ASD-associated microdeletion in the human SHANK2 gene exhibit ASD-like behaviours including reduced social interaction, reduced social communication by ultrasonic vocalizations, and repetitive jumping. These mice show a marked decrease in NMDA (N-methyl-D-aspartate) glutamate receptor (NMDAR) function. Direct stimulation of NMDARs with D-cycloserine, a partial agonist of NMDARs, normalizes NMDAR function and improves social interaction in Shank2(-/-) mice. Furthermore, treatment of Shank2(-/-) mice with a positive allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), which enhances NMDAR function via mGluR5 activation, also normalizes NMDAR function and markedly enhances social interaction. These results suggest that reduced NMDAR function may contribute to the development of ASD-like phenotypes in Shank2(-/-) mice, and mGluR modulation of NMDARs offers a potential strategy to treat ASD.