Electroconvulsive therapy (ECT) has been the most potent treatment option for treatment-resistant schizophrenia (TRS). However, the underlying neural mechanisms of ECT in schizophrenia remain largely unclear. This paper examines studies that investigated structural and functional changes after ECT in patients with schizophrenia.

The effects of the Cichorium intybus root extract (Cii) on alcohol-induced liver disease were investigated using Chang liver cells and male Sprague Dawley rats. Silymarin, a liver-protective agent, was used as a positive control. In cell experiments, after 24 h of treatment with the extract, no cytotoxicity was noted, and death by alcohol was avoided. Migration of Chang liver cells increased after exposure to the extract at a concentration of 400 μg/mL. In animal experiments, alcohol was injected into 6-week-old rats for 1, 3, and 50 days. Oral administration of the drug was performed 30 min before alcohol administration. The control was treated with distilled water, and the drug groups were administered EtOH (40% EtOH + 2.5 mL/kg), EtOH + Cii L (low concentration, 2 mg/kg), EtOH + Cii H (high concentration, 10 mg/kg), or EtOH + silymarin (100 mg/kg). Increased liver weight was observed in the alcohol group, as were increased blood-alcohol concentration and liver damage indicators (glutamic oxalacetic transaminase (GOT), glutamic pyruvate transaminase (GPT), and triglycerides (TG)), decreased alcoholysis enzymes (ADH and ALDH), and increased CYP2E1. In the Cii treatment group, liver weight, blood-alcohol concentration, liver damage indicators (GOT, GPT, and TG), and CYP2E1 were decreased, while alcoholysis enzymes (ADH and ALDH) were increased. The degree of histopathological liver damage was compared visually and by staining with hematoxylin and eosin and oil red O. These results indicated that ingestion of Cii inhibited alcohol-induced liver damage, indicating Cii as a useful treatment for alcohol-induced liver injury.

Functional connectivity between the amygdala and the medial prefrontal cortex (mPFC) has been identified as a neural substrate of emotion regulation that undergoes changes throughout development, with a mature profile typically emerging at 10 years of age. Maternal bonding in childhood has been shown to buffer amygdala reactivity and to influence the trajectory of amygdala-mPFC coupling. The oxytocinergic system is critical in the development of social behavior and maternal bonding. Early-life parental care influences the methylation status of the oxytocin receptor (OXTRm) in animal models and humans, and higher OXTRm is associated with lower amygdala-PFC functional connectivity in adults. Using a neuroimaging-epigenetic approach, we investigated saliva-derived OXTRm as a biological marker of structural and functional connectivity maturation in 57 typically developing children (P < 0.05). We utilized seed-based connectivity analysis during a novel abstract movie paradigm and find that higher levels of OXTRm are associated with a more adult-like functional connectivity profile. Concurrently, more adult-like functional connectivity was associated with higher reported self-control and more diffusion streamlines between the amygdala and mPFC. OXTRm mediates the association between structural and functional connectivity with higher levels of OXTRm being associated with more streamlines. Lastly, we also find that lower OXTRm blunts the association between amygdala-mPFC connectivity and future internalizing behaviors in early adolescence. These findings implicate OXTRm as a biological marker at the interface of the social environment and amygdala-mPFC connectivity in emotional and behavioral regulation. Ultimately, identification of neurobiological markers may lead to earlier detection of children at risk for socio-emotional dysfunction.

Data-driven approaches to subtype transdiagnostic samples are important for understanding heterogeneity within disorders and overlap between disorders. Thus, this study was conducted to determine whether plasma proteomics-based clustering could subtype patients with transdiagnostic psychotic-affective disorder diagnoses. The study population included 504 patients with schizophrenia, bipolar disorder, and major depressive disorder and 160 healthy controls, aged 19 to 65 years. Multiple reaction monitoring was performed using plasma samples from each individual. Pathologic peptides were determined by linear regression between patients and healthy controls. Latent class analysis was conducted in patients after peptide values were stratified by sex and divided into tertile values. Significant demographic and clinical characteristics were determined for the latent clusters. The latent class analysis was repeated when healthy controls were included. Twelve peptides were significantly different between the patients and healthy controls after controlling for significant covariates. Latent class analysis based on these peptides after stratification by sex revealed two distinct classes of patients. The negative symptom factor of the Brief Psychiatric Rating Scale was significantly different between the classes (t = -2.070, p = 0.039). When healthy controls were included, two latent classes were identified, and the negative symptom factor of the Brief Psychiatric Rating Scale was still significant (t = -2.372, p = 0.018). In conclusion, negative symptoms should be considered a significant biological aspect for understanding the heterogeneity and overlap of psychotic-affective disorders.

Cognitive impairments are common in isolated rapid-eye-movement sleep behavior disorder (iRBD), in which the cholinergic system may play an important role. This study aimed to characterize the cortical cholinergic activity using resting-state functional connectivity (FC) of the nucleus basalis of Meynert (NBM) according to the cognitive status of iRBD patients.

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

T-cell position in the tumor microenvironment determines the probability of target encounter and tumor killing. CD8+ T-cell exclusion from the tumor parenchyma is associated with poor response to immunotherapy, and yet the biology that underpins this distinct pattern remains unclear. Here we show that the vascular destabilizing factor angiopoietin-2 (ANGPT2) causes compromised vascular integrity in the tumor periphery, leading to impaired T-cell infiltration to the tumor core. The spatial regulation of ANGPT2 in whole tumor cross-sections was analyzed in conjunction with T-cell distribution, vascular integrity, and response to immunotherapy in syngeneic murine melanoma models. T-cell exclusion was associated with ANGPT2 upregulation and elevated vascular leakage at the periphery of human and murine melanomas. Both pharmacologic and genetic blockade of ANGPT2 promoted CD8+ T-cell infiltration into the tumor core, exerting antitumor effects. Importantly, the reversal of T-cell exclusion following ANGPT2 blockade not only enhanced response to anti-PD-1 immune checkpoint blockade therapy in immunogenic, therapy-responsive mouse melanomas, but it also rendered nonresponsive tumors susceptible to immunotherapy. Therapeutic response after ANGPT2 blockade, driven by improved CD8+ T-cell infiltration to the tumor core, coincided with spatial TIE2 signaling activation and increased vascular integrity at the tumor periphery where endothelial expression of adhesion molecules was reduced. These data highlight ANGPT2/TIE2 signaling as a key mediator of T-cell exclusion and a promising target to potentiate immune checkpoint blockade efficacy in melanoma.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are key therapeutic agents in the management of metastatic hormone-receptor-positive breast cancer. However, the emergence of drug resistance limits their long-term efficacy. Here, we show that breast cancer cells develop CDK4/6i resistance via a sequential two-step process of E2F activation. This process entails retinoblastoma (Rb)-protein degradation, followed by c-Myc-mediated amplification of E2F transcriptional activity. CDK4/6i treatment halts cell proliferation in an Rb-dependent manner but dramatically reduces Rb-protein levels. However, this reduction in Rb levels insufficiently induces E2F activity. To develop CDK4/6i resistance, upregulation or activating mutations in mitogenic or hormone signaling are required to stabilize c-Myc levels, thereby augmenting E2F activity. Our analysis of pre-treatment tumor samples reveals a strong correlation between c-Myc levels, rather than Rb levels, and poor therapeutic outcomes after CDK4/6i treatment. Moreover, we propose that proteasome inhibitors can potentially reverse CDK4/6i resistance by restoring Rb levels.

Although early intervention from the beginning of a psychotic episode is essential for a better prognosis, biomarkers predictive of symptomatic and functional improvement in early psychotic disorders are lacking. This study aimed to investigate whether the spectral power of resting-state electroencephalography (EEG) can be used as a predictive marker of the 1-year prognosis in patients with first-episode psychosis (FEP).

Phosphatidylinositol is critical for intracellular signalling and anchoring of carbohydrates and proteins to outer cellular membranes. The defining step in phosphatidylinositol biosynthesis is catalysed by CDP-alcohol phosphotransferases, transmembrane enzymes that use CDP-diacylglycerol as donor substrate for this reaction, and either inositol in eukaryotes or inositol phosphate in prokaryotes as the acceptor alcohol. Here we report the structures of a related enzyme, the phosphatidylinositol-phosphate synthase from Renibacterium salmoninarum, with and without bound CDP-diacylglycerol to 3.6 and 2.5 Å resolution, respectively. These structures reveal the location of the acceptor site, and the molecular determinants of substrate specificity and catalysis. Functional characterization of the 40%-identical ortholog from Mycobacterium tuberculosis, a potential target for the development of novel anti-tuberculosis drugs, supports the proposed mechanism of substrate binding and catalysis. This work therefore provides a structural and functional framework to understand the mechanism of phosphatidylinositol-phosphate biosynthesis.

Neuroimaging studies have revealed how intrinsic dysconnectivity among cortical regions of the mentalizing network (MENT) and the mirror neuron system (MNS) could explain the theory of mind (ToM) deficit in schizophrenia patients. However, despite the concurrent involvement of the cerebellum with the cortex in social cognition, the dysfunction in intrinsic interplay between the cerebellar nodes of MENT/MNS and the cortex in schizophrenia patients remains unknown. Thus, we aimed to investigate whether resting-state cerebello-cortical dysconnectivity exists in first-episode psychosis (FEP) patients in relationship with their ToM deficit. A total of 37 FEP patients and 80 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging. Using a priori-defined cerebellar seeds that functionally connect to the MENT (right crus II) and MNS (right crus I), we compared cerebello-cortical functional connectivities (FCs) in FEP patients and HCs. Correlations between cerebello-parietal connectivities and ToM performance were investigated in FEP patients. FEP patients showed hyperconnectivity between the right crus II and anterior cingulate gyrus and between the right crus I and supplementary motor area, bilateral postcentral gyrus, and right central/parietal operculum (CO/PO). Hypoconnectivity was found between the right crus II and left supramarginal gyrus (SMG) in FEP patients. FCs between the right crus II and left SMG and between the right crus I and right CO/PO were significantly correlated with ToM scores in FEP patients. In accordance with the "cognitive dysmetria" hypothesis, our results highlight the importance of cerbello-cortical dysconnectivities in understanding social cognitive deficits in schizophrenia patients.

Identifying more homogenous subtypes of patients with obsessive-compulsive disorder (OCD) using biological evidence is critical for understanding complexities of the disorder in this heterogeneous population. Age of onset serves as a useful subtyping scheme for distinguishing OCD into two subgroups that aligns with neurodevelopmental perspectives. The underlying neurobiological markers for these distinct neurodevelopmental differences can be identified by investigating gyrification changes to establish biological evidence-based homogeneous subtypes.

The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in the majority of individuals at psychosis risk may be nested within the range observed in healthy individuals.

Although abnormal cortical gyrification has been consistently reported in patients with schizophrenia, whether gyrification abnormalities reflect a genetic risk for the disorder remains unknown. This study investigated differences in cortical gyrification between unaffected relatives (URs) with high genetic loading for schizophrenia and healthy controls (HCs) to identify potential genetic vulnerability markers. A total of 50 URs of schizophrenia patients and 50 matched HCs underwent T1-weighted magnetic resonance imaging to compare whole-brain gyrification using the local gyrification index (lGI). Then, the lGI clusters showing significant differences were compared between the UR subgroups based on the number of first-degree relatives with schizophrenia to identify the effect of genetic loading on cortical gyrification changes. The URs exhibited significantly lower cortical gyrification than the HCs in clusters including medial parieto-occipital and cingulate regions comprising the bilateral precuneus, cuneus, pericalcarine, lingual, isthmus cingulate, and posterior cingulate gyri. Moreover, URs who had two or more first-degree relatives with schizophrenia showed greater gyrification reductions in these clusters than those who had at least one first-degree relative with schizophrenia. Our findings of reduced gyrification in URs, which are consistent with accumulated evidence of hypogyria observed in regions showing patient-control differences in previous studies, highlight that such hypogyria in posteromedial regions may serve as a genetic vulnerability marker and reflect early neurodevelopmental abnormalities resulting from a genetic risk for schizophrenia.

The COVID-19 pandemic has altered daily routines and family functioning, led to closing schools, and dramatically limited social interactions worldwide. Measuring its impact on mental health of vulnerable children and adolescents is crucial.

Although the thalamus is a key structure in the pathophysiology of obsessive-compulsive disorder (OCD), reports regarding thalamic volume alterations in OCD patients have been inconsistent. Because the thalamus has a complex structure with distinct functions, we investigated subregional volume changes in the thalamus and their relationship with clinical attributes in a large sample of medication-free OCD patients.

The combination of BRAF and MEK inhibitors (BRAFi/MEKi) has shown promising response rates in treating BRAF-mutant melanoma by inhibiting ERK activation. However, treatment efficacy is limited by the emergence of drug-tolerant persister cells (persisters). Here, we show that the magnitude and duration of receptor tyrosine kinase (RTK) activation determine ERK reactivation and persister development. Our single-cell analysis reveals that only a small subset of melanoma cells exhibits effective RTK and ERK activation and develops persisters, despite uniform external stimuli. The kinetics of RTK activation directly influence ERK signaling dynamics and persister development. These initially rare persisters form major resistant clones through effective RTK-mediated ERK activation. Consequently, limiting RTK signaling suppresses ERK activation and cell proliferation in drug-resistant cells. Our findings provide non-genetic mechanistic insights into the role of heterogeneity in RTK activation kinetics in ERK reactivation and BRAFi/MEKi resistance, suggesting potential strategies for overcoming drug resistance in BRAF-mutant melanoma.

Changes in dopamine and fronto-striato-thalamic (FST) circuit functional connectivity are prominent in schizophrenia. Dopamine is thought to underlie connectivity changes, but experimental evidence for this hypothesis is lacking. Previous studies examined the association in some of the connections using positron emission tomography (PET) and functional MRI (fMRI); however, PET has disadvantages in scanning patients, such as invasiveness. Excessive dopamine induces neuromelanin (NM) accumulation, and NM-MRI is suggested as a noninvasive proxy measure of dopamine function. We aimed to investigate the association between NM and FST circuit connectivity at the network level in patients with schizophrenia. We analysed substantia nigra NM-MRI and resting-state fMRI data from 29 schizophrenia patients and 63 age- and sex-matched healthy controls (HCs). We identified the FST subnetwork with abnormal connectivity found in schizophrenia patients compared to that of HCs and investigated the relationship between constituting connectivity and NM-MRI signal. We found a higher NM signal (t = -2.12, p = 0.037) and a hypoconnected FST subnetwork (FWER-corrected p = 0.014) in schizophrenia patients than in HCs. In the hypoconnected subnetwork of schizophrenia patients, lower left supplementary motor area-left caudate connectivity was associated with a higher NM signal (β = -0.38, p = 0.042). We demonstrated the association between NM and FST circuit connectivity. Considering that the NM-MRI signal reflects dopamine function, our results suggest that dopamine underlies changes in FST circuit connectivity, which supports the dopamine hypothesis. In addition, this study reveals implications for the future use of NM-MRI in investigations of the dopamine system.

Two vascular growth factor families, VEGF and the angiopoietins, play critical and coordinate roles in tumor progression and metastasis. A single inhibitor targeting both VEGF and angiopoietins is not available. Here, we developed a chimeric decoy receptor, namely double anti-angiogenic protein (DAAP), which can simultaneously bind VEGF-A and angiopoietins, blocking their actions. Compared to VEGF-Trap or Tie2-Fc, which block either VEGF-A or angiopoietins alone, we believe DAAP is a highly effective molecule for regressing tumor angiogenesis and metastasis in implanted and spontaneous solid tumors; it can also effectively reduce ascites formation and vascular leakage in an ovarian carcinoma model. Thus, simultaneous blockade of VEGF-A and angiopoietins with DAAP is an effective therapeutic strategy for blocking tumor angiogenesis, metastasis, and vascular leakage.

Larger thalamic volume has been found in children with obsessive-compulsive disorder (OCD) and children with clinical-level symptoms within the general population. Particular thalamic subregions may drive these differences. The ENIGMA-OCD working group conducted mega- and meta-analyses to study thalamic subregional volume in OCD across the lifespan. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2649 OCD patients and 2774 healthy controls across 29 sites (50 datasets) were processed using the FreeSurfer built-in ThalamicNuclei pipeline to extract five thalamic subregions. Volume measures were harmonized for site effects using ComBat before running separate multiple linear regression models for children, adolescents, and adults to estimate volumetric group differences. All analyses were pre-registered ( https://osf.io/73dvy ) and adjusted for age, sex and intracranial volume. Unmedicated pediatric OCD patients (<12 years) had larger lateral (d = 0.46), pulvinar (d = 0.33), ventral (d = 0.35) and whole thalamus (d = 0.40) volumes at unadjusted p-values <0.05. Adolescent patients showed no volumetric differences. Adult OCD patients compared with controls had smaller volumes across all subregions (anterior, lateral, pulvinar, medial, and ventral) and smaller whole thalamic volume (d = -0.15 to -0.07) after multiple comparisons correction, mostly driven by medicated patients and associated with symptom severity. The anterior thalamus was also significantly smaller in patients after adjusting for thalamus size. Our results suggest that OCD-related thalamic volume differences are global and not driven by particular subregions and that the direction of effects are driven by both age and medication status.