Gene therapy for CNS disorders: modalities, delivery and translational challenges.

Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.

Multi-omics analysis reveals the potential pathogenesis and therapeutic targets of diabetic kidney disease.

Clinicians have long been interested in understanding the molecular basis of diabetic kidney disease (DKD)and its potential treatment targets. Its pathophysiology involves protein phosphorylation, one of the most recognizable post-transcriptional modifications, that can take part in many cellular functions and control different metabolic processes. In order to recognize the molecular and protein changes of DKD kidney, this study applied Tandem liquid chromatography-mass spectrometry (LC-MS/MS) and Next-Generation Sequencing, along with Tandem Mass Tags (TMT) labeling techniques to evaluate the mRNA, protein and modified phosphorylation sites between DKD mice and model ones. Based on Gene Ontology (GO) and KEGG pathway analyses of transcriptome and proteome, The molecular changes of DKD include accumulation of extracellular matrix, abnormally activated inflammatory microenvironment, oxidative stress and lipid metabolism disorders, leading to glomerulosclerosis and tubulointerstitial fibrosis. Oxidative stress has been emphasized as an important factor in DKD and progression to ESKD, which is directly related to podocyte injury, albuminuria and renal tubulointerstitial fibrosis. A histological study of phosphorylation further revealed that kinases were crucial. Three groups of studies have found that RAS signaling pathway, RAP1 signaling pathway, AMPK signaling pathway, PPAR signaling pathway and HIF-1 signaling pathway were crucial for the pathogenesis of DKD. Through this approach, it was discovered that targeting specific molecules, proteins, kinases and critical pathways could be a promising approach for treating DKD.

Comprehensive exploration of multi-modal and multi-branch imaging markers for autism diagnosis and interpretation: insights from an advanced deep learning model.

Autism spectrum disorder is a complex neurodevelopmental condition with diverse genetic and brain involvement. Despite magnetic resonance imaging advances, autism spectrum disorder diagnosis and understanding its neurogenetic factors remain challenging. We propose a dual-branch graph neural network that effectively extracts and fuses features from bimodalities, achieving 73.9% diagnostic accuracy. To explain the mechanism distinguishing autism spectrum disorder from healthy controls, we establish a perturbation model for brain imaging markers and perform a neuro-transcriptomic joint analysis using partial least squares regression and enrichment to identify potential genetic biomarkers. The perturbation model identifies brain imaging markers related to structural magnetic resonance imaging in the frontal, temporal, parietal, and occipital lobes, while functional magnetic resonance imaging markers primarily reside in the frontal, temporal, occipital lobes, and cerebellum. The neuro-transcriptomic joint analysis highlights genes associated with biological processes, such as "presynapse," "behavior," and "modulation of chemical synaptic transmission" in autism spectrum disorder's brain development. Different magnetic resonance imaging modalities offer complementary information for autism spectrum disorder diagnosis. Our dual-branch graph neural network achieves high accuracy and identifies abnormal brain regions and the neuro-transcriptomic analysis uncovers important genetic biomarkers. Overall, our study presents an effective approach for assisting in autism spectrum disorder diagnosis and identifying genetic biomarkers, showing potential for enhancing the diagnosis and treatment of this condition.

Enhanced group-level dorsolateral prefrontal cortex subregion parcellation through functional connectivity-based distance-constrained spectral clustering with application to autism spectrum disorder.

The dorsolateral prefrontal cortex (DLPFC) assumes a central role in cognitive and behavioral control, emerging as a crucial target region for interventions in autism spectrum disorder neuroregulation. Consequently, we endeavor to unravel the functional subregions within the DLPFC to shed light on the intricate functions of the brain. We introduce a distance-constrained spectral clustering (SC-DW) methodology that leverages functional connection to identify distinctive functional subregions within the DLPFC. Furthermore, we verify the relationship between the functional characteristics of these subregions and their clinical implications. Our methodology begins with principal component analysis to extract the salient features. Subsequently, we construct an adjacency matrix, which is constrained by the spatial properties of the brain, by linearly combining the distance matrix and a similarity matrix. The quality of spectral clustering is further optimized through multiple cluster evaluation coefficient. The results from SC-DW revealed four uniform and contiguous subregions within the bilateral DLPFC. Notably, we observe a substantial positive correlation between the functional characteristics of the third and fourth subregions in the left DLPFC with clinical manifestations. These findings underscore the unique insights offered by our proposed methodology in the realms of brain subregion delineation and therapeutic targeting.

Dietary Quality and Diet-Related Factors Among U.S. Emerging Adults (18-23y) Are a Cause for Concern, NHANES 2015-2018.

BACKGROUND: Poor dietary quality is a risk factor for diet-related chronic disease and suboptimal nutritional patterns often begin early in the life course. While the dietary intakes of young children, adolescents, and middle-aged and older adults are well established, much less is known about emerging adults, who represent a unique timepoint in life, as they are undergoing significant changes in food environments, autonomy, finances, and caregiver and parental involvement. OBJECTIVE: To examine dietary quality, as assessed via the Healthy Eating Index (HEI), by demographic, socioeconomic, and health-related characteristics among U.S. emerging adults (18-23y) who participated in the 2015-2018 National Health and Nutrition Examination Survey (NHANES). METHODS: NHANES data were collected via a household interview and 2 24-hour dietary recalls (24HR). Usual dietary intakes from the 24HRs were approximated using the multivariate National Cancer Institute Method to compute mean HEI-2015 overall and component scores (range 0-100, higher scores indicating higher dietary quality). RESULTS: Overall dietary quality among U.S. emerging adults [HEI-2015: 50.3±1.3] was significantly lower than other U.S. adults (≥24y) [HEI-2015: 56.3±0.5; p<0.0001], with differences primarily driven by lower intakes of whole fruit, vegetables, and whole grains, and higher intakes of sodium, refined grains, and saturated fat. Few differences in HEI-2015 scores were noted across population subgroups by sex, food security, family income, and food assistance program participation, except for added sugar; intakes of added sugar were significantly higher among women, food insecure, and food assistance program participants as compared to their counterparts, respectively. CONCLUSIONS: Dietary quality is poor among U.S. emerging adults and persists across all population subgroups, suggesting a significant need for tailored public health interventions to improve dietary quality among this population. Future research investigating to what extent emerging adults prioritize healthful behaviors and exploring other indicators for identifying nutritionally vulnerable subgroups may be impactful for identifying disparities among this life stage.

Anemia and testosterone deficiency risk: insights from NHANES data analysis and a Mendelian randomization analysis.

BACKGROUND: Previous research has shown that testosterone deficiency (TD) increases the risk of anemia, but it is unclear whether anemia affects testosterone levels. This study investigated the influence of anemia on testosterone levels. METHODS: Utilizing data from six NHANES cycles, including demographic, testosterone levels, and hemoglobin concentrations, we employed multivariable-adjusted logistic regression to investigate the relationship between anemia and testosterone levels. Moreover, a two-sample Mendelian randomization (MR) study employing genome-wide association study (GWAS) data examined the causal relationship. Kaplan-Meier survival estimation was used to compared the overall survival (OS) of anemic and nonanemic patients with low testosterone and normal testosterone levels. RESULTS: The inclusion of 21,786 participants (2318 with anemia and19,468 without anemia) revealed that nonanemic patients exhibited higher testosterone levels than did anemic patients (ß = 22.616, 95% CI: 3.873-41.359, p = 0.01807). MR analysis confirmed anemia as a cause of TD (OR = 1.045, 95% CI: 1.020-1.071, p < 0.001). Anemic males with low testosterone had reduced OS compared to those with normal levels (p < 0.001). CONCLUSIONS: Anemia emerged as a potential risk factor for TD, highlighting a bidirectional relationship between these conditions. Additional prospective investigations are essential for the validation and reinforcement of our findings.

Brain functional activity-based classification of autism spectrum disorder using an attention-based graph neural network combined with gene expression.

Autism spectrum disorder (ASD) is a complex brain neurodevelopmental disorder related to brain activity and genetics. Most of the ASD diagnostic models perform feature selection at the group level without considering individualized information. Evidence has shown the unique topology of the individual brain has a fundamental impact on brain diseases. Thus, a data-constructing method fusing individual topological information and a corresponding classification model is crucial in ASD diagnosis and biomarker discovery. In this work, we trained an attention-based graph neural network (GNN) to perform the ASD diagnosis with the fusion of graph data. The results achieved an accuracy of 79.78%. Moreover, we found the model paid high attention to brain regions mainly involved in the social-brain circuit, default-mode network, and sensory perception network. Furthermore, by analyzing the covariation between functional magnetic resonance imaging data and gene expression, current studies detected several ASD-related genes (i.e. MUTYH, AADAT, and MAP2), and further revealed their links to image biomarkers. Our work demonstrated that the ASD diagnostic framework based on graph data and attention-based GNN could be an effective tool for ASD diagnosis. The identified functional features with high attention values may serve as imaging biomarkers for ASD.

Classification of major depressive disorder using an attention-guided unified deep convolutional neural network and individual structural covariance network.

Major depressive disorder (MDD) is the second leading cause of disability worldwide. Currently, the structural magnetic resonance imaging-based MDD diagnosis models mainly utilize local grayscale information or morphological characteristics in a single site with small samples. Emerging evidence has demonstrated that different brain structures in different circuits have distinct developmental timing, but mature coordinately within the same functional circuit. Thus, establishing an attention-guided unified classification framework with deep learning and individual structural covariance networks in a large multisite dataset could facilitate developing an accurate diagnosis strategy. Our results showed that attention-guided classification could improve the classification accuracy from primary 75.1% to ultimate 76.54%. Furthermore, the discriminative features of regional covariance connectivities and local structural characteristics were found to be mainly located in prefrontal cortex, insula, superior temporal cortex, and cingulate cortex, which have been widely reported to be closely associated with depression. Our study demonstrated that our attention-guided unified deep learning framework may be an effective tool for MDD diagnosis. The identified covariance connectivities and structural features may serve as biomarkers for MDD.

Shared and distinct patterns of dynamic functional connectivity variability of thalamo-cortical circuit in bipolar depression and major depressive disorder.

Evidence has indicated abnormalities of thalamo-cortical functional connectivity (FC) in bipolar disorder during a depressive episode (BDD) and major depressive disorder (MDD). However, the dynamic FC (dFC) within this system is poorly understood. We explored the thalamo-cortical dFC pattern by dividing thalamus into 16 subregions and combining with a sliding-window approach. Correlation analysis was performed between altered dFC variability and clinical data. Classification analysis with a linear support vector machine model was conducted. Compared with healthy controls (HCs), both patients revealed increased dFC variability between thalamus subregions with hippocampus (HIP), angular gyrus and caudate, and only BDD showed increased dFC variability of the thalamus with superior frontal gyrus (SFG), HIP, insula, middle cingulate gyrus, and postcentral gyrus. Compared with MDD and HCs, only BDD exhibited enhanced dFC variability of the thalamus with SFG and superior temporal gyrus. Furthermore, the number of depressive episodes in MDD was significantly positively associated with altered dFC variability. Finally, the disrupted dFC variability could distinguish BDD from MDD with 83.44% classification accuracy. BDD and MDD shared common disrupted dFC variability in the thalamo-limbic and striatal-thalamic circuitries, whereas BDD exhibited more extensive and broader aberrant dFC variability, which may facilitate distinguish between these 2 mood disorders.

The association between shift work, shift work sleep disorders and premature ejaculation in male workers.

OBJECTIVE: Shift work and Shift Work Sleep Disorder (SWSD) are known to affect the secretion of several neurotransmitters and hormones associated with premature ejaculation (PE). However, their specific influence on the regulation of male ejaculation remains unclear. This study explores the relationship between shift work, SWSD, and PE. METHODS: From April to October 2023, a cross-sectional survey was conducted across five regions of China to explore the work schedules, sleep quality, and sexual function of male workers. Participants' sleep quality was evaluated using a validated SWSD questionnaire, and their erectile function and ejaculatory control were assessed with the International Inventory of Erectile Function (IIEF-5) scores and Premature Ejaculation Diagnostic Tool (PEDT) scores, respectively. Univariate and multivariate linear regression analyses were employed to identify risk factors associated with PE. Confounders were controlled using multiple regression models, and clinical prediction models were developed to predict PE onset and assess the contribution of risk factors. RESULTS: The study included 1239 eligible participants, comprising 840 non-shift workers and 399 shift workers (148 with SWSD and 251 without SWSD). Compared to non-shift working males, those involved in shift work (ß 1.58, 95% CI 0.75 - 2.42, p < 0.001) and those suffering from SWSD (ß 2.86, 95% CI 1.86 - 3.85, p < 0.001) they had significantly higher PEDT scores. Additionally, we identified daily sleep of less than six hours, depression, anxiety, diabetes, hyperlipidemia, frequent alcohol consumption (more than twice a week), and erectile dysfunction as risk factors for PE. The predictive model for PE demonstrated commendable efficacy. CONCLUSION: Both shift work and SWSD significantly increase the risk of premature ejaculation, with the risk magnifying in tandem with the duration of shift work. This study reveals the potential impact of shift work and SWSD on PE and provides new theoretical foundations for the risk assessment and prevention of this condition.

Genome-wide chromatin accessibility landscape and dynamics of transcription factor networks during ovule and fiber development in cotton.

BACKGROUND: The development of cotton fiber is regulated by the orchestrated binding of regulatory proteins to cis-regulatory elements associated with developmental genes. The cis-trans regulatory dynamics occurred throughout the course of cotton fiber development are elusive. Here we generated genome-wide high-resolution DNase I hypersensitive sites (DHSs) maps to understand the regulatory mechanisms of cotton ovule and fiber development. RESULTS: We generated DNase I hypersensitive site (DHS) profiles from cotton ovules at 0 and 3 days post anthesis (DPA) and fibers at 8, 12, 15, and 18 DPA. We obtained a total of 1185 million reads and identified a total of 199,351 DHSs through ~ 30% unique mapping reads. It should be noted that more than half of DNase-seq reads mapped multiple genome locations and were not analyzed in order to achieve a high specificity of peak profile and to avoid bias from repetitive genomic regions. Distinct chromatin accessibilities were observed in the ovules (0 and 3 DPA) compared to the fiber elongation stages (8, 12, 15, and 18 DPA). Besides, the chromatin accessibility during ovules was particularly elevated in genomic regions enriched with transposable elements (TEs) and genes in TE-enriched regions were involved in ovule cell division. We analyzed cis-regulatory modules and revealed the influence of hormones on fiber development from the regulatory divergence of transcription factor (TF) motifs. Finally, we constructed a reliable regulatory network of TFs related to ovule and fiber development based on chromatin accessibility and gene co-expression network. From this network, we discovered a novel TF, WRKY46, which may shape fiber development by regulating the lignin content. CONCLUSIONS: Our results not only reveal the contribution of TEs in fiber development, but also predict and validate the TFs related to fiber development, which will benefit the research of cotton fiber molecular breeding.

AQP4-A25Q Point Mutation in Mice Depolymerizes Orthogonal Arrays of Particles and Decreases Polarized Expression of AQP4 Protein in Astrocytic Endfeet at the Blood-Brain Barrier.

Aquaporin-4 (AQP4) is characterized by the formation of orthogonal arrays of particles (OAPs) comprising its M1 and M23 isoforms in the plasma membrane. However, the biological importance of OAP formation is obscure. Here, we developed an OAP depolymerization male mouse model by transgenic knock-in of an AQP4-A25Q mutation. Analyses of the mutant brain tissue using blue native polyacrylamide gel electrophoresis, super-resolution imaging, and immunogold electron microscopy revealed remarkably reduced OAP structures and glial endfeet localization of the AQP4-A25Q mutant protein without effects on its overall mRNA and protein expression. AQP4A25Q/A25Q mice showed better survival and neurologic deficit scores when cerebral edema was induced by water intoxication or middle cerebral artery occlusion/reperfusion. The brain water content and swelling of pericapillary astrocytic endfeet processes in AQP4A25Q/A25Q mice were significantly reduced, functionally supporting decreased AQP4 protein expression at the blood-brain barrier. The infarct volume and neuronal damage were also reduced in AQP4A25Q/A25Q mice in the middle cerebral artery occlusion/reperfusion model. Astrocyte activation in the brain was alleviated in AQP4A25Q/A25Q mice, which may be associated with decreased cell swelling. We conclude that the OAP structure of AQP4 plays a key role in its polarized expression in astrocytic endfeet processes at the blood-brain barrier. Therefore, our study provided new insights into intervention of cerebral cellular edema caused by stroke and traumatic brain injury through regulating AQP4 OAP formation.SIGNIFICANCE STATEMENT Aquaporin-4 (AQP4) is characterized by orthogonal arrays of particles (OAPs) comprising the M1 and M23 isoforms in the membrane. Here, an OAP depolymerization male mouse model induced by AQP4-A25Q mutation was first established, and the functions of OAP depolymerization in cerebral edema have been studied. The results revealed that AQP4 lost its OAP structure without affecting AQP4 mRNA and protein levels in AQP4-A25Q mice. AQP4-A25Q mutation mice has neuroprotective effects on cerebral edema induced by water intoxication and middle cerebral artery occlusion/reperfusion through relieving the activation of astrocytes and suppressed microglia-mediated neuroinflammation. We concluded that the OAP structure of AQP4 plays a key role in its polarized expression in astrocytic endfeet processes at the blood-brain barrier. Therefore, our study provided new insights into intervention of cerebral cellular edema caused by stroke and traumatic brain injury through regulating AQP4 OAP formation.

Path sampling and integration method to calculate speckle patterns.

A stable speckle pattern is generated when a coherent beam illuminates a stationary scattering medium that contains numerous scatterers with fixed positions. To date, there has been no valid method to the best of our knowledge for calculating the speckle pattern of a macro medium with a large number of scatterers. Here, a new method based on possible path sampling with corresponding weights and coherent superposition is presented for the simulation of optical field propagation in a scattering medium and output speckle patterns. In this method, a photon is launched onto a medium with fixed scatterers. It propagates in one direction; upon collision with a scatterer, its direction is updated. The procedure is repeated until it exits the medium. A sampled path is obtained in this manner. By repeatedly launching photons, numerous independent optical paths can be sampled. A speckle pattern, corresponding to the probability density of the photon, is formed by the coherent superposition of sufficiently sampled path lengths ending on a receiving screen. This method can be used in sophisticated studies of the influences of medium parameters, motion of scatterers, sample distortions on speckle distributions, and morphological appearances. It can be used for micro-examination of optical fields in scattering media and may inspire new methods and techniques for non-invasive precision detection and diagnosis of scattering media.

A Freestanding 3D Skeleton with Gradationally Distributed Lithiophilic Sites for Realizing Stable Lithium Anodes.

Lithium (Li) metal anodes are drawing considerable attention owing to their ultrahigh theoretical capacities and low electrochemical reduction potentials. However, their commercialization has been hampered by safety hazards induced by continuous dendrite growth. These issues can be alleviated using the ZnO-modified 3D carbon-based host containing carbon nanotubes (CNTs) and carbon felt (CF) fabricated by electroplating in the present study (denoted as ZnO/CNT@CF). The constructed skeleton has lithiophilic ZnO that is gradationally distributed along its thickness. The utilization of an inverted ZnO/CNT@CF-Li anode obtained by flipping over the carbon skeleton after Li electrodeposition is also reported herein. The synergistic effect of the Li metal and lithiophilic sites reduces the nucleation overpotential, thus inducing Li+ to preferentially deposit inside the porous carbon-based scaffold. The composite electrode compels Li to grow away from the separator, thereby significantly improving battery safety. A symmetric cell with the inverted ZnO/CNT@CF-Li electrode operates steadily for 700 cycles at 1 mA cm-2 and 1 mAh cm-2 . Moreover, the ZnO/CNT@CF-Li|S cell exhibits an initial areal capacity of 10.9 mAh cm-2 at a S loading of 10.4 mg cm-2 and maintains a capacity of 3.0 mAh cm-2 after 320 cycles.

Targeted Drug Delivery Using a Plug-to-Direct Antibody-Nanogel Conjugate.

Targeted drug delivery using antibody-drug conjugates has attracted great attention due to its enhanced therapeutic efficacy compared to traditional chemotherapy. However, the development has been limited due to a low drug-to-antibody ratio and laborious linker-payload optimization. Herein, we present a simple and efficient strategy to combine the favorable features of polymeric nanocarriers with antibodies to generate an antibody-nanogel conjugate (ANC) platform for targeted delivery of cytotoxic agents. Our nanogels stably encapsulate several chemotherapeutic agents with a wide range of mechanisms of action and solubility. We showcase the targetability of ANCs and their selective killing of cancer cells over-expressing disease-relevant antigens such as human epidermal growth factor receptor 2, epidermal growth factor receptor, and tumor-specific mucin 1, which cover a broad range of breast cancer cell types while maintaining low to no toxicity to non-targeted cells. Overall, our system represents a versatile approach that could impact next-generation nanomedicine in antibody-targeted therapeutics.

The role of tyrosine hydroxylase within dapoxetine-assisted therapy against premature ejaculation.

BACKGROUND: There are several investigations that have revealed that cerebral dopamine (DA) plays a pivotal role in the occurrence of premature ejaculation (PE). Although tyrosine hydroxylase (TH) is an essential enzyme for the synthesis of DA, only few investigations have described the role of TH in regulation mechanisms for ejaculation till now. To investigate whether there is a correlation between TH expression level in the brain and different ejaculation behavior in rats. Then explore whether the TH expression in the brain will change after acute dapoxetine treatment in rats with Rapid ejaculation. METHODS AND RESULTS: Rats (male, S-D rats, 6-8 weeks) were separated into three groups based on their ejaculation frequency: Rapid, Normal, and Sluggish. Expression level of DA in the brain was determined by enzyme-linked immune sorbent assay (ELISA) kit, TH expression level in the brain was determined by immunohistochemistry and Western Blot (WB) techniques. Among the three groups, DA and TH expression level were the highest in the Rapid ejaculation group, while the lowest was the Sluggish ejaculation group. The results also showed that TH level was positively associated with ejaculation frequency (r = 0.8038, P < 0.001) and negatively associated with ejaculation latency (r=-0.6199, P = 0.018). Furthermore, acute dapoxetine therapy in rats with Rapid ejaculation downregulated TH level in the brain. CONCLUSION: Changes in ejaculation behavior were significantly linked with TH level. Upregulated TH in selected brain regions related with ejaculation could cause rapid ejaculation. The effect of dapoxetine in prolonging ejaculation could be related to TH downregulation within the brain.

Enhancing Bone Grafting Outcomes: A Comprehensive Review of Antibacterial Artificial Composite Bone Scaffolds.

Bone defects and dysfunctions are prevalent among patients, resulting from various causes such as trauma, tumors, congenital malformations, inflammation, and infection. The demand for bone defect repair materials is second only to blood transfusions. Artificial bone composites offer numerous advantages for bone damage repair, including their availability, absence of rejection or immune reactions, high malleability, exceptional mechanical strength, and outstanding biocompatibility. However, bacterial infections frequently occur during bone transplantation or on graft material structures, leading to severe complications such as osteomyelitis and osteoporosis. Moreover, existing osteogenic materials alone are inadequate to address the challenges posed by traumatic infections, presenting a significant hurdle for clinicians in reconstructing infectious bone defects. Consequently, it is crucial to functionalize artificial bone composites to facilitate effective bone repair and regeneration. Notably, antibacterial capabilities play a critical role in preventing and treating infectious bone defects, and current research is focusing on the interface between artificial bone composites and antibacterial treatments. This article provides an extensive review of the current state of artificial composite bone scaffolds with antibacterial properties for infection prevention in bone grafting.

Antifibrotic mechanism of avitinib in bleomycin-induced pulmonary fibrosis in mice.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by alveolar epithelial cell injury and lung fibroblast overactivation. At present, only two drugs are approved by the FDA for the treatment of IPF, including the synthetic pyridinone drug, pirfenidone, and the tyrosine kinase inhibitor, nintedanib. Avitinib (AVB) is a novel oral and potent third-generation tyrosine kinase inhibitor for treating non-small cell lung cancer (NSCLC). However, the role of avitinib in pulmonary fibrosis has not yet been established. In the present study, we used in vivo and in vitro models to evaluate the role of avitinib in pulmonary fibrosis. In vivo experiments first verified that avitinib significantly alleviated bleomycin-induced pulmonary fibrosis in mice. Further in vitro molecular studies indicated that avitinib inhibited myofibroblast activation, migration and extracellular matrix (ECM) production in NIH-3T3 cells, mainly by inhibiting the TGF-ß1/Smad3 signalling pathways. The cellular experiments also indicated that avitinib improved alveolar epithelial cell injury in A549 cells. In conclusion, the present findings demonstrated that avitinib attenuates bleomycin-induced pulmonary fibrosis in mice by inhibiting alveolar epithelial cell injury and myofibroblast activation.

Observation and Manipulation of a Phase Separated State in a Charge Density Wave Material.

The 1T polytype of TaS2 has been studied extensively as a strongly correlated system. As 1T-TaS2 is thinned toward the 2D limit, its phase diagram shows significant deviations from that of the bulk material. Optoelectronic maps of ultrathin 1T-TaS2 have indicated the presence of nonequilibrium charge density wave phases within the hysteresis region of the nearly commensurate (NC) to commensurate (C) transition. We perform scanning tunneling microscopy on exfoliated ultrathin flakes of 1T-TaS2 within the NC-C hysteresis window, finding evidence that the observed nonequilibrium phases consist of intertwined, irregularly shaped NC-like and C-like domains. After applying lateral electrical signals to the sample, we image changes in the geometric arrangement of the different regions. We use a phase separation model to explore the relationship between electronic inhomogeneity present in ultrathin 1T-TaS2 and its bulk resistivity. These results demonstrate the role of phase competition morphologies in determining the properties of 2D materials.

Enduring effect of abuse: Childhood maltreatment links to altered theory of mind network among adults.

Childhood maltreatment (CM) confers a great risk of maladaptive development outcomes later in life, however, the neurobiological mechanism underlying this vulnerability is still unclear. The present study aimed to investigate the long-term consequences of CM on neural connectivity while controlling for psychiatric conditions, medication, and, substance abuse. A sample including adults with (n = 40) and without CM (n = 50) completed Childhood Trauma Questionnaire (CTQ), personality questionnaires, and resting-state functional magnetic resonance imaging scan were recruited for the current study. The whole-brain functional connectivity (FC) was evaluated using an unbiased, data-driven, multivariate pattern analysis method. Relative to controls, adults with CM suffered a higher level of temperament and impulsivity and showed decreased FC between the insula and superior temporal gyrus (STG) and between inferior parietal lobule (IPL) and middle frontal gyrus, STG, and dorsal anterior cingulate cortex (dACC), while increased FC between IPL and cuneus and superior frontal gyrus (SFG) regions. The FCs of IPL with dACC and SFG were correlated with the anxious and cyclothymic temperament and attentional impulsivity. Moreover, these FCs partially mediated the relationship between CM and attentional impulsivity. Our results suggest that CM has a significant effect on the modulation of FC within theory of mind (ToM) network even decades later in adulthood, and inform a new framework to account for how CM results in the development of impulsivity. The novel findings reveal the neurobiological consequences of CM and provide new clues to the prevention and intervention strategy to reduce the risk of the development of psychopathology.