Heterologous survey of 130 DNA transposons in human cells highlights their functional divergence and expands the genome engineering toolbox.

Experimental studies on DNA transposable elements (TEs) have been limited in scale, leading to a lack of understanding of the factors influencing transposition activity, evolutionary dynamics, and application potential as genome engineering tools. We predicted 130 active DNA TEs from 102 metazoan genomes and evaluated their activity in human cells. We identified 40 active (integration-competent) TEs, surpassing the cumulative number (20) of TEs found previously. With this unified comparative data, we found that the Tc1/mariner superfamily exhibits elevated activity, potentially explaining their pervasive horizontal transfers. Further functional characterization of TEs revealed additional divergence in features such as insertion bias. Remarkably, in CAR-T therapy for hematological and solid tumors, Mariner2_AG (MAG), the most active DNA TE identified, largely outperformed two widely used vectors, the lentiviral vector and the TE-based vector SB100X. Overall, this study highlights the varied transposition features and evolutionary dynamics of DNA TEs and increases the TE toolbox diversity.

A thalamic-primary auditory cortex circuit mediates resilience to stress.

Resilience enables mental elasticity in individuals when rebounding from adversity. In this study, we identified a microcircuit and relevant molecular adaptations that play a role in natural resilience. We found that activation of parvalbumin (PV) interneurons in the primary auditory cortex (A1) by thalamic inputs from the ipsilateral medial geniculate body (MG) is essential for resilience in mice exposed to chronic social defeat stress. Early attacks during chronic social defeat stress induced short-term hyperpolarizations of MG neurons projecting to the A1 (MGA1 neurons) in resilient mice. In addition, this temporal neural plasticity of MGA1 neurons initiated synaptogenesis onto thalamic PV neurons via presynaptic BDNF-TrkB signaling in subsequent stress responses. Moreover, optogenetic mimicking of the short-term hyperpolarization of MGA1 neurons, rather than merely activating MGA1 neurons, elicited innate resilience mechanisms in response to stress and achieved sustained antidepressant-like effects in multiple animal models, representing a new strategy for targeted neuromodulation.

LncRNA CARMN inhibits abdominal aortic aneurysm formation and vascular smooth muscle cell phenotypic transformation by interacting with SRF.

Phenotypic transformation of vascular smooth muscle cells (VSMCs) plays a crucial role in abdominal aortic aneurysm (AAA) formation. CARMN, a highly conserved, VSMC-enriched long noncoding RNA (lncRNA), is integral in orchestrating various vascular pathologies by modulating the phenotypic dynamics of VSMCs. The influence of CARMN on AAA formation, particularly its mechanisms, remains enigmatic. Our research, employing single-cell and bulk RNA sequencing, has uncovered a significant suppression of CARMN in AAA specimens, which correlates strongly with the contractile function of VSMCs. This reduced expression of CARMN was consistent in both 7- and 14-day porcine pancreatic elastase (PPE)-induced mouse models of AAA and in human clinical cases. Functional analyses disclosed that the diminution of CARMN exacerbated PPE-precipitated AAA formation, whereas its augmentation conferred protection against such formation. Mechanistically, we found CARMN's capacity to bind with SRF, thereby amplifying its role in driving the transcription of VSMC marker genes. In addition, our findings indicate an enhancement in CAMRN transcription, facilitated by the binding of NRF2 to its promoter region. Our study indicated that CARMN plays a protective role in preventing AAA formation and restrains the phenotypic transformation of VSMC through its interaction with SRF. Additionally, we observed that the expression of CARMN is augmented by NRF2 binding to its promoter region. These findings suggest the potential of CARMN as a viable therapeutic target in the treatment of AAA.

Oncogenic and immunological roles of RACGAP1 in pan-cancer and its potential value in nasopharyngeal carcinoma.

A particular GTPase-activating protein called RACGAP1 is involved in apoptosis, proliferation, invasion, metastasis, and drug resistance in a variety of malignancies. Nevertheless, the role of RACGAP1 in pan-cancer was less studied, and its value of the expression and prognostic of nasopharyngeal carcinoma (NPC) has not been explored. Hence, the goal of this study was to investigate the oncogenic and immunological roles of RACGAP1 in various cancers and its potential value in NPC. We comprehensively analyzed RACGAP1 expression, prognostic value, function, methylation levels, relationship with immune cells, immune infiltration, and immunotherapy response in pan-cancer utilizing multiple databases. The results discovered that RACGAP1 expression was elevated in most cancers and suggested poor prognosis, which could be related to the involvement of RACGAP1 in various cancer-related pathways such as the cell cycle and correlated with RACGAP1 methylation levels, immune cell infiltration and reaction to immunotherapy, and chemoresistance. RACGAP1 could inhibit anti-tumor immunity and immunotherapy responses by fostering immune cell infiltration and cytotoxic T lymphocyte dysfunction. Significantly, we validated that RACGAP1 mRNA and protein were highly expressed in NPC. The Gene Expression Omnibus database revealed that elevated RACGAP1 expression was associated with shorter PFS in patients with NPC, and RACGAP1 potentially influenced cell cycle progression, DNA replication, metabolism, and immune-related pathways, resulting in the recurrence and metastasis of NPC. This study indicated that RACGAP1 could be a potential biomarker in pan-cancer and NPC.

Irisin ameliorates diabetic kidney disease by restoring autophagy in podocytes.

Many studies have highlighted the importance of moderate exercise. While it can attenuate diabetic kidney disease, its mechanism has remained unclear. The level of myokine irisin in plasma increases during exercise. We found that irisin was decreased in diabetic patients and was closely related to renal function, proteinuria, and podocyte autophagy injury. Muscle-specific overexpression of PGC-1α (mPGC-1α) in a mouse model is known to increase plasma irisin levels. The mPGC-1α mice were crossed with db/m mice to obtain db/db mPGC-1α+ mice in the present study. Compared to db/db mice without mPGC-1α, plasma irisin was increased, and albuminuria and glomerular pathological damage were both alleviated in db/db mPGC-1α+ mice. Impaired autophagy in podocytes was restored as well. Irisin inhibited the activation of the PI3K/AKT/mTOR signaling pathway in cultured human podocytes and improved damaged autophagy induced by high glucose levels. Then, db/db mice were treated with recombinant irisin, which had similar beneficial effects on the kidney as those in db/db mPGC-1α+ mice, with alleviated glomerular injury and albuminuria. Moreover, the autophagy in podocytes was also significantly restored. These results suggest that irisin secreted by skeletal muscles protects the kidney from diabetes mellitus damage. It also restores autophagy in podocytes by inhibiting the abnormal activation of the PI3K/AKT/mTOR signaling pathway. Thus, irisin may become a new drug for the prevention and treatment of diabetic nephropathy.

Comprehensive Investigation of the Temperature-Dependent Electromechanical Behaviors of Carbon Nanotube/Polymer Composites.

The performances of flexible piezoresistive sensors based on polymer nanocomposites are significantly affected by the environmental temperature; therefore, comprehensively investigating the temperature-dependent electromechanical response behaviors of conductive polymer nanocomposites is crucial for developing high-precision flexible piezoresistive sensors in a wide-temperature range. Herein, carbon nanotube (CNT)/polydimethylsiloxane (PDMS) composites widely used for flexible piezoresistive sensors were prepared, and then the temperature-dependent electrical, mechanical, and electromechanical properties of the optimized CNT/PDMS composite in the temperature range from -150 to 150 °C were systematically investigated. At a low temperature of -150 °C, the CNT/PDMS composite becomes brittle with a compressive modulus of ∼1.2 MPa and loses its elasticity and reversible sensing capability. At a high temperature (above 90 °C), the CNT/PDMS composite softens, shows a fluid-like mechanical property, and loses its reversible sensing capability. In the temperature range from -60 to 90 °C, the CNT/PDMS composite exhibits good elasticity and reversible sensing behaviors and its modulus, resistivity, and sensing sensitivity decrease with an increasing temperature. At room temperature (30 °C), the CNT/PDMS composite exhibits better mechanical and piezoresistive stability than those at low and high temperatures. Given that environmental temperature changes have significant effects on the sensing performances of conductive polymer composites, the effect of ambient temperature changes must be considered when flexible piezoresistive sensors are designed and fabricated.

Prognostic Significance of Excision Repair Cross-Complementation Group 1 on Circulating Tumor Cells for Nasopharyngeal Carcinoma.

BACKGROUND: Liquid biopsy, including the detection of circulating tumor cells (CTCs), has emerged as a promising tool for cancer diagnosis and monitoring. However, the prognostic value of CTCs in nasopharyngeal carcinoma (NPC) remains unclear due to the lack of phenotypic characterization. The expression of Excision Repair Cross-Complementation Group 1 (ERCC1) and CTCs epithelial-mesenchymal transition (EMT) have been associated with treatment efficacy. In this study, we aimed to evaluate the prognostic significance of ERCC1 expression on CTCs and their EMT subtypes before treatment in NPC. METHODS: We retrospectively analyzed 108 newly diagnosed locally advanced NPC patients who underwent CanPatrol™ CTC testing between November 2018 and November 2021. CTCs were counted and classified into epithelial, epithelial-mesenchymal hybrid, and mesenchymal subtypes. ERCC1 expression was divided into negative and positive groups. Clinical features and survival outcomes were analyzed. RESULTS: The positive rate of CTCs was 92.6% (100/108), with an ERCC1 positivity rate of 74% (74/100). Further analysis of the subtypes showed that positive ERCC1 on mesenchymal CTCs was associated with a later N stage (P = .01). Positive ERCC1 expression was associated with poor overall survival (OS; P = .039) and disease-free survival (DFS; P = .035). Further analysis of subtypes showed that the positive ERCC1 on mesenchymal-type CTCs was associated with poor OS (P = .012) and metastasis-free survival (MFS; P = .001). CONCLUSION: Our findings suggest that ERCC1 expression on CTCs may serve as a new prognostic marker for NPC patients. Evaluating CTCs subtypes may become an auxiliary tool for personalized and precise treatment.

BackgroundLiquid biopsy, including the detection of circulating tumor cells (CTCs), has emerged as a promising tool for cancer diagnosis and monitoring. However, the prognostic value of CTCs in nasopharyngeal carcinoma (NPC) remains unclear due to the lack of phenotypic characterization. The expression of Excision Repair Cross-Complementation Group 1 (ERCC1) and CTCs epithelial-mesenchymal transition (EMT) have been associated with treatment efficacy. In this study, we aimed to evaluate the prognostic significance of ERCC1 expression on CTCs and their EMT subtypes before treatment in NPC.MethodsWe retrospectively analyzed 108 newly diagnosed locally advanced NPC patients who underwent CanPatrol™ CTC testing between November 2018 and November 2021. CTCs were counted and classified into epithelial, epithelial-mesenchymal hybrid, and mesenchymal subtypes. ERCC1 expression was divided into negative and positive groups. Clinical features and survival outcomes were analyzed.ResultsThe positive rate of CTCs was 92.6% (100/108), with an ERCC1 positivity rate of 74% (74/100). Further analysis of the subtypes showed that positive ERCC1 on mesenchymal CTCs was associated with a later N stage (P = .01). Positive ERCC1 expression was associated with poor overall survival (OS; P = .039) and disease-free survival (DFS; P = .035). Further analysis of subtypes showed that the positive ERCC1 on mesenchymal-type CTCs was associated with poor OS (P = .012) and metastasis-free survival (MFS; P = .001).ConclusionOur findings suggest that ERCC1 expression on CTCs may serve as a new prognostic marker for NPC patients. Evaluating CTCs subtypes may become an auxiliary tool for personalized and precise treatment.

Identifying patients with cognitive motor dissociation using resting-state temporal stability.

Using task-dependent neuroimaging techniques, recent studies discovered a fraction of patients with disorders of consciousness (DOC) who had no command-following behaviors but showed a clear sign of awareness as healthy controls, which was defined as cognitive motor dissociation (CMD). However, existing task-dependent approaches might fail when CMD patients have cognitive function (e.g., attention, memory) impairments, in which patients with covert awareness cannot perform a specific task accurately and are thus wrongly considered unconscious, which leads to false-negative findings. Recent studies have suggested that sustaining a stable functional organization over time, i.e., high temporal stability, is crucial for supporting consciousness. Thus, temporal stability could be a powerful tool to detect the patient's cognitive functions (e.g., consciousness), while its alteration in the DOC and its capacity for identifying CMD were unclear. The resting-state fMRI (rs-fMRI) study included 119 participants from three independent research sites. A sliding-window approach was used to investigate global and regional temporal stability, which measured how stable the brain's functional architecture was across time. The temporal stability was compared in the first dataset (36/16 DOC/controls), and then a Support Vector Machine (SVM) classifier was built to discriminate DOC from controls. Furthermore, the generalizability of the SVM classifier was tested in the second independent dataset (35/21 DOC/controls). Finally, the SVM classifier was applied to the third independent dataset, where patients underwent rs-fMRI and brain-computer interface assessment (4/7 CMD/potential non-CMD), to test its performance in identifying CMD. Our results showed that global and regional temporal stability was impaired in DOC patients, especially in regions of the cingulo-opercular task control network, default-mode network, fronto-parietal task control network, and salience network. Using temporal stability as the feature, the SVM model not only showed good performance in the first dataset (accuracy = 90%), but also good generalizability in the second dataset (accuracy = 84%). Most importantly, the SVM model generalized well in identifying CMD in the third dataset (accuracy = 91%). Our preliminary findings suggested that temporal stability could be a potential tool to assist in diagnosing CMD. Furthermore, the temporal stability investigated in this study also contributed to a deeper understanding of the neural mechanism of consciousness.

Structural Mass Spectrometry Probes the Inhibitor-Induced Allosteric Activation of CDK12/CDK13-Cyclin K Dissociation.

The rational design and development of effective inhibitors for cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) are largely dependent on the understanding of the dynamic inhibition conformations but are difficult to be achieved by conventional characterization tools. Herein, we integrate the structural mass spectrometry (MS) methods of lysine reactivity profiling (LRP) and native MS (nMS) to systematically interrogate both the dynamic molecular interactions and overall protein assembly of CDK12/CDK13-cyclin K (CycK) complexes under the modulation of small molecule inhibitors. The essential structure insights, including inhibitor binding pocket, binding strength, interfacial molecular details, and dynamic conformation changes, can be derived from the complementary results of LRP and nMS. We find the inhibitor SR-4835 binding can greatly destabilize the CDK12/CDK13-CycK interactions in an unusual allosteric activation way, thereby providing a novel alternative for the kinase activity inhibition. Our results underscore the great potential of LRP combination with nMS for the evaluation and rational design of effective kinase inhibitors at the molecular level.

Integrative transcriptome analysis reveals TEKT2 and PIAS2 involvement in diabetic nephropathy.

Cell heterogeneity has impeded the accurate interpretation of the bulk transcriptome data from patients with diabetic nephropathy (DN). We performed an analysis by integrating bulk and single-cell transcriptome datasets to uncover novel mechanisms leading to DN, especially in the podocytes. Microdissected glomeruli and tubules transcriptome datasets were selected from Gene Expression Omnibus (GEO). Then the consistency between datasets was evaluated. The analysis of the bulk dataset and single-nucleus RNA dataset was integrated to reveal the cell type-specific responses to DN. The candidate genes were validated in kidney tissues from DN patients and diabetic mice. We compared 4 glomerular and 4 tubular datasets and found considerable discrepancies among datasets regarding the deferentially expressed genes (DEGs), involved signaling pathways, and the hallmark enrichment profiles. Deconvolution of the bulk data revealed that the variations in cell-type proportion contributed greatly to this discrepancy. The integrative analysis uncovered that the dysregulation of spermatogenesis-related genes, including TEKT2 and PIAS2, was involved in the development of DN. Importantly, the mRNA level of TEKT2 was negatively correlated with the mRNA levels of NPHS1 (r = -.66, p < .0001) and NPHS2 (r = -.85, p < .0001) in human diabetic glomeruli. Immunostaining confirmed that the expression of TEKT2 and PIAS2 were up-regulated in podocytes of DN patients and diabetic mice. Knocking down TEKT2 resisted high glucose-induced cytoskeletal remodeling and down-regulation of NPHS1 protein in the cultured podocyte. In conclusion, the integrative strategy can help us efficiently use the publicly available transcriptomics resources. Using this approach and combining it with classical research methods, we identified TEKT2 and PIAS2, two spermatogenesis-related genes involved in the pathogenesis of DN. Furthermore, TEKT2 is involved in this pathogenesis by regulating the podocyte cytoskeleton.

Discovery of a highly potent NPAS3 heterodimer inhibitor by covalently modifying ARNT.

Neuronal PAS domain protein 3 (NPAS3), a basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) family member, is a pivotal transcription factor in neuronal regeneration, development, and related diseases, regulating the expression of downstream genes. Despite several modulators of certain bHLH-PAS family proteins being identified, the NPAS3-targeted compound has yet to be reported. Herein, we discovered a hit compound BI-78D3 that directly blocks the NPAS3-ARNT heterodimer formation by covalently binding to the aryl hydrocarbon receptor nuclear translocator (ARNT) subunit. Further optimization based on the hit scaffold yielded a highly potent Compound 6 with a biochemical EC50 value of 282 ± 61 nM and uncovered the 5-nitrothiazole-2-sulfydryl as a cysteine-targeting covalent warhead. Compound 6 effectively down-regulated NPAS3's transcriptional function by disrupting the interface of NPAS3-ARNT complexes at cellular level. In conclusion, our study identifies the 5-nitrothiazole-2-sulfydryl as a cysteine-modified warhead and provides a strategy that blocks the NPAS3-ARNT heterodimerization by covalently conjugating ARNT Cys336 residue. Compound 6 may serve as a promising chemical probe for exploring NPAS3-related physiological functions.

A deep learning approach to the diagnosis of atelectasis and attic retraction pocket in otitis media with effusion using otoscopic images.

BACKGROUND: This study aimed to develop and validate a deep learning (DL) model to identify atelectasis and attic retraction pocket in cases of otitis media with effusion (OME) using multi-center otoscopic images. METHOD: A total of 6393 OME otoscopic images from three centers were used to develop and validate a DL model for detecting atelectasis and attic retraction pocket. A threefold random cross-validation procedure was adopted to divide the dataset into training validation sets on a patient level. A team of otologists was assigned to diagnose and characterize atelectasis and attic retraction pocket in otoscopic images. Receiver operating characteristic (ROC) curves, including area under the ROC curve (AUC), accuracy, sensitivity, and specificity were used to assess the performance of the DL model. Class Activation Mapping (CAM) illustrated the discriminative regions in the otoscopic images. RESULTS: Among all OME otoscopic images, 3564 (55.74%) were identified with attic retraction pocket, and 2460 (38.48%) with atelectasis. The diagnostic DL model of attic retraction pocket and atelectasis achieved a threefold cross-validation accuracy of 89% and 79%, AUC of 0.89 and 0.87, a sensitivity of 0.93 and 0.71, and a specificity of 0.62 and 0.84, respectively. Larger and deeper cases of atelectasis and attic retraction pocket showed greater weight, based on the red color depicted in the heat map of CAM. CONCLUSION: The DL algorithm could be employed to identify atelectasis and attic retraction pocket in otoscopic images of OME, and as a tool to assist in the accurate diagnosis of OME.

Graphene nanoplatelet/cellulose acetate film with enhanced antistatic, thermal dissipative and mechanical properties for packaging.

With the increased concern over environment protection, cellulose acetate (CA) has drawn great interests as an alternative for packaging material due to its biodegradability and abundant resources; whereas, the poor antistatic property and thermal conductivity restrict its application in packaging. In this work, we proposed a simple but effective strategy to produce high performance graphene nanoplatelet (GNP)/CA composite films via the consecutive homogenization and solvent casting processes. Relying on the spontaneous absorption of CA during homogenization, the GNP/CA produced shows an excellent dispersibility in the N,N-Dimethylformamide (DMF) solution and many fewer structural defects compared with GNPs alone. As a result, the composite films obtained exhibit simultaneously and significantly enhanced antistatic, heat dissipative and mechanical properties compared with CA. Specifically, the GNP/CA composite with the optimal formula has promising overall performances (namely, surface resistivity of 3.33 × 107 Ω/sq, in-plane thermal conductivity of 5.359 W ( m · K ) , out-of-plane thermal conductivity of 0.785 W ( m · K ) , and tensile strength of 37.1 MPa). Featured by its promising overall properties, simple production processes and biodegradability, the as-prepared GNP/CA composite film shows a great potential for application in packaging. Supplementary Information: The online version contains supplementary material available at 10.1007/s10570-023-05155-2.

Brain-Computer Interfaces for Awareness Detection, Auxiliary Diagnosis, Prognosis, and Rehabilitation in Patients with Disorders of Consciousness.

In recent years, neuroimaging studies have remarkably demonstrated the presence of cognitive motor dissociation in patients with disorders of consciousness (DoC). These findings accelerated the development of brain-computer interfaces (BCIs) as clinical tools for behaviorally unresponsive patients. This article reviews the recent progress of BCIs in patients with DoC and discusses the open challenges. In view of the practical application of BCIs in patients with DoC, four aspects of the relevant literature are introduced: consciousness detection, auxiliary diagnosis, prognosis, and rehabilitation. For each aspect, the paradigm design, brain signal processing methods, and experimental results of representative BCI systems are analyzed. Furthermore, this article provides guidance for BCI design for patients with DoC and discusses practical challenges for future research.

LLPSDB: a database of proteins undergoing liquid-liquid phase separation in vitro.

Liquid-liquid phase separation (LLPS) leads to a conversion of homogeneous solution into a dense phase that often resembles liquid droplets, and a dilute phase. An increasing number of investigations have shown that biomolecular condensates formed by LLPS play important roles in both physiology and pathology. It has been suggested the phase behavior of proteins would be not only determined by sequences, but controlled by micro-environmental conditions. Here, we introduce LLPSDB (http://bio-comp.ucas.ac.cn/llpsdb or http://bio-comp.org.cn/llpsdb), a web-accessible database providing comprehensive, carefully curated collection of proteins involved in LLPS as well as corresponding experimental conditions in vitro from published literatures. The current release of LLPSDB incorporates 1182 entries with 273 independent proteins and 2394 specific conditions. The database provides a variety of data including biomolecular information (protein sequence, protein modification, nucleic acid, etc.), specific phase separation information (experimental conditions, phase behavior description, etc.) and comprehensive annotations. To our knowledge, LLPSDB is the first available database designed for LLPS related proteins specifically. It offers plenty of valuable resources for exploring the relationship between protein sequence and phase behavior, and will enhance the development of phase separation prediction methods, which may further provide more insights into a comprehensive understanding of LLPS in cellular function and related diseases.

Alterations of brain activity and functional connectivity in transition from acute to chronic tinnitus.

The objective of this study was to investigate alterations to brain activity and functional connectivity in patients with tinnitus, exploring neural features in the transition from acute to chronic phantom perception. Twenty-four patients with acute tinnitus, 23 patients with chronic tinnitus, and 32 healthy controls were recruited. High-density electroencephalography (EEG) was used to explore changes in brain areas and functional connectivity in different groups. When compared with healthy subjects, acute tinnitus patients had a significant reduction in superior frontal cortex activity across all frequency bands, whereas chronic tinnitus patients had a significant reduction in the superior frontal cortex at beta 3 and gamma frequency bands as well as a significant increase in the inferior frontal cortex at delta-band and superior temporal cortex at alpha 1 frequency band. When compared to the chronic tinnitus group, the acute tinnitus group activity was significantly increased in the middle frontal and parietal gyrus at the gamma-band. Functional connectivity analysis showed that the chronic tinnitus group had increased connections between the parahippocampus gyrus, posterior cingulate cortex, and precuneus when compared with the healthy group. Alterations of local brain activity and connections between the parahippocampus gyrus and other nonauditory areas appeared in the transition from acute to chronic tinnitus. This indicates that the appearance and development of tinnitus is a dynamic process involving aberrant local neural activity and abnormal connectivity in multifunctional brain networks.

Design, synthesis and biological evaluation of a novel spiro oxazolidinedione as potent p300/CBP HAT inhibitor for the treatment of ovarian cancer.

Histone acetylation is one of the most essential parts of epigenetic modification, mediating a variety of complex biological functions. In these procedure, p300/CBP could catalyze the acetylation of lysine 27 on histone 3 (H3K27ac), and had been reported to mediate tumorigenesis and development in a variety of tumors by enhancing chromatin transcription activity. Ovarian cancer, as an extremely malignant tumor, has also been observed to undergo abnormal acetylation of histones. However, whether the treatment of ovarian cancer could be achieved by inhibiting the acetylation activity of p300/CBP on H3K27 has not been well investigated. In this article, we modified the structure of p300/CBP HAT domain inhibitor A-485 and obtained a highly active small molecule known as 13f, which has an IC50 value of 0.49 nM for inhibiting the in vitro enzyme activity of p300, as well as the anti-proliferation IC50 value on ovarian cancer cell line OVCAR-3 was 153 nM. In addition, 13f had strong acetylase family selectivity, good metabolic stability and promising in vivo anti-tumor activity in OVCAR-3 xenograft model. The discovery of 13f revealed a more active chemical entity of the HATs domain of p300/CBP and provided a novel idea for the application of epigenetic inhibitors in the treatment of ovarian cancer.

Prognosis for patients with cognitive motor dissociation identified by brain-computer interface.

Cognitive motor dissociation describes a subset of patients with disorders of consciousness who show neuroimaging evidence of consciousness but no detectable command-following behaviours. Although essential for family counselling, decision-making, and the design of rehabilitation programmes, the prognosis for patients with cognitive motor dissociation remains under-investigated. The current study included 78 patients with disorders of consciousness who showed no detectable command-following behaviours. These patients included 45 patients with unresponsive wakefulness syndrome and 33 patients in a minimally conscious state, as diagnosed using the Coma Recovery Scale-Revised. Each patient underwent an EEG-based brain-computer interface experiment, in which he or she was instructed to perform an item-selection task (i.e. select a photograph or a number from two candidates). Patients who achieved statistically significant brain-computer interface accuracies were identified as cognitive motor dissociation. Two evaluations using the Coma Recovery Scale-Revised, one before the experiment and the other 3 months later, were carried out to measure the patients' behavioural improvements. Among the 78 patients with disorders of consciousness, our results showed that within the unresponsive wakefulness syndrome patient group, 15 of 18 patients with cognitive motor dissociation (83.33%) regained consciousness, while only five of the other 27 unresponsive wakefulness syndrome patients without significant brain-computer interface accuracies (18.52%) regained consciousness. Furthermore, within the minimally conscious state patient group, 14 of 16 patients with cognitive motor dissociation (87.5%) showed improvements in their Coma Recovery Scale-Revised scores, whereas only four of the other 17 minimally conscious state patients without significant brain-computer interface accuracies (23.53%) had improved Coma Recovery Scale-Revised scores. Our results suggest that patients with cognitive motor dissociation have a better outcome than other patients. Our findings extend current knowledge of the prognosis for patients with cognitive motor dissociation and have important implications for brain-computer interface-based clinical diagnosis and prognosis for patients with disorders of consciousness.

[An electroencephalogram-based study of resting-state spectrogram and attention in tinnitus patients].

The incidence of tinnitus is very high, which can affect the patient's attention, emotion and sleep, and even cause serious psychological distress and suicidal tendency. Currently, there is no uniform and objective method for tinnitus detection and therapy, and the mechanism of tinnitus is still unclear. In this study, we first collected the resting state electroencephalogram (EEG) data of tinnitus patients and healthy subjects. Then the power spectrum topology diagrams were compared of in the band of δ (0.5-3 Hz), θ (4-7 Hz), α (8-13 Hz), ß (14-30 Hz) and γ (31-50 Hz) to explore the central mechanism of tinnitus. A total of 16 tinnitus patients and 16 healthy subjects were recruited to participate in the experiment. The results of resting state EEG experiments found that the spectrum power value of tinnitus patients was higher than that of healthy subjects in all concerned frequency bands. The t-test results showed that the significant difference areas were mainly concentrated in the right temporal lobe of the θ and α band, and the temporal lobe, parietal lobe and forehead area of the ß and γ band. In addition, we designed an attention-related task experiment to further study the relationship between tinnitus and attention. The results showed that the classification accuracy of tinnitus patients was significantly lower than that of healthy subjects, and the highest classification accuracies were 80.21% and 88.75%, respectively. The experimental results indicate that tinnitus may cause the decrease of patients' attention.

SGLT2 inhibitors and atrial fibrillation in type 2 diabetes: a systematic review with meta-analysis of 16 randomized controlled trials.

BACKGROUND: Type 2 diabetes is closely related to an increased risk of atrial fibrillation (AF) and atrial flutter (AFL). Whether sodium-glucose cotransporter 2 (SGLT2) inhibitors can attenuate AF/AFL progression remains unclear. METHODS: We searched electronic databases (PubMed, Embase and ClinicalTrials.gov) from their inception to January 2020 for trials evaluating the AF outcomes of SGLT2 inhibitors in patients with type 2 diabetes. The data search and extraction were conducted with a standardized data form and any conflicts were resolved by consensus. Relative risks (RRs) with 95% confidence intervals (CIs) were used for binary variables, and the weighed mean differences (WMDs) with the standard deviation (SDs) were applied for continuous variables. RESULTS: We included data from 16 identified trials consisting of 38,335 patients with type 2 diabetes. Incorporated data demonstrated that compared to placebo, SGLT2 inhibitors significantly reduced AF/AFL (RR: 0.76; 95% CI 0.65-0.90; p = 0.001) and all-cause mortality (RR: 0.91; 95% CI 0.83-0.99; p = 0.03). AF/AFL reductions were not modified by age, body weight, glycated haemoglobin (HbA1c), or systolic blood pressure (SBP) at baseline (all p-interactions > 0.3). SGLT2 inhibitors also significantly reduced heart failure events (RR: 0.73; 95% CI 0.64-0.84; p < 0.00001), HbA1c (WMD: - 0.62%; 95% CI - 0.89 to - 0.34; p < 0.00001), body weight (WMD: - 2.12 kg; 95% CI - 2.91 to - 1.34; p < 0.00001), SBP (WMD: - 3.34 mmHg; 95% CI - 4.12 to - 2.56; p < 0.00001), and diastolic blood pressure (DBP) (WMD: - 1.11 mmHg; 95% CI - 1.62 to - 0.60; p < 0.0001). Of note, cerebrovascular events and myocardial infarction did not increase in patients taking SGLT2 inhibitors. CONCLUSION: SGLT2 inhibitors may confer a specific AF/AFL-reduction benefit in the susceptible type 2 diabetes population, regardless of age, body weight, HbA1c, and systolic blood pressure at baseline. Such an AF/AFL-reduction benefit may be partly attributed to pharmacological effects on reductions in HbA1c, body weight, blood pressure, and the occurrence of heart failure.