Dysregulation of BRD4 Function Underlies the Functional Abnormalities of MeCP2 Mutant Neurons.

Rett syndrome (RTT), mainly caused by mutations in methyl-CpG binding protein 2 (MeCP2), is one of the most prevalent intellectual disorders without effective therapies. Here, we used 2D and 3D human brain cultures to investigate MeCP2 function. We found that MeCP2 mutations cause severe abnormalities in human interneurons (INs). Surprisingly, treatment with a BET inhibitor, JQ1, rescued the molecular and functional phenotypes of MeCP2 mutant INs. We uncovered that abnormal increases in chromatin binding of BRD4 and enhancer-promoter interactions underlie the abnormal transcription in MeCP2 mutant INs, which were recovered to normal levels by JQ1. We revealed cell-type-specific transcriptome impairment in MeCP2 mutant region-specific human brain organoids that were rescued by JQ1. Finally, JQ1 ameliorated RTT-like phenotypes in mice. These data demonstrate that BRD4 dysregulation is a critical driver for RTT etiology and suggest that targeting BRD4 could be a potential therapeutic opportunity for RTT.

Blue Phosphorescent Pt(II) Compound Based on Tetradentate Carbazole/2,3'-Bipyridine Ligand and Its Application in Organic Light-Emitting Diodes.

The tetradentate ligand, merging a carbazole unit with high triplet energy and dimethoxy bipyridine, renowned for its exceptional quantum efficiency in coordination with metals like Pt, is expected to demonstrate remarkable luminescent properties. However, instances of tetradentate ligands such as bipyridine-based pyridylcarbazole derivatives remain exceptionally scarce in the current literature. In this study, we developed a tetradentate ligand based on carbazole and 2,3'-bipyridine and successfully complexed it with Pt(II) ions. This novel compound (1) serves as a sky-blue phosphorescent material for use in light-emitting diodes. Based on single-crystal X-ray analysis, compound 1 has a distorted square-planar geometry with a 5/6/6 backbone around the Pt(II) core. Bright sky-blue emissions were observed at 488 and 516 nm with photoluminescent quantum yields of 34% and a luminescent lifetime of 2.6 µs. TD-DFT calculations for 1 revealed that the electronic transition was mostly attributed to the ligand-centered (LC) charge transfer transition with a small contribution from the metal-to-ligand charge transfer transition (MLCT, ~14%). A phosphorescent organic light-emitting device was successfully fabricated using this material as a dopant, along with 3'-di(9H-carbazol-9-yl)-1,1'-biphenyl (mCBP) and 9-(3'-carbazol-9-yl-5-cyano-biphenyl-3-yl)-9H-carbazole-3-carbonitrile (CNmCBPCN) as mixed hosts. A maximum quantum efficiency of 5.2% and a current efficiency of 15.5 cd/A were obtained at a doping level of 5%.

Adult Born Dentate Granule Cell Mediated Upregulation of Feedback Inhibition in a Mouse Model of Traumatic Brain Injury.

Post-traumatic epilepsy (PTE) and behavioral comorbidities frequently develop after traumatic brain injury (TBI). Aberrant neurogenesis of dentate granule cells (DGCs) after TBI may contribute to the synaptic reorganization that occurs in PTE, but how neurogenesis at different times relative to the injury contributes to feedback inhibition and recurrent excitation in the dentate gyrus is unknown. Thus, we examined whether DGCs born at different postnatal ages differentially participate in feedback inhibition and recurrent excitation in the dentate gyrus using the controlled cortical impact (CCI) model of TBI. Both sexes of transgenic mice expressing channelrhodopsin2 (ChR2) in postnatally born DGCs were used for optogenetic activation of three DGC cohorts: postnatally early born DGCs, or those born just before or after CCI. We performed whole-cell patch-clamp recordings from ChR2-negative, mature DGCs and parvalbumin-expressing basket cells (PVBCs) in hippocampal slices to determine whether optogenetic activation of postnatally born DGCs increases feedback inhibition and/or recurrent excitation in mice 8-10 weeks after CCI and whether PVBCs are targets of ChR2-positive DGCs. In the dentate gyrus ipsilateral to CCI, activation of ChR2-expressing DGCs born before CCI produced increased feedback inhibition in ChR2-negative DGCs and increased excitation in PVBCs compared with those from sham controls. This upregulated feedback inhibition was less prominent in DGCs born early in life or after CCI. Surprisingly, ChR2-positive DGC activation rarely evoked recurrent excitation in mature DGCs from any cohort. These results support that DGC birth date-related increased feedback inhibition in of DGCs may contribute to altered excitability after TBI.SIGNIFICANCE STATEMENT Dentate granule cells (DGCs) control excitability of the dentate gyrus through synaptic interactions with inhibitory GABAergic interneurons. Persistent changes in DGC synaptic connectivity develop after traumatic brain injury, contributing to hyperexcitability in post-traumatic epilepsy (PTE). However, the impact of DGC neurogenesis on synaptic reorganization, especially on inhibitory circuits, after brain injury is not adequately described. Here, upregulation of feedback inhibition in mature DGCs from male and female mice was associated with increased excitation of parvalbumin-expressing basket cells by postnatally born DGCs, providing novel insights into underlying mechanisms of altered excitability after brain injury. A better understanding of these inhibitory circuit changes can help formulate hypotheses for development of novel, evidence-based treatments for post-traumatic epilepsy by targeting birth date-specific subsets of DGCs.

Robot Death and Human Grief in Films: Qualitative Study.

Extant grief studies examine the way humans mourn the loss of a nonhuman, be it an animal, object, or abstract concept. Yet little is known about grief when it comes to robots. As humans are increasingly brought into contact with more human-like machines, it is relevant to consider the nature of our relationship to these technologies. Centered on a qualitative analysis of 35 films, this study seeks to determine whether humans experience grief when a robot is destroyed, and if so, under what conditions. Our observations of the relevant film scenes suggest that eight variables play a role in determining whether and to what extent a human experiences grief in response to a robot's destruction. As a result, we have devised a psychological mechanism by which different types of grief can be classified as a function of these eight variables.

Engineering of human brain organoids with a functional vascular-like system.

Human cortical organoids (hCOs), derived from human embryonic stem cells (hESCs), provide a platform to study human brain development and diseases in complex three-dimensional tissue. However, current hCOs lack microvasculature, resulting in limited oxygen and nutrient delivery to the inner-most parts of hCOs. We engineered hESCs to ectopically express human ETS variant 2 (ETV2). ETV2-expressing cells in hCOs contributed to forming a complex vascular-like network in hCOs. Importantly, the presence of vasculature-like structures resulted in enhanced functional maturation of organoids. We found that vascularized hCOs (vhCOs) acquired several blood-brain barrier characteristics, including an increase in the expression of tight junctions, nutrient transporters and trans-endothelial electrical resistance. Finally, ETV2-induced endothelium supported the formation of perfused blood vessels in vivo. These vhCOs form vasculature-like structures that resemble the vasculature in early prenatal brain, and they present a robust model to study brain disease in vitro.

Multi-Filter Clustering Fusion for Feature Selection in Rotating Machinery Fault Classification.

In the fault classification process, filter methods that sequentially remove unnecessary features have long been studied. However, the existing filter methods do not have guidelines on which, and how many, features are needed. This study developed a multi-filter clustering fusion (MFCF) technique, to effectively and efficiently select features. In the MFCF process, a multi-filter method combining existing filter methods is first applied for feature clustering; then, key features are automatically selected. The union of key features is utilized to find all potentially important features, and an exhaustive search is used to obtain the best combination of selected features to maximize the accuracy of the classification model. In the rotating machinery examples, fault classification models using MFCF were generated to classify normal and abnormal conditions of rotational machinery. The obtained results demonstrated that classification models using MFCF provide good accuracy, efficiency, and robustness in the fault classification of rotational machinery.

Why Are Dying Individuals Stigmatized and Socially Avoided? Psychological Explanations.

Extant research on the topic of death and dying in modern society frequently includes the observation that death is now rendered invisible, and dying individuals are stigmatized and socially avoided. The current research speculated that lack of contact with a dying individual may promote negative perceptions of the dying, and this may in turn lead to further avoidance of them. Three studies were conducted: The first study examined how frequently the current U.S. participants had social contact with a dying individual; the second study investigated what perceptions they have of the dying, and the third study tested for potential causal links between negative perceptions of the dying and social avoidance of them. The results indicated: Only a small number of the U.S. participants ever had frequent social contact with a dying individual outside their family; they, nevertheless, shared several common negative perceptions of the dying; and those negative perceptions exerted different effects on one's avoidant attitude toward a dying individual-only making males more avoidant, especially in a physically close social relationship. Two concepts, medicalization and masculinism, were suggested as possible explanations for why dying individuals are stigmatized and avoided in modern society.

Personification of Death: What Types of Death Are Personified by Macabre, Gentle Comforter, Gay Deceiver, and Automaton?

Kastenbaum and Aisenberg identified a phenomenon, wherein American subjects personified death in four distinctive figures: Macabre, Gentle Comforter, Gay Deceiver, and Automaton. Until recently, though, researchers did not attempt to answer the question, "What specific aspects of the death experience can be attributed to each of those four personifications?" To answer this question, the current qualitative research asked individuals to envision the causes, places, and contexts of death after imagining each personification of death. The results have revealed that people associated each personification of death with distinct causes, places, and contexts of death: Macabre-murder taking place outside the home, Gentle Comforter-peaceful death by old age at home, Gay Deceiver-death from heart attack, and Automaton-death from cancer in a modern hospital. This article also discusses unanswered questions, limitations, and directions to take its research in the future.

A Deep-Learning Approach for Foot-Type Classification Using Heterogeneous Pressure Data.

The human foot is easily deformed owing to the innate form of the foot or an incorrect walking posture. Foot deformations not only pose a threat to foot health but also cause fatigue and pain when walking; therefore, accurate diagnoses of foot deformations are required. However, the measurement of foot deformities requires specialized personnel, and the objectivity of the diagnosis may be insufficient for professional medical personnel to assess foot deformations. Thus, it is necessary to develop an objective foot deformation classification model. In this study, a model for classifying foot types is developed using image and numerical foot pressure data. Such heterogeneous data are used to generate a fine-tuned visual geometry group-16 (VGG16) and K-nearest neighbor (k-NN) models, respectively, and a stacking ensemble model is finally generated to improve accuracy and robustness by combining the two models. Through k-fold cross-validation, the accuracy and robustness of the proposed method have been verified by the mean and standard deviation of the f1 scores (0.9255 and 0.0042), which has superior performance compared to single models generated using only numerical or image data. Thus, the proposed model provides the objectivity of diagnosis for foot deformation, and can be used for analysis and design of foot healthcare products.

Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts.

Prostate cancer (PC) is a slowly progressing malignancy that often responds to androgen ablation or chemotherapy by becoming more aggressive, acquiring a neuroendocrine phenotype, and undergoing metastatic spread. We found that B lymphocytes recruited into regressing androgen-deprived tumors by C-X-C motif chemokine 13 (CXCL13), a chemokine whose expression correlates with clinical severity, play an important role in malignant progression and metastatic dissemination of PC. We now describe how androgen ablation induces CXCL13 expression. In both allografted and spontaneous mouse PC, CXCL13 is expressed by tumor-associated myofibroblasts that are activated on androgen ablation through a hypoxia-dependent mechanism. The same cells produce CXCL13 after chemotherapy. Myofibroblast activation and CXCL13 expression also occur in the normal prostate after androgen deprivation, and CXCL13 is expressed by myofibroblasts in human PC. Hypoxia activates hypoxia-inducible factor 1 (HIF-1) and induces autocrine TGF-ß signaling that promotes myofibroblast activation and CXCL13 induction. In addition to TGF-ß receptor kinase inhibitors, myofibroblast activation and CXCL13 induction are blocked by phosphodiesterase 5 (PDE5) inhibitors. Both inhibitor types and myofibroblast immunodepletion block the emergence of castration-resistant PC in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of spontaneous metastatic PC with neuroendocrine differentiation.

Spatially heterogeneous choroid plexus transcriptomes encode positional identity and contribute to regional CSF production.

A sheet of choroid plexus epithelial cells extends into each cerebral ventricle and secretes signaling factors into the CSF. To evaluate whether differences in the CSF proteome across ventricles arise, in part, from regional differences in choroid plexus gene expression, we defined the transcriptome of lateral ventricle (telencephalic) versus fourth ventricle (hindbrain) choroid plexus. We find that positional identities of mouse, macaque, and human choroid plexi derive from gene expression domains that parallel their axial tissues of origin. We then show that molecular heterogeneity between telencephalic and hindbrain choroid plexi contributes to region-specific, age-dependent protein secretion in vitro. Transcriptome analysis of FACS-purified choroid plexus epithelial cells also predicts their cell-type-specific secretome. Spatial domains with distinct protein expression profiles were observed within each choroid plexus. We propose that regional differences between choroid plexi contribute to dynamic signaling gradients across the mammalian cerebroventricular system.

Design and fabrication of two-stack tandem-type all-phosphorescent white organic light-emitting diode for achieving high color rendering index and luminous efficacy.

White organic light-emitting diodes (WOLEDs) are regarded as the general lighting source. Although color rendering index (CRI) and luminous efficacy are usually in trade-off relation, we will discuss about the optimization of both characteristics, particularly focusing on the spectrum of a blue emitter. The emission at a shorter wavelength is substantially important for achieving very high CRI (> 90). The luminous efficacy of a phosphorescent blue emitter is low as its color falls in the deeper blue range; however, that does not show any significant influence on the WOLEDs. WOLEDs with different blue dopants are compared to confirm the calculation of the CRI and luminous efficacy, and the optimized WOLEDs exhibit luminous efficacy of 38.3 lm/W and CRI of 90.9.

Guest-induced 2-D metallopolycapsular networks based on a 1,3-alternate calix[4]arene derivative.

Solvothermal reactions of the calix[4]arene tetraacetic acid (H4 CTA) with zinc nitrate in the presence of α,ω-diaminoalkanes afford two-dimensional metallopolycapsular networks of the formula {[Me2 NH2 ]2 [G@(Zn2 (CTA)2 )]⋅(DMF)2 ⋅(H2 O)4 }n (G=(+) NH3 -(CH2 )n -NH3 (+) , n=2, 3, 4; DMF=N,N-dimethylformamide). These metallopolycapsular networks are built up of metallocapsules that consist of two CTA and two Zn(II) ions. Short alkanediyldiammonium ((+) NH3 -(CH2 )n -NH3 (+) , n=2, 3, 4) guest ions are accommodated in each capsule of the metallopolycapsular network through a variety of supramolecular interactions. The thermal behaviours and the solid-state photoluminescent properties of these complexes were also investigated.

Effective mechanical thrombectomy in a patient with hyperacute ischemic stroke associated with cardiac myxoma.

Ischemic stroke is the most common neurologic manifestation of cardiac myxoma. However, there has been no current guideline on the treatment of hyperacute ischemic stroke due to cardiac myxoma. We describe a patient with hyperacute stroke caused by cardiac myxoma who had a good outcome with rapid recanalization through mechanical thrombectomy. A 46-year-old man was admitted with acute symptoms of right side hemiplegia and global aphasia. Brain computed tomography (CT) angiography showed a T occlusion of the left internal carotid artery. Intravenous recombinant tissue plasminogen activator was administered. However, his clinical symptoms did not improve. Thus, we performed endovascular treatment and had a successful outcome. A pathologic examination of the retrieved clot revealed a tumor emboli from a cardiac myxoma. Transthoracic echocardiogram revealed a left atrial myxoma in which a large mass was attached to the posterior wall of the aorta. The patient's neurologic deficits recovered with the exception of left eye blindness. Reperfusion therapy with mechanical thrombectomy might be safe and effective for the rapid revascularization of large vessel occlusions in hyperacute ischemic stroke, from which the tumor thrombi can be retrieved.

Crystal structure of bis-[2-tert-but-oxy-6-fluoro-3-(pyridin-2-yl-κN)pyridin-4-yl-κC (4)](pentane-2,4-dionato-κ(2) O,O')iridium(III).

The title mol-ecule, [Ir(C14H14FN2O)2(C5H7O2)], is located on a twofold rotation axis, which passes through the Ir(III) atom and the central C atom of the pentane-2,4-dionate anion. The Ir(III) atom adopts a distorted octa-hedral coordination geometry, being C,N-chelated by two 2-tert-but-oxy-6-fluoro-3-(pyridin-2-yl)pyridin-4-yl ligands and O,O'-chelated by the pentane-2,4-dionato ligand. The bipyridinate ligands, which are perpendicular to each other [dihedral angle between the two least-squares planes = 89.95 (5)°], are arranged in a cis-C,C' and trans-N,N' fashion relative to the central metal cation. Intra-molecular C-H⋯O and C-H⋯N hydrogen bonds and inter-molecular C-H⋯F hydrogen bonds as well as π-π inter-actions between neighbouring pyridine rings [centroid-centroid distance 3.680 (1) Å] contribute to the stabilization of the mol-ecular and crystal structure, respectively.

2,2'-Bi(9,9-di-ethyl-fluorene).

The title compound, C34H34, systematic name 9,9,9',9'-tetra-ethyl-2,2'-bi(9H-fluorene), crystallized with two crystallographically independent mol-ecules (A and B) in the asymmetric unit. These differ mainly in the orientation of the lateral ethyl chains: in mol-ecule A, they are both on the same side of the mol-ecule whereas in mol-ecule B, one di-ethyl-fluorene moiety has undergone a 180° rotation such that the two pairs of ethyl residues appear on opposite sides of the mol-ecule. The fluorene ring systems subtend dihedral angles of 31.37 (4) and 43.18 (3)° in mol-ecules A and B, respectively. Hence the two fluorene moieties are tilted slightly toward one another. This may be due to the presence of inter-molecular C-H⋯π inter-actions between neighboring mol-ecules. The lateral ethyl chains (excluding H atoms) are also almost planar, with each pair almost perpendicular to the plane of the fluorene system to which they are attached with dihedral angles between the ethyl and fluorene planes in the range 86.04 (8)-89.5 (1)°.

Activation of hypoactive parvalbumin-positive fast-spiking interneuron restores dentate inhibition to prevent epileptiform activity in the mouse intrahippocampal kainate model of temporal lobe epilepsy.

Parvalbumin-positive (PV+) GABAergic interneurons in the dentate gyrus provide powerful perisomatic inhibition of dentate granule cells (DGCs) to prevent overexcitation and maintain the stability of dentate gyrus circuits. Most dentate PV+ interneurons survive status epilepticus, but surviving PV+ interneuron mediated inhibition is compromised in the dentate gyrus shortly after status epilepticus, contributing to epileptogenesis in temporal lobe epilepsy. It is uncertain whether the impaired activity of dentate PV+ interneurons recovers at later times or if it continues for months following status epilepticus. The development of compensatory modifications related to PV+ interneuron circuits in the months following status epilepticus is unknown, although reduced dentate GABAergic inhibition persists long after status epilepticus. We employed PV immunostaining and whole-cell patch-clamp recordings from dentate PV+ interneurons and DGCs in slices from male and female sham controls and intrahippocampal kainate (IHK) treated mice that developed spontaneous seizures months after status epilepticus to study epilepsy-associated changes in dentate PV+ interneuron circuits. We found that the number of dentate PV+ cells was reduced in IHK treated mice. Electrical recordings showed that: 1) Action potential firing rates of dentate PV+ interneurons were reduced in IHK treated mice up to four months after status epilepticus; 2) Spontaneous inhibitory postsynaptic currents (sIPSCs) in DGCs exhibited reduced frequency but increased amplitude in IHK treated mice; and 3) The amplitude of evoked IPSCs in DGCs by optogenetic activation of dentate PV+ cells was upregulated without changes in short-term plasticity. Video-EEG recordings revealed that IHK treated mice showed spontaneous epileptiform activity in the dentate gyrus and that chemogenetic activation of PV+ interneurons abolished the epileptiform activity. Our results suggest not only that the compensatory changes in PV+ interneuron circuits develop after IHK treatment, but also that increased PV+ interneuron mediated inhibition in the dentate gyrus may compensate for cell loss and reduced intrinsic excitability of dentate PV+ interneurons to stop seizures in temporal lobe epilepsy. Highlights: Reduced number of dentate PV+ interneurons in TLE micePersistently reduced action potential firing rates of dentate PV+ interneurons in TLE miceEnhanced amplitude but decreased frequency of spontaneous IPSCs in the dentate gyrus in TLE miceIncreased amplitude of evoked IPSCs mediated by dentate PV+ interneurons in TLE miceChemogenetic activation of PV+ interneurons prevents epileptiform activity in TLE mice.

Revisiting the impact of clinicopathologic characteristics in PD-L1 profile in a large cohort of non-small cell lung cancer.

Background: Immunotherapies using anti-programmed cell death ligand-1 (PD-L1) agents have recently shown remarkable outcomes in patients with non-small cell lung cancer (NSCLC). However, there was a poor correlation between PD-L1 expression and treatment response. Many researchers have focused on the clinicopathological factors associated with prognosis, but the results are conflicting. In the present study, we investigated the clinicopathological significance of PD-L1 overexpression in NSCLC cells. Methods: In total, 344 NSCLC cases with PD-L1 assays were retrospectively analyzed. PD-L1 expression was evaluated via immunohistochemical staining using antibodies against SP263 and SP142. The correlation between clinicopathological factors and PD-L1 expression was analyzed for various clinicopathological features. Results: PD-L1 expression significantly correlated with several poor clinicopathological factors, including the solid component of adenocarcinoma, lymphatic invasion, and recurrence. Squamous cell carcinoma, older age, and male sex were also associated with PD-L1 expression. However, we could not observe correlation between PD-L1 expression and disease-free survival (DFS). A novel finding was that lower metastasis was associated with high PD-L1 expression of SP142 in tumor-infiltrating immune cells (ICs). Conclusions: PD-L1 expression in NSCLC is associated with adverse clinicopathological features and recurrence; therefore, it could be utilized to predict poor prognosis. Furthermore, the high PD-L1 expression of SP142 in tumor-infiltrating ICs could be a potential marker for low metastasis.

BMP4 sufficiency to induce choroid plexus epithelial fate from embryonic stem cell-derived neuroepithelial progenitors.

Choroid plexus epithelial cells (CPECs) have essential developmental and homeostatic roles related to the CSF and blood-CSF barrier they produce. Accordingly, CPEC dysfunction has been implicated in many neurological disorders, such as Alzheimer's disease, and transplant studies have provided proof-of-concept for CPEC-based therapies. However, such therapies have been hindered by the inability to expand or generate CPECs in culture. During development, CPECs differentiate from preneurogenic neuroepithelial cells and require bone morphogenetic protein (BMP) signaling, but whether BMPs suffice for CPEC induction is unknown. Here we provide evidence for BMP4 sufficiency to induce CPEC fate from neural progenitors derived from mouse embryonic stem cells (ESCs). CPEC specification by BMP4 was restricted to an early time period after neural induction in culture, with peak CPEC competency correlating to neuroepithelial cells rather than radial glia. In addition to molecular, cellular, and ultrastructural criteria, derived CPECs (dCPECs) had functions that were indistinguishable from primary CPECs, including self-assembly into secretory vesicles and integration into endogenous choroid plexus epithelium following intraventricular injection. We then used BMP4 to generate dCPECs from human ESC-derived neuroepithelial cells. These findings demonstrate BMP4 sufficiency to instruct CPEC fate, expand the repertoire of stem cell-derived neural derivatives in culture, and herald dCPEC-based therapeutic applications aimed at the unique interface between blood, CSF, and brain governed by CPECs.

Toluene decomposition by DBD-type plasma combined with metal oxide catalysts supported on ferroelectric materials.

We investigated toluene decomposition with a single-stage plasma catalytic system operated at atmospheric pressure and working at reduced temperature (T < 75 degrees C), where a synergistic catalyst was integrated on ferroelectric BaTiO3 beads with a high dielectric constant. The catalyst species were characterized by FE-SEM and XPS before and after the experiment. The MnO2/BaTiO3 catalyst showed high stability in igniting plasma during destruction of toluene for 230 hours in a lifetime test.