Search

The mitochondrial GTPase mitofusin-2 (MFN2) gene can suppress the cell cycle and regulate cell proliferation in a number of cell types. However, its function in hepatic fibrosis remains largely unexplored. We attempted to understand the mechanism of MFN2 in hepatic stellate cell (HSC) proliferation and the development of hepatic fibrosis. Rat HSC-T6 HSC were cultured and transfected by adenovirus- (Ad-) Mfn2 or its negative control (NC) vector (Ad-green fluorescent protein (GFP)); a rat liver cirrhosis model was established via subcutaneous injection with carbon tetrachloride (CCl4). Seventy-two rats were randomly divided into four groups: CCl4, Mfn2, GFP, and NC. Ad-Mfn2 or Ad-GFP was transfected into the circulation via intravenous injection at day 1, 14, 28, 42, or 56 after the first injection of CCl4 in the Mfn2/GFP groups. Biomarkers related to HSC proliferation and the development of hepatic fibrosis were detected using western blotting, hematoxylin-eosin and Masson staining, and immunohistochemistry. In vitro, Mfn2 interfered specifically with platelet-derived growth factor- (PDGF-) induced signaling pathway (phosphatidylinositol 3-kinase- (PI3K-) AKT), inhibiting HSC-T6 cell activation and proliferation. During the process of hepatic fibrosis in vivo, extracellular collagen deposition and the expression of fibrosis-related proteins increased progressively, while Mfn2 expression decreased gradually. Upregulating Mfn2 expression at the early stage of fibrosis impeded the process, triggered the downregulation of type I collagen, and antagonized the formation of factors associated with liver fibrosis. Mfn2 suppresses HSC proliferation and activation and exhibits antifibrotic potential in early-stage hepatic fibrosis. Therefore, it may represent a significant therapeutic target for eradicating hepatic fibrosis.

In a fully mechanized top coal caving mining process, the mechanical properties of the top coal deteriorate constantly, and the stability of the support is determined by the boundary position of the top coal entering the limit equilibrium state. Top coal flaking occurs more easily along the advancing direction owing to an increase in the distance of the boundary from the wall. Moreover, the strength of the coal seam is an important factor that determines the boundary position. The equation of the top coal limit equilibrium zone boundary, used in fully mechanized top coal caving mining, was determined based on the limit equilibrium theory, continuum damage mechanics, and the Hoek–Brown rock empirical strength criterion. Using the RFPA3D and UDEC numerical analysis methods, the effect of top coal strength on the mechanical behavior during the mining process was determined; and the space–time relationship between the top coal deformation failure, damage evolution, and boundary of the limit equilibrium zone was established. The results revealed that when the coal mass entered the limit equilibrium zone, accelerated crack development, accelerated damage, and axial unloading occurred. Moreover, an increase in the coal seam strength caused the boundary of the top coal limit equilibrium zone to be closer to the wall. By comparing the numerical results with the theoretical results, the overall trend was found to be consistent, allowing the verification of the rationality and reliability of the determination equation of the boundary position of the limit equilibrium zone.

To establish a dynamic nomogram based on preoperative clinical data for prediction of lateral lymph node metastasis (LLNM) of papillary thyroid carcinoma.Retrospective study.The Sixth Affiliated Hospital of Sun Yat-Sen University.The data of 477 patients from 2 centers formed the training group and validation group and were retrospectively reviewed. Preoperative clinical factors influencing LLNM were identified by univariable and multivariable analysis and were to construct a predictive dynamic nomogram for LLNM. Receiver operating characteristic analysis and calibration curves were used to evaluate the predictive power of the nomogram.The following were identified as independent risk factors for LLNM: male sex (odds ratio [OR] = 4.6,The dynamic nomogram for preoperative prediction of LLNM in papillary thyroid carcinoma can help surgeons identify high-risk patients and develop individualized treatment plans.

PolarLight is a compact soft X-ray polarimeter onboard a CubeSat, which was launched into a low-Earth orbit on October 29, 2018. In March 2019, PolarLight started full operation, and since then, regular observations with the Crab nebula, Sco X-1, and background regions have been conducted. Here we report the operation, calibration, and performance of PolarLight in the orbit. Based on these, we discuss how one can run a low-cost, shared CubeSat for space astronomy, and how CubeSats can play a role in modern space astronomy for technical demonstration, science observations, and student training., Comment: accepted for publication in Advances in Space Research

Colorectal cancer (CRC) is the third and second most common type of cancer diagnosed in males and females, respectively, and is the fourth leading cause of cancer-associated mortality worldwide. Liver metastasis is the primary cause of mortality in patients with CRC, and therefore requires therapeutic focus. Regulatory T cells (Tregs) and hepatic stellate cells (HSCs) are potentially involved in regulating the immune response during liver metastasis. The aim of the present study was to evaluate the influence of CD4+ forkhead box p3 (Foxp3)+ Tregs and the HGF/c-Met signaling pathway in the liver metastasis of CRC. A model of the latter was established using Balb/c mice via splenic injection of human CRC cells (CT-26 line). The mice were monitored for 3 weeks after being injected, and the spleens and livers were removed on day 22 for further analysis. Moreover, the single-cell suspensions were labeled with CD4 and Foxp3 antibodies, and were analyzed using flow cytometry. Expression levels of α-smooth muscle actin (SMA), hepatocyte growth factor (HGF) and hepatocyte growth factor receptor (c-Met) were analyzed using immunohistochemistry. Mice injected with CT-26 cells exhibited signs of illness and significant weight loss, compared with the control mice (P=0.013), and they also developed liver metastases, at an average of 20.5 tumors per mouse. Pathological evaluation using hematoxylin and eosin staining confirmed the tumors as liver metastases of CRC. The numbers of CD4+ T cells were significantly decreased in the spleen (P

This paper selects the annual panel data of China and its provinces from 1997 to 2015 and explores the impacts of financial development on CO2 emissions based on the extended STIRPAT model. In order to analyze the impacts of financial development on CO2 emissions under different levels of financial development, full-sample panels and sub-panels were estimated. The estimation results show that financial development efficiency and stock trading volume have positive impacts on CO2 emissions, while financial development scale and the market value of listed companies have negative impacts on CO2 emissions. The elasticity coefficients of the financial development variables are different for different sub-panels with different financial development. In addition, we do robustness tests by estimating the panel data model of four different sub-panels, which estimation results are consistent with the previous regression results. Finally, we suggest China's policy makers the following policy implications: China's government should formulate and improve financial credit policies, which can encourage financial institutions to carry out green credit business. Laws and regulations of stock markets should match the environmental protection and carbon emission reduction. China's government should formulate and implement fiscal and taxation policies to encourage enterprises to prevent high energy consumption and carbon emission, especially non-stated owned enterprises and small size enterprises. Moreover, China should gradually develop the domestic carbon finance market and carbon trading market, which can promote carbon emission reduction and doesn't require additional subsidy from the government.

The Gamma-Ray Integrated Detectors (GRID) is a space mission concept dedicated to monitoring the transient gamma-ray sky in the energy range from 10 keV to 2 MeV using scintillation detectors onboard CubeSats in low Earth orbits. The primary targets of GRID are the gamma-ray bursts (GRBs) in the local universe. The scientific goal of GRID is, in synergy with ground-based gravitational wave (GW) detectors such as LIGO and VIRGO, to accumulate a sample of GRBs associated with the merger of two compact stars and study jets and related physics of those objects. It also involves observing and studying other gamma-ray transients such as long GRBs, soft gamma-ray repeaters, terrestrial gamma-ray flashes, and solar flares. With multiple CubeSats in various orbits, GRID is unaffected by the Earth occultation and serves as a full-time and all-sky monitor. Assuming a horizon of 200 Mpc for ground-based GW detectors, we expect to see a few associated GW-GRB events per year. With about 10 CubeSats in operation, GRID is capable of localizing a faint GRB like 170817A with a 90% error radius of about 10 degrees, through triangulation and flux modulation. GRID is proposed and developed by students, with considerable contribution from undergraduate students, and will remain operated as a student project in the future. The current GRID collaboration involves more than 20 institutes and keeps growing. On August 29th, the first GRID detector onboard a CubeSat was launched into a Sun-synchronous orbit and is currently under test., accepted for publication in Experimental Astronomy

Multi-drug resistance (MDR) in breast cancer poses a great threat to chemotherapy. The expression and function of the ATP binding cassette (ABC) transporter are the major cause of MDR. Herein, a linear polyethylene glycol (PEI) conjugated with dicyandiamide, which called polymeric metformin (PolyMet), was successfully synthesized as a simple and biocompatible polymer of metformin. PolyMet showed the potential to reverse MDR by inhibiting the efflux of the substrate of ATP-binding cassette (ABC) transporter from DOX resistant MCF-7 cells (MCF-7/DOX). To test its MDR reversing effect, PolyMet was combined with DOX to treat mice carrying MCF-7/DOX xenografts. In order to decrease the toxicities of DOX and delivery PolyMet and DOX to tumor at the same time, PolyMet was complexed with poly-γ-glutamic acid-doxorubicin (PGA-DOX) electrostatically at the optimal ratio of 2:3, which were further coated with lipid membrane to form lipid/PolyMet-(PGA-DOX) nanoparticles (LPPD). The particle size of LPPD was 165.8 nm, and the zeta potential was +36.5 mV. LPPD exhibited favorable cytotoxicity and cellular uptake in MCF-7/DOX. Meanwhile, the bioluminescence imaging and immunohistochemical analysis indicated that LPPD effectively conquered DOX-associated MDR by blocking ABC transporters (ABCB1 and ABCC1) via PolyMet. Remarkably, LPPD significantly inhibited the tumor growth and lowered the systemic toxicity in a murine MCF-7/DOX tumor model. This is the first time to reveal that PolyMet can enhance the anti-tumor efficacy of DOX by dampening ABC transporters and activating the AMPK/mTOR pathway, which is a promising strategy for drug-resistant breast cancer therapy.

PolarLight is a space-borne X-ray polarimeter that measures the X-ray polarization via electron tracking in an ionization chamber. It is a collimated instrument and thus suffers from the background on the whole detector plane. The majority of background events are induced by high energy charged particles and show ionization morphologies distinct from those produced by X-rays of interest. Comparing on-source and off-source observations, we find that the two datasets display different distributions on image properties. The boundaries between the source and background distributions are obtained and can be used for background discrimination. Such a means can remove over 70% of the background events measured with PolarLight. This approaches the theoretical upper limit of the background fraction that is removable and justifies its effectiveness. For observations with the Crab nebula, the background contamination decreases from 25% to 8% after discrimination, indicative of a polarimetric sensitivity of around 0.2 Crab for PolarLight. This work also provides insights into future X-ray polarimetric telescopes., accepted for publication in Research in Astronomy and Astrophysics

To design potentially more effective therapies, we need to further understand the mechanisms underlying epilepsy. Here, we uncover the role of Rev-erbα in circadian regulation of epileptic seizures. We first show up-regulation of REV-ERBα/Rev-erbα in brain tissues from patients with epilepsy and a mouse model. Ablation or pharmacological modulation of Rev-erbα in mice decreases the susceptibility to acute and chronic seizures, and abolishes diurnal rhythmicity in seizure severity, whereas activation of Rev-erbα increases the animal susceptibility. Rev-erbα ablation or antagonism also leads to prolonged spontaneous inhibitory postsynaptic currents and elevated frequency in the mouse hippocampus, indicating enhanced GABAergic signaling. We also identify the transporters Slc6a1 and Slc6a11 as regulators of Rev-erbα-mediated clearance of GABA. Mechanistically, Rev-erbα promotes the expressions of Slc6a1 and Slc6a11 through transcriptional repression of E4bp4. Our findings propose Rev-erbα as a regulator of synaptic function at the crosstalk between pathways regulating the circadian clock and epilepsy., Rev-erbα is a known regulator of the circadian clock. Here, the authors show that Rev-erbα is also a regulator of synaptic dysfunction in preclinical models of epilepsy.

PolarLight is a gas pixel X-ray polarimeter mounted on a CubeSat, which was launched into a Sun-synchronous orbit in October 2018. We build a mass model of the whole CubeSat with the Geant4 toolkit to simulate the background induced by the cosmic X-ray background (CXB) and high energy charged particles in the orbit. The simulated energy spectra and morphologies of event images both suggest that the measured background with PolarLight is dominated by high energy electrons, with a minor contribution from protons and the CXB. The simulation reveals that, in the energy range of 2-8 keV, there are roughly 28% of the background events are caused by energy deposit from a secondary electron with an energy of a few keV, in a physical process identical to the detection of X-rays. Thus, this fraction of background cannot be discriminated from X-ray events. The background distribution is uneven on the detector plane, with an enhancement near the edges. The edge effect is because high energy electrons tend to produce long tracks, which are discarded by the readout electronics unless they have partial energy deposits near the edges. The internal background rate is expected to be around 6 x 10^-3 counts/s/cm2 in 2-8 keV if an effective particle discrimination algorithm can be applied. This indicates that the internal background should be negligible for future focusing X-ray polarimeters with a focal size in the order of mm., accepted for publication in ApJ

We report follow-up observations of the Crab nebula with the PolarLight X-ray polarimeter, which revealed a possible variation in polarization associated with a pulsar glitch in 2019. The new observations confirm that the polarization has recovered roughly 100 days after the glitch. With the new observations, we find that the polarization angle (PA) measured with PolarLight from the total nebular emission has a difference of 18.0 +- 4.6 (deg) from that measured 42 years ago with OSO-8, indicating a secular evolution of polarization with either the Crab nebula or pulsar. The long-term variation in PA could be a result of multiple glitches in the history, magnetic reconnection or movement of synchrotron emitting structures in the nebula, or secular evolution of the pulsar magnetic geometry., Comment: ApJ Letters to appear

Temporal lobe epilepsy (TLE) is a common drug-resistant epilepsy associated with abundant cell death in the hippocampus. Here, we develop a novel gene therapy-mediated cell therapy that regenerates GABAergic neurons using internal hippocampal astrocytes to suppress seizure activity in a rat TLE model. We discovered that TLE-induced reactive astrocytes in the hippocampal CA1 region can be efficiently converted into GABAergic neurons after overexpressing a neural transcription factor NeuroD1. The astrocyte-converted neurons showed typical markers of GABAergic interneurons, fired action potentials, and formed functional synaptic connections with other neurons. Following NeuroD1-mediated astrocyte-to-neuron conversion, the number of hippocampal interneurons was significantly increased, and the spontaneous recurrent seizure (SRS) activity was significantly decreased. Moreover, NeuroD1 gene therapy treatment rescued total neuronal loss in the CA1 region and ameliorated the cognitive and mood dysfunctions in the TLE rat model. These results suggest that regeneration of GABAergic interneurons through gene therapy approach may provide a novel therapeutic intervention to treat drug-resistant TLE.

We report the detection of X-ray polarization in the neutron star low mass X-ray binary Scorpius (Sco) X-1 with PolarLight. The result is energy dependent, with a non-detection in 3-4 keV but a 4$\sigma$ detection in 4-8 keV; it is also flux dependent in the 4-8 keV band, with a non-detection when the source displays low fluxes but a 5$\sigma$ detection during high fluxes, in which case we obtain a polarization fraction of $0.043 \pm 0.008$ and a polarization angle of $52.6^\circ \pm 5.4^\circ$. This confirms a previous marginal detection with OSO-8 in the 1970s, and marks Sco X-1 the second astrophysical source with a significant polarization measurement in the keV band. The measured polarization angle is in line with the jet orientation of the source on the sky plane ($54^\circ$), which is supposedly the symmetric axis of the system. Combining previous spectral analysis, our measurements suggest that an optically thin corona is located in the transition layer under the highest accretion rates, and disfavor the extended accretion disk corona model., Comment: Submitted to AAS journals. We are grateful to some experts for useful comments

Lentinan is widely used as a therapeutic agent for treatment of malignant tumors in clinical practice. The chemical structure of lentinan is highly associated with its biological activity. In this study, the correlation between the structure of lentinan and its immune activity was investigated to assess the function of key parameters that can influence quality control of lentinan. The results showed that the batch-to-batch consistency of two lentinan samples was satisfactory, indicating the stability of production process of lentinan. However, although the chemical composition and triple-helical conformation (THC) of the tested samples were relatively similar, their Mw, polydispersity index (PDI), and Rgz remarkably varied due to different production processes. In vitro immunomodulatory assay reflects that lentinan could stimulate the macrophages phagocytic capacity. Meanwhile, lentinan samples could improve the spleen and thymus indices, promote the proliferation of lymphocytes and adjust for the percentages of CD4+ and CD8+ T cells in vivo. Furthermore, the immunomodulatory effect of lentinan sample B (Mw: 650,700 g/mol) was superior than that of the sample A (Mw: 4,818,700 g/mol). It was noted that the Mw should be detected as a necessary index for quality control of lentinan to ensure stability and effectiveness of the production process.

Metabolomics has been a potential tool for strain improvement through analyzing metabolite changes in the context of different conditions. However, the availability of a universal metabolite profiling analysis is still a big challenge. In this study, we presented an optimized liquid chromatography-tandem mass spectrometry-based metabolomics methodology for Corynebacterium glutamicum, an important industrial workhorse. It was found that quenching the cellular metabolism with 5-fold volume of - 20 °C 40% methanol was highly recommended due to its lower cell damage rate and higher intracellular metabolite recovery rate. For extracting intracellular metabolites, ethanol/water (3:1, v/v) at 100 °C combined with acidic acetonitrile/water (1:1, v/v, with 0.1% formic acid) at - 20 °C achieved the unbiased metabolite profiling of C. glutamicum. The established methodology was then applied to investigate the intracellular metabolite differences between C. glutamicum ATCC 13032 and an mscCG-deleted mutant under biotin limitation condition. It was observed that in the presence of the functional L-glutamate exporter MscCG, biotin limitation led to accumulation of intracellular 2-oxoglutarate but not L-glutamate. Deletion of mscCG severely inhibited L-glutamate excretion and resulted in a dramatical increase of intracellular L-glutamate, which in turn affected the metabolite profile. The optimized metabolomics methodology holds promise for promoting studies on metabolic mechanism of C. glutamicum.

Additive color mixing modulated by digital pulses enables universal applications in lights and displays. Conventional methods map binarized signals to ordinary red–green–blue color spaces, loosely connected with the color perception of human eyes, causing the complexity of gamut mapping and inaccuracy of chromatic manipulations. Here we developed a complete theory that encodes and decodes digital signals directly to a perceptually nonuniform color space of the commission internationale de l’éclairage, featuring a strict bijection between the duty cycles of each binary pulse and color components of the mixed light and an analytic nonlinear gamut volume. Exemplary applications in biophotonic lighting, active full-color displaying, and metaphotonic sensing confirmed our theory. The method applies to the fields with accurate manipulations of chromaticity and luminosity of a light, opening an avenue toward the next generation of perceptual displays, cameras, and sensors.

AMAP1 was a GTPase-activating protein that regulates cytoskeletal structures in focal adhesions, circular dorsal ruffles, and promote cell differentiation in tumor cells. But the activation and function of AMAP1 in breast cancer remain largely unexplored. Here we show that AMAP1 was phosphorylated and translocated to plasma membrane and formed a stable complex with Pyk2 in response to CCL18. Moreover, CCL18-dependent AMAP1 translocation interfered the AMAP1-IKK-β interaction, resulting in nuclear factor-kappaB (NF-κB) activation. Depletion of AMAP1 expression by RNAi efficiently reversed the CCL18-induced epithelial to mesenchymal transition (EMT) of breast cancer cells and as well as CCL18-induced adhesion, migration and invasion. Strikingly, AMAP1 overexpression was found in breast cancers that had undergone metastasis and was strongly predictive of poor prognosis in breast cancers. Given that AMAP1 mediated CCL18-induce activation of NF-κB and promoted breast cancer metastasis, AMAP1 may represent a therapeutic target for the eradication of breast cancer metastasis.

Colorectal cancer (CRC) is the third and second most common type of cancer diagnosed in males and females, respectively, and is the fourth leading cause of cancer-associated mortality worldwide. Liver metastasis is the primary cause of mortality in patients with CRC, and therefore requires therapeutic focus. Regulatory T cells (Tregs) and hepatic stellate cells (HSCs) are potentially involved in regulating the immune response during liver metastasis. The aim of the present study was to evaluate the influence of CD4+ forkhead box p3 (Foxp3)+ Tregs and the HGF/c-Met signaling pathway in the liver metastasis of CRC. A model of the latter was established using Balb/c mice via splenic injection of human CRC cells (CT-26 line). The mice were monitored for 3 weeks after being injected, and the spleens and livers were removed on day 22 for further analysis. Moreover, the single-cell suspensions were labeled with CD4 and Foxp3 antibodies, and were analyzed using flow cytometry. Expression levels of α-smooth muscle actin (SMA), hepatocyte growth factor (HGF) and hepatocyte growth factor receptor (c-Met) were analyzed using immunohistochemistry. Mice injected with CT-26 cells exhibited signs of illness and significant weight loss, compared with the control mice (P=0.013), and they also developed liver metastases, at an average of 20.5 tumors per mouse. Pathological evaluation using hematoxylin and eosin staining confirmed the tumors as liver metastases of CRC. The numbers of CD4+ T cells were significantly decreased in the spleen (P

SHANK3 mutations, including de novo deletions, have been associated with autism spectrum disorders (ASD). However, the effects of SHANK3 loss of function on neurodevelopment remain poorly understood. Here we generated human induced pluripotent stem cells (iPSC) in vitro, followed by neuro-differentiation and lentivirus-mediated shRNA expression to evaluate how SHANK3 knockdown affects the in vitro neurodevelopmental process at multiple time points (up to 4 weeks). We found that SHANK3 knockdown impaired both early stage of neuronal development and mature neuronal function, as demonstrated by a reduction in neuronal soma size, growth cone area, neurite length and branch numbers. Notably, electrophysiology analyses showed defects in excitatory and inhibitory synaptic transmission. Furthermore, transcriptome analyses revealed that multiple biological pathways related to neuron projection, motility and regulation of neurogenesis were disrupted in cells with SHANK3 knockdown. In conclusion, utilizing a human iPSC-based neural induction model, this study presented combined morphological, electrophysiological and transcription evidence that support that SHANK3 as an intrinsic, cell autonomous factor that controls cellular function development in human neurons.

SHANK3 mutations, including de novo deletions, have been associated with autism spectrum disorders (ASD). However, the effects of SHANK3 loss of function on neurodevelopment remain poorly understood. Here we generated human induced pluripotent stem cells (iPSC) in vitro, followed by neuro-differentiation and lentivirus-mediated shRNA expression to evaluate how SHANK3 knockdown affects the in vitro neurodevelopmental process at multiple time points (up to 4 weeks). We found that SHANK3 knockdown impaired both early stage of neuronal development and mature neuronal function, as demonstrated by a reduction in neuronal soma size, growth cone area, neurite length and branch numbers. Notably, electrophysiology analyses showed defects in excitatory and inhibitory synaptic transmission. Furthermore, transcriptome analyses revealed that multiple biological pathways related to neuron projection, motility and regulation of neurogenesis were disrupted in cells with SHANK3 knockdown. In conclusion, utilizing a human iPSC-based neural induction model, this study presented combined morphological, electrophysiological and transcription evidence that support that SHANK3 as an intrinsic, cell autonomous factor that controls cellular function development in human neurons.

Carbon nanotubes (CNTs) have shown potential applications in neuroscience as growth substrates owing to their numerous unique properties. However, a key concern in the fabrication of homogeneous composites is the serious aggregation of CNTs during incorporation into the biomaterial matrix. Moreover, the regulation mechanism of CNT-based substrates on neural differentiation remains unclear. Here, a novel strategy was introduced for the construction of CNT nanocomposites via layer-by-layer assembly of negatively charged multi-walled CNTs and positively charged poly(dimethyldiallylammonium chloride). Results demonstrated that the CNT-multilayered nanocomposites provided a potent regulatory signal over neural stem cells (NSCs), including cell adhesion, viability, differentiation, neurite outgrowth, and electrophysiological maturation of NSC-derived neurons. Importantly, the dynamic molecular mechanisms in the NSC differentiation involved the integrin-mediated interactions between NSCs and CNT multilayers, thereby activating focal adhesion kinase, subsequently triggering downstream signaling events to regulate neuronal differentiation and synapse formation. This study provided insights for future applications of CNT-multilayered nanomaterials in neural fields as potent modulators of stem cell behavior.

Activity of the dentate gyrus, which gates information flow to the hippocampus, is under tight inhibitory regulation by interneurons with distinctive axonal projections, intrinsic and synaptic characteristics and neurochemical identities. Total molecular layer cells (TML-Cs), a class of morphologically distinct GABAergic neurons with axonal projections across the molecular layer, are among the most frequent interneuronal type in the dentate subgranular region. However, little is known about their synaptic and neurochemical properties. We demonstrate that synapses from morphologically identified TML-Cs to dentate interneurons are characterized by low release probability, facilitating short-term dynamics and asynchronous release. TML-Cs consistently show somatic and axonal labeling for the cannabinoid receptor type 1 (CB1R) yet fail to express cholecystokinin (CCK) indicating their distinctive neurochemical identity. In paired recordings, the release probability at synapses between TML-Cs was increased by the CB1R antagonist AM251, demonstrating baseline endocannabinoid regulation of TML-C synapses. Apart from defining the synaptic and neurochemical features of TML-Cs, our findings reveal the morphological identity of a class of dentate CB1R-positive neurons that do not express CCK. Our findings indicate that TML-Cs can mediate cannabinoid sensitive feed-forward and feedback inhibition of dentate perforant path inputs. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.

Induced pluripotent stem cells (iPSCs) can differentiate into neural progenitor cells (NPC) under proper conditions. NPC can be used as a model and is a useful tool for disease mechanism exploration and drug screening. However, the characteristics of the cells in various stages from NPC to functional neurons have not been fully described. This study investigated the characteristics of iPSC-derived NPCs during differentiation. Morphological characteristics of the NPCs, including soma area, neurite length, and the number of neurite branches, were examined on selected differentiation days. Physiological functions were assessed by recordings of sodium current, spontaneous excitatory postsynaptic current (sEPSC), and spontaneous inhibitory postsynaptic current (sIPSC). Furthermore, gene expression patterns were assessed with RNA-seq. We found that NPCs derived from iPSCs can be differentiated into glutamatergic and gabaergic neurons. Cell growth peaked during differentiation day 7–12, as the soma area decreased after day 12, growth cone and the number of branches peaked at day 9 and decreased afterwards; whereas a functional synapse formed after day 23. RNA-seq analysis found that a differential expression pattern emerged by day 7. Overall, the study provides a framework for the differentiation process of hiPSC-derived NPCs.

Strong perisomatic inhibition by fast-spiking basket cells (FS-BCs) regulates dentate throughput. Homotypic FS-BC interconnections that support gamma oscillations, and heterotypic inputs from diverse groups of interneurons that receive extensive neurochemical regulation, together, shape FS-BC activity patterns. However, whether seizures precipitate functional changes in inhibitory networks and contribute to abnormal network activity in epilepsy is not known. In the first recordings from dentate interneuronal pairs in a model of temporal lobe epilepsy, we demonstrate that status epilepticus (SE) selectively compromises GABA release at synapses from dentate accommodating interneurons (AC-INs) to FS-BCs, while efficacy of homotypic FS-BC synapses is unaltered. The functional decrease in heterotypic cannabinoid receptor type 1 (CB1R)-sensitive inhibition of FS-BCs resulted from enhanced baseline GABAB-mediated suppression of synaptic release after SE. The frequency of CB1R-sensitive inhibitory synaptic events in FS-BCs was depressed early after SE induction and remained reduced in epileptic rats. In biologically based simulations of heterogeneous inhibitory networks and excitatory-inhibitory cell networks, experimentally identified decrease in reliability of AC-IN to FS-BCs synaptic release reduced theta power and theta-gamma coupling and enhanced gamma coherence. Thus, the experimentally identified functional reduction in heterotypic inhibition of FS-BCs can contribute to compromised network oscillations in epilepsy and could precipitate memory and cognitive co-morbidities.