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Three new aromadendrane-type sesquiterpenoids (1–3) and five known compounds (4–8) were isolated from the stems of Strophanthus divaricatus. Their structures were determined by spectroscopic methods including HR-ESI-MS, 1D and 2D NMR. The absolute configurations of 1–3 was determined by comparison of the experimental and computed ECD spectra. Neridienone A (6) exhibited significant cytotoxicity against human cancer cell lines BEL-7402, SGC-7901, K562, A549, and HeLa with IC50 values of 3.30 ± 0.01, 2.25 ± 0.01, 2.02 ± 0.03, 1.55 ± 0.01, 4.73 ± 0.07 μM, respectively.

With the wide adoption of genomic sequencing in children having seizures, an increasing number ofSCN2Agenetic variants have been revealed as genetic causes of epilepsy. Voltage-gated sodium channel Nav1.2, encoded by geneSCN2A, is predominantly expressed in the pyramidal excitatory neurons and supports action potential (AP) firing. One recurrentSCN2Agenetic variant is L1342P, which was identified in multiple patients with epileptic encephalopathy and intractable seizures. However, the mechanism underlying L1342P-mediated seizures and the pharmacogenetics of this variant in human neurons remain unknown. To understand the core phenotypes of the L1342P variant in human neurons, we took advantage of a reference human-induced pluripotent stem cell (hiPSC) line from a male donor, in which L1342P was introduced by CRISPR/Cas9-mediated genome editing. Using patch-clamping and microelectrode array (MEA) recordings, we revealed that cortical neurons derived from hiPSCs carrying heterozygous L1342P variant have significantly increased intrinsic excitability, higher sodium current density, and enhanced bursting and synchronous network firing, suggesting hyperexcitability phenotypes. Interestingly, L1342P neuronal culture displayed a degree of resistance to the anticonvulsant medication phenytoin, which recapitulated aspects of clinical observation of patients carrying the L1342P variant. In contrast, phrixotoxin-3 (PTx3), a Nav1.2 isoform-specific blocker, can potently alleviate spontaneous and chemically-induced hyperexcitability of neurons carrying the L1342P variant. Our results reveal a possible pathogenic underpinning of Nav1.2-L1342P mediated epileptic seizures and demonstrate the utility of genome-edited hiPSCs as anin vitroplatform to advance personalized phenotyping and drug discovery.SIGNIFICANCE STATEMENTA mounting number ofSCN2Agenetic variants have been identified from patients with epilepsy, but howSCN2Avariants affect the function of human neurons contributing to seizures is still elusive. This study investigated the functional consequences of a recurringSCN2Avariant (L1342P) using human iPSC-derived neurons and revealed both intrinsic and network hyperexcitability of neurons carrying a mutant Nav1.2 channel. Importantly, this study recapitulated elements of clinical observations of drug-resistant features of the L1342P variant, and provided a platform forin vitrodrug testing. Our study sheds light on cellular mechanism of seizures resulting from a recurring Nav1.2 variant, and helps to advance personalized drug discovery to treat patients carrying pathogenicSCN2Avariant.

Two new compounds, dendronobilate (1) and 4-O-demethyl-nobilone (2), together with one known fluorenone were isolated from the aerial parts of Dendrobium nobile Lindl. Their structures were characterized by detailed analysis of 1D and 2D NMR spectra, HRESIMS and ECD spectra. Compounds 1–3 showed significant α-glucosidase inhibitory activity with IC50 values of 27.46 ± 3.14, 4.52 ± 0.33, and 10.78 ± 2.05 μM, respectively, which were superior to the acarbose (745.9 ± 3.3 μM). The binding interactions of 1 and 2 with α-glucosidase were investigated using molecular docking simulations. In addition, compound 2 exhibited potent inhibitory effect on NO production in LPS activated RAW264.7 cells with the IC50 value of 35.40 ± 1.77 μM without cytotoxicity observed.

The lack of efficient biomarkers is the main reason for the inaccurate early diagnosis and poor treatment outcomes of patients with metabolic syndrome (MetS). The current study aimed to identify several novel microRNA (miRNA) biomarkers for metabolic syndrome via high-throughput sequencing and comprehensive bioinformatics analysis. Through high-throughput sequencing and differentially expressed miRNA (DEM) analysis, we first identified two upregulated and 36 downregulated DEMs in the plasma samples of patients with MetS compared to the healthy volunteers. Additionally, we also predicted 379 potential target genes and subsequently carried out enrichment analysis and protein–protein interaction network analysis to investigate the signaling pathways and functions of the identified DEMs as well as the interactions between their target genes. Furthermore, we selected two upregulated and top 10 downregulated DEMs with the highest |log2FC| values as the key microRNAs, which may serve as potential biomarkers for MetS. RT-qPCR was performed to validated these result. Finally, hsa-miR-526b-5p, hsa-miR-6516-5p was identified as the novel biomarkers for MetS., Graphical abstract

N-Methyl-d-aspartate receptors (NMDARs) are glutamate-gated Na+ and Ca2+-permeable ion channels involved in excitatory synaptic transmission and synaptic plasticity. NMDAR hypofunction has long been implicated in the pathophysiology including major depressive disorders (MDDs). Herein, we report a series of furan-2-carboxamide analogues as novel NMDAR-positive allosteric modulators (PAMs). Through structure-based virtual screen and electrophysiological tests, FS2921 was identified as a novel NMDAR PAM with potential antidepressant effects. Further structure-activity relationship studies led to the discovery of novel analogues with increased potentiation. Compound 32h caused a significant increase in NMDAR excitability in vitro and impressive activity in the forced swimming test. Moreover, compound 32h showed no significant inhibition of hERG or cell viability and possessed a favorable PK/PD profile. Our study presented a series of novel NMDAR PAMs and provided potential opportunities for discovering of new antidepressants.

In mammals, many organs lack robust regenerative abilities. Lost cells in impaired tissue could potentially be compensated by converting nearby cells in situ through in vivo reprogramming. Small molecule-induced cell reprogramming offers a temporally flexible and non-integrative strategy for altering cell fate, which is, in principle, favorable for in vivo reprogramming in organs with notoriously poor regenerative abilities, such as the brain. Here, we demonstrate that in the adult mouse brain, small molecules can reprogram astrocytes into neurons. The in situ chemically induced neurons resemble endogenous neurons in terms of neuron-specific marker expression, electrophysiological properties, and synaptic connectivity. Our study demonstrates the feasibility of in vivo chemical reprogramming in the adult mouse brain and provides a potential approach for developing neuronal replacement therapies.

CD36 plays a critical role in lipid metabolism, which is closely associated with human immunity. However, the role of CD36 in cancer remains unclear. We performed a pan-cancer analysis to elucidate the potential role of CD36 in cancer by investigating its prognostic value and current predictors for the efficacy of immune checkpoint inhibitors (ICIs) in multiple cancer types. CD36 expression in cancer cell lines, tumor tissue, and their adjacent normal tissues displayed heterogeneity among different cancers. Immunohistochemistry was used to detect CD36 expression and confirmed the results. CD36 expression significantly affects prognosis in the six cancer types. High CD36 expression was marginally associated with poorer prognosis in four of them and improved prognosis in the remaining two types. CD36 expression was significantly correlated with the 6 immune infiltrates in most cancer types. In addition, CD36 gene expression was positively correlated with Stromal score, Immune score, and ESTIMATE score. A total of 47 immune checkpoint genes were collected and their relationship with CD36 expression was analyzed. CD36 expression was significantly associated with multiple stimulatory and inhibitory checkpoint molecules with a disease-specific pattern. As to the genes reported to positively relate to the efficacy of ICIs, CD36 expression was positively correlated with most of them but negatively associated with a small proportion of cancer type-specific patterns. Concerning the genes negatively related to the efficacy of ICIs, CD36 expression was positively correlated with NRP1 and TNFSF15 in multiple cancers. CD36 expression was negatively correlated with tumor neoantigen burden in most cancer types. However, CD36 expression was negatively correlated with tumor mutation burden in most cancer types. The correlation between CD36 expression and the four methyltransferases was also significant in multiple cancers, but also with a cancer type-specific pattern. In summary, the current study found CD36 expression and its prognostic value in multiple cancer types. In addition, the expression of CD36 was significantly associated with current predictors for the efficacy of ICIs. The practical application value of CD36 is disease specific.

A picrotoxane-type sesquiterpene, dendroterpene E (1), together with five benzene derivatives (2-6), were isolated from the stems of Dendrobium nobile Lindl. Their structures were elucidated by spectroscopic analysis and X-ray diffraction analysis. Compound 1 was a new picrotoxane-type sesquiterpene with a C-9/C-1/O/C-11 oxetane ring, which was first encountered in this type of compounds. Compounds 1-3 exhibited inhibitory activities against α-glycosidase.

Introduction Bladder cancer (BC) is the fourth-commones cancer and the sixth-leading cause of cancer-related death among men. However, a lack of reliable biomarkers remains a problem forprognosis and treatment of BC. lncRNAs have been shown to play important roles in various cancers, and have emerged as promising biomarkers for cancer prognosis and treatment. Methods In this study, using univariate and multivariate Cox regression analysis, we examined the differential expression profiles of 1,651 lncRNAs in the TCGA BLCA cohort and created a prognostic gene signature composed of six lncRNAs (for SNHG12, MAFG- DT, ASMTL-AS1, LINC02321, LINC01322, and LINC00922), designed the SMALLL signature. Results The SMALLL signature displayed significant prognostic power for overall survival for BC patients in multiple cohorts. Gene Ontology analysis showed that genes coexpressed with the SMALLL signature were associated with the extracellular matrix network, and immune cell–infiltration analysis showed that activated naive B cells, regulatory T cells, M0 macrophages, eosinophils, resting memory CD4 T cells and resting NK cells were significantly different in high- and low-risk groups. We also confirmed differential expression of the lncRNAs of the SMALLL signature in BC tissue and paracancer normal tissue by qRT-PCR analysis. Cell-invasion and -migration experiments showed that MAFG-AS1, ASMTL-AS1, LINC02321, and LINC00922 significantly affected cell invasion and migration. Conclusion Our study revealed that the lncRNA signature is an important predictive factor of prognosis and provides a promising biomarker for BC.

Four eudesmane sesquiterpene glycosides named pulisignoside A (1), B (2), C (3), and D (4) were isolated in addition to lemmonin C (5) from the Tibetan folk medicine Ming·chen·serpo (Pulicaria insignis Drumm. ex Dunn). Structures of these compounds were elucidated by comprehensive analyses of MS, 1D NMR, and 2D NMR spectroscopic data. In the anti-nematodal bioassays, pulisignoside C (3) showed nematocidal activity against Meloidogyne incognita (IC50 25.42 ± 0.28 μM).

Two new alkaloids (1–2), and four known ones (3–6) were isolated from branches of Cephalotaxus hainanensis Li. The structures of new alkaloids were elucidated by extensive analysis of HRESIMS, 1D and 2D NMR data. The absolute configuration of compound 2 was established on the basis of experimental and computed ECD data. All compounds were evaluated for their cytotoxic activity against K562, BEL-7402, SGC-7901, A549, and Hela human cancer cell lines. Compound 6 exhibited significant activity with IC50 values ranging from 4.86 to 26.56 μM, respectively.

Fatty acid‐binding protein 4 (FABP4) has been confirmed to be involved in the pathogenesis of ischaemia/reperfusion‐ and rhabdomyolysis‐induced acute kidney injury (AKI), and targeting inhibition of FABP4 might be a potential strategy for AKI. Cisplatin as a commonly used cancer chemotherapeutic drug possessed a dose‐limited side effect of nephrotoxicity. However, whether FABP4 inhibition exerted a favourable renoprotection against cisplatin‐induced AKI and the involved mechanisms remained unknown. In the study, cisplatin‐injected mice developed severe AKI symptom as indicated by renal dysfunction and pathological changes, companied by the high expression of FABP4 in tubular epithelial cells. Selective inhibition of FABP4 by BMS309403 at 40 mg/kg/d for 3 days and genetic knockout of FABP4 significantly attenuated the serum creatinine, blood urea nitrogen level and renal tubular damage. Mechanistically, cisplatin injection induced the increased apoptosis and regulated the corresponding protein expression of BCL‐2, BCL‐XL, BAX, cleaved caspase 3 and caspase 12 in the injured kidney tissues. Cisplatin also triggered multiple signal mediators of endoplasmic reticulum (ER) stress including double‐stranded RNA‐activated protein kinase‐like ER kinase, activating transcription factor‐6 and inositol‐requiring enzyme‐1 pathway, as well as CHOP, GRP78 and p‐JNK proteins in the kidneys. Oral administration of BMS309403 significantly reduced the number of renal TUNEL‐positive apoptotic cells. Knockout of FABP4 and BMS309403 notably improved ER stress‐related apoptotic responses. In summary, pharmacological and genetic inhibition of FABP4 modulated apoptosis via the inactivation of ER stress in the tubular epithelial cells of cisplatin‐induced AKI.

Background Major depressive disorder is a prevalent and life-threatening illness in modern society. The susceptibility to major depressive disorder is profoundly influenced by environmental factors, such as stressful lifestyle or traumatic events, which could impose maladaptive transcriptional program through epigenetic regulation. However, the underlying molecular mechanisms remain elusive. Here, we examined the role of histone crotonylation, a novel type of histone modification, and chromodomain Y-like protein (CDYL), a crotonyl-coenzyme A hydratase and histone methyllysine reader, in this process. Methods We used chronic social defeat stress and microdefeat stress to examine the depressive behaviors. In addition, we combined procedures that diagnose behavioral strategy in male mice with histone extraction, viral-mediated CDYL manipulations, RNA sequencing, chromatin immunoprecipitation, Western blot, and messenger RNA quantification. Results The results indicate that stress-susceptible rodents exhibit lower levels of histone crotonylation in the medial prefrontal cortex concurrent with selective upregulation of CDYL. Overexpression of CDYL in the prelimbic cortex, a subregion of the medial prefrontal cortex, increases microdefeat-induced social avoidance behaviors and anhedonia in mice. Conversely, knockdown of CDYL in the prelimbic cortex prevents chronic social defeat stress–induced depression-like behaviors. Mechanistically, we show that CDYL inhibits structural synaptic plasticity mainly by transcriptional repression of neuropeptide VGF nerve growth factor inducible, and this activity is dependent on its dual effect on histone crotonylation and H3K27 trimethylation on the VGF promoter. Conclusions Our results demonstrate that CDYL-mediated histone crotonylation plays a critical role in regulating stress-induced depression, providing a potential therapeutic target for major depressive disorder.

Twelve undescribed compounds including six phenanthrene derivatives (parviphenanthrines A-F), two stilbene derivatives (parvistilbines A-B), three esters (parviesters A-C), and one sesquiterpenoid (parvidiol A) were isolated from the roots of Stemona parviflora, together with twenty-two known ones. The structures of the undescribed compounds were elucidated based on the analyses of their spectroscopic data. The absolute configuration of parviphenanthrine A was determined by the quantum ECD calculations. Parviphenanthrines A and E, stemanthrene A, stilbostenin E, 4-hydroxy-benzenepropanol-α-benzoate, and (E)-4-hydroxycinnamic acid methyl ester showed nematocidal activity against Meloidogyne incognita with IC50 values of 14.02 ± 0.32, 2.51 ± 0.13, 17.10 ± 0.65, 2.05 ± 0.07, 4.22 ± 0.31, and 1.07 ± 0.05 μM, respectively.

Background The main symptoms of congenital chloride diarrhea (CCD) main symptoms are watery diarrhea, hypochloremia, and hypokalemic metabolic alkalosis. Silver–Russell syndrome (SRS) is a heterogeneous imprinting disorder characterized by severe intrauterine retardation, poor postnatal growth, and facial dysmorphism. Methods Parent‐offspring trio whole‐exome sequencing was used to identify the causal variants. Sequencing reads were mapped to the reference of human genome version hg19. Sanger sequencing was performed as a confirmatory experiment. Results The proband was a patient with SRS caused by maternal uniparental disomy 7. The CCD of the proband was caused by homozygous variant c.1515–1 (IVS13) G>A; both mutated alleles were inherited from her mother. Conclusion We report the first clinical case of CCD and SRS occurring together. Patients with milder phenotypes may be difficult to diagnose in early stage, but close monitoring of potential complications is important for identification., We report the first case of a female child presenting with CCD accompanied by maternal segmental UPD of chromosome 7 confirmed by molecular diagnosis. The proband was the only patient in the family and harbored a SLC26A3 variant (NM_000111.3:c.1515‐1G>A). The mother of the patient was heterozygous, whereas the father was wild‐type. After treatment of CCD, the patient still failed to thrive and had a typical dysmorphic feature. In the second genetic analysis, we found that at least 86.51 Mb of genome 7q11q36 (chr7: 65446986–151960086) was maternal uniparental disomy. We revised the diagnosis to CCD combined with SRS.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is the most common subphenotype of non-syndromic orofacial clefts arising from genetic and/or environmental perturbations during embryonic development. We previously identified 2p24.2 as a risk locus associated with NSCL/P in the Chinese Han population, and MYCN is a candidate risk gene in this region. To understand the potential function of MYCN in craniofacial development, we generated Wnt1-Cre;Mycnflox/flox mice that exhibited cleft palate, microglossia and micrognathia, resembling the Pierre Robin sequence (PRS) in humans. Further analyses indicated that the cleft palate was secondary to the delayed elevation of palatal shelves caused by micrognathia. The micrognathia resulted from impaired chondrogenic differentiation in Merkel’s cartilage, which limited tongue development, leading to microglossia. In terms of mechanism, Mycn deficiency in cranial neural crest cells (CNCCs) downregulated Sox9 expression by inhibiting Wnt5a in a CNCC-derived chondrogenic lineage in Merkel’s cartilage. To investigate whether MYCN deficiency contributed to NSCL/P, we performed direct sequencing targeting all exons and exon–intron boundaries of MYCN in 104 multiplex families with Mendelian NSCL/P and identified a novel pathogenic variant in MYCN. Taken together, our data indicate that ablation of Mycn in mouse CNCCs could resemble PRS by suppressing the Wnt5a-Sox9 signaling pathway in Merkel’s cartilage and that mutations in MYCN may be novel potential causes of NSCL/P.

Pinus massoniana is a pioneer reforestation tree species in China. It is crucial to evaluate the seedling vigor of Pinus massoniana for reforestation work, and leaf moisture and nitrogen content are key factors used to achieve it. In this paper, we proposed a non-destructive testing method based on the multi-scale short cut convolutional neural network (MS-SC-CNN) to measure moisture and nitrogen content in leaves of Pinus massoniana seedlings. By designing a reasonable short cut structure, the method realized the transmission of loss function gradient across the multi-layer structure in the network and reduced the information loss caused by the multi-layer transmission in the forward propagation. Meanwhile, in the back propagation stage, the loss caused by the multi-layer transmission of gradient was reduced. Thus, the gradient vanishing problem in training was avoided. Since the method realized cross-layer transmission error, the convolutional layer could be increased appropriately to obtain higher measurement accuracy. To verify the performance of the proposed MS-SC-CNN non-destructive measurement method, the near-infrared hyperspectral data of sample leaves of 219 Pinus massoniana seedlings were collected from the Huangping Forest Farm in Guizhou Province. The correlation coefficient between the measured and real values of the prediction was as high as 0.977 and the root mean square error was 0.242 for the moisture content of Pinus massoniana seedling leaves. For the nitrogen content of Pinus massoniana seedling leaves, the correlation coefficient between the measured and real values of the prediction was 0.906 and the root-mean-square error was 0.061. The results showed that the non-destructive testing method based on MS-SC-CNN that we proposed can accurately measure the moisture and nitrogen content in leaves of Pinus massoniana seedlings.

Scn2a encodes voltage-gated sodium channel NaV1.2, which mediates neuronal firing. The current paradigm suggests that NaV1.2 gain-of-function variants enhance neuronal excitability resulting in epilepsy, whereas NaV1.2 deficiency impairs neuronal excitability contributing to autism. In this paradigm, however, why about a third of patients with NaV1.2 deficiency still develop seizures remains a mystery. Here we challenge the conventional wisdom, reporting that neuronal excitability is increased with severe NaV1.2 deficiency. Using a unique gene-trap knockout mouse model of Scn2a, we found enhanced intrinsic excitabilities of principal neurons in the cortico-striatal circuit, known to be involved in Scn2a-related seizures. This increased excitability is autonomous, and is reversible by genetic restoration of Scn2a expression in adult mice. Mechanistic investigation reveals a compensatory downregulation of potassium channels including KV1.1, which could be targeted to alleviate neuronal hyperexcitability. Our unexpected findings may explain NaV1.2 deficiency-related epileptic seizures in humans and provide molecular targets for potential interventions.TEASERSevere NaV1.2 deficiency results in neuronal hyperexcitability via the compensatory downregulation of potassium channels.HIGHLIGHTSSevere NaV1.2 deficiency results in enhanced excitability of medium spiny neurons (MSNs) and pyramidal neurons in adult mice;Increased neuronal excitability in MSNs is accompanied by elevated voltage threshold;NaV1.2 deficiency-related hyperexcitability is reversible with the restoration of Scn2a expression, and is autonomous;The expression of the KV1.1 channel has a compensatory reduction in neurons with NaV1.2 deficiency, and KV channels openers normalize the neuronal excitability;The enhanced excitability in brain slices translates to elevated in vivo firing commonly associated with seizures.

Large-scale genetic studies revealed SCN2A as one of the most frequently mutated genes in patients with neurodevelopmental disorders. SCN2A encodes for the voltage-gated sodium channel isoform 1.2 (Nav 1.2) expressed in the neurons of the central nervous system. Homozygous knockout (null) of Scn2a in mice is perinatal lethal, whereas heterozygous knockout of Scn2a (Scn2a+/- ) results in mild behavior abnormalities. The Nav 1.2 expression level in Scn2a+/- mice is reported to be around 50-60% of the wild-type (WT) level, which indicates that a close to 50% reduction of Nav 1.2 expression may not be sufficient to lead to major behavioral phenotypes in mice. To overcome this barrier, we characterized a novel mouse model of severe Scn2a deficiency using a targeted gene-trap knockout (gtKO) strategy. This approach produces viable homozygous mice (Scn2agtKO/gtKO ) that can survive to adulthood, with about a quarter of Nav 1.2 expression compared to WT mice. Innate behaviors like nesting and mating were profoundly disrupted in Scn2agtKO/gtKO mice. Notably, Scn2agtKO/gtKO mice have a significantly decreased center duration compared to WT in the open field test, suggesting anxiety-like behaviors in a novel, open space. These mice also have decreased thermal and cold tolerance. Additionally, Scn2agtKO/gtKO mice have increased fix-pattern exploration in the novel object exploration test and a slight increase in grooming, indicating a detectable level of repetitive behaviors. They bury little to no marbles and have decreased interaction with novel objects. These Scn2a gene-trap knockout mice thus provide a unique model to study pathophysiology associated with severe Scn2a deficiency.

Drug discovery focused on target proteins has been a successful strategy, but many diseases and biological processes lack obvious targets to enable such approaches. Here, to overcome this challenge, we describe a deep learning-based efficacy prediction system (DLEPS) that identifies drug candidates using a change in the gene expression profile in the diseased state as input. DLEPS was trained using chemically induced changes in transcriptional profiles from the L1000 project. We found that the changes in transcriptional profiles for previously unexamined molecules were predicted with a Pearson correlation coefficient of 0.74. We examined three disorders and experimentally tested the top drug candidates in mouse disease models. Validation showed that perillen, chikusetsusaponin IV and trametinib confer disease-relevant impacts against obesity, hyperuricemia and nonalcoholic steatohepatitis, respectively. DLEPS can generate insights into pathogenic mechanisms, and we demonstrate that the MEK-ERK signaling pathway is a target for developing agents against nonalcoholic steatohepatitis. Our findings suggest that DLEPS is an effective tool for drug repurposing and discovery.

Recent large-scale genomic studies have revealedSCN2Aas one of the most frequently mutated gene in patients with neurodevelopmental disorders including autism spectrum disorder and intellectual disability.SCN2Aencodes for voltage-gated sodium channel isoform 1.2 (Nav1.2), which is mainly expressed in the central nervous system and responsible for the propagation of neuronal action potentials. Homozygous knockout (null) ofScn2ais perinatal lethal, whereas heterozygous knockout ofScn2aresults in mild behavior abnormalities. To achieve a more substantial, but not complete, reduction ofScn2aexpression, we characterized aScn2adeficient mouse model using a targeted gene trap knockout (gtKO) strategy to recapitulate loss-of-functionSCN2Adisorders. This model produces viable homozygous mice (Scn2agtKO/gtKO) that can survive to adulthood, with markedly low but detectable Nav1.2 expression. AlthoughScn2agtKO/gtKOadult mice possess normal olfactory, taste, hearing, and mechanical sensitivity, they have decreased thermal and cold tolerance. Innate behaviors are profoundly impaired including impaired nesting, marble burying, and mating. These mice also have increased food and water intake with subsequent increases in fecal excretion of more but smaller fecal boli. This novelScn2agene trap knockout mouse thus provides a unique model to study pathophysiology associated withScn2adeficiency.

Lung squamous cell carcinoma (LUSC) is often diagnosed at the advanced stage with poor prognosis. The mechanisms of its pathogenesis and prognosis require urgent elucidation. This study was performed to screen potential biomarkers related to the occurrence, development and prognosis of LUSC to reveal unknown physiological and pathological processes. Using bioinformatics analysis, the lung squamous cell carcinoma microarray datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were analyzed to identify differentially expressed genes (DEGs). Furthermore, PPI and WGCNA network analysis were integrated to identify the key genes closely related to the process of LUSC development. In addition, survival analysis was performed to achieve a prognostic model that accomplished good prediction accuracy. Three hundred and thirty&ndash, seven up&ndash, regulated and 119 down-regulated genes were identified, in which four genes have been found to play vital roles in LUSC development, namely CCNA2, AURKA, AURKB, and FEN1. The prognostic model contained 5 genes, which were all detrimental to prognosis. The AUC of the established prognostic model for predicting the survival of patients at 1, 3, and 5 years was 0.692, 0.722, and 0.651 in the test data, respectively. In conclusion, this study identified several biomarkers of significant interest for additional investigation of the therapies and methods of prognosis of lung squamous cell carcinoma.

Histone deacetylases 6 (HDAC6) has been reported to be involved in the pathogenesis of cisplatin-induced acute kidney injury (AKI). Selective inhibition of HDAC6 might be a potential treatment for AKI. In our previous study, a highly selective HDAC6 inhibitor (HDAC6i) 23BB effectively protected against rhabdomyolysis-induced AKI with good safety. However, whether 23BB possessed favorable renoprotection against cisplatin-induced AKI and the involved mechanisms remained unknown. In the study, cisplatin-injected mice developed severe AKI symptom as indicated by acute kidney dysfunction and pathological changes, companied by the overexpression of HDAC6 in tubular epithelial cells. Pharmacological inhibition of HDAC6 by the treatment of 23BB significantly attenuated sCr, BUN and renal tubular damage. Mechanistically, 23BB enhanced the acetylation of histone H3 to reduce the HDAC6 activity. Cisplatin-induced AKI triggered multiple signal mediators of endoplasmic reticulum (ER) stress including PERK, ATF6 and IRE1 pathway, as well as CHOP, GRP78, p-JNK and caspase 12 proteins. Oral administration of our HDAC6i 23BB at a dose of 40 mg/kg/d for 3 days notably improved above-mentioned responses in the injured kidney tissues. HDAC6 inhibition also reduced the number of TUNEL-positive tubular cells and regulated apoptosis-related protein expression. Overall, these data highlighted that HDAC6 inhibitor 23BB modulated apoptosis via the inhibition of ER stress in the tubular epithelial cells of cisplatin-induced AKI.

One new ergostane steroid, ergosta-4,6,8,22E-tetraen-11β-ol (1), together with five known analogues (2–6), was isolated from the fruiting bodies of Coprinus setulosus for the first time. Their structures were elucidated by analysis of 1D and 2D spectroscopic data as well as MS. The inhibitory activity of these isolates against acetylcholinesterase (AChE) showed that compound 1 exhibited weak inhibitory activity.

An unusual adenine-substituted germacrane sesquiterpene lactone, tomenphantadenine (1), has been isolated from the whole plant of Elephantopus tomentosus L. The structure of this compound was established by comprehensive spectroscopic analysis including high resolution (HR) ESI-MS, 1D and 2D nuclear magnetic resonance (NMR) spectroscopic data. This compound features novel hybrid pattern of germacrane sesquiterpene with adenine through C-N linkage, and a possible biosynthetic pathway for it was proposed. Compound 1 showed potent antibacterial activity against the gram-positive Staphylococcus aureus and weak acetylcholinesterase (AChE) inhibitory activity.

Static magnetic field (SMF) has been shown to biologically affect various microorganisms, but its effects on Enterococcus faecalis, which is associated with multiple dental infections, have not been reported yet. Besides, Enterococcus faecalis was found to be resistant to the alkaline environment provided by a major dental antimicrobial, calcium hydroxide. Therefore, the antibacterial activity of prolonged exposure to moderate SMF (170 mT) and its possible synergistic activity with alkaline pH (pH = 9) were evaluated in the study. The ability to form a biofilm under these conditions was examined by crystal violet assay. Real-time quantitative PCR was performed to evaluate the relative expression of stress (dnaK and groEL) and virulence (efaA, ace, gelE and fsrC) related genes. As the results indicated, cell proliferation was inhibited after 120 h of SMF exposure. What's more, the combined treatment of SMF and alkaline pH showed significantly improved antimicrobial action when compared to single SMF and alkaline pH treatment for more than 24 h and 72 h respectively. However, the ability to form a biofilm was also enhanced under SMF and alkaline pH treatments. SMF can induce stress response by up-regulating the expression of dnaK and elevate virulence gene expression (efaA and ace). These responses were more significant and more genes were up-regulated including groEL, gelE and fsrC when exposed to SMF and alkaline pH simultaneously. Hence, combination of SMF and alkaline pH could be a promising disinfection strategy in dental area and other areas associated with Enterococcus faecalis infections.

Thirty-one Vincan- and two Eburnan-type alkaloids were isolated from the aerial parts of Tabernaemontana bovina, whereas 20 of them are described the first time. Within the purified alkaloids, the firstly described taberbovcamine A features a 6/5/6/6/5 ring system. All the chemical structures were elucidated by employing extensive spectroscopic, computational electronic circular dichroism and X-ray diffraction methods. The two Eburnan-type alkaloids, 10,11-dimethoxy-16-O-methyllisoeburnamenine and 10,11-dimethoxy-isoeburnamenine were simultaneously identified by using the mentioned spectroscopic methods. Within the identified alkaloids, 10-hydroxy-14,15-didehydrovincanmine, 14,15-didehydrovincanmine, 14,15-didehydroapovincanmine, and criocerine increased the glucose consumption in a L6 myotube model.

SUMMARY Scn2a encodes the voltage-gated sodium channel NaV1.2, a main mediator of neuronal action potential firing. The current paradigm suggests that NaV1.2 gain-of-function variants enhance neuronal excitability, resulting in epilepsy, whereas NaV1.2 deficiency impairs neuronal excitability, contributing to autism. However, this paradigm does not explain why ~20%–30% of individuals with NaV1.2 deficiency still develop seizures. Here, we report the counterintuitive finding that severe NaV1.2 deficiency results in increased neuronal excitability. Using a NaV1.2-deficient mouse model, we show enhanced intrinsic excitability of principal neurons in the prefrontal cortex and striatum, brain regions known to be involved in Scn2a-related seizures. This increased excitability is autonomous and reversible by genetic restoration of Scn2a expression in adult mice. RNA sequencing reveals downregulation of multiple potassium channels, including KV1.1. Correspondingly, KV channel openers alleviate the hyperexcitability of NaV1.2-deficient neurons. This unexpected neuronal hyperexcitability may serve as a cellular basis underlying NaV1.2 deficiency-related seizures., Graphical Abstract, In brief Conventional wisdom suggests that the inadequacy of voltage-gated sodium channels impairs intrinsic neuronal excitability. Zhang et al. report that a severe deficiency of the NaV1.2 channel unexpectedly results in hyperexcitability of striatal medium spiny neurons with an elevated voltage threshold.

Two new nortriterpenoids named daqingshones A (1) and B (2), along with two known ganderic acids (3 and 4), were isolated from the fruiting bodies of Ganoderma daqingshanense. Their structures were elucidated by spectroscopic data including MS, 1D and 2D NMR. Compound 2 exhibited weak anti-acetylcholinesterase (AChE) activity with IC50 value of 39.2 μM.

The hormone jasmonate (JA), which functions in plant immunity, regulates resistance to pathogen infection and insect attack through triggering genome-wide transcriptional reprogramming in plants. We show that the basic helix-loop-helix transcription factor (TF) MYC2 in tomato (Solanum lycopersicum) acts downstream of the JA receptor to orchestrate JA-mediated activation of both the wounding and pathogen responses. Using chromatin immunoprecipitation sequencing (ChIP-seq) coupled with RNA sequencing (RNA-seq) assays, we identified 655 MYC2-targeted JA-responsive genes. These genes are highly enriched in Gene Ontology categories related to TFs and the early response to JA, indicating that MYC2 functions at a high hierarchical level to regulate JA-mediated gene transcription. We also identified a group of MYC2-targeted TFs (MTFs) that may directly regulate the JA-induced transcription of late defense genes. Our findings suggest that MYC2 and its downstream MTFs form a hierarchical transcriptional cascade during JA-mediated plant immunity that initiates and amplifies transcriptional output. As proof of concept, we showed that during plant resistance to the necrotrophic pathogen Botrytis cinerea, MYC2 and the MTF JA2-Like form a transcription module that preferentially regulates wounding-responsive genes, whereas MYC2 and the MTF ETHYLENE RESPONSE FACTOR.C3 form a transcription module that preferentially regulates pathogen-responsive genes.

Three new drimane-type sesquiterpenoids named xylariaines A–C (1–3), together with one known analogue (4), were isolated from the ethyl acetate extract of cultures of the fungus Xylaria polymorpha (Pers.: Fr.) Grer. Their structures were elucidated unambiguously by NMR and single-crystal X-ray diffraction analysis. Compounds 1 and 2 exhibited weak anti-acetylcholinesterase activities at a concentration of 50 μg/mL with inhibition ratios of 12.4% and 18.0%, respectively.

Two new compounds, philippin (1) and 3β,9α,14α-trihydroxy-(22E,24R)-ergost-22-en-7-one (2), were isolated from the fruiting bodies of Ganoderma philippii. Their structures were elucidated on the basis of the spectroscopic technologies, including 1D and 2D NMR as well as MS. The bioassay of inhibitory activity against acetylcholinesterase (AChE) showed compound 1 exhibited weak inhibitory activity against AChE.

// Yu-Jie Zhou 1, 2 , Dan-Dan Zhao 1, 2 , Huidi Liu 1, 2 , Hao-Ting Chen 1, 2 , Jia-Jing Li 1, 2 , Xiao-Qin Mu 1, 2 , Zheng Liu 3 , Xia Li 1, 2 , Le Tang 1, 2, 6 , Zhan-Yi Zhao 1, 2 , Ji-Heng Wu 1, 2 , Yu-Xuan Cai 1, 2 , Ya-Zhuo Huang 1, 2 , Peng-Ge Wang 1, 2 , Yi-Yue Jia 1, 2 , Pei-Qiang Liang 1, 2 , Xue Peng 1, 2 , Si-Yu Chen 1, 2 , Zhi-Lin Yue 1, 2 , Xin-Yuan Yuan 1, 2, 7 , Tammy Lu 1, 2, 8 , Bing-Qing Yao 1, 2 , Yong-Guo Li 4 , Gui-Rong Liu 1, 2 and Shu-Lin Liu 1, 2, 4, 5 1 Systemomics Center, College of Pharmacy, and Genomics Research Center, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Harbin Medical University, Harbin, China 2 HMU-UCFM Centre for Infection and Genomics, Harbin Medical University, Harbin, China 3 Colorectal Surgery Department, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China 4 Department of Infectious Diseases, The First Affiliated Hospital, Harbin Medical University, Harbin, China 5 Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Canada 6 Current affiliation: Department of Ecosystems and Public Health, University of Calgary, Calgary, Canada 7 Current affiliation: Life Sciences, Queen’s University, Kingston, Canada 8 Current affiliation: Biomedical Science, University of Calgary, Calgary, Canada Correspondence to: Shu-Lin Liu, email: slliu@hrbmu.edu.cn Keywords: cancer, malignancy killer, Actinobacteria, gut microbiota, leukemia Received: December 12, 2016 Accepted: April 02, 2017 Published: April 21, 2017 ABSTRACT Cancer as a large group of complex diseases is believed to result from the interactions of numerous genetic and environmental factors but may develop in people without any known genetic or environmental risks, suggesting the existence of other powerful factors to influence the carcinogenesis process. Much attention has been focused recently on particular members of the intestinal microbiota for their potential roles in promoting carcinogenesis. Here we report the identification and characterization of intestinal bacteria that exhibited potent anti-malignancy activities on a broad range of solid cancers and leukemia. We collected fecal specimens from healthy individuals of different age groups (preschool children and university students), inspected their effects on cancer cells, and obtained bacteria with potent anti-malignancy activities. The bacteria mostly belonged to Actinobacteria but also included lineages of other phyla such as Proteobacteria and Firmicutes. In animal cancer models, sterile culture supernatant from the bacteria highly effectively inhibited tumor growth. Remarkably, intra-tumor administration of the bacterial products prevented metastasis and even cleared cancer cells at remote locations from the tumor site. This work demonstrates the prevalent existence of potent malignancy-killers in the human intestinal microbiota, which may routinely clear malignant cells from the body before they form cancers.

Four picrotoxane-type sesquiterpenes, dendroterpene A-D (1-4), together with four known compounds (5-8), were isolated from the stems of Dendrobium nobile Lindl. Their structures were elucidated by spectroscopic analysis, X-ray diffraction analysis, analysis of the ECD data according to the Klyne's lactone sector rule, and quantum ECD calculation. Compounds 1 and 2 are two new picrotoxane-type sesquiterpenes with a new carbon skeleton containing a formamide group, which may be derived from the previously reported dendrobiumane B skeleton by the C(9)-C(11) carbon bond cleavage. Compounds 3, 5, 6, and 8 exhibited inhibitory activity against α-glycosidase. Compounds 5 and 6 were cytotoxic against SGC-7901, K562, A549, BEL-7402, and Hela cell lines.

Two new triterpenoids, named kadsuricoccins A and B, together with three known ones, were isolated from the Li folk herb Heilaohu, the stems of Kadsura coccinea (Lem.) A. C. Smith, which was used for food and as a healthy supplement. Their structures were elucidated by comprehensive analyses of mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopic data. To search healthy components, an acetylcholinesterase (AChE) inhibitory activity test by Ellman&rsquo, s Method was conducted, kadsuricoccins A and B showed activity with the AChE inhibit index (AII) up to 68.96% &plusmn, 0.19% and 57.8% &plusmn, 0.11% at 94 nM (compared with positive control tacrine AII 79.80% &plusmn, 0.20%, 9.4 nM), respectively.

BackgroudAquilaria sinensis (Lour.) Spreng is one of the important plant resources involved in the production of agarwood in China. The agarwood resin collected from wounded Aquilaria trees has been used in Asia for aromatic or medicinal purposes from ancient times, although the mechanism underlying the formation of agarwood still remains poorly understood owing to a lack of accurate and high-quality genetic information.FindingsWe report the genomic architecture of A. sinensis by using an integrated strategy combining Nanopore, Illumina, and Hi-C sequencing. The final genome was ∼726.5 Mb in size, which reached a high level of continuity and a contig N50 of 1.1 Mb. We combined Hi-C data with the genome assembly to generate chromosome-level scaffolds. Eight super-scaffolds corresponding to the 8 chromosomes were assembled to a final size of 716.6 Mb, with a scaffold N50 of 88.78 Mb using 1,862 contigs. BUSCO evaluation reveals that the genome completeness reached 95.27%. The repeat sequences accounted for 59.13%, and 29,203 protein-coding genes were annotated in the genome. According to phylogenetic analysis using single-copy orthologous genes, we found that A. sinensis is closely related to Gossypium hirsutum and Theobroma cacao from the Malvales order, and A. sinensis diverged from their common ancestor ∼53.18–84.37 million years ago.ConclusionsHere, we present the first chromosome-level genome assembly and gene annotation of A. sinensis. This study should contribute to valuable genetic resources for further research on the agarwood formation mechanism, genome-assisted improvement, and conservation biology of Aquilaria species.

Chemical probes of epigenetic ‘readers’ of histone post-translational modifications (PTMs) have become powerful tools for mechanistic and functional studies of their target proteins in physiology and pathology. However, only limited ‘reader’ probes have been developed, which restricted our understanding towards these macromolecules and their roles in cells or animals. Here, we reported a structure-guided approach to develop and characterize benzo [d]oxazol-2(3H)-one analogs as the first potent and selective small-molecule inhibitors of chromodomain Y-like (CDYL), a histone methyllysine reader protein. The binding conformation between the chromodomain of CDYL and the modified peptidomimetics was studied via molecular docking and dynamic simulations, facilitating subsequent virtual screening of tens of hits from Specs chemical library validated by SPR technique (KD values: from 271.1 μM to 5.4 μM). Further design and synthesis of 43 compounds helped to interpret the structure-activity relationship (SAR) that lead to the discovery of novel small-molecule inhibitors of CDYL. Compound D03 (KD: 0.5 μM) was discovered and showed excellent selectivity among other chromodomain proteins, including CDYL2 (>140 folds), CDY1 (no observed binding) and CBX7 (>32 folds). Moreover, we demonstrated that D03 engaged with endogenous CDYL in a dose-dependent manner, and perturbed the recruitment of CDYL onto chromatin, resulting in transcriptional derepression of its target genes. Finally, the results showed that D03 promoted the development and branching of neurodendrites by inhibiting CDYL in hippocampal and cortical cultured neurons. This study not only discovers the first selective small-molecule inhibitors of CDYL, but provids a new chemical tool to intervene the dynamic nature of bio-macromolecules involved in epigenetic mechanism.

Root growth potential (RGP) is a popular physiological indicator used to evaluate seedling vigor. However, the time scale used in the RGP test is the order of days, which leads to poor performance of the RGP method. We propose an optical interference method, called statistical interferometry, to measure minute root elongation at a sub-nanometer scale, which can decrease the time used in measuring RGP. The time scale of this method is also 104 times less than that of the RGP method. Because we can measure the length of root elongation continuously, we can compute the root elongation rate (RER), which is the variety of the length of root elongation per second. Continuous monitoring can help determine the quality of Masson pine seedling as soon as possible. To show the effectiveness of our proposed method, we designed an experiment, in which we applied different water stresses to our collected Masson pine seedlings and acquired two groups of pines, representing two different qualities: one stressed by water and one not. After measuring the RER of the groups in our experiments, we found that RER is interrelated with the quality of seedlings.Author summaryLi Wang have worked in Nanjing Forest University. His interesting includes machine learning, computer vision and plant phenotype.

Beta-cypermethrin, a type II synthetic pyrethroid insecticide, is widely used in pest control. Several studies have demonstrated that beta-cypermethrin can affect the reproductive system of mammals. However, there is still a scarcity of information about the reproductive toxicity to fish induced by beta-cypermethrin and its molecular mechanism. Therefore, this study was conducted to address this scientific question, in which the adult zebrafish were exposed to 0 (blank control), 0 (acetone solvent control), 0.1, 0.5, and 2.5 μg/L of beta-cypermethrin for 21 days. A decrease in cumulative egg production of zebrafish was observed, indicating that beta-cypermethrin had a negative impact on reproductive capacity of zebrafish. Regarding the histomorphological analysis of gonads, the delay of gonadal development was observed after exposure for 21 days. In addition, significant changes in plasma 17β-estradiol (E2) and testosterone (T) were found in zebrafish. Further exploration showed that the transcription levels of hypothalamic-pituitary-gonadal (HPG) axis-related genes were remarkably changed, which corresponded well with the alterations of hormone levels. These results demonstrated that beta-cypermethrin might have an adverse effect on the reproduction system of zebrafish through delaying gonadal development, disturbing sex hormone secretion, and affecting HPG axis gene expression. This study suggests that beta-cypermethrin poses a potential threat to the reproduction of fish populations, and the toxicity assessment of beta-cypermethrin plays a vital role in the environmental risk assessment of pesticides.

Three new compounds named penicitor A, aculene E and penicitor B, as well as four known compounds, were isolated from the fermentation broth of Penicillium sp. SCS-KFD08 associated with a marine animal Sipunculus nudus from the Haikou bay of China. Their planar structures and absolute configurations were unambiguously elucidated by spectroscopic data, Mosher's method, CD spectrum analysis along with quantum ECD calculation. Among them, compounds 2-7 showed quorum sensing inhibitory activity against Chromobacterium violaceum CV026, and could significantly reduce violacein production in N-hexanoyl-l-homoserine lactone (C6-HSL) induced C. violaceum CV026 cultures at sub-inhibitory concentrations.

Three new sesquiterpenoids (1-3), together with two known ones were isolated from the EtOAc extract of agarwood originating from Aquilaria crassna. The new compounds were elucidated on the basis of spectroscopic techniques (UV, IR, MS, 1D and 2D NMR). Compounds 1-5 were isolated from agarwood of A. crassna for the first time. In the acetylcholinesterase inhibition experiment of 2-5, compound 3 showed acetylcholinesterase inhibition activity (IR 42.9±0.6%). Compound 5 expressed antibacterial activities against Staphylococcus aureus and Ralstonia solanacearum with diameter of the inhibition zones of 12.35±0.11mm and 16.90±0.09mm, respectively.

Five new compounds named penicillars A⿿E were isolated from the fermentation broth of Penicillium sp. SCS-KFD08 associated with the marine animal Sipunculus nudus from the Haikou bay of China. Their planar structures and absolute configurations were unambiguously elucidated by spectroscopic data, Mo2(OAc)4 induced CD spectrum analysis along with quantum ECD calculation. Among them, compounds 2 and 3, at a concentration of 50 μg/mL, showed weak inhibitory activity against AChE with inhibition rates of 19.5% and 21.3%, respectively.

The chemical investigation on the fruiting bodies of Amauroderma subresinosum led to the isolation of 10 compounds including 2 new ones named amaurosubresin (1) and erythro(23,24)-5α,6α-epoxyergosta-8-ene-7-one-3β,23-diol (2). Their structures were elucidated on the basis of 1D and 2D NMR spectroscopy as well as MS. The bioassay of inhibitory activity against acetylcholinesterase (AChE) of two new isolates exhibited definite inhibitory activity.

Diaspores of myrmecochorous plants often include nutrient rich elaiosomes, which are known as appendages of seeds to attract ants for seed dispersion. The benefits of myrmecochory were investigated thoroughly in previous studies, such as, the diaspores may be carried to the ant nests where the elaiosomes are consumed and the seeds are discarded unharmed. However, it remained unclear whether the secondary dispersers could shape the traits of diaspores in myrmecochory. In this study, we analyzed the nutritional quality of seeds and their corresponding elaiosomes of the myrmecochorous plant Stemona tuberosa (Stemonaceae), whose diaspores are dispersed by ants and/or hornets. Our results show significant differences in the quantitative pattern of nutrients between seeds and elaiosomes, respectively. The elaiosomes of S. tuberosa contain significantly higher concentration of proteins, free fatty acids, free amino acids, soluble carbohydrates, and micronutrients than the seeds. The low mass ratio of seed/elaiosomes in S. tuberosa compared to other myrmecochorous species imply that seed dispersal by hornets might be discriminated from seed dispersal by ants. In conclusion, we suggest that hornets and ants obtain the essential nutrients from the elaiosomes of S. tuberosa and these rewards contribute to shape the hornet/ant-plant mutualism.

Six new prenylated hydroquinones named ganocalidin A–F (1–6) and two new compounds of ganocalicine A (7) and B (8), together with sixteen known compounds (9–24) were isolated from an EtOAc extract of the fruiting body of Ganoderma calidophilum. The new compound structures were elucidated on the basis of spectroscopic data analysis including 1D, 2D NMR and MS. Compounds 1 and 7 showed inhibitory activity effects on β-hexosaminidase activity (IC50 9.44 and 9.14 μM, respectively), and significantly reduced the production of IL-4 and LTB4 by RBL-2H3 cells in response to antigen stimulation, suggesting that 1 and 7 possess anti-allergic activity.

Mammals lack robust regenerative abilities. Lost cells in impaired tissue could potentially be compensated by converting nearby cells in situ through in vivo reprogramming. Small molecule-induced reprogramming is a spatiotemporally flexible and non-integrative strategy for altering cell fate, which is, in principle, favorable for the in vivo reprogramming in organs with poor regenerative abilities, such as the brain. Here, we demonstrate that in the adult mouse brain, small molecules can reprogram resident astrocytes into functional neurons. The in situ chemically induced neurons (CiNs) resemble endogenous neurons in terms of neuron-specific marker expression and electrophysiological properties. Importantly, these CiNs can integrate into the mouse brain. Our study, for the first time, demonstrates in vivo chemical reprogramming in the adult brain, which could be a novel path for generating desired cells in situ for regenerative medicine.

In organism, energy homeostasis is a biological process that involves the coordinated homeostatic regulation of energy intake (food intake) and energy expenditure. The human brain, particularly the hypothalamic proopiomelanocortin (POMC)- and agouti-related protein/neuropeptide Y (AgRP/NPY)-expressing neurons in the arcuate nucleus, plays an essential role in regulating energy homeostasis. The regulation process is mainly dependent upon peripheral hormones such as leptin and insulin, as well as nutrients such as glucose, amino acids, and fatty acids. Although many studies have attempted to illustrate the exact mechanisms of glucose and hormones action on these neurons, we still cannot clearly see the full picture of this regulation action. Therefore, in this review we will mainly discuss those established theories and recent progresses in this area, demonstrating the possible physiological mechanism by which glucose, leptin, and insulin affect neuronal excitability of POMC and AgRP neurons. In addition, we will also focus on some important ion channels which are expressed by POMC and AgRP neurons, such as KATP channels and TRPC channels, and explain how these channels are regulated by peripheral hormones and nutrients and thus regulate energy homeostasis.

Cephalotaxus hainanensis Li is a vulnerably endangered gymnosperm species with medicinal value. Here we performed the chloroplast (cp) genome of C. hainanensis by next generation sequencing...

Auxiliary Kv channel-interacting proteins 1–4 (KChIPs1–4) coassemble with pore-forming Kv4 α-subunits to form channel complexes underlying somatodendritic subthreshold A-type current that regulates neuronal excitability. It has been hypothesized that different KChIPs can competitively bind to Kv4 α-subunit to form variable channel complexes that can exhibit distinct biophysical properties for modulation of neural function. In this study, we use single-molecule subunit counting by total internal reflection fluorescence microscopy in combinations with electrophysiology and biochemistry to investigate whether different isoforms of auxiliary KChIPs, KChIP4a, and KChIP4bl, can compete for binding of Kv4.3 to coassemble heteromultimeric channel complexes for modulation of channel function. To count the number of photobleaching steps solely from cell membrane, we take advantage of a membrane tethered k-ras-CAAX peptide that anchors cytosolic KChIP4 proteins to the surface for reduction of background noise. Single-molecule subunit counting reveals that the number of KChIP4 isoforms in Kv4.3-KChIP4 complexes can vary depending on the KChIP4 expression level. Increasing the amount of KChIP4bl gradually reduces bleaching steps of KChIP4a isoform proteins, and vice versa. Further analysis of channel gating kinetics from different Kv4-KChIP4 subunit compositions confirms that both KChIP4a and KChIP4bl can modulate the channel complex function upon coassembly. Taken together, our findings show that auxiliary KChIPs can heteroassemble with Kv4 in a competitive manner to form heteromultimeric Kv4-KChIP4 channel complexes that are biophysically distinct and regulated under physiological or pathological conditions.