Enhancer-promoter interactions are reconfigured through the formation of long-range multiway hubs as mouse ES cells exit pluripotency.

Enhancers bind transcription factors, chromatin regulators, and non-coding transcripts to modulate the expression of target genes. Here, we report 3D genome structures of single mouse ES cells as they are induced to exit pluripotency and transition through a formative stage prior to undergoing neuroectodermal differentiation. We find that there is a remarkable reorganization of 3D genome structure where inter-chromosomal intermingling increases dramatically in the formative state. This intermingling is associated with the formation of a large number of multiway hubs that bring together enhancers and promoters with similar chromatin states from typically 5-8 distant chromosomal sites that are often separated by many Mb from each other. In the formative state, genes important for pluripotency exit establish contacts with emerging enhancers within these multiway hubs, suggesting that the structural changes we have observed may play an important role in modulating transcription and establishing new cell identities.

HOTTIP-dependent R-loop formation regulates CTCF boundary activity and TAD integrity in leukemia.

HOTTIP lncRNA is highly expressed in acute myeloid leukemia (AML) driven by MLL rearrangements or NPM1 mutations to mediate HOXA topologically associated domain (TAD) formation and drive aberrant transcription. However, the mechanism through which HOTTIP accesses CCCTC-binding factor (CTCF) chromatin boundaries and regulates CTCF-mediated genome topology remains unknown. Here, we show that HOTTIP directly interacts with and regulates a fraction of CTCF-binding sites (CBSs) in the AML genome by recruiting CTCF/cohesin complex and R-loop-associated regulators to form R-loops. HOTTIP-mediated R-loops reinforce the CTCF boundary and facilitate formation of TADs to drive gene transcription. Either deleting CBS or targeting RNase H to eliminate R-loops in the boundary CBS of ß-catenin TAD impaired CTCF boundary activity, inhibited promoter/enhancer interactions, reduced ß-catenin target expression, and mitigated leukemogenesis in xenograft mouse models with aberrant HOTTIP expression. Thus, HOTTIP-mediated R-loop formation directly reinforces CTCF chromatin boundary activity and TAD integrity to drive oncogene transcription and leukemia development.

Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy.

Treatment with therapy targeting BRAF and MEK (BRAF/MEK) has revolutionized care in melanoma and other cancers; however, therapeutic resistance is common and innovative treatment strategies are needed1,2. Here we studied a group of patients with melanoma who were treated with neoadjuvant BRAF/MEK-targeted therapy ( NCT02231775 , n = 51) and observed significantly higher rates of major pathological response (MPR; ≤10% viable tumour at resection) and improved recurrence-free survival (RFS) in female versus male patients (MPR, 66% versus 14%, P = 0.001; RFS, 64% versus 32% at 2 years, P = 0.021). The findings were validated in several additional cohorts2-4 of patients with unresectable metastatic melanoma who were treated with BRAF- and/or MEK-targeted therapy (n = 664 patients in total), demonstrating improved progression-free survival and overall survival in female versus male patients in several of these studies. Studies in preclinical models demonstrated significantly impaired anti-tumour activity in male versus female mice after BRAF/MEK-targeted therapy (P = 0.006), with significantly higher expression of the androgen receptor in tumours of male and female BRAF/MEK-treated mice versus the control (P = 0.0006 and P = 0.0025). Pharmacological inhibition of androgen receptor signalling improved responses to BRAF/MEK-targeted therapy in male and female mice (P = 0.018 and P = 0.003), whereas induction of androgen receptor signalling (through testosterone administration) was associated with a significantly impaired response to BRAF/MEK-targeted therapy in male and female patients (P = 0.021 and P < 0.0001). Together, these results have important implications for therapy.

Metal complexes bearing EGFR-inhibiting ligands as promising anticancer agents.

Overexpression of the epidermal growth factor receptor (EGFR, erbB1) has been observed in a wide range of solid tumors and has frequently been associated with poor prognosis. As a result, EGFR inhibition has become an attractive anticancer drug design strategy, and a large number of small molecular inhibitors have been developed. Despite the widespread clinical use of EGFR tyrosine kinase inhibitors (TKIs), their drug resistance, inadequate accumulation in tumors, and severe side effects have spurred the search for better antitumor drugs. Metal complexes have attracted much attention because of their different mechanisms compared with EGFR-TKIs. Therefore, the combination of metals and inhibitors is a promising anticancer strategy. For example, Ru and Pt centers are introduced to design complexes with double or multiple targets, while Au complexes are combined with inhibitors to overcome drug resistance. Co complexes are designed as prodrugs with weak side effects and enhanced targeting by the hypoxia activation strategy, and other metals such as Rh and Fe enhance the anticancer effect of the complexes. In addition, the introduction of Ga center is beneficial to the development of nuclear imaging tracers. In this paper, metal EGFR-TKI complexes in the last 15 years are reviewed, their mechanisms are briefly introduced, and their advantages are summarized.

LncRNA S100PBP promotes proliferation and steroid hormone synthesis of granulosa cells by sponging MiR-2285bc-BMPR2 in bovine.

In bovine follicular development, the proliferation of bovine granulosa cells (GCs) affect follicular selection, atresia, and cystic follicle formation. With the proliferation of GCs and secretion of steroid hormones, follicles develop further and increase in diameter. However, when cystic follicles appear on the ovaries, GCs stop proliferating, resulting in the reduction of GCs layer. In our previous study, the whole transcriptome sequencing revealed that Bone morphogenetic protein receptor 2 (BMPR2) was differentially expressed (DE) between cystic and normal follicular GCs. We speculated that lncRNA may act as ceRNA targeting miRNAs and then regulating the expression of BMPR2 and the function of GCs, thereby affecting follicular development and cyst formation. In this study, the results elucidated that lncRNA S100PBP (NONBTAT011846.2) directly bound miR-2285bc, which targeted in the BMPR2 3'-UTR. miR-2285bc suppresses GCs proliferation by downregulating BMPR2 expression. Furthermore, lncRNA S100PBP was silenced by small interfering RNA (siRNA), and lncRNA S100PBP regulated BMPR2 expression by sponging miR-2285bc investigated through cross-verification. When siRNA of lncRNA S100PBP was transfected into GCs, the results revealed similar molecular changes as those transfected with miR-2285bc mimics. Silencing lncRNA S100PBP or overexpressing miR-2285bc altered the expressions of some follicular development-related genes, which could be related to follicular cyst occurrence. In conclusion, our findings support that lncRNA S100PBP regulates the expression of BMPR2 through sponge miR-2285bc, promotes the proliferation of GCs, inhibits their apoptosis, and increases the synthesis and secretion of follicular steroid hormones, thus promoting the development of bovine follicles and potentially inhibiting the formation of follicular cysts.

Current research insights into the role of CTLA-4 in hepatitis B virus (HBV) infection.

Chronic hepatitis B virus (HBV) infection is a significant global public health concern, and the clearance of HBV is closely linked to the activity of HBV-specific T cells, which is regulated by various co-suppressor molecules. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is among these co-suppressor molecules which induces T cell exhaustion by competitively inhibiting CD28 and dampening the function of HBV-specific T cells. CTLA-4 also plays a role in the regulation of T helper (Th) cell differentiation and influences cytokine release. In addition, CTLA-4 can impact glucose metabolism in hepatocellular carcinoma through its interaction with T regulatory (Treg) cells. This review aims to provide a comprehensive overview of the existing literature related to the role of CTLA-4 in HBV patients across different subsets of T cells. Additionally, we propose a discussion on the possible mechanisms through which CTLA-4 may contribute to HBV infection, as well as the development of HBV-induced cirrhosis and hepatocellular carcinoma.

Different minimal alcohol consumption in male and female individuals with metabolic dysfunction-associated fatty liver disease.

BACKGROUND AND AIMS: The relationship between moderate alcohol intake and health outcomes among individuals with metabolic dysfunction-associated fatty liver disease (MAFLD) is complex. Our aim was to investigate the association of minimal alcohol consumption with all-cause and cause-specific mortality among MAFLD individuals of different genders. METHODS: Our study included 2630 MAFLD individuals from the Third National Health and Nutrition Examination Survey. Cox regression analysis was performed to assess the association between alcohol use measures and all-cause and cause-specific mortality. Restricted cubic spline curves were used to evaluate the relationship between alcohol consumption per week and all-cause mortality. RESULTS: In the entire MAFLD cohort, we observed significant disparities in clinical characteristics between male and female individuals with MAFLD. Higher weekly alcohol consumption was significantly associated with all-cause and cause-specific mortality (male, hazard ratios [HRs]: 1.009, 95% CIs: 1.004-1.014; female, HRs: 1.032, 95% CIs: 1.022-1.042). In males with MAFLD, a linear association with all-cause mortality was observed for weekly alcohol consumption (p for non-linearity = .21). Conversely, in females with MAFLD, the risk of all-cause mortality remained relatively stable until 2 drinks per week, after which it rapidly increased with each additional drink consumed, and the increase in mortality risk was higher than that observed in males (p for non-linearity < .05). CONCLUSIONS: Our findings indicate that any increase in weekly alcohol consumption was associated with increased all-cause mortality in men with MAFLD. Conversely, consuming less than 2 drinks per week had minimal impact on the risk of mortality among female.

Elongin B promotes breast cancer progression by ubiquitinating tumor suppressor p14/ARF.

Elongin B (ELOB), a pivotal element in the ELOB/c-Cullin2/5-SOCS-box E3 ubiquitin-protein ligase complex, plays a significant role in catalyzing the ubiquitination and subsequent degradation of a broad spectrum of target proteins. Notably, it is documented to facilitate these processes. However, the regulatory role of ELOB in breast cancer remains ambiguous. In this study, through bio-informatic analysis of The Cancer Genome Atlas and Fudan University Shanghai Cancer Center database, we demonstrated that ELOB was over-expressed in breast cancer tissues and was related to unfavorable prognosis. Additionally, pathway enrichment analysis illustrated that high expression of ELOB was associated with multiple cancer promoting pathways, like cell cycle, DNA replication, proteasome and PI3K - Akt signaling pathway, indicating ELOB as a potential anticancer target. Then, we confirmed that both in vivo and in vitro, the proliferation of breast cancer cells could be significantly suppressed by the down-regulation of ELOB. Mechanically, immunoprecipitation and in vivo ubiquitination assays prompted that, as the core element of Cullin2-RBX1-ELOB E3 ligase (CRL2) complex, ELOB regulated the ubiquitination and the subsequent degradation of oncoprotein p14/ARF. Moreover, the anticancer efficacy of erasing ELOB could be rescued by simultaneous knockdown of p14/ARF. Finally, through analyzing breast cancer tissue microarrays and western blot of patient samples, we demonstrated that the expression of ELOB in tumor tissues was elevated in compared to adjacent normal tissues. In conclusion, ELOB is identified to be a promising innovative target for the drug development of breast cancer by promoting the ubiquitination and degradation of oncoprotein p14/ARF.

Fitness effect and transcription profile reveal sublethal effect of nitenpyram on the predator Chrysopa pallens (Neuroptera: Chrysopidae).

Although neonicotinoids are widely used and important insecticide, there are growing concerns about their effect on nontarget insects and other organisms. Moreover, the effects of nitenpyram (NIT), a second generation of neonicotinoid insecticides, on Chrysopa pallens are still unclear. Therefore, this study purposed to investigate the acute toxicity of NIT to C. pallens using the spotting method. To examine the potential effects of a sublethal dose of NIT (LD30 , 1.85 ng of active ingredient per insect) on C. pallens, we constructed the life tables and analyzed the transcriptome data. The life table results showed that the period of second instar larvae, adult pre-oviposition period and total pre-oviposition period were significantly prolonged after exposure to sublethal dose of NIT, but had no significant effects on the other instars, longevity, oviposition days, and fecundity. The population parameters, including the preadult survival rate, gross reproduction rate, net reproductive rate, the intrinsic rate of increase, and finite rate of increase, were not significantly affected, and only the mean generation time was significantly prolonged by NIT. Transcriptome analysis showed that there were 68 differentially expressed genes (DEGs), including 50 upregulated genes and 18 downregulated genes. Moreover, 13 DEGs related to heat shock protein, nose resistant to fluoxetine protein 6, and prophenoloxidas were upregulated. This study showed the potential effects of sublethal doses of NIT on C. pallens and provided a theoretical reference for the comprehensive application of chemical and biological control in integrated pest management.

Experimental and theoretical studies on the compatibility of DNTF and typical hydrocarbon polymer binders.

3,4-bis(3-nitrofurazan-4-yl) furoxan (DNTF) is one of the third-generation energetic compounds with excellent comprehensive properties, which can be added to polymer bonded explosive (PBX) to improve energy levels and regulate sensitivity, so the compatibility of DNTF with other components in PBX, especially the binder, is the first question. Herein, two typical hydrocarbon polymers commonly used in PBX, which are hydroxyl-terminated polybutadiene (HTPB) and polyisobutylene (PIB), were selected as the binder, and the compatibility of HTPB and PIB with DNTF was investigated by differential scanning calorimetry (DSC), the vacuum stability test (VST), and in situ infrared spectroscopy (in situ IR). The results of compatibility experiments were verified by using the binding energy and solubility parameter criteria in molecular dynamics (MD). Experimental and MD simulation results showed that DNTF could be compatible with PIB but incompatible with HTPB. The frontier molecular orbital theory in quantum chemistry (QC) was adopted to explore the frontier orbital electron distribution and energy levels of DNTF/HTPB and DNTF/PIB composite systems to better understand the microscopic compatibility mechanism. The compatibility results of the two composite systems were explained from the perspective of electron transfer. All these can deduce that a hydrocarbon polymer binder with a saturated carbon-hydrogen bond at the end of the molecular chain has good compatibility with DNTF, compared with a hydroxyl group, which has bad compatibility with DNTF.

Efficacy of Core Muscle Exercise Combined with Interferential Therapy in Alleviating Chronic Low Back Pain in High-Performance Fighter Pilots: A Randomized Controlled Trial.

BACKGROUND: Chronic low back pain (LBP) related to flight is a prevalent health issue in military aviation, impacting pilots. The objective of this investigation was to ascertain if the application of core muscle training in conjunction with interferential current (IFC) therapy results in a reduction in pain severity and associated disability, consequently enhancing core muscle functionality in Chinese Air Force high-performance fighter pilots experiencing chronic LBP. METHODS: Fifty-three fighter pilots with chronic LBP were randomized into 3 groups: a core muscle exercise combined with IFC group (CG, n = 19), a core muscle exercise group (EG, n = 19), and an IFC group (IG, n = 15). The three groups underwent therapeutic intervention 5 times a week for 12 weeks. The primary outcomes were pain intensity, Oswestry Disability Index (ODI) score and SF-12 health-related quality of life (PCS and MCS) score. Secondary outcomes included evaluations of trunk muscle strength, endurance, and range of motion (ROM) during medial/lateral rotation to assess muscle functionality. Measurements were obtained both before and after the implementation of the intervention therapy. RESULTS: After 12 weeks of intervention therapy, all the health condition parameters significantly improved among the three groups. However, the CG had a significant improvement in pain intensity compared to the EG (MD = - 0.84 scores; 95% CI = - 1.54 to - 0.15; p = 0.013) and the IG (MD = - 1.22 scores; 95% CI = - 1.96 to - 0.48; p = 0.000). Additionally, the CG led to greater conservation of ODI and improved SF-12 PCS scores than did the IG (p < 0.05). Finally, compared with those at baseline, the core muscle function parameters in the CG and EG improved significantly at the end of the study, but no statistically significant differences were observed between the two groups (p > 0.05). CONCLUSION: Among participants with chronic LBP, three intervention therapies appear effective in reducing pain, diminishing disability, and enhancing quality of life. Also, combined therapy significantly improved pain and disability compared to the other two monotherapies; moreover, combined therapy and core muscle exercise provided similar benefits in terms of core muscle function after 12 weeks of intervention therapy.

Recycling selectable markers via Cre/loxP system for constructing Komagataella phaffii strains co-expressing multiple proteins.

OBJECTIVE: A convenient strategy was developed to recycle selectable markers using Cre/loxP system for constructing Komagataella phaffii strains co-expressing multiple proteins. RESULTS: A plasmid in this strategy was generated from pPICZαA with integration of lox71-Sh ble-lox66. Firstly, the plasmid was inserted with one target protein gene and then transformed into K. phaffii KM71. Secondly, the auxiliary plasmid pPICZαA/cre/his4 containing CRE recombinase gene was further chromosomally inserted to Sh ble gene therein. Finally, methanol induction was conducted to produce CRE for Cre/loxP-mediated recombination, and consequently, the sequence between lox71 and lox66 was deleted, leading to recycling of ZeoR and His- markers. Then the resulted strain expressing the one target protein was used as the host to which another target protein gene could be inserted by the same procedures. CONCLUSIONS: With easy manipulation, the method was effective in recycling of the selectable markers, and consequently two protein genes were sequential integrated chromosomally and successfully co-expressed in the yeast.

Nurses' knowledge, attitudes and practices regarding the application of the injury severity score in emergency departments: A cross-sectional multicentre study.

AIMS AND OBJECTIVES: To investigate knowledge, attitudes, and practices regarding the application of the Injury Severity Score (ISS) among emergency department nurses in China and the factors influencing these variables. BACKGROUND: ISS is the first trauma scoring method to be developed and the most widely used in clinical practice. The correct application of the ISS by emergency department nurses plays an important role in assisting in the diagnosis and treatment of trauma patients, and it is crucial to understand nurses' knowledge, attitudes and practices. DESIGN: A cross-sectional multicentre study. METHODS: Nurses from the emergency departments of 25 grade II and grade III hospitals in Gansu Province, China participated in this study. Data was collected online using a self-administered questionnaire. Student's t-test or analysis of variance was performed to compare the differences between the groups. Multiple logistic regression analysis identified factors influencing nurses' knowledge, attitudes and practices regarding applying ISS. A STROBE checklist was used to report findings. RESULTS: Among 459 nurses, a good level of attitude and passing levels of knowledge and practice regarding applying the ISS were revealed. Nurses in higher hospital grades, who had been exposed to ISS and received training had higher levels of knowledge and practices. Previous exposure to the ISS and training related to it were factors that influenced nurses' attitudes. CONCLUSIONS: Chinese emergency department nurses' knowledge, attitudes and practices of applying the ISS still need to be improved. Hospitals and nursing managers should provide training opportunities for nurses about ISS knowledge and practices, while grade II hospitals should pay more attention to training and continuing education in this area. RELEVANCE TO CLINICAL PRACTICE: In hospitals, nursing managers may benefit from enhancing related education and training to promote the emergency department nurses' knowledge and practice of the ISS, by developing specific curricula and providing continuing education and training opportunities, while grade II hospitals should pay more attention to training and continuing education in this area. NO PATIENT OR PUBLIC CONTRIBUTIONS: This study focused on emergency department nurses' knowledge, attitudes, and practices regarding the application of the ISS. The research questions and design were derived from clinical nursing practice, literature review, and expert panel review, and patients or the public are temporarily not involved.

High Strength MXene/PBONF Heterogeneous Membrane with Excellent Ion Selectivity for Efficient Osmotic Energy Conversion.

Layered MXene nanofluidic membranes still face the problems of low mechanical property, poor ion selectivity, and low output power density. In this work, we successfully constructed heterostructured membranes with the combination of the layered channels of the MXene layer on the top and the nanoscale poly(p-phenylene-benzodioxazole) nanofiber (PBONF) layer on the bottom through a stepwise filtration method. The as-prepared MXene/PBONF-50 heterogeneous membrane exhibits high mechanical properties (strength of 221.6 MPa, strain of 3.2%), high ion selectivity of 0.87, and an excellent output power density of 15.7 W/m2 at 50-fold concentration gradient. Excitingly, the heterogeneous membrane presents a high power density of 6.8 W/m2 at a larger testing area of 0.79 mm2 and long-term stability. This heterogeneous membrane construction provides a viable strategy for the enhancement of mechanical properties and osmotic energy conversion of 2D materials.

Impact of ozonation on disinfection byproducts formation from phenylalanine during chlorination.

As a strong oxidizing agent, ozone is used in some water treatment facilities for disinfection, taste and odor control, and removal of organic micropollutants. Phenylalanine (Phe) was used as the target amino acid to comprehensively investigate variability of disinfection byproducts (DBPs) formation during chlorine disinfection and residual chlorine conditions subsequent to ozonation. The results showed that subsequent to ozonation, the typical regulated and unregulated DBPs formation potential (DBPsFP), including trichloromethane (TCM), dichloroacetonitrile (DCAN), chloral hydrate (CH), dichloroacetic acid (DCAA), trichloroacetic acid (TCAA), and trichloroacetamide (TCAcAm) increased substantially, by 2.4, 3.3, 5.6, 1.2, 2.5, and 6.0 times, respectively, compared with only chlorination. Ozonation also significantly increased the DBPs yield under a 2 day simulated residual chlorine condition that mimicked the water distribution system. DBPs formations followed pseudo first order kinetics. The formation rates of DBPs in the first 6 hr were higher for TCM (0.214 hr-1), DCAN (0.244 hr-1), CH (0.105 hr-1), TCAcAm (0.234 hr-1), DCAA (0.375 hr-1) and TCAA (0.190 hr-1) than thereafter. The peak DBPsFP of TCM, DCAN, CH, TCAcAm, DCAA, and TCAA were obtained when that ozonation time was set at 5-15 min. Ozonation times > 30 min increased the mineralization of Phe and decreased the formation of DBPs upon chlorination. Increasing bromine ion (Br-) concentration increased production of bromine- DBPs and decreased chlorine-DBPs formation by 59.3%-92.2% . Higher ozone dosages and slight alkaline favored to reduce DBP formation and cytotoxicity. The ozonation conditions should be optimized for all application purposes including DBPs reduction.

[Relationship of triglyceride-glucose index and its derivatives with blood pressure abnormalities in adolescents: an analysis based on a restricted cubic spline model]. / åŸºäºŽé™åˆ¶æ€§ç«‹æ–¹æ ·æ¡æ¨¡åž‹åˆ†æžé’å°‘å¹´ä¸‰é °ç”˜æ²¹-è‘¡è„ç³–æŒ‡æ•°åŠå ¶è¡ç”ŸæŒ‡æ•°ä¸Žè¡€åŽ‹å¼‚å¸¸çš„å ³ç³».

OBJECTIVES: To explore the relationship of triglyceride-glucose index (TyG), triglyceride-glucose-body mass index (TyG-BMI), and triglyceride-glucose-waist circumference index (TyG-WC) with blood pressure abnormalities in adolescents, providing theoretical basis for the prevention and control of hypertension in adolescents. METHODS: A stratified cluster sampling method was used to select 1 572 adolescents aged 12 to 18 years in Yinchuan City for questionnaire surveys, physical measurements, and laboratory tests. Logistic regression analysis and restricted cubic spline analysis were employed to examine the relationship of TyG, TyG-BMI, and TyG-WC with blood pressure abnormalities in adolescents. RESULTS: Multivariable logistic regression analysis revealed that after adjusting for confounding factors, the groups with the highest quartile of TyG, TyG-BMI, and TyG-WC had 1.48 times (95%CI: 1.07-2.04), 3.71 times (95%CI: 2.67-5.15), and 4.07 times (95%CI: 2.89-5.73) higher risks of blood pressure abnormalities compared to the groups with the lowest quartile, respectively. Moreover, as the levels of TyG, TyG-BMI, and TyG-WC increased, the risk of blood pressure abnormalities gradually increased (P<0.05). A non-linear dose-response relationship was observed between TyG-BMI and the risk of blood pressure abnormalities (P overall trend<0.001, P non-linearity=0.002). Linear dose-response relationships were found between TyG and the risk of blood pressure abnormalities (P overall trend<0.001, P non-linearit =0.232), and between TyG-WC and the risk of blood pressure abnormalities (P overall trend<0.001, P non-linearity=0.224). CONCLUSIONS: Higher levels of TyG and its derivatives are associated with an increased risk of blood pressure abnormalities in adolescents, with linear or non-linear dose-response relationships.

Extrasynaptic NMDA Receptors Bidirectionally Modulate Intrinsic Excitability of Inhibitory Neurons.

The NMDA subtype glutamate receptors (NMDARs) play important roles in both physiological and pathologic processes in the brain. Compared with their critical roles in synaptic modifications and excitotoxicity in excitatory neurons, much less is understood about the functional contributions of NMDARs to the inhibitory GABAergic neurons. By using selective NMDAR inhibitors and potentiators, we here show that NMDARs bidirectionally modulate the intrinsic excitability (defined as spontaneous/evoked spiking activity and EPSP-spike coupling) in inhibitory GABAergic neurons in adult male and female mice. This modulation depends on GluN2C/2D- but not GluN2A/2B-containing NMDARs. We further show that NMDAR modulator EU1794-4 mostly enhances extrasynaptic NMDAR activity, and by using it we demonstrate a significant contribution of extrasynaptic NMDARs to the modulation of intrinsic excitability in inhibitory neurons. Together, this bidirectional modulation of intrinsic excitability reveals a previously less appreciated importance of NMDARs in the second-to-second functioning of inhibitory GABAergic neurons.SIGNIFICANCE STATEMENT NMDA subtype of glutamate receptors (NMDARs) have important roles in brain functions, including both physiological and pathologic ones. The role of NMDARs in inhibitory neurons has been less elucidated compared with that in excitatory neurons. Our results demonstrate the importance of GluN2C/GluN2D-containing but not GluN2A/GluN2B-containing extrasynaptic NMDARs in modulating the intrinsic excitability of inhibitory neurons. These results further suggest distinct contributions of subsynaptic locations and subunit compositions of NMDARs to their functions in excitatory and inhibitory neurons. The above findings have implications for better understanding of brain diseases, such as schizophrenia.

Enantioselective Divergent Syntheses of Cephalotaxus Alkaloids: (-)-Cephalotaxine, (-)-Cephalotine B, and (-)-Fortuneicyclidins A and B.

A new strategy focusing on the last-stage asymmetric assembly of the ring D, which inherently possesses the densest part of stereogenic centers and functional groups in the A/B/C/D ring system of (-)-cephalotaxine, has been developed, in which a novel Rh-catalyzed asymmetric (2 + 3) annulation of tertiary enamides with enoldiazoacetates is designed and explored for enantioselective construction of the crucial cyclopentane ring D bearing a unique spirocyclic aza-quaternary stereocenter. Based on the expeditious access of chiral functionalized building block with the tetracyclic A/B/C/D ring system, a concise enantioselective total synthesis of (-)-cephalotaxine starting from readily available homopiperonyl alcohol has been achieved in nine steps with only two column chromatography purifications. Following the tactical introduction of the Meinwald rearrangement, enantioselective divergent syntheses of (-)-cephalotine B with an additional C3-O-C11 oxo-bridged bond (14 steps), (-)-fortuneicyclidin B with an unprecedented C3-C10 bond (14 steps), and its 2-epimer (-)-fortuneicyclidin A (16 steps) have been also accomplished for the first time.

Ubiquitin-specific protease 11 promotes partial epithelial-to-mesenchymal transition by deubiquitinating the epidermal growth factor receptor during kidney fibrosis.

The aberrant expression of ubiquitin-specific protease 11 (USP11) is believed to be related to tumor progression. However, few studies have reported the biological function and clinical importance of USP11 in kidney fibrosis. Here, we demonstrated USP11 was highly upregulated in the kidneys from patients with chronic kidney disease and correlated positively with fibrotic lesion but negatively with kidney function. Conditional USP11 deletion or pharmacologic inhibition with Mitoxantrone attenuated pathological lesions and improved kidney function in both hyperuricemic nephropathy (HN)- and folic acid (FA)-induced mouse models of kidney fibrosis. Mechanistically, by RNA sequencing, USP11 was found to be involved in nuclear gene transcription of the epidermal growth factor receptor (EGFR). USP11 co-immunoprecipitated and co-stained with extra-nuclear EGFR and deubiquitinated and protected EGFR from proteasome-dependent degradation. Genetic or pharmacological depletion of USP11 facilitated EGFR degradation and abated augmentation of TGF-ß1 and downstream signaling. This consequently alleviated the partial epithelial-mesenchymal transition, G2/M arrest and aberrant secretome of profibrogenic and proinflammatory factors in uric acid-stimulated tubular epithelial cells. Moreover, USP11 deletion had anti-fibrotic and anti-inflammatory kidney effects in the murine HN and FA models. Thus, our study provides evidence supporting USP11 as a promising target for minimizing kidney fibrosis and that inhibition of USP11 has potential to be an effective strategy for patients with chronic kidney disease.