Histone Hypervariants H2A.Z.1 and H2A.Z.2 Play Independent and Context-Specific Roles in Neuronal Activity-Induced Transcription of Arc/Arg3.1 and Other Immediate Early Genes.

The histone variant H2A.Z is an essential and conserved regulator of eukaryotic gene transcription. However, the exact role of this histone in the transcriptional process remains perplexing. In vertebrates, H2A.Z has two hypervariants, H2A.Z.1 and H2A.Z.2, that have almost identical sequences except for three amino acid residues. Due to such similarity, functional specificity of these hypervariants in neurobiological processes, if any, remain largely unknown. In this study with dissociated rat cortical neurons, we asked if H2A.Z hypervariants have distinct functions in regulating basal and activity-induced gene transcription. Hypervariant-specific RNAi and microarray analyses revealed that H2A.Z.1 and H2A.Z.2 regulate basal expression of largely nonoverlapping gene sets, including genes that code for several synaptic proteins. In response to neuronal activity, rapid transcription of our model gene Arc is impaired by depletion of H2A.Z.2, but not H2A.Z.1. This impairment is partially rescued by codepletion of the H2A.Z chaperone, ANP32E. In contrast, under a different context (after 48 h of tetrodotoxin, TTX), rapid transcription of Arc is impaired by depletion of either hypervariant. Such context-dependent roles of H2A.Z hypervariants, as revealed by our multiplexed gene expression assays, are also evident with several other immediate early genes, where regulatory roles of these hypervariants vary from gene to gene under different conditions. Together, our data suggest that H2A.Z hypervariants have context-specific roles that complement each other to mediate activity-induced neuronal gene transcription

Long-term depression-associated signaling is required for an in vitro model of NMDA receptor-dependent synapse pruning

AbstractActivity-dependent pruning of synaptic contacts plays a critical role in shaping neuronal circuitry in response to the environment during postnatal brain development. Although there is compelling evidence that shrinkage of dendritic spines coincides with synaptic long-term depression (LTD), and that LTD is accompanied by synapse loss, whether NMDA receptor (NMDAR)-dependent LTD is a required step in the progression toward synapse pruning is still unknown. Using repeated applications of NMDA to induce LTD in dissociated rat neuronal cultures, we found that synapse density, as measured by colocalization of fluorescent markers for pre- and postsynaptic structures, was decreased irrespective of the presynaptic marker used, post-treatment recovery time, and the dendritic location of synapses. Consistent with previous studies, we found that synapse loss could occur without apparent net spine loss or cell death. Furthermore, synapse loss was unlikely to require direct contact with microglia, as the number of these cells was minimal in our culture preparations. Supporting a model by which NMDAR-LTD is required for synapse loss, the effect of NMDA on fluorescence colocalization was prevented by phosphatase and caspase inhibitors. In addition, gene transcription and protein translation also appeared to be required for loss of putative synapses. These data support the idea that NMDAR-dependent LTD is a required step in synapse pruning and contribute to our understanding of the basic mechanisms of this developmental process

Androgen receptor as a mediator and biomarker of radioresistance in triple-negative breast cancer.

Increased rates of locoregional recurrence have been observed in triple-negative breast cancer despite chemotherapy and radiation therapy. Thus, approaches that combine therapies for radiosensitization in triple-negative breast cancer are critically needed. We characterized the radiation therapy response of 21 breast cancer cell lines and paired this radiation response data with high-throughput drug screen data to identify androgen receptor as a top target for radiosensitization. Our radiosensitizer screen nominated bicalutamide as the drug most effective in treating radiation therapy-resistant breast cancer cell lines. We subsequently evaluated the expression of androgen receptor in >2100 human breast tumor samples and 51 breast cancer cell lines and found significant heterogeneity in androgen receptor expression with enrichment at the protein and RNA level in triple-negative breast cancer. There was a strong correlation between androgen receptor RNA and protein expression across all breast cancer subtypes (R2 = 0.72, p < 0.01). In patients with triple-negative breast cancer, expression of androgen receptor above the median was associated with increased risk of locoregional recurrence after radiation therapy (hazard ratio for locoregional recurrence 2.9-3.2)) in two independent data sets, but there was no difference in locoregional recurrence in triple-negative breast cancer patients not treated with radiation therapy when stratified by androgen receptor expression. In multivariable analysis, androgen receptor expression was most significantly associated with worse local recurrence-free survival after radiation therapy (hazard ratio of 3.58) suggesting that androgen receptor expression may be a biomarker of radiation response in triple-negative breast cancer. Inhibition of androgen receptor with MDV3100 (enzalutamide) induced radiation sensitivity (enhancement ratios of 1.22-1.60) in androgen receptor-positive triple-negative breast cancer lines, but did not affect androgen receptor-negative triple-negative breast cancer or estrogen-receptor-positive, androgen receptor-negative breast cancer cell lines. androgen receptor inhibition with MDV3100 significantly radiosensitized triple-negative breast cancer xenografts in mouse models and markedly delayed tumor doubling/tripling time and tumor weight. Radiosensitization was at least partially dependent on impaired dsDNA break repair mediated by DNA protein kinase catalytic subunit. Our results implicate androgen receptor as a mediator of radioresistance in breast cancer and identify androgen receptor inhibition as a potentially effective strategy for the treatment of androgen receptor-positive radioresistant tumors

Caffeine-induced synaptic potentiation in hippocampal CA2 neurons

Caffeine enhances cognition, but even high non-physiological doses have modest effects on synapses. A 1 adenosine receptors (A 1 Rs) are antagonized by caffeine and are most highly enriched in hippocampal CA2, which has not been studied in this context. We found that physiological doses of caffeine in vivo or A 1 R antagonists in vitro induced robust, long-lasting potentiation of synaptic transmission in rat CA2 without affecting other regions of the hippocampus

Quantitative Trait Locus Mapping of Soybean Maturity Gene E6

Soybean [ Glycine max (L.) Merr.] sensitivity to photoperiod determines adaptation to a specific range of latitudes for soybean cultivars. When temperate-adapted soybean cultivars are grown in low latitude under short day conditions, they flower early, resulting in low grain yield, and consequently limiting their utility in tropical areas. Most cultivars adapted to low-latitude environments have the trait of delayed flowering under short day conditions, and this trait is commonly called long juvenile (LJ). In this study, the E6 locus, the classical locus conditioning the LJ trait, was molecularly mapped on Gm04 near single-nucleotide polymorphism marker HRM101. Testcross, genetic mapping, and sequencing suggest that the E6 and J loci might be tightly linked. Genetic interaction evaluation between E6 and E1 suggests that E6 has a suppressive effect on E1 and that the function of E6 is dependent on E1. The tagging markers for E6 are very useful for molecular breeding for wide adaptation and stable productivity of soybean under lowlatitude environments. Molecular identification and functional characterization of the E6 gene will greatly facilitate the understanding of the genetic and molecular mechanisms underlying the LJ trait

Effectiveness of problem-based learning combined with lecture based learning methodology in renal pathology education

AbstractTo evaluate the teaching effect of problem-based learning (PBL) combined with lecture-based learning (LBL) compared with that of LBL alone in renal pathology education for trainees receiving standardized training.A total of 65 undergraduate medical students who received standardized training in Xijing Hospital from January 2016 to November 2019 were randomly divided into a PBL+LBL group (33 subjects) and an LBL alone group (32 subjects). The teaching effect was evaluated using the subjects’ diagnostic accuracy of renal pathology, knowledge of renal pathology and teaching satisfaction assessment. The diagnostic accuracy of renal pathology, knowledge of renal pathology and teaching satisfaction assessment in PLB+LBL group (81.0%, 79.99 ± 6.65 and 89.4%, respectively) were significantly higher than those in the LBL alone group (58.5%, 62.89 ± 10.31 and 58.9%, respectively). While teaching renal pathology to undergraduate medical students receiving standardized training, the PBL+LBL group benefited from a teaching effect and gave a better teaching satisfaction

I intermedio con soluzioni

An EST sequence, designated JnRAP2-like, was isolated from tissue at the heartwood/sapwood transition zone (TZ) in black walnut (Juglans nigra L). The deduced amino acid sequence of JnRAP2-like protein consists of a single AP2-containing domain with significant similarity to conserved AP2/ERF DNA-binding domains in other species. Based on multiple sequence alignment, JnRAP2-like appears to be an ortholog of RAP2.6L (At5g13330), which encodes an ethylene response element binding protein in Arabidopsis thaliana. Real-time PCR revealed that the JnRAP2-like was expressed most abundantly in TZ of trees harvested in fall when compared with other xylem tissues harvested in the fall or summer. Independent transgenic lines over-expressing JnRAP2-like in Arabidopsis developed dramatic ethylene-related phenotypes when treated with 50 µM methyl jasmonate (MeJA). Taken together, these results indicated that JnRAP2-like may participate in the integration of ethylene and jasmonate signals in the xylem and other tissues. Given the role of ethylene in heartwood formation, it is possible JnRAP2-like expression in the transition zone is part of the signal transduction pathway leading to heartwood formation in black walnut

A recessive allele for delayed flowering at the soybean maturity locus E9 is a leaky allele of FT2a, a FLOWERING LOCUS T ortholog

Background: Understanding the molecular mechanisms of flowering and maturity is important for improving the adaptability and yield of seed crops in different environments. In soybean, a facultative short-day plant, genetic variation at four maturity genes, E1 to E4, plays an important role in adaptation to environments with different photoperiods. However, the molecular basis of natural variation in time to flowering and maturity is poorly understood. Using a cross between early-maturing soybean cultivars, we performed a genetic and molecular study of flowering genes. The progeny of this cross segregated for two maturity loci, E1 and E9. The latter locus was subjected to detailed molecular analysis to identify the responsible gene. Results: Fine mapping, sequencing, and expression analysis revealed that E9 is FT2a, an ortholog of Arabidopsis FLOWERING LOCUS T. Regardless of daylength conditions, the e9 allele was transcribed at a very low level in comparison with the E9 allele and delayed flowering. Despite identical coding sequences, a number of single nucleotide polymorphisms and insertions/deletions were detected in the promoter, untranslated regions, and introns between the two cultivars. Furthermore, the e9 allele had a Ty1/copia-like retrotransposon, SORE-1, inserted in the first intron. Comparison of the expression levels of different alleles among near-isogenic lines and photoperiod-insensitive cultivars indicated that the SORE-1 insertion attenuated FT2a expression by its allele-specific transcriptional repression. SORE-1 was highly methylated, and did not appear to disrupt FT2a RNA processing. Conclusions: The soybean maturity gene E9 is FT2a, and its recessive allele delays flowering because of lower transcript abundance that is caused by allele-specific transcriptional repression due to the insertion of SORE-1. The FT2a transcript abundance is thus directly associated with the variation in flowering time in soybean. The e9 allele may maintain vegetative growth in early-flowering genetic backgrounds, and also be useful as a long-juvenile allele, which causes late flowering under short-daylength conditions, in low-latitude regions

Facile synthesis of Sb2S3/MoS2 heterostructure as anode material for sodium-ion batteries

A novel Sb2S3/MoS2 heterostructure in which Sb2S3 nanorods are coated with MoS2 nanosheets to form core-shell structure has been fabricated via a facile two-step hydrothermal process. The Sb2S3/MoS2 heterostructure utilized as anode of sodium-ion batteries (SIBs) shows higher capacity, superior rate capability and better cycling performance compared with individual Sb2S3 nanorods and MoS2 nanosheets. Specifically, the Sb2S3/MoS2 electrode shows an initial reversible capacity of 701 mAh g-1 at the current density of 100 mA g-1, which is remained 80.1% of the initial perforance after 100 cycles at the same current density. This outstanding electrochemical performance indicates Sb2S3/MoS2 heterostructure is a very promising anode material for high-performance SIBs