Notes

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Domesticates are an excellent model for understanding biological consequences of rapid climate change. Maize (Zea mays ssp. mays) was domesticated from a tropical grass yet is widespread across temperate regions today. We investigate the biological basis of temperate adaptation in diverse structured nested association mapping (NAM) populations from China, Europe (Dent and Flint) and the United States as well as in the Ames inbred diversity panel, using days to flowering as a proxy. Using cross-population prediction, where high prediction accuracy derives from overall genomic relatedness, shared genetic architecture, and sufficient diversity in the training population, we identify patterns in predictive ability across the five populations. To identify the source of temperate adapted alleles in these populations, we predict top associated genome-wide association study (GWAS) identified loci in a Random Forest Classifier using independent temperate-tropical North American populations based on lines selected from Hapmap3 as predictors. AD-5584 We find that North American populations are well predicted (AUC equals 0.89 and 0.85 for Ames and USNAM, respectively), European populations somewhat well predicted (AUC equals 0.59 and 0.67 for the Dent and Flint panels, respectively) and that the Chinese population is not predicted well at all (AUC is 0.47), suggesting an independent adaptation process for early flowering in China. Multiple adaptations for the complex trait days to flowering in maize provide hope for similar natural systems under climate change.Early-onset epileptic encephalopathies are severe disorders often associated with specific genetic mutations. In this context, the CDKL5 deficiency disorder (CDD) is a neurodevelopmental condition characterized by early-onset seizures, intellectual delay, and motor dysfunction. Although crucial for proper brain development, the precise targets of CDKL5 and its relation to patients' symptoms are still unknown. Here, induced pluripotent stem cells derived from individuals deficient in CDKL5 protein were used to generate neural cells. Proteomic and phosphoproteomic approaches revealed disruption of several pathways, including microtubule-based processes and cytoskeleton organization. While CDD-derived neural progenitor cells have proliferation defects, neurons showed morphological alterations and compromised glutamatergic synaptogenesis. Moreover, the electrical activity of CDD cortical neurons revealed hyperexcitability during development, leading to an overly synchronized network. Many parameters of this hyperactive network were rescued by lead compounds selected from a human high-throughput drug screening platform. Our results enlighten cellular, molecular, and neural network mechanisms of genetic epilepsy that could ultimately promote novel therapeutic opportunities for patients.With reactive astrogliosis being established as one of the hallmarks of Alzheimer's disease (AD), there is high interest in developing novel positron emission tomography (PET) tracers to detect early astrocyte reactivity. BU99008, a novel astrocytic PET ligand targeting imidazoline-2 binding sites (I2BS) on astrocytes, might be a suitable candidate. Here we demonstrate for the first time that BU99008 could visualise reactive astrogliosis in postmortem AD brains and propose a multiple binding site [Super-high-affinity (SH), High-affinity (HA) and Low-affinity (LA)] model for BU99008, I2BS specific ligands (2-BFI and BU224) and deprenyl in AD and control (CN) brains. The proportion (%) and affinities of these sites varied significantly between the BU99008, 2-BFI, BU224 and deprenyl in AD and CN brains. Regional binding studies demonstrated significantly higher 3H-BU99008 binding in AD brain regions compared to CN. Comparative autoradiography studies reinforced these findings, showing higher specific binding for 3H-BU99008 than 3H-Deprenyl in sporadic AD brain compared to CN, implying that they might have different targets. The data clearly shows that BU99008 could detect I2BS expressing reactive astrocytes with good selectivity and specificity and hence be a potential attractive clinical astrocytic PET tracer for gaining further insight into the role of reactive astrogliosis in AD.Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer affecting many people worldwide. Although the 5-year survival rate is 65% in localized disease, after metastasis, the survival rate is less then 10%. Emerging evidence has shown that microRNAs (miRNAs) play a crucial regulatory role in the progression of ccRCC. Here, we show that miR-335, an anti-onco-miRNA, is downregulation in tumor tissue and inhibited ccRCC cell proliferation, invasion, and migration. Our studies further identify the H3K9me1/2 histone demethylase KDM3A as a new miR-335-regulated gene. We show that KDM3A is overexpressed in ccRCC, and its upregulation contributes to the carcinogenesis and metastasis of ccRCC. Moreover, with the overexpression of KDM3A, YAP1 was increased and identified as a direct downstream target of KDM3A. Enrichment of KDM3A demethylase on YAP1 promoter was confirmed by CHIP-qPCR and YAP1 was also found involved in the cell growth and metastasis inhibitory of miR-335. Together, our study establishes a new miR-335/KDM3A/YAP1 regulation axis, which provided new insight and potential targeting of the metastasized ccRCC.In recent years, immune cell-based cancer therapeutics have been utilized broadly in the clinic. Through advances in cellular engineering, chimeric antigen receptor (CAR) T-cell therapies have demonstrated substantial success in treating hematological tumors and have become the most prominent cell-based therapy with three commercialized products in the market. However, T-cell-based immunotherapies have certain limitations, including a restriction to autologous cell sources to avoid severe side-effects caused by human leukocyte antigen (HLA) mismatch. This necessity for personalized treatment inevitably results in tremendous manufacturing and time costs, reducing accessibility for many patients. As an alternative strategy, natural killer (NK) cells have emerged as potential candidates for improved cell-based immunotherapies. NK cells are capable of killing cancer cells directly without requiring HLA matching. Furthermore, NK cell-based therapies can use various allogeneic cell sources, allowing for the possibility of "off-the-shelf" immunotherapies with reduced side-effects and shortened manufacturing times.
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