Design, synthesis and biological activity of oxyevodiamine-based histone deacetylase 6 inhibitors.

Histone deacetylase 6 (HDAC6) was a potential target for Alzheimer's disease (AD). In this study, a series of novel oxyevodiamine-based HDAC6 inhibitors with a variety of linker moieties were designed, synthesized and evaluated. Compound 12 with a benzyl linker was identified as a high potent and selective HDAC6 inhibitor. It inhibited HDAC6 with an IC50 value of 6.2 nM and was more than 200 fold selectivity over HDAC1. It also had lower cytotoxicity and higher anti-H2O2 activity in vitro comparing with other derivatives. Compound 12 might be a good lead as novel HDAC6 inhibitor for the treatment of AD.

Analysis of complex chromosomal rearrangement involving chromosome 6 via the integration of optical genomic mapping and molecular cytogenetic methodologies.

Complex chromosomal rearrangements (CCRs) can result in spontaneous abortions, infertility, and malformations in newborns. In this study, we explored a familial CCR involving chromosome 6 by combining optical genomic mapping (OGM) and molecular cytogenetic methodologies. Within this family, the father and the paternal grandfather were both asymptomatic carriers of an identical balanced CCR, while the two offspring with an unbalanced paternal-origin CCR and two microdeletions presented with clinical manifestation. The first affected child, a 5-year-old boy, exhibited neurodevelopmental delay, while the second, a fetus, presented with hydrops fetalis. SNP-genotype analysis revealed a recombination event during gamete formation in the father that may have contributed to the deletion in his offspring. Meanwhile, the couple's haplotypes will facilitate the selection of normal gametes in the setting of assisted reproduction. Our study demonstrated the potential of OGM in identifying CCRs and its ability to work with current methodologies to refine precise breakpoints and construct accurate haplotypes for couples with a CCR.

Co-pyrolysis of sewage sludge and Ca(H2PO4)2: heavy metal stabilization, mechanism, and toxic leaching.

The presence of unstable heavy metals in sewage sludge (SS) restricts its resource utilization. In this study, Ca(H2PO4)2 and SS were co-pyrolyzed to produce biochar, which contained relatively stable heavy metals. X-ray diffraction spectroscopy, Fourier transform infrared spectroscopy, and inductively coupled plasma atomic emission techniques were used to analyze the physical and chemical properties and heavy metal content of the biochar. The results indicated that co-pyrolysis of SS with Ca(H2PO4)2 resulted in the production of more stable heavy metals in the SS. The optimal co-pyrolysis conditions were a blended ratio of 15% Ca(H2PO4)2, 650 °C final temperature, 15 °C min-1, and 60 min retention time. The potential stabilization mechanisms of heavy metals were as follows: (1) organic decomposition and moisture (sourced from Ca(H2PO4)2 decomposition) evaporation resulted in greater biochar surface porosity; (2) phosphorous substances were complexed with heavy metals to form metal phosphates; and (3) the mixture reactions among inorganic substances, pyrolysis products of organics, and heavy metals resulted in the formation of highly aromatic metallic compounds. Additionally, the potential environmental risks posed by the heavy metals decreased from 65.73 (in SS) to 4.39 (in biochar derived from co-pyrolysis of SS and 15% of Ca(H2PO4)2). This study reports on a good approach for the disposal of SS and the reduction of its environmental risk.

Co-pyrolysis of monobasic potassium phosphate and plastic processing sludge: Characteristics and environmental risks of potentially toxic elements.

A high concentration of potentially toxic elements (PTEs) can be frequently observed in the plastic processing sludge (PPS), thereby restricting its environmental applications. The main objective of this study was to investigate the effects of the co-pyrolysis of PPS and KH2PO4 (0, 5, 10 and 20 wt%) on the characteristics and environmental risks associated with the PTEs in PPS and derived chars. General characteristic analysis revealed that the char yield, ash content, pH, and particle size of the chars prepared with KH2PO4 were greater than those of the char prepared without KH2PO4 by 3.13-4.89 wt%, 2.95-4.4 wt%, 0.77-0.93, and 9.64-30.07 µm, respectively. The results of sequential extraction indicated that co-pyrolysis with KH2PO4 could considerably increase the distribution of PTEs in the F4 fraction (non-bioavailable) in PPS by 1.30-65.90% when compared with that obtained via co-pyrolysis with 5 wt% of KH2PO4. The toxic leaching tests indicated that the leaching concentrations of Cr, Ni, Cu, Zn, Cd, and Pb in the char prepared without KH2PO4 decreased to different extents when PPS was subjected to co-pyrolysis with KH2PO4, especially in case of co-pyrolysis with 5 wt% of KH2PO4. The range of decrease was 26.40-88.34%. However, in case of Cu, Zn, and Pb, the leaching concentration of the chars prepared with more than 10 wt% of KH2PO4 increased owing to the decomposition of (Cu Zn)PbVO4(OH) in an acidic environment. The results obtained using Hakanson's equations revealed that the potential ecological risk associated with the PTEs in chars obtained by co-pyrolysis with KH2PO4 decreased, with a minimum decrease of 38.17%. In addition, the risk level associated with PPS reduced from considerable to low after co-pyrolysis with KH2PO4. The observations of this study imply that the co-pyrolysis of PPS with KH2PO4 can be a promising treatment for PTE immobilization.

Simultaneous Detection of CNVs and SNVs Improves the Diagnostic Yield of Fetuses with Ultrasound Anomalies and Normal Karyotypes.

The routine assessment to determine the genetic etiology for fetal ultrasound anomalies follows a sequential approach, which usually takes about 6-8 weeks turnaround time (TAT). We evaluated the clinical utility of simultaneous detection of copy number variations (CNVs) and single nucleotide variants (SNVs)/small insertion-deletions (indels) in fetuses with a normal karyotype with ultrasound anomalies. We performed CNV detection by chromosomal microarray analysis (CMA) or low pass CNV-sequencing (CNV-seq), and in parallel SNVs/indels detection by trio-based clinical exome sequencing (CES) or whole exome sequencing (WES). Eight-three singleton pregnancies with a normal fetal karyotype were enrolled in this prospective observational study. Pathogenic or likely pathogenic variations were identified in 30 cases (CNVs in 3 cases, SNVs/indels in 27 cases), indicating an overall molecular diagnostic rate of 36.1% (30/83). Two cases had both a CNV of uncertain significance (VOUS) and likely pathogenic SNV, and one case carried both a VOUS CNV and an SNV. We demonstrated that simultaneous analysis of CNVs and SNVs/indels can improve the diagnostic yield of prenatal diagnosis with shortened reporting time, namely, 2-3 weeks. Due to the relatively long TAT for sequential procedure for prenatal genetic diagnosis, as well as recent sequencing technology advancements, it is clinically necessary to consider the simultaneous evaluation of CNVs and SNVs/indels to enhance the diagnostic yield and timely TAT, especially for cases in the late second trimester or third trimester.