Sodium arsenite impairs sperm quality via downregulating the ZMYND15 and ZMYND10.

Zinc finger MYND-type containing 15 (ZMYND15) has been documented to play important roles in spermatogenesis, and mutants contribute to recessive azoospermia, severe oligozoospermia, non-obstructive azoospermia, teratozoospermia, even male infertility. ZMYND10 is involved in sperm motility. Whether environmental pollutants impair male fertility via regulating the expression of ZMYND15 and ZMYND10 has not been studied. Arsenic exposure results in poor sperm quality and male infertility. In order to investigate whether arsenic-induced male reproductive toxicity is related to the expression of ZMYND15, ZMYND10 and their target genes, we established a male rat model of sodium arsenite exposure-induced reproductive injury, measured sperm quality, serum hormone levels, mRNA and protein expressions of intratesticular ZMYND15 and ZMYND10 as well as their target genes. The results showed that, in addition to the increased mRNA expression of Tnp1, sodium arsenite exposure reduced sperm quality, serum hormone levels, and mRNA and protein expression of intratesticular ZMYND15 and ZMYND10 and their target genes in male rats compared with the control group (p < .05). Therefore, our study first showed that the environmental pollutant arsenic impairs sperm quality in male rats by reducing the expression of ZMYND10 and ZMYND15 and their regulatory genes, which provides a possible diagnostic marker for environmental pollutants-induced male infertility.

Sodium arsenite exposure enhances H3K14 acetylation and impairs male spermatogenesis in rat testes.

Histone modifications play important roles in the epigenetic regulation of spermatogenesis via mediating gene transcription. Steroidogenic regulatory enzymes control testosterone biosynthesis, which are essential for spermatogenesis. Arsenic exposure inhibits the expression of steroidogenic genes by significantly increasing tri-methylation of H3K9 (H3K9me3) level in rat testis, finally diminishes testosterone release and lowers the rat sperm quality. Acetylation of H3K14 (H3K14ac) is associated with testosterone production and spermatogenesis. Co-occurrence of H3K9me3/H3K14ac has been identified previously by mass spectrometry in histone H3 isolated from different human cell types. H3K9me3/H3K14ac dually marked regions are in a poised inactive state to inhibit the gene expression. Whereas, whether inorganic arsenic exposure affects spermatogenesis and steroidogenic regulatory enzymes via mediating H3K14ac level has not been studied. Thereupon, the male Sprague-Dawley (SD) rats were exposed to (NaAsO2) for 6 weeks, then the sperm density and motility, testosterone level in serum, arsenic in rat testis were detected. mRNA expression of steroidogenic regulatory enzymes Star, Cyp11a1, Hsd3b and Hsd17b were determined by RT-PCR. H3K14ac level and the expression of histone acetylases of H3K14 (KAT2A and EP300), histone deacetylases of H3K14 (HDAC6 and HDAC3), the reader of H3K14ac (BAZ2A) were determined. The results suggested arsenic enhances H3K14ac in rat testis, which was associated with repression of steroidogenic regulatory genes expression, further reduced testosterone production, and impaired the spermatogenesis.

A novel antibody-TCR (AbTCR) T-cell therapy is safe and effective against CD19-positive relapsed/refractory B-cell lymphoma.

PURPOSE: A barrier to widespread adoption of chimeric antigen receptor (CAR) T-cell therapy is toxicity. To address this, we recently developed a novel antibody-T-cell receptor (AbTCR) platform (trademarked as ARTEMIS®) which was designed to leverage natural immune receptor signaling and regulation. The AbTCR platform includes a gamma/delta (γδ) TCR-based AbTCR construct and a separate co-stimulatory molecule, both engineered to be tumor-specific. Here, we aim to assess the safety and preliminary efficacy of a CD19-directed AbTCR T-cell therapy. METHODS: We generated ET019003 T cells, which are autologous CD19-directed AbTCR T cells. We then conducted an early phase I study to evaluate the safety and preliminary efficacy of ET019003 T cells for the treatment of CD19-positive relapsed/refractory (r/r) B-cell lymphoma. RESULTS: Sixteen patients enrolled in this study and 12 patients were treated. Of the 12 patients treated, 6 patients (50%) achieved a complete response (CR), and 4 (33%) achieved a partial response (PR) (best objective response rate [ORR] of 83%). CRs were durable, including 2 patients with ongoing CRs for 22.7 months and 23.2 months. ET019003 was well-tolerated with an attractive safety profile. No patients experienced severe (grade ≥ 3) cytokine release syndrome (CRS) and only 1 patient experienced immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade. Significant elevations of cytokine levels were not seen, even in patients with marked expansion of ET019003 T cells. CONCLUSION: This study provides initial clinical validation of the AbTCR platform as a novel cancer treatment with the potential to provide durable clinical benefit with low toxicity. TRIAL REGISTRATION: NCT03642496; Date of registration: August 22, 2018.

Intergenerational differences in the urban vibrancy of TOD: Impacts of the built environment on the activities of different age groups.

Transit-oriented development (TOD) has been regarded as an effective way to improve urban vibrancy and facilitate affordable, equitable, and livable communities in metro station areas (MSAs). Previous studies placed great attention on the interplay between the MSA-level built environment and overall human activities while neglecting the heterogeneity among different age groups. To address this gap, we leverage the mobile phone signaling data to quantify the spatio-temporal distribution of the MSA-level human activities among different age groups as measured by the vibrancy index (VI). Furthermore, we investigate the impact of the MSA-level built environment on the VI and its intergenerational differences by employing multiple linear regressions based on multi-sourced data. To this end, Chengdu-a TOD-thriving megacity in China-is chosen as a case study. The results indicate that: (1) Residential and bus stop density are positively associated with the VI. And the magnitudes of the correlation coefficients are similar among different age groups. (2) Distance to CBD is negatively associated with the VI of teenagers (12-18 years), middle-aged adults (40-59 years), and older adults (above 60 years) but unrelated to the VI of young adults (19-39 years). (3) Employment density is positively associated with the VI of young and middle-aged adults but insignificantly associated with the VI of teenagers and older adults. (4) The correlations between the floor area ratio and the VI are positive for all age groups. As age increases, the significance of such correlations becomes more pronounced. (5) Streetscape greenery shows a more significant positive correlation with the VI of teenagers and older adults as compared to those of young and middle-aged adults. (6) Significant negative correlations exist between housing price and the VI of different age groups. The findings can inform the development and design of vibrant TOD communities.