Genetic Polymorphism and mRNA Expression Studies Reveal IL6R and LEPR Gene Associations with Reproductive Traits in Chinese Holsteins

Genetic selection of milk yield traits alters the energy distribution of high producing cows, resulting in gene-induced negative energy balance, and consequently, poor body condition scores and reduced reproductive performances. Here, we investigated two metabolic-syndrome pathway genes, IL6R (Interleukin 6 receptor) and LEPR (Leptin receptor), for their polymorphism effects on reproductive performance in dairy cows, by applying polymorphism association analyses in 1588 Chinese Holstein cows (at population level) and gene expression analyses in granulosa cells isolated from eight cows (at cell level). Among the six single nucleotide polymorphisms we examined (two SNPs for IL6R and four SNPs for LEPR), five were significantly associated with at least one reproductive trait, including female fertility traits covering both the ability to recycle after calving and the ability to conceive and keep pregnancy when inseminated properly, as well as calving traits. Notably, the identified variant SNP g.80143337A/C in LEPR is a missense variant. The role of IL6R and LEPR in cattle reproduction were further confirmed by observed differences in relative gene expression levels amongst granulosa cells with different developmental stages. Collectively, the functional validation of IL6R and LEPR performed in this study improved our understanding of cattle reproduction while providing important molecular markers for genetic selection of reproductive traits in high-yielding dairy cattle

Global measurements of brown carbon and estimated direct radiative effects

Brown carbon (BrC) is an organic aerosol material that preferentially absorbs light of shorter wavelengths. Global-scale radiative impacts of BrC have been difficult to assess due to the lack of BrC observational data. To address this, aerosol filters were continuously collected with near pole-to-pole latitudinal coverage over the Pacific and Atlantic basins in three seasons as part of the Atmospheric Tomography Mission. BrC chromophores in filter extracts were measured. We find that globally, BrC was highly spatially heterogeneous, mostly detected in air masses that had been transported from regions of extensive biomass burning. We calculate the average direct radiative effect due to BrC absorption accounted for approximately 7% to 48% of the top of the atmosphere clear-sky instantaneous forcing by all absorbing carbonaceous aerosols in the remote atmosphere, indicating that BrC from biomass burning is an important component of the global radiative balance

Understanding the global impacts of biomass burning aerosols and marine biogenic VOC

The transport of biomass burning aerosols and the oxidation state of the marine boundary layer (MBL) play significant roles in understanding the background climate condition of the remote regions. Biomass burning is provoked by natural factors or humans and has a profound impact on ecosystems, carbon cycles, climate change, and human society. Biomass burning is one major source of atmospheric aerosols, which is a potential medium in fire-climate interactions because of its role in the global radiative balance and cloud processing. The understanding of biomass burning emissions and its interaction with atmosphere and ecosystems is essential for estimating the climate impact due to biomass burning. On the other hand, the MBL volatile organic carbon (VOC) strongly impacts the MBL oxidation state. For example, glyoxal, a mid-product in biogenic organic carbon emission, can be photolyzed to produce HO2 radicals, which increase the atmospheric oxidation state and affect various oxidation processes such as ozone production. This study focuses on the modeling approach of the effect of marine glyoxal on the MBL atmosphere oxidation state, and the impact of biomass burning on local weather and global radiative effect using the Community Earth System Model (CESM). We present an estimation of the direct radiative effect (DRE) of brown carbon (BrC), which can be emitted by biomass burning, and have potential stronger heating than black carbon (BC) over the region with strong deep convection e.g. remote tropics. We used the Region-Specific ecosystem feedback Fire (RESFire) model in CESM to study the impact of the African biomass burning aerosol on local and regional weather, and its feedback on the future biomass burning. In addition, we estimate the missing source of MBL glyoxal and discuss the impact of marine glyoxal to the MBL oxidation state.Ph.D

iRGD-modified memory-like NK cells exhibit potent responses to hepatocellular carcinoma

Abstract Background Cytokine-induced memory-like natural killer (CIML NK) cells have been found to possess potent antitumor responses and induce complete remissions in patients with leukemia. However, the poor infiltration of transferred NK cells is a major obstacle in developing adoptive cell immunotherapy for solid tumors. In our study, we explored the potential of using the tumor-penetrating peptide iRGD to deliver activated CIML NK cells deep into tumor tissues. Methods After being briefly stimulated with interleukin-12 (IL-12), IL-15, and IL-18, CIML NK cells were assessed for their phenotype and function with flow cytometry. The penetrating and killing capability of iRGD-modified CIML NK cells in tumor spheroids was revealed by confocal microscopy. The anti-tumor efficacy of these modified CIML NK cells was tested in hepatocellular carcinoma (HCC) xenograft mouse models. Results Treating NK cells with cytokines led to a substantial activation, which was evidenced by the upregulation of CD25 and CD137. After a resting period of six days, CIML NK cells were still able to display strong activation when targeting HepG2 and SK-Hep-1 HCC cell lines. Additionally, CIML NK cells produced increased amounts of cytokines (interferon-gamma and tumor necrosis factor alpha) and exhibited heightened cytotoxicity towards HCC cell lines. The iRGD modification enabled CIML NK cells to infiltrate multicellular spheroids (MCSs) and, consequently, to induce cytotoxicity against the target cancer cells. Moreover, the CIML NK cells modified with iRGD significantly decreased tumor growth in a HCC xenograft mouse model. Conclusion Our findings demonstrate that CIML NK cells possess augmented potency and durability against HCC cell lines in vitro. Additionally, we have seen that the incorporation of iRGD to CIML NK cells facilitates enhanced infiltration and targeted destruction of MCSs. Moreover, the application of iRGD-modified CIML NK cells reveal remarkable anti-tumor efficacy against HCC in vivo

Improving radio-chemotherapy efficacy of prostate cancer by co-deliverying docetaxel and dbait with biodegradable nanoparticles

AbstractCombining DNA damage repair inhibitors and chemotherapeutic agents is an emerging strategy in cancer treatment. In this study, we engineered the polycation nanoparticle (NP), which co-encapsulated DNA damage repair inhibitor Dbait and chemotherapeutic drug Docetaxel (Dtxl), using H1 nanopolymer (folate–-polyethylenimine600–cyclodextrin), and the size of H1/Dbait/Dtxl was about 117 nm. We demonstrated that H1/Dbait/Dtxl enhanced the efficiency of radio-chemotherapy in prostate cancer cells by CCK-8 assay and colony-forming assay. Importantly, the improvement of radio-chemotherapy of H1/Dbait/Dtxl in prostate cancer was also validated in vivo, and the NP did not have a high toxicity profile. The results of immunohistochemistry and western blot supported that the improved therapeutic efficacy was through inhibiting DNA damage repair signalling pathway. Our study supports further investigations using NP to co-deliver DNA damage repair inhibitors and chemotherapeutics to improve the therapeutic efficacy of cancer

Pathogenicity and immunogenicity of gI/gE/TK-gene-deleted Felid herpesvirus 1 variants in cats

Abstract Background Felid herpesvirus 1 (FHV-1) is a major pathogenic agent of upper respiratory tract infections and eye damage in felines worldwide. Current FHV-1 vaccines offer limited protection of short duration, and therefore, do not reduce the development of clinical signs or the latency of FHV-1. Methods To address these shortcomings, we constructed FHV ∆gIgE-eGFP, FHV ∆TK mCherry, and FHV ∆gIgE/TK eGFP-mCherry deletion mutants (ΔgI/gE, ΔTK, and ΔgIgE/TK, respectively) using the clustered regularly interspaced palindromic repeats (CRISPR)/CRISP-associated protein 9 (Cas9) system (CRISPR/Cas9), which showed safety and immunogenicity in vitro. We evaluated the safety and efficacy of the deletion mutants administered with intranasal (IN) and IN + subcutaneous (SC) vaccination protocols. Cats in the vaccination group were vaccinated twice at a 4-week interval, and all cats were challenged with infection 3 weeks after the last vaccination. The cats were assessed for clinical signs, nasal shedding, and virus-neutralizing antibodies (VN), and with postmortem histological testing. Results Vaccination with the gI/gE-deleted and gI/gE/TK-deleted mutants was safe and resulted in significantly lower clinical disease scores, fewer pathological changes, and less nasal virus shedding after infection. All three mutants induced virus-neutralizing antibodies after immunization. Conclusions In conclusion, this study demonstrates the advantages of FHV-1 deletion mutants in preventing FHV-1 infection in cats

Genetic Polymorphism and mRNA Expression Studies Reveal <i>IL6R</i> and <i>LEPR</i> Gene Associations with Reproductive Traits in Chinese Holsteins

Genetic selection of milk yield traits alters the energy distribution of high producing cows, resulting in gene-induced negative energy balance, and consequently, poor body condition scores and reduced reproductive performances. Here, we investigated two metabolic-syndrome pathway genes, IL6R (Interleukin 6 receptor) and LEPR (Leptin receptor), for their polymorphism effects on reproductive performance in dairy cows, by applying polymorphism association analyses in 1588 Chinese Holstein cows (at population level) and gene expression analyses in granulosa cells isolated from eight cows (at cell level). Among the six single nucleotide polymorphisms we examined (two SNPs for IL6R and four SNPs for LEPR), five were significantly associated with at least one reproductive trait, including female fertility traits covering both the ability to recycle after calving and the ability to conceive and keep pregnancy when inseminated properly, as well as calving traits. Notably, the identified variant SNP g.80143337A/C in LEPR is a missense variant. The role of IL6R and LEPR in cattle reproduction were further confirmed by observed differences in relative gene expression levels amongst granulosa cells with different developmental stages. Collectively, the functional validation of IL6R and LEPR performed in this study improved our understanding of cattle reproduction while providing important molecular markers for genetic selection of reproductive traits in high-yielding dairy cattle

Genetic Polymorphism and mRNA Expression Studies Reveal IL6R and LEPR Gene Associations with Reproductive Traits in Chinese Holsteins

Genetic selection of milk yield traits alters the energy distribution of high producing cows, resulting in gene-induced negative energy balance, and consequently, poor body condition scores and reduced reproductive performances. Here, we investigated two metabolic-syndrome pathway genes, IL6R (Interleukin 6 receptor) and LEPR (Leptin receptor), for their polymorphism effects on reproductive performance in dairy cows, by applying polymorphism association analyses in 1588 Chinese Holstein cows (at population level) and gene expression analyses in granulosa cells isolated from eight cows (at cell level). Among the six single nucleotide polymorphisms we examined (two SNPs for IL6R and four SNPs for LEPR), five were significantly associated with at least one reproductive trait, including female fertility traits covering both the ability to recycle after calving and the ability to conceive and keep pregnancy when inseminated properly, as well as calving traits. Notably, the identified variant SNP g.80143337A/C in LEPR is a missense variant. The role of IL6R and LEPR in cattle reproduction were further confirmed by observed differences in relative gene expression levels amongst granulosa cells with different developmental stages. Collectively, the functional validation of IL6R and LEPR performed in this study improved our understanding of cattle reproduction while providing important molecular markers for genetic selection of reproductive traits in high-yielding dairy cattle

Deep Learning‐Based Ensemble Forecasts and Predictability Assessments for Surface Ozone Pollution

Abstract The impacts of weather forecast uncertainties have not been quantified in current air quality forecasting systems. To address this, we developed an efficient 2‐D convolutional neural network‐surface ozone ensemble forecast (2DCNN‐SOEF) system using 2‐D convolutional neural network and weather ensemble forecasts, and we applied the system to 216‐hr ozone forecasts in Shenzhen, China. The 2DCNN‐SOEF demonstrated comparable performance to current operating forecast systems and met the air quality level forecast accuracies required by the Chinese authorities up to 144‐hr lead time. Uncertainties in weather forecasts contributed 38%–54% of the ozone forecast errors at 24‐hr lead time and beyond. The 2DCNN‐SOEF enabled an “ozone exceedance probability” metric, which better represented the risks of air pollution given the range of possible weather outcomes. Our ensemble forecast framework can be extended to operationally forecast other meteorology‐dependent environmental risks globally, making it a valuable tool for environmental management

Divergence Analyses of Sperm DNA Methylomes between Monozygotic Twin AI Bulls

Semen quality is critical for fertility. However, it is easily influenced by environmental factors and can induce subfertility in the next generations. Here, we aimed to assess the impacts of differentially methylated regions and genes on semen quality and offspring fertility. A specific pair of monozygotic (MZ) twin artificial insemination (AI) Holstein bulls with moderately different sperm qualities (Bull1 &gt; Bull2) was used in the study, and each twin bull had produced ~6000 recorded daughters nationwide in China. Using whole genome bisulfite sequencing, we profiled the landscape of the twin bulls&rsquo; sperm methylomes, and we observed markedly higher sperm methylation levels in Bull1 than in Bull2. Furthermore, we found 528 differentially methylated regions (DMR) between the MZ twin bulls, which spanned or overlapped with 309 differentially methylated genes (DMG). These DMG were particularly associated with embryo development, organ development, reproduction, and the nervous system. Several DMG were also shown to be differentially expressed in the sperm cells. Moreover, the significant differences in DNA methylation on gene INSL3 between the MZ twin bulls were confirmed at three different age points. Our results provided new insights into the impacts of AI bull sperm methylomes on offspring fertility