Association of vaccination, international travel, public health and social measures with lineage dynamics of SARS-CoV-2.

Continually emerging SARS-CoV-2 variants of concern that can evade immune defenses are driving recurrent epidemic waves of COVID-19 globally. However, the impact of measures to contain the virus and their effect on lineage diversity dynamics are poorly understood. Here, we jointly analyzed international travel, public health and social measures (PHSM), COVID-19 vaccine rollout, SARS-CoV-2 lineage diversity, and the case growth rate (GR) from March 2020 to September 2022 across 63 countries. We showed that despite worldwide vaccine rollout, PHSM are effective in mitigating epidemic waves and lineage diversity. An increase of 10,000 monthly travelers in a single country-to-country route between endemic countries corresponds to a 5.5% (95% CI: 2.9 to 8.2%) rise in local lineage diversity. After accounting for PHSM, natural immunity from previous infections, and waning immunity, we discovered a negative association between the GR of cases and adjusted vaccine coverage (AVC). We also observed a complex relationship between lineage diversity and vaccine rollout. Specifically, we found a significant negative association between lineage diversity and AVC at both low and high levels but not significant at the medium level. Our study deepens the understanding of population immunity and lineage dynamics for future pandemic preparedness and responsiveness.

Synthesis of Multifluoromethylated γ-Sultines by a Photoinduced Radical Addition-Polar Cyclization.

Despite the significance of sultines in synthesis, medicine, and materials science, the chemistry of sultines has remained unexplored due to their inaccessibility. Herein, we demonstrate the development of a photoredox-catalyzed multifluoromethyl radical addition/SO2 incorporation/polar cyclization cascade approach to multifluoromethylated γ-sultines. The reactions proceed by single electron transfer induced multifluoromethyl radical addition to an alkene followed by SO2 incorporation, and single-electron reduction for polar 5-exo-tet cyclization. Key to the success of the protocol is the use of easily oxidizable multifluoroalkanesulfinates as bifunctional reagents. The reactions proceed with excellent functional-group tolerance to deliver γ-sultines in moderate to excellent yields.

Nonlinear effect of air pollution on adult pneumonia hospital visits in the coastal city of Qingdao, China: A time-series analysis.

Many studies have illustrated adverse effects of short-term exposure to air pollution on human health, which usually assumes a linear exposure-response (E-R) function in the delineation of health effects due to air pollution. However, nonlinearity may exist in the association between air pollutant concentrations and health outcomes such as adult pneumonia hospital visits, and there is a research gap in understanding the nonlinearity. Here, we utilized both the distributed lag model (DLM) and nonlinear model (DLNM) to compare the linear and nonlinear impacts of air pollution on adult pneumonia hospital visits in the coastal city of Qingdao, China. While both models show adverse effects of air pollutants on adult pneumonia hospital visits, the DLNM shows an attenuation of E-R curves at high concentrations. Moreover, the DLNM may reveal delayed health effects that may be missed in the DLM, e.g., ozone exposure and pneumonia hospital visits. With the stratified analysis of air pollutants on adult pneumonia hospital visits, both models consistently reveal that the influence of air pollutants is higher during the cold season than during the warm season. Nevertheless, they may behave differently in terms of other subgroups, such as age, gender and visit types. For instance, while no significant impact due to PM2.5 in any of the subgroups abovementioned emerges based on DLM, the results from DLNM indicate statistically significant impacts for the subgroups of elderly, female and emergency department (ED) visits. With respect to adjustment by two-pollutants, PM10 effect estimates for pneumonia hospital visits were the most robust in both DLM and DLNM, followed by NO2 and SO2 based on the DLNM. Considering the estimated health effects of air pollution relying on the assumed E-R functions, our results demonstrate that the traditional linear association assumptions may overlook some potential health risks.

Price Estimation of Coal Seam and Its Application in the Optimization of the Mining Sequence: A Case Study.

Coal price may vary significantly within a given coal seam, and the accurate characterization of coal price plays an important role in the rational development and utilization of coal resources. A geostatistics-block-based method is proposed to obtain the spatial correlation of borehole survey data and map the heterogenous distribution of coal seam thickness and coal quality (including calorific value, volatile content, ash content, and sulfur content). A block model of thermal coal price is next established considering the spatial distribution of coal quality parameters. Taking an undisclosed coal mine as an example, the estimation process of coal price block model is described in detail, and the mining sequence among several panels is optimized considering the heterogenous coal price. The coal price ranges from 814 to 1671 Chinese Yuan/t within the research area, and the net present value is increased by 1.53% after the optimization of the mining sequence. The result indicated that the coal price is generally heterogenous in a coal seam, and it has a significant influence on the mining sequence. The accurate modeling of coal seam properties has wide applications in mining engineering.

Unreprogrammed H3K9me3 prevents minor zygotic genome activation and lineage commitment in SCNT embryos.

Somatic cell nuclear transfer (SCNT) can be used to reprogram differentiated somatic cells to a totipotent state but has poor efficiency in supporting full-term development. H3K9me3 is considered to be an epigenetic barrier to zygotic genomic activation in 2-cell SCNT embryos. However, the mechanism underlying the failure of H3K9me3 reprogramming during SCNT embryo development remains elusive. Here, we perform genome-wide profiling of H3K9me3 in cumulus cell-derived SCNT embryos. We find redundant H3K9me3 marks are closely related to defective minor zygotic genome activation. Moreover, SCNT blastocysts show severely indistinct lineage-specific H3K9me3 deposition. We identify MAX and MCRS1 as potential H3K9me3-related transcription factors and are essential for early embryogenesis. Overexpression of Max and Mcrs1 significantly benefits SCNT embryo development. Notably, MCRS1 partially rescues lineage-specific H3K9me3 allocation, and further improves the efficiency of full-term development. Importantly, our data confirm the conservation of deficient H3K9me3 differentiation in Sertoli cell-derived SCNT embryos, which may be regulated by alternative mechanisms.

Dynamic nucleosome organization after fertilization reveals regulatory factors for mouse zygotic genome activation.

Chromatin remodeling is essential for epigenome reprogramming after fertilization. However, the underlying mechanisms of chromatin remodeling remain to be explored. Here, we investigated the dynamic changes in nucleosome occupancy and positioning in pronucleus-stage zygotes using ultra low-input MNase-seq. We observed distinct features of inheritance and reconstruction of nucleosome positioning in both paternal and maternal genomes. Genome-wide de novo nucleosome occupancy in the paternal genome was observed as early as 1 h after the injection of sperm into ooplasm. The nucleosome positioning pattern was continually rebuilt to form nucleosome-depleted regions (NDRs) at promoters and transcription factor (TF) binding sites with differential dynamics in paternal and maternal genomes. NDRs formed more quickly on the promoters of genes involved in zygotic genome activation (ZGA), and this formation is closely linked to histone acetylation, but not transcription elongation or DNA replication. Importantly, we found that NDR establishment on the binding motifs of specific TFs might be associated with their potential pioneer functions in ZGA. Further investigations suggested that the predicted factors MLX and RFX1 played important roles in regulating minor and major ZGA, respectively. Our data not only elucidate the nucleosome positioning dynamics in both male and female pronuclei following fertilization, but also provide an efficient method for identifying key transcription regulators during development.

Aberrant nucleosome organization in mouse SCNT embryos revealed by ULI-MNase-seq.

Somatic cell nuclear transfer (SCNT) can reprogram terminally differentiated somatic cells into totipotent embryos, but with multiple defects. The nucleosome positioning, as an important epigenetic regulator for gene expression, is largely unexplored during SCNT embryonic development. Here, we mapped genome-wide nucleosome profiles in mouse SCNT embryos using ultra-low-input MNase-seq (ULI-MNase-seq). We found that the nucleosome-depleted regions (NDRs) around promoters underwent dramatic reestablishment, which is consistent with the cell cycle. Dynamics of nucleosome position in SCNT embryos were delayed compared to fertilized embryos. Subsequently, we found that the aberrant gene expression levels in inner cell mass (ICM) were positively correlated with promoter NDRs in donor cells, which indicated that the memory of nucleosome occupancy in donor cells was a potential barrier for SCNT-mediated reprogramming. We further confirmed that the histone acetylation level of donor cells was associated with the memory of promoter NDRs. Our study provides insight into nucleosome reconfiguration during SCNT preimplantation embryonic development.

Stage-specific H3K9me3 occupancy ensures retrotransposon silencing in human pre-implantation embryos.

H3K9me3, as a hallmark of heterochromatin, is important for cell-fate specification. However, it remains unknown how H3K9me3 is reprogrammed during human early embryo development. Here, we profiled genome-wide H3K9me3 in human oocytes and early embryos and discovered stage-specific H3K9me3 deposition on long terminal repeats (LTRs) at the 8-cell and blastocyst stages. We found that 8-cell-specific H3K9me3 was temporarily established in enhancer-like regions, whereas blastocyst-specific H3K9me3 was more stable. DUX and multiple Krüppel-associated box domain zinc finger proteins(KRAB-ZNFs) were identified as potential factors for establishing 8C- and blastocyst-specific H3K9me3, respectively. Intriguingly, our analysis showed that stage-specific H3K9me3 allocation was attenuated by either Dux knockout or Zfp51 knockdown in mouse early embryos. Moreover, we observed the existence of H3K4me3/H3K9me3 and H3K4me3/H3K27me3 bivalent chromatin domains in human blastocysts, priming for lineage differentiation. Together, our data unveil that the epigenetic switch from DNA methylation to H3K9me3 ensures the precise regulation of retrotransposons in human pre-implantation embryos.

Nuclear m6A reader YTHDC1 regulates the scaffold function of LINE1 RNA in mouse ESCs and early embryos.

N6-methyladenosine (m6A) on chromosome-associated regulatory RNAs (carRNAs), including repeat RNAs, plays important roles in tuning the chromatin state and transcription, but the intrinsic mechanism remains unclear. Here, we report that YTHDC1 plays indispensable roles in the self-renewal and differentiation potency of mouse embryonic stem cells (ESCs), which highly depends on the m6A-binding ability. Ythdc1 is required for sufficient rRNA synthesis and repression of the 2-cell (2C) transcriptional program in ESCs, which recapitulates the transcriptome regulation by the LINE1 scaffold. Detailed analyses revealed that YTHDC1 recognizes m6A on LINE1 RNAs in the nucleus and regulates the formation of the LINE1-NCL partnership and the chromatin recruitment of KAP1. Moreover, the establishment of H3K9me3 on 2C-related retrotransposons is interrupted in Ythdc1-depleted ESCs and inner cell mass (ICM) cells, which consequently increases the transcriptional activities. Our study reveals a role of m6A in regulating the RNA scaffold, providing a new model for the RNA-chromatin cross-talk.

Chromatin architecture reorganization in murine somatic cell nuclear transfer embryos.

The oocyte cytoplasm can reprogram the somatic cell nucleus into a totipotent state, but with low efficiency. The spatiotemporal chromatin organization of somatic cell nuclear transfer (SCNT) embryos remains elusive. Here, we examine higher order chromatin structures of mouse SCNT embryos using a low-input Hi-C method. We find that donor cell chromatin transforms to the metaphase state rapidly after SCNT along with the dissolution of typical 3D chromatin structure. Intriguingly, the genome undergoes a mitotic metaphase-like to meiosis metaphase II-like transition following activation. Subsequently, weak chromatin compartments and topologically associating domains (TADs) emerge following metaphase exit. TADs are further removed until the 2-cell stage before being progressively reestablished. Obvious defects including stronger TAD boundaries, aberrant super-enhancer and promoter interactions are found in SCNT embryos. These defects are partially caused by inherited H3K9me3, and can be rescued by Kdm4d overexpression. These observations provide insight into chromatin architecture reorganization during SCNT embryo development.