Targeting translation initiation by synthetic rocaglates for treating MYC-driven lymphomas.

MYC-driven lymphomas, especially those with concurrent MYC and BCL2 dysregulation, are currently a challenge in clinical practice due to rapid disease progression, resistance to standard chemotherapy, and high risk of refractory disease. MYC plays a central role by coordinating hyperactive protein synthesis with upregulated transcription in order to support rapid proliferation of tumor cells. Translation initiation inhibitor rocaglates have been identified as the most potent drugs in MYC-driven lymphomas as they efficiently inhibit MYC expression and tumor cell viability. We found that this class of compounds can overcome eIF4A abundance by stabilizing target mRNA-eIF4A interaction that directly prevents translation. Proteome-wide quantification demonstrated selective repression of multiple critical oncoproteins in addition to MYC in B-cell lymphoma including NEK2, MCL1, AURKA, PLK1, and several transcription factors that are generally considered undruggable. Finally, (-)-SDS-1-021, the most promising synthetic rocaglate, was confirmed to be highly potent as a single agent, and displayed significant synergy with the BCL2 inhibitor ABT199 in inhibiting tumor growth and survival in primary lymphoma cells in vitro and in patient-derived xenograft mouse models. Overall, our findings support the strategy of using rocaglates to target oncoprotein synthesis in MYC-driven lymphomas.P30 CA036727 - NCI NIH HHS; R24 GM111625 - NIGMS NIH HHS; R35 GM118173 - NIGMS NIH HHS; LB506 - Nebraska Department of Health and Human Services (Nebraska DHHS)Accepted manuscriptSupporting documentatio

Dosage Compensation of the X Chromosomes in Bovine Germline, Early Embryos, and Somatic Tissues

Dosage compensation of the mammalian X chromosome (X) was proposed by Susumu Ohno as a mechanism wherein the inactivation of one X in females would lead to doubling the expression of the other. This would resolve the dosage imbalance between eutherian females (XX) versus male (XY) and between a single active X versus autosome pairs (A). Expression ratio of X- and A-linked genes has been relatively well studied in humans and mice, despite controversial results over the existence of upregulation of X-linked genes. Here we report the first comprehensive test of Ohno’s hypothesis in bovine preattachment embryos, germline, and somatic tissues. Overall an incomplete dosage compensation (0.5 \u3c X:A \u3c 1) of expressed genes and an excess X dosage compensation (X:A \u3e 1) of ubiquitously expressed “dosage-sensitive” genes were seen. No significant differences in X:A ratios were observed between bovine female and male somatic tissues, further supporting Ohno’s hypothesis. Interestingly, preimplantation embryos manifested a unique pattern of X dosage compensation dynamics. Specifically, X dosage decreased after fertilization, indicating that the sperm brings in an inactive X to the matured oocyte. Subsequently, the activation of the bovine embryonic genome enhanced expression of X-linked genes and increased the X dosage. As a result, an excess compensation was exhibited from the 8-cell stage to the compact morula stage. The X dosage peaked at the 16-cell stage and stabilized after the blastocyst stage. Together, our findings confirm Ohno’s hypothesis of X dosage compensation in the bovine and extend it by showing incomplete and over-compensation for expressed and “dosage-sensitive” genes, respectively

Transcriptional profiles of bovine in vivo pre-implantation development

© 2014 Jiang et al.; licensee BioMed Central Ltd. Background: During mammalian pre-implantation embryonic development dramatic and orchestrated changes occur in gene transcription. The identification of the complete changes has not been possible until the development of the Next Generation Sequencing Technology.Results: Here we report comprehensive transcriptome dynamics of single matured bovine oocytes and pre-implantation embryos developed in vivo. Surprisingly, more than half of the estimated 22,000 bovine genes, 11,488 to 12,729 involved in more than 100 pathways, is expressed in oocytes and early embryos. Despite the similarity in the total numbers of genes expressed across stages, the nature of the expressed genes is dramatically different. A total of 2,845 genes were differentially expressed among different stages, of which the largest change was observed between the 4- and 8-cell stages, demonstrating that the bovine embryonic genome is activated at this transition. Additionally, 774 genes were identified as only expressed/highly enriched in particular stages of development, suggesting their stage-specific roles in embryogenesis. Using weighted gene co-expression network analysis, we found 12 stage-specific modules of co-expressed genes that can be used to represent the corresponding stage of development. Furthermore, we identified conserved key members (or hub genes) of the bovine expressed gene networks. Their vast association with other embryonic genes suggests that they may have important regulatory roles in embryo development; yet, the majority of the hub genes are relatively unknown/under-studied in embryos. We also conducted the first comparison of embryonic expression profiles across three mammalian species, human, mouse and bovine, for which RNA-seq data are available. We found that the three species share more maternally deposited genes than embryonic genome activated genes. More importantly, there are more similarities in embryonic transcriptomes between bovine and humans than between humans and mice, demonstrating that bovine embryos are better models for human embryonic development.Conclusions: This study provides a comprehensive examination of gene activities in bovine embryos and identified little-known potential master regulators of pre-implantation development

Methylome Dynamics of Bovine Gametes and in vivo Early Embryos

DNA methylation undergoes drastic fluctuation during early mammalian embryogenesis. The dynamics of global DNA methylation in bovine embryos, however, have mostly been studied by immunostaining. We adopted the whole genome bisulfite sequencing (WGBS) method to characterize stage-specific genome-wide DNA methylation in bovine sperm, immature oocytes, oocytes matured in vivo and in vitro, as well as in vivo developed single embryos at the 2-, 4-, 8-, and 16-cell stages. We found that the major wave of genome-wide DNA demethylation was complete by the 8-cell stage when de novo methylation became prominent. Sperm and oocytes were differentially methylated in numerous regions (DMRs), which were primarily intergenic, suggesting that these non-coding regions may play important roles in gamete specification. DMRs were also identified between in vivo and in vitro matured oocytes, suggesting environmental effects on epigenetic modifications. In addition, virtually no (less than 1.5%) DNA methylation was found in mitochondrial DNA. Finally, by using RNA-seq data generated from embryos at the same developmental stages, we revealed a weak inverse correlation between gene expression and promoter methylation. This comprehensive analysis provides insight into the critical features of the bovine embryo methylome, and serves as an important reference for embryos produced in vitro, such as by in vitro fertilization and cloning. Lastly, these data can also provide a model for the epigenetic dynamics in human early embryos

Spatial Econometric Analysis of the Level and Influencing Factors of Coupling and Coordination between Regional Logistics and the Ecological Environment in China

With the logistics industry becoming an important part of economic development, logistics activities have given rise to various environmental problems, which that affect the sustainable development of the ecological environment. In order to understand the status of regional sustainable development, it is of great significance to study the level of coordinated development of regional logistics and the ecological environment, and determine which variables will affect their coordinated development. To accomplish this objective, the entropy method is used to give the corresponding weight to each index and calculate the coupling degree and coordination degree of regional logistics and the ecological environment; next, the coupling coordination level of regional logistics and ecological environment in different provinces from 2010 to 2019 is measured by the coupling coordination degree model; then, we study the spatial effect of the influencing factors on the coordinated development level of regional logistics and ecological environment in 30 provinces of China from 2010 to 2019. At the same time, we investigate the spatial effect of each influencing factor on the coordination level. On the basis of the findings, relevant suggestions and measures are proposed. The main conclusions are as follows: (i) As China’s economy is in the process of transformation to high-quality development, the coordinated development of regional logistics and the ecological environment is still at a relatively low level; (ii) due to the differences in the development basis of each region, the coordinated development level of regional logistics and the ecological environment is characterized by a regional imbalance; (iii) because of the significant spatial spillover effect, the coordinated development level of regional logistics and ecological environment shows obvious correlation in space

Research on the Disequilibrium Development of Output of Regional Innovation Based on R&D Personnel

Regional innovation is of great significance to the sustainable development of a regional economy. However, there exists a disequilibrium development of output of regional innovation in China, which affects the imbalance of regional economic development to a certain extent. In order to explore the process and mechanism of the disequilibrium development in regional innovation, a new perspective is adopted in this paper to analyze the index of R&D (research and development) personnel, which is an important input element of regional innovation output. The regional samples, including 31 provinces in China, are divided into three parts: eastern region, central region, and western region. First, developing the tendency and speed of the disequilibrium of regional innovation output are analyzed by using σ convergent model and β convergent model, respectively, during the period of analyzing the process of the disequilibrium development. Then, the LMDI (logarithmic mean Divisia index) method is used to analyze the character of regional innovation output by using R&D personnel as an important endogenous factor during the period of analyzing the mechanism of the disequilibrium development. At last, we draw the conclusion of the study. We find that: (i) there is a gap in the absolute amount between regions in a long term, but the gap between regions is shrinking and the speed of catching up between regions is different; (ii) the efficiency of R&D personnel is the most positive effect of promoting equilibrium

Research on Spatial Correlation in Regional Innovation Spillover in China Based on Patents

Regional innovation is very important for the sustainable development of regional economies. Innovation development between regions is not independent, and there is spatial correlation in innovation spillover. This paper uses the total amount of regional patent authorization as the measure of regional innovation and uses network analysis to study the spatial relationships among different regions. An unstructured vector autoregressive model is established to determine whether there is an association between any two regions, the causal relationship between which is tested by a Granger causality test. Having established the spatial network relationship, network analysis is used to further analyze the overall characteristics of the network, the individual characteristics of the network, and the block model of the network. We find that the provinces are closely related regarding regional innovation spillovers. However, the spatial correlation between the provinces differs greatly. Also, there is an obvious hierarchy between blocks that have different orientations and functions. Finally, the relationship between the interior of each block differs greatly in closeness degree

Research on Spatial Correlations and Influencing Factors of Logistics Industry Development Level

The logistics industry plays a greater role in the sustainable development of regional economies. The development of the logistics industry between regions is not independent, and there is a spatial correlation due to the existence of spatial spillover effect or spatial expansion among regions. This paper uses the method of entropy weight to evaluate the development level of the logistics industry in 31 provinces in China. On this basis, Moran’s index (Moran’s I), Moran’s I scatter plot, and local indicators of spatial association (LISA) agglomeration plot are used to analyze the overall and local spatial agglomeration characteristics of the logistics industry. Four main factors affecting the spatial relationship of the logistics industry are analyzed by choosing the fixed effect of the spatial error model. We find that: (i) There is spatial agglomeration effect in the development level of the logistics industry from the overall perspective; (ii) regional differentiation of the spatial agglomeration effect of logistics industry development level is obvious from the local perspective; and (iii) the influence of human resource factors on the spatial relationship of logistics development level is declining

Management of Suspected Peripheral Vascular Injuries in Orthopedic Trauma

Objective In orthopedic trauma, identification of extremity trauma combined with vascular injury is challenging. Missed diagnosis may result in amputation or even death. The purpose of this study was to investigate whether physical examination combined with handheld vascular ultrasound Doppler examination could be an effective method of screening for peripheral vascular injury and to explore the characteristics of vascular injuries in orthopedic trauma patients. Methods Retrospective analysis of patients in the emergency department of orthopedic trauma in our hospital from January 2022 to October 2023. Physical examination combined with handheld vascular ultrasound Doppler examination was used as a screening method for suspected vascular injuries. Patients with suspected vascular injury would undergo further angiography and receive multidisciplinary treatment. Angiography was used as the gold standard for diagnosing vascular injuries. Patient demographics, mechanism of injury, location and type of injury, angiographic results, surgical notes, and early treatment outcome data were recorded. Results A total of 55 cases (58 limb injuries) with suspected vascular injury were ultimately included. Angiography revealed that 53 cases (55 limbs, positive rate 94.8%) were considered to have confirmed vascular injuries. Forty‐three were male (81.1%) and 10 were female (18.9%), with mean age 44.1 ± 16.6 years. The main mechanism of injury was traffic accident (30, 56.7%). Most common site of vascular injuries was knee joint (30/55, 54.5%), and popliteal artery (23, 47.9%) was the most commonly injured blood vessel. After multidisciplinary collaborative treatment, overall patient mortality was 3.8% (2/53), and limb survival rate among surviving patients was 81.1% (43/53) in our study. Conclusion In orthopedic trauma, “Hard signs” and “soft signs” combined with handheld vascular ultrasound Doppler examination were effective ways to screen for suspected vascular injuries. Most limbs had associated fractures or dislocations at the site of vascular injury. Collaboration of vascular surgery, microsurgery and orthopedic trauma may help improve patients' prognosis

Traumatic proximal tibiofibular fracture and dislocation

Abstract Background Traumatic proximal tibiofibular fracture and dislocation (PTFD) have been rarely studied and are easily missed in clinical practice. PTFD is considered a marker of severely traumatized knees. The purpose of this study was to retrospectively analyze the incidence and impact of PTFD in traumatized knees with vascular injury. Methods Patients with knee trauma and vascular injury were included from January 2022 to October 2023. X-rays and CT scans of included patients were retrospectively analyzed to determine the presence of PTFD. Patients were further divided into PTFD group and non-PTFD group for further comparative analysis. Results A total of 27 patients (28 limbs) were included. Incidence of PTFD was 39.3% (11/28) in traumatic knee with vascular injury, including 8 anterolateral dislocations and 3 posteromedial dislocations. PTFD group had significantly more limbs with open injuries compared with non-PTFD group (10/11 VS 7/17, p0.05). Conclusions PTFD was easily overlooked or missed. In traumatized knees with vascular injury, incidence of PTFD was high. The presence of PTFD might indicate severe knee trauma and the possibility of open injury. Although there was no significant difference compared with non-PTFD group, PTFD group had a relatively high amputation rate of 40%