An efficient approach toward production of near-zigzag single-chirality carbon nanotubes.

Synthesizing single-walled carbon nanotubes (SWCNTs) with a narrow chirality distribution is essential for obtaining pure chirality materials through postgrowth sorting techniques. Using carbon monoxide chemical vapor deposition, we devise a ruthenium (Ru) catalyst supported by silica for the bulk production of SWCNTs containing only a few (n, m) species. The result is attributed to the limited carbon dissociation on the supported Ru clusters, favoring the growth of only small-diameter SWCNTs at comparable growth rates. The resulting materials expedite high-purity single chirality separation using gel chromatography, leading to unprecedented yields of 3.5% for (9, 1) and 5.2% for (9, 2) nanotubes, which surpass those separated from HiPco SWCNTs by two orders of magnitude. This work sheds light on the large-quantity synthesis of SWCNTs with enriched species beyond near-armchair ones for their high-yield separation.

Eltrombopag can promote platelet implantation after allogeneic hematopoietic stem cell transplantation as safely and similarly to thrombopoietin.

Background: Eltrombopag has demonstrated efficacy in treating low platelet (PLT) levels, but it remains unclear whether eltrombopag can promote PLT engraftment after hematopoietic stem cell transplantation (HSCT). Methods: Forty-one HSCT patients received eltrombopag 50 mg/d from +1 day until PLT >50 × 109/L or 1 month after HSCT. Fifty-one patients in the same period received thrombopoietin (TPO) to promote PLT graft after HSCT and served as a control group. Results: A total of 51 patients who applied TPO during the same period were treated as a control. In the eltrombopag group, the median time to white blood cells (WBC) graft was 12 days (range, 10-17 days) and the PLT graft was 15 days (range, 10-30 days), whereas for the patients in the TPO group, the median time to WBC and PLT graft was 12 days (range, 9-23 days) and 15.5 days (range, 9-41 days), respectively. In the first month after HSCT, the median WBC count in the eltrombopag group was 4.41 × 109/L (range, 0.87-40.01 × 109/L) and the median PLT was 89x109/L (range, 30-401 × 109/L); the median WBC and PLT \counts in the TPO group were 4.65 × 109/L (range, 0.99-23.63 × 109/L) and 86 × 109/L (range, 5-512 × 109/L), respectively. Patients in the TPO or eltrombopag group did not experience serious side effects after drug administration, and the difference in side effects on liver and kidney function between the two groups was not statistically significant. Conclusion: Eltrombopag is safe and similarly promotes platelet engraftment to thrombopoietin after allogeneic HSCT.

Characteristics of Molecular Genetic Mutations and Their Correlation with Prognosis in Adolescent and Adult Patients with Acute Lymphoblastic Leukemia.

INTRODUCTION: The prognosis of acute lymphoblastic leukemia (ALL) in adolescents and adults is poor, and recurrence is an important cause of their death. Changes of genetic information play a vital role in the pathogenesis and recurrence of ALL; however, the impact of molecular genetic mutations on disease diagnosis and prognosis remains unexplored. This study aimed to explore the frequency spectrum of gene mutations and their prognostic significance, along with the minimal residual disease (MRD) level and hematopoietic stem cell transplantation (HSCT), in adolescent and adult patients aged ≥15 years with ALL. METHODS: The basic characteristics, cytogenetics, molecular genetics, MRD level, treatment regimen, and survival outcome of patients with untreated ALL (≥15 years) were collected, and the correlation and survival analysis were performed using the SPSS 25.0 and R software. RESULTS: This study included 404 patients, of which 147 were selected for next-generation sequencing (NGS). NGS results revealed that 91.2% of the patients had at least one mutation, and 67.35% had multiple (≥2) mutations. NOTCH1, PHF6, RUNX1, PTEN, JAK3, TET2, and JAK1 were the most common mutations in T-ALL, whereas FAT1, TET2, NARS, KMT2D, FLT3, and RELN were the most common mutations in B-ALL. Correlation analysis revealed the mutation patterns, which were significantly different between T-ALL and B-ALL. In the prognostic analysis of 107 patients with B-ALL, multivariate analysis showed that the number of mutations ≥5 was an independent risk factor for overall survival and the RELN mutation was an independent poor prognostic factor for event-free survival. DISCUSSION: The distribution of gene mutations and the co-occurrence and repulsion of mutant genes in patients with ALL were closely related to the immunophenotype of the patients. The number of mutations ≥5 and the RELN mutation were significantly associated with poor prognosis in adolescent and adult patients with ALL.

Damage Evolution of Polypropylene-Basalt Hybrid Fiber Ceramsite Concrete under Chloride Erosion and Dry-Wet Cycle.

To investigate the influence of polypropylene-basalt hybrid fibers (PBHFCC) on the durability of ceramsite concrete, this study determined the appearance change, mass loss rate, relative dynamic elastic modulus, compressive strength and splitting tensile strength of ceramsite concrete with four kinds of hybrid fibers volume admixture under chloride erosion and dry-wet cycles. The results reveal that under this effect, the apparent damage of each group of specimens increased with the growth of the erosion time. The quality, compressive strength and splitting tensile strength of the specimens all increased gradually during the erosion age period of the first 72 d and gradually decreased after 72 d. The relative dynamic elastic modulus was similarly mutated in 48 d. When the hybrid fiber content of the specimens is 0.15 vol %, the enhancement effect of ceramsite concrete is better than that of the other three amounts. The relative dynamic elastic modulus value is used as a damage variable to establish the damage equation, and the damage evolution equation of PBHFCC considering the volume of hybrid fiber under chloride erosion and dry-wet cycle is derived. The conclusions can be used as a reference for the durability design and construction of PBHFCC.

iLncDA-RSN: identification of lncRNA-disease associations based on reliable similarity networks.

Identification of disease-associated long non-coding RNAs (lncRNAs) is crucial for unveiling the underlying genetic mechanisms of complex diseases. Multiple types of similarity networks of lncRNAs (or diseases) can complementary and comprehensively characterize their similarities. Hence, in this study, we presented a computational model iLncDA-RSN based on reliable similarity networks for identifying potential lncRNA-disease associations (LDAs). Specifically, for constructing reliable similarity networks of lncRNAs and diseases, miRNA heuristic information with lncRNAs and diseases is firstly introduced to construct their respective Jaccard similarity networks; then Gaussian interaction profile (GIP) kernel similarity networks and Jaccard similarity networks of lncRNAs and diseases are provided based on the lncRNA-disease association network; a random walk with restart strategy is finally applied on Jaccard similarity networks, GIP kernel similarity networks, as well as lncRNA functional similarity network and disease semantic similarity network to construct reliable similarity networks. Depending on the lncRNA-disease association network and the reliable similarity networks, feature vectors of lncRNA-disease pairs are integrated from lncRNA and disease perspectives respectively, and then dimensionality reduced by the elastic net. Two random forests are at last used together on different lncRNA-disease association feature sets to identify potential LDAs. The iLncDA-RSN is evaluated by five-fold cross-validation to analyse its prediction performance, results of which show that the iLncDA-RSN outperforms the compared models. Furthermore, case studies of different complex diseases demonstrate the effectiveness of the iLncDA-RSN in identifying potential LDAs.

The counterpart congenital overgrowth syndromes Beckwith-Wiedemann Syndrome in human and large offspring syndrome in bovine involve alterations in DNA methylation, transcription, and chromatin configuration.

Beckwith-Wiedemann Syndrome (BWS, OMIM #130650) is a congenital epigenetic disorder in humans which affects approximately 1 in 10,340 children. The incidence is likely an underestimation as the condition is usually recognized based on observable phenotypes at birth. BWS children have up to a 28% risk of developing tumors and currently, only 80% of patients can be corroborated molecularly (epimutations/variants). It is unknown how the subtypes of this condition are molecularly similar/dissimilar globally, therefore there is a need to deeply characterize the syndrome at the molecular level. Here we characterize the methylome, transcriptome and chromatin configuration of 18 BWS individuals together with the animal model of the condition, the bovine large offspring syndrome (LOS). Sex specific comparisons are performed for a subset of the BWS patients and LOS. Given that this epigenetic overgrowth syndrome has been characterized as a loss-of-imprinting condition, parental allele-specific comparisons were performed using the bovine animal model. In general, the differentially methylated regions (DMRs) detected in BWS and LOS showed significant enrichment for CTCF binding sites. Altered chromosome compartments in BWS and LOS were positively correlated with gene expression changes, and the promoters of differentially expressed genes showed significant enrichment for DMRs, differential topologically associating domains, and differential A/B compartments in some comparisons of BWS subtypes and LOS. We show shared regions of dysregulation between BWS and LOS, including several HOX gene clusters, and also demonstrate that altered DNA methylation differs between the clinically epigenetically identified BWS patients and those identified as having DNA variants (i.e. CDKN1C microdeletion). Lastly, we highlight additional genes and genomic regions that have the potential to serve as targets for biomarker development to improve current molecular methodologies. In summary, our results suggest that genome-wide alternation of chromosome architecture, which is partially caused by DNA methylation changes, also contribute to the development of BWS and LOS.

Differentially expressed tRNA-derived fragments in bovine fetuses with assisted reproduction induced congenital overgrowth syndrome.

Background: As couples struggle with infertility and livestock producers wish to rapidly improve genetic merit in their herd, assisted reproductive technologies (ART) have become increasingly popular in human medicine as well as the livestock industry. Utilizing ART can cause an increased risk of congenital overgrowth syndromes, such as Large Offspring Syndrome (LOS) in ruminants. A dysregulation of transcripts has been observed in bovine fetuses with LOS, which is suggested to be a cause of the phenotype. Our recent study identified variations in tRNA expression in LOS individuals, leading us to hypothesize that variations in tRNA expression can influence the availability of their processed regulatory products, tRNA-derived fragments (tRFs). Due to their resemblance in size to microRNAs, studies suggest that tRFs target mRNA transcripts and regulate gene expression. Thus, we have sequenced small RNA isolated from skeletal muscle and liver of day 105 bovine fetuses to elucidate the mechanisms contributing to LOS. Moreover, we have utilized our previously generated tRNA sequencing data to analyze the contribution of tRNA availability to tRF abundance. Results: 22,289 and 7,737 unique tRFs were predicted in the liver and muscle tissue respectively. The greatest number of reads originated from 5' tRFs in muscle and 5' halves in liver. In addition, mitochondrial (MT) and nuclear derived tRF expression was tissue-specific with most MT-tRFs and nuclear tRFs derived from LysUUU and iMetCAU in muscle, and AsnGUU and GlyGCC in liver. Despite variation in tRF abundance within treatment groups, we identified differentially expressed (DE) tRFs across Control-AI, ART-Normal, and ART-LOS groups with the most DE tRFs between ART-Normal and ART-LOS groups. Many DE tRFs target transcripts enriched in pathways related to growth and development in the muscle and tumor development in the liver. Finally, we found positive correlation coefficients between tRNA availability and tRF expression in muscle (R = 0.47) and liver (0.6). Conclusion: Our results highlight the dysregulation of tRF expression and its regulatory roles in LOS. These tRFs were found to target both imprinted and non-imprinted genes in muscle as well as genes linked to tumor development in the liver. Furthermore, we found that tRNA transcription is a highly modulated event that plays a part in the biogenesis of tRFs. This study is the first to investigate the relationship between tRNA and tRF expression in combination with ART-induced LOS.

Down-regulated expression of CDK5RAP3 and UFM1 suggests a poor prognosis in gastric cancer patients.

Purpose: The relationship between the CDK5RAP3 and UFM1 expression and the prolonged outcomes of patients who underwent gastric cancer (GC) surgery was investigated. Methods: Single-sample gene set enrichment analysis (ssGSEA), unsupervised clustering and other methods were used to verify the relationship between CDK5RAP3 and UFM1 in GC through public databases. Additionally, CDK5RAP3 and UFM1 expression in cancerous and paracancerous tissues of GC was analysed in the context of patient prognosis. Results: CDK5RAP3 and UFM1 expression was downregulated synchronously, the interaction was observed between the two proteins, and UFM1 and CDK5RAP3 expression was found to be inversely associated to AKT pathway activation. Prognostic analysis showed that the prognosis is poorer for low CDK5RAP3 and UFM1 patients, than for high CDK5RAP3 and/or UFM1 (p<0.001) patients, and this expression pattern was an independent predictor for overall survival of GC. Coexpression of CDK5RAP3 and UFM1 combined with TNM staging can improve the accuracy of prognosis prediction for patients (p <0.001). Conclusions: It is confirmed in our findings that a combination of CDK5RAP3 and UFM1 can produce a more precise prediction model for GC patients' survival.

Identification of large offspring syndrome during pregnancy through ultrasonography and maternal blood transcriptome analyses.

In vitro production (IVP) of embryos in cattle can result in large/abnormal offspring syndrome (LOS/AOS) which is characterized by macrosomia. LOS can cause dystocia and lead to the death of dam and calf. Currently, no test exists to identify LOS pregnancies. We hypothesized that fetal ultrasonography and/or maternal blood markers are useful to identify LOS. Bovine fetuses were generated by artificial insemination (control) or IVP. Fetal ultrasonographies were taken on gestation D55 (D55) and fetal collections performed on D56 or D105 (gestation in cattle ≈ D280). IVP fetuses weighing ≥ 97 percentile of the control weight were considered LOS. Ultrasonography results show that the product of six D55 measurements can be used to identify extreme cases of LOS. To determine whether maternal blood can be used to identify LOS, leukocyte mRNA from 23 females was sequenced. Unsupervised hierarchical clustering grouped the transcriptomes of the two females carrying the two largest LOS fetuses. Comparison of the leukocyte transcriptomes of these two females to the transcriptome of all other females identified several misregulated transcripts on gestation D55 and D105 with LOC783838 and PCDH1 being misregulated at both time-points. Together our data suggest that LOS is identifiable during pregnancy in cattle.

Allele-specific aberration of imprinted domain chromosome architecture associates with large offspring syndrome.

Large offspring syndrome (LOS) and Beckwith-Wiedemann syndrome are similar epigenetic congenital overgrowth conditions in ruminants and humans, respectively. We have reported global loss-of-imprinting, methylome epimutations, and gene misregulation in LOS. However, less than 4% of gene misregulation can be explained with short range (<20kb) alterations in DNA methylation. Therefore, we hypothesized that methylome epimutations in LOS affect chromosome architecture which results in misregulation of genes located at distances >20kb in cis and in trans (other chromosomes). Our analyses focused on two imprinted domains that frequently reveal misregulation in these syndromes, namely KvDMR1 and IGF2R. Using bovine fetal fibroblasts, we identified CTCF binding at IGF2R imprinting control region but not KvDMR1, and allele-specific chromosome architecture of these domains in controls. In LOS, analyses identified erroneous long-range contacts and clustering tendency in the direction of expression of misregulated genes. In conclusion, altered chromosome architecture is associated with LOS.

Spontaneous and ART-induced large offspring syndrome: similarities and differences in DNA methylome.

Large/abnormal offspring syndrome (LOS/AOS) is a congenital overgrowth syndrome reported in ruminants produced by assisted reproduction (ART-LOS) which exhibit global disruption of the epigenome and transcriptome. LOS/AOS shares phenotypes and epigenotypes with the human congenital overgrowth condition Beckwith-Wiedemann syndrome. We have reported that LOS occurs spontaneously (SLOS); however, to date, no study has been conducted to determine if SLOS has the same methylome epimutations as ART-LOS. In this study, we performed whole-genome bisulphite sequencing to examine global DNA methylation in bovine SLOS and ART-LOS tissues. We observed unique patterns of global distribution of differentially methylated regions (DMRs) over different genomic contexts, such as promoters, CpG Islands, shores and shelves, as well as at repetitive sequences. In addition, we included data from two previous LOS studies to identify shared vulnerable genomic loci in LOS. Overall, we identified 320 genomic loci in LOS that have alterations in DNA methylation when compared to controls. Specifically, there are 25 highly vulnerable loci that could potentially serve as molecular markers for the diagnosis of LOS, including at the promoters of DMRT2 and TBX18, at the imprinted gene bodies of IGF2R, PRDM8, and BLCAP/NNAT, and at multiple CpG Islands. We also observed tissue-specific DNA methylation patterns between muscle and blood, and conservation of ART-induced DNA methylation changes between muscle and blood. We conclude that as ART-LOS, SLOS is an epigenetic condition. In addition, SLOS and ART-LOS share similarities in methylome epimutations.

Characterization of tRNA expression profiles in large offspring syndrome.

BACKGROUND: Assisted Reproductive Technologies (ART) use can increase the risk of congenital overgrowth syndromes, such as large offspring syndrome (LOS) in ruminants. Epigenetic variations are known to influence gene expression and differentially methylated regions (DMRs) were previously determined to be associated with LOS in cattle. We observed DMRs overlapping tRNA clusters which could affect tRNA abundance and be associated with tissue specificity or overgrowth. Variations in tRNA expression have been identified in several disease pathways suggesting an important role in the regulation of biological processes. Understanding the role of tRNA expression in cattle offers an opportunity to reveal mechanisms of regulation at the translational level. We analyzed tRNA expression in the skeletal muscle and liver tissues of day 105 artificial insemination-conceived, ART-conceived with a normal body weight, and ART-conceived bovine fetuses with a body weight above the 97th percentile compared to Control-AI. RESULTS: Despite the centrality of tRNAs to translation, in silico predictions have revealed dramatic differences in the number of tRNA genes between humans and cattle (597 vs 1,659). Consistent with reports in human, only a fraction of predicted tRNA genes are expressed. We detected the expression of 474 and 487 bovine tRNA genes in the muscle and liver with the remainder being unexpressed. 193 and 198 unique tRNA sequences were expressed in all treatment groups within muscle and liver respectively. In addition, an average of 193 tRNA sequences were expressed within the same treatment group in different tissues. Some tRNA isodecoders were differentially expressed between treatment groups. In the skeletal muscle and liver, we categorized 11 tRNA isoacceptors with undetected expression as well as an isodecoder that was unexpressed in the liver (SerGGA). Our results identified variation in the proportion of tRNA gene copies expressed between tissues and differences in the highest contributing tRNA anticodon within an amino acid family due to treatment and tissue type. Out of all amino acid families, roughly half of the most highly expressed tRNA isoacceptors correlated to their most frequent codon in the bovine genome. CONCLUSION: Although the number of bovine tRNA genes is nearly triple of that of the tRNA genes in human, there is a shared occurrence of transcriptionally inactive tRNA genes in both species. We detected differential expression of tRNA genes as well as tissue- and treatment- specific tRNA transcripts with unique sequence variations that could modulate translation during protein homeostasis or cellular stress, and give rise to regulatory products targeting genes related to overgrowth in the skeletal muscle and/or tumor development in the liver of LOS individuals. While the absence of certain isodecoders may be relieved by wobble base pairing, missing tRNA species could increase the likelihood of mistranslation or mRNA degradation.

The impact of different doses of antithymocyte globulin conditioning on immune reconstitution upon hematopoietic stem cell transplantation.

INTRODUCTION: Anti-thymocyte globulin (ATG) is used prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) for graft-versus-host disease (GVHD) prophylaxis. Two different ATG doses (7.5 or 10 mg/kg) were evaluated in comparison with a group without ATG therapy. METHODS: We retrospectively analyzed 132 patients who were transplanted with HSCT without ATG (non-ATG), or who received 7.5 mg/kg ATG (ATG-7.5) or 10 mg/kg ATG (ATG-10) prior to transplantation. The immune cells (CD3+CD4+ T cells, CD3+CD8+ T cells, CD19+ B cells and CD16+CD56+ NK cells) were examined in peripheral blood every three months post-HSCT for 12 months. RESULTS: Compared with non-ATG group, combined ATG-7.5/ATG-10 groups had significantly lower CD3+CD4+ T cells and higher CD3+CD8+ T cells at 3, 6, 9, 12 months post-HSCT; thus, displaying a lower CD4/CD8 ratio in the ATG groups compared to non-ATG group. The ratio of CD19+ B cells was statistically lower (at 3rd month, p = .014; at 6th month, p = .025) in combined ATG-7.5/ATG-10 groups at 3 and 6 months post-HSCT, but not at 9 and 12 months after HSCT. The ratios of CD3+CD4+ T cells, CD3+CD8+ T cells, CD19+ B cells and CD16+CD56+ NK cells were similar between the ATG-7.5 and ATG-10 groups at all examined time points. The overall survival (OS), progression-free survival (PFS), relapse and acute GVHD (aGVHD) were comparable among recipients without ATG therapy and with ATG-7.5 or/and ATG-10 therapies. Multivariate analysis revealed that immune cells ratios were not independent factors affecting prognosis. CONCLUSION: The ATG therapy at higher and lower doses led to a delayed reconstitution of T cells and the inversion of CD4/CD8 ratio for at least one year after HSCT.

Traditional and emerging therapies for anaplastic large cell lymphoma (Review).

Anaplastic large cell lymphoma (ALCL) is a rare and highly invasive non­Hodgkin's lymphoma. In the past few decades, traditional chemotherapy regimens, such as as the cyclophosphamide, vincristine, doxorubicin and prednisone regimen, have been recommended for first­line treatment. In order to improve the survival of patients, dose­intensive chemotherapy and hematopoietic stem cell transplantation have been deeply studied and some progress has been made. Recently, with the accumulation of clinical cases and the development of clinical trials, as well improvements to our in­depth understanding of the biological behavior of ALCL, the signaling pathways and the immunotherapy involved, research on this topic is in full swing. The emergence of several targeted drugs and immunotherapies, including anaplastic lymphoma kinase inhibitors, brentuximab vedotin, mTOR inhibitors, programmed cell death protein 1/programmed death ligand 1 inhibitors and chimeric antigen receptor­T cell therapy, seems to provide new opportunities for certain patients with ALCL. The present review focuses on the current use of traditional therapy and the treatment prospects of these new drugs in ALCL.

Risk Stratification for Diffuse Large B-Cell Lymphoma by Integrating Interim Evaluation and International Prognostic Index: A Multicenter Retrospective Study.

The baseline International Prognostic Index (IPI) is not sufficient for the initial risk stratification of patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). The aims of this study were to evaluate the prognostic relevance of early risk stratification in DLBCL and develop a new stratification system that combines an interim evaluation and IPI. This multicenter retrospective study enrolled 314 newly diagnosed DLBCL patients with baseline and interim evaluations. All patients were treated with R-CHOP or R-CHOP-like regimens as the first-line therapy. Survival differences were evaluated for different risk stratification systems including the IPI, interim evaluation, and the combined system. When stratified by IPI, the high-intermediate and high-risk groups presented overlapping survival curves with no significant differences, and the high-risk group still had >50% of 3-year overall survival (OS). The interim evaluation can also stratify patients into three groups, as 3-year OS and progression-free survival (PFS) rates in patients with stable disease (SD) and progressive disease (PD) were not significantly different. The SD and PD patients had significantly lower 3-year OS and PFS rates than complete remission and partial response patients, but the percentage of these patients was only ~10%. The IPI and interim evaluation combined risk stratification system separated the patients into low-, intermediate-, high-, and very high-risk groups. The 3-year OS rates were 96.4%, 86.7%, 46.4%, and 40%, while the 3-year PFS rates were 87.1%, 71.5%, 42.5%, and 7.2%. The OS comparison between the high-risk group and very high-risk group was marginally significant, and OS and PFS comparisons between any other two groups were significantly different. This combined risk stratification system could be a useful tool for the prognostic prediction of DLBCL patients.

Conditions of embryo culture from days 5 to 7 of development alter the DNA methylome of the bovine fetus at day 86 of gestation.

PURPOSE: We tested whether in vitro production (IVP) causes changes in DNA methylation in fetal liver and skeletal muscle and if exposure of cultured embryos to colony-stimulating factor 2 (CSF2) alters DNA methylation. METHODS: Female fetuses were produced by artificial insemination or transfer of an IVP embryo. Embryos were treated from days 5 to 7 after fertilization with CSF2 or vehicle. DNA methylation in fetal liver and skeletal muscle was determined by post-bisulfite adaptor tagging-based sequencing. The degree of DNA methylation for CpG sites in 50-bp windows of the promoter region 500 bp upstream of the transcriptional start site was compared between treatments. RESULTS: For liver, there were 12 genes (6% of those analyzed) in which DNA methylation was affected by treatment, with one 50-bp window per gene affected by treatment. For muscle, the degree of DNA methylation was affected by treatment for 32 windows (19% of the total windows analyzed) representing 28 distinct genes (23% of analyzed genes). For 19 of the 28 genes in muscle, the greatest deviation in DNA methylation was for the CSF2 group. CONCLUSION: Results are consistent with alterations in the methylome being one of the mechanisms by which IVP can result in altered fetal development and postnatal function in the resultant offspring. In addition, results indicate that maternally derived cell-signaling molecules can regulate the pattern of DNA methylation.

Modeling allele-specific expression at the gene and SNP levels simultaneously by a Bayesian logistic mixed regression model.

BACKGROUND: High-throughput sequencing experiments, which can determine allele origins, have been used to assess genome-wide allele-specific expression. Despite the amount of data generated from high-throughput experiments, statistical methods are often too simplistic to understand the complexity of gene expression. Specifically, existing methods do not test allele-specific expression (ASE) of a gene as a whole and variation in ASE within a gene across exons separately and simultaneously. RESULTS: We propose a generalized linear mixed model to close these gaps, incorporating variations due to genes, single nucleotide polymorphisms (SNPs), and biological replicates. To improve reliability of statistical inferences, we assign priors on each effect in the model so that information is shared across genes in the entire genome. We utilize Bayesian model selection to test the hypothesis of ASE for each gene and variations across SNPs within a gene. We apply our method to four tissue types in a bovine study to de novo detect ASE genes in the bovine genome, and uncover intriguing predictions of regulatory ASEs across gene exons and across tissue types. We compared our method to competing approaches through simulation studies that mimicked the real datasets. The R package, BLMRM, that implements our proposed algorithm, is publicly available for download at https://github.com/JingXieMIZZOU/BLMRM . CONCLUSIONS: We will show that the proposed method exhibits improved control of the false discovery rate and improved power over existing methods when SNP variation and biological variation are present. Besides, our method also maintains low computational requirements that allows for whole genome analysis.

Altered microRNA expression profiles in large offspring syndrome and Beckwith-Wiedemann syndrome.

The use of assisted reproductive technologies (ART) can induce a congenital overgrowth condition in humans and ruminants, namely Beckwith-Wiedemann syndrome (BWS) and large offspring syndrome (LOS), respectively. Shared phenotypes and epigenotypes have been found between BWS and LOS. We have observed global misregulation of transcripts in bovine foetuses with LOS. microRNAs (miRNAs) are important post-transcriptional gene expression regulators. We hypothesize that there is miRNA misregulation in LOS and that this misregulation is shared with BWS. In this study, small RNA sequencing was conducted to investigate miRNA expression profiles in bovine and human samples. We detected 407 abundant known miRNAs and predicted 196 putative miRNAs from the bovine sequencing results and identified 505 abundant miRNAs in human tongue. Differentially expressed miRNAs (DE-miRNAs) were identified between control and LOS groups in all tissues analysed as well as between BWS and control human samples. DE-miRNAs were detected from several miRNA clusters including DLK1-DIO3 genomic imprinted cluster in LOS and BWS. DNA hypermethylation was associated with downregulation of miRNAs in the DLK1-DIO3. mRNA targets of the DE-miRNAs were predicted and signalling pathways associated with control of organ size (including the Hippo signalling pathway), cell proliferation, apoptosis, cell survival, cell cycle, and cell adhesion were found to be enriched with these genes. Yes associated protein 1 (YAP1) is the core effector of the Hippo signalling pathway, and increased level of active (non-phosphorylated) YAP1 protein was detected in skeletal muscle of LOS foetuses. Overall, our data provide evidence of miRNA misregulation in LOS and BWS.

Overgrowth Syndrome.

Large offspring syndrome (LOS) is a fetal overgrowth condition in bovines most often observed in offspring conceived with the use of assisted reproductive technologies (ART). Phenotypes observed in LOS include, overgrowth, enlarged tongues, umbilical hernias, muscle and skeleton malformations, abnormal organ growth and placental development. Although LOS cases have only been reported to be associated with ART, fetal overgrowth can occur spontaneously in cattle (S-LOS). S-LOS refers to oversized calves that are born at normal gestation lengths. ART-induced LOS has been characterized as an epigenetic syndrome, more specifically, a loss-of-imprinting condition. We propose that S-LOS is also a loss-of-imprinting condition.

Prognostic Factors and Visual Outcomes of Pyogenic Liver Abscess-Related Endogenous Klebsiella pneumoniae Endophthalmitis: A 20-year retrospective review.

Endogenous K. pneumoniae endophthalmitis (EKE) has a higher incidence among East Asians, and the most common infectious source of EKE is pyogenic liver abscess (PLA). We investigate the risk factors for poor visual outcomes in patients with PLA-related EKE. The retrospective medical records of 104 patients (120 eyes) diagnosed with PLA-related EKE between 1996 and 2015. In univariate logistic regression analysis, the risk factors for poor visual outcomes were initial visual acuity (VA) worse than counting fingers (CF) (p < 0.001), eye pain (p = 0.013), hypopyon (p = 0.003), ocular hypertension (p = 0.003), positive intraocular fluids cultures (p < 0.001), subretinal abscess (p = 0.025), unilateral involvement (p = 0.017), delayed ophthalmologic visit (p = 0.022), initially presented with ocular symptoms ahead of systemic symptoms (p < 0.001), and corneal edema (p < 0.001). Intravitreal dexamethasone reduced the requirement of enucleation or evisceration (p = 0.01). The multivariate logistic regression revealed that poor initial VA worse than CF (p = 0.004) and initially presented with ocular symptoms ahead of systemic symptoms (p = 0.007) were the significant independent factors for poor visual outcomes. Early diagnosis and prompt treatment may salvage useful vision in some eyes.