Effects of aprotic solvents on the physicochemical properties and ferric ion oxidation activity of iron-based ionic liquids.

In recent years, iron-based ionic liquids (e.g. BmimFeCl4, Fe-IL) have been widely used in the catalytic oxidation removal of hydrogen sulfide owing to their excellent redox reversibility and stability. Nevertheless, the high viscosity and poor Fe3+ activity of BmimFeCl4 limit its large-scale industrial application. The addition of aprotic organic solvents to BmimFeCl4 is an effective strategy to enhance its mass transfer efficiency and catalytic oxidation desulfurization performance. In this work, the effects of two kinds of aprotic organic solvents, weak polar polyether alcohols (NHD, PEG200) and strong polar amides (DMAC, DMF, and NMP), on the density, viscosity, conductivity and ferric activity of Fe-IL were investigated. The Eyring equation fitted well for the relationship between the viscosity and the temperature of the composites. When the mass ratio of BmimFeCl4 to solvent was 7 : 3 at 298.2 K, the viscosity of BmimFeCl4/DMAC and BmimFeCl4/NHD was 8.67 mPa s and 27.19 mPa s, respectively. The excess molar volume (VE) and viscosity deviation (Δη) of the two composite systems were calculated and fitted using the Redlich-Kister equation. The study of VE implies that DMAC has stronger solvation to the BmimFeCl4 ion pairs, and NHD could cause a more obvious volume shrinkage. For the composites investigated, Δη of BmimFeCl4/DMAC is negative while that of BmimFeCl4/NHD is positive, showing that DMAC could significantly weaken the combination ability of [Bmim]+ and [FeCl4]-, and NHD may form a stronger interaction with [Bmim]+. The FT-IR spectra and DFT calculations demonstrated that both polyether alcohol and amide could interact with C2-H on [Bmim]+. The CV curves and the MK charges show that the addition of aprotic polar solvents could effectively improve the activity of Fe3+ under the action of a hydrogen bond, and the effect of amide solvents on the activation of Fe3+ is stronger than that of polyether alcohol solvents. In conclusion, it is found that the composites with stronger ferric activity have much better catalytic oxidation ability for the conversion performance of hydrogen sulfide, and the the interactions induced by the molecular weight and the polarity of the solvent have a significant effect on the configuration of the Fe-IL ion pairs.

[Mosaic trisomy 20: discrepancy between cyto-and molecular genetic technologies in prenatal diagnosis].

OBJECTIVE: To provide genetic counseling and prenatal diagnosis for a fetus with mosaic trisomy 20. METHODS: Chromosomal karyotyping, chromosomal microarray analysis (CMA) and fluorescence in situ hybridization (FISH) were carried out for a pregnant woman with advanced maternal age. RESULTS: The karyotype of amniotic fluid sample was 47,XN,+20, whilst the result of CMA was normal. To verify this discrepancy, CMA was performed again with the cultured amniotic fluid, which yielded a result of 47,XN,+20. FISH assay of the amniotic fluid sample was nuc ish(D20Z1)×3[11]/(D20Z1)×2[89], which indicated that about 11% of fetal cells were trisomy 20. After the fetus was born, the karyotype of peripheral blood sample was normal. CONCLUSION: The amniotic fluid sample might be mosaic trisomy 20, and a dominant growth of 47,XN,+20 cells had occurred during the culture process, resulting in alteration of amniotic fluid cell composition. Mosaic trisomy 20 indicated by FISH may be attributed to confined placental mosaicism or somatic mosaicism of trisomy 20.

Influenza Research Database: An integrated bioinformatics resource for influenza virus research.

The Influenza Research Database (IRD) is a U.S. National Institute of Allergy and Infectious Diseases (NIAID)-sponsored Bioinformatics Resource Center dedicated to providing bioinformatics support for influenza virus research. IRD facilitates the research and development of vaccines, diagnostics and therapeutics against influenza virus by providing a comprehensive collection of influenza-related data integrated from various sources, a growing suite of analysis and visualization tools for data mining and hypothesis generation, personal workbench spaces for data storage and sharing, and active user community support. Here, we describe the recent improvements in IRD including the use of cloud and high performance computing resources, analysis and visualization of user-provided sequence data with associated metadata, predictions of novel variant proteins, annotations of phenotype-associated sequence markers and their predicted phenotypic effects, hemagglutinin (HA) clade classifications, an automated tool for HA subtype numbering conversion, linkouts to disease event data and the addition of host factor and antiviral drug components. All data and tools are freely available without restriction from the IRD website at https://www.fludb.org.

Comparison between minimally invasive plate osteosynthesis and open reduction-internal fixation for proximal humeral fractures: a meta-analysis based on 1050 individuals.

BACKGROUND: This meta-analysis aimed to compare the clinical outcomes and complications of minimally invasive plate osteosynthesis (MIPO) and open reduction-internal fixation (ORIF) in patients with proximal humeral fractures. METHODS: We searched PubMed, EMBASE, Ovid, and the Cochrane Library to identify all relevant studies from inception to April 2019. Cochrane Collaboration's Review Manage 5.3 was used for meta-analysis. RESULTS: Sixteen studies involving 1050 patients (464 patients in the MIPO group and 586 patients in the ORIF group) were finally included. According to the meta-analysis, MIPO was superior to ORIF in operation time, blood loss, postoperative pain, fracture union time, and constant score. However, MIPO was associated with more exposure to radiation and axillary nerve injury. No significant differences were found in length of hospital stays and complication except for axillary nerve injury. CONCLUSION: The present evidence indicates that compared to ORIF, MIPO had advantages in functional outcomes, operation time, blood loss, postoperative pain, and fracture union time for the treatment of PHFs. However, the MIPO technique had a higher rate of axillary nerve injury and longer radiation time compared to ORIF.

ViPR: an open bioinformatics database and analysis resource for virology research.

The Virus Pathogen Database and Analysis Resource (ViPR, www.ViPRbrc.org) is an integrated repository of data and analysis tools for multiple virus families, supported by the National Institute of Allergy and Infectious Diseases (NIAID) Bioinformatics Resource Centers (BRC) program. ViPR contains information for human pathogenic viruses belonging to the Arenaviridae, Bunyaviridae, Caliciviridae, Coronaviridae, Flaviviridae, Filoviridae, Hepeviridae, Herpesviridae, Paramyxoviridae, Picornaviridae, Poxviridae, Reoviridae, Rhabdoviridae and Togaviridae families, with plans to support additional virus families in the future. ViPR captures various types of information, including sequence records, gene and protein annotations, 3D protein structures, immune epitope locations, clinical and surveillance metadata and novel data derived from comparative genomics analysis. Analytical and visualization tools for metadata-driven statistical sequence analysis, multiple sequence alignment, phylogenetic tree construction, BLAST comparison and sequence variation determination are also provided. Data filtering and analysis workflows can be combined and the results saved in personal 'Workbenches' for future use. ViPR tools and data are available without charge as a service to the virology research community to help facilitate the development of diagnostics, prophylactics and therapeutics for priority pathogens and other viruses.

LOC646762 Is Involved in Adipogenic Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells.

Long noncoding RNA (lncRNA) has been shown to participate in adipogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). In this study, we aimed to investigate the role of lncRNA-LOC646762 in adipogenic differentiation of BMSCs. Transcriptome sequencing revealed a positive correlation between LOC646762 transcription and expression of adipogenic marker genes in adipogenic differentiation. Moreover, LOC646762 overexpression did not negatively impact the cell proliferation of BMSCs. Besides, LOC646762 plays a crucial role in adipogenic differentiation, as evidenced by its positive correlation with adipogenic marker gene expression. Its possible interaction with its proposed target C/EBPß suggests its involvement in essential pathways governing adipogenesis. Collectively, our study outcomes provide valuable insights into the molecular mechanisms underlying the adipogenic differentiation of BMSCs and lay a strong foundation for further research in regenerative medicine.

Genetic analysis and prenatal diagnosis of a pedigree with developmental retardation due to paternal 8q/18q translocation.

Balanced reciprocal chromosomal translocation carriers will have greater risk to experience recurrent miscarriages, embryonic death, and infertility. We show the pedigree carrying a paternal karyotype which was reported first. This research helps to better understand the clinical manifestations and prognosis of patients with this rare chromosomal abnormality.

Study on the Clinical Value of Noninvasive Prenatal Testing in Screening the Chromosomal Abnormalities of the Fetus in the Elderly Pregnant Women.

Introduction: To explore the clinical value of noninvasive prenatal testing (NIPT) in screening the chromosomal abnormalities of the fetus in the elderly pregnant women. Materials and Methods: Between January 2020 and December 2021, 1949 elderly pregnant women underwent NIPT in our hospital. At the same time, 236 elderly pregnant women received invasive prenatal diagnosis, and the pregnancy outcomes were followed-up. Results: When NIPT was used for prenatal screening of fetal chromosomal aneuploidy, its diagnostic coincidence rate for trisomy 21 was the highest, with a coincidence rate of 90.00%, and the diagnostic coincidence rate for other chromosomal abnormalities was the lowest, only 22.22%. The sensitivity, specificity, positive predictive rate, and negative predictive rate for T21 by NIPT were 100%, 99.97%, 94.28%, and 100%; for T18 were 100%, 99.92%, 72.22%, and 100%, respectively; and for T13 were 100%, 99.95%, 50%, and 100%, respectively. Patients with high risks according to NIPT results further received invasive prenatal diagnosis, and 18 cases were excluded from the follow-up. For the remaining 1933 cases in the NIPT group, there was an incidence of 2.28% of adverse pregnancy outcomes. For the remaining 234 cases in the Amniocentesis group, there was an incidence of 1.28% of adverse pregnancy outcomes. There was no significant difference between the two groups (P > 0.05). The diagnostic rate of fetal chromosomal abnormalities in pregnant women under 40 years old was about 0.39-0.79%; however, the risk for people over 40 is relatively high at 1.32-4.44%. Conclusion: The noninvasive prenatal screening of fetal DNA in the second trimester of pregnancy for elderly pregnant women has high application value in the prediction of pregnancy outcome. The high risk of pregnancy can be determined by detecting trisomy 21, 18, and 13 syndromes, and the probability of adverse pregnancy outcome increases.

Lin28A alleviates ovariectomy-induced osteoporosis through activation of the AMP-activated protein kinase pathway in rats.

AIM: To investigate the role of Lin28A in ovariectomy-induced osteoporosis and to elucidate the underlying molecular mechanism. METHODS: Bilateral ovariectomy was conducted to generate an ovariectomy (OVX) rat model. Western blotting was performed to assess the relative expression levels of Lin28A, osteocalcin (OCN), runt-related transcription factor 2 (RUNX2), adenosine monophosphate-activated protein kinase (AMPK) and phosphorylated AMPK (p-AMPK) proteins. Enzyme-linked immunosorbent assays were performed to detect the serum levels of calcium, E2, alkaline phosphatase (ALP) and interleukin (IL)-1ß. Three-point bending test was used to assess biomechanical parameters of left femoral diaphysis. Hematoxylin and eosin (HE) staining was conducted to detect the trabecular structure of bone tissue. Dihydroethidium assay kit was used to measure the intracellular reactive oxygen species (ROS) level in osteoclasts. Alizarin red staining revealed the calcium deposit in bone marrow stromal cells (BMSC). RESULTS: The expression levels of Lin28A, OCN, RUNX2, AMPK and p-AMPK proteins were significantly decreased in OVX rats. The serum levels of calcium, E2, ALP and IL-1ß were significantly declined in OVX rats. Biomechanical parameters of left femoral diaphysis were significantly decreased in OVX rats. OVX-induced trabecular abnormalities. ROS level was dramatically increased in the bone tissue of OVX rats, and calcium deposit was dramatically decreased in BMSC cells of OVX rats. These effects induced by OVX could be prevented by overexpression of Lin28A. CONCLUSION: Lin28A alleviates ovariectomy-induced osteoporosis through activation of AMPK pathway in rats.

Ginsenoside Rg1 inhibits nucleus pulposus cell apoptosis, inflammation and extracellular matrix degradation via the YAP1/TAZ pathway in rats with intervertebral disc degeneration.

PURPOSE: Intervertebral disc degeneration (IDD) is one of the main causes of low back pain, which not only affects patients' life quality, but also places a great burden on the public health system. Recently, ginsenoside Rg1 has been found to act in IDD; however, the mechanism is still unclear. The purpose of this study is to explore the function of ginsenoside Rg1 and its molecular mechanism in IDD. METHODS: The rat model of IDD and nucleus pulposus (NP) experimental groups treated with ginsenoside Rg1 was constructed for investing the role of ginsenoside Rg1 in IDD rats. In the in vitro and in vivo study, the histological morphological changes, motor threshold (MT), inflammatory factors, oxidative stress, apoptosis and expression of the YAP1/TAZ signaling pathway-related proteins of the intervertebral discs (IVD) were measured by histological staining, mechanical and thermal stimulation, ELISA, qRT-PCR, flow cytometry, and western blot, respectively. RESULTS: Ginsenoside Rg1 significantly increased the threshold for mechanical and thermal stimulation and alleviated histological changes in IDD rats. Ginsenoside Rg1 had a significant inhibitory effect on the secretion level of inflammatory factors, redox activity, extracellular matrix (ECM) degradation in IVD tissue and NP cells, and apoptosis in NP cells. Further investigation revealed that ginsenoside Rg1 significantly inhibited the expression of YAP1/TAZ signaling pathway-related proteins. Additionally, the above inhibitory effect of ginsenoside Rg1 on IDD progression was concentration-dependent, that is, the highest concentration of ginsenoside Rg1 was most effective. CONCLUSION: Ginsenoside Rg1 inhibits IDD progression by suppressing the activation of YAP1/TAZ signaling pathway. This means that ginsenoside Rg1 has the potential to treat IDD.

A prenatal diagnosis case of partial duplication 21q21.1-q21.2 with normal phenotype maternally inherited.

BACKGROUND: Down syndrome is characterized by trisomy 21 or partial duplication of chromosome 21. Extensive studies have focused on the identification of the Down Syndrome Critical Region (DSCR). We aim to provide evidence that duplication of 21q21.1-q21.2 should not be included in the DSCR and it has no clinical consequences on the phenotype. CASE PRESENTATION: Because serological screening was not performed at the appropriate gestational age, noninvasive prenatal testing (NIPT) analysis was performed for a pregnant woman with normal prenatal examinations at 22 weeks of gestation. The NIPT results revealed a 5.8 Mb maternally inherited duplication of 21q21.1-q21.2. To assess whether the fetus also carried this duplication, ultrasound-guided amniocentesis was conducted, and the result of chromosomal microarray analysis (CMA) with amniotic fluid showed a 6.7 Mb duplication of 21q21.1-q21.2 (ranging from position 18,981,715 to 25,707,009). This partial duplication of 21q21.1-q21.2 in the fetus was maternally inherited. After genetic counseling, the pregnant woman and her family decided to continue the pregnancy. CONCLUSION: Our case clearly indicates that 21q21.1-q21.2 duplication is not included in the DSCR and most likely has no clinical consequences on phenotype.

Prenatal diagnosis by whole exome sequencing in a family with a novel TBR1 mutation causing intellectual disability.

OBJECTIVE: To provide prenatal diagnosis for a pregnant woman with genetic history of intellectual disability. CASE REPORT: A Chinese pedigree with intellectual disability was collected in this study. Cytogenetic analysis, chromosomal microarray analysis (CMA) and whole exome sequencing (WES) followed by Sanger validation were conducted to identify the genetic pathogenesis. A novel heterozygous deletion c.370_374delTTCCC in TBR1 gene was identified, leading to a frameshift mutation starting at Phe124 followed by a premature stop codon at position 141 (p.Phe124Valfs∗18). Segregation analysis identified that this novel mutation is co-segregated among the affected family members but absent in unaffected family members. Prenatal diagnosis indicated the absence of this mutation, and the family decided to continue the pregnancy after genetic counseling. CONCLUSION: Our findings demonstrated the significance of genetic testing in the diagnosis of intellectual disability. This work also confirmed the effectiveness of WES in prenatal diagnosis.

Identification of a novel TP63 mutation causing nonsyndromic cleft lip with or without cleft palate.

BACKGROUND: Cleft lip with or without cleft palate (CL/P) is the most common craniofacial anomaly with a high incidence of live births. The specific pathogenesis of CL/P is still unclear, although plenty of studies have been conducted. Variations of tumor protein 63 (TP63) was reported to be related to the phenotype of CL/P. The case discussed in this report involves a pedigree with mutation at TP63 gene, and the variation was not reported before. CASE PRESENTATION: A Chinese pedigree with CL/P was collected in this study. The proband is a 3-year-old boy with the phenotype of CL/P, while his global development and intelligence are normal. After two CL/P repair operations, he looks almost normal. The proband's uncle and grandmother both have the phenotype of CL/P. Cytogenetic analysis and chromosomal microarray analysis (CMA) were performed, followed by whole exome sequencing (WES) and sanger validation. Analysis of WES revealed a variant of C>T at nucleotide position 1324 (1324C>T) of TP63 gene, possibly producing a truncated protein with a premature stop codon at amino acid position 442 (p.Q442*). This mutation was localized at the oligomerization domain (OD) of TP63 and might impair the capacity of p63 oligomerization. CONCLUSION: The mutation in TP63 was recognized to be the possible cause of the phenotype of CL/P in this pedigree. This report provides some evidence for the clinical diagnosis of CL/P. And our study also provides clinical evidence for the molecular mechanism of TP63 gene causing nonsyndromic cleft lip with or without cleft palate (NSCL/P).

Genome sequence of the Brown Norway rat yields insights into mammalian evolution.

The laboratory rat (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development, having made inestimable contributions to human health. We report here the genome sequence of the Brown Norway (BN) rat strain. The sequence represents a high-quality 'draft' covering over 90% of the genome. The BN rat sequence is the third complete mammalian genome to be deciphered, and three-way comparisons with the human and mouse genomes resolve details of mammalian evolution. This first comprehensive analysis includes genes and proteins and their relation to human disease, repeated sequences, comparative genome-wide studies of mammalian orthologous chromosomal regions and rearrangement breakpoints, reconstruction of ancestral karyotypes and the events leading to existing species, rates of variation, and lineage-specific and lineage-independent evolutionary events such as expansion of gene families, orthology relations and protein evolution.

Enoxacin inhibits proliferation and invasion of human osteosarcoma cells and reduces bone tumour volume in a murine xenograft model.

Osteosarcoma is the most prevalent primary bone malignancy in children and adolescents. Neoadjuvant chemotherapy combined with surgical resection, the current standard treatment of osteosarcoma, is associated with a 5-year survival rate of only ~70%. Therefore, it is necessary to identify new, more effective treatment strategies for patients with this lethal disease. Enoxacin is a highly effective broad-spectrum fluoroquinolone antibiotic with low toxicity. The drug inhibits the growth and metastasis of numerous tumour types, but its efficacy has not been studied in osteosarcoma. This study assessed the antitumour effects of enoxacin in osteosarcoma 143B cells and in a murine tumour xenograft model. Enoxacin inhibited the proliferation, invasion and migration of 143B cells, as well as inducing their apoptosis. These effects were thought to be mediated by downregulation of Bcl-xL, Bxl-2, matrix metalloproteinase (MMP)2 and MMP9 expression. Enoxacin also significantly impaired the growth of bone tumours in nude mice without affecting their liver or kidney function, or blood cell count. Collectively, these results indicate that enoxacin is a promising new drug for osteosarcoma that warrants further evaluation in clinical studies.

Adeno-associated virus-mediated Bcl-xL prevents aminoglycoside-induced hearing loss in mice.

BACKGROUND: Recent studies showed that aminoglycosides destroyed the cochlear cells and induced ototoxicity by producing reactive oxygen species, including free radicals in the mitochondria, damaging the membrane of mitochondria and resulting in apoptotic cell death. Bcl-x(L) is a well characterized anti-apoptotic member of the Bcl-2 family. The aim of this study was to determine the potential cochlear protective effect of Bcl-x(L) as a therapeutic agent in the murine model of aminoglycoside ototoxicity. METHODS: Serotype 2 of adeno-associated virus (AAV2) as a vector encoding the mouse Bcl-x(L) gene was injected into mice cochleae prior to injection of kanamycin. Bcl-x(L) expression in vitro and in vivo was examined with Western blotting and immunohistochemistry separately. Cochlear dissection and auditory steady state responses were checked to evaluate the cochlear structure and function. RESULTS: The animals in the AAV2-Bcl-x(L)/kanamycin group displayed better auditory steady state responses hearing thresholds and cochlear structure than those in the artificial perilymph/kanamycin or AAV2-enhanced humanized green fluorescent protein/kanamycin control group at all tested frequencies. The auditory steady state responses hearing thresholds and cochlear structure in the inoculated side were better than that in the contralateral side. CONCLUSIONS: AAV2-Bcl-x(L) afforded significant preservation of the cochlear hair cells against ototoxic insults and protected the cochlear function. AAV2-mediated Bcl-x(L) might be an approach with respect to potential therapeutic application in the cochlear degeneration.

PDX-MI: Minimal Information for Patient-Derived Tumor Xenograft Models.

Patient-derived tumor xenograft (PDX) mouse models have emerged as an important oncology research platform to study tumor evolution, mechanisms of drug response and resistance, and tailoring chemotherapeutic approaches for individual patients. The lack of robust standards for reporting on PDX models has hampered the ability of researchers to find relevant PDX models and associated data. Here we present the PDX models minimal information standard (PDX-MI) for reporting on the generation, quality assurance, and use of PDX models. PDX-MI defines the minimal information for describing the clinical attributes of a patient's tumor, the processes of implantation and passaging of tumors in a host mouse strain, quality assurance methods, and the use of PDX models in cancer research. Adherence to PDX-MI standards will facilitate accurate search results for oncology models and their associated data across distributed repository databases and promote reproducibility in research studies using these models. Cancer Res; 77(21); e62-66. ©2017 AACR.

Association of interferon regulatory factor-1, nucleophosmin, nuclear factor-kappaB, and cyclic AMP response element binding with acquired resistance to Faslodex (ICI 182,780).

To identify genes associated with survival from antiestrogens, both serial analysis of geneexpression and gene expression microarrays were used to explore the transcriptomes of antiestrogen-responsive (MCF7/LCC1) and -resistant variants(MCF7/LCC9) of the MCF-7 human breast cancer cell line. Structure of the gene microarray expression data was visualized at the top level using a novel algorithm that derives the first three principal components,fitted to the antiestrogen-resistant and -responsive gene expression data, from Fisher's information matrix. The differential regulation of several candidate genes was confirmed. Functional studies of the basal expression and endocrine regulation of transcriptional activation of implicated transcription factors were studied using promoter-reporter assays. The putative tumor suppressor interferon regulatory factor-1 is down-regulated in resistant cells, whereas its nucleolar phosphoprotein inhibitor nucleophosmin is up-regulated. Resistant cells also up-regulate the transcriptional activation of cyclic AMP response element (CRE) binding and nuclear factor kappaB (NFkappaB) while down-regulating epidermal growth factor receptor protein expression. Inhibition of NFkappaB activity by ICI 182,780 is lost in resistant cells, but CRE activity is not regulated by ICI 182,780 in either responsive or resistant cells. Parthenolide, a potent and specific inhibitor of NFkappaB, inhibits the anchorage-dependent proliferation of antiestrogen-resistant but not antiestrogen-responsive cells. This observation implies a greater reliance on their increased NFkappaB signaling for proliferation in cells that have survived prolonged exposure to ICI 182,780. These data from serial analysis of gene expression and gene microarray studies implicate changes in a novel signaling pathway, involving interferon regulatory factor-1, nucleophosmin, NFkappaB, and CRE binding in cell survival after antiestrogen exposure. Cells can up-regulate some estrogen-responsive genes while concurrently losing the ability of antiestrogens to regulate their expression. Signaling pathways that are not regulated by estrogens also can be up-regulated. Thus, some breast cancer cells may survive antiestrogen treatment by bypassing specific growth inhibitory signals induced by antagonist-occupied estrogen receptors.

Genetic changes found in a distinct clade of Enterovirus D68 associated with paralysis during the 2014 outbreak.

Enterovirus D68 (EV-D68) caused a severe respiratory illness outbreak in the United States in 2014. Reports of acute flaccid myelitis (AFM)/paralysis (AFP) in several independent epidemiological clusters of children with detectable EV-D68 have raised concerns that genetic changes in EV-D68 could be causing increased disease severity and neurological symptoms. To explore the potential link between EV-D68 genetic variations and symptom changes, we performed a series of comparative genomic analyses of EV-D68 2014 outbreak isolate sequences using data and analytical tools in the Virus Pathogen Resource (ViPR; www.viprbrc.org). Our results suggest that (1) three distinct lineages of EV-D68 were co-circulating in 2013 and 2014; (2) isolates associated with AFM/AFP belong to a single phylogenetic subclade - B1; (3) the majority of isolates from the B1 subclade have 21 unique substitutions that distinguish them from other isolates, including amino acid substitutions in the VP1, VP2, and VP3 capsid proteins and the 3D RNA-dependent RNA polymerase, and nucleotide substitutions in the internal ribosome entry sequence (IRES); (4) at 12 of these positions, B1 isolates carry the same residues observed at equivalent positions in paralysis-causing enteroviruses, including poliovirus, EV-D70 and EV-A71. Based on these results, we hypothesize that unique B1 substitutions may be responsible for the apparent increased incidence of neuropathology associated with the 2014 outbreak.

Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling.

Antiestrogens include agents such as tamoxifen, toremifene, raloxifene, and fulvestrant. Currently, tamoxifen is the only drug approved for use in breast cancer chemoprevention, and it remains the treatment of choice for most women with hormone receptor positive, invasive breast carcinoma. While antiestrogens have been available since the early 1970s, we still do not fully understand their mechanisms of action and resistance. Essentially, two forms of antiestrogen resistance occur: de novo resistance and acquired resistance. Absence of estrogen receptor (ER) expression is the most common de novo resistance mechanism, whereas a complete loss of ER expression is not common in acquired resistance. Antiestrogen unresponsiveness appears to be the major acquired resistance phenotype, with a switch to an antiestrogen-stimulated growth being a minor phenotype. Since antiestrogens compete with estrogens for binding to ER, clinical response to antiestrogens may be affected by exogenous estrogenic exposures. Such exposures include estrogenic hormone replacement therapies and dietary and environmental exposures that directly or indirectly increase a tumor's estrogenic environment. Whether antiestrogen resistance can be conferred by a switch from predominantly ERalpha to ERbeta expression remains unanswered, but predicting response to antiestrogen therapy requires only measurement of ERalpha expression. The role of altered receptor coactivator or corepressor expression in antiestrogen resistance also is unclear, and understanding their roles may be confounded by their ubiquitous expression and functional redundancy. We have proposed a gene network approach to exploring the mechanistic aspects of antiestrogen resistance. Using transcriptome and proteome analyses, we have begun to identify candidate genes that comprise one component of a larger, putative gene network. These candidate genes include NFkappaB, interferon regulatory factor-1, nucleophosmin, and the X-box binding protein-1. The network also may involve signaling through ras and MAPK, implicating crosstalk with growth factors and cytokines. Ultimately, signaling affects the expression/function of the proliferation and/or apoptotic machineries.