Rapid Response to Mycophenolate Mofetil in Combination with Romiplostim in a Case of Severe Refractory Immune Thrombocytopenia Post COVID-19 Vaccination

Vaccine mediated immune mediated thrombocytopenia (ITP) is exceedingly rare. We present a case of a young female who developed severe refractory ITP with multiple bleeding sites post second dose of COVID-19 vaccination. She was treated with a combination of romiplostim and mycophenolate mofetil that resulted in rapid platelet count recovery

Challenges in Medicine: The Odyssey of a Patient with Isolated IgG4-Related Eosinophilic Angiocentric Fibrosis Presenting as a Locally Destructive Sinonasal Mass

Eosinophilic angiocentric fibrosis (EAF) is an exceeding rare clinical entity and is considered a part of the spectrum of IgG4-related disease (IgG4RD). We hereby present such an unusual case of a 60-year-old female who presented to us with recurrent sinonasal mass, after a decade long haul of multiple clinical evaluations, biopsies, and debulking surgery without a definitive diagnosis. Over this period, the mass eroded through the ethmoid cells along with nasal septal destruction leading to saddle nose deformity, extended superiorly through the cribriform plates to right frontal lobe, and compressed the optic nerve leading to visual loss. Although initial biopsy was negative, repeat biopsy was performed owing to high clinical suspicion due to all the classic histopathological findings compatible with the diagnosis of eosinophilic angiocentric fibrosis IgG4-related disease (EAF-IgG4RD). Steroids are the recommended first-line therapy; however, our case was resistant to steroids needing rituximab to halt the disease progression. Our case interestingly also had T-cell clonality and isolated isocitrate dehydrogenase 2 enzyme mutation on next-generation sequencing, suggesting a possible role of novel molecular-targeted therapies in this rare disease. This case highlights the clinical challenges physicians face towards diagnosing and treating EAF-IgG4RD, emphasizing the need for high clinical suspicion and the possible role of targeted therapies for this rare disease

Selection of chromosomal DNA libraries using a multiplex CRISPR system.

The directed evolution of biomolecules to improve or change their activity is central to many engineering and synthetic biology efforts. However, selecting improved variants from gene libraries in living cells requires plasmid expression systems that suffer from variable copy number effects, or the use of complex marker-dependent chromosomal integration strategies. We developed quantitative gene assembly and DNA library insertion into the Saccharomyces cerevisiae genome by optimizing an efficient single-step and marker-free genome editing system using CRISPR-Cas9. With this Multiplex CRISPR (CRISPRm) system, we selected an improved cellobiose utilization pathway in diploid yeast in a single round of mutagenesis and selection, which increased cellobiose fermentation rates by over 10-fold. Mutations recovered in the best cellodextrin transporters reveal synergy between substrate binding and transporter dynamics, and demonstrate the power of CRISPRm to accelerate selection experiments and discoveries of the molecular determinants that enhance biomolecule function

Dopamine dysregulation in the prefrontal cortex relates to cognitive deficits in the sub-chronic PCP-model for schizophrenia: a preliminary investigation

yesRationale: Dopamine dysregulation in the prefrontal cortex (PFC) plays an important role in cognitive dysfunction in schizophrenia. Sub-chronic phencyclidine (scPCP) treatment produces cognitive impairments in rodents and is a thoroughly validated animal model for cognitive deficits in schizophrenia. The aim of our study was to investigate the role of PFC dopamine in scPCP-induced deficits in a cognitive task of relevance to the disorder, novel object recognition (NOR). Methods: Twelve adult female Lister Hooded rats received scPCP (2 mg/kg) or vehicle via the intraperitoneal route twice daily for seven days, followed by seven days washout. In vivo microdialysis was carried out prior to, during and following the NOR task. Results: Vehicle rats successfully discriminated between novel and familiar objects and this was accompanied by a significant increase in dopamine in the PFC during the retention trial (P<0.01). scPCP produced a significant deficit in NOR (P<0.05 vs. control) and no PFC dopamine increase was observed. Conclusions: These data demonstrate an increase in dopamine during the retention trial in vehicle rats that was not observed in scPCP-treated rats accompanied by cognitive disruption in the scPCP group. This novel finding suggests a mechanism by which cognitive deficits are produced in this animal model and support its use for investigating disorders in which PFC dopamine is central to the pathophysiology

Genetic and functional analysis of HIV-1 Rev Responsive Element (RRE) sequences from North-India

HIV-1 Rev protein regulates the expression of HIV-1 transcripts by binding to a highly structured stem loop structure called the Rev Responsive Element (RRE) present in the genomic and partially spliced RNAs. Genetic variation in this structure is likely to affect binding of Rev protein and ultimately overall gene expression and replication. We characterized RRE sequences from 13 HIV-1 infected individuals from North India which also included two mother-child pairs following vertical transmission. We observed high degree of conservation of sequences, including the 9-nt (CACUAUGGG) long sequence in stem-loop B, required for efficient binding of Rev protein. All of our 13 RRE sequences possessed G to A (position 66) mutation located in the critical branched-stem-loop B which is not present in consensus C or B sequence. We derived a consensus RRE structure which showed interesting changes in the stem-loop structures including the stem-loop B. Mother-Child RRE sequences showed conservation of unique polymorphisms as well as some new mutations in child RRE sequences. Despite these changes, the ability to form multiple essential stem-loop structures required for Rev binding was conserved. RRE RNA derived from one of the samples, VT5, retained the ability to bind Rev protein under in vitro conditions although it showed alternate secondary structure. This is the first study from India describing the structural and possible functional implications due to very unique RRE sequence heterogeneity and its possible role in vertical transmission and gene expression

The Role and Therapeutic Potential of miRNAs in Colorectal Liver Metastasis

poster abstractColorectal cancer (CRC) is the third most common malignancy worldwide. Liver metastasis occurs in 60% of CRC patients and responds poorly to the available treatments making it the major cause of their mortality. MicroRNAs (miRNAs) are highly conserved, endogenously encoded small, non-coding RNA molecules that regulate global gene expression. The role of microRNAs in cancer pathogenesis, including CRC, has been well documented. However, in-depth miRNA expression analysis on a large cohort of CRC tumors is needed to identify the clinically relevant miRNAs and explore their potential to target liver metastases. To this purpose, we analyzed miRNA expression data of 406 CRC tumors from the publicly available colorectal cancer genome sequencing project and identified 58 miRNAs that were significantly downregulated. 10 miRNAs were selected for further analyses that were either known to target genes in cellular pathways or located within the commonly lost chromosomal loci associated with CRC liver metastases. Of these 10 miRNAs, miR-132, miR-378f, miR-605 and miR-1976 showed significant downregulation with >2 fold change (p>0.05) in primary and CRC liver metastasis tissues and in CRC cell lines. To investigate their anti-tumorigenic and metastatic properties, we transfected 3 different CRC cell lines (SW620, HCT-116 and CT-26) with miR-mimics and subjected them to cell proliferation, apoptosis and cell transformation assays. Ectopic expression of miR-378f, -605 and -1976 suppressed CRC cell proliferation, anchorage independent growth, migration and invasion and induced apoptosis. Interestingly, CRC patients with high miR-378f and miR-1976 had better survival compared to low expressing patients (p<0.044). Our in vitro data suggest the anti-tumorigenic/metastatic properties of miR-378f, -605 and -1976 in CRC. Further understanding of their functions and in vivo therapeutic evaluations may help in developing novel therapeutic strategies for this malignancy

Discovery and validation of molecular biomarkers for colorectal adenomas and cancer with application to blood testing

Results: Genome-wide analysis uncovered reproducible gene expression signatures for both adenomas and cancers compared to controls. 386/489 (79%) of the adenoma and 439/529 (83%) of the adenocarcinoma biomarkers were validated in independent tissues. We also identified genes differentially expressed in adenomas compared to cancer. KIAA1199 was selected for further analysis based on consistent up-regulation in neoplasia, previous studies and its interest as an uncharacterized gene. Plasma KIAA1199 RNA levels were significantly higher in patients with either cancer or adenoma (31/ 40) compared to neoplasia-free controls (6/20).This work was co-funded by Flinders University of South Australia and the Commonwealth Scientific and Industrial Research Organisation (CSIRO) of Australia. Drs. Dunne, Molloy and Brown are employed by CSIRO. These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding was also provided by Clinical Genomics Pty Ltd., a company involved in the discovery and commercialization of biomarkers for colorectal cancer. Drs. LaPointe, Pedersen, Gaur, McEvoy and Thomas are employed by Clinical Genomics Pty Ltd and Prof. Young is a paid consultant of Clinical Genomics Pty Ltd. The funder thus played roles in study design, data collection and analysis, decision to publish, and preparation of the manuscript. Mrs. Pimlott and Dr. Wattchow have nothing to disclose. This work was co-funded by Clinical Genomics Pty Ltd, a company involved in the discovery and commercialization of biomarkers for colorectal cancer. Drs. LaPointe, Pedersen, Gaur, McEvoy and Thomas are employed by Clinical Genomics Pty Ltd. Prof. Young is a paid consultant of Clinical Genomics Pty Ltd. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials

D1-like receptor activation improves PCP-induced cognitive deficits in animal models: Implications for mechanisms of improved cognitive function in schizophrenia

YesPhencyclidine (PCP) produces cognitive deficits of relevance to schizophrenia in animal models. The aim was to investigate the efficacy of the D1-like receptor agonist, SKF-38393, to improve PCPinduced deficits in the novel object recognition (NOR) and operant reversal learning (RL) tasks. Rats received either sub-chronic PCP (2 mg/kg) or vehicle for 7 days, followed by a 7-day washout. Rats were either tested in NOR or the RL tasks. In NOR, vehicle rats successfully discriminated between novel and familiar objects, an effect abolished in PCP-treated rats. SKF-38393 (6 mg/kg) significantly ameliorated the PCP-induced deficit (Pb0.01) an effect significantly antagonised by SCH-23390 (0.05 mg/kg), a D1-like receptor antagonist (Pb0.01). In the RL task sub-chronic PCP significantly reduced performance in the reversal phase (Pb0.001); SKF-38393 (6.0 mg/kg) improved this PCPinduced deficit, an effect antagonised by SCH-23390 (Pb0.05). These results suggest a role for D1-like receptors in improvement of cognitive function in paradigms of relevance to schizophrenia

Intergalactic UV Background Radiation Field

We have performed proximity effect analysis of low and high resolution data, considering detailed frequency and redshift dependence of the AGN spectra processed through galactic and intergalactic material. We show that such a background flux, calculated using the observed distribution of AGNs, falls short of the value required by the proximity effect analysis by a factor of $\ge$ 2.7. We have studied the uncertainty in the value of the required flux due to its dependence on the resolution, description of column density distribution, systemic redshifts of QSOs etc. We conclude that in view of these uncertainties the proximity effect is consistent with the background contributed by the observed AGNs and that the hypothesized presence of an additional, dust extinct, population of AGNs may not be necessary.Comment: To be published in the Journal of Astronomy and Astrophysics aasms, 2 figures, 2 tables. Paper replaced to include the figure

Day-night variation of acute myocardial infarction in obstructive sleep apnea.

OBJECTIVES: This study sought to evaluate the day-night variation of acute myocardial infarction (MI) in patients with obstructive sleep apnea (OSA). BACKGROUND: Obstructive sleep apnea has a high prevalence and is characterized by acute nocturnal hemodynamic and neurohormonal abnormalities that may increase the risk of MI during the night. METHODS: We prospectively studied 92 patients with MI for which the time of onset of chest pain was clearly identified. The presence of OSA was determined by overnight polysomnography. RESULTS: For patients with and without OSA, we compared the frequency of MI during different intervals of the day based on the onset time of chest pain. The groups had similar prevalence of comorbidities. Myocardial infarction occurred between 12 am and 6 am in 32% of OSA patients and 7% of non-OSA patients (p = 0.01). The odds of having OSA in those patients whose MI occurred between 12 am and 6 am was 6-fold higher than in the remaining 18 h of the day (95% confidence interval: 1.3 to 27.3, p = 0.01). Of all patients having an MI between 12 am and 6 am, 91% had OSA. CONCLUSIONS: The diurnal variation in the onset of MI in OSA patients is strikingly different from the diurnal variation in non-OSA patients. Patients with nocturnal onset of MI have a high likelihood of having OSA. These findings suggest that OSA may be a trigger for MI. Patients having nocturnal onset of MI should be evaluated for OSA, and future research should address the effects of OSA therapy for prevention of nocturnal cardiac events