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Multi-omic studies on missense PLG variants in families with otitis media.Otitis media (OM), a very common disease in young children, can result in hearing loss. In order to potentially replicate previously reported associations between OM and PLG, exome and Sanger sequencing, RNA-sequencing of saliva and middle ear samples, 16S rRNA sequencing, molecular modeling, and statistical analyses including transmission disequilibrium tests (TDT) were performed in a multi-ethnic cohort of 718 families and simplex cases with OM. We identified four rare PLG variants c.112A > G (p.Lys38Glu), c.782G > A (p.Arg261His), c.1481C > T (p.Ala494Val) and c.2045 T > A (p.Ile682Asn), and one common variant c.1414G > A (p.Asp472Asn). However TDT analyses for these PLG variants did not demonstrate association with OM in 314 families. Additionally PLG expression is very low or absent in normal or diseased middle ear in mouse and human, and salivary expression and microbial α-diversity were non-significant in c.1414G > A (p.Asp472Asn) carriers. Based on molecular modeling, the novel rare variants particularly c.782G > A (p.Arg261His) and c.2045 T > A (p.Ile682Asn) were predicted to affect protein structure. Exploration of other potential disease mechanisms will help elucidate how PLG contributes to OM susceptibility in humans. Our results underline the importance of following up findings from genome-wide association through replication studies, preferably using multi-omic datasets.
No evidence of amplified Plasmodium falciparum plasmepsin II gene copy number in an area with artemisinin-resistant malaria along the China-Myanmar borderBACKGROUND: The emergence and spread of artemisinin resistance in Plasmodium falciparum poses a threat to malaria eradication, including China's plan to eliminate malaria by 2020. Piperaquine (PPQ) resistance has emerged in Cambodia, compromising an important partner drug that is widely used in China in the form of dihydroartemisinin (DHA)-PPQ. Several mutations in a P. falciparum gene encoding a kelch protein on chromosome 13 (k13) are associated with artemisinin resistance and have arisen spread in the Great Mekong subregion, including the China-Myanmar border. Multiple copies of the plasmepsin II/III (pm2/3) genes, located on chromosome 14, have been shown to be associated with PPQ resistance. METHODS: The therapeutic efficacy of DHA-PPQ for the treatment of uncomplicated P. falciparum was evaluated along the China-Myanmar border from 2010 to 2014. The dry blood spots samples collected in the efficacy study prior DHA-PPQ treatment and from the local hospital by passive detection were used to amplify k13 and pm2. Polymorphisms within k13 were genotyped by capillary sequencing and pm2 copy number was quantified by relative-quantitative real-time polymerase chain reaction. Treatment outcome was evaluated with the World Health Organization protocol. A linear regression model was used to estimate the association between the day 3 positive rate and k13 mutation and the relationship of the pm2 copy number variants and k13 mutations. RESULTS: DHA-PPQ was effective for uncomplicated P. falciparum infection in Yunnan Province with cure rates > 95%. Twelve non synonymous mutations in the k13 domain were observed among the 268 samples with the prevalence of 44.0% and the predominant mutation was F446I with a prevalence of 32.8%. Only one sample was observed with multi-copies of pm2, including parasites with and without k13 mutations. The therapeutic efficacy of DHA-PPQ was > 95% along the China-Myanmar border, consistent with the lack of amplification of pm2. CONCLUSION: DHA-PPQ for uncomplicated P. falciparum infection still showed efficacy in an area with artemisinin-resistant malaria along the China-Myanmar border. There was no evidence to show PPQ resistance by clinical study and molecular markers survey. Continued monitoring of the parasite population using molecular markers will be important to track emergence and spread of resistance in this region.
Retinoic Acid Improves the Recovery of Replication-Competent Virus from Latent SIV Infected CellsThe accurate estimation and eradication of Human Immunodeficiency Virus (HIV) viral reservoirs is limited by the incomplete reactivation of cells harboring the latent replication-competent virus. We investigated whether the in vitro and in vivo addition of retinoic acid (RA) enhances virus replication and improves the detection of latent virus. Peripheral blood mononuclear cells (PBMCs) from naive and anti-retroviral therapy (ART)-treated SIV-infected rhesus macaques (RMs) were cultured in vitro with anti-CD3/CD28 + IL-2 in the presence/absence of RA. Viral RNA and p27 levels were quantified using RT-qPCR and ELISA, respectively. Viral reservoirs were estimated using the Tat/Rev-Induced Limited Dilution Assay (TILDA) and Quantitative Viral Outgrowth Assay (QVOA). In vitro and in vivo measures revealed that there was also an increase in viral replication in RA-treated versus without RA conditions. In parallel, the addition of RA to either CD3/CD28 or phorbol myristate acetate (PMA)/ionomycin during QVOA and TILDA, respectively, was shown to augment reactivation of the replication-competent viral reservoir in anti-retroviral therapy (ART)-suppressed RMs as shown by a greater than 2.3-fold increase for QVOA and 1 to 2-fold increments for multi-spliced RNA per million CD4+ T cells. The use of RA can be a useful approach to enhance the efficiency of current protocols used for in vitro and potentially in vivo estimates of CD4+ T cell latent reservoirs. In addition, flow cytometry analysis revealed that RA improved estimates of various viral reservoir assays by eliciting broad CD4 T-cell activation as demonstrated by elevated CD25 and CD38 but reduced CD69 and PD-1 expressing cells.
Best Practices for Successfully Writing and Publishing a Genome Announcement in Microbiology Resource AnnouncementsMicrobiology Resource Announcements (MRA) provides peer-reviewed announcements of scientific resources for the microbial research community. We describe the best practices for writing an announcement that ensures that these publications are truly useful resources. Adhering to these best practices can lead to successful publication without the need for extensive revisions.
Sedation patterns and hyperosmolar therapy in emergency departments were associated with blood pressure variability and outcomes in patients with spontaneous intracranial hemorrhageBackground: Spontaneous intracranial hemorrhage (sICH) is associated with high mortality. Little information exists to guide initial resuscitation in the emergency department (ED) setting. However, blood pressure variability (BPV) and mechanical ventilation (MV) are known risk factors for poor outcome in sICH. Objectives: The objective was to examine the associations between BPV and MV in ED (EDMV) and between two ED interventions-post-MV sedation and hyperosmolar therapy for elevated intracranial pressure-and BPV in the ED and in-hospital mortality. Methods: We retrospectively studied adults with sICH and external ventricular drainage who were transferred to a quaternary academic medical center from other hospitals between January 2011 and September 2015. We used multivariable linear and logistic regressions to measure associations between clinical factors, BPV, and outcomes. Results: We analyzed ED records from 259 patients. There were 143 (55%) EDMV patients who had more severe clinical factors and significantly higher values of all BPV indices than NoEDMV patients. Two clinical factors and none of the severity scores (i.e., Hunt and Hess, World Federation of Neurological Surgeons Grades, ICH score) correlated with BPV. Hyperosmolarity therapy without fluid resuscitation positively correlated with all BPV indices, whereas propofol infusion plus a narcotic negatively correlated with one of them. Two BPV indices, i.e., successive variation of blood pressure (BPSV) and absolute difference in blood pressure between ED triage and departure (BPDepart-Triage), were significantly associated with increased mortality rate. Conclusion: Patients receiving MV had significantly higher BPV, perhaps related to disease severity. Good ED sedation, hyperosmolar therapy, and fluid resuscitation were associated with less BPV and lower likelihood of death.