Enhancement of Bordetella parapertussis infection by Bordetella pertussis in mixed infection of the respiratory tract

The epidemiological and pathogenic relationship between Bordetella pertussis and Bordetella parapertussis, the two causes of whooping cough (pertussis), is unclear. We hypothesized that B. pertussis, due to its immunosuppressive activities, might enhance B. parapertussis infection when the two species were present in a coinfection of the respiratory tract. The dynamics of this relationship were examined using the mouse intranasal inoculation model. Infection of the mouse respiratory tract by B. parapertussis was not only enhanced by the presence of B. pertussis, but B. parapertussis significantly outcompeted B. pertussis in this model. Staggered inoculation of the two organisms revealed that the advantage for B. parapertussis is established at an early stage of infection. Coadministration of PT enhanced B. parapertussis single infection, but had no effect on mixed infections. Mixed infection with a PT-deficient B. pertussis strain did not enhance B. parapertussis infection. Interestingly, the depletion of airway macrophages reversed the competitive relationship between these two organisms, but the depletion of neutrophils had no effect on mixed infection or B. parapertussis infection. We conclude that B. pertussis, through the action of PT, can enhance a B. parapertussis infection, possibly by an inhibitory effect on innate immunity.     

Use of a multiethnic approach to identify rheumatoid- arthritis-susceptibility loci, 1p36 and 17q12

We have previously shown that rheumatoid arthritis (RA) risk alleles overlap between different ethnic groups. Here, we utilize a multiethnic approach to show that we can effectively discover RA risk alleles. Thirteen putatively associated SNPs that had not yet exceeded genome-wide significance (p < 5 × 10(-8)) in our previous RA genome-wide association study (GWAS) were analyzed in independent sample sets consisting of 4,366 cases and 17,765 controls of European, African American, and East Asian ancestry. Additionally, we conducted an overall association test across all 65,833 samples (a GWAS meta-analysis plus the replication samples). Of the 13 SNPs investigated, four were significantly below the study-wide Bonferroni corrected p value threshold (p < 0.0038) in the replication samples. Two SNPs (rs3890745 at the 1p36 locus [p = 2.3 × 10(-12)] and rs2872507 at the 17q12 locus [p = 1.7 × 10(-9)]) surpassed genome-wide significance in all 16,659 RA cases and 49,174 controls combined. We used available GWAS data to fine map these two loci in Europeans and East Asians, and we found that the same allele conferred risk in both ethnic groups. A series of bioinformatic analyses identified TNFRSF14-MMEL1 at the 1p36 locus and IKZF3-ORMDL3-GSDMB at the 17q12 locus as the genes most likely associated with RA. These findings demonstrate empirically that a multiethnic approach is an effective strategy for discovering RA risk loci, and they suggest that combining GWASs across ethnic groups represents an efficient strategy for gaining statistical power.     

Inhibition of tristetraprolin deadenylation by poly(A) binding protein

Tristetraprolin (TTP) is the prototype for a family of RNA binding proteins that bind the tumor necrosis factor (TNF) messenger RNA AU-rich element (ARE), causing deadenylation of the TNF poly(A) tail, RNA decay, and silencing of TNF protein production. Using mass spectrometry sequencing we identified poly(A) binding proteins-1 and -4 (PABP1 and PABP4) in high abundance and good protein coverage from TTP immunoprecipitates. PABP1 significantly enhanced TNF ARE binding by RNA EMSA and prevented TTP-initiated deadenylation in an in vitro macrophage assay of TNF poly(A) stability. Neomycin inhibited TTP-promoted deadenylation at concentrations shown to inhibit the deadenylases poly(A) ribonuclease and CCR4. Stably transfected RAW264.7 macrophages overexpressing PABP1 do not oversecrete TNF; instead they upregulate TTP protein without increasing TNF protein production. The PABP1 inhibition of deadenylation initiated by TTP does not require the poly(A) binding regions in RRM1 and RRM2, suggesting a more complicated interaction than simple masking of the poly(A) tail from a 3'-exonuclease. Like TTP, PABP1 is a substrate for p38 MAP kinase. Finally, PABP1 stabilizes cotransfected TTP in 293T cells and prevents the decrease in TTP levels seen with p38 MAP kinase inhibition. These findings suggest several levels of functional antagonism between TTP and PABP1 that have implications for regulation of unstable mRNAs like TNF.     

Thiosemicarbazones active against Clostridium difficile

A set of closely related furylidene thiosemicarbazones was prepared and screened against various clinically important Gram-positive bacteria. One compound containing an ethylene spacer and a 5-nitrofuryl group was found to have promising activity against Clostridium difficile.     

Human platelet vasopressin receptors

Specific saturable binding of 125I-arginine-vasopressin to human platelets is described. For ten normal volunteers the mean (+/- S.D.) KD is 5.6 nM (+/- 2.1) and the mean (+/- S.D.) Bmax is 115 fmoles/mg protein (+/- 30). Association studies indicate that equilibrium is reached after 90 minutes on ice. Pharmacological inhibition studies with analogues indicate that the platelet receptor is very similar to the kidney medulla receptor. The function of the receptor may involve serotonin release and platelet aggregation. Vasopressin binding to platelets should provide a readily means of assessing vasopressin receptor function in man.     

The developmental high wire: Balancing resource investment in immunity and reproduction

The strategic allocation of resources into immunity poses a unique challenge for individuals, where infection at different stages of development may result in unique trade‐offs with concurrent physiological processes or future fitness‐enhancing traits. Here, we experimentally induced an immune challenge in female Gryllus firmus crickets to test whether illness at discrete life stages differentially impacts fitness. We injected heat‐killed Serratia marcescens bacteria into antepenultimate juveniles, penultimate juveniles, sexually immature adults, and sexually mature adults, and then measured body growth, instar duration, mating rate, viability of stored sperm, egg production, oviposition rate, and egg viability. Immune activation significantly impacted reproductive traits, where females that were immune challenged as adults had decreased mating success and decreased egg viability compared to healthy individuals or females that were immune challenged as juveniles. Although there was no effect of an immune challenge on the other traits measured, the stress of handling resulted in reduced mass gain and smaller adult body size in females from the juvenile treatments, and females in the adult treatments suffered from reduced viability of sperm stored within their spermatheca. In summary, we found that an immune challenge does have negative impacts on reproduction, but also that even minor acute stressors can have significant impacts on fitness‐enhancing traits. These findings highlight that the factors affecting fitness can be complex and at times unpredictable, and that the consequences of illness are specific to when during an individual''s life an immune challenge is induced.     

用抗性筛选法选育γ—亚麻酸（GLA）高产菌株

以深黄被孢霉（Mortierella isabellina）为出发菌株,经紫外线诱变处理,采用抗性筛选法,直接在梯度平板上挑选取抗脂肪酸脱氢酶抑制物抑芽丹（maleic hydrazide）的菌株进行初筛,然后经摇瓶发酵法测定相关性能指标进行得筛,获得一株生产性能比出发菌株显提高的突变株M80,其菌体收率达25.10g/L、油脂产率达12.35g/L、γ-亚麻酸（GLA）产率达771.88mg/L。