Enterotoxigenic Escherichia coli (ETEC) strains, which colonize host small intestines and produce one or more enterotoxins, are a major cause of diarrheal disease (40). ETEC strains are responsible for hundreds of thousands of deaths each year worldwide, in addition to causing over one billion diarrheal episodes in immunocompromised individuals, international travelers, and deployed military personnel (14,33,38). The virulence determinants of ETEC in diarrhea disease are bacterial adhesins (colonization factor antigens [CFAs] and E. coli surface antigens) and enterotoxins known as heatlabile (LT) and heat-stable (ST) toxins (5,13,26,38,41). ETEC adhesins mediate initial bacterial attachment to host epithelial cells and subsequent colonization of small intestines. LT and ST type I (STa) enterotoxins disrupt fluid homeostasis and cause hypersecretion of fluid and electrolytes through activation of adenylate cyclase (by LT) or guanylate cyclase (by STa) in host small intestinal epithelial cells. Epidemiological and clinical studies indicated that approximately one-half of the ETEC strains isolated from diarrheal patients produce STa toxin only, one-quarter express LT toxin only, and one-quarter produce both toxins (13, 30,
Diarrhea is the second leading cause of death to young children. Enterotoxigenic Escherichia coli (ETEC) are the most common bacteria causing diarrhea. Adhesins and enterotoxins are the virulence determinants in ETEC diarrhea. Adhesins mediate bacterial attachment and colonization, and enterotoxins including heat-labile (LT) and heat-stable type Ib toxin (STa) disrupt fluid homeostasis in host cells that leads to fluid hyper-secretion and diarrhea. Thus, adhesins and enterotoxins have been primarily targeted in ETEC vaccine development. A recent study reported toxoid fusions with STa toxoid (STaP13F) fused at the N- or C-terminus, or inside the A subunit of LTR192G elicited neutralizing antitoxin antibodies, and suggested application of toxoid fusions in ETEC vaccine development (Liu et al., Infect. Immun. 79:4002-4009, 2011). In this study, we generated a different STa toxoid (STaA14Q) and a triple-mutant LT toxoid (LTS63K/R192G/L211A, tmLT), constructed a toxoid fusion (3xSTaA14Q-tmLT) that carried 3 copies of STaA14Q for further facilitation of anti-STa immunogenicity, and assessed antigen safety and immunogenicity in a murine model to explore its potential for ETEC vaccine development. Mice immunized with this fusion antigen showed no adverse effects, and developed antitoxin antibodies particularly through the IP route. Anti-LT antibodies were detected and were shown neutralizing against CT in vitro. Anti-STa antibodies were also detected in the immunized mice, and serum from the IP immunized mice neutralized STa toxin in vitro. Data from this study indicated that toxoid fusion 3xSTaA14Q-tmLT is safe and can induce neutralizing antitoxin antibodies, and provided helpful information for vaccine development against ETEC diarrhea.
Decoherence due to charge noise is one of the central challenges in using spin qubits in semiconductor quantum dots as a platform for quantum information processing. Recently, it has been experimentally demonstrated in both Si and GaAs singlet-triplet qubits that the effects of charge noise can be suppressed if qubit operations are implemented using symmetric barrier control instead of the standard tilt control. Here, we investigate the key issue of whether the benefits of barrier control persist over the entire set of single-qubit gates by performing randomized benchmarking simulations. We find the surprising result that the improvement afforded by barrier control depends sensitively on the amount of spin noise: for the minimal nuclear spin noise levels present in Si, the coherence time improves by more than 2 orders of magnitude whereas in GaAs, by contrast the coherence time is essentially the same for barrier and tilt control. However, we establish that barrier control becomes beneficial if qubit operations are performed using a new family of composite pulses that reduce gate times by up to 90%. With these optimized pulses, barrier control is the best way to achieve high-fidelity quantum gates in singlet-triplet qubits.
To develop a piglet model for studying diarrheal disease and developing vaccines, we challenged gnotobiotic piglets with isogenic Escherichia coli strains constructed to express porcine 987P(F6) fimbriae and a heat-labile or a heat-stable enterotoxin to examine clinical outcomes. Piglets developed identical diarrheal diseases when inoculated with constructs expressing human or porcine enterotoxins.Enterotoxigenic Escherichia coli (ETEC) strains that colonize the small intestines and produce enterotoxins are the major cause of diarrheal disease in humans and animals (15,29,35,36). The key virulence factors of ETEC in diarrhea include enterotoxins and colonization factor antigens or fimbriae. These colonization factor antigens or fimbriae mediate attachment of bacteria to host epithelium cells and facilitate bacterial colonization. Enterotoxins stimulate fluid secretion in the intestinal lumens, which results in diarrhea. The pathogenesis of ETEC-associated diarrhea has been extensively studied. However, significant progress toward disease prevention is still lacking, partially because most investigators lack a suitable animal model with which to study host-pathogen interactions and to develop prevention strategies.Human subjects, especially highly susceptible young children, have to be excluded from diarrheal studies due to a higher level of risks. Challenge studies with adult human volunteers have been limited and have provided insufficient data to critically assess the contribution of each ETEC virulence determinant (9,18,31). It is therefore necessary to employ animal models to study ETEC pathogenicity and to develop prevention strategies. Mouse and rabbit models have been used to assess the pathology of ETEC enterotoxins (6,14,17,20,22,27). However, mice are not naturally susceptible to ETEC, and fundamental differences in the pathogenicities of ETEC in mice and in humans exist, including the ability to sufficiently adhere to human but not mouse intestinal epithelium. In addition, after being orally inoculated with a human diarrheagenic ETEC strain, mice did not develop diarrhea or become dehydrated and had a significantly low colonization of the ETEC strain in their small intestines (1). A mouse model may have limited value for the study of ETEC, particularly with regard to the study of immune development. Similar to mice, rabbits are not susceptible to ETEC strains. Thus, a rabbit model has the same limitation as a mouse model and is not suitable for studying ETEC diarrhea.In contrast to mice and rabbits, young pigs that express receptors of ETEC adhesins are naturally susceptible to diarrheagenic porcine ETEC strains (11,13,39). Infected young pigs develop typical diarrhea and may become dehydrated (3, 32, 38), similar to clinical outcomes of human diarrheic patients. The similarity between porcine and human ETEC infections in pathogenesis and clinical outcomes suggests that young pigs would be a good model to study human ETEC diarrhea. However, the heat-labile (LT) and heat-stable (ST) enterotoxins produc...
Background Bordetella pertussis colonizes the human respiratory mucosa. Most studies on B. pertussis adherence have relied on cultured mammalian cells that lack key features present in differentiated human airway cells or on animal models that are not natural hosts of B. pertussis. The objectives of this work are to evaluate B. pertussis infection on highly differentiated human airway cells in vitro and to show the role of B. pertussis fimbriae in cell adherence. Methods Primary human airway epithelial (PHAE) cells from human bronchi and a human bronchial epithelial (HBE) cell line were grown in vitro under air-liquid interface conditions. Results PHAE and HBE cells infected with B. pertussis wild type strain revealed bacterial adherence to cell’s apical surface and bacterial induced cytoskeleton changes and cell detachment. Mutations in the major fimbrial subunits Fim2/3 or in the minor fimbrial adhesin subunit FimD affected B. pertussis adherence to predominantly HBE cells. This cell model recapitulates the morphologic features of the human airway infected by B. pertussis and confirms the role of fimbriae in B. pertussis adherence. Furthemore, HBE cells show that fimbrial subunits, and specifically FimD adhesin, are critical in B. pertussis adherence to airway cells. Conclusions The relevance of this model to study host-parasite interaction in pertussis lies in the striking physiologic and morphologic similarity between the PHAE and HBE cells and the human airway ciliated and goblet cells in vivo. These cells can proliferate in vitro, differentiate, and express the same genetic profile as human respiratory cells in vivo.
We present a set of experimentally feasible pulse sequences that implement any single-qubit gate on a singlet-triplet spin qubit and demonstrate that these new sequences are up to three times faster than existing sequences in the literature. We show that these sequences can be extended to incorporate built-in dynamical error correction, yielding gates that are robust to both charge and magnetic field noise and up to twice as fast as previous dynamically corrected gate schemes. We present a thorough comparison of the performance of our new sequences with that of several existing ones using randomized benchmarking, considering both quasistatic and 1/f α noise models. We provide our results both as a function of evolution time and as a function of the number of gates, which respectively yield both an effective coherence time and an estimate of the number of gates that can be performed within this coherence time. We determine which set of pulse sequences gives the best results for a wide range of noise strengths and power spectra. Overall, we find that the traditional, slower sequences perform best when there is no field noise or when the noise contains significant high-frequency components; otherwise, our new, fast sequences exhibit the best performance.
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