Lymph Node Colonization Dynamics after Oral Salmonella Typhimurium Infection in Mice

An understanding of how pathogens colonize their hosts is crucial for the rational design of vaccines or therapy. While the molecular factors facilitating the invasion and systemic infection by pathogens are a central focus of research in microbiology, the population biological aspects of colonization are still poorly understood. Here, we investigated the early colonization dynamics of Salmonella enterica subspecies 1 serovar Typhimurium (S. Tm) in the streptomycin mouse model for diarrhea. We focused on the first step on the way to systemic infection - the colonization of the cecal lymph node (cLN) from the gut - and studied roles of inflammation, dendritic cells and innate immune effectors in the colonization process. To this end, we inoculated mice with mixtures of seven wild type isogenic tagged strains (WITS) of S. Tm. The experimental data were analyzed with a newly developed mathematical model describing the stochastic immigration, replication and clearance of bacteria in the cLN. We estimated that in the beginning of infection only 300 bacterial cells arrive in the cLN per day. We further found that inflammation decreases the net replication rate in the cLN by 23%. In ccr7-/- mice, in which dendritic cell movement is impaired, the bacterial migration rate was reduced 10-fold. In contrast, cybb-/- mice that cannot generate toxic reactive oxygen species displayed a 4-fold higher migration rate from gut to cLN than wild type mice. Thus, combining infections with mixed inocula of barcoded strains and mathematical analysis represents a powerful method for disentangling immigration into the cLN from replication in this compartment. The estimated parameters provide an important baseline to assess and predict the efficacy of interventions. © 2013 Kaiser et al.

Cecum lymph node dendritic cells harbor slow-growing bacteria phenotypically tolerant to antibiotic treatment.

In vivo, antibiotics are often much less efficient than ex vivo and relapses can occur. The reasons for poor in vivo activity are still not completely understood. We have studied the fluoroquinolone antibiotic ciprofloxacin in an animal model for complicated Salmonellosis. High-dose ciprofloxacin treatment efficiently reduced pathogen loads in feces and most organs. However, the cecum draining lymph node (cLN), the gut tissue, and the spleen retained surviving bacteria. In cLN, approximately 10%-20% of the bacteria remained viable. These phenotypically tolerant bacteria lodged mostly within CD103⁺CX₃CR1⁻CD11c⁺ dendritic cells, remained genetically susceptible to ciprofloxacin, were sufficient to reinitiate infection after the end of the therapy, and displayed an extremely slow growth rate, as shown by mathematical analysis of infections with mixed inocula and segregative plasmid experiments. The slow growth was sufficient to explain recalcitrance to antibiotics treatment. Therefore, slow-growing antibiotic-tolerant bacteria lodged within dendritic cells can explain poor in vivo antibiotic activity and relapse. Administration of LPS or CpG, known elicitors of innate immune defense, reduced the loads of tolerant bacteria. Thus, manipulating innate immunity may augment the in vivo activity of antibiotics.

A Novel 4T nMOS-Only SRAM Cell in 32nm Technology Node

This paper proposes a novel loadless 4T SRAM cell composed of nMOS transistors. The SRAM cell is based on 32nm silicon-on-insulator （SO1） technology node. It consists of two access transistors and two pull-down transistors. The pull-down transistors have larger channel length than the access transistors. Due to the significant short channel effect of small-size MOS transistors, the access transistors have much larger leakage current than the pull-down transistors,enabling the SRAM cell to maintain logic ＂1＂ while in standby. The storage node voltages of the cell are fed back to the back-gates of the access transistors,enabling the stable ＂read＂ operation of the cell. The use of back-gate feedback also helps to im- prove the static noise margin （SNM） of the cell. The proposed SRAM cell has smaller area than conventional bulk 6T SRAM cells and 4T SRAM cells. The speed and power dissipation of the SRAM cell are simulated and discussed. The SRAM cell can operate with a 0. 5V supply voltage.

A Coupled Multi-ALU Processing Node for a Highly Parallel Computer

This report describes Processor Coupling, a mechanism for controlling multiple ALUs on a single integrated circuit to exploit both instruction-level and inter-thread parallelism. A compiler statically schedules individual threads to discover available intra-thread instruction-level parallelism. The runtime scheduling mechanism interleaves threads, exploiting inter-thread parallelism to maintain high ALU utilization. ALUs are assigned to threads on a cycle byscycle basis, and several threads can be active concurrently. Simulation results show that Processor Coupling performs well both on single threaded and multi-threaded applications. The experiments address the effects of memory latencies, function unit latencies, and communication bandwidth between function units.

Wireless sensor node design for heterogeneous networks

Two complementary wireless sensor nodes for building two-tiered heterogeneous networks are presented. A larger node with a 25 mm by 25 mm size acts as the backbone of the network, and can handle complex data processing. A smaller, cheaper node with a 10 mm by 10 mm size can perform simpler sensor-interfacing tasks. The 25mm node is based on previous work that has been done in the Tyndall National Institute that created a modular wireless sensor node. In this work, a new 25mm module is developed operating in the 433/868 MHz frequency bands, with a range of 3.8 km. The 10mm node is highly miniaturised, while retaining a high level of modularity. It has been designed to support very energy efficient operation for applications with low duty cycles, with a sleep current of 3.3 μA. Both nodes use commercially available components and have low manufacturing costs to allow the construction of large networks. In addition, interface boards for communicating with nodes have been developed for both the 25mm and 10mm nodes. These interface boards provide a USB connection, and support recharging of a Li-ion battery from the USB power supply. This paper discusses the design goals, the design methods, and the resulting implementation.

A feasibility study evaluating docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer

BACKGROUND AND PURPOSE: Docetaxel is an active agent in the treatment of metastatic breast cancer. We evaluated the feasibility of docetaxel-based sequential and combination regimens as adjuvant therapies for patients with node-positive breast cancer. PATIENTS AND METHODS: Three consecutive groups of patients with node-positive breast cancer or locally-advanced disease, aged < or = 70 years, received one of the following regimens: a) sequential A-->T-->CMF: doxorubicin 75 mg/m2 q 3 weeks x 3, followed by docetaxel 100 mg/m2 q 3 weeks x 3, followed by i.v. CMF days 1 + 8 q 4 weeks x 3; b) sequential accelerated A-->T-->CMF: A and T were administered at the same doses q 2 weeks; c) combination therapy: doxorubicin 50 mg/m2 + docetaxel 75 mg/m2 q 3 weeks x 4, followed by CMF x 4. When indicated, radiotherapy was administered during or after CMF, and tamoxifen started after the end of CMF. RESULTS: Seventy-nine patients have been treated. Median age was 48 years. A 30% rate of early treatment discontinuation was observed in patients receiving the sequential accelerated therapy (23% during A-->T), due principally to severe skin toxicity. Median relative dose-intensity was 100% in the three treatment arms. The incidence of G3-G4 major toxicities by treated patients, was as follows: skin toxicity a: 5%; b: 27%; c: 0%; stomatitis a: 20%; b: 20%; c: 3%. The incidence of neutropenic fever was a: 30%; b: 13%; c: 48%. After a median follow-up of 18 months, no late toxicity has been reported. CONCLUSIONS: The accelerated sequential A-->T-->CMF treatment is not feasible due to an excess of skin toxicity. The sequential non accelerated and the combination regimens are feasible and under evaluation in a phase III trial of adjuvant therapy.

3-year results of docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer: a pilot study.

BACKGROUND: Docetaxel has proven efficacy in metastatic breast cancer. In this pilot study, we explored the efficacy/feasibility of docetaxel-based sequential and combination regimens as adjuvant therapy of node-positive breast cancer. PATIENTS AND METHODS: From March 1996 till March 1998, four consecutive groups of patients with stages II and III breast cancer, aged < or = 70 years, received one of the following regimens: a) sequential Doxorubicin (A) --> Docetaxel (T) --> CMF (Cyclophosphamide+Methotrexate+5-Fluorouracil): A 75 mg/m q 3 wks x 3, followed by T100 mg/m2 q 3 wks x 3, followed by i.v. CMF Days 1+8 q 4 wks x 3; b) sequential accelerated A --> T --> CMF: A and T administered at the same doses q 2 wks with Lenograstin support; c) combination therapy: A 50 mg/m2 + T 75 mg/m2 q 3 wks x 4, followed by CMF x 4; d) sequential T --> A --> CMF: T and A, administered as in group a), with the reverse sequence. When indicated, radiotherapy was administered during or after CMF, and Tamoxifen after CMF. RESULTS: Ninety-three patients were treated. The median age was 48 years (29-66) and the median number of positive axillary nodes was 6 (1-25). Tumors were operable in 94% and locally advanced in 6% of cases. Pathological tumor size was >2 cm in 72% of cases. There were 21 relapses, (18 systemic, 3 locoregional) and 11 patients (12%) have died from disease progression. At median follow-up of 39 months (6-57), overall survival (OS) was 87% (95% CI, 79-94%) and disease-free survival (DFS) was 76% (95% CI, 67%-85%). CONCLUSION: The efficacy of these docetaxel-based regimens, in terms of OS and DFS, appears to be at least as good as standard anthracycline-based adjuvant chemotherapy (CT), in similar high-risk patient populations.

Diminishment of respiratory sinus arrhythmia foreshadows doxorubicin-induced cardiomyopathy.

BACKGROUND: The development of a microcomputer-based device permits quick, simple, and noninvasive quantification of the respiratory sinus arrhythmia (RSA) during quiet breathing. METHODS AND RESULTS: We prospectively and serially measured the radionuclide left ventricular ejection fraction and the RSA amplitude in 34 cancer patients receiving up to nine monthly bolus treatments with doxorubicin hydrochloride (60 mg/m2). Of the eight patients who ultimately developed symptomatic doxorubicin-induced congestive heart failure, seven (87.5%) demonstrated a significant decline in RSA amplitude; five of 26 subjects without clinical symptoms of cardiotoxicity (19.2%) showed a similar RSA amplitude decline. On average, significant RSA amplitude decline occurred 3 months before the last planned doxorubicin dose in patients destined to develop clinical congestive heart failure. CONCLUSION: Overall, RSA amplitude abnormality proved to be a more specific predictor of clinically significant congestive heart failure than did serial resting radionuclide ejection fractions.

A critical examination of node-similarity based graph matching algorithms

In this paper, we shall critically examine a special class of graph matching algorithms that follow the approach of node-similarity measurement. A high-level algorithm framework, namely node-similarity graph matching framework (NSGM framework), is proposed, from which, many existing graph matching algorithms can be subsumed, including the eigen-decomposition method of Umeyama, the polynomial-transformation method of Almohamad, the hubs and authorities method of Kleinberg, and the kronecker product successive projection methods of Wyk, etc. In addition, improved algorithms can be developed from the NSGM framework with respects to the corresponding results in graph theory. As the observation, it is pointed out that, in general, any algorithm which can be subsumed from NSGM framework fails to work well for graphs with non-trivial auto-isomorphism structure.

Dynamics and Function of Langerhans Cells In Vivo: Dermal Dendritic Cells Colonize Lymph Node Areas Distinct from Slower Migrating Langerhans Cells

Langerhans cells (LCs) are prominent dendritic cells (DCs) in epithelia, but their role in immunity is poorly defined. To track and discriminate LCs from dermal DCs in vivo, we developed knockin mice expressing enhanced green fluorescent protein (EGFP) under the control of the langerin (CD207) gene. By using vital imaging, we showed that most EGFP(+) LCs were sessile under steady-state conditions, whereas skin inflammation induced LC motility and emigration to lymph nodes (LNs). After skin immunization, dermal DCs arrived in LNs first and colonized areas distinct from slower migrating LCs. LCs reaching LNs under steady-state or inflammatory conditions expressed similar levels of costimulatory molecules. Langerin and EGFP were also expressed on thymic DCs and on blood-derived, CD8alpha(+) DCs from all secondary lymphoid organs. By using a similar knockin strategy involving a diphtheria toxin receptor (DTR) fused to EGFP, we demonstrated that LCs were dispensable for triggering hapten-specific T cell effectors through skin immunization.

Parameter sensitivity for optimal design of 65 nm node SOI transistors

Mixed-mode simulation, where device simulation is embedded directly within a circuit simulator, is used for the first time to provide scaling guidelines to achieve optimal digital circuit performance for double gate SOI MOSFETs. This significant advance overcomes the lack of availability of SPICE model parameters. The sensitivity of the gate delay and on-off current ratio to each of the key geometric and technological parameters of the transistor is quantified. The impact of the source-drain doping profile on circuit performance is comprehensively investigated.