Deregulation of transition metals homeostasis is a key feature of cadmium toxicity in Salmonella

Cadmium is a highly toxic metal whose presence in the environment represents a challenge for all forms of life. To improve our knowledge on cadmium toxicity, we have explored Salmonella Typhimurium responses to this metal. We have found that cadmium induces the concomitant expression of the cation efflux pump ZntA and of the high affinity zinc import system ZnuABC. This observation suggests that cadmium accumulation within the cell induces a condition of apparent zinc starvation, possibly due to the ability of this metal to compete with zinc for the metal binding site of proteins. This hypothesis is supported by the finding that strains lacking ZntA or ZnuABC are hyper-susceptible to cadmium and that the cadmium-induced growth defect of a znuABC mutant strain is largely relieved by zinc supplementation. A similar growth defect was observed for a mutant with impaired ability to acquire iron, whereas cadmium does not affect growth of a strain defective in manganese import. Cadmium also influences the expression and activity of the two cytoplasmic superoxide dismutases FeSOD and MnSOD, which are required to control cadmium-mediate oxidative stress. Exposure to cadmium causes a reduction of FeSOD activity in Salmonella wild type and the complete abrogation of its expression in the strain defective in iron import. In contrast, although MnSOD intracellular levels increase in response to cadmium, we observed discrepancies between protein levels and enzymatic activity which are suggestive of incorporation of non-catalytic metals in the active site or to cadmium-mediated inhibition of manganese import. Our results indicate that cadmium interferes with the ability of cells to manage transition metals and highlight the close interconnections between the homeostatic mechanisms regulating the intracellular levels of different metals

Competition for zinc binding in the host-pathogen interaction

Due to its favorable chemical properties, zinc is used as a structural or catalytic cofactor in a very large number of proteins. Despite the apparent abundance of this metal in all cell types, the intracellular pool of loosely bound zinc ions available for biological exchanges is in the picomolar range and nearly all zinc is tightly bound to proteins. In addition, to limit bacterial growth, some zinc-sequestering proteins are produced by eukaryotic hosts in response to infections. Therefore, to grow and multiply in the infected host, bacterial pathogens must produce high affinity zinc importers, such as the ZnuABC transporter which is present in most Gram-negative bacteria. Studies carried in different bacterial species have established that disruption of ZnuABC is usually associated with a remarkable loss of pathogenicity. The critical involvement of zinc in a plethora of metabolic and virulence pathways and the presence of very low number of zinc importers in most bacterial species mark zinc homeostasis as a very promising target for the development of novel antimicrobial strategies

APENet: LQCD clusters a la APE

Developed by the APE group, APENet is a new high speed, low latency, 3-dimensional interconnect architecture optimized for PC clusters running LQCD-like numerical applications. The hardware implementation is based on a single PCI-X 133MHz network interface card hosting six indipendent bi-directional channels with a peak bandwidth of 676 MB/s each direction. We discuss preliminary benchmark results showing exciting performances similar or better than those found in high-end commercial network systems.Comment: Lattice2004(machines), 3 pages, 4 figure

A comparison between interparticle forces estimated with direct powder shear testing and with sound assisted fluidization

Understanding the role of the interparticle forces in fluidization of cohesive powders is crucial for a proper application of fluidization to these type of powders. However, a direct measure of the interparticle interactions (IPFs) is challenging, mainly because cohesive particles cannot be fluidized under ordinary conditions. That is the reason why IPFs are typically measured using a rheological approach. The aim of this study is, therefore, to evaluate the IPFs of cohesive powders under actual fluidization conditions, by using an experimental and theoretical approach. In particular, a sound assisted fluidized bed apparatus was used to achieve a fluidization regime of the particles. Then, the cluster/subcluster model was applied to calculate IPFs, starting from the experimental data. The obtained IPFs were then compared to those evaluated by using a shear testing approach

The ZupT transporter plays an important role in zinc homeostasis and contributes to Salmonella enterica virulence

Zinc is an essential metal for cellular homeostasis and function in both eukaryotes and prokaryotes. To acquire this essential nutrient, bacteria employ transporters characterized by different affinity for the metal. Several studies have investigated the role of the high affinity transporter ZnuABC in the bacterial response to zinc shortage, showing that this transporter has a key role in adapting bacteria to zinc starvation. In contrast, the role of the low affinity zinc importer ZupT has been the subject of limited investigations. Here we show that a Salmonella strain lacking ZupT is impaired in its ability to grow in metal devoid environments and that a znuABC zupT strain exhibits a severe growth defect in zinc devoid media, is hypersensitive to oxidative stress and contains reduced levels of intracellular free zinc. Moreover, we show that ZupT also plays a role in the ability of S. Typhimurium to colonize the host tissues. During systemic infections, the single zupT mutant strain was attenuated only in Nramp1(+/+) mice, but competition experiments between znuABC and znuABC zupT mutants revealed that ZupT contributes to metal uptake in vivo independently of the presence of a functional Nramp1 transporter. Altogether, the here reported results show that ZupT plays an important role in Salmonella zinc homeostasis, being involved in metal import both in vitro and in infected animals

Vaginal lactoferrin in prevention of preterm birth in women with bacterial vaginosis

Objective: To evaluate use of vaginal lactoferrin in prevention of preterm birth (PTB) in women with first trimester bacterial vaginosis and prior spontaneous PTB.Methods: This is a retrospective cohort study of all consecutive singleton gestations with prior PTB, and first trimester diagnosis of bacterial vaginosis. Women who were found to have bacterial vaginosis were recommended lactoferrin 300 mg vaginal tablets daily for 21 days. The primary outcome was the incidence of PTB at less than 37 weeks of gestations. Outcomes were compared in women who received daily lactoferrin with those who did notResults: During the study period, 847 pregnant women with prior spontaneous PTB were screened for bacterial vaginosis. Of them, 193 were found to have bacterial vaginosis in the first trimester, with an overall incidence of 22.8%. Out of the 193 women, 125 met the inclusion criteria for the study and were analyzed. Sixty of the included women received vaginal lactoferrin, while 65 did not. Women who received supplementation with lactoferrin had a significantly lower rate of PTB < 37 weeks (25.0 versus 44.6%; p = .02), lower mean gestational age at delivery (37.7 ± 3.2 versus 35.9 ± 4.1 weeks; p = .01), and lower rate of admission for threatened PTL (45.0 versus 70.8%; p = .04). No between-group differences were noticed in the other outcomes, including chorioamnionitis, PPROM < 34 weeks, and neonatal outcomes. No cases of late miscarriage were reported in our cohort. No cases of adverse events were reported.Conclusion: Based on this small single-center retrospective study, supplementation with vaginal lactoferrin in women with first trimester bacterial vaginosis may be an option to reduce the risk of preterm delivery

NaNet: a Low-Latency, Real-Time, Multi-Standard Network Interface Card with GPUDirect Features

While the GPGPU paradigm is widely recognized as an effective approach to high performance computing, its adoption in low-latency, real-time systems is still in its early stages. Although GPUs typically show deterministic behaviour in terms of latency in executing computational kernels as soon as data is available in their internal memories, assessment of real-time features of a standard GPGPU system needs careful characterization of all subsystems along data stream path. The networking subsystem results in being the most critical one in terms of absolute value and fluctuations of its response latency. Our envisioned solution to this issue is NaNet, a FPGA-based PCIe Network Interface Card (NIC) design featuring a configurable and extensible set of network channels with direct access through GPUDirect to NVIDIA Fermi/Kepler GPU memories. NaNet design currently supports both standard - GbE (1000BASE-T) and 10GbE (10Base-R) - and custom - 34~Gbps APElink and 2.5~Gbps deterministic latency KM3link - channels, but its modularity allows for a straightforward inclusion of other link technologies. To avoid host OS intervention on data stream and remove a possible source of jitter, the design includes a network/transport layer offload module with cycle-accurate, upper-bound latency, supporting UDP, KM3link Time Division Multiplexing and APElink protocols. After NaNet architecture description and its latency/bandwidth characterization for all supported links, two real world use cases will be presented: the GPU-based low level trigger for the RICH detector in the NA62 experiment at CERN and the on-/off-shore data link for KM3 underwater neutrino telescope

Mast cells, microRNAs and others: The role of translational research on colorectal cancer in the forthcoming era of precision medicine

Colorectal cancer (CRC) is a heterogeneous disease, molecularly and anatomically, that develops in a multi-step process requiring the accumulation of several genetic or epigenetic mutations that lead to the gradual transformation of normal mucosa into cancer. In fact, tumorigenesis is extremely complex, with many immunologic and non-immunologic factors present in the tumor microenvironment that can influence tumorigenesis. In the last few years, a role for mast cells (MCs), microRNAs (miRNAs), Kirsten rat sarcoma (KRAS) and v-raf murine sarcoma viral oncogene homologue B (BRAF) in cancer development and progression has been suggested, and numerous efforts have been made to thoroughly assess their correlation with CRC to improve patient survival and quality of life. The identification of easily measurable, non-invasive and cost-effective biomarkers, the so-called “ideal biomarkers”, for CRC screening and treatment remains a high priority. The aim of this review is to discuss the emerging role of mast cells (MCs), microRNAs (miRNAs), KRAS and BRAF as diagnostic and prognostic biomarkers for CRC, evaluating their influence as potential therapy targets in the forthcoming era of precision medicine