Structure of HrcQ(B)-C, a conserved component of the bacterial type III secretion systems

Type III secretion systems enable plant and animal bacterial pathogens to deliver virulence proteins into the cytosol of eukaryotic host cells, causing a broad spectrum of diseases including bacteremia, septicemia, typhoid fever, and bubonic plague in mammals, and localized lesions, systemic wilting, and blights in plants. In addition, type III secretion systems are also required for biogenesis of the bacterial flagellum. The HrcQ(B) protein, a component of the secretion apparatus of Pseudomonas syringae with homologues in all type III systems, has a variable N-terminal and a conserved C-terminal domain (HrcQ(B)-C). Here, we report the crystal structure of HrcQ(B)-C and show that this domain retains the ability of the full-length protein to interact with other type III components. A 3D analysis of sequence conservation patterns reveals two clusters of residues potentially involved in protein–protein interactions. Based on the analogies between HrcQ(B) and its flagellum homologues, we propose that HrcQ(B)-C participates in the formation of a C-ring-like assembly

Exploring the Performance and Efficiency of Transformer Models for NLP on Mobile Devices

Deep learning (DL) is characterised by its dynamic nature, with new deep neural network (DNN) architectures and approaches emerging every few years, driving the field's advancement. At the same time, the ever-increasing use of mobile devices (MDs) has resulted in a surge of DNN-based mobile applications. Although traditional architectures, like CNNs and RNNs, have been successfully integrated into MDs, this is not the case for Transformers, a relatively new model family that has achieved new levels of accuracy across AI tasks, but poses significant computational challenges. In this work, we aim to make steps towards bridging this gap by examining the current state of Transformers' on-device execution. To this end, we construct a benchmark of representative models and thoroughly evaluate their performance across MDs with different computational capabilities. Our experimental results show that Transformers are not accelerator-friendly and indicate the need for software and hardware optimisations to achieve efficient deployment.Comment: Accepted at the 3rd IEEE International Workshop on Distributed Intelligent Systems (DistInSys), 202

Sex-specific regulation of chemokine Cxcl5/6 controls neutrophil recruitment and tissue injury in acute inflammatory states

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Barts and The London Trustees Studentship (SM), Marie Curie fellowships (MB, JD), Arthritis Research UK career development fellowship (JW), William Harvey Research Foundation grant (JW/RSS), Kidney Research UK fellowship (NSAP), Barts and The London Vacation Scholarship (ISN), Wellcome Trust senior fellowship (DWG), and a Wellcome Trust career development fellowship (RSS). This work forms part of the research themes contributing to the translational research portfolio of Barts and The London Cardiovascular Biomedical Research Unit, which is supported and funded by National Institute for Health Researc

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

The basal epithelial marker P-cadherin associates with breast cancer cell populations harboring a glycolytic and acid-resistant phenotype

"BMC Cancer 2014 14:734"BACKGROUND: Cancer stem cells are hypoxia-resistant and present a preponderant glycolytic metabolism. These characteristics are also found in basal-like breast carcinomas (BLBC), which show increased expression of cancer stem cell markers.Recently, we demonstrated that P-cadherin, a biomarker of BLBC and a poor prognostic factor in this disease, mediates stem-like properties and resistance to radiation therapy. Thus, the aim of the present study was to evaluate if P-cadherin expression was associated to breast cancer cell populations with an adapted phenotype to hypoxia. METHODS: Immunohistochemistry was performed to address the expression of P-cadherin, hypoxic, glycolytic and acid-resistance biomarkers in primary human breast carcinomas. In vitro studies were performed using basal-like breast cancer cell lines. qRT-PCR, FACS analysis, western blotting and confocal microscopy were used to assess the expression of P-cadherin after HIF-1a stabilization, achieved by CoCl2 treatment. siRNA-mediated knockdown was used to silence the expression of several targets and qRT-PCR was employed to evaluate the effects of P-cadherin on HIF-1a signaling. P-cadherin high and low breast cancer cell populations were sorted by FACS and levels of GLUT1 and CAIX were assessed by FACS and western blotting. Mammosphere forming efficiency was used to determine the stem cell activity after specific siRNA-mediated knockdown, further confirmed by western blotting. RESULTS: We demonstrated that P-cadherin overexpression was significantly associated with the expression of HIF-1a, GLUT1, CAIX, MCT1 and CD147 in human breast carcinomas. In vitro, we showed that HIF-1a stabilization was accompanied by increased membrane expression of P-cadherin and that P-cadherin silencing led to a decrease of the mRNA levels of GLUT1 and CAIX. We also found that the cell fractions harboring high levels of P-cadherin were the same exhibiting more GLUT1 and CAIX expression. Finally, we showed that P-cadherin silencing significantly decreases the mammosphere forming efficiency in the same range as the silencing of HIF-1a, CAIX or GLUT1, validating that all these markers are being expressed by the same breast cancer stem cell population. CONCLUSIONS: Our results establish a link between aberrant P-cadherin expression and hypoxic, glycolytic and acid-resistant breast cancer cells, suggesting a possible role for this marker in cancer cell metabolismo.This work was funded by FEDER funds through the COMPETE Program (Programa Operacional Factores de Competitividade) and by national funds through FCT (Portuguese Foundation for Science and Technology, Portugal), mainly in the context of the scientific project PTDC/SAU-GMG/120049/2010-FCOMP-01-0124-FEDER-021209, and partially by PTDC/SAU-FCF/104347/2008. FCT funded the research grants of BS (SFRH/BD/69353/2010), ASR (SFRH/BPD/75705/2011), ARN (grant from the project PTDC/SAU-GMG/120049/2010), CP (SFRH/BPD/69479/2010), AV (SFRH/BPD/90303/2012), as well as JP, with Programa Ciencia 2007 (Contratacao de Doutorados para o SCTN - financiamento pelo POPH - QREN - Tipologia 4.2 - Promocao do Emprego Cientifico, comparticipado pelo Fundo Social Europeu e por fundos nacionais do MCTES) and Programa IFCT (FCT Investigator). IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education and is partially supported by FCT

A myocutaneous flap variation for management of distal hindlimb wounds in the cat

Management of complex feline hindlimb defects is challenging. However, the use of a split semitendinosus myocutaneous (SST) flap for coverage has not yet been reported. The objective of this study was to describe the SST flap and compare it with second-intention healing for the management of complex tibial defects in cats. Two wounds were created on each tibia of 12 purpose-bred laboratory DSH cats. Wounds in group A (n=12) were covered with SST flaps and those in group B (n=12) were left to heal by second intention. In both groups, clinical assessment scoring and planimetry were performed between 1 and 30 postoperative days. CT angiography (CTA) and histological examination were performed on days 0, 10, and 30 and on days 0, 14, 6, and 12 months postoperatively, respectively. Group A had significantly higher assessment scores on days 7 (p=0.002), 14 (p<0.001), 21 (p=0.001), and 30 (p=0.008). The time to complete healing in group A (32,42 days) was significantly higher than that to complete epithelial coverage in group B (24.67 days) (p=0.001). On CTA, significant differences were observed in ST muscle density which was higher on day 10 compared to 0 on the proximal (dP) (p<0.001) and medial (dM) points (p=0,020, p<0,001, p<0,001 respectively) in all three different phases. For the distal (dD) point, the measurement was significantly higher in the precontrast phase (p=0.001) and on day 10 compared today 30 atn all points in all three phases (p<0.001). The caliber of the distal caudal femoral artery and vein and of the proximal gluteal artery and vein were significantly higher on day 10 than on day 0 (p<0.001), on days 10 to 30 (p<0.001), and on days 30 to 0 (p=0.004, p=0.006, p=0.011, p=0.007, respectively). Histologically significant differences were observed on inflammation and muscle cell degeneration which were higher on day 14 than on day 0 and 6 months (p<0.001, p<0.001, p<0.001, p=0.007 respectively). Neovascularization and fibrosis were significantly higher on day 14 than on day 0 (p=0.010 and p=0.009, respectively). In conclusion, although the ST muscle can be safely longitudinally split and cover tibial defects, the SST flap is less efficient than second-intention healing in terms of the time to complete wound healing

Fully automated production of Zr-89 using IBA Nirta and Pinctada Systems

Few PET isotopes are suitable for antibody labelling since immunoPET requires that the PET isotope can be attached to the mAb with high in-vivo stability and the decay half-life of the isotope should match the pharmacokinetics of the mAb (Phelps 2004). Both 124I (t½ = 4.2 d) and 89Zr (t½ = 3.3 d) have a near ideal half-life for anti-body-based imaging, but there are several ad-vantages of using 89Zr over 124I. For 124I, the high energy of its positrons (2.13 MeV), results in a relatively low PET image resolution and the possible dehalogenation in vivo can lead to significant radioactivity uptake in non-targeted organs. In comparison, for 89Zr the low energy of its positron (395.5 keV), results in a PET images with a higher spatial resolution and furthermore, 89Zr is a residualizing isotope, which is trapped inside the target cell after internalization of the mAb. One disadvantage of 89Zr is its abundant high energy gamma-ray (909 keV), which may limit the radioactive dose that can be administered to the patients. The most popular reaction to produce 89Zr is the 89Y(p,n)89Zr nuclear reaction (Sahar et al., 1966; Link et al., 1986). A proton beam with 14-16MeV energy is used to bombard inexpensive high-purity 89Y metal target (99.9%), avoiding cumbersome recycling of the target material. The yttrium targets could be either a foil (Dejesus and Nickels, 1990), sputtered onto a copper support (Meijs et al., 1994) or Y2O3 pellets (S. A. Kandil, B. Scholten, 2007). Although 89Zr is currently commercially available, its price is prohibitive for routine clinical applications of 89Zr immuno-PET. The motivation of the present work was the fully automated production of small quantities of 89Zr using commercially available automated systems. We also describe a newly designed and tested platinum cradle, capable of holding a metallic foil and being directly transferable/compatible between the IBA NIRTA target and IBA Pinctada Metal dissolution/purification module. Material and Methods The solid target infrastructure used for 89Zr production was identical to the implementation reported earlier for production of 64Cu and 124I (S. Poniger et al. 2012). The commercially avail-able Nirta Solid Target from IBA was coupled to our 18/9 IBA cyclotron using a 2-meter external beam line. A fully automated pneumatic solid target transfer system (STTS) designed by TEMA Sinergie was used to deliver the irradiated tar-gets to a dedicated hotcell. The newly designed platinum cradle holding the yttrium foil (0.127 mm thick, 8 mm d) is shown in FIG. 1. Typical irradiation parameters were 14.9 MeV at 20 μA for 1.5 hours (90o angle of incidence). The irradiated cradle, containing the 89Zr target is then loaded directly into the IBA Pinctada Metal module (see FIG. 2) for dissolution/purification without disassembly. We used the dissolution/purification method described by Holland et al. 2009, without modification (Purification of 89Zr from 89Y, 88Y and other radionuclidic impurities using a hydroxamate column, with 89Zr eluted with 1.0M Oxalic acid). Radionuclidic purities were evaluated by gamma spectroscopy and traces of metallic impurities were determined by ICP-MS. Results and Conclusion FIGURE 3 shows the gamma spectrum of the purified 89Zr solution. Since yttrium has one stable isotope only, relatively pure 89Zr is produced at low energy (14.9 MeV). In these preliminary non-optimized cyclotron productions, average purified 89Zr yield of 0.34 mCi/μAh was achieved, in comparison to values of 1.5 mCi/μAh found in the literature (10° angle of incidence). In these preliminary experiments, no deformation of the foil was observed at 20 μA beam current and higher currents are under investigation

Bifidobacterium bifidum Actively Changes the Gene Expression Profile Induced by Lactobacillus acidophilus in Murine Dendritic Cells

Dendritic cells (DC) play a pivotal regulatory role in activation of both the innate as well as the adaptive immune system by responding to environmental microorganisms. We have previously shown that Lactobacillus acidophilus induces a strong production of the pro-inflammatory and Th1 polarizing cytokine IL-12 in DC, whereas bifidobacteria do not induce IL-12 but inhibit the IL-12 production induced by lactobacilli. In the present study, genome-wide microarrays were used to investigate the gene expression pattern of murine DC stimulated with Lactobacillus acidophilus NCFM and Bifidobacterium bifidum Z9. L. acidophilus NCFM strongly induced expression of interferon (IFN)-β, other virus defence genes, and cytokine and chemokine genes related to the innate and the adaptive immune response. By contrast, B. bifidum Z9 up-regulated genes encoding cytokines and chemokines related to the innate immune response. Moreover, B. bifidum Z9 inhibited the expression of the Th1-promoting genes induced by L. acidophilus NCFM and had an additive effect on genes of the innate immune response and Th2 skewing genes. The gene encoding Jun dimerization protein 2 (JDP2), a transcription factor regulating the activation of JNK, was one of the few genes only induced by B. bifidum Z9. Neutralization of IFN-β abrogated L. acidophilus NCFM-induced expression of Th1-skewing genes, and blocking of the JNK pathway completely inhibited the expression of IFN-β. Our results indicate that B. bifidum Z9 actively inhibits the expression of genes related to the adaptive immune system in murine dendritic cells and that JPD2 via blocking of IFN-β plays a central role in this regulatory mechanism