Dynamic balance of pro‐ and anti‐inflammatory signals controls disease and limits pathology

Immune responses to pathogens are complex and not well understood in many diseases, and this is especially true for infections by persistent pathogens. One mechanism that allows for long‐term control of infection while also preventing an over‐zealous inflammatory response from causing extensive tissue damage is for the immune system to balance pro‐ and anti‐inflammatory cells and signals. This balance is dynamic and the immune system responds to cues from both host and pathogen, maintaining a steady state across multiple scales through continuous feedback. Identifying the signals, cells, cytokines, and other immune response factors that mediate this balance over time has been difficult using traditional research strategies. Computational modeling studies based on data from traditional systems can identify how this balance contributes to immunity. Here we provide evidence from both experimental and mathematical/computational studies to support the concept of a dynamic balance operating during persistent and other infection scenarios. We focus mainly on tuberculosis, currently the leading cause of death due to infectious disease in the world, and also provide evidence for other infections. A better understanding of the dynamically balanced immune response can help shape treatment strategies that utilize both drugs and host‐directed therapies.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146448/1/imr12671.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146448/2/imr12671_am.pd

Boosting BCG with recombinant modified vaccinia ankara expressing antigen 85A: Different boosting intervals and implications for efficacy trials

Objectives. To investigate the safety and immunogenicity of boosting BCG with modified vaccinia Ankara expressing antigen 85A (MVA85A), shortly after BCG vaccination, and to compare this first with the immunogenicity of BCG vaccination alone and second with a previous clinical trial where MVA85A was administered more than 10 years after BCG vaccination. Design. There are two clinical trials reported here: a Phase I observational trial with MVA85A; and a Phase IV observational trial with BCG. These clinical trials were all conducted in the UK in healthy, HIV negative, BCG naı¨ve adults. Subjects were vaccinated with BCG alone; or BCG and then subsequently boosted with MVA85A four weeks later (short interval). The outcome measures, safety and immunogenicity, were monitored for six months. The immunogenicity results from this short interval BCG prime–MVA85A boost trial were compared first with the BCG alone trial and second with a previous clinical trial where MVA85A vaccination was administered many years after vaccination with BCG. Results. MVA85A was safe and highly immunogenic when administered to subjects who had recently received BCG vaccination. When the short interval trial data presented here were compared with the previous long interval trial data, there were no significant differences in the magnitude of immune responses generated when MVA85A was administered shortly after, or many years after BCG vaccination. Conclusions. The clinical trial data presented here provides further evidence of the ability of MVA85A to boost BCG primed immune responses. This boosting potential is not influenced by the time interval between prior BCG vaccination and boosting with MVA85A. These findings have important implications for the design of efficacy trials with MVA85A. Boosting BCG induced anti-mycobacterial immunity in either infancy or adolescence are both potential applications for this vaccine, given the immunological data presented here. Trial Registration. ClinicalTrials.Oxford University was the sponsor for all the clinical trials reported here

Using geographically weighted regression to explore the spatially heterogeneous spread of bovine tuberculosis in England and Wales

An understanding of the factors that affect the spread of endemic bovine tuberculosis (bTB) is critical for the development of measures to stop and reverse this spread. Analyses of spatial data need to account for the inherent spatial heterogeneity within the data, or else spatial autocorrelation can lead to an overestimate of the significance of variables. This study used three methods of analysis—least-squares linear regression with a spatial autocorrelation term, geographically weighted regression (GWR) and boosted regression tree (BRT) analysis—to identify the factors that influence the spread of endemic bTB at a local level in England and Wales. The linear regression and GWR methods demonstrated the importance of accounting for spatial differences in risk factors for bTB, and showed some consistency in the identification of certain factors related to flooding, disease history and the presence of multiple genotypes of bTB. This is the first attempt to explore the factors associated with the spread of endemic bTB in England and Wales using GWR. This technique improves on least-squares linear regression approaches by identifying regional differences in the factors associated with bTB spread. However, interpretation of these complex regional differences is difficult and the approach does not lend itself to predictive models which are likely to be of more value to policy makers. Methods such as BRT may be more suited to such a task. Here we have demonstrated that GWR and BRT can produce comparable outputs

Influence of petrographic textures on the shapes of impact experiment fine fragments measuring several tens of microns: Comparison with Itokawa regolith particles

In 2010, fine regolith particles on asteroid Itokawa were recovered by the Hayabusa mission. The three-dimensional microstructure of 48 Itokawa particles smaller than 120 µm was examined in previous studies. The shape distribution of Itokawa particles is distributed around the mean values of the axial ratio 2:√2:1, which is similar to laboratory impact fragments larger than several mm created in catastrophic disruptions. Thus, the Itokawa particles are considered to be impact fragments on the asteroid's surface. However, there have never been any laboratory impact experiments investigating the shapes of fine fragments smaller than 120 µm, and little is known about the relation between the shapes of fine fragments and the petrographic textures within those fragments. In this study, in order to investigate the relation between the petrographic textures and the shapes of fine fragments by impacts, the shapes of 2163 fine fragments smaller than 120 µm are examined by synchrotron radiation-based microtomography at SPring-8. Most samples are fine fragments from basalt targets, obtained in previous laboratory impact experiments by Michikami et al. (2016). Moreover, two impacts into L5 chondrite targets were carried out and the shapes of their fine fragments are examined for comparison. The results show that the shape distributions of fine fragments in basalt targets are similar regardless of impact energy per target mass (in contract to the shape distribution of relatively large fragments, which are affected by impact energy), and are similar to those in L5 chondrite targets and Itokawa regolith particles. The physical process producing these fine fragments would be due to multiple rarefaction waves in the target. Besides, the petrographic textures do not significantly affect the shapes of fine fragments in our experiments. On the other hand, according to Molaro et al. (2015), the shapes of the fragments produced by thermal fatigue by the day-night temperature cycles on the asteroid surface are influenced by the petrographic textures. Therefore, we conclude that the Itokawa particles are not the products of thermal fatigue but impact fragments on the asteroid surface

Lengthened Predelivery Stay and Antepartum Complications in Women with Depressive Symptoms During Pregnancy

Background: It is crucial to understand the timing and mechanisms behind depression's effect on peripartum stay because attempts to intervene will vary based on the time period involved. We designed this study to compare predelivery and postdelivery length of stay in women with and without elevated depressive symptoms during pregnancy. Methods: This study involved secondary data analysis of a larger study exploring antepartum depression. Each subject completed the Center for Epidemiological Studies Depression Scale (CES-D) during pregnancy at a mean of 25.8 weeks' gestation. We used time-stamped data to compare total peripartum, predelivery, and postdelivery lengths of stay in women with and without elevated depressive symptoms during pregnancy. In addition, we used a Cox proportional hazards regression model to evaluate potential mechanisms for depression's effect on length of stay. Results: The study sample included 802 pregnant women. Overall, 18% of study subjects scored >=16 on the CES-D. Bivariate analyses demonstrated a significant association between elevated depressive symptoms and longer predelivery stays (time from admission to delivery). Interaction analyses demonstrated a significant interaction effect between depressive symptoms and parity, such that depressive symptoms were significantly associated with predelivery length of stay in multiparas but not so in primiparous subjects. In a multivariate model of multiparous subjects, depression's effect on length of stay was partially influenced by sociodemographic confounders but remained significant until antepartum complications were added to the model. Conclusions: Depressive symptoms during pregnancy are significantly associated with a subsequent increase in predelivery length of stay, and this association is mediated in part by antepartum complications, even after controlling for sociodemographic factors. These longer hospital stays can present significant burdens to the patient, her family, and the healthcare system. Future studies should evaluate whether interventions for depression during pregnancy can impact this relationship among depressive symptoms during pregnancy, antepartum complications, and extensive predelivery hospitalizations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90486/1/jwh-2E2010-2E2380.pd

Charmed and Bottom Baryons: a Variational Approach based on Heavy Quark Symmetry

The use of Heavy Quark Symmetry to study bottom and charmed baryons leads to important simplifications of the non-relativistic three body problem, which turns out to be easily solved by a simple variational ansatz. Our simple scheme reproduces previous results (baryon masses, charge and mass radii, $...$) obtained by solving the Faddeev equations with simple non-relativistic quark--quark potentials, adjusted to the light and heavy--light meson spectra. Wave functions, parameterized in a simple manner, are also given and thus they can be easily used to compute further observables. Our method has been also used to find the predictions for strangeness-less baryons of the SU(2) chirally inspired quark-quark interactions. We find that the one pion exchange term of the chirally inspired interactions leads to relative changes of the $\Lambda_b$ and $\Lambda_c$ binding energies as large as 90%.Comment: 20 pages, 5 figures. Revised version to be published in Nucl. Phys.

Performance evaluation of a lossy transmission lines based diode detector at cryogenic temperature

This work is focused on the design, fabrication, and performance analysis of a square-law Schottky diodedetector based on lossy transmission lines working under cryogenic temperature (15 K). The design analysis of a microwave detector, based on a planar gallium-arsenide low effective Schottky barrier height diode, is reported, which is aimed for achieving large input return loss as well as flat sensitivity versus frequency. The designed circuit demonstrates good sensitivity, as well as a good return loss in a wide bandwidth at Ka-band, at both room (300 K) and cryogenic (15 K) temperatures. A good sensitivity of 1000 mV/mW and input return loss better than 12 dB have been achieved when it works as a zero-bias Schottky diodedetector at room temperature, increasing the sensitivity up to a minimum of 2200 mV/mW, with the need of a DC bias current, at cryogenic temperature.This work has been funded by the Spanish Ministry for Economy and Competitiveness under the CONSOLIDER-INGENIO 2010 programme under the Reference No. CSD2010-00064. The authors would like to thank Eva Cuerno and Ana Pérez for the assistance in the assembly of the circuit

Mapping B-cell responses to Salmonella enterica serovars Typhimurium and Enteritidis in chickens for the discrimination of infected from vaccinated animals

Serological surveillance and vaccination are important strategies for controlling infectious diseases of food production animals. However, the compatibility of these strategies is limited by a lack of assays capable of di erentiating infected from vaccinated animals (DIVA tests) for established killed or attenuated vaccines. Here, we used next generation phage-display (NGPD) and a 2-proportion Z score analysis to identify peptides that were preferentially bound by IgY from chickens infected with Salmonella Typhimurium or S. Enteritidis compared to IgY from vaccinates, for both an attenuated and an inactivated commercial vaccine. Peptides that were highly enriched against IgY from at least 4 out of 10 infected chickens were selected: 18 and 12 peptides for the killed and attenuated vaccines, respectively. The ten most discriminatory peptides for each vaccine were identi ed in an ELISA using a training set of IgY samples. These peptides were then used in multi-peptide assays that, when analysing a wider set of samples from infected and vaccinated animals, diagnosed infection with 100% sensitivity and speci city. The data describes a method for the development of DIVA assays for conventional attenuated and killed vaccines

New directions in cellular therapy of cancer: a summary of the summit on cellular therapy for cancer

A summit on cellular therapy for cancer discussed and presented advances related to the use of adoptive cellular therapy for melanoma and other cancers. The summit revealed that this field is advancing rapidly. Conventional cellular therapies, such as tumor infiltrating lymphocytes (TIL), are becoming more effective and more available. Gene therapy is becoming an important tool in adoptive cell therapy. Lymphocytes are being engineered to express high affinity T cell receptors (TCRs), chimeric antibody-T cell receptors (CARs) and cytokines. T cell subsets with more naïve and stem cell-like characteristics have been shown in pre-clinical models to be more effective than unselected populations and it is now possible to reprogram T cells and to produce T cells with stem cell characteristics. In the future, combinations of adoptive transfer of T cells and specific vaccination against the cognate antigen can be envisaged to further enhance the effectiveness of these therapies