Search

We engineer an artificial optical clock transition in 40Ca+ with a continuous dynamical decoupling scheme. It suppresses inhomogeneous tensor shifts as well as the linear Zeeman shift, making it suitable for multi-ion operation. Coherence times approaching the natural lifetime limit ensure low statistical uncertainties on the optical transition. We continuously apply the dressing fields, making the tailored transition robust against magnetic field fluctuations during the entire clock probe time.

Background: People who inject drugs (PWID) are at increased risk for HIV and hepatitis C virus (HCV) infection and also have high levels of homelessness and unstable housing. We assessed whether homelessness or unstable housing is associated with an increased risk of HIV or HCV acquisition among PWID compared with PWID who are not homeless or are stably housed. Methods: In this systematic review and meta-analysis, we updated an existing database of HIV and HCV incidence studies published between Jan 1, 2000, and June 13, 2017. Using the same strategy as for this existing database, we searched MEDLINE, Embase, and PsycINFO for studies, including conference abstracts, published between June 13, 2017, and Sept 14, 2020, that estimated HIV or HCV incidence, or both, among community-recruited PWID. We only included studies reporting original results without restrictions to study design or language. We contacted authors of studies that reported HIV or HCV incidence, or both, but did not report on an association with homelessness or unstable housing, to request crude data and, where possible, adjusted effect estimates. We extracted effect estimates and pooled data using random-effects meta-analyses to quantify the associations between recent (current or within the past year) homelessness or unstable housing compared with not recent homelessness or unstable housing, and risk of HIV or HCV acquisition. We assessed risk of bias using the Newcastle-Ottawa Scale and between-study heterogeneity using the I2 statistic and p value for heterogeneity. Findings: We identified 14 351 references in our database search, of which 392 were subjected to full-text review alongside 277 studies from our existing database. Of these studies, 55 studies met inclusion criteria. We contacted the authors of 227 studies that reported HIV or HCV incidence in PWID but did not report association with the exposure of interest and obtained 48 unpublished estimates from 21 studies. After removal of duplicate data, we included 37 studies with 70 estimates (26 for HIV; 44 for HCV). Studies originated from 16 countries including in North America, Europe, Australia, east Africa, and Asia. Pooling unadjusted estimates, recent homelessness or unstable housing was associated with an increased risk of acquiring HIV (crude relative risk [cRR] 1·55 [95% CI 1·23–1·95; p=0·0002]; I2= 62·7%; n=17) and HCV (1·65 [1·44–1·90; p

Combination immunotherapy (CIT) is currently applied as a treatment for different cancers and is proposed as a cure strategy for chronic viral infections. Whether such therapies are efficient during an acute infection remains elusive. To address this, inhibitory receptors were blocked and regulatory T cells depleted in acutely Friend retrovirus-infected mice. CIT resulted in a dramatic expansion of cytotoxic CD4+ and CD8+ T cells and a subsequent reduction in viral loads. Despite limited viral replication, mice developed fatal immunopathology after CIT. The pathology was most severe in the gastrointestinal tract and was mediated by granzyme B producing CD4+ and CD8+ T cells. A similar post-CIT pathology during acute Influenza virus infection of mice was observed, which could be prevented by vaccination. Melanoma patients who developed immune-related adverse events under immune checkpoint CIT also presented with expanded granzyme-expressing CD4+ and CD8+ T cell populations. Our data suggest that acute infections may induce immunopathology in patients treated with CIT, and that effective measures for infection prevention should be applied., Author summary Combination immunotherapy (CIT) directed against checkpoint mechanisms has been approved for the therapy of cancers and is proposed for the treatment of chronic infections. In cancer therapy patients often develop severe immunopathology under CIT. Here we show that acute viral infections (Friend retrovirus and Influenza virus) posed a significant threat during CIT in mice. The strong activation of cytotoxic T cells after an acute viral infection seemed to lack couterregulation during CIT, which resulted in lethal immunopathology. In case of an Influenza virus infection this could be prevented by vaccination prior to CIT. The expansion of CD4+ and CD8+ T cells expressing cytotoxic molecules were also observed in melanoma patients treated with two checkpoint blockers. Thus, these patients might also be at risk of developing severe immunopathology during an otherwise harmless acute viral infection. This should to be taken into account when cancer patients are undergoing CIT.

The dental pulp is an important soft connective tissue which is able to produce dentin over time as a reaction on external stimuli. It also maintains the biological and physiological vitality of the dentin. Due to this the pulp is essential for teeth homeostasis. However, dental caries is still one of the most prevalent health problems in dentistry and therefore, one major cause for early loss of the dental pulp vitality and subsequent tooth extractions. Meanwhile the potential for successful pulp regeneration therapy is increasing due to advances in the field of regenerative endodontics. Thus, adequate experimental animal models are required for testing and validating these new regenerative therapies. Rodents and rats in particular, are relevant models for experimental periodontal research. The breeding and housing costs of rats are relatively low facilitating studies with sufficient numbers for statistical analysis in comparison to bigger sized mammals like beagle dogs, miniature pigs or monkeys. Additionally, rat molar teeth and pulps are characterized by similar anatomical, histological, biological and physiological features to human teeth. Essential biological reactions of the pulp tissue and the interaction during the different stages of wound healing of rat molar teeth are comparable to that of other mammals. However, despite of the multiple research activities in the field of regenerative endodontics and the above mentioned advantages of the rat model only rare in vivo studies are published. Therefore, the presented study aimed to introduce the rat molar teeth as a valid model for studying dental pulp stem cell based endodontic tissue regeneration. Human dental pulp stem cells were implanted into the pulp of immunodeficient rats (RNU rats). Cell growth was supported by a collagenous membrane, which was applied on top of the cells after implantation. After closing the pulpal cavity with a light-polymerisable resin human dental pulp stem cells were able to maintain cell viability in the rat molar pulp niche for at least three weeks. This demonstrated the suitability of immunodeficient RNU rats for non-autologous dental stem cell based endodontic tissue engineering approaches.

The suppressive capacity of regulatory T cells (Tregs) has been extensively studied and is well established for many diseases. The expansion, accumulation, and activation of Tregs in viral infections are of major interest in order to find ways to alter Treg functions for therapeutic benefit. Tregs are able to dampen effector T cell responses to viral infections and thereby contribute to the establishment of a chronic infection. In the Friend retrovirus (FV) mouse model, Tregs are known to expand in all infected organs. To better understand the characteristics of these Treg populations, their phenotype was analyzed in detail. During acute FV-infection, Tregs became activated in the spleen and bone marrow, as indicated by various T cell activation markers, such as CD43 and CD103. Interestingly, Tregs in the bone marrow, which contains the highest viral loads during acute infection, displayed greater levels of activation than Tregs from the spleen. Treg expansion was driven by proliferation but no FV-specific Tregs could be detected. Activated Tregs in FV-infection did not produce Granzyme B (GzmB) or tumor necrosis factor α (TNFα), which are thought to be a potential mechanism for their suppressive activity. Furthermore, Tregs expressed inhibitory markers, such as TIM3, PD-1 and PD-L1. Blocking TIM3 and PD-L1 with antibodies during chronic FV-infection increased the numbers of activated Tregs. These data may have important implications for the understanding of Treg functions during chronic viral infections.

Implantable long-term central venous port systems (CVPS) are widely used as a permanent means of accessing the vascular system for intravenous delivery of drugs, parenteral nutrition, blood transfusion, and blood sampling. These systems allow easy and repetitive puncture without causing much damage to the vessels. However, the body foreign surface of CVPS induces an inflammatory response with varying intensity (depending on the implant materials) that leads to formation of a fibrous tissue capsule around the implant. This study was designed to investigate the influence of bacterial infection on the tissue reaction induced by implanted CVPS in adult patients. 20 patients (9 women, 11 men, 58 ± 14 yrs of age) were included in this study. These patients received explantation of a polysulfone based CVPS (ChemoSite™, Covidien, Mansfield, USA) due to port related infections (patients with bacterial infections at the implantation site: group A, 5 men, 1 women) or to other reasons such as termination of treatment, thrombosis, or CVPS dysfunction (patients without bacterial infections, group B, 6 men, 8 women) 299.9 ± 261.2 days after CVPS implantation. A sample of the encapsulating tissue covering the CVPS together with surrounding tissue (at least 1 × 1 cm2) was placed in a small container with fixing agent, a buffered neutral 4% formalin solution (pH 7). Histological sections of the samples were prepared for light microscopic analysis after paraffin embedding. Sections of 3 μm were cut and stained with haematoxylin and eosin, Weigert's elastic stain, and Heidenhain's azan stain. There was no difference in thickness, collagen and elastin content, or cell and capillary density of the fibrous capsule between both groups. Due to the wound healing reaction involving angiogenesis and fibroblast activation cell density and number of capillaries in the capsule tissue of all patients showed a positive correlation (r = 0.45, p < 0.05). However, the study demonstrated that at the end of the foreign body reaction the artificial tissue layer which covers the CVPS after implantation due to foreign body reaction shows only low reactivity towards infections.

Worldwide more than 2 billion people are infected with helminths, predominantly in developing countries. Co-infections with viruses such as human immunodeficiency virus (HIV) are common due to the geographical overlap of these pathogens. Helminth and viral infections induce antagonistic cytokine responses in their hosts. Helminths shift the immune system to a type 2-dominated immune response, while viral infections skew the cytokine response towards a type 1 immune response. Moreover, chronic helminth infections are often associated with a generalized suppression of the immune system leading to prolonged parasite survival, and also to a reduced defence against unrelated pathogens. To test whether helminths affect the outcome of a viral infection we set up a filarial/retrovirus co-infection model in C57BL/6 mice. Although Friend virus (FV) infection altered the L. sigmodontis-specific immunoglobulin response towards a type I associated IgG2 isotype in co-infected mice, control of L. sigmodontis infection was not affected by a FV-superinfection. However, reciprocal control of FV infection was clearly impaired by concurrent L. sigmodontis infection. Spleen weight as an indicator of pathology and viral loads in spleen, lymph nodes (LN) and bone marrow (BM) were increased in L. sigmodontis/FV-co-infected mice compared to only FV-infected mice. Numbers of FV-specific CD8+ T cells as well as cytokine production by CD4+ and CD8+ cells were alike in co-infected and FV-infected mice. Increased viral loads in co-infected mice were associated with reduced titres of neutralising FV-specific IgG2b and IgG2c antibodies. In summary our findings suggest that helminth infection interfered with the control of retroviral infection by dampening the virus-specific neutralising antibody response., Author Summary The coincidental infection of a host with two different pathogens is widespread in low-income countries. Regions where helminth infections are endemic strongly overlap with areas where the incidence of viral infections such as HIV is high. HIV is a major public health issue causing more than 1 million deaths per year. To analyse the impact of a pre-existing helminth infection on a viral infection we established a helminth/retrovirus co-infection mouse model. Mice that were first infected with Litomosoides sigmodontis and subsequently with a murine retrovirus showed a more severe course of virus infection, i.e. exaggerated splenomegaly and higher viral loads. Since different lymphocytes such as B and T cells contribute to viral control we analysed the cellular and humoral immune response. While T cell responses were similar in co-infected and virus-infected mice, we observed reduced titres of virus-specific antibodies in co-infected mice. Our results suggest that helminth infection interfered with viral control by dampening the virus-specific antibody response. The viral infection itself altered the humoral immune response against L. sigmodontis without changing the worm burden. In summary, our data highlight the importance of deworming programs or vaccines against helminths in developing countries where the incidence of helminth/HIV co-infections is high.

While Friend retrovirus-infected mice readily mount a vigorous CD8 + T cell response to the leader-gag-derived peptide GagL 85–93 , no GagL 85–93 -specific T cells were detectable in mice immunized against Friend virus (FV) with viral vectors or DNA vaccines. By exchanging one epitope-flanking amino acid or using a scaffold protein we were able to demonstrate for the first time the induction of GagL 85–93 -specific CD8 + T cells by genetic vaccination and show their high protective effect against FV challenge infection.

Hepatitis B virus (HBV) infection shows significant gender-related differences in pathogenesis, disease progression, and development of hepatocellular carcinoma. The gender-associated differences in HBV replication and viral protein levels may be associated with distinct HBV-specific immune responses in the host. In the present study, we examined the impact of gender on HBV-specific immune responses in two different mouse models representing transient and persistent hepadnaviral infection; hydrodynamic injection with the HBV genome mimicked acute HBV infection, whereas the efficacy of therapeutic vaccination was studied in the woodchuck hepatitis virus transgenic mouse model. Consistent with previous reports, significantly higher HBV DNA and protein levels were detected in male compared to female mice. Although hydrodynamic injection with the HBV genome resulted in similar numbers of intrahepatic HBV-specific cluster of differentiation 8-positive (CD8+ ) T cells, their functionality was significantly reduced in males and correlated with higher numbers of intrahepatic regulatory T cells (Tregs). Similar effects were observed in woodchuck hepatitis virus transgenic mice immunized with a DNA prime-recombinant adenovirus boost vaccination protocol. Male mice showed functionally suppressed woodchuck hepatitis virus-specific CD8+ T-cell responses in the liver and significantly higher numbers of intrahepatic Tregs compared to females. Blockade of Treg responses in male mice led to augmented effector functions of specific CD8+ T cells and subsequently improved virus control in both models of transient and persistent hepadnaviral infection. Conclusion The functionality of virus-specific CD8+ T cells in male mice was suppressed by intrahepatic Tregs and inversely correlated with levels of hepadnaviral DNA and viral protein; the induction of intrahepatic Tregs by viral replication and/or protein levels may explain the gender-related differences in the outcomes of HBV infection and limit the success of immunotherapeutic strategies in male patients. (Hepatology 2017;66:69-83).

Regulatory T cells (Tregs) play an important role in counter-regulating effector T cell responses in many infectious diseases. However, they can also contribute to the development of T cell dysfunction and pathogen persistence in chronic infections. Tregs have been reported to suppress virus-specific T cell responses in hepatitis B virus (HBV) infection of human patients as well as in HBV animal models. However, the phenotype and expansion of Tregs has so far only been investigated in other infections, but not in HBV. We therefore performed hydrodynamic injections of HBV plasmids into mice and analyzed the Treg response in the spleen and liver. Absolute Treg numbers significantly increased in the liver but not the spleen after HBV injection. The cells were natural Tregs that surprisingly did not show any activation or proliferation in response to the infection. However, they were able to suppress effector T cell responses, as selective depletion of Tregs significantly increased HBV-specific CD8+ T cell responses and accelerated viral antigen clearance. The data implies that natural Tregs infiltrate the liver in HBV infection without further activation or expansion but are still able to interfere with T cell mediated viral clearance. CA extern

Cytotoxic CD8+ T Lymphocytes (CTL) efficiently control acute virus infections but can become exhausted when a chronic infection develops. Signaling of the inhibitory receptor PD-1 is an important mechanism for the development of virus-specific CD8+ T cell dysfunction. However, it has recently been shown that during the initial phase of infection virus-specific CD8+ T cells express high levels of PD-1, but are fully competent in producing cytokines and killing virus-infected target cells. To better understand the role of the PD-1 signaling pathway in CD8+ T cell cytotoxicity during acute viral infections we analyzed the expression of the ligand on retrovirus-infected cells targeted by CTLs. We observed increased levels of PD-L1 expression after infection of cells with the murine Friend retrovirus (FV) or with HIV. In FV infected mice, virus-specific CTLs efficiently eliminated infected target cells that expressed low levels of PD-L1 or that were deficient for PD-L1 but the population of PD-L1high cells escaped elimination and formed a reservoir for chronic FV replication. Infected cells with high PD-L1 expression mediated a negative feedback on CD8+ T cells and inhibited their expansion and cytotoxic functions. These findings provide evidence for a novel immune escape mechanism during acute retroviral infection based on PD-L1 expression levels on virus infected target cells., Author Summary Virus-specific cytotoxic T cells can eliminate infected cells during acute viral infections, but in chronic infections these cells often become dysfunctional or “exhausted.” The inhibitory receptor PD-1 is involved in the suppression of cytotoxic T cell responses in chronic infections. However, during many acute viral infections cytotoxic T cells up-regulate the PD-1 receptor but initially remain competent in killing virus infected target cells. Here we show that the ligand for PD-1, called PD-L1, can be induced on retrovirus infected cells and that the cells with the highest expression of PD-L1 escaped from cytotoxic T cell killing. Thus, PD-L1high infected target cells accumulated during the course of infection, formed the reservoir of virus persistence, and subsequently mediated a negative feedback on cytotoxic T cells via the PD-1 receptor that ultimately resulted in functional exhaustion of these cells. The current results provide evidence for a novel escape mechanism of viruses from cytotoxic T cell responses and may explain how viral reservoirs are established during chronic infections.

Recent successes in immune therapeutic strategies aimed to improve control over tumor growth have sparked hope that long-lived control of cancer through stimulation of the immune system can be possible. However, the underlying immunological mechanisms that are induced by immunotherapeutic strategies are not well understood. In this study, we used the highly immunogenic Friend virus–induced FBL-3 tumor as a model to study the mechanisms of immunological tumor control by CD4+ T cells in the course of CD137 (4-1BB) agonist immunotherapy in the absence of a CD8 T cell response. We demonstrate that treatment with a CD137 agonist resulted in complete FBL-3 tumor regression in CD8+ T cell–deficient mice. CD137 signaling enhanced the production of proinflammatory cytokines and cytotoxic molecules in tumor-specific CD4+ T cells. Interestingly, a subset of CD4+Foxp3+ regulatory T cells was reprogrammed to eliminate immunogenic virus-induced tumor cells in response to CD137 agonist treatment. These cells expressed markers characteristic for Th cells (CD154) and produced the cytokine TNF-α or the T-box transcriptional factor Eomesodermin and granzyme B without loss of Foxp3 expression. Foxp3 Eomes double-positive CD4+ T cells were capable of eliminating immunogenic virus-induced tumor cells in vivo. Thus, our data show that tumor-induced Foxp3+CD4+ T cells can be reprogrammed into cytotoxic effector cells upon therapeutic costimulatory signaling and restore antitumor immunity.

An analytical expression for the probability density function of the signal-to-noise ratio (SNR) at the output of a two-branch maximal ratio and selection diversity system is given. The two branches are assumed to be Rayleigh fading, correlated, as well as of unequal average SNRs. Measurements of the cumulative distribution functions after selection and maximal ratio combining were made in Rayleigh fading channels and compared with the analytical results. Also presented are the exact analytical average probabilities of symbol error for coherent binary phase-shift keying and coherent quaternary phase-shift keying before and after two-branch maximal ratio combining for a slow and flat fading correlated Rayleigh channel.

T helper type 1 (Th1) immunity was considered to play a dominant role in viral clearance of hepadnaviral infection. However, pre-primed Th2 type responses were able to efficiently control hepadnaviral infection in animal models. We investigated how pre-primed Th1/2 responses control hepadnaviral replication using the newly established mouse models. DNA (pWHcIm, pCTLA-4-C) and protein vaccines based on the nucleocapsid protein (WHcAg) of woodchuck hepatitis virus (WHV) primed specific immune responses with distinct features. The pre-primed responses determined the characteristics of recall responses if challenged with a WHcAg-expressing adenoviral vector. Vaccination with pWHcIm and pCTLA4-C facilitated viral control in the hydrodynamic injection model and reduced WHV loads by about 3 and 2 logs in WHV-transgenic mice, respectively, despite of different kinetics of specific CD8+ T cell responses. Thus, pre-primed Th2-biased responses facilitate the development of CD8+ T cell responses in mice compared with naïve controls and thereby confer better viral control. OA embargo

This paper examines the antenna diversity configurations that improve the performance in handheld radios. Experiments using spatial, polarization, and pattern diversity were conducted for both line-of-sight (LOS) and obstructed outdoor and indoor multipath channels that experienced Ricean fading. Antenna separation, polarization, and pattern were varied independently to the extent possible. Envelope correlation, power imbalance, and diversity gain were calculated from the measurements. Diversity performance is measured by diversity gain, which is the difference in signal-to-noise ratio (SNR) between the output of a diversity combiner and the signal on a single branch, measured at a given probability level. Diversity gain increases with decreasing envelope correlation between the antenna diversity branches. However, diversity gain decreases as the power imbalance between diversity branches increases because a branch that has a weak signal has only a small contribution to the combined signal. Diversity gain values of 7-9 dB at the 99% reliability level were achieved in non-line-of-sight (NLOS) channels for all diversity configurations even with very small antenna spacings. The use of polarization diversity reduced polarization mismatches, improving SNR by up to 12 dB even in LOS channels.

We review diversity and smart antenna research applied to both base-stations and terminals. To illustrate the performance gains possible, the paper describes research being conducted by the Smart Antenna Group at Virginia Tech, in both smart base-stations and smart handheld terminals.

It is well known that clinically relevant concentrations of iodine-containing radiographic contrast media (CM) induce morphological changes in human erythrocytes. However, there are only few reports about CM effects on erythrocytes of animals (e.g. mice, rats, rabbits, and pigs). Thus, two conventional iodine-containing CM (iodixanol, Visipaque™ 320; iomeprol, Iomeprol™ 350) were tested for their effects on the morphology of erythrocytes from these. After venous blood sampling and blood centrifugation, the autologous plasma was supplemented with 40 vol% CM. Then, a defined number of erythrocytes was incubated in this CM-supplemented plasma for 5 min at body temperature (37°C). Subsequently, 10 μL of the cell suspension were transferred to a purified glass slide and the number of discocytes, echinocytes, and acanthocytes was counted within a total number of 100 erythrocytes (40 fold primary magnification, transmitted light mode). Shape changes of the erythrocytes from all animal species strongly depended on the type of CM and compared to the effects which have already been described for human erythrocytes. Incubation in both CM resulted in morphological changes of the erythrocytes. Incubation in a iodixanol/plasma mixture induced the lowest echinocyte or acanthocyte formation. Porcine erythrocytes showed a much more distinct shape change than those of other animal species and humans. These results suggest erythrocytes from mice, rats, and rabbits are a suitable model system for a model system for human erythrocytes when CM effects on the cellular shape of erythrocytes have to be tested. The distinct deformation of the pig erythrocytes could be due to differences in the pig erythrocyte membrane or the physical and chemical constitution of pig erythrocytes.

Chronic infections with human viruses, such as HIV and HCV, or mouse viruses, such as LCMV or Friend Virus (FV), result in functional exhaustion of CD8+ T cells. Two main mechanisms have been described that mediate this exhaustion: expression of inhibitory receptors on CD8+ T cells and expansion of regulatory T cells (Tregs) that suppress CD8+ T cell activity. Several studies show that blockage of one of these pathways results in reactivation of CD8+ T cells and partial reduction in chronic viral loads. Using blocking antibodies against PD-1 ligand and Tim-3 and transgenic mice in which Tregs can be selectively ablated, we compared these two treatment strategies and combined them for the first time in a model of chronic retrovirus infection. Blocking inhibitory receptors was more efficient than transient depletion of Tregs in reactivating exhausted CD8+ T cells and reducing viral set points. However, a combination therapy was superior to any single treatment and further augmented CD8+ T cell responses and resulted in a sustained reduction in chronic viral loads. These results demonstrate that Tregs and inhibitory receptors are non-overlapping factors in the maintenance of chronic viral infections and that immunotherapies targeting both pathways may be a promising strategy to treat chronic infectious diseases., Author Summary A loss of function, the so-called ‘exhaustion’ of CD8+ T cells, is a hallmark of many chronic infections. The T cell exhaustion is mediated by two main mechanisms, the expression of inhibitory receptors on CD8+ T cells and virus-induced expansion of regulatory T cells (Tregs), which suppress CD8+ T cell activity. Several mouse studies revealed a reactivation of CD8+ T cells and reduction in chronic viral loads after blockage of one of these pathways. These results initiated a number of clinical studies mainly with cancer patients, in which blocking antibodies were used to interfere with inhibitory receptor signaling or drugs that deplete Tregs. For the first time we combined the two therapeutic approaches by using transgenic mice in which Tregs can be selectively ablated and injection of blocking antibodies in a chronic retroviral infection. The results indicate that the combination therapy was superior to any single treatment in further augmenting CD8+ T cell responses and reducing chronic viral loads. Our findings demonstrate that Tregs and inhibitory receptors are non-overlapping factors in the maintenance of chronic viral infections and that immunotherapies targeting both pathways may be a promising new strategy to treat chronic infectious diseases.

Liver sinusoidal endothelial cells (LSECs) are unique organ-resident APCs capable of Ag cross-presentation and subsequent tolerization of naive CD8+ T cells. Under certain conditions, LSECs can switch from a tolerogenic to an immunogenic state and promote the development of T cell immunity. However, little is known about the mechanisms of LSECs to induce T cell immunity. In this study, we investigated whether functional maturation of LSECs can be achieved by TLR ligand stimulation and elucidated the mechanisms involved in LSEC-induced T cell immunity. We demonstrate that pretreatment of LSECs with palmitoyl-3-cysteine-serine-lysine-4 (P3C; TLR1/2 ligand) but not poly(I:C) (TLR3 ligand) or LPS (TLR4 ligand) reverted their suppressive properties to induce T cell immunity. Importantly, P3C stimulation caused functional maturation of Ag-presenting LSECs and enabled them to activate virus-specific CD8+ T cells. The LSEC-mediated CD8+ T cell immunity was initiated by soluble mediators, one of which was IL-12 secreted at a low but sustained level after P3C stimulation. P3C stimulation did not induce programmed death ligand 1 expression on LSECs, thereby favoring T cell proliferation and activation instead of suppression. Our data suggest that LSECs undergo maturation exclusively in response to TLR1/2 ligand stimulation and that the immunological status of LSECs was dependent upon the balance between programmed death ligand 1 and IL-12 expression. These results have implications for our understanding of liver-specific tolerance and autoimmunity and for the development of strategies to overcome T cell tolerance in situations such as chronic viral liver infections or liver cancer.

The authors would like to correct panel H in Fig 3 to show the correct MFI values of PD-L1 expression on human CD4+ T cells. The error occurred during preparation of the figure for manuscript revision. The percentages of infected CD4 cells expressing PD-L1 were accidentally duplicated from panel I in Fig 3. Please see the corrected version of Fig 3 here. Fig 3 PD-L1 expression on cells infected in vitro with FV or HIV.

It is difficult to determine the part that international trade has played in the expansion of vector-borne diseases, because of the multitude of factors that affect the transformation of habitats and the interfaces between vectors and hosts. The introduction of pathogens through trade in live animals or products of animal origin, as well as the arrival of arthropod vectors, is probably quite frequent but the establishment of an efficient transmission system that develops into a disease outbreak remains the exception. In this paper, based on well-documented examples, the authors review the ecological and epidemiological characteristics of vector-borne diseases that may have been affected in their spread and change of distribution by international trade. In addition, they provide a detailed analysis of the risks associated with specific trade routes and recent expansions of vector populations. Finally, the authors highlight the importance, as well as the challenges, of preventive surveillance and regulation. The need for improved monitoring of vector populations and a readiness to face unpredictable epidemiological events are also emphasised, since this will require rapid reaction, not least in the regulatory context.

Although chronic infections with viruses such as HIV and hepatitis C virus have been associated with regulatory T cell (Treg)-mediated suppression of virus-specific CD8 + T-cell activity, no causal relationship between Tregs and chronic viral set points has been established. Using transgenic mice in which Tregs can be selectively ablated, we now show that transient depletion of Tregs during a chronic retroviral infection allows exhausted CD8 + T cells to regain antiviral functions, including secretion of cytokines, production of cytotoxic molecules, and virus-specific cytolytic activity. Furthermore, short-term Treg ablation resulted in long-term reductions in chronic virus loads. These results demonstrate that Treg-mediated immunosuppression can be a significant factor in the maintenance of chronic viral infections and that Treg-targeted immunotherapy could be a valuable component in therapeutic strategies to treat chronic infectious diseases.

It was recently reported that inhibitory molecules such as programmed death-1 (PD-1) were upregulated on CD8+ T cells during acute Friend retrovirus infection and that the cells were prematurely exhausted and dysfunctional in vitro. The current study confirms that most activated CD8+ T cells upregulated expression of PD-1 during acute infection and revealed a dichotomy of function between PD-1hi and PD-1lo subsets. More PD-1lo cells produced antiviral cytokines such as IFN-γ and TNF-α, whereas more PD-1hi cells displayed characteristics of cytotoxic effectors such as production of granzymes and surface expression of CD107a. Importantly, CD8+ T cells mediated rapid in vivo cytotoxicity and were critical for control of acute Friend virus replication. Thus, direct ex vivo analyses and in vivo experiments revealed high CD8+ T cell functionality and indicate that PD-1 expression during acute infection is not a marker of T cell exhaustion.

The induction of type I IFN is the most immediate host response to viral infections. Type I IFN has a direct antiviral activity mediated by antiviral enzymes, but it also modulates the function of cells of the adaptive immune system. Many viruses can suppress type I IFN production, and in retroviral infections, the initial type I IFN is weak. Thus, one strategy of immunotherapy in viral infection is the exogenous induction of type I IFN during acute viral infection by TLR ligands. Along these lines, the TLR3/MDA5 ligand polyinosinic-polycytidylic acid [poly(I:C)] has already been used to treat viral infections. However, the immunological mechanisms underlying this successful therapy have not been defined until now. In this study, the Friend retrovirus (FV) mouse model was used to investigate the mode of action of poly(I:C) in antiretroviral immunotherapy. Postexposure, poly(I:C) treatment of FV-infected mice resulted in a significant reduction in viral loads and protection from virus-induced leukemia. This effect was IFN dependent because type I IFN receptor-deficient mice could not be protected by poly(I:C). The poly(I:C)-induced IFN response resulted in the expression of antiviral enzymes, which suppressed FV replication. Also, the virus-specific T cell response was augmented. Interestingly, it did not enhance the number of virus-specific CD4+ and CD8+ T cells, but rather the functional properties of these cells, such as cytokine production and cytotoxic activity. The results demonstrate a direct antiviral and immunomodulatory effect of poly(I:C) and, therefore, suggests its potential for clinical treatment of retroviral infections.

Cytotoxic CD8+ T cells control acute viremia in many viral infections. However, most viruses that establish chronic infections evade destruction by CD8+ T cells, and regulatory T cells (Treg) are thought to be involved in this immune evasion. We have infected transgenic mice, in which Treg can be selectively depleted, with Friend retrovirus (FV) to investigate the influence of Treg on pathogen-specific CD8+ T-cell responses in vivo. We observed that Treg expansion during acute infection was locally defined to organs with high viral loads and massive activation of virus-specific effector CD8+ T cells. Experimental ablation of Treg resulted in a significant increase of peak cytotoxic CD8+ T-cell responses against FV. In addition, it prevented the development of functional exhaustion of CD8+ T cells and significantly reduced FV loads in lymphatic organs. Surprisingly, despite the massive virus-specific CD8+ T-cell response after temporary Treg depletion, no evidence of immunopathology was found. These results demonstrate the important role of Treg in controlling acute retrovirus-specific CD8+ T-cell responses, and suggest that temporary manipulation of Treg might be a possible therapeutic approach in chronic infectious diseases.

In a recent paper in Science, Lund et al. [1] investigated the effect of regulatory T cells (Tregs) on the antiviral immune response to an acute herpes virus infection. Previous studies on the role of Tregs in different viral infections suggested that this T cell population suppresses antiviral effector T cell responses or local immune activation at the sites of viral replication [2],[3], which might subsequently facilitate viral immune evasion and the establishment of chronic infections [4],[5],[6]. Thus, it was quite surprising that ablation of Tregs in HSV-2-infected mice resulted in an accelerated fatal infection with increased viral loads instead of enhanced immunity to the virus [1]. In their fascinating paper, the authors showed that depletion of Tregs amplified the immune responses in draining lymph nodes at the site of infection, but at the same time delayed the entry of the immune cells into the HSV-2-infected tissue. As a general concept, Lund et al. postulated that Tregs promote immune responses in acute infections in which the pathogen replicates in non-lymphoid tissues. However, a number of viruses that induce severe human diseases, like HIV or the measles virus, replicate in primary or secondary lymphoid organs. Therefore, the question arises whether Tregs have a suppressive or promoting effect on antiviral immune responses in infections with viruses that are lymphotropic. We have used the Friend retrovirus (FV) mouse model to address this question. FV is a lymphotropic retroviral complex that replicates efficiently in the spleen of infected mice and can induce a lethal erythroleukemia [7]. It was demonstrated in previous studies that the virus induces a significant expansion of Tregs during acute infection [8]. Similar to Lund et al. [1], we used a transgenic mouse expressing the diphtheria toxin (DT) receptor and GFP under the control of the Foxp3 promoter [9] to selectively deplete Tregs by DT injection during acute FV infection. DT injection into FV-infected mice at days 0, 2, 4, 6, and 8 postinfection depleted all GFP-expressing CD4+ Foxp3+ T cells in the spleen (Figure S1A), which resulted in a slight reduction of the overall CD4+ T cell counts (Figure S1B). However, a small population of cells positive for CD4 and Foxp3 but negative for GFP remained detectable. The DT injection did not significantly influence the overall numbers of CD8+ T cells and CD19+ B cells in the spleen of infected mice, indicating that the general lymphocyte population was not affected. In addition, a recent study clearly indicates that a DT injection into mice expressing a DT receptor/GFP cassette under the control of the Foxp3 promoter leads to a specific ablation of Tregs [10], but not to the depletion of epithelial cells as previously suggested by Liu et al. [11]. Since virus-specific CD8+ T cells are the most important immune cells that control acute FV replication [12], we determined the quantity and quality of these cells in the spleen of mice experimentally ablated of Tregs. At 10 days postinfection, significantly more CD8+ T cells expressing markers of effector T cells (CD43+) were found in the spleen of Treg-depleted mice compared to non-depleted controls (Figure 1A). Treg ablation also enhanced the number of FV-specific CD8+ T cells in the spleen of infected mice, which were stained with a FVgag MHC class I tetramer [4] (Figure 1B). In addition to the magnitude of the CD8+ T cell response, we analyzed the functional properties of these T cells. After Treg ablation, the expression of the cytotoxic molecules granzyme A and B in splenic CD8+ T cells was significantly enhanced during acute FV infection (Figure 1C and 1D), suggesting an improved cytotoxic potential of these cells. To verify that the enhanced granzyme production was associated with an improved degranulation of cytotoxic molecules by CD8+ T cells, expression of the degranulation marker CD107a [13],[14] was also determined. Figure 1E shows that Treg cell depletion significantly increased the number of effector CD8+ T cells expressing CD107a. In addition, Treg ablation not only influenced the production of cytotoxic molecules by antiviral CD8+ T cells, but also influenced their cytokine response. After FV infection, subpopulations of the CD8+ T cells produced IFNγ, TNFα (Figure S2 and [15]), or low amounts of IL-2. Treg depletion increased the percentage of CD8+ T cells producing these cytokines after FV infection (Figure S2). In depleted mice most of the responding CD8+ T cells were multifunctional. Multifunctional T cells simultaneously produce two or more cytokines and have enhanced antiviral effector functions [16]. Most cytokine-producing CD8+ T cells from DT-treated DEREG mice expressed two or three different cytokines, whereas in non-depleted mice the majority of the effector CD8+ T cells expressed only one of the three cytokines measured (unpublished data). In contrast to the results from Lund et al. [1], the augmented virus-specific CD8+ T cell response decreased viral loads in the spleen more than ten times (Figure 1F). Thus, targeted depletion of Treg during acute FV infection resulted in superior control of viral replication rather than an accelerated infection as reported for HSV-2 [1]. The results clearly show that the suppressive activity of Tregs on antiviral immunity is the predominant effect in viral infections in which the primary targets of the virus are cells of the lymphoid organs. This suggests that the concept derived from the study of Lund et al. [1] might mainly apply to pathogens replicating in non-lymphoid tissue during acute infection. Therefore, inhibiting Treg responses therapeutically in infections with lymphotropic viruses might still be an interesting approach for antiviral treatment. Figure 1 Cytotoxic CD8+ T cell responses and spleen viral loads in mice infected with FV and experimentally depleted of Tregs.

An autoradiographical method for the determination of alpha emission rates from plastic packaging materials for VLSI silicon memory devices based on long-time exposures of the samples on CR-39 detectors has been tested. The lower limit of detection will be strongly influenced by the background of the detector material and amounts at time to 0.002 alpha particles cm-2h-1 after 200 days exposure. A mathematical method for the interpretation of very low track densities is discussed. First results of application are presented.

Coherence bandwidth is an important propagation parameter that has direct impact on the design and performance of a wireless communications link contemplating performance enhancement features like smart antenna applications. This paper presents wideband characterization for indoor and outdoor-to-indoor channels and wideband vector channel measurements for an indoor environment. The results show that the coherent bandwidth of about 10 MHz associated with indoor channel can accommodate diversity operations for wideband CDMA (W-CDMA) system. In addition, a study of the envelope cross-correlation points to the feasibility of a smart antenna system. For outdoor-to-indoor channel, the coherence bandwidth indicated that some additional temporal processing would be necessary for a W-CDMA system. Existing narrowband systems, however, would suffice to use simple diversity techniques in such a channel.

This paper presents a technique for measuring and modeling multipath components in wideband vector channels. The technique is useful for analyzing and simulating channels for wideband receiver antenna array systems and wideband MIMO (multiple-input, multiple-output) systems. By performing wideband vector channel measurements, the strengths of the multipath components resolved within the bandwidth of the system are compared across the array. Diffuse scattering and summation of multipath with delay differences within the resolution of the receiver cause received multipath components to fade. Fading of components across the array can be compared and quantified using correlation coefficients. Developed through this research is a method of processing data that produces results useful for modeling, simulation, and characterization of wideband vector channels using measurements.

Optimum beamformer output SINR with one interfering signal is expressed in terms of signal spatial signatures and noise power. The expression, valid for multipath channels, leads to consistent results for the cases of no interference and strong interference. The optimum SINR calculated using the expression is compared to measured SINR achieved using an adaptive beamforming algorithm applied to data recorded using an antenna array testbed.

The next generation CDMA standard, wideband CDMA (W-CDMA), has provision for many performance enhancement options to support high data-rate services. Transmit diversity has been proposed as one mechanism for performance enhancement. This paper presents a real-time implementation of a wideband transmit diversity system. The implementation was carried out to demonstrate transmit diversity in an indoor wireless channel at the handset with a two-element antenna array at 2.05 GHz for a bandwidth of 5 MHz. The diversity algorithm is a closed loop technique and is based on scanning the phase of signal on one antenna relative to the other. Single antenna measurements were also performed to serve as a baseline measure. Measurements were carried out both in line-of-sight (LOS) and in non-LOS (NLOS) environments. The diversity gains when assessed using a cumulative distribution function (CDF), showed gains of 2 dB and 7 dB respectively compared to individual antenna element for the LOS environment (at 1% CDF level). For the NLOS case, the diversity gains were more than 10 dB at the 1% CDF level.

Up to now discrepancies between different evaluations of neutron data for structural materials of FBR as well as for fission products persist. Reactivity measurements as integral data check are usually difficult to interpret because of the simultaneous dependence of sample reactivity worth on absorption and scattering cross-sections. In order to avoid or at least to minimize this disadvantage the method of reactivity measurement has been modified with the goal to separate absorption and scattering effects by designing of special reactor configurations.

The Densitron 4 is a computer aided image analyzer which was developed at our institute especially with the aim to evaluate autoradiograms. One of the important parameters of this evaluation is the optical density. The calibration of the Densitron 4 in units of optical density is described. An example demonstrates the principle of this calibration. The measurement errors are calculated.

The influence of etching time and vaccum processing before, during, and after neutron irradiation on the “signal/noise” ratio of the neutron induced autoradiography of boron using CR-39 track detectors has been investigated. The neutron irradiation was carried out in a vacuum chamber using the Cf-252 neutron source of the Central Institute of Isotope and Radiation Research at Leipzig. Hungarian-made CR-39 type track detectors, MA-ND/p and MA-ND/α, produced in different years, are compared. After a few hours of 2 kPa (about 10 -2 Torr) vacuum treatment, the “signal/noise” ratio for boron determination is improved remarkably in most cases of the detector and etching-time combinations used.