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Giant viruses, with virions larger than 200 nm and genomes larger than 340 kilobase pairs, modified the now outdated perception of the virosphere. With virions now reported reaching up to 1.5 μm in size and genomes of up to 2.5 Mb encoding components shared with cellular life forms, giant viruses exhibit a complexity similar to microbes, such as bacteria and archaea. Here, we review interactions of giant viruses with their hosts and defense strategies of giant viruses against their hosts and coinfecting microorganisms or virophages. We also searched by comparative genomics for homologies with proteins described or suspected to be involved in defense mechanisms. Our search reveals that natural immunity and apoptosis seem to be crucial components of the host defense against giant virus infection. Conversely, giant viruses possess methods of hijacking host functions to counteract cellular antiviral responses. In addition, giant viruses may encode other unique and complex pathways to manipulate the host machinery and eliminate other competing microorganisms. Notably, giant viruses have evolved defense mechanisms against their virophages and they might trigger defense systems against other viruses through sequence integration. We anticipate that comparative genomics may help identifying genes involved in defense strategies of both giant viruses and their hosts., (© 2020 New York Academy of Sciences.)

Despite improvements in operative strategies for esophageal resection, anastomotic leaks, fistula, postoperative pulmonary complications, and chylothorax can occur. Our review seeks to identify potential risk factors, modalities for early diagnosis, and novel interventions that may ameliorate the potential adverse effects of these surgical complications following esophagectomy., (© 2018 New York Academy of Sciences.)

Sixteen neurons, including vestibular-only (VO), eye-head velocity (EHV), and position-vestibular-pause (PVP) neurons sensitive to head tilt were recorded in the rostromedial and in superior vestibular nuclei. Projection of the otolith polarization vector to the horizontal plane (response vector orientation [RVO]) was determined before and after prolonged head orientation in side-down position. The RVO of VO neurons shifted toward alignment with the axis of gravity when the head was in the position of adaptation. PVP neurons had similar changes in RVO. There were also changes in RVO in some EHV neurons, but generally in directions not related to gravity. Modeling studies have suggested that the tendency to align RVOs with gravity leads to tuning of gravity-dependent angular vestibular ocular reflex (aVOR) gain changes to the position of adaptation. Thus, coding of orientation in PVP neurons would contribute significantly to the gravity-dependent adaptation of the aVOR., (© 2011 New York Academy of Sciences.)

Multiple myeloma (MM) is a malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow (BM). Because of the known involvement of thymosin beta4 (Tbeta4) in metastasis of tumor cells, we examined the expression and role of Tbeta4 in MM disease. In a large patient population, we demonstrated that Tbeta4 expression was significantly lower in myeloma cells compared to normal plasma cells and that patients with a high Tbeta4 expression had a longer event free and overall survival. The decreased Tbeta4 expression was also found in the murine 5TMM model. To study its function, we overexpressed the Tbeta4 gene in 5T33MMvt cells by lentiviral transduction. These cells demonstrated a decreased proliferative capability and an increased sensitivity to apoptosis. Mice injected with Tbeta4-overexpressing cells showed a prolonged survival compared to mice injected with controls. In contrast to its role in solid tumors, we found a decreased expression in myeloma cells compared to their normal counterpart and studies with overexpression of the Tbeta4 gene indicated a tumor suppressive function of Tbeta4 in myeloma development.

Integration of the relevant evolutionary paradigm in cardiology has not yet been fully achieved: In the past, heart failure (HF) was mainly ascribed to infections, and the origins of cardiac hypertrophy (CH) were regarded as mechanical. Recent changes in lifestyle have both reduced the incidence of infections and increased lifespan, and HF is now seen as a complex disease--one that is still caused by mechanical disorder, but also associated with ischemia and senescence. The long-held view that CH serves to restore myocardial economy back to normal is still valid. The adaptive process is characterized by a quantitative and a qualitative fetal gene reprogramming, which is now being confirmed by recent advances in microRNA research. It underscores the fact CH is the physiologic reaction of the heart to a pathologic stimulus. The goal for therapy is economic, not inotropic. Another major issue is myocardial fibrosis, a major determinant of diastolic function and arrhythmias. Recent changes in lifestyle have crucially modified the context in which HF occurs.

Interleukin-10 (IL-10) is central in immune downregulation, but so far its use in inflammatory diseases remains cumbersome. For treatment of inflammatory bowel disease, adequate amounts of IL-10 must reach the intestinal lining. Systemic injection of a pharmacologically active doses of recombinant human (rh) IL-10 results in very low mucosal levels of protein and severe toxicity and side effects. In animal models, topical and active delivery of IL-10 by ingestion of recombinant Lactococcus lactis (L. lactis) was shown to be a valuable alternative. Starting thereof we have developed a novel pharmaceutical platform. Our expertise and TopAct (topical and active) delivery technology allows use of recombinant L. lactis- ActoBiotics- in clinical practice. Here we discuss the development of recombinant L. lactis for intestinal delivery of rhIL-10 in humans.

Otolith-only neurons were recorded extracellularly in the vestibular nuclei before and after cynomolgus monkeys were held on-side for up to 3 hr. The aim was to determine whether the polarization vectors of these neurons reorient toward the spatial vertical as do canal-otolith convergent neurons. Otolith input was characterized by tilting the animal 30 degrees from the upright position while positioning the head in different directions in yaw. This determined the response vector orientation (RVO), that is, the projection of the otolith polarization vector onto the head horizontal plane. Changes in the RVO of otolith-only neurons ranged from 2 degrees -16 degrees , which was on average considerably less than the changes previously noted in canal-otolith convergent vestibulo-only (VO) and vestibular plus saccade (VPS) neurons, which ranged up to 109 degrees. Some of the otolith-only neurons had marked sensitivity changes. These findings suggest that otolith-only neurons tend to maintain a head-fixed orientation during prolonged head tilts relative to gravity. In contrast, canal-convergent VO and VPS neurons optimize their response vector orientation to gravity when the head is oriented for prolonged periods.

The cervico-ocular reflex (COR) has a low gain in normal animals. In this study, we determined whether COR gain increases were specific to the low/midband frequency range, which is the range over which the angular vestibulo-ocular reflex (aVOR) is compromised by plugging. The gain and phase of the yaw and pitch COR and aVOR were compared in normal monkeys and those with all six semicircular canals or only the lateral canal plugged. During experiments animals sat with the body fixed to a chair and the head fixed in space. The body was oscillated about body-yaw and body-pitch axes over a frequency range of 0.05-6 Hz, with amplitude <10 degrees. For normal animals, both yaw and pitch eye velocities were compensatory to the relative velocity of the head with respect to the body. The gains were 0.1-0.2 at frequencies below 1 Hz and decreased to zero as stimulus frequency increased above 1 Hz. Canal-plugged animals had COR gains close to 1.0 at low frequencies, decreasing to approximately 0.6 at 0.5 Hz and to 0.2 for stimulus frequencies above 3 Hz. The phase of eye velocity was 180 degrees relative to head-re-body velocity at frequencies below 0.5 Hz and shifted toward 270 degrees as frequencies were increased to 4 Hz. This study demonstrates that adaptation of COR gain is tuned to a frequency range at which the aVOR is compromised by the canal plugging., Competing Interests: The authors declare no conflicts of interest.

The vestibular system plays an important role in controling gait, but where in the labyrinths relevant activity arises is largely unknown. After the semicircular canals are plugged, low frequency (0.01-2 Hz) components of the angular vestibulo-ocular reflex (aVOR) and angular vestibulo-collic reflex (aVCR) are lost, but high frequency (3-20 Hz) components remain. We determined how loss of low frequency canal afference affects limb and head movements during quadrupedal locomotion. Head, body, and limb movements were recorded in three dimensions (3-D) in a cynomolgus monkey with a motion detection system, while the animal walked on a treadmill. All six canals were plugged, reducing the canal time constants from approximately 4.0 sec to approximately 0.07 sec. Major changes in the control of the limbs occurred after surgery. Fore and hind limbs were held farther from the body, producing a broad-based gait. Swing-phase trajectories were inaccurate, and control of medial-lateral limb movement was erratic. These changes in gait were present immediately after surgery, as well as 15 months later, when the animal had essentially recovered. Thus, control of the limbs in the horizontal plane was defective after loss of the low-frequency semicircular canal input and never recovered. Cycle-averaged pitch and roll head rotations, and 3-D head translations were also significantly larger and more erratic after than before surgery. Head rotations in yaw could not be quantified due to intrusion of voluntary head turns. These findings indicate that the semicircular canals provide critical low frequency information to maximize the accuracy of stepping and stabilize the head during normal quadrupedal locomotion., Competing Interests: The authors declare no conflicts of interest.

The aim of the study was to determine whether accommodation to the relative motion of a target along the visual axis of one eye during fore-aft movement of the head could induce accurate vergence over a wide range of viewing distances and frequencies of oscillation, despite lack of vision in the second eye. This was compared to the vergence when both eyes viewed the target. Two rhesus monkeys were trained to fixate a visual target located 216-336 mm in front and along the visual axis of one eye, while being sinusoidally translated in the fore-aft direction. There was no movement of the seeing eye while the other eye converged, regardless of whether there was vision in the converged eye. Gain and phase of the convergence were determined based on the ratio of actual versus expected eye position if the target was accurately fixated. During translation at frequencies from 0.05 to 2 Hz, the eye converged on the target with an eye position gain of approximately 1, and a phase close to zero. When vision was occluded in the converging eye, gains of convergence were 0.6-0.8 Hz up to 2 Hz, and the phases remained close to zero. At low frequencies of fore-aft movement, when the acceleration was negligible, convergence was driven by accommodation in the seeing eye. At higher frequencies, vergence could also be driven by the linear vestibulo-ocular reflex (lVOR). Thus, vision in one nonmoving eye and the lVOR combine to generate convergence over a wide range of frequencies and viewing distances.

This paper presents an update of the role of minimally invasive surgery (MIS) in gastrointestinal malignancy. A review of indications, surgical technique, and radicality of laparoscopy in the field of gastrointestinal cancer surgery is discussed. The feasibility and safety of laparoscopic procedures are compared with established and implemented standards in the diagnosis and treatment of oncological disorders. It is important to appreciate that only the "access" is different with all its attendant advantages. The use of laparoscopy in tumor staging and palliative and curative resection is evaluated on review of the literature, and special indications for a laparoscopic approach in gastrointestinal malignancy in different organs are discussed. In conclusion, MIS is safe and feasible, with many short-term advantages; long-term results should be further assessed in randomized controlled studies. Until the outcomes of such studies are available MIS for malignant disease should be performed by experienced surgeons in specialized centers.

The cytotoxic proteins released by activated eosinophils should play a role in the development of Churg-Strauss syndrome (CSS). Eighteen patients (15 males and 3 females, age 41 +/- 13.3 years) with CSS according to the American College of Rheumatology criteria were included in the study. Thirteen serum samples from 11 patients were obtained at the time of disease flare, and the sera from 6 of them were also obtained at the time of clinical remission. Sera from seven other patients were obtained in clinical remission. Anti-neutrophil cytoplasm antibodies were detected in four (22.2%) patients. Fifteen healthy individuals were used as controls. Mean eosinophil count differed significantly between CSS patients with active disease and patients in clinical remission (3,407/mm(3) vs. 258/mm(3); P < 0.01), between CSS patients with active disease and healthy individuals (3,407/mm(3) vs. 211/mm(3); P < 0.01). Mean serum ECP levels differed significantly between patients with active or inactive disease (219 microg/L vs. 56.8 microg/L; P < 0.0001), between patients with active disease and healthy individuals (219 microg/L vs. 26.2 microg/L; P < 0.0001), but not between patients with inactive disease and healthy individuals (ns). Peripheral blood eosinophils count correlated with serum ECP during CSS flares disease (R = 0.6264; P < 0.05) and during periods of remission (R = 0.4798; P < 0.05). Our results support that ECP might be used as a disease activity marker in CSS.

The aim of the 5-year European Union (EU)-Integrated Project GEnetics of Healthy Aging (GEHA), constituted by 25 partners (24 from Europe plus the Beijing Genomics Institute from China), is to identify genes involved in healthy aging and longevity, which allow individuals to survive to advanced old age in good cognitive and physical function and in the absence of major age-related diseases. To achieve this aim a coherent, tightly integrated program of research that unites demographers, geriatricians, geneticists, genetic epidemiologists, molecular biologists, bioinfomaticians, and statisticians has been set up. The working plan is to: (a) collect DNA and information on the health status from an unprecedented number of long-lived 90+ sibpairs (n = 2650) and of younger ethnically matched controls (n = 2650) from 11 European countries; (b) perform a genome-wide linkage scannning in all the sibpairs (a total of 5300 individuals); this investigation will be followed by linkage disequilibrium mapping (LD mapping) of the candidate chromosomal regions; (c) study in cases (i.e., the 2650 probands of the sibpairs) and controls (2650 younger people), genomic regions (chromosome 4, D4S1564, chromosome 11, 11.p15.5) which were identified in previous studies as possible candidates to harbor longevity genes; (d) genotype all recruited subjects for apoE polymorphisms; and (e) genotype all recruited subjects for inherited as well as epigenetic variability of the mitochondrial DNA (mtDNA). The genetic analysis will be performed by 9 high-throughput platforms, within the framework of centralized databases for phenotypic, genetic, and mtDNA data. Additional advanced approaches (bioinformatics, advanced statistics, mathematical modeling, functional genomics and proteomics, molecular biology, molecular genetics) are envisaged to identify the gene variant(s) of interest. The experimental design will also allow (a) to identify gender-specific genes involved in healthy aging and longevity in women and men stratified for ethnic and geographic origin and apoE genotype; (b) to perform a longitudinal survival study to assess the impact of the identified genetic loci on 90+ people mortality; and (c) to develop mathematical and statistical models capable of combining genetic data with demographic characteristics, health status, socioeconomic factors, lifestyle habits.

The Ferlo area (north-central Senegal) is characterized by a system of temporary ponds favorable to arboviruses among which West Nile fever (WNF) was already identified. During the rainy season in 2003, a serological study was undertaken on horses to assess the activity of the WNF virus (WNFV) in Barkedji (Ferlo). The observed serological prevalence rate was 78.3% for neutralizing antibodies, with a 95% confidence interval (CI) of [64.0, 92.7]. This prevalence rate significantly increased with age (P = 10(-5)). This study confirmed that WNF was endemic in the Ferlo. The transmission risks depended on the introduction of the WNFV in the ecosystem--probably with migrating birds, on its amplification in hosts and on the vector-population dynamic. Further studies are needed to investigate how the cycle is initiated in Barkedji at the beginning of the rainy season and the impact of climatic variations on the risk of transmission of WNF. A surveillance system should be implemented: (a) to assess the clinical impact of the WNF on human and equine populations, (b) to provide an early detection of virulent strains, and (c) to assess the risk of WNF transmission to disease-free ecosystems via migrating birds.

Both innate and adaptative immune responses contribute to the control of infectious diseases, including by limiting the spreading of zoonotic diseases from animal reservoirs to humans. Pigs represent an important animal reservoir for influenza virus infection of human populations and are also naturally infected by coronaviruses, an important group of viruses, which includes the recently emerged severe acute respiratory syndrome (SARS) virus. Studies on both innate and adaptative immune responses of pigs to influenza virus and coronaviruses contribute, therefore, to a better control of these infections in their natural hosts and will be briefly reviewed in this article. Pro-inflammatory cytokines, including type I interferon (IFN), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6), were found in lung secretions of influenza virus infected pigs, and correlated with the intensity of clinical signs, whereas prior vaccination against influenza strongly reduced the production of infectious virus and cytokines in the lungs upon challenge, which was associated with clinical protection. An early type I IFN production was also found in coronavirus infected pigs, including at mucosal sites. IFN induction by coronavirus is shown to involve interaction between a viral glycoprotein and a leukocyte subset, likely equivalent to plasmacytoid dendritic cells, present in the mucosae and associated lymphoid tissues. Given the IFN mediated antiviral and immunomodulatory effects, the use of IFN or IFN inducers may prove an efficient strategy for a better control of influenza virus and coronavirus infections in pigs. Because influenza and coronaviruses target mucosal surfaces, adaptative immune responses have to be characterized at mucosal sites. Thus, nasal and pulmonary antibody responses were analyzed in influenza virus infected or vaccinated pigs showing short-lived, but potentially protective local IgA and IgG antibody (Ab) responses. Interestingly, primary influenza virus infection induced long-lived increase of lung CD8(+) T cells and local lymphoproliferative responses. Pigs infected by a respiratory coronavirus (PRCV) showed virus-specific IgG Ab-secreting cells in the bronchial lymph nodes, whereas the transmissible gastroenteritis coronavirus (TGEV) induced more IgA Ab-secreting cells in gut tissues, which illustrates the importance of the route of antigen administration for inducing local immune effector mechanisms. Porcine viral infections provide, therefore, valuable models for evaluating the immune parameters that are important for controlling transmission of important viral zoonotic infections.

Canine monocytic ehlichiosis (CME), an enzootic disease in Africa, has been studied in canine blood samples (serum). These dogs, without any clinical sign of disease, were living in Abidjan (Ivory Coast) and in several small villages located in northeasst Gabon (Ogooué Ivindo). The results obtained by indirect fluorescent antibody (IFA) test, used as a point of reference, and by a quick test dot-Elisa were compared. Blood samples taken from 390 asymptomatic dogs in 2003 (137 in Ivory Coast and 253 in Gabon) were screened by IFA (antigen from Symbiotics Europe, Lyon) with a positive threshold set at 1/80. Afterwards, CME was detected by the commercial test kit Dot-Elisa in solid phase Snap 3Dx (Idexx, Westbrook, Maine, USA), using recombinant proteins which belong to Ehrlichia canis, p30 and p30-1. Using the IFA test, CME seroprevalence in the Ivory Coast is found to be 67.8%. Among 93 Ivorian seropositive blood samples, 76 samples show an antibody titer >1/2560. In Gabon, IFA showed that seroprevalence is only 3.1%. Among 8 seropositive Gabonese dogs, only one sample shows an antibody test titer> 1/2560. Results from the Snap 3Dx test used on 390 blood samples are 100 positive samples and 290 negative ones. Comparison between IFA and Snap test 3DX revealed that the Snap test shows 97.9% specificity, 93.1% sensitivity, a 94% positive predictive value, a 97.6%, negative predictive value, and 96.6% reliability. In conclusion, CME seroprevalence in Abidjan is very high. Dogs studied for CME were watchdogs, living in kennels, where infection transmitted by Rhipicephalus sanguineus seems to be higher in the Gabonese area called Ogooué Ivindo, where semi-stray dogs were subjected to the test. These dogs where carried ticks identified as Haemaphysalis leachi, but this kind of tick is not considered as bearing Ehrlichia canis. Finally, results of the Snap 3Dx show that it is a simple and reliablemeans for quickly detecting dogs suspected of asymptomatic canine ehrlichiosis.

This study attemps to clarify the virulence and the pathogenicity of the Borgo 89 strain of Ehrlichia canis isolated from a sick dog in Corsica (France). Four unscathed beagles were intravenously injected with an inoculum of leukocytes infected with the Borgo 89 strain and the animals were examined daily for clinical signs of disease, and blood samples were drawn at frequent intervals for biochemical and hematologic assessment. Serologic (IFI) and PCR assays were also carried out. The results at autopsy are presented in this paper, leading to the conclusion that the Borgo 89 strain has a pathogenicity comparable to that of the known strains. However, the discovery of a case of completely unapparent infection raises the question of a possible individual immunization whose origin remains unexplained.

Bovine babesiosis, caused by Babesia bovis, B. bigemina, and B. divergens, is a significant impediment to livestock production in countries with tropical/subtropical and temperate climates. Previous studies conducted on the immunoprophylaxis against the disease and diagnosis of these parasites has demonstrated the presence of similar antigens. The objective of this article was to identify and partially characterize antigens conserved among these three species. Immunochemical analysis using sera from cattle immunized individually with antigens from these three Babesia species revealed a number of antigens recognized by heterologous antisera. Cross-reactions were more evident in sera from cattle immunized with B. bovis/B. bigemina which recognized several antigens (15 kDa to >200 kDa) in B. divergens. Immunoscreening of a B. divergens cDNA library with bovine serum to B. bigemina allowed the isolation of five clones and DNA sequencing of plasmid BdJF5 showed a 680 bp cDNA insert. Basic Local Alignment Search Tool (BLAST) analysis of the predicted amino acid sequence revealed 47% identity with a protein identified as alphaNAC. Serum from mice immunized with a recombinant Glutathione S-Transferase-BdJF5 fusion protein immunoprecipitated a 20 kDa B. bovis antigen. However, 30 kDa and 18 kDa antigens were immunoprecipitated from B. divergens and immunoblotting analysis revealed the recognition of a 35 kDa B. bigemina antigen. An indirect fluorescence antibody assay on merozoites showed strong reaction with B. divergens and weak recognition of B. bovis and B. bigemina. Despite the existent antigenic polymorphism among the Babesia spp., these results demonstrated that common antigens occur between European B. divergens and Mexican B. bovis/B. bigemina.