Nipah virus uses leukocytes for efficient dissemination within a host

Nipah virus (NiV) is a recently emerged zoonotic paramyxovirus whose natural reservoirs are several species of Pteropus fruit bats. NiV provokes a widespread vasculitis often associated with severe encephalitis, with up to 75% mortality in humans. We have analyzed the pathogenesis of NiV infection, using human leukocyte cultures and the hamster animal model, which closely reproduces human NiV infection. We report that human lymphocytes and monocytes are not permissive for NiV and a low level of virus replication is detected only in dendritic cells. Interestingly, despite the absence of infection, lymphocytes could efficiently bind NiV and transfer infection to endothelial and Vero cells. This lymphocyte-mediated transinfection was inhibited after proteolytic digestion and neutralization by NiV-specific antibodies, suggesting that cells could transfer infectious virus to other permissive cells without the requirement for NiV internalization. In NiV-infected hamsters, leukocytes captured and carried NiV after intraperitoneal infection without themselves being productively infected. Such NiV-loaded mononuclear leukocytes transfer lethal NiV infection into naïve animals, demonstrating efficient virus transinfection in vivo. Altogether, these results reveal a remarkable capacity of NiV to hijack leukocytes as vehicles to transinfect host cells and spread the virus throughout the organism. This mode of virus transmission represents a rapid and potent method of NiV dissemination, which may contribute to its high pathogenicity.     

Dry stone walls favour biodiversity: a case-study from the Appennines

One of the classical and traditional wall typology built in agricultural or pastoral landscapes are dry stone walls (walls built only of stones without concrete). These vertical surfaces are expected to increase habitat heterogeneity and to play an important role for biodiversity. This study focused on two groups of organisms: amphibians, represented by the rock-dwelling salamander Hydromantes strinatii, that are expected to use walls mainly as shelters, and molluscs, which use of walls may be affected mainly by the trophic resources available. A mountain area of the northern Appennines (NW-Italy) was surveyed to assess the differences between dry stone walls and the wall typologies in terms of morphology, surrounding landscape and salamander and mollusc occurrence; the relationships between wall typology features and salamander and mollusc distribution were assessed. Dry stone walls were more heterogeneous than concrete walls and hosted more lichens than natural rocky walls. They were more used by H. strinatii juveniles than the other walls and played an important role for their distribution. They were positively related to the occurrence of several molluscan species, including species with high ecological plasticity and rock-dwelling species. Among wall features, the most important for molluscs species distribution was vegetation cover, followed by lichen cover and heterogeneity, confirming the importance of trophic content for mollusc exploitation, while vegetated without concrete walls hosted higher number of species. The results suggest that dry stone walls can be important for fauna biodiversity and should be maintained and preserved as a part of landscape management.     

Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome

The Hennekam lymphangiectasia–lymphedema syndrome is a genetically heterogeneous disorder. It can be caused by mutations in CCBE1 which are found in approximately 25 % of cases. We used homozygosity mapping and whole-exome sequencing in the original HS family with multiple affected individuals in whom no CCBE1 mutation had been detected, and identified a homozygous mutation in the FAT4 gene. Subsequent targeted mutation analysis of FAT4 in a cohort of 24 CCBE1 mutation-negative Hennekam syndrome patients identified homozygous or compound heterozygous mutations in four additional families. Mutations in FAT4 have been previously associated with Van Maldergem syndrome. Detailed clinical comparison between van Maldergem syndrome and Hennekam syndrome patients shows that there is a substantial overlap in phenotype, especially in facial appearance. We conclude that Hennekam syndrome can be caused by mutations in FAT4 and be allelic to Van Maldergem syndrome.     

Effects of the FecL major gene in the Lacaune meat sheep population

Background

The major prolificacy gene FecL was first described in the Lacaune sheep meat breed Ovi-Test in 1998. A few studies estimated the effect of this gene on prolificacy but little data is available. In 2010, the Ovi-Test cooperative started genotyping FecL in all of their replacement ewe lambs. Thanks to the large amount of genotyping data that is available now, gene effects on litter size and other relevant traits can be estimated more accurately.

Methods

Our study included 5775 ewes genotyped since 2010 and 1025 sires genotyped since 2002. Performances and pedigrees were extracted from the French national database for genetic evaluation and research. Analysis of the effect of the gene on different traits was based on linear or threshold genetic animal models using the ASReml software.

Results

The female population was composed of 71% homozygous wild type ewes (++), 27% heterozygous ewes for the FecL mutation (L+) and 2% homozygous mutant (LL) ewes. On average, L + ewes produced 0.5 more lambs per lambing than ++ ewes. The FecL gene not only affected the mean litter size but also its variability, which was lower for ++ than for L + ewes. Fertility after insemination was higher for L + ewes than for ++ ewes. Lambs from ++ dams were heavier (+300 g) than the lambs of L + dams and the mortality of twin lambs born from ++ dams was lower than those from L + dams. In addition, bias in estimated breeding values for prolificacy when ignoring the existence of this major gene was quantified.

Conclusions

The effect of the FecL gene on prolificacy was estimated more accurately and we show that this gene affects both the mean and the variability of litter size and other traits. This paper also shows that ignoring the existence of this major gene in genetic evaluation of prolificacy can lead to a large overestimation of polygenic breeding values.     

Somatic and axonal LIGHT signaling elicit degenerative and regenerative responses in motoneurons,respectively

A receptor–ligand interaction can evoke a broad range of biological activities in different cell types depending on receptor identity and cell type‐specific post‐receptor signaling intermediates. Here, we show that the TNF family member LIGHT, known to act as a death‐triggering factor in motoneurons through LT‐βR, can also promote axon outgrowth and branching in motoneurons through the same receptor. LIGHT‐induced axonal elongation and branching require ERK and caspase‐9 pathways. This distinct response involves a compartment‐specific activation of LIGHT signals, with somatic activation‐inducing death, while axonal stimulation promotes axon elongation and branching in motoneurons. Following peripheral nerve damage, LIGHT increases at the lesion site through expression by invading B lymphocytes, and genetic deletion of Light significantly delays functional recovery. We propose that a central and peripheral activation of the LIGHT pathway elicits different functional responses in motoneurons.     

The Rationale for Optimal Combination Therapy With Sipuleucel-T for Patients With Castration-resistant Prostate Cancer

Immunotherapy encourages the recipient’s own immune response to destroy cancer cells, and current evidence suggests that immunotherapies may be most beneficial in early metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T is the first therapeutic cancer vaccine to be approved by both the US Food and Drug Administration and European Medicines Agency for the treatment of asymptomatic or minimally symptomatic mCRPC. Combining immunotherapy with other treatments may have potent anticancer effects; cytoreductive therapies can release tumor antigens and promote a proinflammatory environment that could augment immunotherapies. However, some cytoreductive agents or coadministered drugs may be immunosuppressive. Understanding these interactions between different mCRPC treatment modalities may offer further potential to improve patient outcomes.Key words: Combination therapy, Prostate cancer, Sipuleucel-TImmunotherapy has emerged as a powerful tool against prostate cancer, in addition to surgery, radiotherapy, hormone therapy, and chemotherapy. For 30 years, investigators tried to rebalance the compromised immune system in patients with urologic cancers using a number of different agents.^1,2 In April 2010, the autologous cellular immunotherapy sipuleucel-T became the first therapeutic cancer vaccine to be approved by the US Food and Drug Administration (FDA).³ This therapy targets the prostatic acid phosphatase (PAP) and has been indicated for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), based on results from three randomized, controlled, phase 3 studies.^3–6 Recently, sipuleucel-T was also approved by the European Medicines Agency (EMA) for the treatment of asymptomatic or minimally symptomatic mCRPC in men in whom chemotherapy is not yet clinically indicated.⁷Although this immunotherapy has been shown to extend overall survival (OS),⁵ sequencing or combining immunotherapy with other treatments for mCRPC has the potential to further improve outcomes.^8,9 However, before immunotherapy-based combination regimens can be integrated into clinical practice, it is critical to have a better understanding of the interactions between these different modalities.     

Quantiferon-TB Gold: Performance for Ruling out Active Tuberculosis in HIV-Infected Adults with High CD4 Count in C?te d'Ivoire,West Africa

Objective

To assess the performance of QuantiFERON-TB Gold In-Tube (QFT-GIT) test for active tuberculosis (TB) in HIV adults, and its variation over time in patients on antiretroviral therapy (ART) and/or isoniazide preventive therapy (IPT).

Methods

Transversal study and cohort nested in the Temprano ANRS 12136 randomized controlled trial assessing benefits of initiating ART earlier than currently recommended by World Health Organization, with or without a 6-month IPT. Performance of QFT-GIT for detecting active TB at baseline in the first 50% participants, and 12-month incidence of conversion/reversion in the first 25% participants were assessed. QFT-GIT threshold for positivity was 0.35 IU/ml.

Results

Among the 975 first participants (median baseline CD4 count 383/mm³, positive QFT-GIT test 35%), 2.7% had active TB at baseline. QFT-GIT sensitivity, specificity, positive and negative predictive value for active TB were 88.0%, 66.6%, 6.5% and 99.5%. For the 444 patients with a second test at 12 months, rates for conversion and reversion were 9.3% and 14%. Reversion was more frequent in patients without ART and younger patients. IPT and early ART were not associated with reversion/conversion.

Conclusion

A negative QFT-GIT could rule out active TB in HIV-infected adults not severely immunosuppressed, thus avoiding repeated TB testing and accelerating diagnosis and care for other diseases.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00495651","term_id":"NCT00495651"}}NCT00495651.     

Long Term Expression of Drosophila melanogaster Nucleoside Kinase in Thymidine Kinase 2-deficient Mice with No Lethal Effects Caused by Nucleotide Pool Imbalances

Mitochondrial DNA depletion caused by thymidine kinase 2 (TK2) deficiency can be compensated by a nucleoside kinase from Drosophila melanogaster (Dm-dNK) in mice. We show that transgene expression of Dm-dNK in Tk2 knock-out (Tk2^−/−) mice extended the life span of Tk2^−/− mice from 3 weeks to at least 20 months. The Dm-dNK^+/−Tk2^−/− mice maintained normal mitochondrial DNA levels throughout the observation time. A significant difference in total body weight due to the reduction of subcutaneous and visceral fat in the Dm-dNK^+/−Tk2^−/− mice was the only visible difference compared with control mice. This indicates an effect on fat metabolism mediated through residual Tk2 deficiency because Dm-dNK expression was low in both liver and fat tissues. Dm-dNK expression led to increased dNTP pools and an increase in the catabolism of purine and pyrimidine nucleotides but these alterations did not apparently affect the mice during the 20 months of observation. In conclusion, Dm-dNK expression in the cell nucleus expanded the total dNTP pools to levels required for efficient mitochondrial DNA synthesis, thereby compensated the Tk2 deficiency, during a normal life span of the mice. The Dm-dNK^+/− mouse serves as a model for nucleoside gene or enzyme substitutions, nucleotide imbalances, and dNTP alterations in different tissues.     

Hatching asynchrony that maintains egg viability also reduces brood reduction in a subtropical bird

In birds, hatching failure is pervasive and incurs an energetic and reproductive cost to breeding individuals. The egg viability hypothesis posits that exposure to warm temperatures prior to incubation decreases viability of early laid eggs and predicts that females in warm environments minimize hatching failure by beginning incubation earlier in the laying period, laying smaller clutches, or both. However, beginning incubation prior to clutch completion may incur a cost by increasing hatching asynchrony and possibly brood reduction. We examined whether Florida scrub jays (Aphelocoma coerulescens) began incubation earlier relative to clutch completion when laying larger clutches or when ambient temperatures increased, and whether variation in incubation onset influenced subsequent patterns of hatching asynchrony and brood reduction. We compared these patterns between a suburban and wildland site because site-specific differences in hatching failure match a priori predictions of the egg viability hypothesis. Females at both sites began incubation earlier relative to clutch completion when laying larger clutches and as ambient temperatures increased. Incubation onset was correlated with patterns of hatching asynchrony at both sites; however, brood reduction increased only in the suburbs, where nestling food is limiting, and only during the late nestling period. Hatching asynchrony may be an unintended consequence of beginning incubation early to minimize hatching failure of early laid eggs. Food limitation in the suburbs appears to result in increased brood reduction in large clutches that hatch asynchronously. Therefore, site-specific rates of brood reduction may be a consequence of asynchronous hatching patterns that result from parental effort to minimize hatching failure in first-laid eggs. This illustrates how anthropogenic change, such as urbanization, can lead to loss of fitness when animals use behavioral strategies intended to maximize fitness in natural landscapes.