Invariant NKT cell defects in vitamin D receptor knockout mice prevents experimental lung inflammation

Vitamin D receptor (VDR) deficiency (knockout [KO]) results in a failure of mice to generate an airway hyperreactivity (AHR) response on both the BALB/c and C57BL/6 background. The cause of the failed AHR response is the defective population of invariant NKT (iNKT) cells in the VDR KO mice because wild-type (WT) iNKT cells rescued the AHR response. VDR KO mice had significantly fewer iNKT cells and normal numbers of T cells in the spleen compared with WT mice. In BALB/c VDR KO mice, the reduced frequencies of iNKT cells were not apparent in the liver or thymus. VDR KO and WT Th2 cells produced similar levels of IFN-γ and IL-5. On the BALB/c background, Th2 cells from VDR KO mice produced less IL-13, whereas on the C57BL/6 background, Th2 cells from VDR KO mice produced less IL-4. Conversely, VDR KO iNKT cells were defective for the production of multiple cytokines (BALB/c: IL-4, IL-5, and IL-13; C57BL/6: IL-4 and IL-17). Despite relatively normal Th2 responses, BALB/c and C57BL/6 VDR KO mice failed to develop AHR responses. The defect in iNKT cells as a result of the VDR KO was more important than the highly susceptible Th2 background of the BALB/c mice. Defective iNKT cell responses in the absence of the VDR result in the failure to generate AHR responses in the lung. The implication of these mechanistic findings for human asthma requires further investigation.     

May the wild male loose? Male wing fanning performances and mating success in wild and mass-reared strains of the aphid parasitoid Aphidius colemani Viereck (Hymenoptera: Braconidae: Aphidiinae)

Aphidius colemani Viereck (Hymenoptera: Braconidae) is a pan-tropical broadly oligophagous endoparasitoid of many aphids of economic importance, including Aphis gossypii Glover and Myzus persicae (Sulzer). While the trophic interactions occurring among A. colemani and its hosts have been extensively studied, little is known about the male- and female-borne cues that guide mating dynamics. Male wing fanning has been found to play a key role in A. colemani courtship, as successful mounting of females without initial wing fanning has never been observed. In this research, we analyzed wing fanning performance and mating ability of males from three different strains of A. colemani: wasps commercially mass-reared on A. gossypii, wild wasps from parasitized A. gossypii, and wild wasps from parasitized Aphis nerii Boyer de Fonscolombe. Results showed that virgin females did not rely on particular male fanning features during mate choice. Moreover, when A. colemani individuals developed on A. gossypii, no major differences were detected in courtship and mating ability between field collected and mass-reared wasps. In contrast, courtship performance and mating success varied between wild A. colemani males reared on different hosts, with those developing on A. nerii having lower quality wing fanning performance during the mounting attempt phase, and reduced ability to compete for females with other males reared on A. gossypii.     

Deep White Matter in Huntington's Disease

White matter (WM) abnormalities have already been shown in presymptomatic (Pre-HD) and symptomatic HD subjects using Magnetic Resonance Imaging (MRI). In the present study, we examined the microstructure of the long-range large deep WM tracts by applying two different MRI approaches: Diffusion Tensor Imaging (DTI) -based tractography, and T2*weighted (iron sensitive) imaging. We collected Pre-HD subjects (n = 25), HD patients (n = 25) and healthy control subjects (n = 50). Results revealed increased axial (AD) and radial diffusivity (RD) and iron levels in Pre-HD subjects compared to controls. Fractional anisotropy decreased between the Pre-HD and HD phase and AD/RD increased and although impairment was pervasive in HD, degeneration occurred in a pattern in Pre-HD. Furthermore, iron levels dropped for HD patients. As increased iron levels are associated with remyelination, the data suggests that Pre-HD subjects attempt to repair damaged deep WM years before symptoms occur but this process fails with disease progression.     

Ethnicity and Child Health in Northern Tanzania: Maasai Pastoralists Are Disadvantaged Compared to Neighbouring Ethnic Groups

The Maasai of northern Tanzania, a semi-nomadic ethnic group predominantly reliant on pastoralism, face a number of challenges anticipated to have negative impacts on child health, including marginalisation, vulnerabilities to drought, substandard service provision and on-going land grabbing conflicts. Yet, stemming from a lack of appropriate national survey data, no large-scale comparative study of Maasai child health has been conducted. Savannas Forever Tanzania surveyed the health of over 3500 children from 56 villages in northern Tanzania between 2009 and 2011. The major ethnic groups sampled were the Maasai, Sukuma, Rangi, and the Meru. Using multilevel regression we compare each ethnic group on the basis of (i) measurements of child health, including anthropometric indicators of nutritional status and self-reported incidence of disease; and (ii) important proximate determinants of child health, including food insecurity, diet, breastfeeding behaviour and vaccination coverage. We then (iii) contrast households among the Maasai by the extent to which subsistence is reliant on livestock herding. Measures of both child nutritional status and disease confirm that the Maasai are substantially disadvantaged compared to neighbouring ethnic groups, Meru are relatively advantaged, and Rangi and Sukuma intermediate in most comparisons. However, Maasai children were less likely to report malaria and worm infections. Food insecurity was high throughout the study site, but particularly severe for the Maasai, and reflected in lower dietary intake of carbohydrate-rich staple foods, and fruits and vegetables. Breastfeeding was extended in the Maasai, despite higher reported consumption of cow''s milk, a potential weaning food. Vaccination coverage was lowest in Maasai and Sukuma. Maasai who rely primarily on livestock herding showed signs of further disadvantage compared to Maasai relying primarily on agriculture. We discuss the potential ecological, socioeconomic, demographic and cultural factors responsible for these differences and the implications for population health research and policy.     

PDCD10 Gene Mutations in Multiple Cerebral Cavernous Malformations

Cerebral cavernous malformations (CCMs) are vascular abnormalities that may cause seizures, intracerebral haemorrhages, and focal neurological deficits. Familial form shows an autosomal dominant pattern of inheritance with incomplete penetrance and variable clinical expression. Three genes have been identified causing familial CCM: KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3. Aim of this study is to report additional PDCD10/CCM3 families poorly described so far which account for 10-15% of hereditary cerebral cavernous malformations. Our group investigated 87 consecutive Italian affected individuals (i.e. positive Magnetic Resonance Imaging) with multiple/familial CCM through direct sequencing and Multiplex Ligation-Dependent Probe Amplification (MLPA) analysis. We identified mutations in over 97.7% of cases, and PDCD10/CCM3 accounts for 13.1%. PDCD10/CCM3 molecular screening revealed four already known mutations and four novel ones. The mutated patients show an earlier onset of clinical manifestations as compared to CCM1/CCM2 mutated patients. The study of further families carrying mutations in PDCD10/CCM3 may help define a possible correlation between genotype and phenotype; an accurate clinical follow up of the subjects would help define more precisely whether mutations in PDCD10/CCM3 lead to a characteristic phenotype.     

Linking Environmental Forcing and Trophic Supply to Benthic Communities in the Vercelli Seamount Area (Tyrrhenian Sea)

Seamounts and their influence on the surrounding environment are currently being extensively debated but, surprisingly, scant information is available for the Mediterranean area. Furthermore, although the deep Tyrrhenian Sea is characterised by a complex bottom morphology and peculiar hydrodynamic features, which would suggest a variable influence on the benthic domain, few studies have been carried out there, especially for soft-bottom macrofaunal assemblages. In order to fill this gap, the structure of the meio-and macrofaunal assemblages of the Vercelli Seamount and the surrounding deep area (northern Tyrrhenian Sea – western Mediterranean) were studied in relation to environmental features. Sediment was collected with a box-corer from the seamount summit and flanks and at two far-field sites in spring 2009, in order to analyse the metazoan communities, the sediment texture and the sedimentary organic matter. At the summit station, the heterogeneity of the habitat, the shallowness of the site and the higher trophic supply (water column phytopigments and macroalgal detritus, for instance) supported a very rich macrofaunal community, with high abundance, biomass and diversity. In fact, its trophic features resembled those observed in coastal environments next to seagrass meadows. At the flank and far-field stations, sediment heterogeneity and depth especially influenced the meiofaunal distribution. From a trophic point of view, the low content of the valuable sedimentary proteins that was found confirmed the general oligotrophy of the Tyrrhenian Sea, and exerted a limiting influence on the abundance and biomass of the assemblages. In this scenario, the rather refractory sedimentary carbohydrates became a food source for metazoans, which increased their abundance and biomass at the stations where the hydrolytic-enzyme-mediated turnover of carbohydrates was faster, highlighting high lability.     

The Lantibiotic NAI-107 Binds to Bactoprenol-bound Cell Wall Precursors and Impairs Membrane Functions

The lantibiotic NAI-107 is active against Gram-positive bacteria including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. To identify the molecular basis of its potency, we studied the mode of action in a series of whole cell and in vitro assays and analyzed structural features by nuclear magnetic resonance (NMR). The lantibiotic efficiently interfered with late stages of cell wall biosynthesis and induced accumulation of the soluble peptidoglycan precursor UDP-N-acetylmuramic acid-pentapeptide (UDP-MurNAc-pentapeptide) in the cytoplasm. Using membrane preparations and a complete cascade of purified, recombinant late stage peptidoglycan biosynthetic enzymes (MraY, MurG, FemX, PBP2) and their respective purified substrates, we showed that NAI-107 forms complexes with bactoprenol-pyrophosphate-coupled precursors of the bacterial cell wall. Titration experiments indicate that first a 1:1 stoichiometric complex occurs, which then transforms into a 2:1 (peptide: lipid II) complex, when excess peptide is added. Furthermore, lipid II and related molecules obviously could not serve as anchor molecules for the formation of defined and stable nisin-like pores, however, slow membrane depolarization was observed after NAI-107 treatment, which could contribute to killing of the bacterial cell.     

Control of SARS-CoV-2 infection after Spike DNA or Spike DNA+Protein co-immunization in rhesus macaques

The speed of development, versatility and efficacy of mRNA-based vaccines have been amply demonstrated in the case of SARS-CoV-2. DNA vaccines represent an important alternative since they induce both humoral and cellular immune responses in animal models and in human trials. We tested the immunogenicity and protective efficacy of DNA-based vaccine regimens expressing different prefusion-stabilized Wuhan-Hu-1 SARS-CoV-2 Spike antigens upon intramuscular injection followed by electroporation in rhesus macaques. Different Spike DNA vaccine regimens induced antibodies that potently neutralized SARS-CoV-2 in vitro and elicited robust T cell responses. The antibodies recognized and potently neutralized a panel of different Spike variants including Alpha, Delta, Epsilon, Eta and A.23.1, but to a lesser extent Beta and Gamma. The DNA-only vaccine regimens were compared to a regimen that included co-immunization of Spike DNA and protein in the same anatomical site, the latter of which showed significant higher antibody responses. All vaccine regimens led to control of SARS-CoV-2 intranasal/intratracheal challenge and absence of virus dissemination to the lower respiratory tract. Vaccine-induced binding and neutralizing antibody titers and antibody-dependent cellular phagocytosis inversely correlated with transient virus levels in the nasal mucosa. Importantly, the Spike DNA+Protein co-immunization regimen induced the highest binding and neutralizing antibodies and showed the strongest control against SARS-CoV-2 challenge in rhesus macaques.