Pairwise perturbation of flagellin subunits. The structural basis for the differences between plain and complex bacterial flagellar filaments

Although plain and complex bacterial flagellar filaments differ in their physical properties and helical symmetry, they both appear to derive from a common underlying structure. Analysis of electron micrographs of complex filaments of Rhizobium lupini revealed that the unit cell has twice the length of that of plain filaments, with a corresponding reduction in helical symmetry whereby the six-start helical family present in plain filaments collapses into a three-start family. Mass per unit length measurements were made by scanning transmission electron microscopy. These, together with the unit cell dimensions and the molecular weight of the flagellin monomer, enabled the number of monomers per unit cell to be estimated. Whereas plain filaments have a single monomer per unit cell, complex filaments have two. These results suggest that complex filament structure differs from plain filament structure by a pairwise perturbation, or interaction, of the flagellin monomers. The additional bonding interactions involved in the perturbation in the complex filament may make it more rigid than the plain filament, which has no such perturbation.     

Turning regenerative technologies into treatment to repair myocardial injuries

Regenerative therapies including stem cell treatments hold promise to allow curing patients affected by severe cardiac muscle diseases. However, the clinical efficacy of stem cell therapy remains elusive, so far. The two key roadblocks that still need to be overcome are the poor cell engraftment into the injured myocardium and the limited knowledge of the ideal mixture of bioactive factors to be locally delivered for restoring heart function. Thus, therapeutic strategies for cardiac repair are directed to increase the retention and functional integration of transplanted cells in the damaged myocardium or to enhance the endogenous repair mechanisms through cell-free therapies. In this context, biomaterial-based technologies and tissue engineering approaches have the potential to dramatically impact cardiac translational medicine. This review intends to offer some consideration on the cell-based and cell-free cardiac therapies, their limitations and the possible future developments.     

Phosphoproteomics identifies microglial Siglec‐F inflammatory response during neurodegeneration

Alzheimer’s disease (AD) is characterized by the appearance of amyloid‐β plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Using mass spectrometry, we have quantified the phosphoproteome of the CK‐p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. We identified a shared response involving Siglec‐F which was upregulated on a subset of reactive microglia. The human paralog Siglec‐8 was also upregulated on microglia in AD. Siglec‐F and Siglec‐8 were upregulated following microglial activation with interferon gamma (IFNγ) in BV‐2 cell line and human stem cell‐derived microglia models. Siglec‐F overexpression activates an endocytic and pyroptotic inflammatory response in BV‐2 cells, dependent on its sialic acid substrates and immunoreceptor tyrosine‐based inhibition motif (ITIM) phosphorylation sites. Related human Siglecs induced a similar response in BV‐2 cells. Collectively, our results point to an important role for mouse Siglec‐F and human Siglec‐8 in regulating microglial activation during neurodegeneration.     

The Viral Chemokine MCK-2 of Murine Cytomegalovirus Promotes Infection as Part of a gH/gL/MCK-2 Complex

Human cytomegalovirus (HCMV) forms two gH/gL glycoprotein complexes, gH/gL/gO and gH/gL/pUL(128,130,131A), which determine the tropism, the entry pathways and the mode of spread of the virus. For murine cytomegalovirus (MCMV), which serves as a model for HCMV, a gH/gL/gO complex functionally homologous to the HCMV gH/gL/gO complex has been described. Knock-out of MCMV gO does impair, but not abolish, virus spread indicating that also MCMV might form an alternative gH/gL complex. Here, we show that the MCMV CC chemokine MCK-2 forms a complex with the glycoprotein gH, a complex which is incorporated into the virion. We could additionally show that mutants lacking both, gO and MCK-2 are not able to produce infectious virus. Trans-complementation of these double mutants with either gO or MCK-2 showed that both proteins can promote infection of host cells, although through different entry pathways. MCK-2 has been extensively studied in vivo by others. It has been shown to be involved in attracting cells for virus dissemination and in regulating antiviral host responses. We now show that MCK-2, by forming a complex with gH, strongly promotes infection of macrophages in vitro and in vivo. Thus, MCK-2 may play a dual role in MCMV infection, as a chemokine regulating the host response and attracting specific target cells and as part of a glycoprotein complex promoting entry into cells crucial for virus dissemination.     

Increasing Adolescent HIV Prevalence in Eastern Zimbabwe – Evidence of Long-Term Survivors of Mother-to-Child Transmission?

Recent data from the Manicaland HIV/STD Prevention Project, a general-population open HIV cohort study, suggested that between 2004 and 2007 HIV prevalence amongst males aged 15–17 years in eastern Zimbabwe increased from 1.20% to 2.23%, and in females remained unchanged at 2.23% to 2.39%, while prevalence continued to decline in the rest of the adult population. We assess whether the more likely source of the increase in adolescent HIV prevalence is recent sexual HIV acquisition, or the aging of long-term survivors of perinatal HIV acquisition that occurred during the early growth of the epidemic. Using data collected between August 2006 and November 2008, we investigated associations between adolescent HIV and (1) maternal orphanhood and maternal HIV status, (2) reported sexual behaviour, and (3) reporting recurring sickness or chronic illness, suggesting infected adolescents might be in a late stage of HIV infection. HIV-infected adolescent males were more likely to be maternal orphans (RR = 2.97, p<0.001) and both HIV-infected adolescent males and females were more likely to be maternal orphans or have an HIV-infected mother (male RR = 1.83, p<0.001; female RR = 16.6, p<0.001). None of 22 HIV-infected adolescent males and only three of 23 HIV-infected females reported ever having had sex. HIV-infected adolescents were 60% more likely to report illness than HIV-infected young adults. Taken together, all three hypotheses suggest that recent increases in adolescent HIV prevalence in eastern Zimbabwe are more likely attributable to long-term survival of mother-to-child transmission rather than increases in risky sexual behaviour. HIV prevalence in adolescents and young adults cannot be used as a surrogate for recent HIV incidence, and health systems should prepare for increasing numbers of long-term infected adolescents.     

Serological detection of yam viruses in farmers' fields in Ogun State,Nigeria

A field survey was conducted in eight local government areas (LGA) of Ogun state, Nigeria to assess the incidence of viral diseases of yams in the areas. Leaf samples were collected from 90 yam plants which were either symptomatic or asymptomatic. These were bulked into 45 during serological tests and the viruses indexed include yam mosaic virus (YMV); Dioscorea alata bacilliform virus (DaBV) and cucumber mosaic virus (CMV). DaBV was the most prevalent virus on the field with incidence of 48.9% (22/45) followed by YMV which occurred in 42.2% (19/45). CMV had the lowest percentage of incidence; 2.2% (1/45). Of all the LGAs visited, Abeokuta north and Abeokuta south had the highest incidence of YMV and DaBV, respectively. Mixed virus infections were also detected.