Reduced immunoglobulin A transcytosis associated with immunoglobulin A nephropathy and nasopharyngeal carcinoma

Polymeric IgA (pIgA) is transcytosed by the pIgA receptor (pIgR) across mucosal epithelial cells. After transcytosis to the apical surface, the extracellular, ligand-binding portion of the pIgR is proteolytically cleaved. A missense mutation in human pIgR, A580V, is associated with IgA nephropathy and nasopharyngeal carcinoma. We report that this mutation reduces the rate of transcytosis of pIgR and pIgA, and seemingly the rate of pIgR cleavage. We propose that the defects in pIgR trafficking caused by the A580V mutation may underlie the pathogenesis of both diseases.     

Long-lasting decrease in viremia in macaques chronically infected with simian immunodeficiency virus SIVmac251 after therapeutic DNA immunization

Rhesus macaques chronically infected with highly pathogenic simian immunodeficiency virus (SIV) SIVmac251 were treated with antiretroviral drugs and vaccinated with combinations of DNA vectors expressing SIV antigens. Vaccination during therapy increased cellular immune responses. After the animals were released from therapy, the virus levels of 12 immunized animals were significantly lower (P = 0.001) compared to those of 11 animals treated with only antiretroviral drugs. Vaccinated animals showed a persistent increase in immune responses, thus indicating both a virological and an immunological benefit following DNA therapeutic vaccination. Several animals show a long-lasting decrease in viremia, suggesting that therapeutic vaccination may provide an additional benefit to antiretroviral therapy.     

In vivo activity of an azole series of CCR2 antagonists

Optimisation of a series of biaryl sulphonamides resulted in the identification of compound 7 which demonstrated dose-dependent and strain-specific inhibition of monocyte recruitment in a thioglycollate-induced peritonitis model of inflammation.     

Detection of dementia in primary care: comparison of the original and a modified Mini-Cog Assessment with the Mini-Mental State Examination

Background Dementia is considered widely under-detected in primary care, and general practitioners (GPs) frequently ask for easy to use tools to assist in its early detection.Aim To determine the degree of correlation between the Mini-Cog Assessment (Mini-Cog) as performed by GPs and the Mini-Mental State Examination (MMSE).Design of study This was a prospective study (2005, 2006) comparing two cognitive screening instruments.Setting Ten general practices in Austria, with patients with a hitherto undiagnosed suspicion of dementia seen consecutively.Method Sensitivity, specificity and positive and negative predictive values (PPVs and NPVs) of the Mini-Cog (applying both a colour-coded and the original rating method) were assessed for degree of correlation with the MMSE. In phase one GPs examined patients suspected of having dementia using the Mini-Cog; in phase two a neurologist retested them applying the MMSE, a clock-drawing test (CDT) and a routine clinical examination. A questionnaire on the practicability of the Mini-Cog was answered by GPs.Results Of the 107 patients who participated 86 completed the whole study protocol. The Mini-Cog, as performed by the ten GPs, displayed a sensitivity of 0.85 (95% CI: 0.71, 0.98), a specificity of 0.58 (95% CI: 0.46, 0.71), a PPV of 0.47 (95% CI: 0.33, 0.61) and an NPV of 0.90 (95% CI: 0.80, 0.99) as against the MMSE carried out by neurologists. The GPs judged the Mini-Cog useful and time saving.Conclusion The Mini-Cog has a high sensitivity and acceptable specificity in the general practice setting and has proved to be a practicable tool for the diagnosis of dementia in primary care.     

Identification of a sulfonamide series of CCR2 antagonists

A series of sulfonamide CCR2 antagonists was identified by high-throughput screening. Management of molecular weight and physical properties, in particular moderation of lipophilicity and study of pK_a, yielded highly potent CCR2 antagonists exhibiting good pharmacokinetic properties and improved potency in the presence of human plasma.     

The p11 subunit of annexin II heterotetramer is regulated by basic carboxypeptidase

The Ca(2+)-dependent phospholipid-binding protein annexin II heterotetramer (AIIt) is composed of two copies of annexin II and a p11 dimer. The interaction of the carboxyl-terminal lysine residues of the p11 subunit of AIIt with the lysine-binding kringle domains of plasminogen is believed to play a key role in plasminogen binding and stimulation of the tPA-catalyzed cleavage of plasminogen to plasmin. In the current report, we show that AIIt-stimulated plasminogen activation is regulated by basic carboxypeptidases, in vitro. The incubation of AIIt with a 1/400 molar ratio of carboxypeptidase B for periods as short as 2 min resulted in a significant loss in AIIt-stimulated plasminogen activation. Carboxypeptidase B (CpB) as well as thrombin-activated fibrinolysis inhibitor (TAFIa) and carboxypeptidase N (CpN) rapidly reduced AIIt-stimulated plasminogen activation by 80%. The molar ratio of carboxypeptidase/AIIt for half-maximal inhibition of AIIt was 1/4700, 1/700, and 1/500 for CpB, TAFIa, and CpN, respectively. Treatment of AIIt with carboxypeptidase resulted in loss of both carboxyl-terminal lysine residues from the p11 subunit, which correlated with a decrease in the k(cat) and an increase in the K(m) for plasminogen activation. The data reveal a novel mechanism for the regulation of AIIt-stimulated plasminogen activation.     

Mutational inactivation of an inhibitory sequence in human immunodeficiency virus type 1 results in Rev-independent gag expression.

We have characterized an inhibitory RNA element in the human immunodeficiency virus type 1 (HIV-1) gag coding sequence that prevents gag expression. The inhibition exerted by this element could be overcome by the presence of the Rev-responsive element in cis and of Rev protein in trans. To understand the mechanism of function, we inactivated the inhibitory element by mutagenesis while maintaining an intact gag coding region. A constitutive high level of Rev-independent gag expression was achieved only after the introduction of 28 point mutations over a large region of 270 nucleotides within the gag coding region. To our knowledge, this is the first demonstration of inactivation of a negative RNA element within a coding region without alteration of the expressed protein. Elimination of the inhibitory element in the p17gag region, named INS-1, offered the opportunity to detect a second inhibitory element in the gag-pol region. The presence of either INS element is sufficient to inhibit gag expression, demonstrating that multiple INS elements acting independently can inhibit HIV RNA expression. Expression of gag from Rous sarcoma virus, a retrovirus that does not require Rev-like regulatory proteins, revealed that the Rous sarcoma virus p19gag region does not contain inhibitory elements. These results demonstrate the presence of a strong inhibitory element acting at the level of mRNA and provide a general method for the removal of such elements from mRNA coding regions. The inhibitory element functions in the absence of any HIV-1 proteins, suggesting that cellular factors are responsible for this inhibition.     

Assessing the impact of ancient Maya animal use

Tropical forest animals are at high risk worldwide as a result of over-exploitation and forest clearing. Zooarchaeological studies of animal use by the ancient Maya of the southern lowland regions of Guatemala, Honduras, Belize, and Mexico provide long-term historical information on animal populations under conditions of human population growth and climatic change that is valuable to both archaeology and conservation biology. In this paper, zooarchaeological data from 35 chronologically defined faunal sub-samples recovered from 25 ancient Maya archaeological sites are used to assess the effects of ancient hunting on animal populations of the Maya region between the Preclassic and Colonial periods (2000 BC–AD 1697). The variations in species abundance are used as a proxy for describing changes in ancient Maya hunting practices and hunted animal populations, interpreted on the basis of hunting efficiency models from foraging ecology. A significant reduction in the proportion of large mammals, particularly Odocoileus virginianus, in zooarchaeological assemblages between the Late Classic (AD 600–850) and Terminal Classic/Postclassic periods (AD 850–1519) suggest that over-hunting during the Late Classic may have led to a reduction in availability of these animals to the ancient Maya hunters in the later periods. This finding is discussed in relation to important social and environmental variations to evaluate the impact of hunting and other factors such as forest clearance and climate on ancient animal populations in the Maya region.