An angiotensin II antagonist with strongly prolonged action

A highly hydrophobic analogue of angiotensin II (AT), [Sar1,(2',3',4',5',6'-Br5)Phe8]AT exhibited strong and persistent specific antagonism against AT, both in vitro and in vivo. This peptide exhibited 32% of the binding affinity of [Sar1]AT towards membranes of bovine adrenal cortex, it was a specific AT antagonist of irreversible character on smooth muscle assays, and it also suppressed for over 120 min at 7.10(-8) M/kg the blood pressure response towards AT in the rat blood pressure assay. This compound harbours therefore the potential of a new class of AT-specific antihypotensive drugs.     

Purification and cloning of sakacin 674, a bacteriocin from Lactobacillus sake Lb674

Abstract Sakacin 674, a bacteriocin produced by Lactobacillus sake Lb764 and which inhibits the growth of Listeria monocytogenes , was purified to homogeneity by ammonium sulphate precipitation and sequential ion exchange, hydrophobic interaction and reversed phase chromatography. The complete amino acid sequence of sakacin 674 was determined by Edman degradation. The bacteriocin consisted of 43 amino acid residues and had a calculated molecular mass of 4436.6 Da, which is in good agreement with the molecular mass of 4437.2 as determined by mass spectrometry. The structural gene encoding sakacin 674 ( sakR ) was located on the chromosome. This gene was cloned and sequenced. It encoded a primary translation product of 61 amino acid residues which was cleaved between amino acids 18 and 19 to yield the active sakacin 674. Sakacin 674 resembled other known bacteriocins and was very similar to sakacin P.     

Seasonal dynamics and bioavailability of dissolved organic matter in two contrasting temperate estuaries

Production and bioavailability of dissolved organic matter (DOM) were followed during a year in the nutrient-rich estuary, Roskilde Fjord (RF), and the more oligotrophic strait, Great Belt (GB), in Denmark. Bioavailability of dissolved organic carbon (DOC), nitrogen (DON), and phosphorous (DOP) was determined during incubations over six months. Overall, RF had three to five times larger pools of total nitrogen (TN) and total phosphorous (TP) and five to eight times higher concentrations of inorganic nutrients compared to GB. However, the allocation of carbon, nitrogen, and phosphorous into different pools were remarkably similar between the two systems. DON and DOP contributed with about equal relative fractions in the two systems: 72 ± 13% of total nitrogen and 21 ± 12% of total phosphorous. The average bioavailability of DOM was 25 ± 15, 17 ± 5.5, and 49 ± 29% for carbon, nitrogen, and phosphorous, respectively. The observed release of DIN from degradation of DON amounted to between 0.1 (RF winter) and 14 times (GB summer) the loadings from land and contributed with half of the total input of bioavailable nitrogen during summer. Hence, this study shows that nitrogen in DOM is important for the nitrogen cycling, especially during summer. The sum of inorganic nutrients, particulate organic matter, and bioavailable DOM (the dynamic pools of nutrients) accounted for 42 and 92% of nitrogen, and phosphorous, respectively, and was remarkably similar between the two systems compared to the difference in nutrient richness. It is hypothesized that the pelagic metabolism of nutrients in marine systems dictates a rather uniform distribution of the different fractions of nitrogen and phosphorous containing compounds regardless of eutrophication level.     

Hypoalbuminemia Is a Strong Predictor of 30-Day All-Cause Mortality in Acutely Admitted Medical Patients: A Prospective,Observational, Cohort Study

Objective

Emergency patients with hypoalbuminemia are known to have increased mortality. No previous studies have, however, assessed the predictive value of low albumin on mortality in unselected acutely admitted medical patients. We aimed at assessing the predictive power of hypoalbuminemia on 30-day all-cause mortality in a cohort of acutely admitted medical patients.

Methods

We included all acutely admitted adult medical patients from the medical admission unit at a regional teaching hospital in Denmark. Data on mortality was extracted from the Danish Civil Register to ensure complete follow-up. Patients were divided into three groups according to their plasma albumin levels (0–34, 35–44 and ≥45 g/L) and mortality was identified for each group using Kaplan-Meier survival plot. Discriminatory power (ability to discriminate patients at increased risk of mortality) and calibration (precision of predictions) for hypoalbuminemia was determined.

Results

We included 5,894 patients and albumin was available in 5,451 (92.5%). A total of 332 (5.6%) patients died within 30 days of admission. Median plasma albumin was 40 g/L (IQR 37–43). Crude 30-day mortality in patients with low albumin was 16.3% compared to 4.3% among patients with normal albumin (p<0.0001). Patients with low albumin were older and admitted for a longer period of time than patients with a normal albumin, while patients with high albumin had a lower 30-day mortality, were younger and were admitted for a shorter period. Multivariable logistic regression analyses confirmed the association of hypoalbuminemia with mortality (OR: 1.95 (95% CI: 1.31–2.90)). Discriminatory power was good (AUROC 0.73 (95% CI, 0.70–0.77)) and calibration acceptable.

Conclusion

We found hypoalbuminemia to be associated with 30-day all-cause mortality in acutely admitted medical patients. Used as predictive tool for mortality, plasma albumin had acceptable discriminatory power and good calibration.     

Ultrasonography,magnetic resonance imaging,radiography, and clinical assessment of inflammatory and destructive changes in fingers and toes of patients with psoriatic arthritis

The aim of the present study was to assess ultrasonography (US) for the detection of inflammatory and destructive changes in finger and toe joints, tendons, and entheses in patients with psoriasis-associated arthritis (PsA) by comparison with magnetic resonance imaging (MRI), projection radiography (x-ray), and clinical findings. Fifteen patients with PsA, 5 with rheumatoid arthritis (RA), and 5 healthy control persons were examined by means of US, contrast-enhanced MRI, x-ray, and clinical assessment. Each joint of the 2nd–5th finger (metacarpophalangeal joints, proximal interphalangeal [PIP] joints, and distal interphalangeal [DIP] joints) and 1st–5th metatarsophalangeal joints of both hands and feet were assessed with US for the presence of synovitis, bone erosions, bone proliferations, and capsular/extracapsular power Doppler signal (only in the PIP joints). The 2nd–5th flexor and extensor tendons of the fingers were assessed for the presence of insertional changes and tenosynovitis. One hand was assessed by means of MRI for the aforementioned changes. X-rays of both hands and feet were assessed for bone erosions and proliferations. US was repeated in 8 persons by another ultrasonographer. US and MRI were more sensitive to inflammatory and destructive changes than x-ray and clinical examination, and US showed a good interobserver agreement for bone changes (median 96% absolute agreement) and lower interobserver agreement for inflammatory changes (median 92% absolute agreement). A high absolute agreement (85% to 100%) for all destructive changes and a more moderate absolute agreement (73% to 100%) for the inflammatory pathologies were found between US and MRI. US detected a higher frequency of DIP joint changes in the PsA patients compared with RA patients. In particular, bone changes were found exclusively in PsA DIP joints. Furthermore, bone proliferations were more common and tenosynovitis was less frequent in PsA than RA. For other pathologies, no disease-specific pattern was observed. US and MRI have major potential for improved examination of joints, tendons, and entheses in fingers and toes of patients with PsA.     

Strong Selective Sweeps on the X Chromosome in the Human-Chimpanzee Ancestor Explain Its Low Divergence

The human and chimpanzee X chromosomes are less divergent than expected based on autosomal divergence. We study incomplete lineage sorting patterns between humans, chimpanzees and gorillas to show that this low divergence can be entirely explained by megabase-sized regions comprising one-third of the X chromosome, where polymorphism in the human-chimpanzee ancestral species was severely reduced. We show that background selection can explain at most 10% of this reduction of diversity in the ancestor. Instead, we show that several strong selective sweeps in the ancestral species can explain it. We also report evidence of population specific sweeps in extant humans that overlap the regions of low diversity in the ancestral species. These regions further correspond to chromosomal sections shown to be devoid of Neanderthal introgression into modern humans. This suggests that the same X-linked regions that undergo selective sweeps are among the first to form reproductive barriers between diverging species. We hypothesize that meiotic drive is the underlying mechanism causing these two observations.     

Mitochondrial genomes reveal the extinct Hippidion as an outgroup to all living equids

Hippidions were equids with very distinctive anatomical features. They lived in South America 2.5 million years ago (Ma) until their extinction approximately 10 000 years ago. The evolutionary origin of the three known Hippidion morphospecies is still disputed. Based on palaeontological data, Hippidion could have diverged from the lineage leading to modern equids before 10 Ma. In contrast, a much later divergence date, with Hippidion nesting within modern equids, was indicated by partial ancient mitochondrial DNA sequences. Here, we characterized eight Hippidion complete mitochondrial genomes at 3.4–386.3-fold coverage using target-enrichment capture and next-generation sequencing. Our dataset reveals that the two morphospecies sequenced (H. saldiasi and H. principale) formed a monophyletic clade, basal to extant and extinct Equus lineages. This contrasts with previous genetic analyses and supports Hippidion as a distinct genus, in agreement with palaeontological models. We date the Hippidion split from Equus at 5.6–6.5 Ma, suggesting an early divergence in North America prior to the colonization of South America, after the formation of the Panamanian Isthmus 3.5 Ma and the Great American Biotic Interchange.     

HLA-B*57 Micropolymorphism shapes HLA allele-specific epitope immunogenicity, selection pressure, and HIV immune control

The genetic polymorphism that has the greatest impact on immune control of human immunodeficiency virus (HIV) infection is expression of HLA-B*57. Understanding of the mechanism for this strong effect remains incomplete. HLA-B*57 alleles and the closely related HLA-B*5801 are often grouped together because of their similar peptide-binding motifs and HIV disease outcome associations. However, we show here that the apparently small differences between HLA-B*57 alleles, termed HLA-B*57 micropolymorphisms, have a significant impact on immune control of HIV. In a study cohort of >2,000 HIV C-clade-infected subjects from southern Africa, HLA-B*5703 is associated with a lower viral-load set point than HLA-B*5702 and HLA-B*5801 (medians, 5,980, 15,190, and 19,000 HIV copies/ml plasma; P = 0.24 and P = 0.0005). In order to better understand these observed differences in HLA-B*57/5801-mediated immune control of HIV, we undertook, in a study of >1,000 C-clade-infected subjects, a comprehensive analysis of the epitopes presented by these 3 alleles and of the selection pressure imposed on HIV by each response. In contrast to previous studies, we show that each of these three HLA alleles is characterized both by unique CD8(+) T-cell specificities and by clear-cut differences in selection pressure imposed on the virus by those responses. These studies comprehensively define for the first time the CD8(+) T-cell responses and immune selection pressures for which these protective alleles are responsible. These findings are consistent with HLA class I alleles mediating effective immune control of HIV through the number of p24 Gag-specific CD8(+) T-cell responses generated that can drive significant selection pressure on the virus.     

C-terminal modification of osteopontin inhibits interaction with the αVβ3-integrin

Osteopontin (OPN) is a multifunctional phosphorylated protein containing the integrin binding sequence Arg-Gly-Asp through which it interacts with several integrin receptors, such as the α(V)β(3)-integrin. OPN exists in many different isoforms differing in phosphorylation status that are likely to interact differently with integrins. The C-terminal region of OPN is particularly well conserved among mammalian species, which suggests an important functional role of this region. In this study, we show that modification of the extreme C terminus of OPN plays an important regulatory role for the interaction with the α(V)β(3)-integrin. It is demonstrated that highly phosphorylated OPN has a much reduced capability to promote cell adhesion via the α(V)β(3)-integrin compared with lesser phosphorylated forms. The cell attachment promoted by highly phosphorylated OPN could be greatly increased by both dephosphorylation and proteolytic removal of the C terminus. Using recombinantly expressed OPN containing a tag in the N or C terminus, it is shown that a modification in the C-terminal part significantly reduces the adhesion of cells to OPN via the α(V)β(3)-integrin, whereas modification of the N terminus does not influence the binding. The inhibited binding of the α(V)β(3)-integrin to OPN could be restored by proteolytic removal of the C terminus by thrombin and plasmin. These data illustrate a novel mechanism regulating the interaction of OPN and the α(V)β(3)-integrin by modification of the highly conserved C-terminal region of the protein.