The reaction mechanism of type I phosphomannose isomerases: new information from inhibition and polarizable molecular mechanics studies

Type I phosphomannose isomerases (PMIs) are zinc-dependent metalloenzymes involved in the reversible isomerization of D-mannose 6-phosphate (M6P) and D-fructose 6-phosphate (F6P). 5-Phospho-D-arabinonohydroxamic acid (5PAH), an inhibitor endowed with nanomolar affinity for yeast (Type I) and Pseudomonas aeruginosa (Type II) PMIs (Roux et al., Biochemistry 2004; 43:2926-2934), strongly inhibits human (Type I) PMI (for which we report an improved expression and purification procedure), as well as Escherichia coli (Type I) PMI. Its K(i) value of 41 nM for human PMI is the lowest value ever reported for an inhibitor of PMI. 5-Phospho-D-arabinonhydrazide, a neutral analogue of the reaction intermediate 1,2-cis-enediol, is about 15 times less efficient at inhibiting both enzymes, in accord with the anionic nature of the postulated high-energy reaction intermediate. Using the polarizable molecular mechanics, sum of interactions between fragments ab initio computed (SIBFA) procedure, computed structures of the complexes between Candida albicans (Type I) PMI and the cyclic substrate β-D-mannopyranose 6-phosphate (β-M6P) and between the enzyme and the high-energy intermediate analogue inhibitor 5PAH are reported. Their analysis allows us to identify clearly the nature of each individual active site amino acid and to formulate a hypothesis for the overall mechanism of the reaction catalyzed by Type I PMIs, that is, the ring-opening and isomerization steps, respectively. Following enzyme-catalyzed ring-opening of β-M6P by zinc-coordinated water and Gln111 ligands, Lys136 is identified as the probable catalytic base involved in proton transfer between the two carbon atoms C1 and C2 of the substrate D-mannose 6-phosphate.     

Systematic revision of the endemic deerHaploidoceros n. gen.mediterraneus (Bonifay, 1967) (Mammalia, Cervidae) from the Middle Pleistocene of Southern France

New osteological material of the endemic deer from Lunel-Viel and l’Igue des Rameaux (France) reveals its evolutionary specialization, and gives reason for establishing a new genus,Haploidoceros, with a single speciesH. mediterraneus (Bonifay, 1967). The cranial proportions and morphology suggest thatH. mediterraneus is close to the Late Villafranchian speciesMetacervocerus rhenanus, which may be a possible forerunner of the deer under study. The evolutionary origin ofH. mediterraneus took place in the Iberian glacial refugia during the “Mindel glaciation” of the early Middle Pleistocene. The North-East distribution ofH. mediterraneus was limited by unfavorable climate influence of the Arctic and Alpine Ice Shields.      

Les sites archéologiques plio-pléistocènes de la formation de Nachukui, Ouest-Turkana, Kenya : bilan synthétique 1997–2001

Plio-Pleistocene archaeological sites in the Nachukui Formation, West Turkana, Kenya: synthetic results 1997–2001. Stretched along the western side of the Turkana Basin, the Nachukui Formation preserves a large number of Plio-Pleistocene archaeological sites. Research carried out by the WTAP documents hominid behavioral evolution and technical diversity, through a time period ranging from 2.35 Myr to 0.7 Myr and within a relatively precise chronostratigraphic and paleoenvironmental frame. This work is based on comprehensive excavations conducted between 1997 and 2001 at the Late Pliocene and Early Pleistocene site complexes of the formation. To cite this article: H. Roche et al., C.R. Palevol 2 (2003).     

Later Middle Pleistocene human remains from the Almonda Karstic system, Torres Novas, Portugal

Later Middle Pleistocene archeological deposits of the Galeria Pesada (Gruta da Aroeira), Almonda Karstic System, Torres Novas, Portugal, yielded two archaic human teeth, a mandibular canine and a maxillary third molar. The C(1)presents moderate and asymmetrical shoveling with a stout root. The slightly worn M(3)exhibits at least four cusps with a large hypocone, three roots with large radicular plates, and an absence of taurodontism. They are moderately large for later Middle Pleistocene humans in their buccolingual crown diameters, although the M(3)mesiodistal diameter is modest. The C(1)exhibits labial calculus and multiple linear hypoplastic defects, but the M(3)is lesion free. Both teeth are morphologically similar to those of other Middle Pleistocene European humans and reinforce a pattern of dental hypertrophy among these archaic Homo.     

Cytometry of breast carcinoma: significance of plo?dy balance and proliferation index

Image cytometry of DNA distribution in fine needle biopsies of breast carcinomas at first diagnosis was performed to see if there were significant differences in DNA histograms between patients having very different outcome but same tumor histological typing and similar therapy. Two groups of patients were considered retrospectively: the first (20 patients) with survival time shorter than 5 years and the second (20 patients) with survival time longer than 10 years. Seven benign tumors were used as controls. Ten plo?dy classes were defined. The frequencies of cells in those classes were used as independent features in a supervised multivariate analysis. The advantages of this approach was pointed out with respect to the four-type classification of Auer. The scattering of DNA histograms within the feature space showed that a subgroup of patients with poor prognosis was clearly separated from a subgroup of patients with good prognosis but both long survival patients and short survival patients were scattered in between. In order to replace the multivariate classification of histograms by a simpler approach, two parameters were computed which explained most of the scattering in the feature space: the plo?dy balance (difference between the percentages of euploid and aneuplo?d cells) and the proliferation index (percentage of cells between peaks). The scattergram of patients according to these parameters showed again that some DNA distributions were specific for either good or bad prognosis. But the separation was uncertain for seven short-survival patients and six long-survival patients. For six patients, the DNA distributions were very similar between long and short survival times. Those patients thus could not be separated even by means of discriminant analysis. The main conclusion of this study was that, for a significant number of patients, the objective multivariate classification of tumors DNA profiles is of little assistance to the pathologist who has to give a prognosis for the one patient under consideration.     

Job Loss,Unemployment and the Incidence of Hazardous Drinking during the Late 2000s Recession in Europe among Adults Aged 50–64 Years

Background

To estimate the incidence of hazardous drinking in middle-aged people during an economic recession and ascertain whether individual job loss and contextual changes in unemployment influence the incidence rate in that period.

Methods

Longitudinal study based on two waves of the SHARE project (Survey of Health, Ageing and Retirement in Europe). Individuals aged 50–64 years from 11 European countries, who were not hazardous drinkers at baseline (n = 7,615), were selected for this study. We estimated the cumulative incidence of hazardous drinking (≥40g and ≥20g of pure alcohol on average in men and women, respectively) between 2006 and 2012. Furthermore, in the statistical analysis, multilevel Poisson regression models with robust variance were fitted and obtained Risk Ratios (RR) and their 95% Confidence Intervals (95%CI).

Results

Over a 6-year period, 505 subjects became hazardous drinkers, with cumulative incidence of 6.6 per 100 persons between 2006 and 2012 (95%CI:6.1–7.2). Age [RR = 1.02 (95%CI:1.00–1.04)] and becoming unemployed [RR = 1.55 (95%CI:1.08–2.23)] were independently associated with higher risk of becoming a hazardous drinker. Conversely, having poorer self-perceived health was associated with lower risk of becoming a hazardous drinker [RR = 0.75 (95%CI:0.60–0.95)]. At country-level, an increase in the unemployment rate during the study period [RR = 1.32 (95%CI:1.17–1.50)] and greater increases in the household disposable income [RR = 0.97 (95%CI:0.95–0.99)] were associated with risk of becoming a hazardous drinker.

Conclusions

Job loss among middle-aged individuals during the economic recession was positively associated with becoming a hazardous drinker. Changes in country-level variables were also related to this drinking pattern.     

Faunes et paléoenvironnements des principaux sites archéologiques plio-pléistocènes de la formation de Nachukui (Ouest-Turkana, Kenya)

Faunas and paleoenvironments from main archaeological Plio-Pleistocene sites of the Nachukui Formation (West Turkana, Kenya). The Nachukui Formation is currently under archaeological investigation, especially within the Kalochoro (2.35 – 1.9 Myr) and Kaitio (1.9 – 1.65 Myr) Members. Six main archaeological sites have been excavated from this time period, which yield rich vertebrate faunas collected in situ or in close vicinity to the site. Paleontological studies help to precise the specific diversity for each site and increase our documentation for each Member with the discovery of new taxa. They allow to provide new informations about the biotope diversities exploited by Hominids and show a climatic tendency towards more humid environment between the Members. To cite this article: J.-P. Brugal et al., C.R. Palevol 2 (2003).     

Nouvelles découvertes de dents d’hominidés dans le membre Kaitio de la formation de Nachukui (1,65–1,9 Ma), Ouest du lac Turkana (Kenya)

New hominid teeth from the Kaitio member (1.65–1.9 Myr) in West Turkana (Kenya). New hominid teeth have been recovered from the archaeological sites of Kokiselei 1 and Naiyena Engol 1. These two sites are located in the west side of the Turkana Basin and belong to the Kaitio member of the Nachukui Formation. They are dated between 1.65-1.79 and 1.7-1.8 Myr respectively. The four teeth (left maxillary canine and first molar, right maxillary third molar and left mandibular third molar) discovered in Kokiselei 1 are attributed to Australopithecus boisei. The right mandibular first premolar found in Naiyena Engol 1 is referred to Homo sp. aff. ergaster. To cite this article: S. Prat et al., C. R. Palevol 2 (2003).     

Posttranslational modification impact on the mechanism by which amyloid‐β induces synaptic dysfunction

Oligomeric amyloid‐β (Aβ) 1‐42 disrupts synaptic function at an early stage of Alzheimer's disease (AD). Multiple posttranslational modifications of Aβ have been identified, among which N‐terminally truncated forms are the most abundant. It is not clear, however, whether modified species can induce synaptic dysfunction on their own and how altered biochemical properties can contribute to the synaptotoxic mechanisms. Here, we show that a prominent isoform, pyroglutamated Aβ3(pE)‐42, induces synaptic dysfunction to a similar extent like Aβ1‐42 but by clearly different mechanisms. In contrast to Aβ1‐42, Aβ3(pE)‐42 does not directly associate with synaptic membranes or the prion protein but is instead taken up by astrocytes and potently induces glial release of the proinflammatory cytokine TNFα. Moreover, Aβ3(pE)‐42‐induced synaptic dysfunction is not related to NMDAR signalling and Aβ3(pE)‐42‐induced impairment of synaptic plasticity cannot be rescued by D1‐agonists. Collectively, the data point to a scenario where neuroinflammatory processes together with direct synaptotoxic effects are caused by posttranslational modification of soluble oligomeric Aβ and contribute synergistically to the onset of synaptic dysfunction in AD.