Early events in the cellular formation of proparathyroid hormone

Early events in the cellular synthesis and subsequent transfer into membrane-limited compartments of pre-proparathyroid hormone (pre-proPTH) and proparathyroid hormone (proPTH) were investigated by electrophoretic analyses of newly synthesized proteins in subcellular fractions of parthyroid gland slices pulse-labeled for 0.5-5 min with [(35)S] methionine. During these short times of incubation, both pre-proPTH and proPTH were confined to the microsomal fraction. Labeled pre-proPTH and proPTH were detected in a 30-s interval between 0.5 and 1.0 min of incubation. The radioactivity in proPTH became relatively constant between 3 and 5 min, whereas the radioactivity in ProPTH increased markedly over this period. When corrected for the known content of methionine in the prohormone and the prohormone, we found four times as much radiolabeled prohormone as prehormone between 0.5 and 1.0 min of synthesis. Sequestration of labeled prohomrone into endoplasmic reticulum compartments was shown by treatment of the microsomal fraction with chymotrypsin and trypsin, which resulted in the degradation of the prehormone but not of the prohormones. Approximately 50 percent of pre-prohormone and 25 percent of prohormone were released from the microsomes by their extraction with 1.0 M KCl, whereas 80-90 percent of both was released by treatment with Triton X-100. These results in intact cells support the signal hypothesis proposed by Blobel and his co-workers in studies utilizing cell-free systems, inasmuch as the results indicate transfer of prohormone into the cisternal space of the rough endoplasmic reticulum concomitant with the growth of the nascent polypeptide chain. Appearance of membrane-sequestered proPTH takes place without entry of pre-proPTH into the cisternal space, suggesting that proteolytic removal of the leader peptide occurs during transfer of the polypeptide through the lipid bilayer. Further evidence in support of this process is that pre-proPTH is only partly extracted from the microsomes by treatment with 1.0 M KCl, suggesting that a substantial fraction of the nascent pre-proPTH is integrally inserted into the membranes before it is cleaved to form proPTH.     

Phylogenetic relationships within the Alcidae (Charadriiformes: Aves) inferred from total molecular evidence

The Alcidae is a unique assemblage of Northern Hemisphere seabirds that forage by "flying" underwater. Despite obvious affinities among the species, their evolutionary relationships are unclear. We analyzed nucleotide sequences of 1,045 base pairs of the mitochondrial cytochrome b gene and allelic profiles for 37 allozyme loci in all 22 extant species. Trees were constructed on independent and combined data sets using maximum parsimony and distance methods that correct for superimposed changes. Alternative methods of analysis produced only minor differences in relationships that were supported strongly by bootstrapping or standard error tests. Combining sequence and allozyme data into a single analysis provided the greatest number of relationships receiving strong support. Addition of published morphological and ecological data did not improve support for any additional relationship. All analyses grouped species into six distinct lineages: (1) the dovekie (Alle alle) and auks, (2) guillemots, (3) brachyramphine murrelets, (4) synthliboramphine murrelets, (5) true auklets, and (6) the rhinoceros auklet (Cerorhinca monocerata) and puffins. The two murres (genus Uria) were sister taxa, and the black guillemot (Cepphus grylle) was basal to the other guillemots. The Asian subspecies of the marbled murrelet (Brachyramphus marmoratus perdix) was the most divergent brachyramphine murrelet, and two distinct lineages occurred within the synthliboramphine murrelets. Cassin's auklet (Ptychoramphus aleuticus) and the rhinoceros auklet were basal to the other auklets and puffins, respectively, and the Atlantic (Fratercula arctica) and horned (Fratercula corniculata) puffins were sister taxa. Several relationships among tribes, among the dovekie and auks, and among the auklets could not be resolved but resembled "star" phylogenies indicative of adaptive radiations at different depths within the trees.      

Evidence for para Dechlorination of Polychlorobiphenyls by Methanogenic Bacteria

When microorganisms eluted from upper Hudson River sediment were cultured without any substrate except polychlorobiphenyl (PCB)-free Hudson River sediment, methane formation was the terminal step of the anaerobic food chain. In sediments containing Aroclor 1242, addition of eubacterium-inhibiting antibiotics, which should have directly inhibited fermentative bacteria and thereby should have indirectly inhibited methanogens, resulted in no dechlorination activity or methane production. However, when substrates for methanogenic bacteria were provided along with the antibiotics (to free the methanogens from dependence on eubacteria), concomitant methane production and dechlorination of PCBs were observed. The dechlorination of Aroclor 1242 was from the para positions, a pattern distinctly different from, and more limited than, the pattern observed with untreated or pasteurized inocula. Both methane production and dechlorination in cultures amended with antibiotics plus methanogenic substrates were inhibited by 2-bromoethanesulfonic acid. These results suggest that the methanogenic bacteria are among the physiological groups capable of anaerobic dechlorination of PCBs, but that the dechlorination observed with methanogenic bacteria is less extensive than the dechlorination observed with more complex anaerobic consortia.     

Monthly day/night changes and seasonal daily rhythms of sexual steroids in Senegal sole (Solea senegalensis) under natural fluctuating or controlled environmental conditions

In this paper we attempted to investigate the existence of daily fluctuations on plasma sexual steroids (17beta-estradiol, E(2) and testosterone, T) in Senegal sole (Solea senegalensis) females. We described the monthly day/night concentrations and seasonal daily rhythms in animals reared under natural photo- and thermo-period. In addition, the influence of the natural annual fluctuation of the water temperature on the plasma concentration of these steroids was investigated, using one group of Senegal sole under a natural photoperiod, but with an attenuated thermal cycle (around 17-20 degrees C) for one year. Although no significant day/night differences were detected in monthly samplings, the existence of an annual rhythm of E(2) and T (p<0.01) with an acrophase in February was revealed by COSINOR analysis. Maximum values were reached in March for both steroids (6.1+/-1.7 ng mL(-1) at mid-dark, MD and 4.0+/-0.6 ng mL(-1) at mid-light, ML for E2 and 1.4+/-0.4 ng mL(-1) at MD and 0.8+/-0.1 ng mL(-1) at ML for T) in anticipation of the spawning season (May-June). As regards seasonal daily rhythms, the presence of daily oscillations was revealed. At the spring solstice (21st March) a daily rhythm was observed for both steroids (COSINOR, p<0.01), with an acrophase at 20:00 h (E(2)) and at 21:08 h (T). In summer, autumn and winter no daily rhythms were observed due to the low steroid levels at those seasons. When Senegal sole females were submitted to an attenuated annual thermal cycle, the steroid rhythm disappeared (there was no surge in spring, as in the control group) and these fish did not spawn, despite being subjected to natural photoperiod conditions. This result underlined the importance of the natural annual fluctuation of water temperature and photoperiod on the synchronization of the spawning season and on the onset of steroidogenesis.     

Glutamine synthetase sequence evolution in the mycobacteria and their use as molecular markers for Actinobacteria speciation

Background  

Although the gene encoding for glutamine synthetase (gln A) is essential in several organisms, multiple glnA copies have been identified in bacterial genomes such as those of the phylum Actinobacteria, notably the mycobacterial species. Intriguingly, previous reports have shown that only one copy (gln A1) is essential for growth in M. tuberculosis, while the other copies (gln A2, gln A3 and gln A4) are not.     

Random change point model for joint modeling of cognitive decline and dementia

We propose a joint model for cognitive decline and risk of dementia to describe the pre-diagnosis phase of dementia. We aim to estimate the time when the cognitive evolution of subjects in the pre-dementia phase becomes distinguishable from normal evolution and to study whether the shape of cognitive decline depends on educational level. The model combines a piecewise polynomial mixed model with a random change point for the evolution of the cognitive test and a log-normal model depending on the random change point for the time to dementia. Parameters are estimated by maximum likelihood using a Newton-Raphson-like algorithm. The expected cognitive evolution given age to dementia is then derived and the marginal distribution of dementia is estimated to check the log-normal assumption.     

Changes in genomic methylation patterns during the formation of triploid asexual dandelion lineages

DNA methylation is an epigenetic mechanism that has the potential to affect plant phenotypes and that is responsive to environmental and genomic stresses such as hybridization and polyploidization. We explored de novo methylation variation that arises during the formation of triploid asexual dandelions from diploid sexual mother plants using methylation‐sensitive amplified fragment length polymorphism (MS‐AFLP) analysis. In dandelions, triploid apomictic asexuals are produced from diploid sexual mothers that are fertilized by polyploid pollen donors. We asked whether the ploidy level change that accompanies the formation of new asexual lineages triggers methylation changes that contribute to heritable epigenetic variation within novel asexual lineages. Comparison of MS‐AFLP and AFLP fragment inheritance in a diploid × triploid cross revealed de novo methylation variation between triploid F₁ individuals. Genetically identical offspring of asexual F₁ plants showed modest levels of methylation variation, comparable to background levels as observed among sibs in a long‐established asexual lineage. Thus, the cross between ploidy levels triggered de novo methylation variation between asexual lineages, whereas it did not seem to contribute directly to variation within new asexual lineages. The observed background level of methylation variation suggests that considerable autonomous methylation variation could build up within asexual lineages under natural conditions.     

Lifelong Exposure to Multilingualism: New Evidence to Support Cognitive Reserve Hypothesis

Objective

Investigate the protective effect of multilingualism on cognition in seniors.

Methods

As part of the MemoVie study conducted on 232 non-demented volunteers aged 65 and more, neurogeriatric and neuropsychological evaluations were performed. Participants were classified as presenting either cognitive impairment without dementia (CIND) or being free of any cognitive impairment (CIND-free). Language practices, socio-demographic data and lifestyle habits were recorded. In this retrospective nested case-control design, we used as proxies of multilingualism: number of languages practiced, age of acquisition and duration of practice, emphasizing the temporal pattern of acquisition, and the resulting practice of several languages sequentially or concomitantly during various periods of life. This special angle on the matter offered to our work a dimension particularly original and innovative.

Results

44 subjects (19%) had CIND, the others were cognitively normal. All practiced from 2 to 7 languages. When compared with bilinguals, participants who practiced more than 2 languages presented a lower risk of CIND, after adjustment for education and age (odds ratio (OR) = 0.30, 95% confidence limits (95%CL) = [0.10–0.92]). Progressing from 2 to 3 languages, instead of staying bilingual, was associated with a 7-fold protection against CIND (OR = 0.14, 95%CL = [0.04–0.45], p = 0.0010). A one year delay to reach multilingualism (3 languages practiced being the threshold) multiplied the risk of CIND by 1.022 (OR = 1.022, 95%CL = [1.01–1.04], p = 0.0044). Also noteworthy, just as for multilingualism, an impact of cognitively stimulating activities on the occurrence of CIND was found as well (OR = 0.979, 95%CL = [0.961–0.998], p = 0.033).

Conclusion

The study did not show independence of multilingualism and CIND. Rather it seems to show a strong association toward a protection against CIND. Practicing multilingualism from early life on, and/or learning it at a fast pace is even more efficient. This protection might be related to the enhancement of cognitive reserve and brain plasticity, thereby preserving brain functions from alterations during aging.     

Effectiveness of disease-management programs for improving diabetes care: a meta-analysis

Background

We conducted a meta-analysis of randomized controlled trials to assess the effectiveness of disease-management programs for improving glycemic control in adults with diabetes mellitus and to study which components of programs are associated with their effectiveness.

Methods

We searched several databases for studies published up to December 2009. We included randomized controlled trials involving adults with type 1 or 2 diabetes that evaluated the effect of disease-management programs on glycated hemoglobin (hemoglobin A_1C) concentrations. We performed a meta-regression analysis to determine the effective components of the programs.

Results

We included 41 randomized controlled trials in our review. Across these trials, disease-management programs resulted in a significant reduction in hemoglobin A_1C levels (pooled standardized mean difference between intervention and control groups −0.38 [95% confidence interval −0.47 to −0.29], which corresponds to an absolute mean difference of 0.51%). The finding was robust in the sensitivity analyses based on quality assessment. Programs in which the disease manager was able to start or modify treatment with or without prior approval from the primary care physician resulted in a greater improvement in hemoglobin A_1C levels (standardized mean difference −0.60 v. −0.28 in trials with no approval to do so; p < 0.001). Programs with a moderate or high frequency of contact reported a significant reduction in hemoglobin A_1C levels compared with usual care; nevertheless, only programs with a high frequency of contact led to a significantly greater reduction compared with low-frequency contact programs (standardized mean difference −0.56 v. −0.30, p = 0.03).

Interpretation

Disease-management programs had a clinically moderate but significant impact on hemoglobin A_1C levels among adults with diabetes. Effective components of programs were a high frequency of patient contact and the ability for disease managers to adjust treatment with or without prior physician approval.Despite well-established recommendations for diabetes care,^1–3 quality of care still needs to be improved. Although many nonpharmacologic strategies (patient education, psychological intervention, dietary education, self-monitoring and telemedicine) have been developed, their effectiveness is still unclear.^4–6 “Disease management” is a structured, multi-faceted intervention that includes several of the above-mentioned components. In two recent meta-analyses, disease management was associated with an improvement in glycemic control, as assessed by a mean reduction in hemoglobin A_1C concentration of 0.52% and 0.81%.^7,8 Disease management seems to be more effective than single strategies such as clinician education, patient education or promotion of self-management.⁷Because disease-management programs are heterogeneous, the effective components need to be identified to improve program implementation. Previous studies have evaluated the efficacy of some program components.^7,8 Independent medication changes by the disease manager appear to be particularly effective.⁷ However, other important factors such as the intensity of the intervention have not been previously evaluated.We conducted a meta-analysis of randomized controlled trials (RCTs) involving adults with type 1 or 2 diabetes mellitus that evaluated the effect of disease-management programs on hemoglobin A_1C levels. We determined the effective components of the programs, considering both the type of component and the intensity of the intervention.