Evolutionary Descent of Prion Genes from the ZIP Family of Metal Ion Transporters

In the more than twenty years since its discovery, both the phylogenetic origin and cellular function of the prion protein (PrP) have remained enigmatic. Insights into a possible function of PrP may be obtained through the characterization of its molecular neighborhood in cells. Quantitative interactome data demonstrated the spatial proximity of two metal ion transporters of the ZIP family, ZIP6 and ZIP10, to mammalian prion proteins in vivo. A subsequent bioinformatic analysis revealed the unexpected presence of a PrP-like amino acid sequence within the N-terminal, extracellular domain of a distinct sub-branch of the ZIP protein family that includes ZIP5, ZIP6 and ZIP10. Additional structural threading and orthologous sequence alignment analyses argued that the prion gene family is phylogenetically derived from a ZIP-like ancestral molecule. The level of sequence homology and the presence of prion protein genes in most chordate species place the split from the ZIP-like ancestor gene at the base of the chordate lineage. This relationship explains structural and functional features found within mammalian prion proteins as elements of an ancient involvement in the transmembrane transport of divalent cations. The phylogenetic and spatial connection to ZIP proteins is expected to open new avenues of research to elucidate the biology of the prion protein in health and disease

Consumo de botellas y vasos de plástico en desayunos carretilleros nuevas pautas de comportamiento Lima 2019-2020

The greatest risk is not in the consumption of plastic but is the management of single-use plastic waste, there is a socially accepted behavior of not valuing recycling or reuse, The objective was to analyze the relationship between behavior patterns in consumption of food with the single-use plastic bottles and cups in the cart breakfast trade. Surveys were applied to students from different universities, vendors of wheelbarrow breakfasts. Breakfast is still accessible and affordable for the popular economy. The pandemic accelerated changes in the economy and social life of sellers and consumers that modified safety and hygiene measures. The plastic bottle trade is in a process of expansion and its replacement is not perceived in the short term. There is an important sector of the population that has the perception that the use of plastic is safe, the belief that plastic is a non-substitutable product is cheaper to use and dispose of than to refuse, recycle. There are no explicit or tacit rules on the management of the final disposal of single-use plastic articles. It is recommended, Awareness of society including companies and explicit regulations to promote recycling behaviors and reuse of single-use plastic bottles.El mayor riesgo no está en el consumo del plástico, sino en el manejo de residuos plásticos de un solo uso, existe un comportamiento socialmente aceptado de no valorar el reciclaje o el reúso. El objetivo fue analizar la relación entre las pautas de comportamiento en el consumo de alimentos con las botellas y vasos de plástico de un solo uso en el comercio de desayunos carretilleros. Se aplicó encuestas a estudiantes de diferentes universidades y a vendedores de desayunos en carretilla. El desayuno sigue siendo accesible y alcanzable para la economía popular. La pandemia aceleró los cambios en la economía y la vida social de los vendedores y consumidores, que modificaron las medidas de seguridad e higiene. El comercio de las botellas de plástico se encuentra en un proceso de expansión y no se percibe su reemplazo en el corto plazo. Existe un sector importante de la población que tiene la percepción que el uso del plástico es inocuo, la creencia que el plástico es un producto no sustituible, es más barato usar y tirar que rehusar, reciclar. No existen normas explícitas ni tácitas sobre gestión de la disposición final de los artículos plásticos de un solo uso. Se recomienda sensibilización de la sociedad, incluyendo empresas y normas explícitas para promover conductas de reciclaje y reúso de las botellas de plásticos de un solo uso

Evolution after Anti-TNF Discontinuation in Patients with Inflammatory Bowel Disease: A Multicenter Long-Term Follow-Up Study

OBJECTIVES:The aims of this study were to assess the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) drugs in patients with inflammatory bowel disease (IBD), to identify the factors associated with relapse, and to evaluate the overcome after retreatment with the same anti-TNF in those who relapsed.METHODS:This was a retrospective, observational, multicenter study. IBD patients who had been treated with anti-TNFs and in whom these drugs were discontinued after clinical remission was achieved were included.RESULTS:A total of 1, 055 patients were included. The incidence rate of relapse was 19% and 17% per patient-year in Crohn''s disease and ulcerative colitis patients, respectively. In both Crohn''s disease and ulcerative colitis patients in deep remission, the incidence rate of relapse was 19% per patient-year. The treatment with adalimumab vs. infliximab (hazard ratio (HR)=1.29; 95% confidence interval (CI)=1.01-1.66), elective discontinuation of anti-TNFs (HR=1.90; 95% CI=1.07-3.37) or discontinuation because of adverse events (HR=2.33; 95% CI=1.27-2.02) vs. a top-down strategy, colonic localization (HR=1.51; 95% CI=1.13-2.02) vs. ileal, and stricturing behavior (HR=1.5; 95% CI=1.09-2.05) vs. inflammatory were associated with a higher risk of relapse in Crohn''s disease patients, whereas treatment with immunomodulators after discontinuation (HR=0.67; 95% CI=0.51-0.87) and age (HR=0.98; 95% CI=0.97-0.99) were protective factors. None of the factors were predictive in ulcerative colitis patients. Retreatment of relapse with the same anti-TNF was effective (80% responded) and safe.CONCLUSIONS:The incidence rate of inflammatory bowel disease relapse after anti-TNF discontinuation is relevant. Some predictive factors of relapse after anti-TNF withdrawal have been identified. Retreatment with the same anti-TNF drug was effective and safe

Comparative genome analysis of PHB gene family reveals deep evolutionary origins and diverse gene function

<p>Abstract</p> <p>Background</p> <p>PHB (Prohibitin) gene family is involved in a variety of functions important for different biological processes. PHB genes are ubiquitously present in divergent species from prokaryotes to eukaryotes. Human PHB genes have been found to be associated with various diseases. Recent studies by our group and others have shown diverse function of PHB genes in plants for development, senescence, defence, and others. Despite the importance of the PHB gene family, no comprehensive gene family analysis has been carried to evaluate the relatedness of PHB genes across different species. In order to better guide the gene function analysis and understand the evolution of the PHB gene family, we therefore carried out the comparative genome analysis of the PHB genes across different kingdoms.</p> <p>Results</p> <p>The relatedness, motif distribution, and intron/exon distribution all indicated that PHB genes is a relatively conserved gene family. The PHB genes can be classified into 5 classes and each class have a very deep evolutionary origin. The PHB genes within the class maintained the same motif patterns during the evolution. With<it> Arabidopsis</it> as the model species, we found that PHB gene intron/exon structure and domains are also conserved during the evolution. Despite being a conserved gene family, various gene duplication events led to the expansion of the PHB genes. Both segmental and tandem gene duplication were involved in Arabidopsis PHB gene family expansion. However, segmental duplication is predominant in Arabidopsis. Moreover, most of the duplicated genes experienced neofunctionalization. The results highlighted that PHB genes might be involved in important functions so that the duplicated genes are under the evolutionary pressure to derive new function.</p> <p>Conclusion</p> <p>PHB gene family is a conserved gene family and accounts for diverse but important biological functions based on the similar molecular mechanisms. The highly diverse biological function indicated that more research needs to be carried out to dissect the PHB gene function. The conserved gene evolution indicated that the study in the model species can be translated to human and mammalian studies.</p

Ionospheric response modeling under eclipse conditions: Evaluation of 14 December 2020, total solar eclipse prediction over the South American sector

In this work, we evaluate the SUPIM-INPE model prediction of the 14 December 2020, total solar eclipse over the South American continent. We compare the predictions with data from multiple instruments for monitoring the ionosphere and with different obscuration percentages (i.e., Jicamarca, 12.0°S, 76.8°W, 17%; Tucumán 26.9°S, 65.4° W, 49%; Chillán 36.6°S, 72.0°W; and Bahía Blanca, 38.7°S, 62.3°W, reach 95% obscuration) due to the eclipse. The analysis is done under total eclipse conditions and non-total eclipse conditions. Results obtained suggest that the model was able to reproduce with high accuracy both the daily variation and the eclipse impacts of E and F1 layers in the majority of the stations evaluated (except in Jicamarca station). The comparison at the F2 layer indicates small differences (&lt;7.8%) between the predictions and observations at all stations during the eclipse periods. Additionally, statistical metrics reinforce the conclusion of a good performance of the model. Predicted and calibrated Total Electron Content (TEC, using 3 different techniques) are also compared. Results show that, although none of the selected TEC calibration methods have a good agreement with the SUPIM-INPE prediction, they exhibit similar trends in most of the cases. We also analyze data from the Jicamarca Incoherent Scatter Radar (ISR), and Swarm-A and GOLD missions. The electron temperature changes observed in ISR and Swarm-A are underestimated by the prediction. Also, important changes in the O/N2 ratio due to the eclipse, have been observed with GOLD mission data. Thus, future versions of the SUPIM-INPE model for eclipse conditions should consider effects on thermospheric winds and changes in composition, specifically in the O/N2 ratio

Distinct Regions within the Erlins Are Required for Oligomerization and Association with High Molecular Weight Complexes*S⃞

The group of stomatin/prohibitin/flotillin/HflK/C (SPFH) domain-containing proteins comprise members of diverse subcellular localization and function. Association with detergent-resistant membranes (DRMs) and the propensity to form oligomers are two common properties of SPFH domain proteins and likely important for the function of these proteins. Our laboratory recently discovered two novel members of this protein group, which, based on their endoplasmic reticulum (ER) localization and association with DRMs, were named ER lipid raft-associated protein (erlin)-1 and -2. Here we characterized erlin oligomerization and identified domains within the erlins responsible for oligomerization and DRM association. Using co-immunoprecipitation and sucrose density gradient centrifugation approaches on endogenous and ectopically expressed erlin proteins, we found that they formed homo- and hetero-oligomers and were part of large multimeric complexes. These properties were independent of their DRM association. By analyzing truncation and point mutants of erlin-2 we discovered that interaction between erlin monomers (oligomerization) and association with high molecular weight complexes require distinct regions within the protein. Although oligomerization and DRM association were mediated by a region immediately downstream of the SPFH domain (residues 228–300), integration into high molecular weight complexes was absolutely dependent on a phenylalanine residue C-terminal of this region (Phe-305), which lies within a short stretch of hydrophobic residues. Our data demonstrate that lower order oligomerization and incorporation into multimeric complexes are two separate biochemical properties of the erlins, because they are mediated by distinct regions

Reggies/flotillins interact with Rab11a and SNX4 at the tubulovesicular recycling compartment and function in transferrin receptor and E-cadherin trafficking.

The lipid raft proteins reggie-1 and -2 (flotillins) are implicated in membrane protein trafficking but exactly how has been elusive. We find that reggie-1 and -2 associate with the Rab11a, SNX4, and EHD1-decorated tubulovesicular recycling compartment in HeLa cells and that reggie-1 directly interacts with Rab11a and SNX4. Short hairpin RNA-mediated down-regulation of reggie-1 (and -2) in HeLa cells reduces association of Rab11a with tubular structures and impairs recycling of the transferrin-transferrin receptor (TfR) complex to the plasma membrane. Overexpression of constitutively active Rab11a rescues TfR recycling in reggie-deficient HeLa cells. Similarly, in a Ca(2+) switch assay in reggie-depleted A431 cells, internalized E-cadherin is not efficiently recycled to the plasma membrane upon Ca(2+) repletion. E-cadherin recycling is rescued, however, by overexpression of constitutively active Rab11a or SNX4 in reggie-deficient A431 cells. This suggests that the function of reggie-1 in sorting and recycling occurs in association with Rab11a and SNX4. Of interest, impaired recycling in reggie-deficient cells leads to de novo E-cadherin biosynthesis and cell contact reformation, showing that cells have ways to compensate the loss of reggies. Together our results identify reggie-1 as a regulator of the Rab11a/SNX4-controlled sorting and recycling pathway, which is, like reggies, evolutionarily conserved

The prion protein knockout mouse: a phenotype under challenge

The key pathogenic event in prion disease involves misfolding and aggregation of the cellular prion protein (PrP). Beyond this fundamental observation, the mechanism by which PrP misfolding in neurons leads to injury and death remains enigmatic. Prion toxicity may come about by perverting the normal function of PrP. If so, understanding the normal function of PrP may help to elucidate the molecular mechansim of prion disease. Ablation of the Prnp gene, which encodes PrP, was instrumental for determining that the continuous production of PrP is essential for replicating prion infectivity. Since the structure of PrP has not provided any hints to its possible function, and there is no obvious phenotype in PrP KO mice, studies of PrP function have often relied on intuition and serendipity. Here, we enumerate the multitude of phenotypes described in PrP deficient mice, many of which manifest themselves only upon physiological challenge. We discuss the pleiotropic phenotypes of PrP deficient mice in relation to the possible normal function of PrP. The critical question remains open: which of these phenotypes are primary effects of PrP deletion and what do they tell us about the function of PrP