Crystal Structure of the Hemochromatosis Protein HFE and Characterization of Its Interaction with Transferrin Receptor

AbstractHFE is an MHC-related protein that is mutated in the iron-overload disease hereditary hemochromatosis. HFE binds to transferrin receptor (TfR) and reduces its affinity for iron-loaded transferrin, implicating HFE in iron metabolism. The 2.6 Å crystal structure of HFE reveals the locations of hemochromatosis mutations and a patch of histidines that could be involved in pH-dependent interactions. We also demonstrate that soluble TfR and HFE bind tightly at the basic pH of the cell surface, but not at the acidic pH of intracellular vesicles. TfR:HFE stoichiometry (2:1) differs from TfR:transferrin stoichiometry (2:2), implying a different mode of binding for HFE and transferrin to TfR, consistent with our demonstration that HFE, transferrin, and TfR form a ternary complex

Structure of the Reaction Center from Rhodopseudomonas sphaeroides R-26 and 2.4.1: Protein-Cofactor (Bacteriochlorophyll, Bacteriopheophytin and Carotenoid) Interactions

The three-dimensional structures of the cofactors and protein subunits of the reaction center (RC) from the carotenoidless mutant strain of Rhodobacter sphaeroides R-26 and the wild-type strain 2.4.1 have been determined by x-ray diffraction to resolutions of 2.8 Å and 3.0 Å with R values of 24% and 26%, respectively. The bacteriochlorophyll dimer (D), bacteriochlorophyll monomers (B), and bacteriopheophytin monomers (φ) form two branches, A and B, that are approximately related by a twofold symmetry axis. The cofactors are located in hydrophobic environments formed by the L and M subunits. Differences in the cofactor-protein interactions between the A and B cofactors, as well as between the corresponding cofactors of Rb, sphaeroides and Rhodopseudomonas viridis [Michel, H., Epp, O. & Deisenhofer, J. (1986) EMBO J. 3, 2445-2451], are delineated. The roles of several structural features in the preferential electron transfer along the A branch are discussed. Two bound detergent molecules of beta-octyl glucoside have been located near B_A and B_B. The environment of the carotenoid, C, that is present in RCs from Rb. sphaeroides 2.4.1 consists largely of aromatic residues of the M subunit. A role of B_B in the triplet energy transfer from D to C and the reason for the preferential ease of removal of B_B from the RC is proposed

Diabetes-related excess mortality in Mexico: a comparative analysis of National Death Registries between 2017-2019 and 2020

OBJECTIVE: To estimate diabetes-related mortality in Mexico in 2020 compared with 2017-2019 after the onset of the coronavirus disease 2019 (COVID-19) pandemic. RESEARCH DESIGN AND METHODS: This retrospective, state-level study used national death registries of Mexican adults aged ≥20 years for the 2017-2020 period. Diabetes-related death was defined using ICD-10 codes listing diabetes as the primary cause of death, excluding certificates with COVID-19 as the primary cause of death. Spatial and negative binomial regression models were used to characterize the geographic distribution and sociodemographic and epidemiologic correlates of diabetes-related excess mortality, estimated as increases in diabetes-related mortality in 2020 compared with average 2017-2019 rates. RESULTS: We identified 148,437 diabetes-related deaths in 2020 (177 per 100,000 inhabitants) vs. an average of 101,496 deaths in 2017-2019 (125 per 100,000 inhabitants). In-hospital diabetes-related deaths decreased by 17.8% in 2020 versus 2017-2019, whereas out-of-hospital deaths increased by 89.4%. Most deaths were attributable to type 2 diabetes (130 per 100,000 inhabitants). Compared with 2018-2019 data, hyperglycemic hyperosmolar state and diabetic ketoacidosis were the two contributing causes with the highest increase in mortality (128% and 116% increase, respectively). Diabetes-related excess mortality clustered in southern Mexico and was highest in states with higher social lag, rates of COVID-19 hospitalization, and prevalence of HbA1c ≥7.5%. CONCLUSIONS: Diabetes-related deaths increased among Mexican adults by 41.6% in 2020 after the onset of the COVID-19 pandemic, occurred disproportionately outside the hospital, and were largely attributable to type 2 diabetes and hyperglycemic emergencies. Disruptions in diabetes care and strained hospital capacity may have contributed to diabetes-related excess mortality in Mexico during 2020

La cultura impresa en los avisos publicitarios de la prensa gráfica en la Argentina durante el siglo XX : Alcances y proyecciones

En la construcción de la historia del libro, la edición y la lectura en Argentina, una serie de investigaciones están aportado nuevos enfoques y reflexiones, lo que posibilita estudiar el cómo, el cuándo, los porqué, los usos del libro y los modos de la lectura, así como de las circunstancias y las estrategias desplegadas por la actividad editorial, la relación autor/editor, la comercialización, el perfil de los lectores y las prácticas que permitieron la apropiación de la cultura de lo impreso. Al inicio del siglo XX surgieron proyectos democratizadores del acceso al libro, acompañados por procesos de urbanización y escolarización que signaron y modelaron a los “futuros públicos lectores”. Tomando esto como punto de partida el proyecto La cultura impresa en los avisos publicitarios de la prensa gráfica en la Argentina durante el siglo XX. Alcances y proyecciones se propone indagar acerca de algunas de las múltiples razones por las que hombres y mujeres han leído, dirigiendo la mirada a los avisos y folletos publicitarios en la comercialización de libros.Pósters presentadosDepartamento de Bibliotecologí

La cultura impresa en los avisos publicitarios de la prensa gráfica en la Argentina durante el siglo XX : Alcances y proyecciones

En la construcción de la historia del libro, la edición y la lectura en Argentina, una serie de investigaciones están aportado nuevos enfoques y reflexiones, lo que posibilita estudiar el cómo, el cuándo, los porqué, los usos del libro y los modos de la lectura, así como de las circunstancias y las estrategias desplegadas por la actividad editorial, la relación autor/editor, la comercialización, el perfil de los lectores y las prácticas que permitieron la apropiación de la cultura de lo impreso. Al inicio del siglo XX surgieron proyectos democratizadores del acceso al libro, acompañados por procesos de urbanización y escolarización que signaron y modelaron a los “futuros públicos lectores”. Tomando esto como punto de partida el proyecto La cultura impresa en los avisos publicitarios de la prensa gráfica en la Argentina durante el siglo XX. Alcances y proyecciones se propone indagar acerca de algunas de las múltiples razones por las que hombres y mujeres han leído, dirigiendo la mirada a los avisos y folletos publicitarios en la comercialización de libros.Pósters presentadosDepartamento de Bibliotecologí

La cultura impresa en los avisos publicitarios de la prensa gráfica en la Argentina durante el siglo XX : Alcances y proyecciones

En la construcción de la historia del libro, la edición y la lectura en Argentina, una serie de investigaciones están aportado nuevos enfoques y reflexiones, lo que posibilita estudiar el cómo, el cuándo, los porqué, los usos del libro y los modos de la lectura, así como de las circunstancias y las estrategias desplegadas por la actividad editorial, la relación autor/editor, la comercialización, el perfil de los lectores y las prácticas que permitieron la apropiación de la cultura de lo impreso. Al inicio del siglo XX surgieron proyectos democratizadores del acceso al libro, acompañados por procesos de urbanización y escolarización que signaron y modelaron a los “futuros públicos lectores”. Tomando esto como punto de partida el proyecto La cultura impresa en los avisos publicitarios de la prensa gráfica en la Argentina durante el siglo XX. Alcances y proyecciones se propone indagar acerca de algunas de las múltiples razones por las que hombres y mujeres han leído, dirigiendo la mirada a los avisos y folletos publicitarios en la comercialización de libros.Pósters presentadosDepartamento de Bibliotecologí

Riboflavin Ameliorates Cisplatin Induced Toxicities under Photoillumination

BACKGROUND: Cisplatin is an effective anticancer drug that elicits many side effects mainly due to induction of oxidative and nitrosative stresses during prolonged chemotherapy. The severity of these side effects consequently restricts its clinical use under long term treatment. Riboflavin is an essential vitamin used in various metabolic redox reactions in the form of flavin adenine dinucleotide and flavin mononucleotide. Besides, it has excellent photosensitizing property that can be used to ameliorate these toxicities in mice under photodynamic therapy. METHODS AND FINDINGS: Riboflavin, cisplatin and their combinations were given to the separate groups of mice under photoilluminated condition under specific treatment regime. Their kidney and liver were excised for comet assay and histopathological studies. Furthermore, Fourier Transform Infrared Spectroscopy of riboflavin-cisplatin combination in vitro was also conducted to investigate any possible interaction between the two compounds. Their comet assay and histopathological examination revealed that riboflavin in combination with cisplatin was able to protect the tissues from cisplatin induced toxicities and damages. Moreover, Fourier Transform Infrared Spectroscopy analysis of the combination indicated a strong molecular interaction among their constituent groups that may be assigned for the protective effect of the combination in the treated animals. CONCLUSION: Inclusion of riboflavin diminishes cisplatin induced toxicities which may possibly make the cisplatin-riboflavin combination, an effective treatment strategy under chemoradiotherapy in pronouncing its antineoplastic activity and sensitivity towards the cancer cells as compared to cisplatin alone

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Cytogenetic analysis of three species of Pseudacteon (Diptera, Phoridae) parasitoids of the fire ants using standard and molecular techniques

Pseudacteon flies, parasitoids of worker ants, are being intensively studied as potentially effective agents in the biological control of the invasive pest fire ant genus Solenopsis (Hymenoptera: Formicidae). This is the first attempt to describe the karyotype of P. curvatus Borgmeier, P. nocens Borgmeier and P. tricuspis Borgmeier. The three species possess 2n = 6; chromosomes I and II were metacentric in the three species, but chromosome pair III was subtelocentric in P. curvatus and P. tricuspis, and telocentric in P. nocens. All three species possess a C positive band in chromosome II, lack C positive heterochromatin on chromosome I, and are mostly differentiated with respect to chromosome III. P. curvatus and P. tricuspis possess a C positive band, but at different locations, whereas this band is absent in P. nocens. Heterochromatic bands are neither AT nor GC rich as revealed by fluorescent banding. In situ hybridization with an 18S rDNA probe revealed a signal on chromosome II in a similar location to the C positive band in the three species. The apparent lack of morphologically distinct sex chromosomes is consistent with proposals of environmental sex determination in the genus. Small differences detected in chromosome length and morphology suggests that chromosomes have been highly conserved during the evolutionary radiation of Pseudacteon. Possible mechanisms of karyotype evolution in the three species are suggested

Nationwide genetic analysis of more than 600 families with inherited eye diseases in Argentina

This study corresponds to the first large-scale genetic analysis of inherited eye diseases (IED) in Argentina and describes the comprehensive genetic profile of a large cohort of patients. Medical records of 22 ophthalmology and genetics services throughout 13 Argentinian provinces were analyzed retrospectively. Patients with a clinical diagnosis of an ophthalmic genetic disease and a history of genetic testing were included. Medical, ophthalmological and family history was collected. A total of 773 patients from 637 families were included, with 98% having inherited retinal disease. The most common phenotype was retinitis pigmentosa (RP, 62%). Causative variants were detected in 379 (59%) patients. USH2A, RPGR, and ABCA4 were the most common disease-associated genes. USH2A was the most frequent gene associated with RP, RDH12 early-onset severe retinal dystrophy, ABCA4 Stargardt disease, PROM1 cone-rod dystrophy, and BEST1 macular dystrophy. The most frequent variants were RPGR c.1345 C > T, p.(Arg449*) and USH2A c.15089 C > A, p.(Ser5030*). The study revealed 156/448 (35%) previously unreported pathogenic/likely pathogenic variants and 8 possible founder mutations. We present the genetic landscape of IED in Argentina and the largest cohort in South America. This data will serve as a reference for future genetic studies, aid diagnosis, inform counseling, and assist in addressing the largely unmet need for clinical trials to be conducted in the region