Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling.

An estimated 50 million dengue virus (DENV) infections occur annually and more than forty percent of the human population is currently at risk of developing dengue fever (DF) or dengue hemorrhagic fever (DHF). Despite the prevalence and potential severity of DF and DHF, there are no approved vaccines or antiviral therapeutics available. An improved understanding of DENV immune evasion is pivotal for the rational development of anti-DENV therapeutics. Antagonism of type I interferon (IFN-I) signaling is a crucial mechanism of DENV immune evasion. DENV NS5 protein inhibits IFN-I signaling by mediating proteasome-dependent STAT2 degradation. Only proteolytically-processed NS5 can efficiently mediate STAT2 degradation, though both unprocessed and processed NS5 bind STAT2. Here we identify UBR4, a 600-kDa member of the N-recognin family, as an interacting partner of DENV NS5 that preferentially binds to processed NS5. Our results also demonstrate that DENV NS5 bridges STAT2 and UBR4. Furthermore, we show that UBR4 promotes DENV-mediated STAT2 degradation, and most importantly, that UBR4 is necessary for efficient viral replication in IFN-I competent cells. Our data underscore the importance of NS5-mediated STAT2 degradation in DENV replication and identify UBR4 as a host protein that is specifically exploited by DENV to inhibit IFN-I signaling via STAT2 degradation

Dengue virus genomic variation associated with mosquito adaptation defines the pattern of viral non-coding RNAs and fitness in human cells

The Flavivirus genus includes a large number of medically relevant pathogens that cycle between humans and arthropods. This host alternation imposes a selective pressure on the viral population. Here, we found that dengue virus, the most important viral human pathogen transmitted by insects, evolved a mechanism to differentially regulate the production of viral non-coding RNAs in mosquitos and humans, with a significant impact on viral fitness in each host. Flavivirus infections accumulate non-coding RNAs derived from the viral 3'UTRs (known as sfRNAs), relevant in viral pathogenesis and immune evasion. We found that dengue virus host adaptation leads to the accumulation of different species of sfRNAs in vertebrate and invertebrate cells. This process does not depend on differences in the host machinery; but it was found to be dependent on the selection of specific mutations in the viral 3'UTR. Dissecting the viral population and studying phenotypes of cloned variants, the molecular determinants for the switch in the sfRNA pattern during host change were mapped to a single RNA structure. Point mutations selected in mosquito cells were sufficient to change the pattern of sfRNAs, induce higher type I interferon responses and reduce viral fitness in human cells, explaining the rapid clearance of certain viral variants after host change. In addition, using epidemic and pre-epidemic Zika viruses, similar patterns of sfRNAs were observed in mosquito and human infected cells, but they were different from those observed during dengue virus infections, indicating that distinct selective pressures act on the 3'UTR of these closely related viruses. In summary, we present a novel mechanism by which dengue virus evolved an RNA structure that is under strong selective pressure in the two hosts, as regulator of non-coding RNA accumulation and viral fitness. This work provides new ideas about the impact of host adaptation on the variability and evolution of flavivirus 3'UTRs with possible implications in virulence and viral transmission.Fil: Filomatori, Claudia Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Carballeda, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Villordo, Sergio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Aguirre, Sebastian. Cedars Sinai Medical Center; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pallarés, Horacio Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Maestre, Ana M.. Cedars Sinai Medical Center; Estados UnidosFil: Sánchez Vargas, Irma. State University of Colorado - Fort Collins; Estados UnidosFil: Blair, Carol D.. State University of Colorado - Fort Collins; Estados UnidosFil: Fabri, Cintia. Instituto Nacional de Enfermedades Virales Humanas "Dr. Julio I. Maiztegui"; ArgentinaFil: Morales, Maria A.. Instituto Nacional de Enfermedades Virales Humanas "Dr. Julio I. Maiztegui"; ArgentinaFil: Fernandez Sesma, Ana. Cedars Sinai Medical Center; Estados UnidosFil: Gamarnik, Andrea Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

Prevalence of dementia in Latin America: a collaborative study of population-based cohorts

Background: Dementia is becoming a major public health problem in Latin America (LA), yet epidemiological information on dementia remains scarce in this region. This study analyzes data from epidemiological studies on the prevalence of dementia in LA and compares the prevalence of dementia and its causes across countries in LA and attempts to clarify differences from those of developed regions of the world. Methods: A database search for population studies on rates of dementia in LA was performed. Abstracts were also included in the search. Authors of the publications were invited to participate in this collaborative study by sharing missing or more recent data analysis with the group. Results: Eight studies from six countries were included. The global prevalence of dementia in the elderly (≥65 years) was 7.1% (95% CI: 6.8–7.4), mirroring the rates of developed countries. However, prevalence in relatively young subjects (65–69 years) was higher in LA studies The rate of illiteracy among the elderly was 9.3% and the prevalence of dementia in illiterates was two times higher than in literates. Alzheimer’s disease was the most common cause of dementia. Conclusions: Compared with studies from developed countries, the global prevalence of dementia in LA proved similar, although a higher prevalence of dementia in relatively young subjects was evidenced, which may be related to the association between low educational level and lower cognitive reserve, causing earlier emergence of clinical signs of dementia in the LA elderly population

Passalidae (Coleoptera, Scarabaeoidea) from the Caribbean coast of Colombia: synopsis, key, and new species description

Bess beetles (Passalidae) are a subsocial family of Coleoptera with approximately 1000 known species of saproxylophagous diet and pantropical distribution, with few extratropical species. Because of their high levels of endemism (especially in mountains), feeding habits, and complex subsociability; Passalidae is considered an excellent biological subject for taxonomic, biogeographical, and evolutionary studies. Colombia is the richest country with more than 118 recorded species of Passalidae, most of the species being related to humid and mountain areas. Colombia’s Caribbean region constitutes the northern portion of the country, extending for more than 130,000 km2 and includes four of the eight biogeographical provinces of Colombia. Since the 2000s this region has been the subject of systematic surveys for Passalidae; as a result, 18 passalid species have been recorded to date. After new explorations and review of entomological collections, the knowledge of the passalid fauna for the region is updated, recording 28 species (8 new records, 2 new species) for which are provided species diagnoses, photographs, and a taxonomic key. The dry plain, characteristic of the lowlands, is dominated by widely distributed species such as Passalus punctiger and Passalus interstitialis, while the mountainous systems provide species of more restricted distributions, some of them endemic to the Colombian Caribbean

Soil resources and element stocks in drylands to face global issues

Drylands (hyperarid, arid, semiarid, and dry subhumid ecosystems) cover almost half of Earth’s land surface and are highly vulnerable to environmental pressures. Here we provide an inventory of soil properties including carbon (C), nitrogen (N), and phosphorus (P) stocks within the current boundaries of drylands, aimed at serving as a benchmark in the face of future challenges including increased population, food security, desertification, and climate change. Aridity limits plant production and results in poorly developed soils, with coarse texture, low C:N and C:P, scarce organic matter, and high vulnerability to erosion. Dryland soils store 646 Pg of organic C to 2 m, the equivalent of 32% of the global soil organic C pool. The magnitude of the historic loss of C from dryland soils due to human land use and cover change and their typically low C:N and C:P suggest high potential to build up soil organic matter, but coarse soil textures may limit protection and stabilization processes. Restoring, preserving, and increasing soil organic matter in drylands may help slow down rising levels of atmospheric carbon dioxide by sequestering C, and is strongly needed to enhance food security and reduce the risk of land degradation and desertification

Autologous Platelet-Rich Plasma in the Treatment of Perianal Fistula in Crohn’s Disease

[Aim] To assess clinical healing in patients with perianal Crohn’s disease with local intrafistular injection of autologous platelet-rich plasma.[Method] The pilot study was conducted at a single centre between January 2013 and December 2015. Autologous platelet-rich plasma was prepared in platelet-rich and platelet-poor fractions for local intrafistular injection in patients with proven, established perianal Crohn’s disease. Patients were permitted biological therapies, and the Perianal Crohn’s Disease Activity Index was recorded. Patients were followed for 48 weeks for clinical signs of healing (complete, partial or non-healing), monitoring fistula drainage, closure and epithelialization.[Results] The study included 29 patients (19 males; mean age 38 ± 12.8 years) with four exclusions in the operating room because surgery was not indicated and four lost to follow-up. Five adverse events were recorded, with two requiring the drainage of abscess collections. Of the 21 patients assessable at 24 weeks, there was complete healing, partial healing and non-healing in 7 (33.3%), 8 (38.1%) and 6 (28.6%) patients, respectively. By 48 weeks, there was complete healing, partial healing and non-healing in 6 (40%), 6 (40%) and 3 (20%) patients, respectively, with a reduction in the number of visible external fistula openings at both time points (P = 0.021). By the end of the study, there was a higher trend of healing if biological therapies were continued (85.7% with biologics vs. 75% without, P = 0.527), but there were no statistically significant differences and no differences in the Perianal Crohn’s Disease Activity Index.[Conclusion]Autologous platelet-rich plasma is safe in patients with perianal Crohn’s disease, with an acceptable healing rate over a medium-term follow-up, particularly if biological therapies are used concomitantly

Strain modulation of Si vacancy emission from SIC micro- and nanoparticles

Single-photon emitting point defects in semiconductors have emerged as strong candidates for future quantum technology devices. In the present work, we exploit crystalline particles to investigate relevant defect localizations, emission shifting, and waveguiding. Specifically, emission from 6H-SiC micro- and nanoparticles ranging from 100 nm to 5 mu m in size is collected using cathodoluminescence (CL), and we monitor signals attributed to the Si vacancy (V_Si) as a function of its location. Clear shifts in the emission wavelength are found for emitters localized in the particle center and at the edges. By comparing spatial CL maps with strain analysis carried out in transmission electron microscopy, we attribute the emission shifts to compressive strain of 2-3% along the particle a-direction. Thus, embedding V_Si, qubit defects within SiC nanoparticles offers an interesting and versatile opportunity to tune single-photon emission energies while simultaneously ensuring ease of addressability via a self-assembled SiC nanoparticle matrix

Unanchored K48-Linked Polyubiquitin Synthesized by the E3-Ubiquitin Ligase TRIM6 Stimulates the Interferon-IKKε Kinase-Mediated Antiviral Response.

Type I interferons (IFN-I) are essential antiviral cytokines produced upon microbial infection. IFN-I elicits this activity through the upregulation of hundreds of IFN-I-stimulated genes (ISGs). The full breadth of ISG induction demands activation of a number of cellular factors including the IκB kinase epsilon (IKKε). However, the mechanism of IKKε activation upon IFN receptor signaling has remained elusive. Here we show that TRIM6, a member of the E3-ubiquitin ligase tripartite motif (TRIM) family of proteins, interacted with IKKε and promoted induction of IKKε-dependent ISGs. TRIM6 and the E2-ubiquitin conjugase UbE2K cooperated in the synthesis of unanchored K48-linked polyubiquitin chains, which activated IKKε for subsequent STAT1 phosphorylation. Our work attributes a previously unrecognized activating role of K48-linked unanchored polyubiquitin chains in kinase activation and identifies the UbE2K-TRIM6-ubiquitin axis as critical for IFN signaling and antiviral response

Addressing the disparities in dementia risk, early detection and care in Latino populations: Highlights from the Second Latinos and Alzheimer's Symposium

The Alzheimer's Association hosted the second Latinos & Alzheimer's Symposium in May 2021. Due to the COVID-19 pandemic, the meeting was held online over 2 days, with virtual presentations, discussions, mentoring sessions, and posters. The Latino population in the United States is projected to have the steepest increase in Alzheimer's disease (AD) in the next 40 years, compared to other ethnic groups. Latinos have increased risk for AD and other dementias, limited access to quality care, and are severely underrepresented in AD and dementia research and clinical trials. The symposium highlighted developments in AD research with Latino populations, including advances in AD biomarkers, and novel cognitive assessments for Spanish-speaking populations, as well as the need to effectively recruit and retain Latinos in clinical research, and how best to deliver health-care services and to aid caregivers of Latinos living with AD

Equine Torovirus (BEV) Induces Caspase-Mediated Apoptosis in Infected Cells

Toroviruses are gastroenteritis causing agents that infect different animal species and humans. To date, very little is known about how toroviruses cause disease. Here, we describe for the first time that the prototype member of this genus, the equine torovirus Berne virus (BEV), induces apoptosis in infected cells at late times postinfection. Observation of BEV infected cells by electron microscopy revealed that by 24 hours postinfection some cells exhibited morphological characteristics of apoptotic cells. Based on this finding, we analyzed several apoptotic markers, and observed protein synthesis inhibition, rRNA and DNA degradation, nuclear fragmentation, caspase-mediated cleavage of PARP and eIF4GI, and PKR and eIF2α phosphorylation, all these processes taking place after peak virus production. We also determined that both cell death receptor and mitochondrial pathways are involved in the apoptosis process induced by BEV. BEV-induced apoptosis at late times postinfection, once viral progeny are produced, could facilitate viral dissemination in vivo and contribute to viral pathogenesis