Leber hereditary optic neuropathy is a mitochondrial disease mainly due to pathologic mutations in mitochondrial genes related to the respiratory complex I of the oxidative phosphorylation system. ...Genetic, physiological, and environmental factors modulate the penetrance of these mutations. We report two patients suffering from this disease and harboring a m.15950G > A mutation in the mitochondrial DNA‐encoded gene for the threonine transfer RNA. We also provide evidences supporting the pathogenicity of this mutation.
Current therapeutic options for Chagas' disease are limited to benznidazole and nifurtimox, which have been associated with low cure rates in the chronic stage of the disease and which have ...considerable toxicity. Posaconazole has shown trypanocidal activity in murine models.
We performed a prospective, randomized clinical trial to assess the efficacy and safety of posaconazole as compared with the efficacy and safety of benznidazole in adults with chronic Trypanosoma cruzi infection. We randomly assigned patients to receive posaconazole at a dose of 400 mg twice daily (high-dose posaconazole), posaconazole at a dose of 100 mg twice daily (low-dose posaconazole), or benznidazole at a dose of 150 mg twice daily; all the study drugs were administered for 60 days. We assessed antiparasitic activity by testing for the presence of T. cruzi DNA, using real-time polymerase-chain-reaction (rt-PCR) assays, during the treatment period and 10 months after the end of treatment. Posaconazole absorption was assessed on day 14.
The intention-to-treat population included 78 patients. During the treatment period, all the patients tested negative for T. cruzi DNA on rt-PCR assay beyond day 14, except for 2 patients in the low-dose posaconazole group who tested positive on day 60. During the follow-up period, in the intention-to-treat analysis, 92% of the patients receiving low-dose posaconazole and 81% receiving high-dose posaconazole, as compared with 38% receiving benznidazole, tested positive for T. cruzi DNA on rt-PCR assay (P<0.01 for the comparison of the benznidazole group with either posaconazole group); in the per-protocol analysis, 90% of the patients receiving low-dose posaconazole and 80% of those receiving high-dose posaconazole, as compared with 6% receiving benznidazole, tested positive on rt-PCR assay (P<0.001 for the comparison of the benznidazole group with either posaconazole group). In the benznidazole group, treatment was discontinued in 5 patients because of severe cutaneous reactions; in the posaconazole groups, 4 patients had aminotransferase levels that were more than 3 times the upper limit of the normal range, but there were no discontinuations of treatment.
Posaconazole showed antitrypanosomal activity in patients with chronic Chagas' disease. However, significantly more patients in the posaconazole groups than in the benznidazole group had treatment failure during follow-up. (Funded by the Ministry of Health, Spain; CHAGASAZOL ClinicalTrials.gov number, NCT01162967.).
The first wave of COVID-19 pandemic may have significantly impacted antimicrobial consumption in hospitals. The objective of this study was to assess the evolution of antimicrobial consumption during ...this period
: A retrospective quasi-experimental before-after study was conducted in a Spanish tertiary care hospital. The study compared two periods: pre-pandemic, from January 2018 to February 2020, and during the COVID-19 pandemic from March to June 2020. Antimicrobial consumption was analyzed monthly as defined daily doses (DDD)/100 bed-days and overall hospital and ICU consumption were evaluated.
An increase in the hospital consumption was noticed. Although only ceftaroline achieved statistical significance (
= 0.014), a rise was observed in most of the studied antimicrobials. A clear temporal pattern was detected. While an increase in ceftriaxone and azithromycin was observed during March, an increment in the consumption of daptomycin, carbapenems, linezolid, ceftaroline, novel cephalosporin/β-lactamase inhibitors or triazoles during April-May was noticed. In the ICU, these findings were more evident, namely ceftriaxone (
= 0.029), carbapenems (
= 0.002), daptomycin (
= 0.002), azithromycin (
= 0.030), and linezolid (
= 0.011) but followed a similar temporal pattern.
: An increase in the antimicrobial consumption during the first wave of COVID-19 pandemic was noticed, especially in the ICU. Availability of updated protocols and antimicrobial stewardship programs are essential to optimize these outcomes.
Article Note: Belen Perez-Duenas and Davide Tonduti are both senior authors of this manuscript. Relevant conflicts of interest/financial disclosures: The authors have no potential conflicts of ...interest to disclose. Funding agencies: For #2genetic diagnosis was performed based on a research project funded by Instituto de Salud Carlos III, grant/award number: PI18/01319. Corrections added on 12 March 2021 after first online publication: Correspondence address updated for Belen Perez-Duenas. CAPTION(S): Figure S1. Xxx APPENDIX S1. Supporting Information Byline: Silvia Masnada, Diego Martinelli, Marta Correa-Vela, Emanuele Agolini, Heidy Baide-Mairena, Anna Marce-Grau, Cecilia Parazzini, Pierangelo Veggiotti, Belen Perez-Duenas, Davide Tonduti
Gam-COVID-Vac (SPUTNIK V) has been granted emergency use authorization in 70 nations and has been administered to millions worldwide. However, there are very few peer-reviewed studies describing its ...effects. Independent reports regarding safety and effectiveness could accelerate the final approval by the WHO. We aimed to study the long-term humoral immune response in naïve and previously infected volunteers who received SPUTNIK V.
Humoral immune responses, assayed by anti-SARS-CoV-2-spike-RBD IgG ELISA and neutralization assays, were measured in 602 healthcare workers at 0, 14, 28, 60 and 180 days after receiving SPUTNIK V between December 2020 and July 2021 in Tucumán, Argentina.
Seroconversion was detected in 97% of individuals after 28 days post-vaccination (dpv) (N = 405). Anti-RBD titers began to decrease after 60 dpv (N = 328), but remained detectable in 94% at 90 dpv (N = 224). At 180 dpv, anti-RDB titers persisted in 31% (N = 146). Previous infection triggered an increased immune response to the first dose and increased neutralization activity against variants of concern (VOC). Second doses in previously infected individuals further increased titers, even 90 dpv (N = 75). Basal antibody titers had more influence on post-vaccination anti-RBD responses than the time elapsed between diagnosis and vaccination (N = 274).
Data presented herein provides essential knowledge regarding the kinetics of antibodies induced by SPUTNIK V up to six months after immunization, and suggests that when considering one-dose vaccination policies for individuals with previous SARS-CoV-2 infection, serological studies to determine basal titers may be important, independent of when diagnosis occurred.
Tucumán Public Health System (SIPROSA), Argentinean National Research Council (CONICET), National University of Tucumán (UNT).
The core microbiome, which refers to a set of consistent microbial features across populations, is of major interest in microbiome research and has been addressed by numerous studies. Understanding ...the core microbiome can help identify elements that lead to dysbiosis, and lead to treatments for microbiome-related health states. However, defining the core microbiome is a complex task at several levels. In this review, we consider the current state of core human microbiome research. We consider the knowledge that has been gained, the factors limiting our ability to achieve a reliable description of the core human microbiome, and the fields most likely to improve that ability. DNA sequencing technologies and the methods for analyzing metagenomics and amplicon data will most likely facilitate higher accuracy and resolution in describing the microbiome. However, more effort should be invested in characterizing the microbiome’s interactions with its human host, including the immune system and nutrition. Other components of this holobiontic system should also be emphasized, such as fungi, protists, lower eukaryotes, viruses, and phages. Most importantly, a collaborative effort of experts in microbiology, nutrition, immunology, medicine, systems biology, bioinformatics, and machine learning is probably required to identify the traits of the core human microbiome.
The present study marks a pioneering investigation into the reproductive cycle of the scleractinian coral
Dendrophyllia ramea
. This is one of the first reproduction studies conducted in the ...Mediterranean Sea for a colonial azooxanthellate coral. Coral samples were collected in 2017 (May and October) and 2018 (February and July) in the Alborán Sea (SW Mediterranean). This location was selected due to its rarity as one of the few sites where this species thrives at depths shallower than 40 m. These samples were used to study the sexual patterns, fertilization mechanisms and gametogenic cycles by means of histological techniques. To broaden the scope, Sea Surface Temperature (SST) and Chlorophyll-a (Chl-a) data from open access databases have been considered to explore the potential influence of these environmental factors as triggers for gamete development and spawning time. The findings cast
D. ramea
as a gonochoric species, since no hermaphroditic specimens were observed among the analysed samples. Additionally, the lack of larvae and embryos in any of the analysed polyps, suggest that this species is fertilised externally. Two oocyte cohorts have been detected simultaneously, hinting at a yearly reproductive cycle, characterised by a prolonged oocyte maturation and seasonal spawning period taking place between August and October. Nevertheless,
D. ramea
display a low fecundity compared to other scleractinians inhabiting deep waters. Lastly, the early stages of gametogenesis seem to be coupled with the highest Chl-a values (
i.e
., March and December), whereas spawning takes place throughout the warmest period of the year (August to October).
Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways.
Genome Research at Fundacio ACE (GR@ACE) is a ...genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets.
We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444.
The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.
•We detected three gene categories operating differently in AD subgroups of patients.•Vasculature regulation may be an essential part of the causative mechanism in pure AD.•Two novel signals reached genome-wide significance in ANKRD31 and NDUFAF6loci.•We confirmed SCIMP-rs7225151 and CD33-rs3865444 to be genome-wide significant.•Genetic discoveries are strongly impacted by the presence of subgroups of AD.
1. Litter decomposition recycles nutrients and causes large fluxes of carbon dioxide into the atmosphere. It is typically assumed that climate, litter quality and decomposer communities determine ...litter decay rates, yet few comparative studies have examined their relative contributions in tropical forests. 2. We used a short-term litterbag experiment to quantify the effects of litter quality, placement and mesofaunal exclusion on decomposition in 23 tropical forests in 14 countries. Annual precipitation varied among sites (760-5797 mm). At each site, two standard substrates (Raphia farinifera and Laurus nobilis) were decomposed in fine- and coarse-mesh litterbags both above and below ground for approximately 1 year. 3. Decomposition was rapid, with >95% mass loss within a year at most sites. Litter quality, placement and mesofaunal exclusion all independently affected decomposition, but the magnitude depended upon site. Both the average decomposition rate at each site and the ratio of above- to below-ground decay increased linearly with annual precipitation, explaining 60-65% of among-site variation. Excluding mesofauna had the largest impact on decomposition, reducing decomposition rates by half on average, but the magnitude of decrease was largely independent of climate. This suggests that the decomposer community might play an important role in explaining patterns of decomposition among sites. Which litter type decomposed fastest varied by site, but was not related to climate. 4. Synthesis. A key goal of ecology is to identify general patterns across ecological communities, as well as relevant site-specific details to understand local dynamics. Our pan-tropical study shows that certain aspects of decomposition, including average decomposition rates and the ratio of above- to below-ground decomposition are highly correlated with a simple climatic index: mean annual precipitation. However, we found no relationship between precipitation and effects of mesofaunal exclusion or litter type, suggesting that site-specific details may also be required to understand how these factors affect decomposition at local scales.
Integral membrane proteins are assembled into the ER membrane via a continuous ribosome-translocon channel. The hydrophobicity and thickness of the core of the membrane bilayer leads to the ...expectation that transmembrane (TM) segments minimize the cost of harbouring polar polypeptide backbones by adopting a regular pattern of hydrogen bonds to form α-helices before integration. Co-translational folding of nascent chains into an α-helical conformation in the ribosomal tunnel has been demonstrated previously, but the features governing this folding are not well understood. In particular, little is known about what features influence the propensity to acquire α-helical structure in the ribosome. Using in vitro translation of truncated nascent chains trapped within the ribosome tunnel and molecular dynamics simulations, we show that folding in the ribosome is attained for TM helices but not for soluble helices, presumably facilitating SRP (signal recognition particle) recognition and/or a favourable conformation for membrane integration upon translocon entry.
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