Amyotrophic lateral sclerosis (ALS) is an adult onset disorder characterized by progressive neuromuscular junction (NMJ) dismantling and degeneration of motor neurons leading to atrophy and paralysis ...of voluntary muscles responsible for motion and breathing. Except for a minority of patients harbouring genetic mutations, the origin of most ALS cases remains elusive. Peripheral tissues, and particularly skeletal muscle, have lately demonstrated an active contribution to disease pathology attracting a growing interest for these tissues as therapeutic targets in ALS. In this sense, molecular mechanisms essential for cell and tissue homeostasis have been shown to be deregulated in the disease. These include muscle metabolism and mitochondrial activity, RNA processing, tissue‐resident stem cell function responsible for muscle regeneration, and proteostasis that regulates muscle mass in adulthood. This review aims to compile scientific evidence that demonstrates the role of skeletal muscle in ALS pathology and serves as reference for development of novel therapeutic strategies targeting this tissue to delay disease onset and progression.
LINKED ARTICLES
This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc
Summary
The helical shape of the human stomach pathogen Helicobacter pylori has been suggested to provide mechanical advantage for penetrating the viscous stomach mucus layer. Using single‐cell ...tracking and quantitative morphology analysis, we document marked variation in cell body helical parameters and flagellum number among H. pylori strains leading to distinct and broad speed distributions in broth and viscous gastric mucin media. These distributions reflect both temporal variation in swimming speed and morphologic variation within the population. Isogenic mutants with straight‐rod morphology showed 7–21% reduction in speed and a lower fraction of motile bacteria. Mutational perturbation of flagellum number revealed a 19% increase in speed with 4 versus 3 median flagellum number. Resistive force theory modeling incorporating variation of both cell shape and flagellum number predicts qualitative speed differences of 10–30% among strains. However, quantitative comparisons suggest resistive force theory underestimates the influence of cell body shape on speed for helical shaped bacteria.
Bacterial genetics combined with biophysical measurements and modeling reveals distinct contributions of helical cell morphology and flagellum number on the motility of the stomach pathogen Helicobacter pylori in gastric mucin.
Guillain-Barré syndrome (GBS) is an acute inflammatory neuropathy with a heterogeneous presentation. Although some evidences support the role of autoantibodies in its pathogenesis, the target ...antigens remain unknown in a substantial proportion of GBS patients. The objective of this study is to screen for autoantibodies targeting peripheral nerve components in Guillain-Barré syndrome.
Autoantibody screening was performed in serum samples from all GBS patients included in the International GBS Outcome study by 11 different Spanish centres. The screening included testing for anti-ganglioside antibodies, anti-nodo/paranodal antibodies, immunocytochemistry on neuroblastoma-derived human motor neurons and murine dorsal root ganglia (DRG) neurons, and immunohistochemistry on monkey peripheral nerve sections. We analysed the staining patterns of patients and controls. The prognostic value of anti-ganglioside antibodies was also analysed.
None of the GBS patients (n = 100) reacted against the nodo/paranodal proteins tested, and 61 (61%) were positive for, at least, one anti-ganglioside antibody. GBS sera reacted strongly against DRG neurons more frequently than controls both with IgG (6% vs 0%; p = 0.03) and IgM (11% vs 2.2%; p = 0.02) immunodetection. No differences were observed in the proportion of patients reacting against neuroblastoma-derived human motor neurons. Reactivity against monkey nerve tissue was frequently detected both in patients and controls, but specific patterns were only detected in GBS patients: IgG from 13 (13%) patients reacted strongly against Schwann cells. Finally, we confirmed that IgG anti-GM1 antibodies are associated with poorer outcomes independently of other known prognostic factors.
Our study confirms that (1) GBS patients display a heterogeneous repertoire of autoantibodies targeting nerve cells and structures; (2) gangliosides are the most frequent antigens in GBS patients and have a prognostic value; (3) further antigen-discovery experiments may elucidate other potential antigens in GBS.
Multidrug efflux pumps have emerged as relevant elements in the intrinsic and acquired antibiotic resistance of bacterial pathogens. In contrast with other antibiotic resistance genes that have been ...obtained by virulent bacteria through horizontal gene transfer, genes coding for multidrug efflux pumps are present in the chromosomes of all living organisms. In addition, these genes are highly conserved (all members of the same species contain the same efflux pumps) and their expression is tightly regulated. Together, these characteristics suggest that the main function of these systems is not resisting the antibiotics used in therapy and that they should have other roles relevant to the behavior of bacteria in their natural ecosystems. Among the potential roles, it has been demonstrated that efflux pumps are important for processes of detoxification of intracellular metabolites, bacterial virulence in both animal and plant hosts, cell homeostasis and intercellular signal trafficking.
Abstract Ribosome profiling experiments support the translation of a range of novel human open reading frames. By contrast, most peptides from large-scale proteomics experiments derive from just one ...source, 5′ untranslated regions. Across the human genome we find evidence for 192 translated upstream regions, most of which would produce protein isoforms with extended N-terminal ends. Almost all of these N-terminal extensions are from highly abundant genes, which suggests that the novel regions we detect are just the tip of the iceberg. These upstream regions have characteristics that are not typical of coding exons. Their GC-content is remarkably high, even higher than 5′ regions in other genes, and a large majority have non-canonical start codons. Although some novel upstream regions have cross-species conservation - five have orthologues in invertebrates for example - the reading frames of two thirds are not conserved beyond simians. These non-conserved regions also have no evidence of purifying selection, which suggests that much of this translation is not functional. In addition, non-conserved upstream regions have significantly more peptides in cancer cell lines than would be expected, a strong indication that an aberrant or noisy translation initiation process may play an important role in translation from upstream regions.
1. Lianas are a key component of tropical forests, where they compete intensely with trees, reducing tree recruitment, growth and survival. One of the most important potential outcomes of liana ...competition is the reduction of tree reproduction; however, no previous study has experimentally determined the effects of lianas on tree reproduction beyond a single tree species. 2. We used a large-scale liana removal experiment to quantify the effect of lianas on community-level canopy and understorey tree and palm reproduction. In 2011, we removed lianas from eight 6,400-m² plots (eight plots served as controls) and surveyed understorey tree reproduction in 2012, canopy tree and palm reproduction in 2013, and a second census of all plants in 2016. 3. We found that lianas significantly reduced canopy tree community flowering and fruiting after liana removal. Two years after liana removal, the number of canopy trees with fruits was 173% higher, fruiting individuals had 50% more of their canopy covered by fruits and the number of tree species with fruits was 169% higher than in control plots where lianas were present. Five years after liana removal, the number of canopy trees with fruits was 150% higher, fruiting individuals had 31% more of their canopy covered by fruits and the number of tree species with fruits was 109% higher than in unmanipulated control plots. 4. Liana removal had only a slight positive effect on palms and on understorey tree flower and fruit production, even though understorey light levels had increased 20% following liana cutting. 5. Synthesis. Our findings provide the first experimental demonstration that competition from lianas significantly reduces community-level canopy tree reproduction. Reduced reproduction increases canopy tree seed and dispersal limitations, and may interfere with deterministic mechanisms thought to maintain tropical canopy tree species diversity, as well as reduce food availability to many animal species. Because lianas are increasing in abundance in many neotropical forests, the effects of lianas on tree reproduction will likely increase, and if the effects of lianas on tree reproduction vary with tree species identity, lianas ultimately could have a destabilizing effect on both tree and animal population dynamics.
Glucose-6-phosphate dehydrogenase deficiency (G6PDd) is the most common enzymatic disease worldwide and the prevalence is not well established because of the lack of screening. This study aimed to ...estimate the prevalence of G6PDd in a Hispanic population from Northeast Mexico.
In this retrospective study, a database was used to analyze the G6PDd in neonates included in the expanded newborn metabolic screening of inherited metabolic disorders during a period of 4 years through the GSP Neonatal G6 kit (PerkinElmer).
Among 96,152 (48,462 male) neonates screened for G6PD enzyme activity, a total of 566 (0.58%) cases were deficient for G6PD. Of those 566 patients, 469 (82.8%) attended the second test and the other 97 (17.2%) patients were lost. Of those 469 who did attend, 384 (81.9%) neonates were deficient in the second test and 85 (18.1%) were normal. With the data collected, 384 neonates were confirmed with G6PDd, 348 (88.6%) were male and 36 (11.4%) patients were female. The calculated prevalence for this population was 0.72 cases per 100 male newborns.
The prevalence of G6PDd in the Northeastern Mexican population is high. Since migration is increasing in the United States, pediatricians should be aware of the need to search for G6PDd in newborns and the wide clinical manifestations they can present.
· The calculated prevalence of glucose-6-phosphate dehydrogenase deficiency in Northeast Mexico is 3.99 cases per 1,000 newborns.. · Glucose-6-phosphate dehydrogenase deficiency screenings should be included in all newborn metabolic screenings.. · Glucose-6-phosphate dehydrogenase deficiency is a common erythroenzymopathy that must be addressed as a public health concern. To anticipate clinical complications, target population monitoring is required..
We report the synthesis of various binary and ternary inorganic and hybrid organic–inorganic iodide nanocrystals (NCs) starting from molecular iodine (I2). The synthesis described herein utilizes a ...reaction between I2 and oleylamine, which results in oleylammonium iodide, an iodide precursor that can be directly used in the preparation of iodide-based NCs. The generality of the synthesis was demonstrated by synthesizing KI, RbI, CsI, AgI, CsPbI3, FAPbI3, Cs4PbI6, Cs3Bi2I9, FA3Bi2I9, and RbAg4I5 NCs. Furthermore, the syntheses are facile and are carried out in vials heated on a hot plate in air. They exhibit not only narrow size distributions, but also, in the case of lead-based perovskites NCs, 70–80% photoluminescence quantum yields. To further prove the high quality of the CsPbI3 and FAPbI3 perovskite NCs, red and infrared bright light-emitting diodes were fabricated, with external quantum efficiencies (EQEs) exceeding 3%, without following any extensive washing procedures.
Immune-related adverse events (irAEs) are unpredictable autoimmune-like toxicities induced by immune checkpoint inhibitors (ICI). irAEs are a consequence of a breakdown in self-tolerance. ICIs can ...induce autoantibody formation, and the presence of antinuclear autoantibodies (ANAs) has been reported in patients who developed irAEs. Our goal was to compare ANA patterns by indirect immunofluorescence at different timepoints before (baseline) and after the initiation of ICI treatment and to analyze the role of ANA pattern changes as predictors of irAEs. This is a 2-year-follow-up prospective study of 152 consecutive patients with solid tumors treated with anti-PD-(L)1 blockade agents. They were included from September 2018 until March 2020 in the Hospital de la Santa Creu I Sant Pau (Barcelona, Spain). We grouped patients into three groups: ANA de novo (patients who showed new ANA patterns at any time after ICI initiation), ANA (ANA positive at baseline without changes in the ANA patterns after initiation of treatment) and non-ANA (ANA negative at baseline and after ICI initiation). We did not find any association between the appearance of ANAs and irAE rates or the number and types of irAEs. However, patients in the ANA de novo group showed higher severe irAE rates (grade ≥ 3) than the other groups. Additionally, in most of the patients with severe irAEs (83.3%), changes in ANA patterns preceded irAE onset. In conclusion, we found ANA induction during ICI therapies in 22 patients and our results suggest that the appearance of ANAs may predict the severity of the irAE.
The influence of the processing conditions during the spray drying of mixtures of blueberry juice (BJ) and maltodextrin (MX) was determined quantitatively by the analysis of variance (ANOVA), and ...qualitatively by the surface response plots (SRP). The effect of two independent variables (inlet temperature, and MX concentration), and one categorical variable (type of MX), was determined on the yield (Y), content (Q), and retention (R) of the antioxidant quercetin 3-d-galactoside. From the ANOVA results, the concentration was the main variable affecting Y and Q, while temperature had a negligible effect, and the low molecular weight MXs exhibited a better response. The physicochemical characterization showed that the powder appearance and microstructure remained unaffected, but size and morphology of the particles varied with the processing conditions. This study established the optimal processing conditions for the spray drying of BJ-MX, and the application limits of the MXs based on the molecular weight distribution.
PDF
