Brain-machine interfaces (BMIs) involving electrodes implanted into the human cerebral cortex have recently been developed in an attempt to restore function to profoundly paralyzed individuals. ...Current BMIs for restoring communication can provide important capabilities via a typing process, but unfortunately they are only capable of slow communication rates. In the current study we use a novel approach to speech restoration in which we decode continuous auditory parameters for a real-time speech synthesizer from neuronal activity in motor cortex during attempted speech.
Neural signals recorded by a Neurotrophic Electrode implanted in a speech-related region of the left precentral gyrus of a human volunteer suffering from locked-in syndrome, characterized by near-total paralysis with spared cognition, were transmitted wirelessly across the scalp and used to drive a speech synthesizer. A Kalman filter-based decoder translated the neural signals generated during attempted speech into continuous parameters for controlling a synthesizer that provided immediate (within 50 ms) auditory feedback of the decoded sound. Accuracy of the volunteer's vowel productions with the synthesizer improved quickly with practice, with a 25% improvement in average hit rate (from 45% to 70%) and 46% decrease in average endpoint error from the first to the last block of a three-vowel task.
Our results support the feasibility of neural prostheses that may have the potential to provide near-conversational synthetic speech output for individuals with severely impaired speech motor control. They also provide an initial glimpse into the functional properties of neurons in speech motor cortical areas.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that promotes erythropoiesis through increasing endogenous erythropoietin, improving iron regulation, ...and reducing hepcidin. Study Design Phase 2, randomized (3:1), open-label, active-comparator, safety and efficacy study. Setting & Participants Patients with stable end-stage renal disease treated with hemodialysis who previously had hemoglobin (Hb) levels maintained with epoetin alfa. Intervention Part 1: 6-week dose-ranging study in 54 individuals of thrice-weekly oral roxadustat doses versus continuation of intravenous epoetin alfa. Part 2: 19-week treatment in 90 individuals in 6 cohorts with various starting doses and adjustment rules (1.0-2.0 mg/kg or tiered weight based) in individuals with a range of epoetin alfa responsiveness. Intravenous iron was prohibited. Outcomes Primary end point was Hb level response, defined as end-of-treatment Hb level change (ΔHb) of −0.5 g/dL or greater from baseline (part 1) and as mean Hb level ≥ 11.0 g/dL during the last 4 treatment weeks (part 2). Measurements Hepcidin, iron parameters, cholesterol, and plasma erythropoietin (the latter in a subset). Results Baseline epoetin alfa doses were 138.3 ± 51.3 (SD) and 136.3 ± 47.7 U/kg/wk in part 1 and 152.8 ± 80.6 and 173.4 ± 83.7 U/kg/wk in part 2, in individuals randomly assigned to roxadustat and epoetin alfa, respectively. Hb level responder rates in part 1 were 79% in pooled roxadustat 1.5 to 2.0 mg/kg compared to 33% in the epoetin alfa control arm ( P = 0.03). Hepcidin level reduction was greater at roxadustat 2.0 mg/kg versus epoetin alfa ( P < 0.05). In part 2, the average roxadustat dose requirement for Hb level maintenance was ∼1.7 mg/kg. The least-squares-mean ΔHb in roxadustat-treated individuals was comparable to that in epoetin alfa–treated individuals (about −0.5 g/dL) and the least-squares-mean difference in ΔHb between both treatment arms was −0.03 (95% CI, −0.39 to 0.33) g/dL (mixed effect model-repeated measure). Roxadustat significantly reduced mean total cholesterol levels, not observed with epoetin alfa. No safety concerns were raised. Limitations Short treatment duration and small sample size. Conclusions In this phase 2 study of anemia therapy in patients with end-stage renal disease on maintenance hemodialysis therapy, roxadustat was well tolerated and effectively maintained Hb levels.
Dissolved oxygen concentration is a crucial organizing principle in marine ecosystems. As oxygen levels decline, energy is increasingly diverted away from higher trophic levels into microbial ...metabolism, leading to loss of fixed nitrogen and to production of greenhouse gases, including nitrous oxide and methane. In this Review, we describe current efforts to explore the fundamental factors that control the ecological and microbial biodiversity in oxygen-starved regions of the ocean, termed oxygen minimum zones. We also discuss how recent advances in microbial ecology have provided information about the potential interactions in distributed co-occurrence and metabolic networks in oxygen minimum zones, and we provide new insights into coupled biogeochemical processes in the ocean.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
These agents are not first-line treatments for many of the conditions for which they are used. When they are used, there should be a plan in place for deprescribing.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) clinical variant interpretation guidelines established criteria for different types of evidence. ...This includes the strong evidence codes PS3 and BS3 for "well-established" functional assays demonstrating a variant has abnormal or normal gene/protein function, respectively. However, they did not provide detailed guidance on how functional evidence should be evaluated, and differences in the application of the PS3/BS3 codes are a contributor to variant interpretation discordance between laboratories. This recommendation seeks to provide a more structured approach to the assessment of functional assays for variant interpretation and guidance on the use of various levels of strength based on assay validation.
The Clinical Genome Resource (ClinGen) Sequence Variant Interpretation (SVI) Working Group used curated functional evidence from ClinGen Variant Curation Expert Panel-developed rule specifications and expert opinions to refine the PS3/BS3 criteria over multiple in-person and virtual meetings. We estimated the odds of pathogenicity for assays using various numbers of variant controls to determine the minimum controls required to reach moderate level evidence. Feedback from the ClinGen Steering Committee and outside experts were incorporated into the recommendations at multiple stages of development.
The SVI Working Group developed recommendations for evaluators regarding the assessment of the clinical validity of functional data and a four-step provisional framework to determine the appropriate strength of evidence that can be applied in clinical variant interpretation. These steps are as follows: (1) define the disease mechanism, (2) evaluate the applicability of general classes of assays used in the field, (3) evaluate the validity of specific instances of assays, and (4) apply evidence to individual variant interpretation. We found that a minimum of 11 total pathogenic and benign variant controls are required to reach moderate-level evidence in the absence of rigorous statistical analysis.
The recommendations and approach to functional evidence evaluation described here should help clarify the clinical variant interpretation process for functional assays. Further, we hope that these recommendations will help develop productive partnerships with basic scientists who have developed functional assays that are useful for interrogating the function of a variety of genes.
Late-stage rehabilitation programs often incorporate 'sport-specific' demands, but may not optimally simulate the in-game volume or intensity of such activities as sprinting, cutting, jumping, and ...lateral movement.
The aim of this review was to characterize, quantify, and compare straight-line running and multi-directional demands during sport competition.
A systematic review of PubMed, CINAHL, SPORTDiscus, and Cochrane Central Register of Controlled Trials databases was conducted.
Studies that reported time-motion analysis data on straight-line running, accelerations/decelerations, activity changes, jumping, cutting, or lateral movement over the course of an entire competition in a multi-directional sport (soccer, basketball, lacrosse, handball, field hockey, futsal, volleyball) were included.
Data was organized based on sport, age level, and sex and descriptive statistics of the frequency, intensity, time, and volume of the characteristics of running and multi-directional demands were extracted from each study.
Eighty-one studies were included in the review (n = 47 soccer, n = 11 basketball, n = 9 handball, n = 7 field hockey, n = 3 futsal, n = 4 volleyball). Variability of sport demand data was found across sports, sexes, and age levels. Specifically, soccer and field hockey demanded the most volume of running, while basketball required the highest ratio of high-intensity running to sprinting. Athletes change activity between 500 and 3000 times over the course of a competition, or once every 2-4 s. Studies of soccer reported the most frequent cutting (up to 800 per game), while studies of basketball reported the highest frequency of lateral movement (up to 450 per game). Basketball (42-56 per game), handball (up to 90 per game), and volleyball (up to 35 per game) were found to require the most jumping.
These data may provide an incomplete view of an athlete's straight-line running load, considering that only competition and not practice data was provided.
Considerable variability exists in the demands of straight-line running and multi-directional demands across sports, competition levels, and sexes, indicating the need for sports medicine clinicians to design future rehabilitation programs with improved specificity (including the type of activity and dosage) to these demands.
Neutrophils are central to the pathology of inflammatory diseases, where they can damage host tissue through release of reactive oxygen metabolites and proteases, and drive inflammation via secretion ...of cytokines and chemokines. Many cytokines, such as those generated during inflammation, can induce a similar "primed" phenotype in neutrophils, but it is unknown if different cytokines utilise common or cytokine-specific pathways to induce these functional changes. Here, we describe the transcriptomic changes induced in control human neutrophils during priming in vitro with pro-inflammatory cytokines (TNF-α and GM-CSF) using RNA-seq. Priming led to the rapid expression of a common set of transcripts for cytokines, chemokines and cell surface receptors (CXCL1, CXCL2, IL1A, IL1B, IL1RA, ICAM1). However, 580 genes were differentially regulated by TNF-α and GM-CSF treatment, and of these 58 were directly implicated in the control of apoptosis. While these two cytokines both delayed apoptosis, they induced changes in expression of different pro- and anti-apoptotic genes. Bioinformatics analysis predicted that these genes were regulated via differential activation of transcription factors by TNF-α and GM-CSF and these predictions were confirmed using functional assays: inhibition of NF-κB signalling abrogated the protective effect of TNF-α (but not that of GM-CSF) on neutrophil apoptosis, whereas inhibition of JAK/STAT signalling abrogated the anti-apoptotic effect of GM-CSF, but not that of TNF-α (p<0.05). These data provide the first characterisation of the human neutrophil transcriptome following GM-CSF and TNF-α priming, and demonstrate the utility of this approach to define functional changes in neutrophils following cytokine exposure. This may provide an important, new approach to define the molecular properties of neutrophils after in vivo activation during inflammation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The phyllosphere—the aerial surfaces of plants, including leaves—is a ubiquitous global habitat that harbors diverse bacterial communities. Phyllosphere bacterial communities have the potential to ...influence plant biogeography and ecosystem function through their influence on the fitness and function of their hosts, but the host attributes that drive community assembly in the phyllosphere are poorly understood. In this study we used high-throughput sequencing to quantify bacterial community structure on the leaves of 57 tree species in a neotropical forest in Panama. We tested for relationships between bacterial communities on tree leaves and the functional traits, taxonomy, and phylogeny of their plant hosts. Bacterial communities on tropical tree leaves were diverse; leaves from individual trees were host to more than 400 bacterial taxa. Bacterial communities in the phyllosphere were dominated by a core microbiome of taxa including Actinobacteria, Alpha-, Beta-, and Gammaproteobacteria, and Sphingobacteria. Host attributes including plant taxonomic identity, phylogeny, growth and mortality rates, wood density, leaf mass per area, and leaf nitrogen and phosphorous concentrations were correlated with bacterial community structure on leaves. The relative abundances of several bacterial taxa were correlated with suites of host plant traits related to major axes of plant trait variation, including the leaf economics spectrum and the wood density–growth/mortality tradeoff. These correlations between phyllosphere bacterial diversity and host growth, mortality, and function suggest that incorporating information on plant–microbe associations will improve our ability to understand plant functional biogeography and the drivers of variation in plant and ecosystem function.
Significance In this study we sequenced bacterial communities present on tree leaves in a neotropical forest in Panama, to quantify the poorly understood relationships between bacterial biodiversity on leaves (the phyllosphere) vs. host tree attributes. Bacterial community structure on leaves was highly correlated with host evolutionary relatedness and suites of plant functional traits related to host ecological strategies for resource uptake and growth/mortality tradeoffs. The abundance of several bacterial taxa was correlated with host growth, mortality, and function. Our study quantifies the drivers of variation in plant-associated microbial biodiversity; our results suggest that incorporating information on plant-associated microbes will improve our understanding of the functional biogeography of plants and plant–microbe interactions.
Rheumatoid arthritis (RA) is a chronic inflammatory disorder affecting synovial joints. Neutrophils are believed to play an important role in both the initiation and progression of RA, and large ...numbers of activated neutrophils are found within both synovial fluid (SF) and synovial tissue from RA joints. In this study we analyzed paired blood and SF neutrophils from patients with severe, active RA (DAS28>5.1, n=3) using RNA-seq. 772 genes were significantly different between blood and SF neutrophils. IPA analysis predicted that SF neutrophils had increased expression of chemokines and ROS production, delayed apoptosis, and activation of signaling cascades regulating the production of NETs. This activated phenotype was confirmed experimentally by incubating healthy control neutrophils in cell-free RA SF, which was able to delay apoptosis and induce ROS production in both unprimed and TNFα primed neutrophils (p<0.05). RA SF significantly increased neutrophil migration through 3μM transwell chambers (p<0.05) and also increased production of NETs by healthy control neutrophils (p<0.001), including exposure of myeloperoxidase (MPO) and citrullinated histone-H3-positive DNA NETs. IPA analysis predicted NET production was mediated by signaling networks including AKT, RAF1, SRC, and NF-κB. Our results expand the understanding of the molecular changes that take place in the neutrophil transcriptome during migration into inflamed joints in RA, and the altered phenotype in RA SF neutrophils. Specifically, RA SF neutrophils lose their migratory properties, residing within the joint to generate signals that promote joint damage, as well as inflammation
recruitment and activation of both innate and adaptive immune cells. We propose that this activated SF neutrophil phenotype contributes to the chronic inflammation and progressive damage to cartilage and bone observed in patients with RA.
Adequate sleep timed appropriately during the circadian night is important for numerous biological processes and systems. New evidence suggests that both sleep timing and duration may be important ...for optimal bone health as well. This review examines the diurnal variation of bone turnover markers (BTMs) and the importance of circadian clock genes in regulating bone mass. In addition, this review explores the evidence for a link between shift work (and its associated disturbances in sleep duration/quality and circadian alignment) and alterations in bone metabolism and bone health. Finally, we review how commonly used medications and over-the-counter substances (e.g. caffeine, melatonin) complicate the relationship between sleep and circadian disorders and bone health.
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