The elderly have reduced humoral immunity, as manifested by increased susceptibility to infections and impaired vaccine responses. To investigate the effects of aging on B-cell receptor (BCR) ...repertoire evolution during an immunological challenge, we used a phylogenetic distance metric to analyze Ig heavy-chain transcript sequences in both young and elderly individuals before and after influenza vaccination. We determined that BCR repertoires become increasingly specialized over a span of decades, but less plastic. In 50% of the elderly individuals, a large space in the repertoire was occupied by a small number of recall lineages that did not decline during vaccine response and contained hypermutated IgD⁺ B cells. Relative to their younger counterparts, older subjects demonstrated a contracted naive repertoire and diminished intralineage diversification, signifying a reduced substrate for mounting novel responses and decreased fine-tuning of BCR specificities by somatic hypermutation. Furthermore, a larger proportion of the repertoire exhibited premature stop codons in some elderly subjects, indicating that aging may negatively affect the ability of B cells to discriminate between functional and nonfunctional receptors. Finally, we observed a decreased incidence of radical mutations compared with conservative mutations in elderly subjects’ vaccine responses, which suggests that accumulating original antigenic sin may be limiting the accessible space for paratope evolution. Our findings shed light on the complex interplay of environmental and gerontological factors affecting immune senescence, and provide direct molecular characterization of the effects of senescence on the immune repertoire.
Super-Earths belong to a class of planet not found in the Solar system, but which appear common in the Galaxy. Given that some super-Earths are rocky, while others retain substantial atmospheres, ...their study can provide clues as to the formation of both rocky and gaseous planets, and – in particular – they can help to constrain the role of photoevaporation in sculpting the exoplanet population. GJ 9827 is a system already known to host three super-Earths with orbital periods of 1.2, 3.6, and 6.2 d. Here, we use new HARPS-N radial velocity measurements, together with previously published radial velocities, to better constrain the properties of the GJ 9827 planets. Our analysis cannot place a strong constraint on the mass of GJ 9827 c, but does indicate that GJ 9827 b is rocky with a composition that is probably similar to that of the Earth, while GJ 9827 d almost certainly retains a volatile envelope. Therefore, GJ 9827 hosts planets on either side of the radius gap that appears to divide super-Earths into pre-dominantly rocky ones that have radii below ∼1.5Rꚛ, and ones that still retain a substantial atmosphere and/or volatile components, and have radii above ∼2Rꚛ. That the less heavily irradiated of the three planets still retains an atmosphere, may indicate that photoevaporation has played a key role in the evolution of the planets in this system.
The char produced in the thermolysis of granulated scrap tyres has few market outlets, reducing the economic viability of the thermolytic process. This paper reports the potential of this char as a ...low-cost precursor of porous carbons. The tyre-derived char was demineralized in either alkaline or acidic media to reduce its ash, zinc, sulfur, and silica contents. The lowest impurity content was achieved with an HNO
3
/H
2
O treatment. The resulting demineralized char was then subjected to activation by KOH or CO
2
. The Brunauer-Emmett-Teller (BET)-specific surface area of the activated carbon produced by the KOH treatment was 242 m
2
/g, whereas that of the CO
2
-activated carbon was 720 m
2
/g. The textural properties of the latter product were similar to those of some commercial activated carbons. The use of tyre-derived char as a precursor of porous carbons could render the thermolytic treatment of scrap tyres more economically attractive.
We propose a protocol to perform quantum reinforcement learning with quantum technologies. At variance with recent results on quantum reinforcement learning with superconducting circuits, in our ...current protocol coherent feedback during the learning process is not required, enabling its implementation in a wide variety of quantum systems. We consider diverse possible scenarios for an agent, an environment, and a register that connects them, involving multiqubit and multilevel systems, as well as open-system dynamics. We finally propose possible implementations of this protocol in trapped ions and superconducting circuits. The field of quantum reinforcement learning with quantum technologies will enable enhanced quantum control, as well as more efficient machine learning calculations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
To aid the development of treatment for cognitive impairment in bipolar disorder, the International Society for Bipolar Disorders (ISBD) convened a task force to create a consensus‐based ...guidance paper for the methodology and design of cognition trials in bipolar disorder.
Methods
The task force was launched in September 2016, consisting of 18 international experts from nine countries. A series of methodological issues were identified based on literature review and expert opinion. The issues were discussed and expanded upon in an initial face‐to‐face meeting, telephone conference call and email exchanges. Based upon these exchanges, recommendations were achieved.
Results
Key methodological challenges are: lack of consensus on how to screen for entry into cognitive treatment trials, define cognitive impairment, track efficacy, assess functional implications, and manage mood symptoms and concomitant medication. Task force recommendations are to: (i) enrich trials with objectively measured cognitively impaired patients; (ii) generally select a broad cognitive composite score as the primary outcome and a functional measure as a key secondary outcome; and (iii) include remitted or partly remitted patients. It is strongly encouraged that trials exclude patients with current substance or alcohol use disorders, neurological disease or unstable medical illness, and keep non‐study medications stable. Additional methodological considerations include neuroimaging assessments, targeting of treatments to illness stage and using a multimodal approach.
Conclusions
This ISBD task force guidance paper provides the first consensus‐based recommendations for cognition trials in bipolar disorder. Adherence to these recommendations will likely improve the sensitivity in detecting treatment efficacy in future trials and increase comparability between studies.
Non-fibrillar soluble oligomeric forms of amyloid-β peptide (oAβ) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease ...etiopathogenesis is that oAβ initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aβ, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAβ levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAβ to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aβ on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aβ and tau pathology.
For biological monitoring of heavy metal exposure in occupational toxicology, usually whole blood and urine samples are the most widely used and accepted matrix to assess internal xenobiotic ...exposure. Hair samples and saliva are also of interest in occupational and environmental health surveys but procedures for the determination of metals in saliva and hair are very scarce and to our knowledge there is no validation of a method to quantify Cr, Cd, Mn, Ni and Pb in four different human biological materials (whole blood, urine, saliva and axilary hair) by electrothermal atomization atomic absorption spectrometry (ETAAS). In the present study, quantification methods for the determination of Cr, Cd, Mn, Ni and Pb in whole blood, urine, saliva and axilary hair were validated according to the EU common standards. Pyrolisis and atomization temperatures have been determined. The main parameters evaluated were: detection and quantification limits, linearity range, repeatability, reproducibility, recovery and uncertainty. Accuracy of the methods was tested with the whole blood, urine and hair certified reference materials and recoveries of the spiked samples were acceptable ranged from 96.3 to 107.8%.
Influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus are the most common viruses associated with acute lower respiratory infections in young children (<5 years) and ...older people (≥65 years). A global report of the monthly activity of these viruses is needed to inform public health strategies and programmes for their control.
In this systematic analysis, we compiled data from a systematic literature review of studies published between Jan 1, 2000, and Dec 31, 2017; online datasets; and unpublished research data. Studies were eligible for inclusion if they reported laboratory-confirmed incidence data of human infection of influenza virus, respiratory syncytial virus, parainfluenza virus, or metapneumovirus, or a combination of these, for at least 12 consecutive months (or 52 weeks equivalent); stable testing practice throughout all years reported; virus results among residents in well-defined geographical locations; and aggregated virus results at least on a monthly basis. Data were extracted through a three-stage process, from which we calculated monthly annual average percentage (AAP) as the relative strength of virus activity. We defined duration of epidemics as the minimum number of months to account for 75% of annual positive samples, with each component month defined as an epidemic month. Furthermore, we modelled monthly AAP of influenza virus and respiratory syncytial virus using site-specific temperature and relative humidity for the prediction of local average epidemic months. We also predicted global epidemic months of influenza virus and respiratory syncytial virus on a 5° by 5° grid. The systematic review in this study is registered with PROSPERO, number CRD42018091628.
We initally identified 37 335 eligible studies. Of 21 065 studies remaining after exclusion of duplicates, 1081 full-text articles were assessed for eligibility, of which 185 were identified as eligible. We included 246 sites for influenza virus, 183 sites for respiratory syncytial virus, 83 sites for parainfluenza virus, and 65 sites for metapneumovirus. Influenza virus had clear seasonal epidemics in winter months in most temperate sites but timing of epidemics was more variable and less seasonal with decreasing distance from the equator. Unlike influenza virus, respiratory syncytial virus had clear seasonal epidemics in both temperate and tropical regions, starting in late summer months in the tropics of each hemisphere, reaching most temperate sites in winter months. In most temperate sites, influenza virus epidemics occurred later than respiratory syncytial virus (by 0·3 months 95% CI −0·3 to 0·9) while no clear temporal order was observed in the tropics. Parainfluenza virus epidemics were found mostly in spring and early summer months in each hemisphere. Metapneumovirus epidemics occurred in late winter and spring in most temperate sites but the timing of epidemics was more diverse in the tropics. Influenza virus epidemics had shorter duration (3·8 months 3·6 to 4·0) in temperate sites and longer duration (5·2 months 4·9 to 5·5) in the tropics. Duration of epidemics was similar across all sites for respiratory syncytial virus (4·6 months 4·3 to 4·8), as it was for metapneumovirus (4·8 months 4·4 to 5·1). By comparison, parainfluenza virus had longer duration of epidemics (6·3 months 6·0 to 6·7). Our model had good predictability in the average epidemic months of influenza virus in temperate regions and respiratory syncytial virus in both temperate and tropical regions. Through leave-one-out cross validation, the overall prediction error in the onset of epidemics was within 1 month (influenza virus −0·2 months −0·6 to 0·1; respiratory syncytial virus 0·1 months −0·2 to 0·4).
This study is the first to provide global representations of month-by-month activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus. Our model is helpful in predicting the local onset month of influenza virus and respiratory syncytial virus epidemics. The seasonality information has important implications for health services planning, the timing of respiratory syncytial virus passive prophylaxis, and the strategy of influenza virus and future respiratory syncytial virus vaccination.
European Union Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).
No clinical trials have compared osteoporosis drugs with incident fractures as the primary outcome. We compared the anti-fracture efficacy of teriparatide with risedronate in patients with severe ...osteoporosis.
In this double-blind, double-dummy trial, we enrolled post-menopausal women with at least two moderate or one severe vertebral fracture and a bone mineral density T score of less than or equal to −1·50. Participants were randomly assigned to receive 20 μg of teriparatide once daily plus oral weekly placebo or 35 mg of oral risedronate once weekly plus daily injections of placebo for 24 months. The primary outcome was new radiographic vertebral fractures. Secondary, gated outcomes included new and worsened radiographic vertebral fractures, clinical fractures (a composite of non-vertebral and symptomatic vertebral), and non-vertebral fractures. This study is registered with ClinicalTrials.gov (NCT01709110) and EudraCT (2012-000123-41).
We enrolled 680 patients in each group. At 24 months, new vertebral fractures occurred in 28 (5·4%) of 680 patients in the teriparatide group and 64 (12·0%) of 680 patients in the risedronate group (risk ratio 0·44, 95% CI 0·29–0·68; p<0·0001). Clinical fractures occurred in 30 (4·8%) of 680 patients in the teriparatide group compared with 61 (9·8%) of 680 in the risedronate group (hazard ratio 0·48, 95% CI 0·32–0·74; p=0·0009). Non-vertebral fragility fractures occurred in 25 (4·0%) patients in the teriparatide group and 38 (6·1%) in the risedronate group (hazard ratio 0·66; 95% CI 0·39–1·10; p=0·10).
Among post-menopausal women with severe osteoporosis, the risk of new vertebral and clinical fractures is significantly lower in patients receiving teriparatide than in those receiving risedronate.
Lilly.
The generally low bioavailability of iron in aerobic soil systems forced plants to evolve sophisticated genetic strategies to improve the acquisition of iron from sparingly soluble and immobile iron ...pools. To distinguish between conserved and species-dependent components of such strategies, we analyzed iron deficiency-induced changes in the transcriptome of two model species, Arabidopsis (Arabidopsis thaliana) and Medicago truncatula. Transcriptional profiling by RNA sequencing revealed a massive upregulation of genes coding for enzymes involved in riboflavin biosynthesis in M. truncatula and phenylpropanoid synthesis in Arabidopsis upon iron deficiency. Coexpression and promoter analysis indicated that the synthesis of flavins and phenylpropanoids is tightly linked to and putatively coregulated with other genes encoding proteins involved in iron uptake. We further provide evidence that the production and secretion of phenolic compounds is critical for the uptake of iron from sources with low bioavailability but dispensable under conditions where iron is readily available. In Arabidopsis, homozygous mutations in the Fe(II)- and 2-oxoglutarate-dependent dioxygenase family gene F6'H1 and defects in the expression of PLEIOTROPIC DRUG RESISTANCE9, encoding a putative efflux transporter for products from the phenylpropanoid pathway, compromised iron uptake from an iron source of low bioavailability. Both mutants were partially rescued when grown alongside wild-type Arabidopsis or M. truncatula seedlings, presumably by secreted phenolics and flavins. We concluded that production and secretion of compounds that facilitate the uptake of iron is an essential but poorly understood aspect of the reduction-based iron acquisition strategy, which is likely to contribute substantially to the efficiency of iron uptake in natural conditions.
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