The recent development of human exome sequencing technology has revealed that our immune system is riddled with more genetic defects than anyone imagined. As a legacy of the recent human population ...explosion, we each inherit hundreds of rare mutations that alter the sequence of proteins. This mutation load is ten times higher than that induced by experimental treatment of mice by ethylnitrosourea; a high fraction of which has substantial effects on immune function. This mutation burden is likely to be a major factor in the incidence of many human immune disorders, but understanding this at the level of individual patients will require new bioinformatics and experimental strategies to assess the impact of individual and combined mutations on immune response pathways.
AbstractObjectiveTo estimate the change in odds of covid-19 over time following primary series completion of the inactivated whole virus vaccine CoronaVac (Sinovac Biotech) in São Paulo State, ...Brazil.DesignTest negative case-control study.SettingCommunity testing for covid-19 in São Paulo State, Brazil.ParticipantsAdults aged ≥18 years who were residents of São Paulo state, had received two doses of CoronaVac, did not have a laboratory confirmed SARS-CoV-2 infection before vaccination, and underwent reverse transcription polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 from 17 January to 14 December 2021. Cases were matched to test negative controls by age (in 5 year bands), municipality of residence, healthcare worker status, and epidemiological week of RT-PCR test.Main outcome measuresRT-PCR confirmed symptomatic covid-19 and associated hospital admissions and deaths. Conditional logistic regression was adjusted for sex, number of covid-19 associated comorbidities, race, and previous acute respiratory illness.ResultsFrom 202 741 eligible people, 52 170 cases with symptomatic covid-19 and 69 115 test negative controls with covid-19 symptoms were formed into 43 257 matched sets. Adjusted odds ratios of symptomatic covid-19 increased with time since completion of the vaccination series. The increase in odds was greater in younger people and among healthcare workers, although sensitivity analyses suggested that this was in part due to bias. In addition, the adjusted odds ratios of covid-19 related hospital admission or death significantly increased with time compared with the odds 14-41 days after series completion: from 1.25 (95% confidence interval 1.04 to 1.51) at 70-97 days up to 1.94 (1.41 to 2.67) from 182 days onwards.ConclusionsSignificant increases in the risk of moderate and severe covid-19 outcomes occurred three months after primary vaccination with CoronaVac among people aged 65 and older. These findings provide supportive evidence for the implementation of vaccine boosters in these populations who received this inactivated vaccine. Studies of waning should include analyses designed to uncover common biases.
Developing biomaterial constructs that closely mimic the natural tissue microenvironment with its complex chemical and physical cues is essential for improving the function and reliability of ...implantable devices, especially those that require direct neural-electrical interfaces. Here we demonstrate that free-standing vertically aligned carbon nanofiber (VACNF) arrays can be used as a multifunctional 3-D brush-like nanoengineered matrix that interpenetrates the neuronal network of PC12 cells. We found that PC12 neuron cells cultured on VACNF substrates can form extended neural network upon proper chemical and biochemical modifications. The soft 3-D VACNF architecture provides a new platform to fine-tune the topographical, mechanical, chemical, and electrical cues at subcellular nanoscale. This new biomaterial platform can be used for both fundamental studies of material-cell interactions and the development of chronically stable implantable neural devices. Micropatterned multiplex VACNF arrays can be selectively controlled by electrical and electrochemical methods to provide localized stimulation with extraordinary spatiotemporal resolution. Further development of this technology may potentially result in a highly multiplex closed-loop system with multifunctions for neuromodulation and neuroprostheses
Accurate identification of sparse heterozygous single-nucleotide variants (SNVs) is a critical challenge for identifying the causative mutations in mouse genetic screens, human genetic diseases and ...cancer. When seeking to identify causal DNA variants that occur at such low rates, they are overwhelmed by false-positive calls that arise from a range of technical and biological sources. We describe a strategy using whole-exome capture, massively parallel DNA sequencing and computational analysis, which identifies with a low false-positive rate the majority of heterozygous and homozygous SNVs arising de novo with a frequency of one nucleotide substitution per megabase in progeny of N-ethyl-N-nitrosourea (ENU)-mutated C57BL/6j mice. We found that by applying a strategy of filtering raw SNV calls against known and platform-specific variants we could call true SNVs with a false-positive rate of 19.4 per cent and an estimated false-negative rate of 21.3 per cent. These error rates are small enough to enable calling a causative mutation from both homozygous and heterozygous candidate mutation lists with little or no further experimental validation. The efficacy of this approach is demonstrated by identifying the causative mutation in the Ptprc gene in a lymphocyte-deficient strain and in 11 other strains with immune disorders or obesity, without the need for meiotic mapping. Exome sequencing of first-generation mutant mice revealed hundreds of unphenotyped protein-changing mutations, 52 per cent of which are predicted to be deleterious, which now become available for breeding and experimental analysis. We show that exome sequencing data alone are sufficient to identify induced mutations. This approach transforms genetic screens in mice, establishes a general strategy for analysing rare DNA variants and opens up a large new source for experimental models of human disease.
The embryonic chicken is commonly used as a reliable model organism for vertebrate development. Its accessibility and short incubation period makes it ideal for experimentation. Currently, the study ...of these developmental pathways in the chicken embryo is conducted by applying inhibitors and drugs at localized sites and at low concentrations using a variety of methods. In vitro tissue culturing is a technique that enables the study of tissues separated from the host organism, while simultaneously bypassing many of the physical limitations present when working with whole embryos, such as the susceptibility of embryos to high doses of potentially lethal chemicals. Here, we present an organotypic culturing protocol for culturing the embryonic chicken half head in vitro, which presents new opportunities for the examination of developmental processes beyond the currently established methods.
Periodic motion of Saturn's nightside plasma sheet Arridge, C. S.; André, N.; Khurana, K. K. ...
Journal of Geophysical Research: Space Physics,
November 2011, Letnik:
116, Številka:
A11
Journal Article
Recenzirano
Odprti dostop
Saturn's magnetosphere is replete with magnetospheric periodicities; magnetic fields, plasma parameters, energetic particle fluxes, and radio emissions have all been observed to vary at a period ...close to that of Saturn's assumed sidereal rotation rate. In particular, periodicities in Saturn's magnetotail can be interpreted in terms of periodic vertical motion of Saturn's outer magnetospheric plasma sheet. The phase relationships between periodicities in different measurable quantities are a key piece of information in validating the various published models that attempt to relate periodicities in different quantities at different locations. It is important to empirically extract these phase relationships from the data in order to distinguish between these models, and to provide further data on which to base new conceptual models. In this paper a simple structural model of the flapping of Saturn's plasma sheet is developed and fitted to plasma densities in the outer magnetosphere, measured by the Cassini electron spectrometer. This model is used to establish the phase relationships between magnetic field periodicities in the cam region of the magnetosphere and the flapping of the plasma sheet. We find that the plasma sheet flaps in phase with Br and Bθ and in quadrature with the Bϕ component in the core/cam region. The plasma sheet phase also has a strong local time asymmetry. These results support some conceptual periodicity models but are in apparent contradiction with others, suggesting that future work is required to either modify the models or study additional phase relationships that are important for these models.
Key Points
Saturn's nightside plasma sheet flaps up and down producing periodicities
A wavy magnetodisc model can be used to extract phase and radial propagation data
The plasma sheet has a robust phase relationship with other periodic data sets
Nicotinamide riboside (NR), a newly recognised form of vitamin B
and a precursor to nicotinamide adenine dinucleotide (NAD
), has been demonstrated to show therapeutic potential and the possibility ...of becoming a drug compound in addition to its proven role in rejuvenating ageing cells in mice. However, current literature is devoid of information relating to the physicochemical characterisation of NR and its respective impact upon formulation and final product processing. Here we report physicochemical properties of NR including p
a, log
, solubility, melting point, degradation mechanics, and kinetics, with a special focus on its stability under thermal and physiologically relevant conditions. A simple and rapid HPLC method confirms a base-catalysed hydrolysis degradation of NRCl to nicotinamide and sugar in simulated gastrointestinal (GI) fluids. Given the antagonising effect of nicotinamide against NR, the presented data have a profound impact on how NRCl should be handled both during formulation and storage to prevent formation and to limit accumulation of nicotinamide. The innovative combinatorial use of
H NMR and Differential Scanning Calorimetry (DSC) was employed to investigate thermal events during NR melting. NRCl degrades upon melting and in solution undergoes hydrolysis in a buffer and in simulated intestinal environments. The results suggest that a proper and evidence-based formulation of NRCl is vital to enable further investigation and clinical analysis of this promising and novel nutrient. Any formulation would need to promote the stability of NRCl and protect it from hostile environments to prevent the accumulation of a potentially antagonistic degradation product. With the current work, we have filled a niche but vital gap in NR literature and the data presented may prove useful in furthering the understanding, specifically the formulation and processing of NRCl.
We outline a plausible, albeit extreme, managed realignment scenario (‘Extended Deep Green’ scenario) for a large UK estuary to demonstrate the maximum possible biogeochemical effects and economic ...outcomes of estuarine management decisions. Our interdisciplinary approach aims to better inform the policy process, by combining biogeochemical and socioeconomic components of managed realignment schemes. Adding 7494 ha of new intertidal area to the UK Humber estuary through managed realignment leads to the annual accumulation of a 1.2×105 t of ‘new’ sediment and increases the current annual sink of organic C and N, and particle reactive P in the estuary by 150%, 83% and 50%, respectively. The increase in intertidal area should also increase denitrification. However, this positive outcome is offset by the negative effect of enhanced greenhouse gas emissions in new marshes in the low salinity region of the estuary. Short-term microbial reactions decrease the potential benefits of CO2 sequestration through gross organic carbon burial by at least 50%. Net carbon storage is thus most effective where oxidation and denitrification reactions are reduced. In the Humber this translates to wet, saline marshes at the seaward end of estuaries. Cost–benefit analysis (CBA) was used to determine the economic efficiency of the Extended Deep Green managed realignment. When compared to a ‘Hold-the-Line’ future scenario, i.e. the present state/extent of sea defences in the estuary, the CBA shows that managed realignment is cost effective when viewed on >25 year timescales. This is because capital costs are incurred in the first years, whereas the benefits from habitat creation, carbon sequestration and reduced maintenance costs build up over time. Over 50- and 100-year timescales, the Extended Deep Green managed realignment scenario is superior in efficiency terms. The increased sediment accumulation is also likely to enhance storage of contaminant metals. In the case of Cu, a metal that currently causes significant water quality issues, Cu removal due to burial of suspended sediment in realigned areas translates to a value of approximately £1000 a−1 (avoided clean up costs). Although this is not formally included in the CBA it illustrates another likely positive economic outcome of managed realignment. Although we focus on the Humber, the history of reclamation and its biogeochemistry is common to many estuaries in northern Europe.
There are few studies on visceral pain in infants, despite its clinical importance. We have used the abdominal skin reflex (ASR) to measure changes in abdominal sensitivity in the presence of ...visceral pathology in infants. The reflex was elicited by applying calibrated von Frey hairs to each side of the abdomen and the mechanical threshold and the degree of reflex radiation as denoted by hip flexion were measured. The developmental progression of ASR properties during the first year of life was studied in a cross-sectional sample of healthy infants ranging from 30 to 95 weeks postconceptional age (PCA). These properties were compared to those in infants with unilateral hydronephrosis (UH) using a blinded protocol. Infants with UH were studied at their first outpatient appointment after birth, and postoperatively following surgery if this was indicated. The investigators were blinded to laterality and severity of hydronephrosis until data were analysed, or until surgery. A total of 30 patients with UH and 77 healthy infants were included in the study. In 21 (70%) patients, the side of hydronephrosis had a significantly lower ASR threshold than the contralateral side of the abdomen. There was a significant increase in reflex threshold and decrease in reflex radiation with increasing PCA in control infants. However, in UH infants, this relationship did not exist, even on the unaffected side of the abdomen.
Our results show that infants with prenatally diagnosed UH demonstrate increased abdominal sensitivity compared with control infants. Using the ASR, we have provided the first evidence of referred visceral hypersensitivity in infants.
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