4,358 research outputs found

    Self-replication and evolution of DNA crystals

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    Is it possible to create a simple physical system that is capable of replicating itself? Can such a system evolve interesting behaviors, thus allowing it to adapt to a wide range of environments? This paper presents a design for such a replicator constructed exclusively from synthetic DNA. The basis for the replicator is crystal growth: information is stored in the spatial arrangement of monomers and copied from layer to layer by templating. Replication is achieved by fragmentation of crystals, which produces new crystals that carry the same information. Crystal replication avoids intrinsic problems associated with template-directed mechanisms for replication of one-dimensional polymers. A key innovation of our work is that by using programmable DNA tiles as the crystal monomers, we can design crystal growth processes that apply interesting selective pressures to the evolving sequences. While evolution requires that copying occur with high accuracy, we show how to adapt error-correction techniques from algorithmic self-assembly to lower the replication error rate as much as is required

    Human central nervous system (CNS) ApoE isoforms are increased by age, differentially altered by amyloidosis, and relative amounts reversed in the CNS compared with plasma

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    The risk of Alzheimer's disease (AD) is highly dependent on apolipoprotein-E (apoE) genotype. The reasons for apoE isoform-selective risk are uncertain; however, both the amounts and structure of human apoE isoforms have been hypothesized to lead to amyloidosis increasing the risk for AD. To address the hypothesis that amounts of apoE isoforms are different in the human CNS, we developed a novel isoform-specific method to accurately quantify apoE isoforms in clinically relevant samples. The method utilizes an antibody-free enrichment step and isotope-labeled physiologically relevant lipoprotein particle standards produced by immortalized astrocytes. We applied this method to a cohort of well characterized clinical samples and observed the following findings. The apoE isoform amounts are not different in cerebrospinal fluid (CSF) from young normal controls, suggesting that the amount of apoE isoforms is not the reason for risk of amyloidosis prior to the onset of advanced age. We did, however, observe an age-related increase in both apoE isoforms. In contrast to normal aging, the presence of amyloid increased apoE3, whereas apoE4 was unchanged or decreased. Importantly, for heterozygotes, the apoE4/apoE3 isoform ratio was increased in the CNS, although the reverse was true in the periphery. Finally, CSF apoE levels, but not plasma apoE levels, correlated with CSF β-amyloid levels. Collectively, these findings support the hypothesis that CNS and peripheral apoE are separate pools and differentially regulated. Furthermore, these results suggest that apoE mechanisms for the risk of amyloidosis and AD are related to an interaction between apoE, aging, and the amount of amyloid burden

    Simulations of Electron Acceleration at Collisionless Shocks: The Effects of Surface Fluctuations

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    Energetic electrons are a common feature of interplanetary shocks and planetary bow shocks, and they are invoked as a key component of models of nonthermal radio emission, such as solar radio bursts. A simulation study is carried out of electron acceleration for high Mach number, quasi-perpendicular shocks, typical of the shocks in the solar wind. Two dimensional self-consistent hybrid shock simulations provide the electric and magnetic fields in which test particle electrons are followed. A range of different shock types, shock normal angles, and injection energies are studied. When the Mach number is low, or the simulation configuration suppresses fluctuations along the magnetic field direction, the results agree with theory assuming magnetic moment conserving reflection (or Fast Fermi acceleration), with electron energy gains of a factor only 2 - 3. For high Mach number, with a realistic simulation configuration, the shock front has a dynamic rippled character. The corresponding electron energization is radically different: Energy spectra display: (1) considerably higher maximum energies than Fast Fermi acceleration; (2) a plateau, or shallow sloped region, at intermediate energies 2 - 5 times the injection energy; (3) power law fall off with increasing energy, for both upstream and downstream particles, with a slope decreasing as the shock normal angle approaches perpendicular; (4) sustained flux levels over a broader region of shock normal angle than for adiabatic reflection. All these features are in good qualitative agreement with observations, and show that dynamic structure in the shock surface at ion scales produces effective scattering and can be responsible for making high Mach number shocks effective sites for electron acceleration.Comment: 26 pages, 12 figure

    Challenges of HIV diagnosis and management in the context of pre-exposure prophylaxis (PrEP), post-exposure prophylaxis (PEP), test and start and acute HIV infection: a scoping review

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    Introduction: Knowledge of HIV status relies on accurate HIV testing, and is the first step towards access to HIV treatment and prevention programmes. Globally, HIV-status unawareness represents a significant challenge for achieving zero new HIV infections and deaths. In order to enhance knowledge of HIV status, the World Health Organisation (WHO) recommends a testing strategy that includes the use of HIV-specific antibody point-of-care tests (POCT). These POCTs do not detect acute HIV infection, the stage of disease when viral load is highest but HIV antibodies are undetectable. Complicating things further, in the presence of antiretroviral therapy (ART) for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP), other currently available testing technologies, such as viral load detection for diagnosis of acute HIV infection, may yield false negative results. In this scoping review, we evaluate the evidence and discuss alternative HIV testing algorithms that may mitigate diagnostic dilemmas in the setting of increased utilisation of ART for immediate treatment and prevention of HIV infection. Discussion: Missed acute HIV infection prevents people living with HIV (PLWH) from accessing early treatment, increases likelihood of onward transmission, and allows for inappropriate initiation or continuation of PrEP, which may result in HIV drug resistance. Whilst immediate ART is recommended for all PLWH, studies have shown that starting ART in the setting of acute HIV infection may result in a delayed or complete absence of development of HIV-specific antibodies, posing a diagnostic challenge that is particularly pertinent to resource-limited, high HIV burden settings where HIV-antibody POCTs are standard of care. Similarly, ART used as PrEP or PEP may supress HIV RNA viral load, complicating current HIV testing algorithms in resource-wealthy settings where viral detection is included. As roll-out of PrEP continues, HIV testing algorithms may need to be modified. Conclusions: With increasing use of PrEP and ART in acute infection we anticipate diagnostic challenges using currently available HIV testing strategies. Research and surveillance is needed to determine the most appropriate assays and optimal testing algorithms that are accurate, affordable and sustainable

    Dopaminergic, serotonergic, and noradrenergic deficits in Parkinson disease

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    OBJECTIVE: People with Parkinson disease (PD) frequently develop dementia, which is associated with neocortical deposition of alpha-synuclein (α-syn) in Lewy bodies and Lewy neurites. In addition, neuronal loss and deposition of aggregated α-syn also occur in multiple subcortical nuclei that project to neocortical, limbic, and basal ganglia regions. Therefore, we quantified regional deficits in innervation from these PD-affected subcortical nuclei, by measuring the neurotransmitters and neurotransmitter transporter proteins originating from projections of dopaminergic neurons in substantia nigra pars compacta, serotonergic neurons in dorsal raphé nuclei, noradrenergic neurons in locus coeruleus, and cholinergic neurons in nucleus basalis of Meynert. METHODS: High-performance liquid chromatography and novel enzyme-linked immunosorbent assays were performed to quantify dopaminergic, serotonergic, noradrenergic, and cholinergic innervation in postmortem brain tissue. Eight brain regions from 15 PD participants (with dementia and Braak stage 6 α-syn deposition) and six age-matched controls were tested. RESULTS: PD participants compared to controls had widespread reductions of dopamine transporter in caudate, amygdala, hippocampus, inferior parietal lobule (IPL), precuneus, and visual association cortex (VAC) that exceeded loss of dopamine, which was only significantly reduced in caudate and amygdala. In contrast, PD participants had comparable deficits of both serotonin and serotonin transporter in caudate, middle frontal gyrus, IPL, and VAC. PD participants also had significantly reduced norepinephrine levels for all eight brain regions tested. Vesicular acetylcholine transporter levels were only quantifiable in caudate and hippocampus and did not differ between PD and control groups. INTERPRETATION: These results demonstrate widespread deficits in dopaminergic, serotonergic, and noradrenergic innervation of neocortical, limbic, and basal ganglia regions in advanced PD with dementia

    Construction of a generalised farm typology to aid selection, targeting and scaling of on farm research

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    Farm typologies are often used to reduce the complexity in categorising diverse farming systems, particularly in sub-Saharan Africa. The resulting typologies can then be used in multiple ways including designing efficient sampling schemes that capture the diversity in smallholder farms, prescribing the selection of certain farm types to which interventions can be targeted or upscaled, or to give context into derived relationships. However, the construction of farm typologies consists of many subjective decisions that are not always obvious or evident to the end-user. By developing a generalized framework for constructing farm typologies, we clarify where these subjective decisions are and quantify the impact they have on the resulting typologies. Further, this framework has been encapsulated in the open source RShiny App: TypologyGenerator to enable users to focus on the decisions and not the underlying implementation

    Delusions in frontotemporal lobar degeneration

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    We assessed the significance and nature of delusions in frontotemporal lobar degeneration (FTLD), an important cause of young-onset dementia with prominent neuropsychiatric features that remain incompletely characterised. The case notes of all patients meeting diagnostic criteria for FTLD attending a tertiary level cognitive disorders clinic over a three year period were retrospectively reviewed and eight patients with a history of delusions were identified. All patients underwent detailed clinical and neuropsychological evaluation and brain MRI. The diagnosis was confirmed pathologically in two cases. The estimated prevalence of delusions was 14 %. Delusions were an early, prominent and persistent feature. They were phenomenologically diverse; however paranoid and somatic delusions were prominent. Behavioural variant FTLD was the most frequently associated clinical subtype and cerebral atrophy was bilateral or predominantly right-sided in most cases. We conclude that delusions may be a clinical issue in FTLD, and this should be explored further in future work
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