The origin of large molecules in primordial autocatalytic reaction networks

Large molecules such as proteins and nucleic acids are crucial for life, yet their primordial origin remains a major puzzle. The production of large molecules, as we know it today, requires good catalysts, and the only good catalysts we know that can accomplish this task consist of large molecules. Thus the origin of large molecules is a chicken and egg problem in chemistry. Here we present a mechanism, based on autocatalytic sets (ACSs), that is a possible solution to this problem. We discuss a mathematical model describing the population dynamics of molecules in a stylized but prebiotically plausible chemistry. Large molecules can be produced in this chemistry by the coalescing of smaller ones, with the smallest molecules, the `food set', being buffered. Some of the reactions can be catalyzed by molecules within the chemistry with varying catalytic strengths. Normally the concentrations of large molecules in such a scenario are very small, diminishing exponentially with their size. ACSs, if present in the catalytic network, can focus the resources of the system into a sparse set of molecules. ACSs can produce a bistability in the population dynamics and, in particular, steady states wherein the ACS molecules dominate the population. However to reach these steady states from initial conditions that contain only the food set typically requires very large catalytic strengths, growing exponentially with the size of the catalyst molecule. We present a solution to this problem by studying `nested ACSs', a structure in which a small ACS is connected to a larger one and reinforces it. We show that when the network contains a cascade of nested ACSs with the catalytic strengths of molecules increasing gradually with their size (e.g., as a power law), a sparse subset of molecules including some very large molecules can come to dominate the system.Comment: 49 pages, 17 figures including supporting informatio

Genome-Wide Association Analysis Identifies a Mutation in the Thiamine Transporter 2 (SLC19A3) Gene Associated with Alaskan Husky Encephalopathy

Alaskan Husky Encephalopathy (AHE) has been previously proposed as a mitochondrial encephalopathy based on neuropathological similarities with human Leigh Syndrome (LS). We studied 11 Alaskan Husky dogs with AHE, but found no abnormalities in respiratory chain enzyme activities in muscle and liver, or mutations in mitochondrial or nuclear genes that cause LS in people. A genome wide association study was performed using eight of the affected dogs and 20 related but unaffected control AHs using the Illumina canine HD array. SLC19A3 was identified as a positional candidate gene. This gene controls the uptake of thiamine in the CNS via expression of the thiamine transporter protein THTR2. Dogs have two copies of this gene located within the candidate interval (SLC19A3.2 – 43.36–43.38 Mb and SLC19A3.1 – 43.411–43.419 Mb) on chromosome 25. Expression analysis in a normal dog revealed that one of the paralogs, SLC19A3.1, was expressed in the brain and spinal cord while the other was not. Subsequent exon sequencing of SLC19A3.1 revealed a 4bp insertion and SNP in the second exon that is predicted to result in a functional protein truncation of 279 amino acids (c.624 insTTGC, c.625 C>A). All dogs with AHE were homozygous for this mutation, 15/41 healthy AH control dogs were heterozygous carriers while 26/41 normal healthy AH dogs were wild type. Furthermore, this mutation was not detected in another 187 dogs of different breeds. These results suggest that this mutation in SLC19A3.1, encoding a thiamine transporter protein, plays a critical role in the pathogenesis of AHE.University of California, Davis. School of Veterinary Medicine. Center for Companion Animal Healt

Effects of chronic ascariasis and trichuriasis on cytokine production and gene expression in human blood: a cross-sectional study.

Background Chronic soil-transmitted helminth (STH) infections are associated with effects on systemic immune responses that could be caused by alterations in immune homeostasis. To investigate this, we measured the impact in children of STH infections on cytokine responses and gene expression in unstimulated blood. Methodology/Principal Findings Sixty children were classified as having chronic, light, or no STH infections. Peripheral blood mononuclear cells were cultured in medium for 5 days to measure cytokine accumulation. RNA was isolated from peripheral blood and gene expression analysed using microarrays. Different infection groups were compared for the purpose of analysis: STH infection (combined chronic and light vs. uninfected groups) and chronic STH infection (chronic vs. combined light and uninfected groups). The chronic STH infection effect was associated with elevated production of GM-CSF (P = 0.007), IL-2 (P = 0.03), IL-5 (P = 0.01), and IL-10 (P = 0.01). Data reduction suggested that chronic infections were primarily associated with an immune phenotype characterized by elevated IL-5 and IL-10, typical of a modified Th2-like response. Chronic STH infections were associated with the up-regulation of genes associated with immune homeostasis (IDO, P = 0.03; CCL23, P = 0.008, HRK, P = 0.005), down-regulation of microRNA hsa-let-7d (P = 0.01) and differential regulation of several genes associated with granulocyte-mediated inflammation (IL-8, down-regulated, P = 0.0002; RNASE2, up-regulated, P = 0.009; RNASE3, up-regulated, p = 0.03). Conclusions/Significance Chronic STH infections were associated with a cytokine response indicative of a modified Th2 response. There was evidence that STH infections were associated with a pattern of gene expression suggestive of the induction of homeostatic mechanisms, the differential expression of several inflammatory genes and the down-regulation of microRNA has-let-7d. Effects on immune homeostasis and the development of a modified Th2 immune response during chronic STH infections could explain the systemic immunologic effects that have been associated with these infections such as impaired immune responses to vaccines and the suppression of inflammatory diseases

Slower is not always better: Response-time evidence clarifies the limited role of miserly information processing in the Cognitive Reflection Test

We report a study examining the role of `cognitive miserliness' as a determinant of poor performance on the standard three-item Cognitive Reflection Test (CRT). The cognitive miserliness hypothesis proposes that people often respond incorrectly on CRT items because of an unwillingness to go beyond default, heuristic processing and invest time and effort in analytic, reflective processing. Our analysis (N = 391) focused on people's response times to CRT items to determine whether predicted associations are evident between miserly thinking and the generation of incorrect, intuitive answers. Evidence indicated only a weak correlation between CRT response times and accuracy. Item-level analyses also failed to demonstrate predicted response time differences between correct analytic and incorrect intuitive answers for two of the three CRT items. We question whether participants who give incorrect intuitive answers on the CRT can legitimately be termed cognitive misers and whether the three CRT items measure the same general construct

Predicting change in quality of life from age 79 to 90 in the Lothian Birth Cohort 1921

Purpose: Quality of life (QoL) decreases in very old age, and is strongly related to health outcomes and mortality. Understanding the predictors of QoL and change in QoL amongst the oldest old may suggest potential targets for intervention. This study investigated change in QoL from age 79 to 90 years in a group of older adults in Scotland, and identified potential predictors of that change. Method: Participants were members of the Lothian Birth Cohort 1921 who attended clinic visits at age 79 (n = 554) and 90 (n = 129). Measures at both time points included QoL (WHOQOL-BREF: four domains and two single items), anxiety and depression, objective health, functional ability, self-rated health, loneliness, and personality. Results: Mean QoL declined from age 79 to 90. Participants returning at 90 had scored significantly higher at 79 on most QoL measures, and exhibited better objective health and functional ability, and lower anxiety and depression than non-returners. Hierarchical multiple regression models accounted for 20.3–56.3% of the variance in QoL at age 90. Baseline QoL was the strongest predictor of domain scores (20.3–35.6% variance explained), suggesting that individual differences in QoL judgements remain largely stable. Additional predictors varied by the QoL domain and included self-rated health, loneliness, and functional and mood decline between age 79 and 90 years. Conclusions: This study has identified potential targets for interventions to improve QoL in the oldest old. Further research should address causal pathways between QoL and functional and mood decline, perceived health and loneliness

Long-term efficacy of botulinum toxin A for treatment of blepharospasm,hemifacial spasm, and spastic entropion: a multicentre study using two drug-dose escalation indexes

PURPOSE: To investigate the long-term effectiveness and safety of botulinum neurotoxin A (BoNT-A) treatment in patients with blepharospasm (BEB), hemifacial spasm (HFS), and entropion (EN) and to use for the first time two modified indexes, 'botulin toxin escalation index-U' (BEI-U) and 'botulin toxin escalation index percentage' (BEI-%), in the dose-escalation evaluation. METHODS: All patients in this multicentre study were followed for at least 10 years and main outcomes were clinical efficacy, duration of relief, BEI-U and BEI-%, and frequency of adverse events. RESULTS: BEB, HFS, and EN patients received a mean BoNT-A dose with a significant inter-group difference (P<0.0005, respectively). The mean (+/-SD) effect duration was statistically different (P=0.009) among three patient groups. Regarding the BoNT-A escalation indexes, the mean (+/-SD) values of BEI-U and BEI-% were statistically different (P=0.035 and 0.047, respectively) among the three groups. In BEB patients, the BEI-% was significantly increased in younger compared with older patients (P=0.008). The most frequent adverse events were upper lid ptosis, diplopia, ecchymosis, and localized bruising. CONCLUSIONS: This long-term multicentre study supports a high efficacy and good safety profile of BoNT-A for treatment of BEB, HFS, and EN. The BEI indexes indicate a significantly greater BoNT-A-dose escalation for BEB patients compared with HFS or EN patients and a significantly greater BEI-% in younger vsolder BEB patients. These results confirm a greater efficacy in the elderly and provide a framework for long-term studies with a more flexible and reliable evaluation of drug-dose escalation

Genes involved in ethylene and gibberellins metabolism are required for endosperm-limited germiantion of Sisymbrium officinales L. Seeds

The rupture of the seed coat and that of the endosperm were found to be two sequential events in the germination of Sisymbrium officinale L. seeds, and radicle protrusion did not occur exactly in the micropylar area but in the neighboring zone. The germination patterns were similar both in the presence of gibberellins (GA4+7) and in presence of ethrel. The analysis of genes involved in GAs synthesis and breakdown demonstrated that (1) SoGA2ox6 expression peaked just prior to radicle protrusion (20–22 h), while SoGA3ox2 and SoGA20ox2 expression was high at early imbibition (6 h) diminishing sharply thereafter; (2) the accumulation of SoGA20ox2 transcript was strongly inhibited by paclobutrazol (PB) as well as by inhibitors of ET synthesis and signaling (IESS) early after imbibition (6 h), while SoGA3ox2 and SoGA2ox6 expression was slowly depressed as germination progressed; (3) ethrel and GA4+7 positively or negatively affected expression of SoGA3ox2, SoGA20ox2, and SoGA2ox6, depending on the germination period studied. Regarding genes involved in ET synthesis, our results showed that SoACS7 was expressed, just prior to radicle emergence while SoACO2 expression slowly increased as germination progressed. Both genes were strongly inhibited by PB but were almost unaffected by externally added ethrel or GA4+7. These results suggest that GAs are more important than ET during the early stages of imbibition, while ET is more important at the late phases of germination of S. officinale L. seed

Comparative assessment of multiple COVID-19 serological technologies supports continued evaluation of point-of-care lateral flow assays in hospital and community healthcare settings

There is a clear requirement for an accurate SARS-CoV-2 antibody test, both as a complement to existing diagnostic capabilities and for determining community seroprevalence. We therefore evaluated the performance of a variety of antibody testing technologies and their potential use as diagnostic tools. Highly specific in-house ELISAs were developed for the detection of anti-spike (S), -receptor binding domain (RBD) and -nucleocapsid (N) antibodies and used for the cross-comparison of ten commercial serological assays-a chemiluminescence-based platform, two ELISAs and seven colloidal gold lateral flow immunoassays (LFIAs)-on an identical panel of 110 SARS-CoV-2-positive samples and 50 pre-pandemic negatives. There was a wide variation in the performance of the different platforms, with specificity ranging from 82% to 100%, and overall sensitivity from 60.9% to 87.3%. However, the head-to-head comparison of multiple sero-diagnostic assays on identical sample sets revealed that performance is highly dependent on the time of sampling, with sensitivities of over 95% seen in several tests when assessing samples from more than 20 days post onset of symptoms. Furthermore, these analyses identified clear outlying samples that were negative in all tests, but were later shown to be from individuals with mildest disease presentation. Rigorous comparison of antibody testing platforms will inform the deployment of point-of-care technologies in healthcare settings and their use in the monitoring of SARS-CoV-2 infections

A systematic review of patient and health system characteristics associated with late referral in chronic kidney disease

<p>Abstract</p> <p>Background</p> <p>To identify patient and health system characteristics associated with late referral of patients with chronic kidney disease to nephrologists.</p> <p>Methods</p> <p>MEDLINE, CENTRAL, and CINAHL were searched using the appropriate MESH terms in March 2007. Two reviewers individually and in duplicate reviewed the abstracts of 256 articles and selected 18 observational studies for inclusion. The reasons for late referral were categorized into patient or health system characteristics. Data extraction and content appraisal were done using a prespecified protocol.</p> <p>Results</p> <p>Older age, the existence of multiple comorbidities, race other than Caucasian, lack of insurance, lower socioeconomic status and educational levels were patient characteristics associated with late referral of patients with chronic kidney disease. Lack of referring physician knowledge about the appropriate timing of referral, absence of communication between referring physicians and nephrologists, and dialysis care delivered at tertiary medical centers were health system characteristics associated with late referral of patients with chronic kidney disease. Most studies identified multiple factors associated with late referral, although the relative importance and the combined effect of these factors were not systematically evaluated.</p> <p>Conclusion</p> <p>A combination of patient and health system characteristics is associated with late referral of patients with chronic kidney disease. Overall, being older, belonging to a minority group, being less educated, being uninsured, suffering from multiple comorbidities, and the lack of communication between primary care physicians and nephrologists contribute to late referral of patients with chronic kidney disease. Both primary care physicians and nephrologists need to engage in multisectoral collaborative efforts that ensure patient education and enhance physician awareness to improve the care of patients with chronic kidney disease.</p