Notions of Infinity in Quantum Physics

In this article we will review some notions of infiniteness that appear in Hilbert space operators and operator algebras. These include proper infiniteness, Murray von Neumann's classification into type I and type III factors and the class of F{/o} lner C*-algebras that capture some aspects of amenability. We will also mention how these notions reappear in the description of certain mathematical aspects of quantum mechanics, quantum field theory and the theory of superselection sectors. We also show that the algebra of the canonical anti-commutation relations (CAR-algebra) is in the class of F{/o} lner C*-algebras.Comment: 11 page

Hands-On Parameter Search for Neural Simulations by a MIDI-Controller

Computational neuroscientists frequently encounter the challenge of parameter fitting – exploring a usually high dimensional variable space to find a parameter set that reproduces an experimental data set. One common approach is using automated search algorithms such as gradient descent or genetic algorithms. However, these approaches suffer several shortcomings related to their lack of understanding the underlying question, such as defining a suitable error function or getting stuck in local minima. Another widespread approach is manual parameter fitting using a keyboard or a mouse, evaluating different parameter sets following the users intuition. However, this process is often cumbersome and time-intensive. Here, we present a new method for manual parameter fitting. A MIDI controller provides input to the simulation software, where model parameters are then tuned according to the knob and slider positions on the device. The model is immediately updated on every parameter change, continuously plotting the latest results. Given reasonably short simulation times of less than one second, we find this method to be highly efficient in quickly determining good parameter sets. Our approach bears a close resemblance to tuning the sound of an analog synthesizer, giving the user a very good intuition of the problem at hand, such as immediate feedback if and how results are affected by specific parameter changes. In addition to be used in research, our approach should be an ideal teaching tool, allowing students to interactively explore complex models such as Hodgkin-Huxley or dynamical systems

Dendritic Polyglycerol Amine: An Enhanced Substrate to Support Long-Term Neural Cell Culture

Long-term stable cell culture is a critical tool to better understand cell function. Most adherent cell culture models require a polymer substrate coating of poly-lysine or poly-ornithine for the cells to adhere and survive. However, polypeptide-based substrates are degraded by proteolysis and it remains a challenge to maintain healthy cell cultures for extended periods of time. Here, we report the development of an enhanced cell culture substrate based on a coating of dendritic polyglycerol amine (dPGA), a non-protein macromolecular biomimetic of poly-lysine, to promote the adhesion and survival of neurons in cell culture. We show that this new polymer coating provides enhanced survival, differentiation and long-term stability for cultures of primary neurons or neurons derived from human induced pluripotent stem cells (hiPSCs). Atomic force microscopy analysis provides evidence that greater nanoscale roughness contributes to the enhanced capacity of dPGA-coated surfaces to support cells in culture. We conclude that dPGA is a cytocompatible, functionally superior, easy to use, low cost and highly stable alternative to poly-cationic polymer cell culture substrate coatings such as poly-lysine and poly-ornithine. Summary statement Here, we describe a novel dendritic polyglycerol amine-based substrate coating, demonstrating superior performance compared to current polymer coatings for long-term culture of primary neurons and neurons derived from induced pluripotent stem cells

Consequences of converting graded to action potentials upon neural information coding and energy efficiency

Information is encoded in neural circuits using both graded and action potentials, converting between them within single neurons and successive processing layers. This conversion is accompanied by information loss and a drop in energy efficiency. We investigate the biophysical causes of this loss of information and efficiency by comparing spiking neuron models, containing stochastic voltage-gated Na+ and K+ channels, with generator potential and graded potential models lacking voltage-gated Na+ channels. We identify three causes of information loss in the generator potential that are the by-product of action potential generation: (1) the voltage-gated Na+ channels necessary for action potential generation increase intrinsic noise and (2) introduce non-linearities, and (3) the finite duration of the action potential creates a ‘footprint’ in the generator potential that obscures incoming signals. These three processes reduce information rates by ~50% in generator potentials, to ~3 times that of spike trains. Both generator potentials and graded potentials consume almost an order of magnitude less energy per second than spike trains. Because of the lower information rates of generator potentials they are substantially less energy efficient than graded potentials. However, both are an order of magnitude more efficient than spike trains due to the higher energy costs and low information content of spikes, emphasizing that there is a two-fold cost of converting analogue to digital; information loss and cost inflation

The Efficacy, Safety, and Immunogenicity of Switching Between Reference Biopharmaceuticals and Biosimilars: A Systematic Review

To date, no consensus exists among stakeholders about the safety of switching between reference biological products (RPs) and biosimilars, which may have been curbing the implementation of biosimilars in clinical practice. This study synthesizes the available data on switching and assesses whether switching patients from a RP to its biosimilar or vice versa affects efficacy, safety, or immunogenicity outcomes. A total of 178 studies, in which switch outcomes from a RP to a biosimilar were reported, was identified. Data were derived from both randomized controlled trials and real-world evidence. Despite the limitations stemming from a lack of a robust design for most of the studies, the available switching data do not indicate that switching from a RP to a biosimilar is associated with any major efficacy, safety, or immunogenicity issues. Some open-label and observational studies reported increased discontinuation rates after switching, which were mainly attributed to nocebo effects. Involvement of the prescriber in any decision to switch should remain and attention should be paid to the mitigation of a potential nocebo effect

Partial complementation of Sinorhizobium meliloti bacA mutant phenotypes by the Mycobacterium tuberculosis BacA protein

The Sinorhizobium meliloti BacA ABC transporter protein plays an important role in its nodulating symbiosis with the legume alfalfa (Medicago sativa). The Mycobacterium tuberculosis BacA homolog was found to be important for the maintenance of chronic murine infections, yet its in vivo function is unknown. In the legume plant as well as in the mammalian host, bacteria encounter host antimicrobial peptides (AMPs). We found that the M. tuberculosis BacA protein was able to partially complement the symbiotic defect of an S. meliloti BacA-deficient mutant on alfalfa plants and to protect this mutant in vitro from the antimicrobial activity of a synthetic legume peptide, NCR247, and a recombinant human \u3b2-defensin 2 (HBD2). This finding was also confirmed using an M. tuberculosis insertion mutant. Furthermore, M. tuberculosis BacA-mediated protection of the legume symbiont S. meliloti against legume defensins as well as HBD2 is dependent on its attached ATPase domain. In addition, we show that M. tuberculosis BacA mediates peptide uptake of the truncated bovine AMP, Bac71-16. This process required a functional ATPase domain. We therefore suggest that M. tuberculosis BacA is important for the transport of peptides across the cytoplasmic membrane and is part of a complete ABC transporter. Hence, BacA-mediated protection against host AMPs might be important for the maintenance of latent infections

Retrotransposon vectors for gene delivery in plants

<p>Abstract</p> <p>Background</p> <p>Retrotransposons are abundant components of plant genomes, and although some plant retrotransposons have been used as insertional mutagens, these mobile genetic elements have not been widely exploited for plant genome manipulation. In vertebrates and yeast, retrotransposons and retroviruses are routinely altered to carry additional genes that are copied into complementary (c)DNA through reverse transcription. Integration of cDNA results in gene delivery; recombination of cDNA with homologous chromosomal sequences can create targeted gene modifications. Plant retrotransposon-based vectors, therefore, may provide new opportunities for plant genome engineering.</p> <p>Results</p> <p>A retrotransposon vector system was developed for gene delivery in plants based on the Tnt1 element from <it>Nicotiana tabacum</it>. Mini-Tnt1 transfer vectors were constructed that lack coding sequences yet retain the 5' and 3' long terminal repeats (LTRs) and adjacent <it>cis </it>sequences required for reverse transcription. The internal coding region of Tnt1 was replaced with a neomycin phosphotransferase gene to monitor replication by reverse transcription. Two different mini-Tnt1 s were developed: one with the native 5' LTR and the other with a chimeric 5' LTR that had the first 233 bp replaced by the CaMV 35 S promoter. After transfer into tobacco protoplasts, both vectors undergo retrotransposition using GAG and POL proteins provided in <it>trans </it>by endogenous Tnt1 elements. The transposition frequencies of mini-Tnt1 vectors are comparable with native Tnt1 elements, and like the native elements, insertion sites are within or near coding sequences. In this paper, we provide evidence that template switching occurs during mini-Tnt1 reverse transcription, indicating that multiple copies of Tnt1 mRNA are packaged into virus-like particles.</p> <p>Conclusions</p> <p>Our data demonstrate that mini-Tnt1 vectors can replicate efficiently in tobacco cells using GAG and POL proteins provided in <it>trans </it>by native Tnt1 elements. This suggests that helper Tnt1 constructs can be developed to enable a Tnt1-based two-component vector system that could be used in other plant species. Such a vector system may prove useful for gene delivery or the production of cDNA that can serve as a donor molecule for gene modification through homologous recombination.</p

Population Genetics of Duplicated Alternatively Spliced Exons of the Dscam Gene in Daphnia and Drosophila

In insects and crustaceans, the Down syndrome cell adhesion molecule (Dscam) occurs in many different isoforms. These are produced by mutually exclusive alternative splicing of dozens of tandem duplicated exons coding for parts or whole immunoglobulin (Ig) domains of the Dscam protein. This diversity plays a role in the development of the nervous system and also in the immune system. Structural analysis of the protein suggested candidate epitopes where binding to pathogens could occur. These epitopes are coded by regions of the duplicated exons and are therefore diverse within individuals. Here we apply molecular population genetics and molecular evolution analyses using Daphnia magna and several Drosophila species to investigate the potential role of natural selection in the divergence between orthologs of these duplicated exons among species, as well as between paralogous exons within species. We found no evidence for a role of positive selection in the divergence of these paralogous exons. However, the power of this test was low, and the fact that no signs of gene conversion between paralogous exons were found suggests that paralog diversity may nonetheless be maintained by selection. The analysis of orthologous exons in Drosophila and in Daphnia revealed an excess of non-synonymous polymorphisms in the epitopes putatively involved in pathogen binding. This may be a sign of balancing selection. Indeed, in Dr. melanogaster the same derived non-synonymous alleles segregate in several populations around the world. Yet other hallmarks of balancing selection were not found. Hence, we cannot rule out that the excess of non-synonymous polymorphisms is caused by segregating slightly deleterious alleles, thus potentially indicating reduced selective constraints in the putative pathogen binding epitopes of Dscam

Acute vasoreactivity testing in pediatric idiopathic pulmonary arterial hypertension:an international survey on current practice

The aim of this study was to determine practice patterns and inter-institutional variability in how acute vasoreactivity testing (AVT) is performed and interpreted in pediatrics throughout the world. A survey was offered to physicians affiliated with the Pediatric & Congenital Heart Disease Taskforce of the Pulmonary Vascular Research Institute (PVRI), the Pediatric Pulmonary Hypertension Network (PPHNET), or the Spanish Registry for Pediatric Pulmonary Hypertension (REHIPED), from February to December 2016. The survey requested data about the site-specific protocol for AVT and subsequent management of pediatric patients with idiopathic pulmonary arterial hypertension (IPAH) or heritable PAH (HPAH). Twenty-eight centers from 13 countries answered the survey. AVT is performed in most centers using inhaled nitric oxide (iNO). Sitbon criteria was used in 39% of the centers, Barst criteria in 43%, and other criteria in 18%. First-line therapy for positive AVT responders in functional class (FC) I/II was calcium channel blocker (CCB) in 89%, but only in 68% as monotherapy. Most centers (71%) re-evaluated AVT-positive patients hemodynamics after 6-12 months; 29% of centers re-evaluated based only on clinical criteria. Most centers (64%) considered a good response as remaining in FC I or II, with near normalization of pulmonary arterial pressure and pulmonary vascular resistance, but a stable FC I/II alone was sufficient criteria in 25% of sites. Protocols and diagnostic criteria for AVT, and therapeutic approaches during follow-up, were highly variable across the world. Reported clinical practice is not fully congruent with current guidelines, suggesting the need for additional studies that better define the prognostic value of AVT for pediatric IPAH patients

Physical Confirmation and Mapping of Overlapping Rat Mammary Carcinoma Susceptibility QTLs, Mcs2 and Mcs6

Only a portion of the estimated heritability of breast cancer susceptibility has been explained by individual loci. Comparative genetic approaches that first use an experimental organism to map susceptibility QTLs are unbiased methods to identify human orthologs to target in human population-based genetic association studies. Here, overlapping rat mammary carcinoma susceptibility (Mcs) predicted QTLs, Mcs6 and Mcs2, were physically confirmed and mapped to identify the human orthologous region. To physically confirm Mcs6 and Mcs2, congenic lines were established using the Wistar-Furth (WF) rat strain, which is susceptible to developing mammary carcinomas, as the recipient (genetic background) and either Wistar-Kyoto (WKy, Mcs6) or Copenhagen (COP, Mcs2), which are resistant, as donor strains. By comparing Mcs phenotypes of WF.WKy congenic lines with distinct segments of WKy chromosome 7 we physically confirmed and mapped Mcs6 to ∼33 Mb between markers D7Rat171 and gUwm64-3. The predicted Mcs2 QTL was also physically confirmed using segments of COP chromosome 7 introgressed into a susceptible WF background. The Mcs6 and Mcs2 overlapping genomic regions contain multiple annotated genes, but none have a clear or well established link to breast cancer susceptibility. Igf1 and Socs2 are two of multiple potential candidate genes in Mcs6. The human genomic region orthologous to rat Mcs6 is on chromosome 12 from base positions 71,270,266 to 105,502,699. This region has not shown a genome-wide significant association to breast cancer risk in pun studies of breast cancer susceptibility