Answering Mermin's Challenge with Conservation per No Preferred Reference Frame

In 1981, Mermin published a now famous paper titled, "Bringing home the atomic world: Quantum mysteries for anybody" that Feynman called, "One of the most beautiful papers in physics that I know." Therein, he presented the "Mermin device" that illustrates the conundrum of quantum entanglement per the Bell spin states for the "general reader." He then challenged the "physicist reader" to explain the way the device works "in terms meaningful to a general reader struggling with the dilemma raised by the device." Herein, we show how "conservation per no preferred reference frame (NPRF)" answers that challenge. In short, the explicit conservation that obtains for Alice and Bob's Stern-Gerlach spin measurement outcomes in the same reference frame holds only on average in different reference frames, not on a trial-by-trial basis. This conservation is SO(3) invariant in the relevant symmetry plane in real space per the SU(2) invariance of its corresponding Bell spin state in Hilbert space. Since NPRF is also responsible for the postulates of special relativity, and therefore its counterintuitive aspects of time dilation and length contraction, we see that the symmetry group relating non-relativistic quantum mechanics and special relativity via their "mysteries" is the restricted Lorentz group.Comment: 18 pages, 9 figures. This version as revised and resubmitted to Scientific Report

Sustained Activation of Cell Adhesion Is a Differentially Regulated Process in B Lymphopoiesis

It is largely unknown how hematopoietic progenitors are positioned within specialized niches of the bone marrow microenvironment during development. Chemokines such as CXCL12, previously called stromal cell–derived factor 1, are known to activate cell integrins of circulating leukocytes resulting in transient adhesion before extravasation into tissues. However, this short-term effect does not explain the mechanism by which progenitor cells are retained for prolonged periods in the bone marrow. Here we show that in human bone marrow CXCL12 triggers a sustained adhesion response specifically in progenitor (pro- and pre-) B cells. This sustained adhesion diminishes during B cell maturation in the bone marrow and, strikingly, is absent in circulating mature B cells, which exhibit only transient CXCL12-induced adhesion. The duration of adhesion is tightly correlated with CXCL12-induced activation of focal adhesion kinase (FAK), a known molecule involved in integrin-mediated signaling. Sustained adhesion of progenitor B cells is associated with prolonged FAK activation, whereas transient adhesion in circulating B cells is associated with short-lived FAK activation. Moreover, sustained and transient adhesion responses are differentially affected by pharmacological inhibitors of protein kinase C and phosphatidylinositol 3-kinase. These results provide a developmental cell stage–specific mechanism by which chemokines orchestrate hematopoiesis through sustained rather than transient activation of adhesion and cell survival pathways

Chronic migraine plus medication overuse headache: two entities or not?

Chronic migraine (CM) represents migraine natural evolution from its episodic form. It is realized through a chronicization phase that may require months or years and varies from patient to patient. The transition to more frequent attacks pattern is influenced by lifestyle, life events, comorbid conditions and personal genetic terrain, and it often leads to acute drugs overuse. Medication overuse headache (MOH) may complicate every type of headache and all the drugs employed for headache treatment can cause MOH. The first step in the management of CM complicated by medication overuse must be the withdrawal of the overused drugs and a detoxification treatment. The goal is not only to detoxify the patient and stop the chronic headache but also to improve responsiveness to acute or prophylactic drugs. Different methods have been suggested: gradual or abrupt withdrawal; home treatment, hospitalization, or a day-hospital setting; re-prophylaxes performed immediately or at the end of the wash-out period. Up to now, only topiramate and local injection of onabotulinumtoxinA have shown efficacy as therapeutic agents for re-prophylaxis after detoxification in patients with CM with and without medication overuse. Although the two treatments showed similar efficacy, onabotulinumtoxinA is associated with a better adverse events profile. Recently, the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program proved that patients with CM, even those with MOH, are the ones most likely to benefit from onabotulinumtoxinA treatment. Furthermore, it provided an injection paradigm that can be used as a guide for a correct administration of onabotulinumtoxinA

Primary chronic cold agglutinin disease: An update on pathogenesis, clinical features and therapy

Chronic cold agglutinin disease (CAD) is a subgroup of autoimmune hemolytic anemia. Primary CAD has traditionally been defined by the absence of any underlying or associated disease. The results of therapy with corticosteroids, alkylating agents and interferon-a have been poor. Cold reactive immunoglobulins against erythrocyte surface antigens are essential to pathogenesis of CAD. These cold agglutinins are monoclonal, usually IgMκ auto antibodies with heavy chain variable regions encoded by the VH4-34 gene segment. By flowcytometric and immunohistochemical assessments, a monoclonal CD20+κ+B-lymphocyte population has been demonstrated in the bone marrow of 90% of the patients, and lymphoplasmacytic lymphoma is a frequent finding. Novel attempts at treatment for primary CAD have mostly been directed against the clonal B-lymphocytes. Phase 2 studies have shown that therapy with the chimeric anti-CD20 antibody rituximab produced partial response rates of more than 50% and occasional complete responses. Median response duration, however, was only 11 months. In this review, we discuss the clinical and pathogenetic features of primary CAD, emphasizing the more recent data on its close association with clonal lymphoproliferative bone marrow disorders and implications for therapy. We also review the management and outline some perspectives on new therapy modalities

A High-Density EEG Investigation into Steady State Binaural Beat Stimulation

Binaural beats are an auditory phenomenon that has been suggested to alter physiological and cognitive processes including vigilance and brainwave entrainment. Some personality traits measured by the NEO Five Factor Model have been found to alter entrainment using pulsing light stimuli, but as yet no studies have examined if this occurs using steady state presentation of binaural beats for a relatively short presentation of two minutes. This study aimed to examine if binaural beat stimulation altered vigilance or cortical frequencies and if personality traits were involved. Thirty-one participants were played binaural beat stimuli designed to elicit a response at either the Theta (7 Hz) or Beta (16 Hz) frequency bands while undertaking a zero-back vigilance task. EEG was recorded from a high-density electrode cap. No significant differences were found in vigilance or cortical frequency power during binaural beat stimulation compared to a white noise control period. Furthermore, no significant relationships were detected between the above and the Big Five personality traits. This suggests a short presentation of steady state binaural beats are not sufficient to alter vigilance or entrain cortical frequencies at the two bands examined and that certain personality traits were not more susceptible than others

Identification of a Mutation Associated with Fatal Foal Immunodeficiency Syndrome in the Fell and Dales Pony

The Fell and Dales are rare native UK pony breeds at risk due to falling numbers, in-breeding, and inherited disease. Specifically, the lethal Mendelian recessive disease Foal Immunodeficiency Syndrome (FIS), which manifests as B-lymphocyte immunodeficiency and progressive anemia, is a substantial threat. A significant percentage (∼10%) of the Fell ponies born each year dies from FIS, compromising the long-term survival of this breed. Moreover, the likely spread of FIS into other breeds is of major concern. Indeed, FIS was identified in the Dales pony, a related breed, during the course of this work. Using a stepwise approach comprising linkage and homozygosity mapping followed by haplotype analysis, we mapped the mutation using 14 FIS–affected, 17 obligate carriers, and 10 adults of unknown carrier status to a ∼1 Mb region (29.8 – 30.8 Mb) on chromosome (ECA) 26. A subsequent genome-wide association study identified two SNPs on ECA26 that showed genome-wide significance after Bonferroni correction for multiple testing: BIEC2-692674 at 29.804 Mb and BIEC2-693138 at 32.19 Mb. The associated region spanned 2.6 Mb from ∼29.6 Mb to 32.2 Mb on ECA26. Re-sequencing of this region identified a mutation in the sodium/myo-inositol cotransporter gene (SLC5A3); this causes a P446L substitution in the protein. This gene plays a crucial role in the regulatory response to osmotic stress that is essential in many tissues including lymphoid tissues and during early embryonic development. We propose that the amino acid substitution we identify here alters the function of SLC5A3, leading to erythropoiesis failure and compromise of the immune system. FIS is of significant biological interest as it is unique and is caused by a gene not previously associated with a mammalian disease. Having identified the associated gene, we are now able to eradicate FIS from equine populations by informed selective breeding

Characterizing Loop Dynamics and Ligand Recognition in Human- and Avian-Type Influenza Neuraminidases via Generalized Born Molecular Dynamics and End-Point Free Energy Calculations

The comparative dynamics and inhibitor binding free energies of group-1 and group-2 pathogenic influenza A subtype neuraminidase (NA) enzymes are of fundamental biological interest and relevant to structure-based drug design studies for antiviral compounds. In this work, we present seven generalized Born molecular dynamics simulations of avian (N1)- and human (N9)-type NAs in order to probe the comparative flexibility of the two subtypes, both with and without the inhibitor oseltamivir bound. The enhanced sampling obtained through the implicit solvent treatment suggests several provocative insights into the dynamics of the two subtypes, including that the group-2 enzymes may exhibit similar motion in the 430-binding site regions but different 150-loop motion. End-point free energy calculations elucidate the contributions to inhibitor binding free energies and suggest that entropic considerations cannot be neglected when comparing across the subtypes. We anticipate the findings presented here will have broad implications for the development of novel antiviral compounds against both seasonal and pandemic influenza strains

Resolving confusions about jarrah dieback - don’t forget the plants

The name jarrah dieback has been used for two different disorders, leading to considerable confusion. It was coined in the 1940s to describe the sudden death of groups of jarrah (Eucalyptus marginata) trees in south western Western Australia, which occurred on poorly drained sites, following exceptionally heavy rainfall. In the 1960s these sites were shown to be infested by Phytophthora cinnamomi and jarrah deaths were attributed to it, even though it was only isolated from 5 % of sampled trees. Also the definition of jarrah dieback was expanded to include deaths of many other plants on infested sites, from which P. cinnamomi was more readily isolated. Jarrah trees die from severe water deficiency, indicating problems with water conduction through roots. Xylem vessel diameters vary along roots, being narrow at the root collar, while distally they are larger, providing water storage. Jarrah transpires vigorously during summer, accessing water at depth on sites with deep soil, but being more dependent on internally stored water when root systems are shallower. Following waterlogging, sapwood vessels become blocked with tyloses, reducing both conductivity and potential water storage; such trees may have insufficient water reserves for summer survival. In jarrah P. cinnamomi is unlikely to cause water deficiency because sapwood invasion is rapidly contained in healthy roots. Recent investigations into P. cinnamomi invasion and host responses in other plants show that it can potentially cause a vascular wilt in Banksia spp. and chronic, symptomless infections in herbaceous plants. Susceptibility to waterlogging damage, and/or mortality resulting from infection by P. cinnamomi can only be clarified by detailed knowledge of the hosts and their vulnerabilities. This is essential for making diagnoses, devising management strategies, and avoiding the confusions of the past

Antibody Repertoires in Humanized NOD-scid-IL2Rγnull Mice and Human B Cells Reveals Human-Like Diversification and Tolerance Checkpoints in the Mouse

Immunodeficient mice reconstituted with human hematopoietic stem cells enable the in vivo study of human hematopoiesis. In particular, NOD-scid-IL2Rγnull engrafted mice have been shown to have reasonable levels of T and B cell repopulation and can mount T-cell dependent responses; however, antigen-specific B-cell responses in this model are generally poor. We explored whether developmental defects in the immunoglobulin gene repertoire might be partly responsible for the low level of antibody responses in this model. Roche 454 sequencing was used to obtain over 685,000 reads from cDNA encoding immunoglobulin heavy (IGH) and light (IGK and IGL) genes isolated from immature, naïve, or total splenic B cells in engrafted NOD-scid-IL2Rγnull mice, and compared with over 940,000 reads from peripheral B cells of two healthy volunteers. We find that while naïve B-cell repertoires in humanized mice are chiefly indistinguishable from those in human blood B cells, and display highly correlated patterns of immunoglobulin gene segment use, the complementarity-determining region H3 (CDR-H3) repertoires are nevertheless extremely diverse and are specific for each individual. Despite this diversity, preferential DH-JH pairings repeatedly occur within the CDR-H3 interval that are strikingly similar across all repertoires examined, implying a genetic constraint imposed on repertoire generation. Moreover, CDR-H3 length, charged amino-acid content, and hydropathy are indistinguishable between humans and humanized mice, with no evidence of global autoimmune signatures. Importantly, however, a statistically greater usage of the inherently autoreactive IGHV4-34 and IGKV4-1 genes was observed in the newly formed immature B cells relative to naïve B or total splenic B cells in the humanized mice, a finding consistent with the deletion of autoreactive B cells in humans. Overall, our results provide evidence that key features of the primary repertoire are shaped by genetic factors intrinsic to human B cells and are principally unaltered by differences between mouse and human stromal microenvironments

Persistent Growth of a Human Plasma-Derived Hepatitis C Virus Genotype 1b Isolate in Cell Culture

HCV (hepatitis C virus) research, including therapeutics and vaccine development, has been hampered by the lack of suitable tissue culture models. Development of cell culture systems for the growth of the most drug-resistant HCV genotype (1b) as well as natural isolates has remained a challenge. Transfection of cultured cells with adenovirus-associated RNAI (VA RNAI), a known interferon (IFN) antagonist and inhibitor of dsRNA-mediated antiviral pathways, enhanced the growth of plasma-derived HCV genotype 1b. Furthermore, persistent viral growth was achieved after passaging through IFN-α/β-deficient VeroE6 cells for 2 years. Persistently infected cells were maintained in culture for an additional 4 years, and the virus rescued from these cells induced strong cytopathic effect (CPE). Using a CPE-based assay, we measured inhibition of viral production by anti-HCV specific inhibitors, including 2′-C-Methyl-D-Adenosine, demonstrating its utility for the evaluation of HCV antivirals. This virus constitutes a novel tool for the study of one of the most relevant strains of HCV, genotype 1b, which will now be available for HCV life cycle research and useful for the development of new therapeutics