Crystal growth and quantum oscillations in the topological chiral semimetal CoSi

We survey the electrical transport properties of the single-crystalline, topological chiral semimetal CoSi which was grown via different methods. High-quality CoSi single crystals were found in the growth from tellurium solution. The sample's high carrier mobility enables us to observe, for the first time, quantum oscillations (QOs) in its thermoelectrical signals. Our analysis of QOs reveals two spherical Fermi surfaces around the R point in the Brillouin zone corner. The extracted Berry phases of these electron orbits are consistent with the -2 chiral charge as reported in DFT calculations. Detailed analysis on the QOs reveals that the spin-orbit coupling induced band-splitting is less than 2 meV near the Fermi level, one order of magnitude smaller than our DFT calculation result. We also report the phonon-drag induced large Nernst effect in CoSi at intermediate temperatures

MicroRNAs regulate Ca2+ homeostasis in murine embryonic stem cells

MicroRNAs (miRNAs) are important regulators of embryonic stem cell (ESC) biology, and their study has identified key regulatory mechanisms. To find novel pathways regulated by miRNAs in ESCs, we undertook a bioinformatics analysis of gene pathways differently expressed in the absence of miRNAs due to the deletion of Dicer, which encodes an RNase that is essential for the synthesis of miRNAs. One pathway that stood out was Ca2+ signaling. Interestingly, we found that Dicer-/- ESCs had no difference in basal cytoplasmic Ca2+ levels but were hyperresponsive when Ca2+ import into the endoplasmic reticulum (ER) was blocked by thapsigargin. Remarkably, the increased Ca2+ response to thapsigargin in ESCs resulted in almost no increase in apoptosis and no differences in stress response pathways, despite the importance of miRNAs in the stress response of other cell types. The increased Ca2+ response in Dicer-/- ESCs was also observed during purinergic receptor activation, demonstrating a physiological role for the miRNA regulation of Ca2+ signaling pathways. In examining the mechanism of increased Ca2+ responsiveness to thapsigargin, neither store-operated Ca2+ entry nor Ca2+ clearance mechanisms from the cytoplasm appeared to be involved. Rather, it appeared to involve an increase in the expression of one isoform of the IP3 receptors (Itpr2). miRNA regulation of Itpr2 expression primarily appeared to be indirect, with transcriptional regulation playing a major role. Therefore, the miRNA regulation of Itpr2 expression offers a unique mechanism to regulate Ca2+ signaling pathways in the physiology of pluripotent stem cells

Mastocytosis presenting with mast cell-mediator release-associated symptoms elicited by cyclo oxygenase inhibitors: prevalence, clinical, and laboratory features

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently avoided in mastocytosis, because of a potential increased risk for drug hypersensitivity reactions (DHRs) due to inhibition of cyclo-oxygenase (COX), subsequent depletion of prostaglandin E2 and release of leukotrienes. Objectives: Here, we aimed at determining the prevalence of mast cell (MC) mediator release symptoms triggered by NSAIDs in mastocytosis patients and the associated clinical and laboratory features of the disease. Methods: Medical records from 418 adults to 223 pediatric mastocytosis patients were retrospectively reviewed. Patients were classified according to tolerance patterns to NSAIDs and other COX inhibitors (COXi) and compared for epidemiological, clinical and laboratory findings. Results: Overall, 87% of adults and 91% of pediatric patients tolerated NSAIDs and other COXi. Among adult and pediatric patients presenting DHRs, 5% and 0% reacted to multiple NSAIDs, 4% and 0.7% were single reactors, and 3% and 8% were single reactors with known tolerance to paracetamol but unknown tolerance to other COXi, respectively. Among adults, hypersensitivity to ≥2 drugs was more frequent among females (p = 0.009), patients with prior history of anaphylaxis to triggers other than NSAIDs or other COXi and Hymenoptera venom (p = 0.009), presence of baseline flushing (p = 0.02), baseline serum tryptase ≥48 ng/ml (p = 0.005) and multilineage KIT mutation (p = 0.02). In contrast, tolerance to NSAIDs and other COXi was more frequent among males (p = 0.02), in patients with anaphylaxis caused by Hymenoptera venom (p = 0.02), among individuals who had skin lesions due to mastocytosis (p = 0.01), and in cases that had no baseline pruritus (p = 0.006). Based on these parameters, a score model was designed to stratify mastocytosis patients who have never received NSAIDs or other COXi apart from paracetamol, according to their risk of DHR. Conclusions: Our results suggest that despite the frequency of MC mediator related symptoms elicited by NSAIDs and other COXi apart from paracetamol is increased among mastocytosis patients versus the general population, it is lower than previously estimated and associated with unique disease features. Patients that tolerated NSAIDs and other COXi following disease onset should keep using them. In turn, adults with unknown tolerance to such drugs and a positive score should be challenged with a preferential/selective COX-2 inhibitor, while the remaining may be challenged with ibuprofen. © 2022 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.Funding text 1: This work was supported by grants from the Carlos III Health Institute co‐financed by the European Regional Development Fund (PI19/01166) and CIBERONC CB16/12/00400, Ministerio de Ciencia e Innovación (Madrid, Spain), Asociación Española de Mastocitosis y Enfermedades Relacionadas (AEDM 2019), Fondos de Investigación para Enfermedades Raras del Ministerio de Sanidad, Servicios Sociales e Igualdad (Madrid, Spain). ; Funding text 2: This work was supported by grants from the Carlos III Health Institute co-financed by the European Regional Development Fund (PI19/01166) and CIBERONC CB16/12/00400, Ministerio de Ciencia e Innovación (Madrid, Spain), Asociación Española de Mastocitosis y Enfermedades Relacionadas (AEDM 2019), Fondos de Investigación para Enfermedades Raras del Ministerio de Sanidad, Servicios Sociales e Igualdad (Madrid, Spain)

Sliding charge density wave in manganites

The so-called stripe phase of the manganites is an important example of the complex behaviour of metal oxides, and has long been interpreted as the localisation of charge at atomic sites. Here, we demonstrate via resistance measurements on La_{0.50}Ca_{0.50}MnO_3 that this state is in fact a prototypical charge density wave (CDW) which undergoes collective transport. Dramatic resistance hysteresis effects and broadband noise properties are observed, both of which are typical of sliding CDW systems. Moreover, the high levels of disorder typical of manganites result in behaviour similar to that of well-known disordered CDW materials. Our discovery that the manganite superstructure is a CDW shows that unusual transport and structural properties do not require exotic physics, but can emerge when a well-understood phase (the CDW) coexists with disorder.Comment: 13 pages; 4 figure

Photorhabdus adhesion modification protein (Pam) binds extracellular polysaccharide and alters bacterial attachment.

Journal ArticleResearch Support, Non-U.S. Gov'tBACKGROUND: Photorhabdus are Gram-negative nematode-symbiotic and insect-pathogenic bacteria. The species Photorhabdus asymbiotica is able to infect humans as well as insects. We investigated the secreted proteome of a clinical isolate of P. asymbiotica at different temperatures in order to identify proteins relevant to the infection of the two different hosts. RESULTS: A comparison of the proteins secreted by a clinical isolate of P. asymbiotica at simulated insect (28 degrees C) and human (37 degrees C) temperatures led to the identification of a small and highly abundant protein, designated Pam, that is only secreted at the lower temperature. The pam gene is present in all Photorhabdus strains tested and shows a high level of conservation across the whole genus, suggesting it is both ancestral to the genus and probably important to the biology of the bacterium. The Pam protein shows limited sequence similarity to the 13.6 kDa component of a binary toxin of Bacillus thuringiensis. Nevertheless, injection or feeding of heterologously produced Pam showed no insecticidal activity to either Galleria mellonella or Manduca sexta larvae. In bacterial colonies, Pam is associated with an extracellular polysaccharide (EPS)-like matrix, and modifies the ability of wild-type cells to attach to an artificial surface. Interestingly, Surface Plasmon Resonance (SPR) binding studies revealed that the Pam protein itself has adhesive properties. Although Pam is produced throughout insect infection, genetic knockout does not affect either insect virulence or the ability of P. luminescens to form a symbiotic association with its host nematode, Heterorhabditis bacteriophora. CONCLUSIONS: We studied a highly abundant protein, Pam, which is secreted in a temperature-dependent manner in P. asymbiotica. Our findings indicate that Pam plays an important role in enhancing surface attachment in insect blood. Its association with exopolysaccharide suggests it may exert its effect through mediation of EPS properties. Despite its abundance and conservation in the genus, we find no evidence for a role of Pam in either virulence or symbiosis.BBSRCWellcome TrustEMBEK

Outcomes of TB Treatment by HIV Status in National Recording Systems in Brazil, 2003–2008

BACKGROUND: Although the Brazilian national reporting system for tuberculosis cases (SINAN) has enormous potential to generate data for policy makers, formal assessments of treatment outcomes and other aspects of TB morbidity and mortality are not produced with enough depth and rigor. In particular, the effect of HIV status on these outcomes has not been fully explored, partly due to incomplete recording in the national database. METHODOLOGY/PRINCIPAL FINDINGS: In a retrospective cohort study, we assessed TB treatment outcomes, including rates of cure, default, mortality, transfer and multidrug resistant TB (MDR-TB) among a purposively chosen sample of 161,481 new cases reported in SINAN between 2003 and 2008. The study population included all new cases reported in the six States with the highest level of completeness of the HIV status field in the system. These cases were mostly male (67%), white (62%), had pulmonary TB (79%) and a suspect chest X ray (83%). Treatment outcomes were best for those HIV negative cases and worst for those known HIV positive patients (cure rate of 85.7% and 55.7% respectively). In multivariate modeling, the risk of having an unfavorable outcome (all outcomes except cure) was 3.09 times higher for those HIV positive compared with those HIV negative (95% CI 3.02-3.16). The risk of death and default also increased with HIV positivity. The group without a known HIV status showed intermediate outcomes between the groups above, suggesting that this group includes some with HIV infection. CONCLUSIONS: HIV status played an important role in TB treatment outcomes in the study period. The outcomes observed in those with known HIV were poor and need to be improved. Those in the group with unknown HIV status indicate the need for wider HIV testing among new TB cases

Gain control network conditions in early sensory coding

Gain control is essential for the proper function of any sensory system. However, the precise mechanisms for achieving effective gain control in the brain are unknown. Based on our understanding of the existence and strength of connections in the insect olfactory system, we analyze the conditions that lead to controlled gain in a randomly connected network of excitatory and inhibitory neurons. We consider two scenarios for the variation of input into the system. In the first case, the intensity of the sensory input controls the input currents to a fixed proportion of neurons of the excitatory and inhibitory populations. In the second case, increasing intensity of the sensory stimulus will both, recruit an increasing number of neurons that receive input and change the input current that they receive. Using a mean field approximation for the network activity we derive relationships between the parameters of the network that ensure that the overall level of activity of the excitatory population remains unchanged for increasing intensity of the external stimulation. We find that, first, the main parameters that regulate network gain are the probabilities of connections from the inhibitory population to the excitatory population and of the connections within the inhibitory population. Second, we show that strict gain control is not achievable in a random network in the second case, when the input recruits an increasing number of neurons. Finally, we confirm that the gain control conditions derived from the mean field approximation are valid in simulations of firing rate models and Hodgkin-Huxley conductance based models

Bone and Cytokine Markers Associated With Bone Disease in Systemic Mastocytosis

Background Mastocytosis encompasses a heterogeneous group of diseases characterized by tissue accumulation of clonal mast cells, which frequently includes bone involvement. Several cytokines have been shown to play a role in the pathogenesis of bone mass loss in systemic mastocytosis (SM), but their role in SM-associated osteosclerosis remains unknown. Objective To investigate the potential association between cytokine and bone remodeling markers with bone disease in SM, aiming at identifying biomarker profiles associated with bone loss and/or osteosclerosis. Methods A total of 120 adult patients with SM, divided into 3 age and sex-matched groups according to their bone status were studied: (1) healthy bone (n = 46), (2) significant bone loss (n = 47), and (3) diffuse bone sclerosis (n = 27). Plasma levels of cytokines and serum baseline tryptase and bone turnover marker levels were measured at diagnosis. Results Bone loss was associated with significantly higher levels of serum baseline tryptase (P = .01), IFN-γ (P = .05), IL-1β (P = .05), and IL-6 (P = .05) versus those found in patients with healthy bone. In contrast, patients with diffuse bone sclerosis showed significantly higher levels of serum baseline tryptase (P < .001), C-terminal telopeptide (P < .001), amino-terminal propeptide of type I procollagen (P < .001), osteocalcin (P < .001), bone alkaline phosphatase (P < .001), osteopontin (P < .01), and the C-C Motif Chemokine Ligand 5/RANTES chemokine (P = .01), together with lower IFN-γ (P = .03) and RANK-ligand (P = .04) plasma levels versus healthy bone cases. Conclusions SM with bone mass loss is associated with a proinflammatory cytokine profile in plasma, whereas diffuse bone sclerosis shows increased serum/plasma levels of biomarkers related to bone formation and turnover, in association with an immunosuppressive cytokine secretion profile.This study was supported by grants from the Instituto de Salud Carlos III (ISCIII, Spain) (PI19/01166, CIBERONC: CB16/12/00400) and Fondo Europeo de Desarrollo Regional (FEDER) (EQC2019-005419-P), within the Subprograma Estatal de Infraestructuras de Investigación y Equipamiento Científico Técnico de 2019 del Ministerio de Ciencia, Innovación y Universidades, Fundación Española de Mastocitosis (FEM, Madrid, Spain ref.: FEM2019-MAGPIX and FEM2021-SAM); Asociación Española de Mastocitosis y Enfermedades Relacionadas (AEDM-CTMC-2019). We also thank the Biobank at the Hospital Virgen de la Salud (BioB-HVS) No. B.0000520, Toledo, Spain. TAR was supported by the 2019 European Academy of Allergy and Clinical Immunology Research Fellowship award. We thank our patients for their willingness to participate in this study

Bowel associated dermatosis – arthritis syndrome: a case report

We report a rare case of Bowel Associated Dermatosis – Arthritis Syndrome in a young patient with complex Crohn's disease who presented with fever, arthritis, rash and worsening of diarrhea with abdominal pain, who promptly responded to a short course of steroids