Degenerate Variational Integrators for Magnetic Field Line Flow and Guiding Center Trajectories

Symplectic integrators offer many advantages for the numerical solution of Hamiltonian differential equations, including bounded energy error and the preservation of invariant sets. Two of the central Hamiltonian systems encountered in plasma physics --- the flow of magnetic field lines and the guiding center motion of magnetized charged particles --- resist symplectic integration by conventional means because the dynamics are most naturally formulated in non-canonical coordinates, i.e., coordinates lacking the familiar $(q, p)$ partitioning. Recent efforts made progress toward non-canonical symplectic integration of these systems by appealing to the variational integration framework; however, those integrators were multistep methods and later found to be numerically unstable due to parasitic mode instabilities. This work eliminates the multistep character and, therefore, the parasitic mode instabilities via an adaptation of the variational integration formalism that we deem ``degenerate variational integration''. Both the magnetic field line and guiding center Lagrangians are degenerate in the sense that their resultant Euler-Lagrange equations are systems of first-order ODEs. We show that retaining the same degree of degeneracy when constructing a discrete Lagrangian yields one-step variational integrators preserving a non-canonical symplectic structure on the original Hamiltonian phase space. The advantages of the new algorithms are demonstrated via numerical examples, demonstrating superior stability compared to existing variational integrators for these systems and superior qualitative behavior compared to non-conservative algorithms

Are the physicochemical properties of antibacterial compounds really different from other drugs?

Background: It is now widely recognized that there is an urgent need for new antibacterial drugs, with novel mechanisms of action, to combat the rise of multi-drug resistant bacteria. However, few new compounds are reaching the market. Antibacterial drug discovery projects often succeed in identifying potent molecules in biochemical assays but have been beset by difficulties in obtaining antibacterial activity. A commonly held view, based on analysis of marketed antibacterial compounds, is that antibacterial drugs possess very different physicochemical properties to other drugs, and that this profile is required for antibacterial activity. Results: We have re-examined this issue by performing a cheminformatics analysis of the literature data available in the ChEMBL database. The physicochemical properties of compounds with a recorded activity in an antibacterial assay were calculated and compared to two other datasets extracted from ChEMBL, marketed antibacterials and drugs marketed for other therapeutic indications. The chemical class of the compounds and Gram-negative/Grampositive profile were also investigated. This analysis shows that compounds with antibacterial activity have physicochemical property profiles very similar to other drug classes. Conclusions: The observation that many current antibacterial drugs lie in regions of physicochemical property space far from conventional small molecule therapeutics is correct. However, the inference that a compound must lie in one of these “outlier” regions in order to possess antibacterial activity is not supported by our analysis

Identification of an IL-4-Inducible Gene Expressed in Differentiating Lymphocytes and Male Germ Cells

Interleukin 4 (IL-4) is a cytokine that is involved in the differentiation of B and T lymphocytes. In this report, we describe the identification of a novel gene, N.52, which was cloned from the murine pre-B cell line R8205 grown in the presence of IL-4 for 48 hr. Although N.52 expression is detectable at low levels in unstimulated R8205 cells, the level of N.52 dramatically increases after only .4 hr exposure to IL-4 and remains at a high .level up to 48 hr. Although N.52 expression is low or absent in normal spleen B and T cells, its expression can be induced by the differentiation signals delivered by LPS in B cells and by Con A in T-cell hybrids. While N.52 mRNA is absent in all highly differentiated organs, it is detectable in stem cell harboring lymphoid tissues such as bone marrow, fetal liver, and thymus. Furthermore, N.52 mRNA is expressed at strikingly high levels in the testis, specifically in differentiating male germ cells. It is induced by differentiation signals triggered by the combination of cyclic AMP and retinoic acid in teratocarcinoma F9 cells. Taken together, these data suggest that N.52 is a developmentally regulated gene whose expression in cells of the immune and reproductive systems may be controlled by stimuli that induce differentiation

NuSTAR Observations of the Magnetar 1E 2259+586

We report on new broad band spectral and temporal observations of the magnetar 1E 2259+586, which is located in the supernova remnant CTB 109. Our data were obtained simultaneously with the Nuclear Spectroscopic Telescope Array (NuSTAR) and Swift, and cover the energy range from 0.5-79 keV. We present pulse profiles in various energy bands and compare them to previous RXTE results. The NuSTAR data show pulsations above 20 keV for the first time and we report evidence that one of the pulses in the double-peaked pulse profile shifts position with energy. The pulsed fraction of the magnetar is shown to increase strongly with energy. Our spectral analysis reveals that the soft X-ray spectrum is well characterized by an absorbed double-blackbody or blackbody plus power-law model in agreement with previous reports. Our new hard X-ray data, however, suggests that an additional component, such as a power-law, is needed to describe the NuSTAR and Swift spectrum. We also fit the data with the recently developed coronal outflow model by Beloborodov for hard X-ray emission from magnetars. The outflow from a ring on the magnetar surface is statistically preferred over outflow from a polar cap.Comment: 37 pages, 9 figures, corresponding author, [email protected]

15 kDa Granulysin versus GM-CSF for monocytes differentiation: analogies and differences at the transcriptome level

<p>Abstract</p> <p>Background</p> <p>Granulysin is an antimicrobial and proinflammatory protein with several isoforms. While the 9 kDa isoform is a well described cytolytic molecule with pro-inflammatory activity, the functions of the 15 kDa isoform is less well understood. Recently it was shown that 15 kDa Granulysin can act as an alarmin that is able to activate monocytes and immature dendritic cells. Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) is a growth factor widely used in immunotherapy both for <it>in vivo </it>and <it>ex vivo </it>applications, especially for its proliferative effects.</p> <p>Methods</p> <p>We analyzed gene expression profiles of monocytes cultured with 15 kDa Granulysin or GM-CSF for 4, 12, 24 and 48 hours to unravel both similarities and differences between the effects of these stimulators.</p> <p>Results</p> <p>The analysis revealed a common signature induced by both factors at each time point, but over time, a more specific signature for each factor became evident. At all time points, 15 kDa Granulysin induced immune response, chemotaxis and cell adhesion genes. In addition, only 15 kDa Granulsyin induced the activation of pathways related to fundamental dendritic cell functions, such as co-stimulation of T-cell activation and Th1 development. GM-CSF specifically down-regulated genes related to cell cycle arrest and the immune response. More specifically, cytokine production, lymphocyte mediated immunity and humoral immune response were down-regulated at late time points.</p> <p>Conclusion</p> <p>This study provides important insights on the effects of a novel agent, 15 kDa granulysin, that holds promise for therapeutic applications aimed at the activation of the immune response.</p

Putative histidine kinase inhibitors with antibacterial effect against multi-drug resistant clinical isolates identified by in vitro and in silico screens

Novel antibacterials are urgently needed to address the growing problem of bacterial resistance to conventional antibiotics. Two-component systems (TCS) are widely used by bacteria to regulate gene expression in response to various environmental stimuli and physiological stress and have been previously proposed as promising antibacterial targets. TCS consist of a sensor histidine kinase (HK) and an effector response regulator. The HK component contains a highly conserved ATP-binding site that is considered to be a promising target for broad-spectrum antibacterial drugs. Here, we describe the identification of putative HK autophosphorylation inhibitors following two independent experimental approaches: in vitro fragment-based screen via differential scanning fluorimetry and in silico structure-based screening, each followed up by the exploration of analogue compounds as identified by ligand-based similarity searches. Nine of the tested compounds showed antibacterial effect against multi-drug resistant clinical isolates of bacterial pathogens and include three novel scaffolds, which have not been explored so far in other antibacterial compounds. Overall, putative HK autophosphorylation inhibitors were found that together provide a promising starting point for further optimization as antibacterials

NuSTAR Spectroscopy of Multi-Component X-ray Reflection from NGC 1068

We report on observations of NGC1068 with NuSTAR, which provide the best constraints to date on its $>10$~keV spectral shape. We find no strong variability over the past two decades, consistent with its Compton-thick AGN classification. The combined NuSTAR, Chandra, XMM-Newton, and Swift-BAT spectral dataset offers new insights into the complex reflected emission. The critical combination of the high signal-to-noise NuSTAR data and a spatial decomposition with Chandra allow us to break several model degeneracies and greatly aid physical interpretation. When modeled as a monolithic (i.e., a single N_H) reflector, none of the common Compton-reflection models are able to match the neutral fluorescence lines and broad spectral shape of the Compton reflection. A multi-component reflector with three distinct column densities (e.g., N_H~1.5e23, 5e24, and 1e25 cm^{-2}) provides a more reasonable fit to the spectral lines and Compton hump, with near-solar Fe abundances. In this model, the higher N_H components provide the bulk of the Compton hump flux while the lower N_H component produces much of the line emission, effectively decoupling two key features of Compton reflection. We note that ~30% of the neutral Fe Kalpha line flux arises from >2" (~140 pc), implying that a significant fraction of the <10 keV reflected component arises from regions well outside of a parsec-scale torus. These results likely have ramifications for the interpretation of poorer signal-to-noise observations and/or more distant objects [Abridged].Comment: Submitted to ApJ; 23 pages (ApJ format); 11 figures and 3 tables; Comments welcomed

Impact of Surgical Timing on Neurological Outcomes for Spinal Arachnoid Cyst: A Single Institution Series

Objective Spinal arachnoid cysts (SACs) are rare lesions that often present with back pain and myelopathy. There is a paucity of literature evaluating the impact of surgical timing on neurological outcomes for primary SAC management. To compare long-term neurological outcomes in patients who were managed differently and to understand natural progression of SAC. Methods We conducted a retrospective analysis of adult patients treated for SAC at our institution from 2010 to 2021, stratified into 3 groups (conservative management only, surgical management, or conservative followed by surgical management). Study outcome measures were neurological outcomes as measured by modified McCormick Neurologic Scale (MNS), postoperative complications, and cyst recurrence. Nonparametric analysis was performed to evaluate differences between groups for selected endpoints. Results Thirty-six patients with SAC were identified. Eighteen patients were managed surgically. The remaining 18 patients were managed conservatively with outpatient serial imaging, 7 of whom (38.9%) ultimately underwent surgical treatment due to neurological decline. Most common presenting symptoms included back pain (50.0%), extremity weakness (36.1%), and numbness/paresthesia (36.1%). Initial/preoperative (p = 0.017) and 1-year postoperative (p = 0.006) MNS were significantly different between the 3 groups, but not at 6 weeks or 6 months postoperatively (p > 0.05). Additionally, at 1 year, there was no difference in MNS between patients managed surgically and those managed conservatively but ultimately underwent surgery (p > 0.99). Conclusion Delayed surgical intervention in minimally symptomatic patients does not seem to result in worse long-term neurofunctional outcomes. At 1 year, postoperative MNS were significantly higher in both surgical groups, when compared to the conservative group highlighting worsening clinical picture regardless of preoperative observational status

Cytoplasmic expression systems triggered by mRNA yield increased gene expression in post-mitotic neurons

Non-viral vectors are promising vehicles for gene therapy but delivery of plasmid DNA to post-mitotic cells is challenging as nuclear entry is particularly inefficient. We have developed and evaluated a hybrid mRNA/DNA system designed to bypass the nuclear barrier to transfection and facilitate cytoplasmic gene expression. This system, based on co-delivery of mRNA(A64) encoding for T7 RNA polymerase (T7 RNAP) with a T7-driven plasmid, produced between 10- and 2200-fold higher gene expression in primary dorsal root ganglion neuronal (DRGN) cultures isolated from Sprague–Dawley rats compared to a cytomegalovirus (CMV)-driven plasmid, and 30-fold greater expression than the enhanced T7-based autogene plasmid pR011. Cell-free assays and in vitro transfections highlighted the versatility of this system with small quantities of T7 RNAP mRNA required to mediate expression at levels that were significantly greater than with the T7-driven plasmid alone or supplemented with T7 RNAP protein. We have also characterized a number of parameters, such as mRNA structure, intracellular stability and persistence of each nucleic acid component that represent important factors in determining the transfection efficiency of this hybrid expression system. The results from this study demonstrate that co-delivery of mRNA is a promising strategy to yield increased expression with plasmid DNA, and represents an important step towards improving the capability of non-viral vectors to mediate efficient gene transfer in cell types, such as in DRGN, where the nuclear membrane is a significant barrier to transfection

Neurologic Outcomes for Adult Spinal Cord Ependymomas Stratified by Tumor Location: A Retrospective Cohort Study and 2-Year Outlook

Determine whether craniocaudal spinal cord tumor location affects long-term neurologic outcomes in adults diagnosed with spinal ependymomas (SE). A retrospective cohort analysis of patients aged ≥ 18 years who underwent surgical resection for SE over a ten-year period was conducted. Tumor location was classified as cervical, thoracic, or lumbar/conus. Primary endpoints were post-operative McCormick Neurologic Scale (MNS) scores at \u3c 3 days, 6 weeks, 1 year, and 2 years. One-way ANOVA was performed to detect significant differences in MNS scores between tumor locations. Twenty-eight patients were identified. The average age was 44.2 ± 15.4 years. Sixteen were male, and 13 were female. There were 10 cervical-predominant SEs, 13 thoracic-predominant SEs, and 5 lumbar/conus-predominant SEs. No significant differences were observed in pre-operative MNS scores between tumor locations (p = 0.73). One-way ANOVA testing demonstrated statistically significant differences in post-operative MNS scores between tumor locations at \u3c 3 days (p = 0.03), 6 weeks (p = 0.009), and 1 year (p = 0.003); however, no significant difference was observed between post-operative MNS scores at 2 years (p = 0.13). The mean MNS score for patients with thoracic SEs were higher at all follow-up time points. Tumors arising in the thoracic SE are associated with worse post-operative neurologic outcomes in comparison to SEs arising in other spinal regions. This is likely multifactorial in etiology, owing to both anatomical differences including spinal cord volume as well as variations in tumor characteristics. No significant differences in 2-year MNS scores were observed, suggesting that patients ultimately recover from neurological insult sustained at the time of surgery