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Characterizing Europa’s subsurface ocean is essential for assessing Europa’s habitability. The suite of instruments on the Europa Clipper spacecraft will, among others, magnetically sound Europa’s interior by measuring the ocean’s induced magnetic field. This magnetic field is generated in response to the Jovian time-varying magnetic environment in which Europa is immersed. However, the dynamic magnetized plasma flow of the Jovian magnetosphere creates electrical currents that give rise to magnetic perturbations near Europa. These perturbations complicate the interpretation of the induction signal, and hence the characterization and inferences on potential habitability. Thus, characterization of the ocean by magnetic sounding requires an accurate characterization of the plasma as it flows across Europa. We present the Plasma Instrument for Magnetic Sounding (PIMS), the instrument for the Europa Clipper mission that will measure the plasma contribution to the magnetic field perturbations sensed by the Europa Clipper Magnetometer. PIMS is composed of four Faraday Cup plasma spectrometers that use voltage-biased gridded apertures to dissect the space plasmas that they encounter. The instrument uses sensitive preamplifiers and processing electronics to measure the current that results when charged particles strike the instrument’s metal collector plates, thus enabling a measure of the plasma characteristics near Europa to produce a more accurate magnetic sounding of Europa’s subsurface ocean. PIMS consists of two sensors: one placed near the top of the Europa Clipper spacecraft and one near the bottom. Each sensor contains two Faraday Cups with a 90° full-width field-of-view. The sensors were specifically designed to withstand the Europa environment, measure both ions and electrons, and have two separate voltage ranges intended to analyze the magnetospheric and ionospheric environments, respectively. In this paper, we describe the scientific motivation for this experiment, the design considerations for the PIMS instrument, the details of the ground calibration, and other details pertinent to understanding the scientific data retrieved by PIMS.

Second-harmonic generation (SHG) results for Ni and Co films on Cu (001) have been reinvestigated regarding the depth sensitivity of this technique for thin films. We find that tangential components of the nonlinear susceptibility are much more sensitive to real film properties than normal components, which are confined to surfaces and interfaces. In consequence, for SHG experiments on ultra-thin metal films, polarization combinations should be favored that possess only tangential susceptibility components, even though the yield is weaker. Additional phase measurements are necessary to obtain full information about the film.

During the past decade, research has revealed that the vast community of micro-organisms that inhabit the gut — known as the gut microbiota — is intricately linked to human health and disease, partly as a result of its influence on systemic immune responses. Accumulating evidence demonstrates that these effects on immune function are important in neuroinflammatory diseases, such as multiple sclerosis (MS), and that modulation of the microbiome could be therapeutically beneficial in these conditions. In this Review, we examine the influence that the gut microbiota have on immune function via modulation of serotonin production in the gut and through complex interactions with components of the immune system, such as T cells and B cells. We then present evidence from studies in mice and humans that these effects of the gut microbiota on the immune system are important in the development and course of MS. We also consider how strategies for manipulating the composition of the gut microbiota could be used to influence disease-related immune dysfunction and form the basis of a new class of therapeutics. The strategies discussed include the use of probiotics, supplementation with bacterial metabolites, transplantation of faecal matter or defined microbial communities, and dietary intervention. Carefully designed studies with large human cohorts will be required to gain a full understanding of the microbiome changes involved in MS and to develop therapeutic strategies that target these changes.In this Review, the authors provide detailed insight into how the gut microbiota influences the immune system, with implications for neuroinflammation, and discuss the accumulating evidence that the gut microbiota is an important factor in multiple sclerosis pathogenesis and a potential therapeutic target.

Background: An increasing body of empirical evidence suggests that early intervention has positive outcomes for parents of children with neurodevelopmental disabilities. Parental selfefficacy has been used as an outcome measure in some empirical studies; however, there is a lack of evidence of the impact of parent training programmes on parenting self-efficacy beliefs. Objectives: This systematic review sought to assess the effectiveness of parenting interventions to increase parental self-efficacy levels in parents of young children with neurodevelopmental disabilities. Method: We conducted a broad literature search, which included grey literature, such as dissertations and unpublished conference presentations, to identify all relevant prospective studies reporting on our study objective. Articles were selected for inclusion using predefined criteria and data were extracted onto a purposely designed data extraction form. Twenty-five articles met our search criteria. We extracted parenting self-efficacy scores before, and on, completion of parenting interventions and performed a meta-analysis using standardised mean difference. We also conducted a risk of bias assessment for all the included studies. Results: Parent training programmes resulted in a statistically significant increase in parental self-efficacy levels (standardised mean difference, 0.60 [95% confidence interval {CI}, 0.38–0.83]; I2, 74%) relative to baseline measurements. Parents of children younger than 5 years demonstrated the highest increase in levels of parental self-efficacy after parenting interventions. Furthermore, this review showed that psychologists and other healthcare practitioners are successfully able to implement training programmes that enhance parenting self-efficacy. Conclusion: Parent training programmes are effective in increasing parental self-efficacy in parents of children with neurodevelopmental disabilities.

In this 24-month, randomized trial involving patients with relapsing–remitting multiple sclerosis, oral fingolimod reduced the rates of relapse and disability progression, as compared with placebo. Adverse events reported in patients treated with fingolimod included bradycardia, atrioventricular conduction block, macular edema, elevations in liver-enzyme levels, and mild hypertension. In patients with relapsing–remitting multiple sclerosis, oral fingolimod reduced the rates of relapse and disability progression, as compared with placebo. Adverse events included bradycardia, atrioventricular conduction block, macular edema, elevations in liver-enzyme levels, and mild hypertension. Fingolimod (FTY720) is an oral sphingosine-1-phosphate–receptor modulator 1 that is currently being evaluated for the treatment of multiple sclerosis. There is evidence that fingolimod acts by preventing lymphocyte egress from lymph nodes. 2 , 3 This leads to a reduced infiltration of potentially autoaggressive lymphocytes into the central nervous system. 4 , 5 Preclinical findings also suggest that fingolimod may promote neuroprotective and reparative processes within the central nervous system through modulation of sphingosine-1-phosphate receptors expressed on neural cells. 6 – 12 A 6-month, phase 2, placebo-controlled study 13 and its open-label extension study 14 showed sustained suppression, for up to 5 years, of both relapse and inflammatory activity . . .

It is proposed that the event horizon of a black hole is a quantum phase transition of the vacuum of space-time analogous to the liquid-vapor critical point of a bose fluid. The equations of classical general relativity remain valid arbitrarily close to the horizon yet fail there through the divergence of a characteristic coherence length. The integrity of global time, required for conventional quantum mechanics to be defined, is maintained. The metric inside the event horizon is different from that predicted by classical general relativity and may be de Sitter space. The deviations from classical behavior lead to distinct spectroscopic and bolometric signatures that can, in principle, be observed at large distances from the black hole.

There is emerging evidence that the commensal microbiota has a role in the pathogenesis of multiple sclerosis (MS), a putative autoimmune disease of the CNS. Here, we compared the gut microbial composition of 34 monozygotic twin pairs discordant for MS. While there were no major differences in the overall microbial profiles, we found a significant increase in some taxa such as Akkermansia in untreated MS twins. Furthermore, most notably, when transplanted to a transgenic mouse model of spontaneous brain autoimmunity, MS twin-derived microbiota induced a significantly higher incidence of autoimmunity than the healthy twinderived microbiota. The microbial profiles of the colonized mice showed a high intraindividual and remarkable temporal stability with several differences, including Sutterella, an organism shown to induce a protective immunoregulatory profile in vitro. Immune cells from mouse recipients of MS-twin samples produced less IL-10 than immune cells from mice colonized with healthy-twin samples. IL-10 may have a regulatory role in spontaneous CNS autoimmunity, as neutralization of the cytokine in mice colonized with healthy-twin fecal samples increased disease incidence. These findings provide evidence that MS-derived microbiota contain factors that precipitate an MS-like autoimmune disease in a transgenic mouse model. They hence encourage the detailed search for protective and pathogenic microbial components in human MS.

Increasing evidence supports a role for B cells and antibodies in the pathogenesis of multiple sclerosis (MS). Here, Meinl and colleagues discuss the proinflammatory contribution of B-cell signalling in MS, and consider potential targets of autoantibodies. The B-cell response to various MS therapies is also summarized. B cells and antibodies account for the most prominent immunodiagnostic feature in patients with multiple sclerosis (MS), namely oligoclonal bands. Furthermore, evidence is accumulating that B cells and antibodies contribute to MS pathogenesis in at least a subset of patients. The CNS provides a B-cell-fostering environment that includes B-cell trophic factors such as BAFF (B-cell-activating factor of the TNF family), APRIL (a proliferation-inducing ligand), and the plasma-cell survival factor CXCL12. Owing to this environment, the CNS of patients with MS is not only the target of the immunopathological process, but also becomes the site of local antibody production. B cells can increase or dampen CNS inflammation, but their proinflammatory effects seem to be more prominent in most patients, as B-cell depletion is a promising therapeutic strategy. Other therapies not primarily designed to target B cells have numerous effects on the B-cell compartment. This Review summarizes key features of B-cell biology, the role of B cells and antibodies in CNS inflammation, and current attempts to identify the targets of pathogenic antibodies in MS. We also review the effects of approved and investigational interventions—including CD20-depleting antibodies, BAFF/APRIL-depleting agents, alemtuzumab, natalizumab, FTY720, IFN-β, glatiramer acetate, steroids and plasma exchange—on B-cell immunology. Key Points B cells regulate CNS inflammation in various ways The CNS in multiple sclerosis (MS) provides a B-cell-fostering environment Cerebrospinal fluid levels of the B-cell-attracting chemokine CXCL13 are linked to CNS inflammation and local IgG production, and have prognostic value in MS B-cell depletion is a promising MS therapy, largely unrelated to effects on IgG production Many immunomodulatory therapies in MS affect the B-cell compartment Identification and validation of novel autoantibodies in MS is a current research focus; candidate antigens include myelin oligodendrocyte protein, axoglial targets around the node of Ranvier, and the potassium channel KIR4.1

The aim of the study was to assess the effects of epidural analgesia on pelvic floor function. Eighty-two primiparous women (group 1, consisting of 41 given an epidural, and group 2 of 41 not given an epidural) were investigated during pregnancy and at 2 and 10 months after delivery by a questionnaire, clinical examination, and assessment of bladder neck behavior, urethral sphincter function and intravaginal/intra-anal pressures. The prevalence of stress urinary incontinence was similar in both groups at 2 months (24% vs. 17%, P = 0.6) and 10 months (22% vs. 7%, P = 0.1), as was the prevalence of decreased sexual vaginal response at 10 months (27% vs. 10%, P = 0.08). Bladder neck behavior, urethral sphincter function and intravaginal and intra-anal pressures showed no significant differences between the two groups. Ten months after spontaneous delivery, there were no significant differences in the prevalence of stress urinary incontinence and decreased sexual vaginal response, or in bladder neck behavior, urethral sphincter function and pelvic floor muscle strength between women who had or had not had epidural analgesia.[PUBLICATION ABSTRACT]

Abstract Rationale Epidermal growth factor receptor (EGFR) activation is implicated in mucin hypersecretion in chronic obstructive pulmonary disease (COPD). Objectives To investigate the safety and efficacy of an inhaled EGFR antagonist (BIBW 2948) in COPD. Methods Multicenter, double-blind, placebo-controlled trial of 4 weeks of treatment with two doses of BIBW 2948 (15 and 30 mg twice a day) on safety and mucin-related outcomes in 48 patients with COPD. The effect of BIBW 2948 on EGFR activation in airway epithelial cells was assessed using an ex vivo assay. Efficacy measures included the volume of mucin in the airway epithelium (Vs mu,bala) in bronchial biopsies and the expression of mucin genes in bronchial brushings. Measurements and Main Results Inhaled BIBW 2948 induced a dose-related inhibition of EGFR internalization (reflecting decreased EGFR activation) in epithelial cells from treated subjects. However, BIBW 2948 was associated with a dose-related increase in adverse events, including reversible liver enzyme elevation (n = 2), and reduction in FEV1. The changes in mucin stores and mucin gene expression were not significantly different in the pooled BIBW 2948 group versus placebo (volume of mucin per surface area of basal lamina = 0.22 ± 7.11 vs. 0.47 ± 8.06 μm3/μm2; P = 0.93). However, in the 30 mg twice a day group, the reduction in epithelial mucin stores was greatest in subjects with the greatest degree of EGFR inhibition (Pearson r = 0.98; 95% confidence interval, 0.71–0.99). Conclusions Four-week treatment with BIBW 2948 did not significantly decrease epithelial mucin stores and was poorly tolerated in patients with COPD. Ex vivo analyses suggest that higher doses may be more effective at both EGFR inhibition and decreases in mucin stores but that adverse events should be expected. Clinical trial registered with www.clinicaltrials.gov (NCT00423137).