Abstract Intermittent nociceptive stimulation following a complete transection or contused spinal cord injury (SCI) has been shown to exert several short- and long-lasting negative consequences. ...These include maladaptive spinal plasticity, enhanced mechanical allodynia, and impaired functional recovery of locomotor and bladder functions. The neurotrophin, brain-derived neurotrophic factor (BDNF) has been shown to play an important role in adaptive plasticity and also to restore functions following SCI. This suggests that the negative behavioral effects of shock are most likely related to corresponding changes in BDNF spinal levels. In this study, we investigated the cellular effects of nociceptive stimulation in contused adult rats focusing on BDNF, its receptor, tropomyosin-receptor kinase (TrkB), and the subsequent downstream signaling system. The goal was to determine whether the behavioral effect of stimulation is associated with concomitant cellular changes induced during the initial post-injury period. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to assess changes in the mRNA and/or protein levels of BDNF, TrkB, and the downstream signaling proteins calcium-calmodulin kinase II (CaMKII) and extracellular related kinase 1/2 (ERK1/2) at 1 h, 24 h, and 7 days following administration of intermittent noxious shock to the tail of contused subjects. In addition, recovery of locomotor function (Basso, Beattie, and Bresnahan BBB score) was assessed daily for the first week after injury. The results showed that, although nociceptive stimulation failed to induce any changes in gene expression at 1 h, it significantly reduced the expression of BDNF, TrkB, ERK2, and CaMKII at 24 h. In general, changes in gene expression were spatially localized to the dorsal spinal cord. In addition, locomotor recovery was impaired by shock. Evidence is also provided suggesting that shock engages a neuronal circuitry without having any negative effects on neuronal survival at 24 h. These results suggest that nociceptive activity following SCI decreases BDNF and TrkB levels, which may significantly contribute to diminished functional recovery.
It has been proposed that Jupiter's satellite Europa currently possesses a global subsurface ocean of liquid water. Galileo gravity data verify that the satellite is differentiated into an outer H2O ...layer about 100 km thick but cannot determine the current physical state of this layer (liquid or solid). Here we summarize the geological evidence regarding an extant subsurface ocean, concentrating on Galileo imaging data. We describe and assess nine pertinent lines of geological evidence: impact morphologies, lenticulae, cryovolcanic features, pull‐apart bands, chaos, ridges, surface frosts, topography, and global tectonics. An internal ocean would be a simple and comprehensive explanation for a broad range of observations; however, we cannot rule out the possibility that all of the surface morphologies could be due to processes in warm, soft ice with only localized or partial melting. Two different models of impact flux imply very different surface ages for Europa; the model favored here indicates an average age of ∼50 Myr. Searches for evidence of current geological activity on Europa, such as plumes or surface changes, have yielded negative results to date. The current existence of a global subsurface ocean, while attractive in explaining the observations, remains inconclusive. Future geophysical measurements are essential to determine conclusively whether or not there is a liquid water ocean within Europa today.
Increased understanding of whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection is an urgent requirement. We aimed to investigate whether antibodies ...against SARS-CoV-2 were associated with a decreased risk of symptomatic and asymptomatic reinfection.
A large, multicentre, prospective cohort study was done, with participants recruited from publicly funded hospitals in all regions of England. All health-care workers, support staff, and administrative staff working at hospitals who could remain engaged in follow-up for 12 months were eligible to join The SARS-CoV-2 Immunity and Reinfection Evaluation study. Participants were excluded if they had no PCR tests after enrolment, enrolled after Dec 31, 2020, or had insufficient PCR and antibody data for cohort assignment. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2–4 weeks) and completed questionnaires every 2 weeks on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive, or previous positive PCR or antibody test) or negative cohort (antibody negative, no previous positive PCR or antibody test). The primary outcome was a reinfection in the positive cohort or a primary infection in the negative cohort, determined by PCR tests. Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, or possible) and symptom-status, depending on the hierarchy of evidence. Primary infections in the negative cohort were defined as a first positive PCR test and seroconversions were excluded when not associated with a positive PCR test. A proportional hazards frailty model using a Poisson distribution was used to estimate incidence rate ratios (IRR) to compare infection rates in the two cohorts.
From June 18, 2020, to Dec 31, 2020, 30 625 participants were enrolled into the study. 51 participants withdrew from the study, 4913 were excluded, and 25 661 participants (with linked data on antibody and PCR testing) were included in the analysis. Data were extracted from all sources on Feb 5, 2021, and include data up to and including Jan 11, 2021. 155 infections were detected in the baseline positive cohort of 8278 participants, collectively contributing 2 047 113 person-days of follow-up. This compares with 1704 new PCR positive infections in the negative cohort of 17 383 participants, contributing 2 971 436 person-days of follow-up. The incidence density was 7·6 reinfections per 100 000 person-days in the positive cohort, compared with 57·3 primary infections per 100 000 person-days in the negative cohort, between June, 2020, and January, 2021. The adjusted IRR was 0·159 for all reinfections (95% CI 0·13–0·19) compared with PCR-confirmed primary infections. The median interval between primary infection and reinfection was more than 200 days.
A previous history of SARS-CoV-2 infection was associated with an 84% lower risk of infection, with median protective effect observed 7 months following primary infection. This time period is the minimum probable effect because seroconversions were not included. This study shows that previous infection with SARS-CoV-2 induces effective immunity to future infections in most individuals.
Department of Health and Social Care of the UK Government, Public Health England, The National Institute for Health Research, with contributions from the Scottish, Welsh and Northern Irish governments.
The surface morphology of icy moons is affected by several processes implicating exchanges between their subsurfaces and atmospheres (if any). The possible exchange of material between the subsurface ...and the surface is mainly determined by the mechanical properties of the lithosphere, which isolates the deep, warm and ductile ice material from the cold surface conditions. Exchanges through this layer occur only if it is sufficiently thin and/or if it is fractured owing to tectonic stresses, melt intrusion or impact cratering. If such conditions are met, cryomagma can be released, erupting fresh volatile-rich materials onto the surface. For a very few icy moons (Titan, Triton, Enceladus), the emission of gas associated with cryovolcanic activity is sufficiently large to generate an atmosphere, either long-lived or transient. For those moons, atmosphere-driven processes such as cryovolcanic plume deposition, phase transitions of condensable materials and wind interactions continuously re-shape their surfaces, and are able to transport cryovolcanically generated materials on a global scale. In this chapter, we discuss the physics of these different exchange processes and how they affect the evolution of the satellites’ surfaces.
Polyol-solubilized 3-(dichloroamino)-3-methylbutylsulfones 1a–m and sulfonamides 2a–b show fast-acting, broad spectrum antimicrobial activity against bacterial and viral pathogens as tested by 1-h ...MBC’s against E. coli and S. aureus, and 1-h IC50’s against Ad5 and HSV-1.
The discovery and development of antimicrobial agents that do not give rise to resistance remains an ongoing challenge. Our efforts in this regard continue to reveal new potential therapeutic agents with differing physicochemical properties while retaining the effective N,N-dichloroamine pharmacophore as the key antimicrobial warhead. In this Letter, we disclose agents containing polyol units as a water solubilizing group. These sulfonyl-polyol agents show broad spectrum bactericidal and virucidal activity. These compounds show 1h MBC’s of 16–512μg/mL against Escherichia coli and 4–256μg/mL against Staphylococcus aureus at neutral pH, and 1-h IC50’s of 4.5–32μM against Adenovirus 5 and 0.7–3.0μM against Herpes simplex virus 1. The lead compounds were tested in a tissue culture irritancy assay and showed only minimal irritation at the highest concentrations tested.
A novel series of
N-chloroheterocycles has been prepared and the biological properties are reported.
Antimicrobial compounds with broad-spectrum activity and minimal potential for antibiotic ...resistance are urgently needed. Toward this end, we prepared and investigated a novel series of
N-chloroheterocycles. Of the compounds examined, the
N-chloroamine series were found superior over
N-chloroamide series in regards to exhibiting high antimicrobial activity, low cytotoxicity, and long-term aqueous stability.
Antimicrobial resistance against many known therapeutics is on the rise. We examined derivatives of 3-chlorooxazolidin-2-one
1a (X
=
H) as antibacterial and antifungal agents. The key findings were ...that the activity and apparent in vitro cytotoxicity could be controlled by the substitution of charged solubilizers at the 4- and 5- positions. These changes both significantly increase the antifungal potency and decrease cytotoxicity. Particularly effective were trialkylammonium groups which led to 400- to 600-fold increases in the antifungal therapeutic index when compared to their unsubstituted counterparts.
This study identified a new class of solution-stable, topical, antimicrobial agents. These agents are sulfone-stabilized and possess either a quaternary ammonium or sulfonate as a water solubilizing ...group.
Structure stability/activity relationships (SXR) of a new class of
N,
N-dichloroamine compounds were explored to improve antimicrobial activity against
Escherichia coli,
Staphylococcus aureus, and
Candida albicans while maintaining aqueous solution stability. This study identified a new class of solution-stable and topical antimicrobial agents. These agents are sulfone-stabilized and possess either a quaternary ammonium or sulfonate appendages as a water solubilizing group. Several unique challenges were confronted in the synthesis of these novel compounds which are highlighted in the discussion.
Saturn׳s moons, Titan and Enceladus, are two of the Solar System׳s most enigmatic bodies and are prime targets for future space exploration. Titan provides an analogue for many processes relevant to ...the Earth, more generally to outer Solar System bodies, and a growing host of newly discovered icy exoplanets. Processes represented include atmospheric dynamics, complex organic chemistry, meteorological cycles (with methane as a working fluid), astrobiology, surface liquids and lakes, geology, fluvial and aeolian erosion, and interactions with an external plasma environment. In addition, exploring Enceladus over multiple targeted flybys will give us a unique opportunity to further study the most active icy moon in our Solar System as revealed by Cassini and to analyse in situ its active plume with highly capable instrumentation addressing its complex chemistry and dynamics. Enceladus׳ plume likely represents the most accessible samples from an extra-terrestrial liquid water environment in the Solar system, which has far reaching implications for many areas of planetary and biological science. Titan with its massive atmosphere and Enceladus with its active plume are prime planetary objects in the Outer Solar System to perform in situ investigations. In the present paper, we describe the science goals and key measurements to be performed by a future exploration mission involving a Saturn–Titan orbiter and a Titan balloon, which was proposed to ESA in response to the call for definition of the science themes of the next Large-class mission in 2013. The mission scenario is built around three complementary science goals: (A) Titan as an Earth-like system; (B) Enceladus as an active cryovolcanic moon; and (C) Chemistry of Titan and Enceladus – clues for the origin of life. The proposed measurements would provide a step change in our understanding of planetary processes and evolution, with many orders of magnitude improvement in temporal, spatial, and chemical resolution over that which is possible with Cassini–Huygens. This mission concept builds upon the successes of Cassini–Huygens and takes advantage of previous mission heritage in both remote sensing and in situ measurement technologies.
•Titan and Enceladus, two of the Solar System׳s most enigmatic bodies, are prime targets for future space exploration.•Titan provides an analogue for many processes relevant to the Earth.•Enceladus׳ plume represents the most accessible samples from an extra-terrestrial liquid water environment in the Solar system.•We propose in situ investigations of the two moons from orbit, and of Titan from an aerial platform.•This would provide a step change in our understanding of planetary process and of exobiological potential of icy moons.
The Solid‐State Imaging (SSI) instrument provided the first high‐ and medium‐resolution views of Io as the Galileo spacecraft closed in on the volcanic body in late 1999 and early 2000. While each ...volcanic center has many unique features, the majority can be placed into one of two broad categories. The “Promethean” eruptions, typified by the volcanic center Prometheus, are characterized by long‐lived steady eruptions producing a compound flow field emplaced in an insulating manner over a period of years to decades. In contrast, “Pillanian” eruptions are characterized by large pyroclastic deposits and short‐lived but high effusion rate eruptions from fissures feeding open‐channel or open‐sheet flows. Both types of eruptions commonly have ∼100‐km‐tall, bright, SO2‐rich plumes forming near the flow fronts and smaller deposits of red material that mark the vent for the silicate lavas.
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