Atmospheric methane grew very rapidly in 2014 (12.7 ± 0.5 ppb/year), 2015 (10.1 ± 0.7 ppb/year), 2016 (7.0 ± 0.7 ppb/year), and 2017 (7.7 ± 0.7 ppb/year), at rates not observed since the 1980s. The ...increase in the methane burden began in 2007, with the mean global mole fraction in remote surface background air rising from about 1,775 ppb in 2006 to 1,850 ppb in 2017. Simultaneously the 13C/12C isotopic ratio (expressed as δ13CCH4) has shifted, now trending negative for more than a decade. The causes of methane's recent mole fraction increase are therefore either a change in the relative proportions (and totals) of emissions from biogenic and thermogenic and pyrogenic sources, especially in the tropics and subtropics, or a decline in the atmospheric sink of methane, or both. Unfortunately, with limited measurement data sets, it is not currently possible to be more definitive. The climate warming impact of the observed methane increase over the past decade, if continued at >5 ppb/year in the coming decades, is sufficient to challenge the Paris Agreement, which requires sharp cuts in the atmospheric methane burden. However, anthropogenic methane emissions are relatively very large and thus offer attractive targets for rapid reduction, which are essential if the Paris Agreement aims are to be attained.
Plain Language Summary
The rise in atmospheric methane (CH4), which began in 2007, accelerated in the past 4 years. The growth has been worldwide, especially in the tropics and northern midlatitudes. With the rise has come a shift in the carbon isotope ratio of the methane. The causes of the rise are not fully understood, and may include increased emissions and perhaps a decline in the destruction of methane in the air. Methane's increase since 2007 was not expected in future greenhouse gas scenarios compliant with the targets of the Paris Agreement, and if the increase continues at the same rates it may become very difficult to meet the Paris goals. There is now urgent need to reduce methane emissions, especially from the fossil fuel industry.
Key Points
Atmospheric methane is rising; its carbon isotopic ratio has become more depleted in C‐13
The possible causes of the change include an increase in emissions, with changing relative proportions of source inputs, or a decline in methane destruction, or both
If this rise continues, there are significant consequences for the UN Paris Agreement
Background and purpose: Antidepressants, which raise the CNS concentrations of 5‐HT and noradrenaline, are frequently used in the treatment of chronic pain; however, it is not known if increasing ...CNS noradrenaline levels alone is sufficient for efficacy, in part resulting from a lack of small molecules with sufficient selectivity.
Experimental approach: In this report, we present the in vitro pharmacological and in vivo pharmacokinetic and pharmacological properties of the novel, orally available and CNS penetrant inhibitor of the noradrenaline transporter (NET), WAY‐318068 (1‐(1S,2R)‐1‐(3,5‐difluorophenyl)‐2‐hydroxy‐3‐(methylamino)propyl‐7‐fluoro‐3,3‐dimethyl‐1,3‐dihydro‐2H‐indol‐2‐one).
Key results: WAY‐318068 is a potent and effective inhibitor of the NET with a Ki of 8.7 nM in a binding assay, and an IC50 of 6.8 nM in an assay of transporter function, without significant binding to the dopamine transporter. Furthermore, the compound has only weak activity at the 5‐HT transporter, leading to a functional selectivity of greater than 2500‐fold. It is orally bioavailable with substantial quantities of the compound found in the CNS after oral dosing. As measured by microdialysis in rats, the compound causes a robust and significant increase in cortical noradrenaline levels without affecting 5‐HT. WAY‐318068 was effective in models of acute, visceral, inflammatory, osteoarthritic, neuropathic, diabetic and bone cancer pain, as well as in traditional models of depression at doses that do not cause motor deficits.
Conclusions and implications: Collectively, the present results support the conclusion that selectively increasing CNS levels of noradrenaline is sufficient for efficacy in models of depression and pain.
Salmonella constitutes a genus of zoonotic bacteria of
worldwide economic and health importance. The
current view of salmonella taxonomy assigns the
members of this genus to two species: S. enterica ...and
S. bongori. S. enterica itself is divided into six
subspecies, enterica, salamae, arizonae, diarizonae,
indica, and houtenae, also known as subspecies I, II,
IIIa, IIIb, IV, and VI, respectively 1. Members of
Salmonella enterica subspecies enterica are mainly
associated with warm-blooded vertebrates and are
usually transmitted by ingestion of food or water
contaminated by infected faeces. The pathogenicity of
most of the distinct serotypes remains undefined, and
even within the most common serotypes, many
questions remain to be answered regarding the
interactions between the organism and the infected
host. Salmonellosis manifests itself in three major forms:
enteritis, septicaemia, and abortion, each of which
may be present singly or in combination, depending
on both the serotype and the host involved. Although
currently over 2300 serovars of Salmonella are
recognized, only about 50 serotypes are isolated in
any significant numbers as human or animal
pathogens 2, 3 and they all belong to subspecies
enterica. Of these, most cause acute gastroenteritis
characterized by a short incubation period and a
severe systemic disease in man or animals, characterized by septicaemia, fever and/or abortion, and
such serotypes are often associated with one or few
host species 4–6. It is the intention of this review to present a
summary of current knowledge of these host-adapted
serotypes of S. enterica. The taxonomic relationships
between the serotypes will be discussed together with
a comparison of the pathology and pathogenesis of
the disease that they cause in their natural host(s).
Since much of our knowledge on salmonellosis is
based on the results of work on Typhimurium, this
serotype will often be used as the baseline in
discussion. It is hoped that an appreciation of the
differences that exist in the way these serotypes
interact with the host will lead to a greater understanding of the complex host–parasite relationship
that characterizes salmonella infections.
An ethological approach to attention predicts that organisms orient preferentially to valuable sources of information in the environment. For many gregarious species, orienting to other individuals ...provides valuable social information but competes with food acquisition, water consumption and predator avoidance. Individual variation in vigilance behaviour in humans spans a continuum from inattentive to pathological levels of interest in others. To assess the comparative biology of this behavioural variation, we probed vigilance rates in free-ranging macaques during water drinking, a behaviour incompatible with the gaze and postural demands of vigilance. Males were significantly more vigilant than females. Moreover, vigilance showed a clear genetic component, with an estimated heritability of 12%. Monkeys carrying a relatively infrequent ‘long’ allele of TPH2, a regulatory gene that influences serotonin production in the brain, were significantly less vigilant compared to monkeys that did not carry the allele. These findings resonate with the hypothesis that the serotonin pathway regulates vigilance in primates and by extension provoke the idea that individual variation in vigilance and its underlying biology may be adaptive rather than pathological.
•In rhesus macaques, individual variation in vigilance has a genetic basis (heritability ∼12%).•Males are more vigilant than females, but vigilance declines with age.•High-status monkeys tend to be more vigilant than low-status monkeys.•Gene polymorphism in TPH2 influences vigilance and is linked to social isolation.•Less common ‘long’ allele carriers (high TPH2) are less vigilant than ‘short’ allele homozygotes.
Hepatitis C virus (HCV) infection is common in persons who inject drugs (PWID).
To evaluate elbasvir-grazoprevir in treating HCV infection in PWID.
Randomized, placebo-controlled, double-blind trial. ...(ClinicalTrials.gov: NCT02105688).
Australia, Canada, France, Germany, Israel, the Netherlands, New Zealand, Norway, Spain, Taiwan, the United Kingdom, and the United States.
301 treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection who were at least 80% adherent to visits for opioid agonist therapy (OAT).
The immediate-treatment group (ITG) received elbasvir-grazoprevir for 12 weeks; the deferred-treatment group (DTG) received placebo for 12 weeks, no treatment for 4 weeks, then open-label elbasvir-grazoprevir for 12 weeks.
The primary outcome was sustained virologic response at 12 weeks (SVR12), evaluated separately in the ITG and DTG. Other outcomes included SVR24, viral recurrence or reinfection, and adverse events.
The SVR12 was 91.5% (95% CI, 86.8% to 95.0%) in the ITG and 89.5% (95% CI, 81.5% to 94.8%) in the active phase of the DTG. Drug use at baseline and during treatment did not affect SVR12 or adherence to HCV therapy. Among 18 patients with posttreatment viral recurrence through 24-week follow-up, 6 had probable reinfection. If the probable reinfections were assumed to be responses, SVR12 was 94.0% (CI, 89.8% to 96.9%) in the ITG. One patient in the ITG (1 of 201) and 1 in the placebo-phase DTG (1 of 100) discontinued treatment because of an adverse event.
These findings may not be generalizable to PWID who are not receiving OAT, nor do they apply to persons with genotype 3 infection, a common strain in PWID.
Patients with HCV infection who were receiving OAT and treated with elbasvir-grazoprevir had high rates of SVR12, regardless of ongoing drug use. These results support the removal of drug use as a barrier to interferon-free HCV treatment for patients receiving OAT.
Merck & Co.
Storm surge associated with Hurricane Katrina and the breach of levees protecting New Orleans, Louisiana allowed floodwaters from Lake Pontchartrain to inundate 80% of the city. Environmental samples ...were collected during September 16−18, 2005 to determine immediate human and wildlife health hazards from pathogens and toxicants in the floodwaters. Baseline information on potential long-term environmental damage resulting from contaminants in water and sediments pumped into Lake Pontchartrain was also collected. Concentrations of aldrin, arsenic, lead, and seven semivolatile organic compounds in sediments/soils exceeded one or more United States Environmental Protection Agency (USEPA) thresholds for human health soil screening levels and high priority bright line screening levels. High numbers of Aeromonas spp., pathogenic Vibrio spp., and other coliform bacteria were found in floodwater samples. Alligator and snake tissues did not contain excessive toxicant concentrations. Initial findings suggest numerous environmental contaminants are present in New Orleans and support the need for further evaluation of the extent of those threats.
To assess the mortality and resource utilization that results from acute renal failure associated with amphotericin B therapy, 707 adult admissions in which parenteral amphotericin B therapy was ...given were studied at a tertiary-care hospital. Main outcome measures were mortality, length of stay, and costs; we controlled for potential confounders, including age, sex, insurance status, baseline creatinine level, length of stay before beginning amphotericin B therapy, and severity of illness. Among 707 admissions, there were 212 episodes (30%) of acute renal failure. When renal failure developed, the mortality rate was much higher: 54% versus 16% (adjusted odds of death, 6.6). When acute renal failure occurred, the mean adjusted increase in length of stay was 8.2 days, and the adjusted total cost was $29,823. Although residual confounding exists despite adjustment, the increases in resource utilization that we found are large and the associated mortality is high when acute renal failure occurs following amphotericin B therapy.
Necdin (NDN) expression is downregulated in telomerase-immortalised normal human urothelial cells. Telomerase-immortalised normal human urothelial cells have no detected genetic alterations. ...Accordingly, many of the genes whose expression is altered following immortalisation are those for which epigenetic silencing is reported.
NDN expression was examined in normal tissues and tumour cell lines by quantitative real-time PCR and immunoblotting. Immunohistochemistry was performed on urothelial carcinoma (UC). Urothelial carcinoma and UC cell lines were subject to HumanMethylation27 BeadChip Array-based methylation analyses. Mutation screening was performed. The functional significance of NDN expression was investigated using retroviral-mediated downregulation or overexpression.
NDN protein was widely expressed in normal tissues. Loss of expression was observed in 38 out of 44 (86%) of UC cell lines and 19 out of 25 (76%) of non-UC cell lines. Loss of NDN protein was found in the majority of primary UC. Oncomine analysis demonstrated downregulation of expression in multiple tumour types. In UC, tumour-specific hypermethylation of NDN and key CpG sites where hypermethylation correlated with reduced expression were identified. Six novel mutations, including some of predicted functional significance, were identified in colorectal and ovarian cancer cell lines. Functional studies showed that NDN could suppress colony formation at low cell density and affect anchorage-independent growth and anoikis in vitro.
NDN is a novel tumour suppressor candidate that is downregulated and hypermethylated or mutated in cancer.
Glaucoma is a common optic neuropathy characterized by retinal ganglion cell death. Elevated intraocular pressure (IOP), a key risk factor for glaucoma, leads to significant biomechanical deformation ...of optic nerve head (ONH) cells and tissues. ONH astrocytes respond to this deformation by transforming to a reactive, proliferative phenotype, which has been implicated in the progression of glaucomatous vision loss. However, little is known about the mechanisms of this transformation. In this study, we developed a 3D collagen gel culture system to mimic features of ONH deformation due to elevated IOP. Compressive loading of astrocyte-seeded collagen gels led to cell alignment perpendicular to the direction of strain, and increased astrocyte activation, as assayed by GFAP, vimentin, and s100β levels, as well as MMP activity. This proof-of-concept study shows that this system has potential for studying mechanisms of astrocyte mechanobiology as related to the pathogenesis of glaucoma. Further work is needed to establish the possible interplay of mechanical stimulation, matrix properties, and hypoxia on the observed response of astrocytes.
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