Characterisation of hCG responses and LH/CGR action in the human endometrium

Human endometrial stromal cells (HESCs) undergo cyclic differentiation, termed decidualisation, into highly specialised cells, which prepares them to respond appropriately to embryonic signals and this is critical to facilitate successful implantation. Human chorionic gonadotrophin (hCG) is secreted by the embryo and is known classically to maintain progesterone production from the corpus luteum during early pregnancy yet emerging evidence reports that it signals in a paracrine manner at the embryo-endometrial interface. Its cognate receptor, the LH/CGR, is a G-protein coupled receptor (GPCR) that is expressed in the endometrium but the role of hCG and its underlying signalling mechanisms here are largely unknown. I show that in HESCs hCG acts via a non-classical Gαi pathway and that signalling via this pathway can negatively regulate important decidua-specific genes. Furthermore, the LH/CGR undergoes ‘reprogramming’ during decidualisation, which changes both its trafficking and MAPK signalling profiles, where only a subset of pathways are activated by hCG upon decidualisation. I further show that the majority of the LH/CGR localises to an endocytic compartment which is distinct from the early endosome, termed the very early endosome (VEE) and that this is dependent on the C-terminal tail of the receptor. Moreover, cellular depletion of an essential VEE component, GIPC, can cause hCG-induced modulation of downstream decidual genes to be reversed. Importantly, in HESCs from recurrent miscarriage (RM) patients, hCG-induced signalling opposes that of signalling in control patients and in addition, LH/CGR trafficking and recycling may be disordered. Together, these findings provide novel insights of the mode of action of hCG and the LH/CGR in the endometrium and highlight how perturbation of their signalling and trafficking profiles may contribute to pregnancy loss.Open Acces

Space Weather Monitor at the L5 Point: A Case Study of a CME Observed with STEREO B

An important location for future space weather monitoring is the Lagrange point 5 (L5) of the Sun-Earth system. We test the performance of L5 for space weather monitoring using STEREO B observations of an Earth-directed coronal mass ejection (CME), seen as a partial halo by SOHO at L1. STEREO B (located close to L5) continuously tracked the CME. By using these data in combination with methods to calculate the CME arrival time at the Earth (extrapolation, drag-based model, and a magnetohydrodynamic model), we demonstrate that the estimation of the CME arrival time can be drastically improved by adding L5 data. Based on the L1 data alone, one could predict that the CME would arrive at the Earth. Using only the L5 data, one would not expect an arrival, as the estimations of the CME 3-D configuration is uncertain. The combination of L1 and L5 data leads to an ambiguous prediction of the CME arrival due to low CME brightness in L1 data. To obtain an unambiguous prediction, one needs its 3-D configuration, from observing the CME material close to the plane of the sky from at least two viewpoints (in this case L5 and, coincidentally, L4). This event demonstrates that L1 observations may be better to determine CME arrival, but L5 observations are superior for constraining arrival time. In this work, the advantages and caveats of using data from a space weather monitor at L5 for predicting interplanetary propagation of CMEs are discussed and demonstrated in a direct case study

Expert opinion on risks to the long-term viability of residential recycled water schemes: an Australian study

The water sector needs to make efficient and prudent investment decisions by carefully considering the long-term viability of water infrastructure projects. To support the assessment and planning of residential recycled water schemes in Australia, we have sought to clarify scheme objectives and to further define the array of critical risks that can impact the long-term viability of schemes. Building on historical information, we conducted a national survey which elicited responses from 88 Australian expert practitioners, of which 64% have over 10 years of industry experience and 42% have experience with more than five residential recycled water schemes. On the basis of expert opinion, residential recycled water schemes are considered to be highly relevant for diversifying and improving water supply security, reducing wastewater effluent discharge and pollutant load to waterways and contributing to sustainable urban development. At present however, the inability to demonstrate an incontestable business case is posing a significant risk to the long-term viability of residential recycled water schemes. Political, regulatory, organisational and financial factors were also rated as critical risks, in addition to community risk perception and fall in demand. The survey results shed further light on the regulatory environment of residential recycled water schemes, with regulatory participants rating the level and impact of risk factors higher than other survey participants in most cases. The research outcomes provide a comprehensive understanding of the critical risks to the long-term viability of residential recycled water schemes, thereby enabling the specification of targeted risk management measures at the assessment and planning stage of a scheme

Effects of microRNA-146a on the proliferation and apoptosis of human osteochondrocytes by targeting TRAF6 through the NF- κB signalling pathway

MicroRNAs are important cellular mediators of mRNA degradation and translation repression, which in turn can have an impact on various processes and, if their function is perturbed, can cause disease. Here, we summarize the recent manuscript by Zhong et al. [(2017) Biosci. Rep. 37, BSR20160578], which explores microRNA-146a and how it may play an indirect yet vital role in the proliferation of osteoarthritis (OA) chondrocytes. The data presented by the authors could have important implications for future OA therapies

Socioeconomic inequalities in the incidence of alcohol-related liver disease: A nationwide Danish study.

BackgroundThere is socio-economic inequality in total alcohol-related harm, but knowledge of inequality in the incidence of specific alcohol-related diseases would be beneficial for prevention. Registry-based studies with nationwide coverage may reveal the full burden of socioeconomic inequality compared to what can be captured in questionnaire-based studies. We examined the incidence of alcohol-related liver disease (ALD) according to socioeconomic status and age.MethodsWe used national registries to identify patients with an incident diagnosis of ALD and their socioeconomic status in 2009-2018 in Denmark. We computed ALD incidence rates by socioeconomic status (education and employment status) and age-group (30-39, 40-49, 50-59, 60-69 years) and quantified the inequalities as the absolute and relative difference in incidence rates between low and high socioeconomic status.FindingsOf 17,473 patients with newly diagnosed ALD, 78% of whom had cirrhosis, 86% had a low or medium-low educational level and only 20% were employed. ALD patients were less likely to be employed in the 10 years prior to diagnosis than controls. The incidence rate of ALD correlated inversely with educational level, from 181 (95% CI, 167-197) to 910 (95% CI, 764-1086) per million person-years from the highest to the lowest educational level. By employment status, the incidence rate per million person-years was 211 (95% CI, 189-236) for employed and 3449 (95% CI, 2785-4271) for unemployed. Incidence rates increased gradually with age leading to larger inequalities in absolute numbers for older age-groups. Although ALD was rare in the younger age-groups, the relative differences in incidence rates between high and low socioeconomic status were large for these ages. The pattern of socioeconomic inequality in ALD incidence was similar for men and women.InterpretationThis study showed substantial socioeconomic inequalities in ALD incidence for people aged 30-69 years.FundingThe study was supported by grants from the Novo Nordisk Foundation (NNF18OC0054612) and the Research Fund of Bispebjerg Hospital

Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability

Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2 ) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2 mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability

Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats

Diabetes is a strong risk factor for premature and severe stroke. The GLP-1R (glucagon-like peptide-1 receptor) agonist Ex-4 (exendin-4) is a drug for the treatment of T2D (Type 2 diabetes) that may also have neuroprotective effects. The aim of the present study was to determine the efficacy of Ex-4 against stroke in diabetes by using a diabetic animal model, a drug administration paradigm and a dose that mimics a diabetic patient on Ex-4 therapy. Furthermore, we investigated inflammation and neurogenesis as potential cellular mechanisms underlying the Ex-4 efficacy. A total of seven 9-month-old Type 2 diabetic Goto–Kakizaki rats were treated peripherally for 4 weeks with Ex-4 at 0.1, 1 or 5 μg/kg of body weight before inducing stroke by transient middle cerebral artery occlusion and for 2–4 weeks thereafter. The severity of ischaemic damage was measured by evaluation of stroke volume and by stereological counting of neurons in the striatum and cortex. We also quantitatively evaluated stroke-induced inflammation, stem cell proliferation and neurogenesis. We show a profound anti-stroke efficacy of the clinical dose of Ex-4 in diabetic rats, an arrested microglia infiltration and an increase of stroke-induced neural stem cell proliferation and neuroblast formation, while stroke-induced neurogenesis was not affected by Ex-4. The results show a pronounced anti-stroke, neuroprotective and anti-inflammatory effect of peripheral and chronic Ex-4 treatment in middle-aged diabetic animals in a preclinical setting that has the potential to mimic the clinical treatment. Our results should provide strong impetus to further investigate GLP-1R agonists for their neuroprotective action in diabetes, and for their possible use as anti-stroke medication in non-diabetic conditions

Targeted AntiBiotics for Chronic pulmonary diseases (TARGET ABC):can targeted antibiotic therapy improve the prognosis of Pseudomonas aeruginosa-infected patients with chronic pulmonary obstructive disease, non-cystic fibrosis bronchiectasis, and asthma? A multicenter, randomized, controlled, open-label trial

BACKGROUND: Pseudomonas aeruginosa infection is seen in chronic pulmonary disease and is associated with exacerbations and poor long-term prognosis. However, evidence-based guidelines for the management and treatment of P. aeruginosa infection in chronic, non-cystic fibrosis (CF) pulmonary disease are lacking. The aim of this study is to investigate whether targeted antibiotic treatment against P. aeruginosa can reduce exacerbations and mortality in patients with chronic obstructive pulmonary disease (COPD), non-CF bronchiectasis, and asthma. METHODS: This study is an ongoing multicenter, randomized, controlled, open-label trial. A total of 150 patients with COPD, non-CF bronchiectasis or asthma, and P. aeruginosa-positive lower respiratory tract samples will be randomly assigned with a 1:1 ratio to either no antibiotic treatment or anti-pseudomonal antibiotic treatment with intravenous beta-lactam and oral ciprofloxacin for 14 days. The primary outcome, analyzed with two co-primary endpoints, is (i) time to prednisolone and/or antibiotic requiring exacerbation or death, in the primary or secondary health sector, within days 20–365 from study allocation and (ii) days alive and without exacerbation within days 20–365 from the study allocation. DISCUSSION: This trial will determine whether targeted antibiotics can benefit future patients with chronic, non-CF pulmonary disease and P. aeruginosa infection in terms of reduced morbidity and mortality, thus optimizing therapeutic approaches in this large group of chronic patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03262142. Registered on August 25, 2017. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13063-022-06720-z