The effects of sildenafil on ciliary beat frequency in patients with pulmonary nontuberculous mycobacteria disease: A phase I/II trial

Rationale: Pulmonary nontuberculous mycobacterial disease (PNTM) has increased over the past several decades, especially in older women. Abnormal mucociliary clearance and abnormal nasal nitric oxide (NO) have been associated with PNTM disease in other patient cohorts. Mucociliary clearance can be affected by NO-cGMP signaling, and therefore modulation of the pathway may be possible with phosphodiesterase inhibitors such as sildenafil as a novel therapeutic approach. Objective: To define ex vivo characteristics of pulmonary nontuberculous mycobacterial disease affected of sildenafil. Methods: Subjects with PNTM infections were recruited into an open-label dose escalation trial of sildenafil. Laboratory measurements and muccociliary measurements: ciliary beat frequency, nasal nitric oxide, and 24-hour sputum production, were collected throughout the study period. Patients received sildenafil daily during the study period, with escalation from 20 mg to 40 mg three times daily. Measurements and Main Results: Increased ciliary beat frequency occurred after a single dose of 40 mg sildenafil and after extended dosing of 40 mg sildenafil. The increase ciliary beat frequency was not seen with 20 mg sildenafil dosing. There were no changes in sputum production, nasal nitric oxide production, Quality of Life- Bronchiectasis- NTM module (QOL-B-NTM) questionnaire, or the St. George’s Respiratory Questionnaire during the study period. Conclusion: Sildenafil, 40 mg, increased ciliary beat frequency acutely as well as with extended administration.National Institute of Healt

Pattern recognition receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Pattern Recognition Receptors (PRRs, [89]) (nomenclature as agreed by NC-IUPHAR sub-committee on Pattern Recognition Receptors, [17]) participate in the innate immune response to microbial agents, the stimulation of which leads to activation of intracellular enzymes and regulation of gene transcription. PRRs express multiple leucine-rich regions to bind a range of microbially-derived ligands, termed PAMPs or pathogen-associated molecular patterns or endogenous ligands, termed DAMPS or damage-associated molecular patterns. These include peptides, carbohydrates, peptidoglycans, lipoproteins, lipopolysaccharides, and nucleic acids. PRRs include both cell-surface and intracellular proteins. PRRs may be divided into signalling-associated members, identified here, and endocytic members, the function of which appears to be to recognise particular microbial motifs for subsequent cell attachment, internalisation and destruction. Some are involved in inflammasome formation, and modulation of IL-1β cleavage and secretion, and others in the initiation of the type I interferon response. PRRs included in the Guide To PHARMACOLOGY are:Catalytic PRRs (see links below this overview)Toll-like receptors (TLRs)Nucleotide-binding oligomerization domain, leucine-rich repeat containing receptors (NLRs, also known as NOD (Nucleotide oligomerisation domain)-like receptors)RIG-I-like receptors (RLRs)Caspase 4 and caspase 5 Non-catalytic PRRsAbsent in melanoma (AIM)-like receptors (ALRs)C-type lectin-like receptors (CLRs)Other pattern recognition receptorsAdvanced glycosylation end-product specific receptor (RAGE

Pattern recognition receptors in GtoPdb v.2021.3

Pattern Recognition Receptors (PRRs, [104]) (nomenclature as agreed by NC-IUPHAR sub-committee on Pattern Recognition Receptors, [18]) participate in the innate immune response to microbial agents, the stimulation of which leads to activation of intracellular enzymes and regulation of gene transcription. PRRs express multiple leucine-rich regions to bind a range of microbially-derived ligands, termed PAMPs or pathogen-associated molecular patterns or endogenous ligands, termed DAMPS or damage-associated molecular patterns. These include peptides, carbohydrates, peptidoglycans, lipoproteins, lipopolysaccharides, and nucleic acids. PRRs include both cell-surface and intracellular proteins. PRRs may be divided into signalling-associated members, identified here, and endocytic members, the function of which appears to be to recognise particular microbial motifs for subsequent cell attachment, internalisation and destruction. Some are involved in inflammasome formation, and modulation of IL-1β cleavage and secretion, and others in the initiation of the type I interferon response. PRRs included in the Guide To PHARMACOLOGY are:Catalytic PRRs (see links below this overview)Toll-like receptors (TLRs)Nucleotide-binding oligomerization domain, leucine-rich repeat containing receptors (NLRs, also known as NOD (Nucleotide oligomerisation domain)-like receptors)RIG-I-like receptors (RLRs)Caspase 4 and caspase 5 Non-catalytic PRRsAbsent in melanoma (AIM)-like receptors (ALRs)C-type lectin-like receptors (CLRs)Other pattern recognition receptorsAdvanced glycosylation end-product specific receptor (RAGE

Pattern recognition receptors in GtoPdb v.2023.1

Pattern Recognition Receptors (PRRs, [110]) (nomenclature as agreed by NC-IUPHAR sub-committee on Pattern Recognition Receptors, [20]) participate in the innate immune response to microbial agents, the stimulation of which leads to activation of intracellular enzymes and regulation of gene transcription. PRRs express multiple leucine-rich regions to bind a range of microbially-derived ligands, termed PAMPs or pathogen-associated molecular patterns or endogenous ligands, termed DAMPS or damage-associated molecular patterns. These include peptides, carbohydrates, peptidoglycans, lipoproteins, lipopolysaccharides, and nucleic acids. PRRs include both cell-surface and intracellular proteins. PRRs may be divided into signalling-associated members, identified here, and endocytic members, the function of which appears to be to recognise particular microbial motifs for subsequent cell attachment, internalisation and destruction. Some are involved in inflammasome formation, and modulation of IL-1β cleavage and secretion, and others in the initiation of the type I interferon response. PRRs included in the Guide To PHARMACOLOGY are:Catalytic PRRs (see links below this overview)Toll-like receptors (TLRs)Nucleotide-binding oligomerization domain, leucine-rich repeat containing receptors (NLRs, also known as NOD (Nucleotide oligomerisation domain)-like receptors)RIG-I-like receptors (RLRs)Caspase 4 and caspase 5 Non-catalytic PRRsAbsent in melanoma (AIM)-like receptors (ALRs)C-type lectin-like receptors (CLRs)Other pattern recognition receptorsAdvanced glycosylation end-product specific receptor (RAGE

Toll-like receptor expression in C3H/HeN and C3H/HeJ mice during Salmonella enterica serovar Typhimurium infection

Here, we have investigated the mRNA expression of Toll-like receptor 2 (TLR-2), TLR-4, and MD-2 in spleens and livers of C3H/HeN mice (carrying wild-type TLR-4) and C3H/HeJ mice (carrying mutated TLR-4) in response to Salmonella infection. During Salmonella infections, TLR-4 is activated, leading to increased TLR-2 and decreased TLR-4 expression

Caspase-8 functions as a key mediator of inflammation and pro-IL-1β processing via both canonical and non-canonical pathways.

Caspase-8 is an apical component of cell death pathways. Activated caspase-8 can drive classical caspase-dependent apoptosis and actively inhibits cell death mediated by RIPK3-driven necroptosis. Genetic deletion of Casp8 results in embryonic lethality as a result of uncontrolled necroptosis. This lethality can be rescued by simultaneous deletion of Ripk3. Recently, caspase-8 has been additionally connected to inflammatory pathways within the cell. In particular, caspase-8 has been shown to be crucially involved in the induction of pro-IL-1β synthesis and processing via both non-canonical and canonical pathways. In this review, we bring together current knowledge regarding the role of caspase-8 in cellular inflammation with a particular emphasis on the interplay between caspase-8 and the classical and non-canonical inflammasomes.The authors received financial support of the Wellcome Trust (TPM; WT085090MA) and the Biotechnology and Biological Sciences Research Council (CEB; BB/K006436/1).This is the accepted manuscript. The final version is available from Wiley at http://onlinelibrary.wiley.com/doi/10.1111/imr.12284/abstract

Inflammasomes as regulators of mechano-immunity

Mechano-immunity, the intersection between cellular or tissue mechanics and immune cell function, is emerging as an important factor in many inflammatory diseases. Mechano-sensing defines how cells detect mechanical changes in their environment. Mechano-response defines how cells adapt to such changes, e.g. form synapses, signal or migrate. Inflammasomes are intracellular immune sensors that detect changes in tissue and cell homoeostasis during infection or injury. We and others recently found that mechano-sensing of tissue topology (swollen tissue), topography (presence and distribution of foreign solid implant) or biomechanics (stiffness), alters inflammasome activity. Once activated, inflammasomes induce the secretion of inflammatory cytokines, but also change cellular mechanical properties, which influence how cells move, change their shape, and interact with other cells. When overactive, inflammasomes lead to chronic inflammation. This clearly places inflammasomes as important players in mechano-immunity. Here, we discuss a model whereby inflammasomes integrate pathogen- and tissue-injury signals, with changes in tissue mechanics, to shape the downstream inflammatory responses and allow cell and tissue mechano-adaptation. We will review the emerging evidence that supports this model

Responding to COVID-19 in the National Health Service in England: positive changes and learning for Knowledge for Healthcare

The article provides an overview of the response from the Health Education England library and knowledge services team to the COVID-19 pandemic. The article covers activity and initiatives that were put in place in England from March 2020 to address challenges and issues arising for library and knowledge services delivering to the National Health Service. The article reflects on the learning from the developments that have been implemented to date and considers the positive changes that have arisen in the continued delivery against five national, strategic drivers

The COP II adaptor protein TMED7 is required to initiate and mediate the delivery of TLR4 to the plasma membrane.

Toll-like receptor 4 (TLR4), the receptor for the bacterial product endotoxin, is subject to multiple points of regulation at the levels of signaling, biogenesis, and trafficking. Dysregulation of TLR4 signaling can cause serious inflammatory diseases, such as sepsis. We found that the p24 family protein TMED7 (transmembrane emp24 protein transport domain containing 7) is required for the trafficking of TLR4 from the endoplasmic reticulum to the cell surface through the Golgi. TMED7 formed a stable complex with the ectodomain of TLR4, an interaction that required the coiled-coil and Golgi dynamics (GOLD) domains, but not the cytosolic, coat protein complex II (COP II) sorting motif, of TMED7. Depletion of TMED7 reduced TLR4 signaling mediated by the adaptor protein MyD88 (myeloid differentiation marker 88), but not that mediated by the adaptor proteins TRIF [Toll-interleukin-1 receptor (TIR) domain-containing adaptor protein inducing interferon-β] and TRAM (TRIF-related adaptor molecule). Truncated forms of TMED7 lacking the COP II sorting motif or the transmembrane domain were mislocalized and resulted in ligand-independent signaling that probably arises from receptors accumulated intracellularly. Together, these results support the hypothesis that p24 proteins perform a quality control step by recognizing correctly folded anterograde cargo, such as TLR4, in early secretory compartments and facilitating the translocation of this cargo to the cell surface.We thank B. Verstak for his assistance in lentivirus production, J. Sakai for his help with setting up the ELISA assays, and C. Green and M. Wayland for confocal microscopy. Funding: This work was supported by program grants from the Wellcome Trust (WT081744/Z/06/Z) and the UK Medical Research Council (G1000133) to N.J.G. and C.E.B. and a Wellcome Investigator award to N.J.G. (WT100321/z/12/Z).This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Signaling on 29 July 2014 Vol. 7, Issue 336, p. ra70, DOI: 10.1126/scisignal.2005275

Integrating local knowledge into a national programme: Evidence from a community-based diabetes prevention education programme

Type 2 diabetes prevention is a major priority for healthcare services and public health. This study aimed to evaluate how a local authority in England piloted a diabetes prevention programme. The South Gloucestershire Diabetes Prevention (Pilot) Programme (SGDPP) comprised a group health education course over six weeks with subsequent support provision up to six months post-enrolment. Of the 300 patients invited onto the programme, 32% enrolled and 29% completed the full six-month programme. There was an attendance rate of 84% throughout group sessions and at a six-month follow-up. There were significant improvements across most measures at six months, including a 4 kg mean weight loss and a 3.45 mmol/mol mean HbA1c reduction. Clear goals, high quality organization and personal qualities of educators were identified as central for the programme’s success. The unit costs were similar to pilots of other healthy lifestyle programmes. The evaluation found evidence of reduced type 2 diabetes risk markers, positive impacts for dietary and physical activity, and potential cost-effectiveness for this format of group-based diabetes prevention intervention. Feedback from multiple stakeholders provided insight on how to successfully embed and scale-up delivery of diabetes prevention work. This evidence enables the integration of learning in local service delivery and provides a basis to support development of the national diabetes prevention programme