The IFT81-IFT74 complex acts as an unconventional RabL2 GTPase-activating protein during intraflagellar transport.

Cilia are important cellular organelles for signaling and motility and are constructed via intraflagellar transport (IFT). RabL2 is a small GTPase that localizes to the basal body of cilia via an interaction with the centriolar protein CEP19 before downstream association with the IFT machinery, which is followed by initiation of IFT. We reconstituted and purified RabL2 with CEP19 or IFT proteins to show that a reconstituted pentameric IFT complex containing IFT81/74 enhances the GTP hydrolysis rate of RabL2. The binding site on IFT81/74 that promotes GTP hydrolysis in RabL2 was mapped to a 70-amino-acid-long coiled-coil region of IFT81/74. We present structural models for RabL2-containing IFT complexes that we validate in vitro and in cellulo and demonstrate that Chlamydomonas IFT81/74 enhances GTP hydrolysis of human RabL2, suggesting an ancient evolutionarily conserved activity. Our results provide an architectural understanding of how RabL2 is incorporated into the IFT complex and a molecular rationale for why RabL2 dissociates from anterograde IFT trains soon after departure from the ciliary base.

Fatal fetal anomaly: Experiences of women and their partners.

OBJECTIVE: This study explored the care experiences of parents whose pregnancy was diagnosed with a fatal fetal anomaly following the legalisation of termination of pregnancy in 2019 in Ireland. METHODS: A qualitative study using in-depth semi-structured interviews and interpretative phenomenological analysis was undertaken. Purposeful sampling was used to recruit 10 parents, six women and four of their male partners. Parents recruited included those who terminated and continued the pregnancy. RESULTS: Three superordinate themes were identified: 'Attachment and coping', 'There's no place for you in the pregnancy world' and 'Consistency of quality care'. Parents shared the different approaches and level of attachment to their baby that supported their coping. Regardless of the level of attachment, many parents benefited from the acts of remembrance. Parents expressed how they no longer felt they belonged in the 'pregnancy world' and described a need for healthcare professionals to recognise their loss and create a safe and supportive environment in which they could share their grief. Despite this, parents' accounts highlighted variations and inconsistencies in care and service provision. CONCLUSION: Our study highlighted parents' need for consistent, well communicated, and comprehensive care, which encourages an individualised perinatal palliative care approach to meet parental needs.

Specialized pro-resolving mediators as modulators of immune responses.

Specialized pro-resolving mediators (SPMs) are endogenous small molecules produced mainly from dietary omega-3 polyunsaturated fatty acids by both structural cells and cells of the active and innate immune systems. Specialized pro-resolving mediators have been shown to both limit acute inflammation and promote resolution and return to homeostasis following infection or injury. There is growing evidence that chronic immune disorders are characterized by deficiencies in resolution and SPMs have significant potential as novel therapeutics to prevent and treat chronic inflammation and immune system disorders. This review focuses on important breakthroughs in understanding how SPMs are produced by, and act on, cells of the adaptive immune system, specifically macrophages, B cells and T cells. We also highlight recent evidence demonstrating the potential of SPMs as novel therapeutic agents in topics including immunization, autoimmune disease and transplantation.

All sorts of tests, only one question: an unexpected cause of hypertension.

A 48-year-old woman presented to the Accident and Emergency department with a 4 month history of headaches, nausea and dizziness. She was found to have severe hypertension and hypokalaemia. Extensive investigations did not find any secondary cause for hypertension. The patient was discharged with oral doxazosin therapy which controlled the blood pressure. Before the follow-up appointment at the hypertension clinic, the patient and her husband identified that her headaches coincided with liquorice tea consumption of up to three cups per day. This information was not obtained in the clinical assessment. The patient is now headache and medication free after cessation of liquorice tea. Liquorice ingestion is often a forgotten reversible cause of hypertension. A good history is key to this diagnosis.

Use of pantothenate as a metabolic switch increases the genetic stability of farnesene producing Saccharomyces cerevisiae.

We observed that removing pantothenate (vitamin B5), a precursor to co-enzyme A, from the growth medium of Saccharomyces cerevisiae engineered to produce ß-farnesene reduced the strain׳s farnesene flux by 70%, but increased its viability, growth rate and biomass yield. Conversely, the growth rate and biomass yield of wild-type yeast were reduced. Cultivation in media lacking pantothenate eliminates the growth advantage of low-producing mutants, leading to improved production upon scale-up to lab-scale bioreactor testing. An omics investigation revealed that when exogenous pantothenate levels are limited, acyl-CoA metabolites decrease, ß-oxidation decreases from unexpectedly high levels in the farnesene producer, and sterol and fatty acid synthesis likely limits the growth rate of the wild-type strain. Thus pantothenate supplementation can be utilized as a "metabolic switch" for tuning the synthesis rates of molecules relying on CoA intermediates and aid the economic scale-up of strains producing acyl-CoA derived molecules to manufacturing facilities.

Neuropeptide Y family receptors traffic via the Bardet-Biedl syndrome pathway to signal in neuronal primary cilia.

Human monogenic obesity syndromes, including Bardet-Biedl syndrome (BBS), implicate neuronal primary cilia in regulation of energy homeostasis. Cilia in hypothalamic neurons have been hypothesized to sense and regulate systemic energy status, but the molecular mechanism of this signaling remains unknown. Here, we report a comprehensive localization screen of 42 G-protein-coupled receptors (GPCR) revealing seven ciliary GPCRs, including the neuropeptide Y (NPY) receptors NPY2R and NPY5R. We show that mice modeling BBS disease or obese tubby mice fail to localize NPY2R to cilia in the hypothalamus and that BBS mutant mice fail to activate c-fos or decrease food intake in response to the NPY2R ligand PYY3-36. We find that cells with ciliary NPY2R show augmented PYY3-36-dependent cAMP signaling. Our data demonstrate that ciliary targeting of NPY receptors is important for controlling energy balance in mammals, revealing a physiologically defined ligand-receptor pathway signaling within neuronal cilia.

Supplementation of nicotinic acid with NAMPT inhibitors results in loss of in vivo efficacy in NAPRT1-deficient tumor models.

Nicotinamide adenine dinucleotide (NAD) is a metabolite essential for cell survival and generated de novo from tryptophan or recycled from nicotinamide (NAM) through the nicotinamide phosphoribosyltransferase (NAMPT)-dependent salvage pathway. Alternatively, nicotinic acid (NA) is metabolized to NAD through the nicotinic acid phosphoribosyltransferase domain containing 1 (NAPRT1)-dependent salvage pathway. Tumor cells are more reliant on the NAMPT salvage pathway making this enzyme an attractive therapeutic target. Moreover, the therapeutic index of NAMPT inhibitors may be increased by in NAPRT-deficient tumors by NA supplementation as normal tissues may regenerate NAD through NAPRT1. To confirm the latter, we tested novel NAMPT inhibitors, GNE-617 and GNE-618, in cell culture- and patient-derived tumor models. While NA did not protect NAPRT1-deficient tumor cell lines from NAMPT inhibition in vitro, it rescued efficacy of GNE-617 and GNE-618 in cell culture- and patient-derived tumor xenografts in vivo. NA co-treatment increased NAD and NAM levels in NAPRT1-deficient tumors to levels that sustained growth in vivo. Furthermore, NAM co-administration with GNE-617 led to increased tumor NAD levels and rescued in vivo efficacy as well. Importantly, tumor xenografts remained NAPRT1-deficient in the presence of NA, indicating that the NAPRT1-dependent pathway is not reactivated. Protection of NAPRT1-deficient tumors in vivo may be due to increased circulating levels of metabolites generated by mouse liver, in response to NA or through competitive reactivation of NAMPT by NAM. Our results have important implications for the development of NAMPT inhibitors when considering NA co-treatment as a rescue strategy.

Heterogeneity in the treatment of moderately severe scalp psoriasis in Scotland - results of a survey of Scottish health professionals.

BACKGROUND: Scalp psoriasis is a chronic recalcitrant condition. An aging literature for topical treatments used in clinical practice and no treatment guidelines means there is no current gold standard for its management in Scotland. There are no Scottish data on the resources and costs of treatment of the scalp psoriasis patient. OBJECTIVE: Conduct a survey of Scottish healthcare professionals to understand how patients are typically managed to support the development of a model estimating the cost-effectiveness of a new treatment for moderately severe scalp psoriasis in Scotland. RESEARCH DESIGN AND METHODS: Experts from primary and secondary care were invited to participate in an interview programme to collect information on the management of scalp psoriasis in Scotland. This was further informed by Scottish prescribing statistics. Simple descriptive statistics were performed. RESULTS: Forty-three healthcare professionals (33 from primary care and ten in secondary care) completed the survey which illuminated national prescribing statistics. While an overall 72% response rate was achieved, representation from five of 14 Health Boards was not available. There was significant variation in stated patient pathways but some common themes. Most patients were treated initially with coal tar preparations and shampoos, then often progressing to topical potent corticosteroids. There was no consensus on the order patients might receive topicals thereafter although if referred for specialist review they would typically have been treated with three topicals in primary care first. Treatment in secondary care comprised application of topicals available in primary care or alternative preparations with nurse assistance to improve compliance. Phototherapy and systemic agents were not given to patients with scalp psoriasis alone. Study limitations are not considered to impact on the study observations. CONCLUSIONS: There was a large variety in first-, second- and third-line agents in primary care in scalp psoriasis although our interview programme and prescribing data confirmed which treatments were most frequently prescribed. Treatment heterogeneity reflects the limitations in current therapies, paucity of evidence-based effectiveness data and lack of clinical guidelines. Experts agreed 'current standard practice' in Scotland was best described as an average across five plausible treatment pathways.