Cold, clumpy accretion onto an active supermassive black hole.

Supermassive black holes in galaxy centres can grow by the accretion of gas, liberating energy that might regulate star formation on galaxy-wide scales. The nature of the gaseous fuel reservoirs that power black hole growth is nevertheless largely unconstrained by observations, and is instead routinely simplified as a smooth, spherical inflow of very hot gas. Recent theory and simulations instead predict that accretion can be dominated by a stochastic, clumpy distribution of very cold molecular clouds--a departure from the 'hot mode' accretion model--although unambiguous observational support for this prediction remains elusive. Here we report observations that reveal a cold, clumpy accretion flow towards a supermassive black hole fuel reservoir in the nucleus of the Abell 2597 Brightest Cluster Galaxy (BCG), a nearby (redshift z = 0.0821) giant elliptical galaxy surrounded by a dense halo of hot plasma. Under the right conditions, thermal instabilities produce a rain of cold clouds that fall towards the galaxy's centre, sustaining star formation amid a kiloparsec-scale molecular nebula that is found at its core. The observations show that these cold clouds also fuel black hole accretion, revealing 'shadows' cast by the molecular clouds as they move inward at about 300 kilometres per second towards the active supermassive black hole, which serves as a bright backlight. Corroborating evidence from prior observations of warmer atomic gas at extremely high spatial resolution, along with simple arguments based on geometry and probability, indicate that these clouds are within the innermost hundred parsecs of the black hole, and falling closer towards it.

Enhanced rapid review of the applicability of ultrasound in the assessment of sucking, swallowing and laryngeal function in the paediatric population.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has renewed interest in the use of ultrasound (US) amongst dysphagia-trained clinicians working with infants and children. US is a portable, minimally intrusive tool which carries reduced risk of aerosol-generation provoked by other instrumental swallowing assessment tools such as fibreoptic endoscopic evaluation of swallowing (FEES). For this reason, US could be a valuable addition to the dysphagia assessment toolkit. A recently published rapid review of US evidence for the assessment of swallowing and laryngeal function in the adult population provided a framework for this neonatal and paediatric review. AIMS: This enhanced rapid review aimed to establish the applicability of US as an instrumental assessment tool for sucking, swallowing and laryngeal function in the neonatal and paediatric populations. METHODS & PROCEDURES: A rapid review of six electronic databases was conducted to identify articles using US to assess sucking, swallowing or laryngeal function in the selected populations, compared with varied reference tests. Abstract screening was completed according to pre-defined inclusion/exclusion criteria with 10% of articles assessed by a second screener. Data was extracted from the included studies using a pre-developed form. A modified QUADAS-2 tool was used to assess study quality. Results from the included studies were summarised and grouped into sucking, swallowing and laryngeal function data. OUTCOMES & RESULTS: Twelve studies using US in the assessment of swallowing and/or laryngeal function met inclusion criteria. No studies using US for assessment of sucking met the inclusion criteria. All were peer-reviewed, primary studies across a range of clinical populations and with a wide geographical spread. Five studies had an overall low risk of bias. Seven studies had at least one domain where risk of bias was judged as high. All studies had high applicability. The two studies assessing swallowing differed in terms of aims and use of US. The studies assessing laryngeal function predominately investigated vocal fold movement and laryngeal pathology. Sensitivity and specificity data were provided or calculated from raw data for nine of the laryngeal function studies (respective ranges of 75%-100% and 80%-100%). CONCLUSIONS & IMPLICATIONS: Emerging evidence exists to support the use of US as adjunct to clinical assessment of swallowing and laryngeal function in the neonatal and paediatric population. A paucity of evidence to support use of US in the assessment of sucking exists. Further research is needed to establish evidence-based assessment and analysis protocols as well as development of paediatric data.

Design and optimization of (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones as potent PLK4 inhibitors with oral antitumor efficacy.

Previous efforts from our laboratory demonstrated that (E)-3-((3-(E)-vinylaryl)-1H-indazol-6-yl)methylene)-indolin-2-ones are potent PLK4 inhibitors with in vivo anticancer efficacy upon IP dosing. As part of a continued effort to develop selective and orally efficacious inhibitors, we examined variations on this theme wherein 'directly-linked' aromatics, pendant from the indazole core, replace the arylvinyl moiety. Herein, we describe the design and optimization of this series which was ultimately superseded by (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones. The latter compounds are potent and selective inhibitors of PLK4 with oral exposure in rodents and in vivo anticancer activity. Compound 13b, in particular, has a bioavailability of 22% and achieved a 96% tumor growth inhibition in an MDA-MB-468 xenograft study.

Discovery of inhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)-acetamides and carboxamides.

TTK kinase was identified by in-house siRNA screen and pursued as a tractable, novel target for cancer treatment. A screening campaign and systematic optimization, supported by computer modeling led to an indazole core with key sulfamoylphenyl and acetamido moieties at positions 3 and 5, respectively, establishing a novel chemical class culminating in identification of 72 (CFI-400936). This potent inhibitor of TTK (IC50=3.6nM) demonstrated good activity in cell based assay and selectivity against a panel of human kinases. A co-complex TTK X-ray crystal structure and results of a xenograft study with TTK inhibitors from this class are described.

Transitions in tracheostomy care: from childhood to adulthood.

PURPOSE OF REVIEW: The purpose of this review is to explore the evidence around children and young people who require a tracheostomy and transition into adult services, reflecting on the challenges and considerations for clinical practice as these needs increase. RECENT FINDINGS: There are a lack of data on the incidence and prevalence of children and young people with a tracheostomy transitioning to adult services for ongoing care. There are significant variations in care needs, technology and previous experiences that demand more than a simple handover process. Examples of service models that support the transition of care exist, however these lack specificity for children and young people with a tracheostomy. SUMMARY: Further exploration of the needs of children and young people requiring airway technology is indicated, particularly considering the short and long-term education, health, and social care needs.

Discovery and characterization of AZD9272 and AZD6538-Two novel mGluR5 negative allosteric modulators selected for clinical development.

AZD9272 and AZD6538 are two novel mGluR5 negative allosteric modulators selected for further clinical development. An initial high-throughput screening revealed leads with promising profiles, which were further optimized by minor, yet indispensable, structural modifications to bring forth these drug candidates. Advantageously, both compounds may be synthesized in as little as one step. Both are highly potent and selective for the human as well as the rat mGluR5 where they interact at the same binding site than MPEP. They are orally available, allow for long interval administration due to a high metabolic stability and long half-lives in rats and permeate the blood brain barrier to a high extent. AZD9272 has progressed into phase I clinical studies.

Socioeconomic differences in recruitment and sickness absence in a large NHS health organisation: a cross-sectional study.

OBJECTIVE: This study investigates the distribution of the workforce of one large National Health Service (NHS) employer in relation to socioeconomic deprivation and how sickness absence rates varied across these levels of deprivation. DESIGN: Share of the working age population that was employed at the NHS organisation mapped by area deprivation. The study used negative binomial regression models to investigate the extent to which wage level, occupational group and area deprivation were associated with sickness absence among employees. SETTING: The study used electronic staff records (2018-2019) of a large NHS organisation in the North West of England. RESULTS: In the most deprived areas, an additional person per 1000 working age population were employed at this NHS organisation compared with the most affluent areas. Employees from the most deprived quintile had 1.41 (95% CI 1.16 to 1.70) times the higher sickness rates than the employees from the least deprived quintile, when adjusting for age and sex. These differences were largely explained by differences in wage levels and occupation groups, with the lowest wage employees having 2.5 (95% CI 1.87 to 3.42) times the sickness absence rate as the highest wage group and the nursing and midwifery employees having 1.8 (95% CI 1.50 to 2.24) times the sickness absence rate as the administrative and clerical group. CONCLUSION: This large NHS organisation employed people disproportionately from deprived areas. They were considerably more likely to experience sickness absence compared with people from affluent areas. This appears to be because they were more likely to be in lower wage employment and employed in nursing and nursing assistant. Workplace health policies need to target these workers, adapting to their needs while enabling improvements in their working conditions, pay and career progression.

Recent advances in non-competitive mGlu5 receptor antagonists and their potential therapeutic applications.

Extensive research into the functions of glutamate and glutamate receptors in the central nervous system (CNS) has shown an essential role of metabotropic glutamate (mGlu) receptors in normal brain functions, but also in neurological and psychiatric disorders. The precise functions of these receptors remain undefined, and progress toward understanding their functions has been hampered by the lack of selective ligands with appropriate pharmacokinetic properties. The Group I mGlu receptor, mGlu5, is well positioned to regulate and fine-tune neuronal excitability and synaptic transmission through its modulation of various signal transduction pathways and interactions with other transmitter systems. Therefore, the mGlu5 receptor may be an important therapeutic target for the treatment of disorders of the central nervous system. The discovery of MPEP 3, a non-competitive mGlu5 receptor antagonist, provided a potent, selective, systemically active tool compound for proof of concept studies in animal models of various disease states. These studies have led to greater understanding of possible therapeutic applications of mGlu5 receptor antagonists in recent years, suggesting their use in a number of disease states, including chronic pain, various psychiatric and neurological disorders, substance abuse and withdrawal, obesity and gastroesophageal reflux disease (GERD). Together, these findings have intensified efforts to find other non-competitive mGlu5 receptor antagonists and have led to the discovery of several second-generation compounds, a few of which are in preclinical evaluations. There have been several recent reviews on mGlu receptor. This article highlights recent efforts on the design, synthesis and development of novel, non-competitive mGlu5 receptor antagonists and studies to understand their in vitro mechanisms of action and in vivo pharmacological profiles. Emphasis is also given to recent advances in the potential therapeutic applications of non-competitive mGlu5 receptor antagonists.

A qualitative study exploring the experiences and views of mothers, health visitors and family support centre workers on the challenges and difficulties of parenting.

Successive policy documents have referred to the need to support parents as an approach to reducing social exclusion, behaviour problems among young people and crime rates. Much of the rhetoric focuses on professional intervention, and there is less attention paid to the views and experiences of parents themselves. The present study explores the experiences and views of mothers, health visitors and family support centre workers who work with parents on the challenges and difficulties of parenting children under the age of 6 years. It provides an appreciation of their views on effective parenting and how parents can be helped to feel more effective in the parenting role. Focus groups, which were exploratory and interactive in form, were conducted across three primary care trusts in Hertfordshire, UK. Three samples were purposively selected in order to examine the range and diversity of experiences and views about parenting, and included the parents of children up to the age of 6 years, health visitors and family support centre workers. The mothers were those waiting to attend a parenting programme, and included first-time mothers and those with more than one child. The health visitors and family support workers had a range of experience in working with parents and children, and included those who were facilitating parenting programmes and those who were not. A number of themes emerged surrounding the challenges and difficulties of parenting and effective parenting, including expectations of others, establishing routines, play, behavioural issues and discipline, empathy, and communication. Similar themes emerged from all groups; however, there were qualitative differences between parents and professionals in the way in which these issues were expressed. Key statements from the parent focus groups have been developed into self-efficacy statements, which will be used as input to the development of a tool to measure the effectiveness of parenting programmes.

The discovery of Polo-like kinase 4 inhibitors: design and optimization of spiro[cyclopropane-1,3'[3H]indol]-2'(1'H).ones as orally bioavailable antitumor agents.

Polo-like kinase 4 (PLK4), a unique member of the polo-like kinase family of serine-threonine kinases, is a master regulator of centriole duplication that is important for maintaining genome integrity. Overexpression of PLK4 is found in several human cancers and is linked with a predisposition to tumorigenesis. Previous efforts to identify potent and efficacious PLK4 inhibitors resulted in the discovery of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones, which are superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones reported herein. Optimization of this new cyclopropane-linked series was based on a computational model of a PLK4 X-ray structure and SAR attained from the analogous alkenelinked series. The racemic cyclopropane-linked compounds showed PLK4 affinity and antiproliferative activity comparable to their alkene-linked congeners with improved hysicochemical, ADME, and pharmacokinetic properties. Positive xenograft results from the MDA-MB-468 human breast cancer xenograft model for compound 18 support the investigation of PLK4 inhibitors as anticancer therapeutics. A PLK4 X-ray co-structure with racemate 18 revealed preferential binding of the 1R,2S enantiomer to the PLK4 kinase domain.

The discovery of Polo-like kinase 4 inhibitors: identification of (1R,2S).2-(3-((E).4-(((cis).2,6-dimethylmorpholino)methyl)styryl). 1H.indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (CFI-400945) as a potent, orally active antitumor agent.

Previous publications from our laboratory have introduced novel inhibitors of Polo-like kinase 4 (PLK4), a mitotic kinase identified as a potential target for cancer therapy. The search for potent and selective PLK4 inhibitors yielded (E)-3-((1Hindazol-6-yl)methylene)indolin-2-ones, which were superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones, e.g., 3. The later scaffold confers improved drug-like properties and incorporates two stereogenic centers. This work reports the discovery of a novel one-pot double SN2 displacement reaction for the stereoselective installation of the desired asymmetric centers and confirms the stereochemistry of the most potent stereoisomer, e.g., 44. Subsequent work keys on the optimization of the oral exposure of nanomolar PLK4 inhibitors with potent cancer cell growth inhibitory activity. A short list of compounds with superior potency and pharmacokinetic properties in rodents and dogs was studied in mouse models of tumor growth. We conclude with the identification of compound 48 (designated CFI-400945) as a novel clinical candidate for cancer therapy.

The Discovery of Orally Bioavailable Tyrosine Threonine Kinase (TTK) Inhibitors: 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides as Anticancer Agents.

The acetamido and carboxamido substituted 3-(1H-indazol-3-yl)benzenesulfonamides are potent TTK inhibitors. However, they display modest ability to attenuate cancer cell growth; their physicochemical properties, and attendant pharmacokinetic parameters, are not drug-like. By eliminating the polar 3-sulfonamide group and grafting a heterocycle at the 4 position of the phenyl ring, potent inhibitors with oral exposure were obtained. An X-ray cocrystal structure and a refined binding model allowed for a structure guided approach. Systematic optimization resulted in novel TTK inhibitors, namely 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides. Compounds incorporating the 3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl bicyclic system were potent (TTK IC50 < 10 nM, HCT116 GI50 < 0.1 µM), displayed low off-target activity (>500×), and microsomal stability (T(1/2) > 30 min). A subset was tested in rodent PK and mouse xenograft models of human cancer. Compound 75 (CFI-401870) recapitulated the phenotype of TTK RNAi, demonstrated in vivo tumor growth inhibition upon oral dosing, and was selected for preclinical evaluation.

The discovery of PLK4 inhibitors: (E)-3-((1H-Indazol-6-yl)methylene)indolin-2-ones as novel antiproliferative agents.

The family of Polo-like kinases is important in the regulation of mitotic progression; this work keys on one member, namely Polo-like kinase 4 (PLK4). PLK4 has been identified as a candidate anticancer target which prompted a search for potent and selective inhibitors of PLK4. The body of the paper describes lead generation and optimization work which yielded nanomolar PLK4 inhibitors. Lead generation began with directed virtual screening, using a ligand-based focused library and a PLK4 homology model. Validated hits were used as starting points for the design and discovery of PLK4 inhibitors of novel structure, namely (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones. Computational models, based on a published X-ray structure (PLK4 kinase domain), were used to understand and optimize the in vitro activity of the series; potent antiproliferative activity was obtained. The kinase selectivity profile and cell cycle analysis of selected inhibitors are described. The results of a xenograft study with an optimized compound 50 (designated CFI-400437) support the potential of these novel PLK4 inhibitors for cancer therapy.

3-(2-pyrrolidin-1-ylethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives as high affinity human 5-HT(1B/1D) ligands.

A series of 3-(2-pyrrolidin-1-ylethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives (2) has been prepared using parallel synthesis techniques, and their structure-activity relationships studied. High affinity human 5-HT(1B/1D) (h5-HT(1B/1D)) ligands have been identified.

(R)-3-(N-methylpyrrolidin-2-ylmethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives as high affinity h5-HT1B/1D ligands.

A series of (R)-3-(N-methylpyrrolidin-2-ylmethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives (2) have been prepared using parallel synthesis, and their structure-activity relationship studied. High affinity human 5-HT(1B/1D) (h5-HT(1B/1D)) ligands have been identified.

Design, synthesis and biological activity of novel dimethyl-[2-[6-substituted-indol-1-yl]-ethyl]-amine as potent, selective, and orally-bioavailable 5-HT(1D) agonists.

A novel series of highly potent human 5-HT(1D) agonists, dimethyl-[2-[6-substituted-indol-1-yl]-ethyl]-amine, was synthesized. Structure-activity relationship (SAR) investigation revealed 4-[1-(2-dimethylamino-ethyl)-1H-indol-6-yl]-tetrahydro-thiopyran-4-ol, 11b (ALX-2732), as a potent (K(i)=2.4 nM) agonist at the human 5-HT(1D) receptor with good selectivity over the other serotonin receptor subtypes. This compound demonstrated favorable in vitro metabolic stability in human and rat liver microsomes and was found to be orally bioavailable in rats (F(po)=51%).