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"Clarke, Paul"
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Stable long-term individual differences in 50-kHz vocalization rate and call subtype prevalence in adult male rats: Comparisons with sucrose preference
Sucrose preference (SP) is a widely used measure of anhedonia in rat models of depression, yet depressed patients do not reliably show an analogous deficit. As an alternative affect-related measure, adult rat ultrasonic vocalizations (USVs) are attracting interest, but it is unclear whether SP and USVs provide independent measures. Here, we have assessed whether SP and USV emission are correlated in the absence of a depressogenic procedure. To this end, 24 male Long-Evans rats were tested daily for 24 days, with alternating SP tests and USV recordings; after a 3-month hiatus, USV emission was re-evaluated for 6 more days. SP was measured in simultaneous two-bottle choice tests, and USVs were recorded in an open field. The main measures were: SP, 50-kHz call rate, and relative prevalence of trill and flat call subtypes. These measures showed temporally-stable individual differences across the initial 24-day testing period, and at the 3-month USV follow-up tests. Correlational analysis revealed no significant relationships between SP and the three main USV measures. Rats differed consistently, not only in their 50-kHz call rates but also in their 50-kHz call profiles (i.e., the relative prevalence of 14 call subtypes); most rats preferentially emitted either trill or flat calls. Several inter-call subtype associations were detected, including a strong negative relationship between the relative prevalence of flat and trill calls. The 50-kHz call rate was correlated with the relative prevalence of only one call subtype (short calls, negative correlation), but was positively correlated with absolute emission rates for almost all subtypes. In conclusion, adult rats exhibited temporally-stable individual differences over weeks (SP) or months (USVs) of testing. This trait-like stability helped to reveal a lack of relationship between SP and the USV-related variables under study, suggesting that these measures may capture different constructs of possible relevance to animal models of depression.
Journal Article
Making policy move : towards a politics of translation and assemblage
\"Responding to increasing interest in the movement of policies between places, sites and settings, this timely book presents a critical alternative to approaches centred on ideas of policy transfer, dissemination or learning. Mixing collectively written chapters with individual case studies of policies and practices, the book provides a powerful and productive introduction to rethinking policy studies through translation. It ends with a commitment to the possibilities of thinking and doing 'policy otherwise'\".--Provided by publisher
Book
Identification of multiple call categories within the rich repertoire of adult rat 50-kHz ultrasonic vocalizations: effects of amphetamine and social context
Rationale
50-kHz ultrasonic vocalizations (USVs) emitted by adult rats are heterogeneous; they occur over a wide frequency range, show varying degrees of frequency modulation, and appear to differ in their behavioral significance. However, they have not been extensively categorized.
Objectives
The main objective of this study was to identify subtypes of 50-kHz USVs emitted by adult rats and to determine how amphetamine (AMPH) or social testing condition affects their relative and absolute production rate and acoustic characteristics. A second objective was to determine the extent of individual differences in call rate, call subtype profile, and acoustic parameters (i.e., duration, bandwidth, and mean peak frequency).
Methods
Adult male Long–Evans rats were administered systemic amphetamine (0.25–2 mg/kg, IP) and tested individually or with a cage mate for 20 min. Call categories were defined based on visual inspection of over 20,000 USV spectrograms. Surgical devocalization was performed on a subset of AMPH-tested rats in order to confirm the authenticity of call subtypes.
Results
Fourteen categories of 50-kHz USVs were recognized. Call subtypes were differentially affected by social context, AMPH dose, and time within session. In contrast, the acoustic characteristics of call subtypes were notably stable. Marked and stable inter-individual differences occurred with respect to overall 50-kHz call rate, acoustic parameters, and call profile.
Conclusions
The present findings, obtained under saline and amphetamine test conditions, provide the first detailed classification of adult rat 50-kHz USVs. Consideration of 50-kHz USV subtypes may advance our understanding of inter-rat communication and affective state.
Journal Article
Schmidt happens
\"My wife had just given birth to a baby that wasn't mine. My son had just walked out on his bride-to-be on the eve of their wedding. And my old dear was making threats of revenge against me for allowing her to choke on the olive from her breakfast Martini. Throw into the mix three infant sons who were banned from every public park and children's play centre in the city; a father who was working with dodgy Russian business interests to put himself in the Taoiseach's office; and a daughter who was about to do something truly shocking - even by her standards. But then, one day, totally out of the blue, I received a very unexpected phone call ... And let's just say that Schmidt got real.\"--Back cover.
Book
Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer
Cyclin-dependent kinases (CDKs) contribute to the cancer hallmarks of uncontrolled proliferation and increased survival. As a result, over the last two decades substantial efforts have been directed towards identification and development of pharmaceutical CDK inhibitors. Insights into the biological consequences of CDK inhibition in specific tumor types have led to the successful development of CDK4/6 inhibitors as treatments for certain types of breast cancer. More recently, a new generation of pharmaceutical inhibitors of CDK enzymes that regulate the transcription of key oncogenic and pro-survival proteins, including CDK9, have entered clinical development. Here, we provide the first disclosure of the chemical structure of fadraciclib (CYC065), a CDK inhibitor and clinical candidate designed by further optimization from the aminopurine scaffold of seliciclib. We describe its synthesis and mechanistic characterization. Fadraciclib exhibits improved potency and selectivity for CDK2 and CDK9 compared to seliciclib, and also displays high selectivity across the kinome. We show that the mechanism of action of fadraciclib is consistent with potent inhibition of CDK9-mediated transcription, decreasing levels of RNA polymerase II C-terminal domain serine 2 phosphorylation, the pro-survival protein Myeloid Cell Leukemia 1 (MCL1) and MYC oncoprotein, and inducing rapid apoptosis in cancer cells. This cellular potency and mechanism of action translate to promising anti-cancer activity in human leukemia mouse xenograft models. Studies of leukemia cell line sensitivity identify mixed lineage leukemia ( MLL ) gene status and the level of B-cell lymphoma 2 (BCL2) family proteins as potential markers for selection of patients with greater sensitivity to fadraciclib. We show that the combination of fadraciclib with BCL2 inhibitors, including venetoclax, is synergistic in leukemic cell models, as predicted from simultaneous inhibition of MCL1 and BCL2 pro-survival pathways. Fadraciclib preclinical pharmacology data support its therapeutic potential in CDK9- or CDK2-dependent cancers and as a rational combination with BCL2 inhibitors in hematological malignancies. Fadraciclib is currently in Phase 1 clinical studies in patients with advanced solid tumors ( NCT02552953 ) and also in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) ( NCT03739554 ) and relapsed refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) ( NCT04017546 ).
Journal Article
Affluence, austerity and electoral change in Britain
\"Investigates the political economy of party support for British political parties since Tony Blair led New Labour to power in 1997. Using valence politics models of electoral choice and marshalling an unprecedented wealth of survey data collected in the British Election Study's monthly Continuous Monitoring Surveys, the authors trace forces affecting support for New Labour during its 13 years in office\" --Provided by publisher.
Book
Discovery of small molecule cancer drugs: Successes, challenges and opportunities
The discovery and development of small molecule cancer drugs has been revolutionised over the last decade. Most notably, we have moved from a one-size-fits-all approach that emphasized cytotoxic chemotherapy to a personalised medicine strategy that focuses on the discovery and development of molecularly targeted drugs that exploit the particular genetic addictions, dependencies and vulnerabilities of cancer cells. These exploitable characteristics are increasingly being revealed by our expanding understanding of the abnormal biology and genetics of cancer cells, accelerated by cancer genome sequencing and other high-throughput genome-wide campaigns, including functional screens using RNA interference. In this review we provide an overview of contemporary approaches to the discovery of small molecule cancer drugs, highlighting successes, current challenges and future opportunities. We focus in particular on four key steps: Target validation and selection; chemical hit and lead generation; lead optimization to identify a clinical drug candidate; and finally hypothesis-driven, biomarker-led clinical trials. Although all of these steps are critical, we view target validation and selection and the conduct of biology-directed clinical trials as especially important areas upon which to focus to speed progress from gene to drug and to reduce the unacceptably high attrition rate during clinical development. Other challenges include expanding the envelope of druggability for less tractable targets, understanding and overcoming drug resistance, and designing intelligent and effective drug combinations. We discuss not only scientific and technical challenges, but also the assessment and mitigation of risks as well as organizational, cultural and funding problems for cancer drug discovery and development, together with solutions to overcome the ‘Valley of Death’ between basic research and approved medicines. We envisage a future in which addressing these challenges will enhance our rapid progress towards truly personalised medicine for cancer patients.
► Here we review small molecule cancer drug discovery and development. ► We focus on Target selection, hit identification, lead optimization and clinical trials. ► A particular emphasis of this article is personalized medicine.
Journal Article
Effects of nicotine, nornicotine and cotinine, alone or in combination, on locomotor activity and ultrasonic vocalization emission in adult rats
RationaleThe behavioral effects of the nicotine metabolites nornicotine and cotinine have not been investigated extensively.ObjectivesTo evaluate the effects of nicotine, cotinine, and nornicotine, given alone or in combination, on locomotor activity and emission of ultrasonic vocalizations in male adult rats.MethodsRats were first given home cage nicotine injections to make them tolerant to the drug’s locomotor depressant effects. On subsequent days, locomotor activity (LMA) and ultrasonic vocalizations were recorded in an open field, for 60 min after challenge injection, using repeated measures designs. In single-drug experiments, subjects were tested with nicotine 0.05–0.4 mg/kg, cotinine 0.03–3 mg/kg, or nornicotine 0.1–10 mg/kg. In drug-combination experiments, saline or nicotine 0.2 mg/kg challenge was preceded by cotinine (0, 0.3, 3 mg/kg) or nornicotine (0, 0.1, 0.3, 1, 3 mg/kg) injection.ResultsHigh doses of nornicotine increased LMA and blunted the locomotor stimulant effect of nicotine. Less consistently, nicotine and high doses of nornicotine decreased the 50-kHz call rate, with no clear evidence of a nornicotine × nicotine interaction. Cotinine, given alone or before nicotine injection, altered neither LMA nor the call rate. No drug altered the relative prevalence of flat vs. trill 50-kHz call subtypes, except that the highest dose of nornicotine promoted flat calls over trills. No drug evoked 22-kHz calls.ConclusionNornicotine can exert an acute anti-nicotine effect in vivo, as previously reported in vitro. The finding that nicotine did not detectably alter the 50-kHz call profile appears consistent with this drug’s mild subjective effects in human subjects.
Journal Article