Addressing the dauntingness of formulation: The value of considering empathy as "grasping".

Aims And Objectives: To explore the value of using Karl Jaspers' lived experience concept of 'grasping' in remediating the reported dauntingness of formulation.

Conclusions: Formulation can be construed as both the process and explication of understanding why a patient is presenting in a particular way. In an automatic process of abduction, 'feeling into' the mind of the other, hypotheses are posted to consciousness with little mental effort as meaningful connections are grasped.

Why is formulation daunting? A response to Bagster et al.'s 'instructions' for developing skills in formulation.

Objective: To explore the theme identified by Bagster et al. in their selective psychiatric literature review that formulation can appear daunting.

Conclusion: Formulation is understandably daunting, even though it occurs in all human encounters.

Development and evaluation of a nanopore 16S rRNA gene sequencing service for same day targeted treatment of bacterial respiratory infection in the intensive care unit.

Objectives: Assess the feasibility and impact of nanopore-based 16S rRNA gene sequencing (Np16S) service on antibiotic treatment for acute severe pneumonia on the intensive care unit (ICU).

Methods: Speciation and sequencing accuracy of Np16S on isolates with bioinformatics pipeline optimisation, followed by technical evaluation including quality checks and clinical-reporting criteria analysing stored respiratory samples using single-sample flow cells. Pilot service comparing Np16S results with all routine respiratory tests and impact on same-day antimicrobial prescribing.

Functional and regulatory profiling of energy metabolism in fission yeast.

Background: The control of energy metabolism is fundamental for cell growth and function and anomalies in it are implicated in complex diseases and ageing. Metabolism in yeast cells can be manipulated by supplying different carbon sources: yeast grown on glucose rapidly proliferates by fermentation, analogous to tumour cells growing by aerobic glycolysis, whereas on non-fermentable carbon sources metabolism shifts towards respiration.

Results: We screened deletion libraries of fission yeast to identify over 200 genes required for respiratory growth.

AnGeLi: A Tool for the Analysis of Gene Lists from Fission Yeast.

Genome-wide assays and screens typically result in large lists of genes or proteins. Enrichments of functional or other biological properties within such lists can provide valuable insights and testable hypotheses. To systematically detect these enrichments can be challenging and time-consuming, because relevant data to compare against query gene lists are spread over many different sources.

Widespread exon skipping triggers degradation by nuclear RNA surveillance in fission yeast.

Exon skipping is considered a principal mechanism by which eukaryotic cells expand their transcriptome and proteome repertoires, creating different splice variants with distinct cellular functions. Here we analyze RNA-seq data from 116 transcriptomes in fission yeast (Schizosaccharomyces pombe), covering multiple physiological conditions as well as transcriptional and RNA processing mutants. We applied brute-force algorithms to detect all possible exon-skipping events, which were widespread but rare compared to normal splicing events.

LaSSO, a strategy for genome-wide mapping of intronic lariats and branch points using RNA-seq.

Both canonical and alternative splicing of RNAs are governed by intronic sequence elements and produce transient lariat structures fastened by branch points within introns. To map precisely the location of branch points on a genomic scale, we developed LaSSO (Lariat Sequence Site Origin), a data-driven algorithm which utilizes RNA-seq data. Using fission yeast cells lacking the debranching enzyme Dbr1, LaSSO not only accurately identified canonical splicing events, but also pinpointed novel, but rare, exon-skipping events, which may reflect aberrantly spliced transcripts.

Revisiting formulation: part 2. The task of addressing the concept of the unique individual. Remediating problems with formulation.

Objective: The purpose of this paper is to review the theoretical basis of addressing the concept of the unique individual, one of the tasks prescribed in the Royal Australian and New Zealand College of Psychiatrists (RANZCP) Formulation guidelines for candidates, and to propose a rational basis for remediation of the problems that many candidates and other professionals have with formulation.

Conclusion: The difficulty that RANZCP candidates and other mental health professionals have in producing a completely integrated account of an individual is multi-determined, but is partly explainable on theoretical grounds. Understanding why this task (and other tasks of formulation) is problematic requires knowledge of its intellectual history, its rationale, the tools of reasoning that it requires and the nature of the challenges that it can pose to individuals.

Revisiting formulation: part 1. The tasks of formulation: their rationale and philosophic basis.

Objective: This paper notes the continuing problems that Royal Australian and New Zealand College of Psychiatry (RANZCP) candidates and other professionals have with the task of formulation. It re-establishes this as a problematic to be understood and reviews its intellectual history, its rationale, the tools of reasoning that it requires and the nature of the challenges that it can pose to individuals. Its premise is that an understanding of the theoretical basis of formulation is required prior to application of pedagogical tools in teaching and remediation.

1-substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones endowed with dual DNA-PK/PI3-K inhibitory activity.

Analogues of (dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441), a potent inhibitor of DNA-dependent protein kinase (DNA-PK; IC50 = 42 ± 2 nM), have been synthesized in which water-solubilizing groups [NHCO(CH₂)nNR¹R², where n = 1 or 2 and the moiety R¹R²N was derived from a library of primary and secondary amines, e.g., morpholine] were placed at the 1-position.

Chemosensitization of cancer cells by KU-0060648, a dual inhibitor of DNA-PK and PI-3K.

DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by topoisomerase II poisons. Nonhomologous end joining (NHEJ) is a major pathway for DSB repair and requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK catalytic subunit (DNA-PKcs) is structurally similar to PI-3K, which promotes cell survival and proliferation and is upregulated in many cancers.

Targeting the DNA double strand break repair machinery in prostate cancer.

Regardless of the achievable remissions with first line hormone therapy in patients with prostate cancer (CaP), the disease escapes the hormone dependent stage to a more aggressive status where chemotherapy is the only effective treatment and no treatment is curative. This makes it very important to identify new targets that can improve the outcome of treatment. ATM and DNA-PK are the two kinases responsible for signalling and repairing double strand breaks (DSB).

p21(WAF1) is component of a positive feedback loop that maintains the p53 transcriptional program.

The regulation of p53 activity through the MDM2 negative feedback loop is driven in part by an extrinsic ATM-pulse that maintains p53 oscillations in response to DNA damage. We report here that the p53 pathway has evolved an intrinsic positive feedback loop that is maintained by the p53-inducible gene product p21(WAF1). p21-null cancer cells have defects in p53 protein turnover, reductions in MDM2-mediated degradation of p53, and reduced DNA damage-induced ubiquitination of p53.

DNA-dependent protein kinase (DNA-PK) inhibitors. Synthesis and biological activity of quinolin-4-one and pyridopyrimidin-4-one surrogates for the chromen-4-one chemotype.

Following the discovery of dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441) ( Leahy , J. J. J.

Prospective quality-of-life monitoring of simultaneous pancreas and kidney transplant recipients using the 36-item short form health survey.

Background: Few risk factors for quality-of-life outcomes of simultaneous pancreas and kidney transplant recipients are known because of a paucity of data from prospective studies.

Study Design: Pretransplant assessment and prospective 3-year follow-up.

Setting & Participants: Consecutive potential recipients at a university teaching hospital assessed by Liaison Psychiatry.

AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity.

The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, cell survival, and autophagy. Allosteric inhibitors of mTORC1, such as rapamycin, have been extensively used to study tumor cell growth, proliferation, and autophagy but have shown only limited clinical utility. Here, we describe AZD8055, a novel ATP-competitive inhibitor of mTOR kinase activity, with an IC50 of 0.

Which factors predict the persistence of DSM-IV depression, anxiety, and somatoform disorders in the medically ill three months post hospital discharge?

Objective: This study sought to assess the persistence of DSM-IV depression, anxiety, and somatoform disorders in a sample of 206 medical patients 3 months after hospital discharge and to examine which baseline factors predicted the persistence of disorder.

Methods: Patients were interviewed using the Monash Interview for Liaison Psychiatry (a structured psychiatric interview for the medically ill) during admission and again at 3 months post discharge. Scales completed during admission elicited sociodemographic data, psychiatric history, mental and physical functioning, illness behavior, coping modes, and number of close relationships.

Poly(ADP-Ribose) polymerase-1 and DNA-dependent protein kinase have equivalent roles in double strand break repair following ionizing radiation.

Purpose: Radiation-induced DNA double strand breaks (DSBs) are predominantly repaired by nonhomologous end joining (NHEJ), involving DNA-dependent protein kinase (DNA-PK). Poly(ADP-ribose) polymerase-1 (PARP-1), well characterized for its role in single strand break repair, may also facilitate DSB repair. We investigated the activation of these enzymes by differing DNA ends and their interaction in the cellular response to ionizing radiation (IR).

Identification and optimisation of novel and selective small molecular weight kinase inhibitors of mTOR.

A pharmacophore mapping approach, derived from previous experience of PIKK family enzymes, was used to identify a hit series of selective inhibitors of the mammalian target of rapamycin (mTOR). Subsequent refinement of the SAR around this hit series based on a tri-substituted triazine scaffold has led to the discovery of potent and selective inhibitors of mTOR.

Translational reprogramming following UVB irradiation is mediated by DNA-PKcs and allows selective recruitment to the polysomes of mRNAs encoding DNA repair enzymes.

UVB-induced lesions in mammalian cellular DNA can, through the process of mutagenesis, lead to carcinogenesis. However, eukaryotic cells have evolved complex mechanisms of genomic surveillance and DNA damage repair to counteract the effects of UVB radiation. We show that following UVB DNA damage, there is an overall inhibition of protein synthesis and translational reprogramming.

Poly(ADP-ribose) polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin.

Germ-line heterozygosity of the BRCA2 gene in women predisposes to breast and ovarian cancers. Successful therapies targeted specifically at these neoplasms have thus far remained elusive. Recent studies in mice have shown that inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) targets cells lacking Brca2 and xenografts derived from BRCA2-deficient ES cells or Chinese hamster ovary cells.

From consultation-liaison psychiatry to integrated care for multiple and complex needs.

The aim of the present study was to review the ways in which contemporary medicine addresses physical/psychiatric multimorbidity, to review the underlying concepts and methodologies used, and to propose a novel approach that may help consultation-liaison psychiatry (CLP) position itself better in the health-care field. A Medline search of the terms 'consultation-liaison psychiatry', 'integrated care', 'quality assurance' and 'qualitative methodology', was complemented by study of the literature on complexity theory and by discussions with colleagues in both the health science and sociology fields. There is a growing realization that presentation with multimorbidity of both physical and psychiatric disorders is the norm.

4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1.

Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose a novel series of substituted 4-benzyl-2 H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 and PARP-2. Optimized compounds from the series also demonstrate good pharmacokinetic profiles, oral bioavailability, and activity in vivo in an SW620 colorectal cancer xenograft model.

8-Biarylchromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK).

The synthesis and biological evaluation of libraries of 8-biarylchromen-4-ones enabled the elucidation of structure-activity relationships for inhibition of the DNA-dependent protein kinase (DNA-PK), with 8-(3-(thiophen-2-yl)phenyl)chromen-4-one and 8-(3-(thiophen-3-yl)phenyl)chromen-4-one being especially potent inhibitors.

What do general practitioners think depression is? A taxonomy of distress and depression for general practice.

Objective: To create a taxonomy of distress and depression for use in primary care, that mirrors the thinking and practice of experienced general practitioners.

Design: Qualitative study, using an ethnomethodological approach, with observation of videotaped routine GP-patient consultations and in-depth interviews with GPs.

Setting And Participants: The study was conducted in metropolitan Melbourne in 2005.