Single-copy Snail upregulation causes partial epithelial-mesenchymal transition in colon cancer cells.

BACKGROUND: Epithelial-mesenchymal transition (EMT) is an embryonic programme implicated in cancer stem cells, metastasis and therapeutic resistance. Its role in cancer progression remains controversial because the transition can be partial or complete in different models and contexts. METHODS: Using human colon cancer DLD-1 cells, we engineered a cell line with a single-copy of Snail that was doxycycline-inducible and compared it to existing EMT models in DLD-1. The effect of Snail upregulation was characterised functionally, morphologically, and by transcriptional profiling and protein expression. RESULTS: Induction with doxycycline increased Snail expression to a level similar to that observed in cancer cell lines spontaneously expressing Snail and results in partial EMT. In comparison, higher levels of overexpression arising from introduction of episomal-Snail, results in complete EMT. DLD-1 cells with partial EMT show chemoresistance in vitro, increased tumour growth in vivo and decreased apoptosis. CONCLUSIONS: These findings highlight that the amount of bioavailable Snail can dictate phenotypic outcome and that partial EMT may be a preferred outcome of models operating within a natural range of Snail overexpression.

A Diffusion-like Process Accommodates New Crypts During Clonal Expansion in Human Colonic Epithelium.

BACKGROUND & AIMS: Colorectal cancer (CRC) is thought to arise when the cumulative mutational burden within colonic crypts exceeds a certain threshold that leads to clonal expansion and ultimately neoplastic transformation. Therefore, quantification of the fixation and subsequent expansion of somatic mutations in normal epithelium is key to understanding colorectal cancer initiation. The aim of the present study was to determine how advantaged expansions can be accommodated in the human colon. METHODS: Immunohistochemistry was used to visualize loss of the cancer driver KDM6A in formalin-fixed paraffin-embedded (FFPE) normal human colonic epithelium. Combining microscopy with neural network-based image analysis, we determined the frequencies of KDM6A-mutant crypts and fission/fusion intermediates as well as the spatial distribution of clones. Mathematical modeling then defined the dynamics of their fixation and expansion. RESULTS: Interpretation of the age-related behavior of KDM6A-negative clones revealed significant competitive advantage in intracrypt dynamics as well as a 5-fold increase in crypt fission rate. This was not accompanied by an increase in crypt fusion. Mathematical modeling of crypt spacing identifies evidence for a crypt diffusion process. We define the threshold fission rate at which diffusion fails to accommodate new crypts, which can be exceeded by KRAS activating mutations. CONCLUSIONS: Advantaged gene mutations in KDM6A expand dramatically by crypt fission but not fusion. The crypt diffusion process enables accommodation of the additional crypts up to a threshold value, beyond which polyp growth may occur. The fission rate associated with KRAS mutations offers a potential explanation for KRAS-initiated polyps.

The impact of recall timing on the preservation of eyewitness memory.

Two studies investigated the impact of recall timing on eyewitness memory. In Study 1, participants viewed a crime video and then completed the Self-Administered Interview (SAI©) either immediately, after a 24-h delay, after a 1-week delay, or not at all. All participants completed a final recall questionnaire 2 weeks after they had viewed the stimulus video. Study 2 aimed to determine how long the beneficial impact of the SAI© on witnesses' long-term memory lasts. Participants watched a crime video and then either completed the SAI© or did not engage in an immediate recall attempt. Participants then completed a final recall questionnaire after a delay of 24 h, 1 week, 2 weeks, or 1 month. The results indicated that initial recall should be completed within 24 h of an incident and that under these conditions, the beneficial impact of early recall on long-term memory endures for at least 1 month.

Characteristics and re-offending outcomes of 'limiting-term' forensic patients found unfit to stand trial in New South Wales, Australia.

There are little published data on the characteristics or outcomes of offenders found unfit to stand trial who receive a 'qualified finding of guilt' in a Special Hearing in New South Wales (NSW) and are detained for a 'limiting term' (LT) under the supervision of the NSW Mental Health Review Tribunal (MHRT). We examined NSW MHRT records linked to re-offending data, to report on the characteristics and outcomes of 69 LT patients in a cohort spanning two decades. The most common diagnoses were schizophrenia (54%) and intellectual disability (33%). Patients were detained on average for 4.2 years, which is slightly shorter than the average maximum term imposed. Of the 55 people for whom criminal record data were available, 9.1% were charged with an offence during the first year post-release and 60% overall were charged for at least one post-release offence during a follow-up period ranging from 4.7 to 11.1 years.

Heavy Metals Make a Chain: A Catenated Bismuth Compound.

Catenation is common for the light main-group elements whereas it is rare for the heavy elements. Herein, we report the first example of a neutral molecule containing a Bi4 chain. It is prepared in a one-step reaction between bismuth trichloride and bis(diisopropylphosphino)amine in methanol suspension. The same reaction carried out in dichloromethane gives quite different products. All products have been characterized spectroscopically and using single-crystal X-ray analysis.

Hydrogenolysis of Dinuclear PCNR Ligated PdII µ-Hydroxides and Their Mononuclear PdII Hydroxide Analogues.

The hydrogenolysis of mono- and dinuclear PdII hydroxides was investigated both experimentally and computationally. It was found that the dinuclear µ-hydroxide complexes {[(PCNR )Pd]2 (µ-OH)}(OTf) (PCNH =1-[3-[(di-tert-butylphosphino)methyl]phenyl]-1H-pyrazole; PCNMe =1-[3-[(di-tert-butylphosphino)methyl]phenyl]-5-methyl-1H-pyrazole) react with H2 to form the analogous dinuclear hydride species {[(PCNR )Pd]2 (µ-H)}(OTf). The dinuclear µ-hydride complexes were fully characterized, and are rare examples of structurally characterized unsupported singly bridged µ-H PdII dimers. The {[(PCNMe )Pd]2 (µ-OH)}(OTf) hydrogenolysis mechanism was investigated through experiments and computations. The hydrogenolysis of the mononuclear complex (PCNH )Pd-OH resulted in a mixed ligand dinuclear species [(PCNH )Pd](µ-H)[(PCC)Pd] (PCC=a dianionic version of PCNH bound through phosphorus P, aryl C, and pyrazole C atoms) generated from initial ligand "rollover" C-H activation. Further exposure to H2 yields the bisphosphine Pd0 complex Pd[(H)PCNH ]2 . When the ligand was protected at the pyrazole 5-position in the (PCNMe )Pd-OH complex, no hydride formed under the same conditions; the reaction proceeded directly to the bisphosphine Pd0 complex Pd[(H)PCNMe ]2 . Reaction mechanisms for the hydrogenolysis of the monomeric and dimeric hydroxides are proposed.

Intestinal label-retaining cells are secretory precursors expressing Lgr5.

The rapid cell turnover of the intestinal epithelium is achieved from small numbers of stem cells located in the base of glandular crypts. These stem cells have been variously described as rapidly cycling or quiescent. A functional arrangement of stem cells that reconciles both of these behaviours has so far been difficult to obtain. Alternative explanations for quiescent cells have been that they act as a parallel or reserve population that replace rapidly cycling stem cells periodically or after injury; their exact nature remains unknown. Here we show mouse intestinal quiescent cells to be precursors that are committed to mature into differentiated secretory cells of the Paneth and enteroendocrine lineage. However, crucially we find that after intestinal injury they are capable of extensive proliferation and can give rise to clones comprising the main epithelial cell types. Thus, quiescent cells can be recalled to the stem-cell state. These findings establish quiescent cells as an effective clonogenic reserve and provide a motivation for investigating their role in pathologies such as colorectal cancers and intestinal inflammation.

The effects of perceived memory ability on memory conformity for an event.

The present study investigated the impact of false feedback about individual memory performance relative to a co-witness on susceptibility to misinformation. Pairs of participants (n = 130; 65 pairs) completed a visual memory test and received false feedback on their performance indicating that the memory ability of one participant in the pair was stronger relative to the other participant. The participants then viewed a crime video (either the same video or one slightly different to their partner) and discussed their memories for this video with their co-witness. Participants completed a semi-cued recall task and a recognition test about the video. False memory feedback indicating lower relative performance was associated with significant increases in sensitivity to misinformation. The results are discussed in reference to the potential contributions that co-witnesses' perceptions of both their partner's reliability and their own reliability have on event memory.

Synthesis and Characterization of Structurally Diverse Alkaline-Earth Salen Compounds for Subterranean Fluid Flow Tracking.

A family of magnesium and calcium salen-derivatives was synthesized and characterized for use as subterranean fluid flow monitors. For the Mg complexes, di- n-butyl magnesium ([Mg(Bu n)2]) was reacted with N, N'-ethylene bis(salicylideneimine) (H2-salen), N, N'-bis(salicylidene)-1,2-phenylenediamine (H2-saloPh), N, N'-bis(3,5-di- t-butylsalicylidene)-ethylenediamine (H2-salo-Bu t), or N, N'-bis(3,5-di- t-butylsalicylidene)-1,2-phenylenediamine (H2-saloPh-Bu t), and the products were identified by single-crystal X-ray diffraction as [(κ3-(O,N,N'),µ-(O')saloPh)(µ-(O),(κ2-(N,N'),µ-(O')saloPh)2(µ-(O),κ3-(N,N',O')saloPh')Mg4]·2tol (1·2tol; saloPh' = an alkyl-modified saloPh derivative generated in situ), [(κ4-(O,N,N',O')saloPh)Mg(py)2]·py (2·py), [(κ4-(O,N,N',O')salo-Bu t)Mg(py)2] (3), [(κ4-(O,N,N',O')saloPh-Bu t)Mg(py)2]·tol (4·tol), and [(κ3-(O,N,N'),µ-(O')saloPh-Bu t)Mg]2 (5), where tol = toluene; py = pyridine. For the Ca species, a calcium amide was independently reacted with H2-salo-Bu t and H2-saloPh-Bu t to generate the crystallographcially characterized compounds: [(κ4-(O,N,N',O')salo-Bu t)Ca(py)3] (6), [(κ4-(O,N,N',O')saloPh-Bu t)Ca(py)3]·py (7·py). The bulk powders of these compounds were further characterized by a number of analytical tools, where 2-7 were found to be distinguishable by Fourier transform infrared and resonance Raman spectroscopies. Structural properties obtained from quantum calculations of gas-phase analogues are in good agreement with the single-crystal results. The potential utility of these compounds as taggants for monitoring subterranean fluid flows was demonstrated through a series of experiments to evaluate their stability to high temperature and pressure, interaction with mineral surfaces, and elution behavior from a loaded proppant pack.

Validation studies in forensic odontology - Part 1: Accuracy of radiographic matching.

As part of a series of studies aimed at validating techniques in forensic odontology, this study aimed to validate the accuracy of ante-mortem (AM)/postmortem (PM) radiographic matching by dentists and forensic odontologists. This study used a web-based interface with 50 pairs of AM and PM radiographs from real casework, at varying degrees of difficulty. Participants were shown both radiographs as a pair and initially asked to decide if they represented the same individual using a yes/no binary choice forced-decision. Participants were asked to assess their level of confidence in their decision, and to make a conclusion using one of the ABFO (American Board of Forensic Odontology), INTERPOL (International Criminal Police Organisation) and DVISys™ (DVI System International, Plass Data Software) identification scale degrees. The mean false-positive rate using the binary choice scale was 12%. Overall accuracy was 89% using this model, however, 13% of participants scored below 80%. Only 25% of participants accurately answered yes or no >90% of the time, with no individual making the correct yes/no decision for all 50 pairs of radiographs. Non-odontologists (lay participants) scored poorly, with a mean accuracy of only 60%. Use of the graded ABFO, DVISYS and INTERPOL scales resulted in general improvements in performance, with the false-positive and false-negative rates falling to approximately 2% overall. Inter-examiner agreement in assigning scale degrees was good (ICC=0.64), however there was little correlation between confidence and both accuracy or agreement among practitioners. These results suggest that use of a non-binary scale is supported over a match/non-match call as it reduces the frequency of false positives and negatives. The use of the terms "possible" and "insufficient information" in the same scale appears to create confusion, reducing inter-examiner agreement. The lack of agreement between higher-performing and lower-performing groups suggests that there is an inconsistency in the cognitive processes used to determine similarity between radiographs.

P- and N-Coordination of the Ambidentate Ligand HN[P(i-Pr)2]2 with Group 13 Trihalides.

Five different coordination motifs were observed upon reaction of the simple group 13 Lewis acids MCl3 (M = In, Ga, Al, B) or BF3·Et2O with the ambidentate bis(diisopropylphosphino)amine ligand HN[P(i-Pr)2]2. In a 1:1 reaction mixture, the softer Lewis acids InCl3, GaCl3 and BCl3 coordinate to one of the two P atoms of the ligand. In contrast, AlCl3 and BF3 prefer coordination to the harder N atom. In all cases, the acidic N-H proton is shifted to P upon complexation with a metal. By altering the reaction stoichiometry, 2:1 metal-ligand complexes could be isolated for three of the combinations. BCl3 gives a bis-adduct via the two P atoms. GaCl3 produces a salt consisting of a [GaCl4]- anion and a P,P-chelated [LGaCl2]+ cation. Most unexpectedly, the reaction with InCl3 in methanol resulted in solvent deprotonation by the ligand to give two symmetric [(i-Pr2PH)2N]+ cations in which all the basic P sites are coordinated to H rather than the group 13 Lewis acid. These cations are balanced by the unique complex dianion [(MeO)6In4Cl8·2MeOH]2-. All complexes were characterized with a combination of multinuclear NMR spectroscopy and single-crystal X-ray diffraction.

The Amplification of Common Somatic Symptoms by Posttraumatic Stress Disorder in Firefighters.

Posttraumatic stress disorder (PTSD) in emergency service personnel and other trauma-exposed populations is known to be associated with a variety of physical health problems. However, little attention has been paid to the health of ageing emergency service personnel, who may be forced into early medical retirement because of a combination of these issues. Currently employed (N = 274) Australian firefighters completed a cross-sectional survey using validated, self-report measures of PTSD and somatic symptoms. Analyses examined the association between probable PTSD and a range of common somatic symptoms, and whether any association differed depending on the age of the firefighters. Firefighters with PTSD reported greater levels of neurological (p = .024), gastrointestinal (p = .015), and cardiorespiratory (p = .027) symptoms compared to those without PTSD. After adjusting for sex, age, and rank, linear regression analysis demonstrated that PTSD was significantly associated with increased total somatic symptom severity (p = .024), with PTSD accounting for 9.8% of the variance in levels of somatic symptoms. There was no interaction between age and the association between PTSD and somatic symptom severity. These results suggest that PTSD is associated with a significant increase in a wide range of somatic symptoms among firefighters, regardless of age. The implications for the identification and treatment of PTSD are discussed.

Do emotional stimuli enhance or impede recall relative to neutral stimuli? An investigation of two "false memory" tasks.

Many eyewitness memory situations involve negative and distressing events; however, many studies investigating "false memory" phenomena use neutral stimuli only. The aim of the present study was to determine how both the Deese-Roediger-McDermott (DRM) procedure and the Misinformation Effect Paradigm tasks were related to each other using distressing and neutral stimuli. Participants completed the DRM (with negative and neutral word lists) and viewed a distressing or neutral film. Misinformation for the film was introduced and memory was assessed. Film accuracy and misinformation susceptibility were found to be greater for those who viewed the distressing film relative to the neutral film. Accuracy responses on both tasks were related, however, susceptibility to the DRM illusion and Misinformation Effect were not. The misinformation findings support the Paradoxical Negative Emotion (PNE) hypothesis that negative stimuli will lead to remembering more accurate details but also greater likelihood of memory distortion. However, the PNE hypothesis was not supported for the DRM results. The findings also suggest that the DRM and Misinformation tasks are not equivalent and may have differences in underlying mechanisms. Future research should focus on more ecologically valid methods of assessing false memory.

Thinking forensics: Cognitive science for forensic practitioners.

Human factors and their implications for forensic science have attracted increasing levels of interest across criminal justice communities in recent years. Initial interest centred on cognitive biases, but has since expanded such that knowledge from psychology and cognitive science is slowly infiltrating forensic practices more broadly. This article highlights a series of important findings and insights of relevance to forensic practitioners. These include research on human perception, memory, context information, expertise, decision-making, communication, experience, verification, confidence, and feedback. The aim of this article is to sensitise forensic practitioners (and lawyers and judges) to a range of potentially significant issues, and encourage them to engage with research in these domains so that they may adapt procedures to improve performance, mitigate risks and reduce errors. Doing so will reduce the divide between forensic practitioners and research scientists as well as improve the value and utility of forensic science evidence.

The mental health of fire-fighters: An examination of the impact of repeated trauma exposure.

OBJECTIVE: Emergency workers, such as fire-fighters, are routinely exposed to potentially traumatic events. While a number of studies have examined the occurrence of post-traumatic stress disorder, the role of multiple traumas on other mental health sequelae, such as depression and alcohol misuse, among emergency workers remains unclear. This study aimed to assess the prevalence of post-traumatic stress disorder, depression and alcohol misuse in a sample of current and retired fire-fighters and examine their relationship with cumulative trauma exposure. METHOD: A cross-sectional survey was completed by current (n = 488) and retired (n = 265) fire-fighters from Fire and Rescue New South Wales, Australia. Demographic and occupational information was collected, including the number of fatal incidents fire-fighters reported attending across years of service. Validated, self-report measures were used to determine probable caseness for post-traumatic stress disorder, depression and heavy drinking. RESULTS: Among current fire-fighters, rates of post-traumatic stress disorder and depression were 8% and 5%, respectively, while 4% reported consumption of more than 42 alcoholic drinks per week. Retired fire-fighters reported significantly greater levels of symptomatology, with the prevalence estimates of post-traumatic stress disorder at 18% (p = 0.001), depression at 18% (p < 0.001) and heavy drinking at 7%. There was a significant positive linear relationship between the number of fatal incidents attended and rates of post-traumatic stress disorder, depression and heavy drinking. CONCLUSION: Fire-fighters suffer from high rates of mental disorders, with rates of post-traumatic stress disorder, depression and heavy drinking continuing to rise in a linear manner with each additional trauma exposure. The level of psychiatric morbidity among retired fire-fighters appears to be particularly high. Our findings have important implications for the ongoing debates surrounding the detection of mental disorders in high-risk occupations and for policy considerations around the welfare of current and retired emergency workers.

Cortisol response and psychological distress predict susceptibility to false memories for a trauma film.

For eyewitness testimony to be considered reliable, it is important to ensure memory remains accurate following the event. As many testimonies involve traumatic, as opposed to neutral, events, it is important to consider the role of distress in susceptibility to false memories. The aim of this study was to investigate whether cortisol response following a stressor would be associated with susceptibility to false memories. Psychological distress responses were also investigated, specifically, dissociation, intrusions, and avoidance. Participants were allocated to one of three conditions: those who viewed a neutral film (N = 35), those who viewed a real trauma film (N = 35), and a trauma "reappraisal" group where participants were told the film was not real (N = 35). All received misinformation about the film in the form of a narrative. Participants provided saliva samples (to assess cortisol) and completed distress and memory questionnaires. Cortisol response was a significant predictor of the misinformation effect. Dissociation and avoidance were related to confabulations. In conclusion, following a stressor an individual may differ with regard to their psychological response to the event, and also whether they experience a cortisol increase. This may affect whether they are more distressed later on, and also whether they remember the event accurately.

Delay discounting, self-control, and substance use among adult drug court participants.

The current study examined the relationship between two measures of impulsiveness and the odds of substance use among a sample of participants on an Australian drug court (n=80). Participants completed a computer-based delay discounting task, a paper-based delay discounting task, and a questionnaire-based measure of self-control. The delay discounting tasks measured individual differences in the value attributed to distal outcomes, which is one aspect of impulsive behavior that has been found to be over-represented among illicit drug users. The relationship between the measures of impulsiveness and the odds of substance use was assessed by fitting longitudinal panel regression models with adjustment for informative treatment dropout. Consistent with previous research, drug court participants were found to have higher discount rates (i.e. were more impulsive) than a noncriminal population of university students (n=101). Drug court participants also discounted delayed gains more than delayed losses. Delay discounting was not significantly associated with the odds of substance use on the drug court program. There was a positive relationship between the survey-based measure of impulsivity and the mean substance use frequency. The authors conclude that impulsivity is correlated with substance use among drug court participants but not when measuring impulsivity using a delay discounting paradigm.

Rapid, Reversible, Solid-Gas and Solution-Phase Insertion of CO2 into In-P Bonds.

The P,P-chelated heteroleptic complex bis[bis(diisopropylphosphino)amido]indium chloride [(i-Pr2P)2N]2InCl was prepared in high yield by treating InCl3 with 2 equiv of (i-Pr2P)2NLi in Et2O/tetrahydrofuran solution. Samples of [(i-Pr2P)2N]2InCl in a pentane slurry, a CH2Cl2 solution, or in the solid state were exposed to CO2, resulting in the insertion of CO2 into two of the four M-P bonds to produce [O2CP(i-Pr2)NP(i-Pr2)]2InCl in each case. Compounds were characterized by multinuclear NMR and IR spectroscopy, as well as single-crystal X-ray diffraction. ReactIR solution studies show that the reaction is complete in less than 1 min at room temperature in solution and in less than 2 h in the solid-gas reaction. The CO2 complex is stable up to at least 60 °C under vacuum, but the starting material is regenerated with concomitant loss of carbon dioxide upon heating above 75 °C. The compound [(i-Pr2P)2N]2InCl also reacts with CS2 to give a complicated mixture of products, one of which was identified as the CS2 cleavage product [S═P(i-Pr2)NP(i-Pr2)]2InCl]2(µ-Cl)[µ-(i-Pr2P)2N)].

A 21-year retrospective outcome study of New South Wales forensic patients granted conditional and unconditional release.

AIM: To retrospectively examine the outcomes of forensic patients found not guilty by reason of mental illness (NGMI) in New South Wales (NSW) and subsequently released into the community, as measured by reoffending, conditional release revocation and psychiatric hospital readmission. METHOD: Data were collected from the NSW Mental Health Review Tribunal (MHRT) files for all patients who received an NGMI verdict between January 1990 and December 2010, and who were released into the community during this period. The outcome measures of conditional release revocation and psychiatric hospital readmission were extracted from these files. Information about subsequent criminal charges, convictions and penalties were obtained from the Bureau of Crime Statistics and Research's reoffending database. RESULTS: During the 21-year period studied, 364 offenders received an NGMI verdict and were placed under the supervision of the MHRT. Of these, 197 were released into the community, including 85 who were granted unconditional release. Over a follow-up period averaging 8.4 years, 18% of conditionally released patients reoffended, 11.8% were convicted of a further offence, 8.7% were charged with a violent offence, 3.1% were convicted of a violent offence and 3.7% were sentenced to a term of imprisonment. Five (3.1%) conditionally released forensic patients received a further NGMI verdict. One-quarter of the conditionally released patients had their conditional release revoked and half were readmitted to hospital. Of the forensic patients granted unconditional release, 12.5% were charged with an offence, 9.4% received convictions for an offence, 6.3% were charged with a violent offence and 4.7% were convicted of a violent offence, in a mean follow-up period of 7.6 years. None committed a further serious offence resulting in a term of imprisonment, nor a second NGMI verdict. CONCLUSIONS: The results of this study suggest that the treatment and rehabilitation of forensic patients in NSW, together with the decision-making procedures of the MHRT, is effective in protecting the community from further offending by forensic patients.

NH/PH isomerization and a Lewis pair for carbon dioxide capture.

Bis(di-i-propylphosphino)amine 1 reacts with B(C6F5)3 to form an adduct with concomitant N/P H-isomerization. This species reacts smoothly with carbon dioxide. An attempt to prepare an anionic derivative resulted in the formation of a novel heterocycle derived from the PNP ligand and B(C6F5)3.