Cognitive remediation therapy - implementation and translation into clinical practice in rural and metropolitan New South Wales mental health services.

OBJECTIVE: Cognitive Remediation Therapy (CRT) is an effective intervention in managing the significant cognitive deficits experienced by those living with psychosis. Given its strong evidence base CRT is recommended in Australian and international guidelines for rehabilitation of people with psychosis, however, access to CRT remains limited. In this commentary, we describe recent efforts to implement CRT programs within NSW mental health services. Development of CRT delivery has been successfully achieved in both rural and metropolitan settings, utilising both face-to-face and telehealth methods. CONCLUSIONS: The delivery of CRT in public mental health services is feasible and adaptable to diverse settings. We strongly advocate for sustainable implementation of CRT into routine clinical practice. This will require policy and practice change to enable resources for CRT training and delivery to become embedded in the roles of the clinical workforce.

Lethal and sublethal implications of low temperature exposure for three intertidal predators.

Benthic invertebrate predators play a key role in top-down trophic regulation in intertidal ecosystems. While the physiological and ecological consequences of predator exposure to high temperatures during summer low tides are increasingly well-studied, the effects of cold exposure during winter low tides remain poorly understood. To address this knowledge gap, we measured the supercooling points, survival, and feeding rates of three intertidal predator species in British Columbia, Canada - the sea stars Pisaster ochraceus and Evasterias troschelii and the dogwhelk Nucella lamellosa - in response to exposure to sub-zero air temperatures. Overall, we found that all three predators exhibited evidence of internal freezing at relatively mild sub-zero temperatures, with sea stars exhibiting an average supercooling point of -2.50 °C, and the dogwhelk averaging approximately -3.99 °C. None of the tested species are strongly freeze tolerant, as evidenced by moderate-to-low survival rates after exposure to -8 °C air. All three predators exhibited significantly reduced feeding rates over a two-week period following a single 3-h sublethal (-0.5 °C) exposure event. We also quantified variation in predator body temperature among thermal microhabitats during winter low tides. Predators that were found at the base of large boulders, on the sediment, and within crevices had higher body temperatures during winter low tides, as compared to those situated in other microhabitats. However, we did not find evidence of behavioural thermoregulation via selective microhabitat use during cold weather. Since these intertidal predators are less freeze tolerant than their preferred prey, winter low temperature exposures can have important implications for organism survival and predator-prey dynamics across thermal gradients at both local (habitat-driven) and geographic (climate-driven) scales.

Ocean acidification increases susceptibility to sub-zero air temperatures in ecosystem engineers and limits poleward range shifts.

Ongoing climate change has caused rapidly increasing temperatures and an unprecedented decline in seawater pH, known as ocean acidification. Increasing temperatures are redistributing species toward higher and cooler latitudes that are most affected by ocean acidification. While the persistence of intertidal species in cold environments is related to their capacity to resist sub-zero air temperatures, studies have never considered the interacting impacts of ocean acidification and freeze stress on species survival and distribution. Here, a full-factorial experiment was used to study whether ocean acidification increases mortality in subtidal Mytilus trossulus and subtidal M. galloprovincialis, and intertidal M. trossulus following sub-zero air temperature exposure. We examined physiological processes behind variation in freeze tolerance using 1H NMR metabolomics, analyses of fatty acids, and amino acid composition. We show that low pH conditions (pH = 7.5) significantly decrease freeze tolerance in both intertidal and subtidal populations of Mytilus spp. Under current day pH conditions (pH = 7.9), intertidal M. trossulus was more freeze tolerant than subtidal M. trossulus and subtidal M. galloprovincialis. Conversely, under low pH conditions, subtidal M. trossulus was more freeze tolerant than the other mussel categories. Differences in the concentration of various metabolites (cryoprotectants) or in the composition of amino acids and fatty acids could not explain the decrease in survival. These results suggest that ocean acidification can offset the poleward range expansions facilitated by warming and that reduced freeze tolerance could result in a range contraction if temperatures become lethal at the equatorward edge.

Proteostasis in ice: the role of heat shock proteins and ubiquitin in the freeze tolerance of the intertidal mussel, Mytilus trossulus.

The bay mussel, Mytilus trossulus, is an animal that can survive extracellular ice formation. Depending on air and ocean temperatures, freeze tolerant intertidal organisms, like M. trossulus, may freeze and thaw many times during the winter. Freezing can cause protein denaturation, leading to an induction of the heat shock response with expression of chaperone proteins like the 70 kDa heat shock protein (HSP70), and an increase in ubiquitin-conjugated proteins. There has been little work on the mechanisms of freeze tolerance in intertidal species, limiting our understanding of this survival strategy. Additionally, this limited research has focused solely on the effects of single freezing events, but the act of repeatedly crossing the freezing threshold may present novel physiological or biochemical stressors that have yet to be discovered. Mytilus are important ecosystem engineers and provide habitat for other intertidal species, thus understanding their physiology under thermal extremes is important for preserving shoreline health. We predicted that repeated freeze exposures would increase mortality, upregulate HSP70 expression, and increase ubiquitin conjugates in mussels, relative to single, prolonged freeze exposures. Mytilus trossulus from Vancouver, Canada were repeatedly frozen for a combination of 1 × 8 h, 2 × 4 h, or 4 × 2 h. We then compared mortality, HSP70 expression, and the quantity of ubiquitin-conjugated proteins across experimental groups. We found a single 8-h freeze caused significantly more mortality than repeated freeze-thaw cycles. We also found that HSP70 and ubiquitinated protein was upregulated exclusively after freeze-thaw cycles, suggesting that freeze-thaw cycles offer a period of damage repair between freezes. This indicates that freeze-thaw cycles, which happen naturally in the intertidal, are crucial for M. trossulus survival in sub-zero temperatures.

Does hoodwinking others pay? The psychological and relational consequences of undetected negotiator deception.

Lies often go undetected, and we know little about the psychological and relational consequences of successfully deceiving others. While the evidence to date indicates that undetected dishonesty induces positive affect in independent decision contexts, we propose that it may elicit guilt and undermine satisfaction in negotiations despite facilitating better deals for deceivers. Across four studies, we find support for a deceiver's guilt account, whereby dishonesty triggers guilt and lessens negotiators' satisfaction with the bargaining experience. This pattern is robust to several factors, including the size of negotiators' incentives and individual differences in negotiators' moral character. It holds for both lies issued of negotiators' own volition and in compliance with others' orders. Large incentives also exacerbated dishonesty-induced guilt. Further, dissatisfaction stemming from dishonesty-induced guilt had downstream relational consequences. Despite going undetected, dishonesty in a focal negotiation reduced deceivers' likelihood of choosing to interact again with the same counterpart and adversely impacted their satisfaction in future negotiations with that counterpart. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A large Australian longitudinal cohort registry demonstrates sustained safety and efficacy of oral medicinal cannabis for at least two years.

INTRODUCTION: Oral medicinal cannabis (MC) has been increasingly prescribed for a wide range of clinical conditions since 2016. Despite an exponential rise in prescriptions and publications, high quality clinical efficacy and safety studies are lacking. The outcomes of a large Australian clinical electronic registry cohort are presented. METHODS: A prospective cannabis-naïve patient cohort prescribed oral MC participated in an ongoing longitudinal registry at a network of specialised clinics. Patient MC dose, safety and validated outcome data were collected regularly over two years and analysed. RESULTS: 3,961 patients (mean age 56.07 years [SD 19.08], 51.0% female) with multimorbidity (mean diagnoses 5.14 [SD 4.08]) and polypharmacy (mean 6.26 medications [SD 4.61]) were included in this analysis. Clinical indications were for: chronic pain (71.9%), psychiatric (15.4%), neurological (2.1%), and other diagnoses (10.7%). Median total oral daily dose was 10mg for Δ9-tetrahydrocannabinol (THC) and 22.5mg for cannabidiol (CBD). A stable dose was observed for over two years. 37.3% experienced treatment related adverse events. These were graded mild (67%), moderate (31%), severe (<2%, n = 23) and two (0.1%) serious adverse events. Statistically significant improvements at a p value of <0.001 across all outcomes were sustained for over two years, including: clinical global impression (CGI-E, +39%: CGI-I, +52%; p<0.001), pain interference and severity (BPI, 26.1% and 22.2%; p<0.001), mental health (DASS-21, depression 24.5%, anxiety 25.5%, stress 27.7%; p<0.001), insomnia (ISI, 35.0%; p<0.001), and health status (RAND SF36: physical function, 34.4%: emotional well-being, 37.3%; p<0.001). Mean number of concomitant medications did not significantly change over 2 years (p = 0.481). CONCLUSIONS: Oral MC was demonstrated to be safe and well-tolerated for a sustained period in a large complex cohort of cannabis-naïve, multimorbid patients with polypharmacy. There was significant improvement (p<0.001) across all measured clinical outcomes over two years. Results are subject to limitations of Real World Data (RWD) for causation and generalisability. Future high quality randomised controlled trials are awaited.

Gender similarities and differences in dishonesty.

We review the evidence linking gender to dishonesty and conclude that men are often more dishonest than women, especially in competitive settings where lies advance self-interest. However, gender differences in dishonesty are often small and mutable across situations. We propose that attending to self-regulatory constructs such as moral identity might help researchers move beyond the evolutionary-cultural debates over the origin of gender differences toward identifying factors that promote honesty from both genders.

Outcomes of non-cystic fibrosis-related bronchiectasis post-lung transplantation.

BACKGROUND: Lung transplantation is a recognised treatment for end-stage lung disease due to bronchiectasis. Non-cystic fibrosis (CF) bronchiectasis and CF are often combined into one cohort; however, outcomes for non-CF bronchiectasis patients vary between centres, and in comparison with those for CF. AIMS: To compare lung transplantation mortality and morbidity of bronchiectasis (non-CF) patients with those with CF and other indications. METHODS: Retrospective analysis of patients undergoing lung transplantation between 1 January 2008 and 31 December 2013. Time to and cause of lung allograft loss was censored on 1 April 2018. A case-note review was conducted on a subgroup of 78 patients, to analyse hospital admissions as a marker of morbidity. RESULTS: A total of 341 patients underwent lung transplantation; 22 (6%) had bronchiectasis compared with 69 (20%) with CF. The 5-year survival for the bronchiectasis group was 32%, compared with CF (69%), obstructive lung disease (OLD) (64%), pulmonary hypertension (62%) and ILD (55%) (P = 0.008). Lung allograft loss due to chronic lung allograft dysfunction with predominant infection was significantly higher in the bronchiectasis group at 2 years. The rate of acute admissions was 2.24 higher in the bronchiectasis group when compared with OLD (P = 0.01). Patients with bronchiectasis spent 45.81 days in hospital per person year after transplantation compared with 18.21 days for CF. CONCLUSIONS: Bronchiectasis patients in the present study had a lower 5-year survival and poorer outcomes in comparison with other indications including CF. Bronchiectasis should be considered a separate entity to CF in survival analysis.

Drivers of plasticity in freeze tolerance in the intertidal mussel Mytilus trossulus.

Freezing is an extreme stress to living cells, and so freeze-tolerant animals often accumulate protective molecules (termed cryoprotectants) to prevent the cellular damage caused by freezing. The bay mussel, Mytilus trossulus, is an ecologically important intertidal invertebrate that can survive freezing. Although much is known about the biochemical correlates of freeze tolerance in insects and vertebrates, the cryoprotectants that are used by intertidal invertebrates are not well characterized. Previous work has proposed two possible groups of low-molecular weight cryoprotectants in intertidal invertebrates: osmolytes and anaerobic byproducts. In our study, we examined which group of candidate cryoprotectants correlate with plasticity in freeze tolerance in mussels using 1H NMR metabolomics. We found that the freeze tolerance of M. trossulus varies on a seasonal basis, along an intertidal shore-level gradient, and with changing salinity. Acclimation to increased salinity (30 ppt compared with 15 ppt) increased freeze tolerance, and mussels were significantly more freeze tolerant during the winter. Mussel freeze tolerance also increased with increasing shore level. There was limited evidence that anaerobic byproduct accumulation was associated with increased freeze tolerance. However, osmolyte accumulation was correlated with increased freeze tolerance after high salinity acclimation and in the winter. The concentration of most low molecular weight metabolites did not vary with shore level, indicating that another mechanism is likely responsible for this pattern of variation in freeze tolerance. By identifying osmolytes as a group of molecules that assist in freezing tolerance, we have expanded the known biochemical repertoire of the mechanisms of freeze tolerance.

Structural Motifs Critical for In Vivo Function and Stability of the RecQ-Mediated Genome Instability Protein Rmi1.

Rmi1 is a member of the Sgs1/Top3/Rmi1 (STR) complex of Saccharomyces cerevisiae and has been implicated in binding and catalytic enhancement of Top3 in the dissolution of double Holliday junctions. Deletion of RMI1 results in a severe growth defect resembling that of top3Δ. Despite the importance of Rmi1 for cell viability, little is known about its functional domains, particularly in Rmi1 of S. cerevisiae, which does not have a resolved crystal structure and the primary sequence is poorly conserved. Here, we rationally designed point mutations based on bioinformatics analysis of order/disorder and helical propensity to define three functionally important motifs in yeast Rmi1 outside of the proposed OB-fold core. Replacing residues F63, Y218 and E220 with proline, designed to break predicted N-terminal and C-terminal α-helices, or with lysine, designed to eliminate hydrophobic residues at positions 63 and 218, while maintaining α-helical structure, caused hypersensitivity to hydroxyurea. Further, Y218P and E220P mutations, but not F63P and F63K mutations, led to reduced Rmi1 levels compared to wild type Rmi1, suggesting a role of the C-terminal α-helix in Rmi1 stabilization, most likely by protecting the integrity of the OB-fold core. Our bioinformatics analysis also suggests the presence of a disordered linker between the N-terminal α-helix and the OB fold core; a P88A mutation, designed to increase helicity in this linker, also impaired Rmi1 function in vivo. In conclusion, we propose a model that maps all functionally important structural features for yeast Rmi1 based on biological findings in yeast and structure-prediction-based alignment with the recently established crystal structure of the N-terminus of human Rmi1.

A transient α-helical molecular recognition element in the disordered N-terminus of the Sgs1 helicase is critical for chromosome stability and binding of Top3/Rmi1.

The RecQ-like DNA helicase family is essential for the maintenance of genome stability in all organisms. Sgs1, a member of this family in Saccharomyces cerevisiae, regulates early and late steps of double-strand break repair by homologous recombination. Using nuclear magnetic resonance spectroscopy, we show that the N-terminal 125 residues of Sgs1 are disordered and contain a transient α-helix that extends from residue 25 to 38. Based on the residue-specific knowledge of transient secondary structure, we designed proline mutations to disrupt this α-helix and observed hypersensitivity to DNA damaging agents and increased frequency of genome rearrangements. In vitro binding assays show that the defects of the proline mutants are the result of impaired binding of Top3 and Rmi1 to Sgs1. Extending mutagenesis N-terminally revealed a second functionally critical region that spans residues 9-17. Depending on the position of the proline substitution in the helix functional impairment of Sgs1 function varied, gradually increasing from the C- to the N-terminus. The multiscale approach we used to interrogate structure/function relationships in the long disordered N-terminal segment of Sgs1 allowed us to precisely define a functionally critical region and should be generally applicable to other disordered proteins.

A status-enhancement account of overconfidence.

In explaining the prevalence of the overconfident belief that one is better than others, prior work has focused on the motive to maintain high self-esteem, abetted by biases in attention, memory, and cognition. An additional possibility is that overconfidence enhances the person's social status. We tested this status-enhancing account of overconfidence in 6 studies. Studies 1-3 found that overconfidence leads to higher social status in both short- and longer-term groups, using naturalistic and experimental designs. Study 4 applied a Brunswikian lens analysis (Brunswik, 1956) and found that overconfidence leads to a behavioral signature that makes the individual appear competent to others. Studies 5 and 6 measured and experimentally manipulated the desire for status and found that the status motive promotes overconfidence. Together, these studies suggest that people might so often believe they are better than others because it helps them achieve higher social status.

Sgs1 truncations induce genome rearrangements but suppress detrimental effects of BLM overexpression in Saccharomyces cerevisiae.

RecQ-like DNA helicases are conserved from bacteria to humans. They perform functions in the maintenance of genome stability, and their mutation is associated with cancer predisposition and premature aging syndromes in humans. Here, a series of C-terminal deletions and point mutations of Sgs1, the only RecQ-like helicase in yeast, show that the Helicase/RNase D C-terminal domain and the Rad51 interaction domain are dispensable for Sgs1's role in suppressing genome instability, whereas the zinc-binding domain and the helicase domain are required. BLM expression from the native SGS1 promoter had no adverse effects on cell growth and was unable to complement any sgs1Δ defects. BLM overexpression, however, significantly increased the rate of accumulating gross-chromosomal rearrangements in a dosage-dependent manner and greatly exacerbated sensitivity to DNA-damaging agents. Co-expressing sgs1 truncations of up to 900 residues, lacking all known functional domains of Sgs1, suppressed the hydroxyurea sensitivity of BLM-overexpressing cells, suggesting a functional relationship between Sgs1 and BLM. Protein disorder prediction analysis of Sgs1 and BLM was used to produce a functional Sgs1-BLM chimera by replacing the N-terminus of BLM with the disordered N-terminus of Sgs1. The functionality of this chimera suggests that it is the disordered N-terminus, a site of protein binding and posttranslational modification, that confers species specificity to these two RecQ-like proteins.

Role of Sox2 in the development of the mouse neocortex.

The mammalian neocortex is established from neural stem and progenitor cells that utilize specific transcriptional and environmental factors to create functional neurons and astrocytes. Here, we examined the mechanism of Sox2 action during neocortical neurogenesis and gliogenesis. We established a robust Sox2 expression in neural stem and progenitor cells within the ventricular zone, which persisted until the cells exited the cell cycle. Overexpression of constitutively active Sox2 in neural progenitors resulted in upregulation of Notch1, recombination signal-sequence binding protein-J (RBP-J) and hairy enhancer of split 5 (Hes5) transcripts and the Sox2 high mobility group (HMG) domain seemed sufficient to confer these effects. While Sox2 overexpression permitted the differentiation of progenitors into astroglia, it inhibited neurogenesis, unless the Notch pathway was blocked. Moreover, neuronal precursors engaged a serine protease(s) to eliminate the overexpressed Sox2 protein and relieve the repression of neurogenesis. Glial precursors and differentiated astrocytes, on the other hand, maintained Sox2 expression until they reached a quiescent state. Sox2 expression was re-activated by signals that triggered astrocytic proliferation (i.e., injury, mitogenic and gliogenic factors). Taken together, Sox2 appears to act upstream of the Notch signaling pathway to maintain the cell proliferative potential and to ensure the generation of sufficient cell numbers and phenotypes in the developing neocortex.

Phosphatidylserine receptor-mediated recognition of archaeosome adjuvant promotes endocytosis and MHC class I cross-presentation of the entrapped antigen by phagosome-to-cytosol transport and classical processing.

Archaeal isopranoid glycerolipid vesicles (archaeosomes) serve as strong adjuvants for cell-mediated responses to entrapped Ag. We analyzed the processing pathway of OVA entrapped in archaeosomes composed of Methanobrevibacter smithii lipids, high in archaetidylserine (OVA-archaeosomes). In vitro, OVA-archaeosomes stimulated spleen cells from OVA-TCR-transgenic mice, D011.10 (CD4(+) cells expressing OVA(323-339) TCR) or OT1 (>90% CD8(+) OVA(257-264) cells), indicating both MHC class I and II presentations. In vivo, when naive (Thy1.2(+)) CFSE-labeled OT1 cells were transferred into OVA-archaeosome-immunized Thy 1.1(+) recipient mice, there was profound accumulation and cycling of donor-specific cells, and differentiation of H-2K(b)Ova(257-264) CD8(+) T cells into CD44(high)CD62L(low) effectors. Both macrophages and dendritic cells (DCs) efficiently cross-presented OVA-archaeosomes on MHC class I. Blocking phagocytosis by phosphatidylserine-specific receptor agonists strongly inhibited MHC class I presentation of OVA-archaeosomes, whereas blocking mannose receptors or FcRs lacked effect, indicating specific recognition of the archaetidylserine head group of M. smithii lipids by APCs. In addition, inhibitors of endosomal acidification blocked MHC class I processing of OVA-archaeosomes, whereas endosomal protease inhibitors lacked effect, suggesting acidification-dependent phagosome-to-cytosol diversion. Proteasomal inhibitors blocked OVA-archaeosome MHC class I presentation, confirming cytosolic processing. Both in vitro and in vivo, OVA-archaeosome MHC class I presentation required TAP. Ag-free archaeosomes also activated DC costimulation and cytokine production, without overt inflammation. Phosphatidylserine-specific receptor-mediated endocytosis is a mechanism of apoptotic cell clearance and DCs cross-present Ags sampled from apoptotic cells. Our results reveal the novel ability of archaeosomes to exploit this mechanism for cytosolic MHC class I Ag processing, and provide an effective particulate vaccination strategy.

Prostaglandin levels in seminal plasma and sperm extracts of the domestic turkey, and the effects of cyclooxygenase inhibitors on sperm mobility.

BACKGROUND: Turkey reproduction is by artificial insemination using pooled semen so there is interest in storing semen. Fertilizing capacity declines after six hours storage, possibly due to poor sperm mobility. Prostaglandins (PG) affect mammalian sperm motility, but avian sperm has not been widely studied. For this study, levels of PG E1, E2, and F2 alpha in turkey seminal plasma and sperm extract, and effects of cyclooxygenase (COX) inhibitors on sperm mobility were determined. METHODS: Seminal Plasma and sperm extract PG E1, E2, and F2 alpha, from 1.0 mL pooled semen, were measured by ELISA. In Trial 1, PG were determined from 122 wk old toms (n = 4). Trial 2 used 36 wk old toms (n = 7). For Trial 3, PGE2 only was measured from 48 wk (n = 6) and 154 wk old toms (n = 3). The effects of non-specific COX inhibitors indomethacin, diclofenac, tolmetin, or aspirin (n = 10), or specific COX-1 or COX-2 inhibitors (n = 3) on sperm mobility were measured (Accudenz swim-down test). RESULTS: Seminal plasma PG (pg/mL) in Trials 1 and 2, respectively, were 185.2 +/- 88.4 and 187.2 +/- 33.7 for PGE1; 141.4 +/- 43.1 and 100.4 +/- 14.6 for PGF2 alpha; and 431.0 +/- 155.1 for PGE2 (Trial 1 only). Sperm extract PG (pg/10 billion cells) in Trials 1 and 2, respectively, were 215.1 +/- 38.1 and 208.9 +/- 41.5 for PGE1; 133.7 +/- 51.7 and 49.8 +/- 8.3 for PGF2 alpha; and 52.3 +/- 8.6 for PGE2 (Trial 1 only). In Trial 3, seminal plasma PGE2 (pg/mL) in older versus younger males was 1097.9 +/- 99.3 versus 853.2 +/- 144.6 and sperm extract PGE2 (pg/10 billion cells) was 208.0 +/- 56.1 versus 102.4 +/- 14.8. Cyclooxygenase inhibitors (0.001 to 10 mM) decreased sperm mobility: indomethacin 15 to 100%; diclofenac 4 to 100%; tolmetin 27 to 74%; aspirin (tested at 0.01 to 15 mM) 22 to 42%; resveratrol (COX-1) and NS-398 (COX-2), both tested at 0.1 to 10 mM, 38 to 98% and 44 to 85%, respectively. CONCLUSION: These results indicate that PG are present in turkey seminal plasma and sperm, and COX inhibitors decrease turkey sperm mobility.