HaloClass: Salt-Tolerant Protein Classification with Protein Language Models.

Salt-tolerant proteins, also known as halophilic proteins, have unique adaptations to function in high-salinity environments. These proteins have naturally evolved in extremophilic organisms, and more recently, are being increasingly applied as enzymes in industrial processes. Due to an abundance of salt-tolerant sequences and a simultaneous lack of experimental structures, most computational methods to predict stability are sequence-based only. These approaches, however, are hindered by a lack of structural understanding of these proteins. Here, we present HaloClass, an SVM classifier that leverages ESM-2 protein language model embeddings to accurately identify salt-tolerant proteins. On a newer and larger test dataset, HaloClass outperforms existing approaches when predicting the stability of never-before-seen proteins that are distal to its training set. Finally, on a mutation study that evaluated changes in salt tolerance based on single- and multiple-point mutants, HaloClass outperforms existing approaches, suggesting applications in the guided design of salt-tolerant enzymes.

Prospective single-arm trial on feasibility and safety of endoscopic robotic system for colonic endoscopic submucosal dissection.

Introduction The development of EndoMaster EASE system aims to enhance safety and efficacy of colonic ESD through two flexible robotic arms for tissue retraction and dissection. This is the first clinical trial to evaluate the performance of colorectal ESD using EndoMaster. Method Patients with early mucosal colorectal neoplasia not feasible for en-bloc resection with snare-based techniques were recruited. The EndoMaster EASE robotic system consisted of an independently designed flexible robotic platform with 2 robotic arms. The primary outcome was complete resection rate using EndoMaster. Secondary outcomes included operating time, hospital stay, procedure-related complications and oncological outcomes. Results From May 2020 to Jan 2022, 43 patients received robotic ESD with median age of 66 years (40-83). The mean robotic dissection time was 62.0 ± 45.1 minutes. All procedures except six were completed using EndoMaster with technical success rate of 86.1% (37/43). The en-bloc resection rate among cases with technical success was 94.6% (35/37) while the complete resection rate was 83.8% (31/37). The median size of specimen was 35mm (15-90mm). The mean hospital stay was 2.6 ± 1.2 days and there was one delayed bleeding 4 days after ESD which was controlled by endoscopy. One patient sustained perforation during procedure which was completely closed using clips without sequelae. 2 patients required salvage surgery due to deep margin involvement by adenocarcinoma in histopathology. Conclusion This first clinical trial confirmed the safety and efficacy of performing colorectal ESD using EndoMaster EASE robotic system (Clinicaltrial.gov: NCT04196062).

Entrustable professional activities, emergency medicine and medical education: a systematic review.

INTRODUCTION: Entrustable professional activities (EPAs) are one way to assess competencies, and are designed to bridge the gap between theoretical competencies and real world clinical practice. AIMS: This was a systematic review which aims to answer the question: "Which EPAs related to Emergency Medicine are described for medical schools?". METHODS: We included original qualitative, interventional and observational studies (cross-sectional, case-control, and cohort studies) that described EPAs relevant to Emergency Medicine for Medical School. The search strategy was created using a combination of keywords and standardized index terms related to EPAs and Emergency Medicine. RESULTS: The search strategy identified 991 citations. After screening the titles and abstracts, we identified 85 potentially relevant studies. After the full-text review, a total of 11 reports met the criteria for inclusion. CONCLUSION: Recognizing a patient requiring urgent or emergent care and initiating evaluation and management is the most common EPA related to Emergency Medicine described at Medical Schools. Use of EPAs is associated with increased student satisfaction and improved competences. However, there is a lack of undergraduate EM specific EPAs being systematically developed and published, and this should be an area to be explored in future studies.

IFEM model curriculum: emergency medicine learning outcomes for undergraduate medical education.

BACKGROUND: The International Federation for Emergency Medicine (IFEM) published its model curriculum for medical student education in emergency medicine in 2009. Because of the evolving principles of emergency medicine and medical education, driven by societal, professional, and educational developments, there was a need for an update on IFEM recommendations. The main objective of the update process was creating Intended Learning Outcomes (ILOs) and providing tier-based recommendations. METHOD: A consensus methodology combining nominal group and modified Delphi methods was used. The nominal group had 15 members representing eight countries in six regions. The process began with a review of the 2009 curriculum by IFEM Core Curriculum and Education Committee (CCEC) members, followed by a three-phase update process involving survey creation [The final survey document included 55 items in 4 sections, namely, participant & context information (16 items), intended learning outcomes (6 items), principles unique to emergency medicine (20 items), and content unique to emergency medicine (13 items)], participant selection from IFEM member countries and survey implementation, and data analysis to create the recommendations. RESULTS: Out of 112 invitees (CCEC members and IFEM member country nominees), 57 (50.9%) participants from 27 countries participated. Eighteen (31.6%) participants were from LMICs, while 39 (68.4%) were from HICs. Forty-four (77.2%) participants have been involved with medical students' emergency medicine training for more than five years in their careers, and 56 (98.2%) have been involved with medical students' training in the last five years. Thirty-five (61.4%) participants have completed a form of training in medical education. The exercise resulted in the formulation of tiered ILO recommendations. Tier 1 ILOs are recommended for all medical schools, Tier 2 ILOs are recommended for medical schools based on perceived local healthcare system needs and/or adequate resources, and Tier 3 ILOs should be considered for medical schools based on perceived local healthcare system needs and/or adequate resources. CONCLUSION: The updated IFEM ILO recommendations are designed to be applicable across diverse educational and healthcare settings. These recommendations aim to provide a clear framework for medical schools to prepare graduates with essential emergency care capabilities immediately after completing medical school. The successful distribution and implementation of these recommendations hinge on support from faculty and administrators, ensuring that future healthcare professionals are well-prepared for emergency medical care.

Aggressiveness, inhibitory control, and emotional states: A provocation paradigm.

The current study examines the effects of trait aggressiveness, inhibitory control and emotional states on aggressive behavior in a laboratory paradigm. One hundred and fifty-one adult participants took part (73 men, 71 women, and 7 nondisclosed). Event Related Potentials (ERPs) during a Go/No-Go task were utilized to capture the extent of inhibitory processing, with a laboratory provocation paradigm used to assess aggression. Contrary to the expectations, negative affective responses to provocation were negatively associated only with short-lived aggression and only among those with high past aggressiveness. Furthermore, past aggressiveness was related to a continuous increase in laboratory aggressive behavior regardless of the level of inhibitory control (P3 difference amplitude). However, feeling hostile was associated with short-lived aggressive behavior, only in those with lower levels of inhibitory control. These findings demonstrate the effect of distinct mechanisms on different patterns of aggressive behavior.

Protein stability prediction by fine-tuning a protein language model on a mega-scale dataset.

Protein stability plays a crucial role in a variety of applications, such as food processing, therapeutics, and the identification of pathogenic mutations. Engineering campaigns commonly seek to improve protein stability, and there is a strong interest in streamlining these processes to enable rapid optimization of highly stabilized proteins with fewer iterations. In this work, we explore utilizing a mega-scale dataset to develop a protein language model optimized for stability prediction. ESMtherm is trained on the folding stability of 528k natural and de novo sequences derived from 461 protein domains and can accommodate deletions, insertions, and multiple-point mutations. We show that a protein language model can be fine-tuned to predict folding stability. ESMtherm performs reasonably on small protein domains and generalizes to sequences distal from the training set. Lastly, we discuss our model's limitations compared to other state-of-the-art methods in generalizing to larger protein scaffolds. Our results highlight the need for large-scale stability measurements on a diverse dataset that mirrors the distribution of sequence lengths commonly observed in nature.

Dual α-globin and truncated EPO receptor knockin restores hemoglobin production in α-thalassemia-derived red blood cells.

Alpha-thalassemia is an autosomal recessive disease with increasing worldwide prevalence. The molecular basis is due to mutation or deletion of one or more duplicated α-globin genes, and disease severity is directly related to the number of allelic copies compromised. The most severe form, α-thalassemia major (αTM), results from loss of all four copies of α-globin and has historically resulted in fatality in utero. However, in utero transfusions now enable survival to birth. Postnatally, patients face challenges similar to ß-thalassemia, including severe anemia and erythrotoxicity due to imbalance of ß-globin and α-globin chains. While curative, hematopoietic stem cell transplantation (HSCT) is limited by donor availability and potential transplant-related complications. Despite progress in genome editing treatments for ß-thalassemia, there is no analogous curative option for patients suffering from α-thalassemia. To address this, we designed a novel Cas9/AAV6-mediated genome editing strategy that integrates a functional α-globin gene into the ß-globin locus in αTM patient-derived hematopoietic stem and progenitor cells (HSPCs). Incorporation of a truncated erythropoietin receptor transgene into the α-globin integration cassette dramatically increased erythropoietic output from edited HSPCs and led to the most robust production of α-globin, and consequently normal hemoglobin. By directing edited HSPCs toward increased production of clinically relevant RBCs instead of other divergent cell types, this approach has the potential to mitigate the limitations of traditional HSCT for the hemoglobinopathies, including low genome editing and low engraftment rates. These findings support development of a definitive ex vivo autologous genome editing strategy that may be curative for α-thalassemia.

Risk and protective factors in risk assessment: Predicting inpatient aggression in adult males detained in a forensic mental health setting.

Structured clinical risk assessments represent a preferred means of assessing levels of aggression risk at different times and in different individuals. Increasing attention has been given to capturing protective factors, with sound risk assessment critical to high-secure forensic mental health care. The aim was to assess the predictive value of the HCR-20v3 for aggression risk and the long-term care pilot version of the SAPROF (the SAPROF-LC-pilot) in a high-secure forensic mental health inpatient population and to determine the incremental value of protective over risk factors. Participants were adult males detained in a high secure forensic mental health service, with a primary diagnosis of schizophrenia and/or personality disorder. The focus was on examining hospital based aggression (self- and other-directed) at two time points; up to 6 months (T1) and between 7 and 12 months (T2). The HCR-20V3 and SAPROF-LC-pilot demonstrated good predictive validity but with variability across subscales and aggression types/periods. Historical factors of the HCR-20V3 and External factors of the SAPROF-LC-pilot failed to predict, aside from a medium effect at T1 for verbal aggression and self-harm, for Historical factors. There was evidence for protective factors adding to prediction over risk factors alone, with the integration of protective and risk factors into a risk judgement particularly helpful in improving prediction accuracy. Protective factors contributed to risk estimates and particularly if integrated with risk factors. Combining risk and protective factors has clear predictive advantages, ensuring that protective factors are not supplementary but important to the aggression assessment process.

Current progress in international pediatric emergency medicine.

PURPOSE OF REVIEW: Over the past four decades, pediatric emergency Medicine (PEM) has witnessed significant global development, with a notable increase in training programs and official recognition by regulatory bodies. However, disparities persist in the recognition of PEM as an independent subspecialty, availability of training programs on a global scale, academic recognition, and the ability to provide high-quality care to children worldwide. There is paucity of published literature regarding development of PEM globally. This review explores the current trends and challenges in international pediatric emergency medicine. RECENT FINDINGS: Current trends in international pediatric emergency medicine encompass the provision of training in pediatric-focused emergency and acute care, increased propagation of evidence-based guidelines specific to the care of children, the growth of collaborative research networks and interest groups within national and international societies. Simultaneously, the field continues to face challenges such as the lack of recognition, inequities in access, and a lack of dissemination of global PEM initiatives. SUMMARY: While recent advancements have significantly enhanced the state of international pediatric emergency medicine, including pediatric specific research networks and training programs, barriers still hinder its overall quality. Many of these obstacles are not unique to pediatric emergency medicine but are directly affected by financial disparities and lack of governmental and public recognition of the essential role of pediatric emergency care.

Patient-Derived Xenograft Models for Ovarian Cancer.

Patient-derived xenograft (PDX) models play a crucial role for in vivo research. They maintain the original molecular characteristics of the human tumor and provide a more accurate tumor microenvironment, which cannot be replicated by in vitro models. This chapter describes four different transplantation methods, namely, intra-bursal, intrarenal capsule, intraperitoneal, and subcutaneous, to develop PDX models for ovarian cancer research.

Anchored-fusion enables targeted fusion search in bulk and single-cell RNA sequencing data.

Here, we present Anchored-fusion, a highly sensitive fusion gene detection tool. It anchors a gene of interest, which often involves driver fusion events, and recovers non-unique matches of short-read sequences that are typically filtered out by conventional algorithms. In addition, Anchored-fusion contains a module based on a deep learning hierarchical structure that incorporates self-distillation learning (hierarchical view learning and distillation [HVLD]), which effectively filters out false positive chimeric fragments generated during sequencing while maintaining true fusion genes. Anchored-fusion enables highly sensitive detection of fusion genes, thus allowing for application in cases with low sequencing depths. We benchmark Anchored-fusion under various conditions and found it outperformed other tools in detecting fusion events in simulated data, bulk RNA sequencing (bRNA-seq) data, and single-cell RNA sequencing (scRNA-seq) data. Our results demonstrate that Anchored-fusion can be a useful tool for fusion detection tasks in clinically relevant RNA-seq data and can be applied to investigate intratumor heterogeneity in scRNA-seq data.

Effect of Real-Time Computer-Aided Polyp Detection System (ENDO-AID) on Adenoma Detection in Endoscopists-in-Training: A Randomized Trial.

BACKGROUND: The effect of computer-aided polyp detection (CADe) on adenoma detection rate (ADR) among endoscopists-in-training remains unknown. METHODS: We performed a single-blind, parallel-group, randomized controlled trial in Hong Kong between April 2021 and July 2022 (NCT04838951). Eligible subjects undergoing screening/surveillance/diagnostic colonoscopies were randomized 1:1 to receive colonoscopies with CADe (ENDO-AID[OIP-1]) or not (control) during withdrawal. Procedures were performed by endoscopists-in-training with <500 procedures and <3 years' experience. Randomization was stratified by patient age, sex, and endoscopist experience (beginner vs intermediate level, <200 vs 200-500 procedures). Image enhancement and distal attachment devices were disallowed. Subjects with incomplete colonoscopies or inadequate bowel preparation were excluded. Treatment allocation was blinded to outcome assessors. The primary outcome was ADR. Secondary outcomes were ADR for different adenoma sizes and locations, mean number of adenomas, and non-neoplastic resection rate. RESULTS: A total of 386 and 380 subjects were randomized to CADe and control groups, respectively. The overall ADR was significantly higher in the CADe group than in the control group (57.5% vs 44.5%; adjusted relative risk, 1.41; 95% CI, 1.17-1.72; P < .001). The ADRs for <5 mm (40.4% vs 25.0%) and 5- to 10-mm adenomas (36.8% vs 29.2%) were higher in the CADe group. The ADRs were higher in the CADe group in both the right colon (42.0% vs 30.8%) and left colon (34.5% vs 27.6%), but there was no significant difference in advanced ADR. The ADRs were higher in the CADe group among beginner (60.0% vs 41.9%) and intermediate-level (56.5% vs 45.5%) endoscopists. Mean number of adenomas (1.48 vs 0.86) and non-neoplastic resection rate (52.1% vs 35.0%) were higher in the CADe group. CONCLUSIONS: Among endoscopists-in-training, the use of CADe during colonoscopies was associated with increased overall ADR. (ClinicalTrials.gov, Number: NCT04838951).

How social media can help to understand treatment experiences of survivors of rare cancers: Findings from the Granulosa Cell Tumor Survivor Sisters Facebook group member survey.

BACKGROUND: Engaging with online social media consumer groups for rare cancers may help to develop collaborations between consumers and researchers. This study, a collaboration with the Granulosa Cell Tumor-Survivor Sisters (GCT-SS) Facebook group, explores the results of their survey of member's treatment and follow-up experiences. METHODS: Members of the closed multinational GCT-SS Facebook group completed a 43-item survey covering symptoms, diagnosis, treatment, recurrence, follow-up, and possible risk factors for GCT. Group members could have adult (aGCT) or juvenile (jGCT) disease. Data was collected via an online survey between 2014 and 2019. RESULTS: A total of 743 members (average 4.4 years [SD = 5.9] post-diagnosis) participated including 52 with jGCT. A total of 67% had stage I disease and 8% had stage III-IV at diagnosis, although 30% of aGCT and 25% of jGCT reported recurrent disease at survey completion. A total of 48% of aGCT had laparoscopic surgery, tumor encapsulation was reported by 49%, and tumor bagging reported by 29% overall (37% laparoscopic; 8% open). Recurrence rates were higher when the tumor was cut or ruptured (ruptured: p < .001; cut: p = .01). A total of 19% of aGCT had chemotherapy with this most common for stage II-III disease. Bleomycin, etoposide, and cisplatin protocols became less common over time (diagnosed before 2015: 47% vs. diagnosed post-2015: 21%). CONCLUSIONS: This is one of the largest surveys of GCT treatment. Members of the GCT-SS group report treatment patterns generally in line with those found from clinical audits. Using naturally forming consumer groups may assist with developing the evidence base for care and supporting those living with GCT ovarian cancer. PLAIN LANGUAGE SUMMARY: This study is a collaboration between members of Granulosa Cell Tumor-Survivor Sisters (GCT-SS) Facebook group and researchers to assess members' experiences of treatment and follow-up. A total of 743 members (52 with juvenile GCT) completed an online survey. A total of 67% had stage I disease at diagnosis. Treatment patterns were generally in line with those found from clinical audits: 95% had surgery and 19% of those with adult GCT had chemotherapy. A total of 30% reported recurrent disease, with recurrence occurring within 5 years of diagnosis for 33%. Using naturally forming consumer groups may assist with developing the evidence base for care and supporting those living with GCT ovarian cancer.

Delaying surgery for optimization after colonic stent bridging is safe for left-sided malignant large bowel obstruction: Result from 10-year experience and risks factor analysis.

AIM: To evaluate the operative and oncological results after colonic stent bridging for left-sided malignant large bowel intestinal obstruction and the risk factors for survival and recurrence after definitive surgery. METHODOLOGY: Consecutive patients who underwent colonic stenting for malignant left-sided colonic obstruction were included. Patients for palliative stenting or emergency surgery, patient with low rectal tumour or peritoneal metastasis were excluded. The primary outcome was overall survival. Secondary outcomes included stent success rate, stenting related complications, rate of stoma formation and long-term oncological outcome including recurrence rate and recurrence free survival rate. RESULTS: From June 2011 to June 2021, a total of 222 patients underwent colonic stenting. 112 patients were bridged to surgery after initial stenting, but 7 patients dropped out. Overall survival was 35 months (IQR = 17.75-75.25 months) in the early operation group, 30 months (IQR = 17.5-49.5 months) in the delayed surgery group HR 0.981 (95%CI 0.70-1.395, p = 0.907). Sensitivity analysis performed by excluding stent complications and emergency surgery yielded the same conclusion. Overall stenting complications rate was 17.1%. 11 patients (10.4%) required emergency surgery. CONCLUSION: There was no difference between early and delayed surgery groups (>4weeks) in the overall survival and recurrence in patients who had stent-bridge to surgery for malignant left colonic obstruction. It is safe to defer definitive surgery to optimize patients and allow better recovery from initial obstruction after colonic stenting before definitive surgery without adversely affecting the oncological outcomes.

Droplet nuclei are generated during colonoscopy and are decreased by the use of carbon dioxide and water immersion technique.

OBJECTIVES: The COVID-19 pandemic has raised concerns on whether colonoscopies (CS) carry a transmission risk. The aim was to determine whether CS are aerosol-generating procedures. METHODS: This was a prospective observational trial including all patients undergoing CS at the Prince of Wales Hospital from 1 June to 31 July 2020. Three particle counters were placed 10 cm from each patient's anus and near the mouth of endoscopists and nurses. The particle counter recorded the number of particles of size 0.3, 0.5, 0.7, 1, 5, and 10 µm. Patient demographics, seniority of endoscopists, use of CO2 and water immersion technique, and air particle count (particles/cubic foot, dCF) were recorded. Multilevel modeling was used to test all the hypotheses with a post-hoc analysis. RESULTS: A total of 117 patients were recruited. During CS, the level of 5 µm and 10 µm were significantly higher than the baseline period (P = 0.002). Procedures performed by trainees had a higher level of aerosols when compared to specialists (0.3 µm, P < 0.001; 0.5 µm and 0.7 µm, P < 0.001). The use of CO2 and water immersion techniques had significantly lower aerosols generated when compared to air (CO2 : 0.3, 0.5, and 0.7 µm: P < 0.001; water immersion: 0.3 µm: P = 0.048; 0.7 µm: P = 0.03). There were no significant increases in any particle sizes during the procedure at the endoscopists' and nurses' mouth. However, 8/117 (6.83%) particle count tracings showed a simultaneous surge of all particle sizes at the patient's anus and endoscopists' and nurses' level during rectal extubation. CONCLUSION: Colonoscopy generates droplet nuclei especially during rectal extubation. The use of CO2 and water immersion techniques may mitigate these risks.

Knock down of TIMP-2 by siRNA and CRISPR/Cas9 mediates diverse cellular reprogramming of metastasis and chemosensitivity in ovarian cancer.

BACKGROUND: The endogenous tissue inhibitor of metalloproteinase-2 (TIMP-2), through its homeostatic action on certain metalloproteinases, plays a vital role in remodelling extracellular matrix (ECM) to facilitate cancer progression. This study investigated the role of TIMP-2 in an ovarian cancer cell line in which the expression of TIMP-2 was reduced by either siRNA or CRISPR/Cas9. METHODS: OVCAR5 cells were transiently and stably transfected with either single or pooled TIMP-2 siRNAs (T2-KD cells) or by CRISPR/Cas9 under the influence of two distinct guide RNAs (gRNA1 and gRNA2 cell lines). The expression of different genes was analysed at the mRNA level by quantitative real time PCR (qRT-PCR) and at the protein level by immunofluorescence (IF) and western blot. Proliferation of cells was investigated by 5-Ethynyl-2'-deoxyuridine (EdU) assay or staining with Ki67. Cell migration/invasion was determined by xCELLigence. Cell growth in vitro was determined by 3D spheroid cultures and in vivo by a mouse xenograft model. RESULTS: Approximately 70-90% knock down of TIMP-2 expression were confirmed in T2-KD, gRNA1 and gRNA2 OVCAR5 ovarian cancer cells at the protein level. T2-KD, gRNA1 and gRNA2 cells exhibited a significant downregulation of MMP-2 expression, but concurrently a significant upregulation in the expression of membrane bound MMP-14 compared to control and parental cells. Enhanced proliferation and invasion were exhibited in all TIMP-2 knocked down cells but differences in sensitivity to paclitaxel (PTX) treatment were observed, with T2-KD cells and gRNA2 cell line being sensitive, while the gRNA1 cell line was resistant to PTX treatment. In addition, significant differences in the growth of gRNA1 and gRNA2 cell lines were observed in in vitro 3D cultures as well as in an in vivo mouse xenograft model. CONCLUSIONS: Our results suggest that the inhibition of TIMP-2 by siRNA and CRISPR/Cas-9 modulate the expression of MMP-2 and MMP-14 and reprogram ovarian cancer cells to facilitate proliferation and invasion. Distinct disparities in in vitro chemosensitivity and growth in 3D culture, and differences in tumour burden and invasion to proximal organs in a mouse model imply that selective suppression of TIMP-2 expression by siRNA or CRISPR/Cas-9 alters important aspects of metastasis and chemosensitivity in ovarian cancer.

The centrality of cognition and coping styles in driving aggressive responses.

OBJECTIVE: Despite the presence of theoretical frameworks explaining aggression, they still require refinement in the form of a specification of mechanisms that facilitate such behaviour. METHOD: Study 1 recruited participants (N = 31) from the general population (N = 20) and from a forensic hospital (N = 11). It was expected that aggression supportive cognitions and stress would be positively associated with aggressive behaviour. An experimental paradigm was used to induce stress and participants were subsequently given the opportunity to aggress. Study 2 was based on self-report questionnaires in community sample (N = 462). It was expected that aggressive behaviour and traits would be associated with experienced stress, hostile attributions, coping styles, and attitudes to violence. Specifically, that criminal attitudes to violence will mediate the effect of hostile attribution on aggression, while coping styles will mediate the effect of perceived stress. RESULTS: An Implicit Theory "I am the law" was found to be associated with aggression. Furthermore, elevated skin conductance, but not changes in the heart rate, during the stress task was positively associated with aggression, and only among patients. Structural Equation Model confirmed the mediating role of criminal attitudes to violence and of maladaptive coping style for aggressive behaviour. CONCLUSION: Aggression-supportive cognitions and maladaptive coping style are specific mechanisms through which external demands or subjective perception of a situation can result in aggressive behaviour.

Structural plasticity enables evolution and innovation of RuBisCO assemblies.

Oligomerization is a core structural feature that defines the form and function of many proteins. Most proteins form molecular complexes; however, there remains a dearth of diversity-driven structural studies investigating the evolutionary trajectory of these assemblies. Ribulose-1,5-bisphosphate carboxylase-oxygenase (RuBisCO) is one such enzyme that adopts multiple assemblies, although the origins and distribution of its different oligomeric states remain cryptic. Here, we retrace the evolution of ancestral and extant form II RuBisCOs, revealing a complex and diverse history of oligomerization. We structurally characterize a newly discovered tetrameric RuBisCO, elucidating how solvent-exposed surfaces can readily adopt new interactions to interconvert or give rise to new oligomeric states. We further use these principles to engineer and demonstrate how changes in oligomerization can be mediated by relatively few mutations. Our findings yield insight into how structural plasticity may give rise to new oligomeric states.

Understanding the sleep-aggression relationship in a forensic mental health sample.

The contribution of cognition to the sleep-aggression relationship is explored via three connected studies, involving adult male forensic patients detained in a high secure hospital. Study 1 included 31 patients, interviewed to examine their experiences of specific sleep problems. In Study 2, 42 patients completed a series of measures examining sleep dysfunction, aggression, and cognition, while Study 3 was designed to impact on sleep via a cognitive approach. In the latter, 48 patients were randomly assigned as part of a feasibility trial to one of three conditions: mindfulness (cognitive approach), sleep education, and treatment as usual. Collectively, the studies demonstrated the multifaceted nature of cognition in the sleep-aggression relationship, with a need to account fully for cognitive factors. A preliminary conceptual model is outlined - the Cognitive Sleep Model for Aggression and Self Harm (CoSMASH), as a direction for future research to consider.