Cryo-EM structure of a helicase loading intermediate containing ORC-Cdc6-Cdt1-MCM2-7 bound to DNA

In eukaryotes, the Cdt1-bound replicative helicase core MCM2-7 is loaded onto DNA by the ORC-Cdc6 ATPase to form a prereplicative complex (pre-RC) with an MCM2-7 double hexamer encircling DNA. Using purified components in the presence of ATP-γS, we have captured in vitro an intermediate in pre-RC assembly that contains a complex between the ORC-Cdc6 and Cdt1-MCM2-7 heteroheptamers called the OCCM. Cryo-EM studies of this 14-subunit complex reveal that the two separate heptameric complexes are engaged extensively, with the ORC-Cdc6 N-terminal AAA+ domains latching onto the C-terminal AAA+ motor domains of the MCM2-7 hexamer. The conformation of ORC-Cdc6 undergoes a concerted change into a right-handed spiral with helical symmetry that is identical to that of the DNA double helix. The resulting ORC-Cdc6 helicase loader shows a notable structural similarity to the replication factor C clamp loader, suggesting a conserved mechanism of action

MiR-107 and MiR-185 Can Induce Cell Cycle Arrest in Human Non Small Cell Lung Cancer Cell Lines

Background: MicroRNAs (miRNAs) are short single stranded noncoding RNAs that suppress gene expression through either translational repression or degradation of target mRNAs. The annealing between messenger RNAs and 5' seed region of miRNAs is believed to be essential for the specific suppression of target gene expression. One miRNA can have several hundred different targets in a cell. Rapidly accumulating evidence suggests that many miRNAs are involved in cell cycle regulation and consequentially play critical roles in carcinogenesis. Methodology/Principal Findings: Introduction of synthetic miR-107 or miR-185 suppressed growth of the human non-small cell lung cancer cell lines. Flow cytometry analysis revealed these miRNAs induce a G1 cell cycle arrest in H1299 cells and the suppression of cell cycle progression is stronger than that by Let-7 miRNA. By the gene expression analyses with oligonucleotide microarrays, we find hundreds of genes are affected by transfection of these miRNAs. Using miRNA-target prediction analyses and the array data, we listed up a set of likely targets of miR-107 and miR-185 for G1 cell cycle arrest and validate a subset of them using real-time RT-PCR and immunoblotting for CDK6. Conclusions/Significance: We identified new cell cycle regulating miRNAs, miR-107 and miR-185, localized in frequently altered chromosomal regions in human lung cancers. Especially for miR-107, a large number of down-regulated genes are annotated with the gene ontology term 'cell cycle'. Our results suggest that these miRNAs may contribute to regulate cell cycle in human malignant tumors.Full Tex

Design and development of a complex narrative intervention delivered by text messages to reduce binge drinking among socially disadvantaged men

Background: Socially disadvantaged men are at high risk of suffering from alcohol-related harm. Disadvantaged groups are less likely to engage with health promotion. There is a need for interventions that reach large numbers at low cost and which promote high levels of engagement with the behaviour change process. The aim of this study was to design a theoretically and empirically based text message intervention to reduce binge drinking by socially disadvantaged men. Results: Following MRC guidance, the intervention was developed in four stages. Stage 1 developed a detailed behaviour change strategy based on existing literature and theory from several areas. These included the psychological theory that would underpin the intervention, alcohol brief interventions, text message interventions, effective behaviour change techniques, narratives in behaviour change interventions and communication theory. In addition, formative research was carried out. A logic model was developed to depict the pathways between intervention inputs, processes and outcomes for behaviour change. Stage 2 created a narrative which illustrated and modelled key steps in the strategy. Stage 3 rendered the intervention into a series of text messages and ensured that appropriate behavioural change techniques were incorporated. Stage 4 revised the messages to ensure comprehensive coverage of the behaviour change strategy and coherence of the narrative. It also piloted the intervention and made final revisions to it. Conclusions: The structured, systematic approach to design created a narrative intervention which had a strong theoretical and empirical basis. The use of a narrative helped make the intervention realistic and allowed key behaviour change techniques to be modelled by characters. The narrative was intended to promote engagement with the intervention. The intervention was rendered into a series of short text messages, and subsequent piloting showed they were acceptable in the target group. Delivery of an intervention by text message offers a low-cost, low-demand method that can reach large numbers of people. This approach provides a framework for the design of behaviour change interventions which could be used for interventions to tackle other health behaviours

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Internet-based early intervention to prevent poststraumatic stress disorder in injury patients: Randomized controlled trial.

Background: Posttraumatic stress disorder (PTSD) develops in 10-20% of injury patients. We developed a novel, self-guided Internet-based intervention (called Trauma TIPS) based on techniques from cognitive behavioral therapy (CBT) to prevent the onset of PTSD symptoms. Objective: To determine whether Trauma TIPS is effective in preventing the onset of PTSD symptoms in injury patients. Methods: Adult, level 1 trauma center patients were randomly assigned to receive the fully automated Trauma TIPS Internet intervention (n=151) or to receive no early intervention (n=149). Trauma TIPS consisted of psychoeducation, in vivo exposure, and stress management techniques. Both groups were free to use care as usual (nonprotocolized talks with hospital staff). PTSD symptom severity was assessed at 1, 3, 6, and 12 months post injury with a clinical interview (Clinician-Administered PTSD Scale) by blinded trained interviewers and self-report instrument (Impact of Event Scale-Revised). Secondary outcomes were acute anxiety and arousal (assessed online), self-reported depressive and anxiety symptoms (Hospital Anxiety and Depression Scale), and mental health care utilization. Intervention usage was documented. Results: The mean number of intervention logins was 1.7, SD 2.5, median 1, interquartile range (IQR) 1-2. Thirty-four patients in the intervention group did not log in (22.5%), 63 (41.7%) logged in once, and 54 (35.8%) logged in multiple times (mean 3.6, SD 3.5, median 3, IQR 2-4). On clinician-assessed and self-reported PTSD symptoms, both the intervention and control group showed a significant decrease over time (P<.001) without significant differences in trend. PTSD at 12 months was diagnosed in 4.7% of controls and 4.4% of intervention group patients. There were no group differences on anxiety or depressive symptoms over time. Post hoc analyses using latent growth mixture modeling showed a significant decrease in PTSD symptoms in a subgroup of patients with severe initial symptoms (n=20) (P<.001). Conclusions: Our results do not support the efficacy of the Trauma TIPS Internet-based early intervention in the prevention of PTSD symptoms for an unselected population of injury patients. Moreover, uptake was relatively low since one-fifth of individuals did not log in to the intervention. Future research should therefore focus on innovative strategies to increase intervention usage, for example, adding gameplay, embedding it in a blended care context, and targeting high-risk individuals who are more likely to benefit from the intervention

Оценка качества образования на основе компетентностного подхода

В работе представлен практический опыт оценки качества образования в новом формате компетентностного подход

Prevalence and treatment implications of ICD-11 complex PTSD in Australian treatment-seeking current and ex-serving military members

Background: Despite growing support for the distinction between posttraumatic stress disorder (PTSD) and complex PTSD (CPTSD) as separate diagnoses within the ICD-11 psychiatric taxonomy, the prevalence and treatment implications of CPTSD among current and ex-serving military members have not been established. Objective: The study aims were to a) establish the prevalence of provisional ICD-11 CPTSD diagnosis relative to PTSD in an Australian sample of treatment-seeking current and ex-serving military members, and b) examine the implications of CPTSD diagnosis for intake profile and treatment response. Methods: The study analysed data collected routinely from Australian-accredited treatment programmes for military-related PTSD. Participants were 480 current and ex-serving military members in this programmes who received a provisional ICD-11 diagnosis of PTSD or CPTSD at intake using proxy measures. Measures of PTSD symptoms, disturbances in self-organisation, psychological distress, mental health and social relationships were considered at treatment intake, discharge, and 3-month follow-up. Results: Among participants with a provisional ICD-11 diagnosis, 78.2% were classified as having CPTSD, while 21.8% were classified as having PTSD. When compared to ICD-11 PTSD, participants with CPTSD reported greater symptom severity and psychological distress at intake, and lower scores on relationship and mental health dimensions of the quality of life measure. These relative differences persisted at each post-treatment assessment. Decreases in PTSD symptoms between intake and discharge were similar across PTSD (dRM = −0.81) and CPTSD (dRM = −0.76) groups, and there were no significant post-treatment differences between groups when controlling for initial scores. Conclusions: CPTSD is common among treatment-seeking current and ex-serving military members, and is associated with initially higher levels of psychiatric severity, which persist over time. Participants with CPTSD were equally responsive to PTSD treatment; however, the tendency for those with CPTSD to remain highly symptomatic post-treatment suggests additional treatment components should be considered

Mental health: A cause or consequence of injury? A population-based matched cohort study

BACKGROUND: While a number of studies report high prevalence of mental health problems among injured people, the temporal relationship between injury and mental health service use has not been established. This study aimed to quantify this relationship using 10 years of follow-up on a population-based cohort of hospitalised injured adults. METHODS: The Manitoba Injury Outcome Study is a retrospective population-based matched cohort study that utilised linked administrative data from Manitoba, Canada, to identify an inception cohort (1988–1991) of hospitalised injured cases (ICD-9-CM 800–995) aged 18–64 years (n = 21,032), which was matched to a non-injured population-based comparison group (n = 21,032). Pre-injury comorbidity and post-injury mental health data were obtained from hospital and physician claims records. Negative Binomial regression was used to estimate adjusted rate ratios (RRs) to measure associations between injury and mental health service use. RESULTS: Statistically significant differences in the rates of mental health service use were observed between the injured and non-injured, for the pre-injury year and every year of the follow-up period. The injured cohort had 6.56 times the rate of post-injury mental health hospitalisations (95% CI 5.87, 7.34) and 2.65 times the rate of post-injury mental health physician claims (95% CI 2.53, 2.77). Adjusting for comorbidities and pre-existing mental health service use reduced the hospitalisations RR to 3.24 (95% CI 2.92, 3.60) and the physician claims RR to 1.53 (95% CI 1.47, 1.59). CONCLUSION: These findings indicate the presence of pre-existing mental health conditions is a potential confounder when investigating injury as a risk factor for subsequent mental health problems. Collaboration with mental health professionals is important for injury prevention and care, with ongoing mental health support being a clearly indicated service need by injured people and their families. Public health policy relating to injury prevention and control needs to consider mental health strategies at the primary, secondary and tertiary level

Incidence of synchronous appendiceal neoplasm in patients with colorectal cancer and its clinical significance

<p>Abstract</p> <p>Background</p> <p>The aims of this study were to evaluate the incidence of synchronous appendiceal neoplasm in patients with colorectal cancer, and to determine its clinical significance.</p> <p>Methods</p> <p>Pathological reports and medical records were reviewed of patients with colorectal adenocarcinoma who underwent oncological resection of the tumor together with appendectomy at the Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand between September 2000 and April 2008.</p> <p>Results</p> <p>This study included 293 patients with an average age of 62 years (range 19–95) and 51 percent were male. Of the patients studied, 228 (78 percent) had right hemicolectomy, whereas the others (22 percent) had surgery for left-sided colon cancer or rectal cancer. One patient (0.3 percent) had epithelial appendiceal neoplasm (mucinous cystadenoma) and 3 patients (1.0 percent) had metastatic colorectal cancer in the mesoappendix. However, the presence of synchronous appendiceal tumors and/or metastasis did not alter postoperative management, as these patients had received adjuvant therapy and were scheduled for surveillance program because of nodal involvement.</p> <p>Conclusion</p> <p>The incidence of synchronous primary appendiceal neoplasm and secondary (metastatic) appendiceal neoplasm in colorectal cancer patients was 0.3 and 1.0 percent, respectively. However, these findings did not change the postoperative clinical management.</p

Prediction of posttraumatic stress disorder among adults in flood district

<p>Abstract</p> <p>Background</p> <p>Flood is one of the most common and severe forms of natural disasters. Posttraumatic stress disorder (PTSD) is a common disorder among victims of various disasters including flood. Early prediction for PTSD could benefit the prevention and treatment of PTSD. This study aimed to establish a prediction model for the occurrence of PTSD among adults in flood districts.</p> <p>Methods</p> <p>A cross-sectional survey was carried out in 2000 among individuals who were affected by the 1998 floods in Hunan, China. Multi-stage sampling was used to select subjects from the flood-affected areas. Data was collected through face-to-face interviews using a questionnaire. PTSD was diagnosed according to DSM-IV criteria. Study subjects were randomly divided into two groups: group 1 was used to establish the prediction model and group 2 was used to validate the model. We first used the logistic regression analysis to select predictive variables and then established a risk score predictive model. The validity of model was evaluated by using the model in group 2 and in all subjects. The area under the receiver operation characteristic (ROC) curve was calculated to evaluate the accuracy of the prediction model.</p> <p>Results</p> <p>A total of 2336 (9.2%) subjects were diagnosed as probable PTSD-positive individuals among a total of 25,478 study subjects. Seven independent predictive factors (age, gender, education, type of flood, severity of flood, flood experience, and the mental status before flood) were identified as key variables in a risk score model. The area under the ROC curve for the model was 0.853 in the validation data. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of this risk score model were 84.0%, 72.2%, 23.4%, and 97.8%, respectively, at a cut-off value of 67.5 in the validation data.</p> <p>Conclusions</p> <p>A simple risk score model can be used to predict PTSD among victims of flood.</p