Molecular mechanism and energetics of coupling between substrate binding and product release in the F1-ATPase catalytic cycle.

F1-ATPase is a motor protein that couples the rotation of its rotary [Formula: see text] subunit with ATP synthesis or hydrolysis. Single-molecule experiments indicate that nucleotide binding and release events occur almost simultaneously during the synthesis cycle, allowing the energy gain due to spontaneous binding of ADP to one catalytic [Formula: see text] subunit to be directly harnessed for driving the release of ATP from another rather than being dissipated as heat. Here, we examine the unknown mechanism of this coupling that is critical for an exceptionally high mechanochemical efficiency of F1-ATPase by means of all-atom free-energy simulations. We find that nondissipative and kinetically fast progression of the motor in the synthesis direction requires a concerted conformational change involving the closure of the ADP-binding [Formula: see text] subunit followed by the gradual opening of the ATP-releasing [Formula: see text] subunit over the course of the 30 to 40° rotary substep of the [Formula: see text] subunit. This rotary substep, preceding the ATP-dependent metastable state, allows for the recovery of a large portion of the ADP binding energy in the conformation of ATP-bound [Formula: see text] that gradually adopts the low-affinity conformation, captured also by the recent cryo-EM structure of this elusive state. The release of ATP from this nearly open conformation leads to its further opening, which enables the progression of the motor to the next catalytic metastable state. Our simulations explain this energy conversion mechanism in terms of intersubunit and ligand-protein interactions.

Measured and predicted freeze-thaw days frequencies in climate change conditions in central Poland.

The rate of progression of geomorphological phenomena is greatly influenced by freeze-thaw processes. In the face of air temperature increasing over the past few decades, a question of the future impact of these processes arises, notably in the temperate and cold climate zones. Using the mean, maximum and minimum daily air temperature data in the period 1951-2018 obtained from three weather stations located in the vicinity of Jeziorsko reservoir (central Poland), we have determined the mathematical correlation, described with a polynomial function, between the mean monthly air temperature and the monthly number of freeze-thaw days (FTD). A freeze-thaw day is a day when the maximum air temperature is above 0 °C while the minimum air temperature equals or is below this threshold. The number of FTDs within the study area averaged 64-71 and demonstrated a downward trend of 2-4 FTDs/10 years. The study period (1951-2018), includes a clearly marked distinct sub-period (1991-2018), when the reservoir was in operation, which experienced 58-68 FTDs. Considering the assumed rise in temperature, one should expect a further, though slightly slower, decline in the future number of FTDs. Depending on the accepted model of the temperature increase, which for the area of Poland (Central Europe) in the perspective of 30 years oscillates between +1.1 to +1.3 °C, the number of FTDs within the study area is expected to decline by -4.5 to -5.3 FTD, i.e. 6-7% and 5.4-5.5 FTD i.e. 8-9% respectively.

Accuracy of Pretreatment Ultrasonography Assessment of Intra-Abdominal Spread in Epithelial Ovarian Cancer: A Prospective Study.

The aim of this study was to test the accuracy of ultrasonography performed by gynecological oncologists for the preoperative assessment of epithelial ovarian cancer (EOC) spread in the pelvis and abdominal cavity. A prospective, observational cohort study was performed at a single tertiary cancer care unit. Patients with suspected EOC were recruited and underwent comprehensive transvaginal and abdominal ultrasonography performed by a gynecological oncologist. Sixteen intra-abdominal localizations and parameters were assessed using ultrasonography and compared with surgical-pathological status (reference standard). Sensitivity, specificity, positive and negative predictive values, and overall accuracy were calculated. Differences were analyzed using Fisher's exact and chi-square tests. Ultimately, we included 132 patients (median age 62 years), of whom 67% were in stage IIIC-IVB and 72% had serous cancer. Overall prediction accuracies for the involvement of the omentum, small bowel mesentery root, and frozen pelvis, and detecting ascites were >90%. Detecting the involvement of the pelvis peritoneum, liver and spleen hilum, and rectosigmoid colon, and predictions of disease stage and residual disease had overall accuracies of 80-90%. The lowest accuracy was for involvement of the abdominal peritoneum (69%) and diaphragm peritoneum (right 71%; left 75%) and surgical complexity prediction (77%). Stratification of results by presence or absence of ascites revealed significantly higher specificity of ultrasonography (clinically meaningful) for assessments of the abdominal/pelvic peritoneum, spleen hilum, and rectum wall, if there were ascites. A gynecological oncologist, experienced in surgery and sonology, performing comprehensive ultrasonography on patients with EOC can accurately detect intraperitoneal lesions and recognize critical disease manifestations and predict stage, surgical complexity, and residual disease, which allow accurate qualification of patients for primary debulking surgery or neoadjuvant chemotherapy.

Development and validation of a model that includes two ultrasound parameters and the plasma D-dimer level for predicting malignancy in adnexal masses: an observational study.

BACKGROUND: Pre-operative discrimination of malignant from benign adnexal masses is crucial for planning additional imaging, preparation, surgery and postoperative care. This study aimed to define key ultrasound and clinical variables and develop a predictive model for calculating preoperative ovarian tumor malignancy risk in a gynecologic oncology referral center. We compared our model to a subjective ultrasound assessment (SUA) method and previously described models. METHODS: This prospective, single-center observational study included consecutive patients. We collected systematic ultrasound and clinical data, including cancer antigen 125, D-dimer (DD) levels and platelet count. Histological examinations served as the reference standard. We performed univariate and multivariate regressions, and Bayesian information criterion (BIC) to assess the optimal model. Data were split into 2 subsets: training, for model development (190 observations) and testing, for model validation (n = 100). RESULTS: Among 290 patients, 52% had malignant disease, including epithelial ovarian cancer (72.8%), metastatic disease (14.5%), borderline tumors (6.6%), and non-epithelial malignancies (4.6%). Significant variables were included into a multivariate analysis. The optimal model, included three independent factors: solid areas, the color score, and the DD level. Malignant and benign lesions had mean DD values of 2.837 and 0.354 µg/ml, respectively. We transformed established formulae into a web-based calculator ( http://gin-onc-calculators.com/gynonc.php ) for calculating the adnexal mass malignancy risk. The areas under the curve (AUCs) for models compared in the testing set were: our model (0.977), Simple Rules risk calculation (0.976), Assessment of Different NEoplasias in the adneXa (ADNEX) (0.972), Logistic Regression 2 (LR2) (0.969), Risk of Malignancy Index (RMI) 4 (0.932), SUA (0.930), and RMI3 (0.912). CONCLUSIONS: Two simple ultrasound predictors and the DD level (also included in a mathematical model), when used by gynecologist oncologist, discriminated malignant from benign ovarian lesions as well or better than other more complex models and the SUA method. These parameters (and the model) may be clinically useful for planning adequate management in the cancer center. The model needs substantial validation.

Result of the 6-min walk test is an independent prognostic factor of surgically treated non-small-cell lung cancer.

OBJECTIVES: Pathological tumour, node and metastasis (TNM) stage remains the most significant prognostic factor of non-small-cell lung cancer (NSCLC). Meanwhile, age, gender, pulmonary function tests, the extent of surgical resection and the presence of concomitant diseases are commonly used to complete the prognostic profile of the patient with early stage of NSCLC. The aim of this study is to assess how the result of a 6-min walk test (6MWT) further assists in predicting the prognosis of NSCLC surgical candidates. METHODS: Six hundred and twenty-four patients who underwent surgical treatment for NSCLC between April 2009 and October 2011 were enrolled in this study. All patients were accepted for surgery on the basis of a standard evaluation protocol. Additionally, patients completed the 6MWT on the day before the surgery, and threshold values of the test were assessed based on both the Akaike information criterion and the coefficient of determination R2. Cox proportional hazards regression analysis was used to analyse the effect of important prognostic factors on the overall survival. RESULTS: Three hundred and ninety men and 234 women with a mean age of 64 years underwent radical surgical treatment for primary lung cancer. Five hundred and twenty-five lobectomies (84%), 77 pneumonectomies (12%) and 24 (4%) lesser resections were performed. Three hundred and thirty-one patients (53%) were treated for stage I NSCLC, 191 patients (31%) for stage II and 102 patients (16%) for stages IIIA-IV. A distance of 525 m in the 6MWT [hazard ratio (HR) = 0.57, 95% confidence interval (CI) 0.41-0.78, P < 0.001] was the threshold value differentiating the patients' prognoses (P < 0.001). Using the Cox proportional hazards regression analysis, pathological TNM stage (IIA: HR = 1.87, 95% CI 1.95-2.92, P = 0.006; IIB: HR = 2.03, 95% CI 1.23-3.37, P = 0.006; IIIA-IV: HR = 2.37, 95% CI 1.49-3.75, P < 0.001), male gender (HR = 1.88, 95% CI 1.26-2.79, P = 0.001), pneumonectomy (HR = 1.78, 95% CI 1.17-2.70, P < 0.001) and the results of the 6MWT (HR = 0.50, 95% CI 0.36-0.70, P < 0.001) were considered as independent predictive factors of overall survival. CONCLUSIONS: The result of a 6MWT is an independent and convenient prognostic factor of surgically treated non-small-cell lung cancer.