Probabilistic sequential matrix factorization

We introduce the probabilistic sequential matrix factorization (PSMF) method for factorizing time-varying and non-stationary datasets consisting of high-dimensional time-series. In particular, we consider nonlinear Gaussian state-space models where sequential approximate inference results in the factorization of a data matrix into a dictionary and time-varying coefficients with potentially nonlinear Markovian dependencies. The assumed Markovian structure on the coefficients enables us to encode temporal dependencies into a low-dimensional feature space. The proposed inference method is solely based on an approximate extended Kalman filtering scheme, which makes the resulting method particularly efficient. PSMF can account for temporal nonlinearities and, more importantly, can be used to calibrate and estimate generic differentiable nonlinear subspace models. We also introduce a robust version of PSMF, called rPSMF, which uses Student-t filters to handle model misspecification. We show that PSMF can be used in multiple contexts: modeling time series with a periodic subspace, robustifying changepoint detection methods, and imputing missing data in several high-dimensional time-series, such as measurements of pollutants across London.Comment: Accepted for publication at AISTATS 202

Probabilistic sequential matrix factorization

We introduce the probabilistic sequential matrix factorization (PSMF) method for factorizing time-varying and non-stationary datasets consisting of high-dimensional time-series. In particular, we consider nonlinear Gaussian state-space models where sequential approximate inference results in the factorization of a data matrix into a dictionary and time-varying coefficients with potentially nonlinear Markovian dependencies. The assumed Markovian structure on the coefficients enables us to encode temporal dependencies into a low-dimensional feature space. The proposed inference method is solely based on an approximate extended Kalman filtering scheme, which makes the resulting method particularly efficient. PSMF can account for temporal nonlinearities and, more importantly, can be used to calibrate and estimate generic differentiable nonlinear subspace models. We also introduce a robust version of PSMF, called rPSMF, which uses Student-t filters to handle model misspecification. We show that PSMF can be used in multiple contexts: modeling time series with a periodic subspace, robustifying changepoint detection methods, and imputing missing data in several high-dimensional time-series, such as measurements of pollutants across London

The effect of cavity-filling mutations on the thermostability of Bacillus stearothermophilus neutral protease

Cavities in the hydrophobic core of the neutral protease of Bacillus stearothermophilus were analyzed using a three-dimensional model that was inferred from the crystal structure of thermolysin, the highly homologous neutral protease of B.thermoproteolyticus (85% sequence identity). Site-directed mutagenesis was used to fill some of these cavities, thereby improving hydrophobic packing in the protein interior. The mutations had small effects on the thermostability, even after drastic changes, such as Leu284 --> Trp and Met168 --> Trp. The effects on T50, the temperature at which 50% of the enzyme is irreversibly inactivated in 30 min, ranged from 0.0 to +0.4-degrees-C. These results can be explained by assuming that the mutations have positive and negative structural effects of approximately the same magnitude. Alternatively, it could be envisaged that the local unfolding steps, which render the enzyme susceptible towards autolysis and which are rate limiting in the process of thermal inactivation, are only slightly affected by alterations in the hydrophobic core

Weekly high-dose cisplatin is a feasible treatment option: Analysis on prognostic factors for toxicity in 400 patients

In the present study we describe the toxicity of weekly high-dose (70-85 mg m-2) cisplatin in 400 patients (203 men, 197 women; median age 54 years) with advanced solid tumours treated in the period 1990-2001 who took part in phase I/II trials, investigating the feasibility and efficacy of weekly cisplatin alone, or in combination with paclitaxel or etoposide. Cisplatin was administered in 250 ml NaCl 3% over 3 h, for six intended administrations. The mean number of administrations was 53 (range, 1-6 administrations). Reasons not to complete six cycles were disease progression (7.5%), haematological toxicity (9%), nephrotoxicity (7%), ototoxicity (2.5%), neurotoxicity (1%), gastrointestinal toxicity (1%), cardiovascular complications (0.5%) or a combination of reasons including noncompliance and patient's request (5.5%). Logistic regression analysis was used to evaluate baseline parameters for prognostic value regarding toxicity. Leukopenia correlated with etoposide cotreatment, and thrombocytopenia with cisplatin dose and prior (platinum-based) chemotherapy. Risk factors for nephrotoxicity were older age, female gender, smoking, hypoalbuminaemia and paclitaxel coadministration. Neurotoxicity >grade I (11% of patients) was associated with prior chemotherapy and paclitaxel coadministration. Symptomatic hearing loss occurred in 15% with anaemia as the predisposing factor. We conclude that weekly high-dose cisplatin administered in hypertonic saline is a feasible treatment regimen

A phase II study of weekly high-dose cisplatin combined with oral etoposide in advanced non-small-cell lung cancer

As a dose-response relationship has been suggested for cisplatin, it appeared attractive to explore high-dose-intensity regimens in non-small-cell lung cancer. In a phase I study of weekly administration of cisplatin combined with oral etoposide we achieved a cisplatin dose intensity of 52.5-60 mg/m2 per week in most patients. We subsequently explored this regimen in advanced non-small-cell lung cancer. Patients were treated with cisplatin infused at 70 mg/m2 on days 1, 8, 15 and 29, 36, 43 in combination with oral etoposide given at 50 mg on days 1-15 and 29-43. Patients showing stable disease or a better response were continued on treatment with oral etoposide given at 50 mg/m2 per day on days 1-21 every 28 days for a maximum of four cycles. In all, 22 patients with stage III disease and 31 patients with stage IV disease entered the study. The median number of cisplatin administration was 6 per patient; 17 patients reached the planned cisplatin dose intensity of 60 mg/m2 per week, 11 patients achieved 52.5 mg/m2 per week, and 7 patients reached 47 mg/m2 per week. Overall, 11 of 21 stage III patients had a partial response [response rate 51%, 95% confidence interval (CI) 36-81%], as did 9 of 28 patients with stage IV disease (32%; 95% CI 15-49%). Toxicity was mainly hematologic, with leukocytopenia being the most frequent cause of treatment delay. Nephrotoxicity of grade 1 was observed in seven patients. Two patients developed clinical hearing loss. With this schedule a high median cisplatin dose intensity of 52.5-60 mg/m2 per week was reached. The 51% response rate achieved in stage III disease makes this schedule attractive for further exploration; however, it is not recommended for routine use in stage IV disease

INCREASING THE THERMOSTABILITY OF A NEUTRAL PROTEASE BY REPLACING POSITIVELY CHARGED AMINO-ACIDS IN THE N-TERMINAL TURN OF ALPHA-HELICES

The 247-260 and 289-299 alpha-helices of Bacillus subtilis neutral protease have a lysine in their N-terminal turn. These lysines were replaced by Ser or Asp in order to improve electrostatic interactions with the alpha-helix dipole. After replacing Lys by Ser at positions 249 or 290, the thermostability of the enzyme was increased by 0.3 and 1.0-degrees-C, respectively. The Asp249 and Asp290 mutants exhibited a stabilization of 0.6 and 1.2-degrees-C, respectively. The results show the feasibility of stabilizing enzymes by introducing favourable residues at the end of alpha-helices