The human Shu complex promotes RAD51 activity by modulating RPA dynamics on ssDNA.

Templated DNA repair that occurs during homologous recombination and replication stress relies on RAD51. RAD51 activity is positively regulated by BRCA2 and the RAD51 paralogs. The Shu complex is a RAD51 paralog-containing complex consisting of SWSAP1, SWS1, and SPIDR.

The human Shu complex promotes RAD51 activity by modulating RPA dynamics on ssDNA.

Templated DNA repair that occurs during homologous recombination and replication stress relies on RAD51. RAD51 activity is positively regulated by BRCA2 and the RAD51 paralogs. The Shu complex is a RAD51 paralog-containing complex consisting of SWSAP1 and SWS1.

Variants in the first methionine of RAD51C are homologous recombination proficient due to an alternative start site.

In the 20+ years since the discovery of RAD51C, scientists have been perplexed as to how missense variants in this tumor suppressor gene impacts its function and pathogenicity. With a strong connection to breast and ovarian cancer, classifying these variants as pathogenic or benign aids in the diagnosis and treatment of patients with RAD51C variants. In particular, variants at translational starts sites are disruptive as they prevent protein expression.

Finding significance: New perspectives in variant classification of the RAD51 regulators, BRCA2 and beyond.

For many individuals harboring a variant of uncertain functional significance (VUS) in a homologous recombination (HR) gene, their risk of developing breast and ovarian cancer is unknown. Integral to the process of HR are BRCA1 and regulators of the central HR protein, RAD51, including BRCA2, PALB2, RAD51C and RAD51D. Due to advancements in sequencing technology and the continued expansion of cancer screening panels, the number of VUS identified in these genes has risen significantly.

Homologous recombination-deficient mutation cluster in tumor suppressor identified by comprehensive analysis of cancer variants.

Mutations in homologous recombination (HR) genes, including , , and the RAD51 paralog , predispose to tumorigenesis and sensitize cancers to DNA-damaging agents and poly(ADP ribose) polymerase inhibitors. However, ∼800 missense variants of unknown significance have been identified for RAD51C alone, impairing cancer risk assessment and therapeutic strategies. Here, we interrogated >50 RAD51C missense variants, finding that mutations in residues conserved with RAD51 strongly predicted HR deficiency and disrupted interactions with other RAD51 paralogs.

A Bayesian neural network predicts the dissolution of compact planetary systems.

We introduce a Bayesian neural network model that can accurately predict not only if, but also when a compact planetary system with three or more planets will go unstable. Our model, trained directly from short N-body time series of raw orbital elements, is more than two orders of magnitude more accurate at predicting instability times than analytical estimators, while also reducing the bias of existing machine learning algorithms by nearly a factor of three. Despite being trained on compact resonant and near-resonant three-planet configurations, the model demonstrates robust generalization to both nonresonant and higher multiplicity configurations, in the latter case outperforming models fit to that specific set of integrations.

RAD51 paralog function in replicative DNA damage and tolerance.

RAD51 paralog gene mutations are observed in both hereditary breast and ovarian cancers. Classically, defects in RAD51 paralog function are associated with homologous recombination (HR) deficiency and increased genomic instability. Several recent investigative advances have enabled characterization of non-canonical RAD51 paralog function during DNA replication.

Distinct pathways of homologous recombination controlled by the SWS1-SWSAP1-SPIDR complex.

Homology-directed repair (HDR), a critical DNA repair pathway in mammalian cells, is complex, leading to multiple outcomes with different impacts on genomic integrity. However, the factors that control these different outcomes are often not well understood. Here we show that SWS1-SWSAP1-SPIDR controls distinct types of HDR.

Predicting the long-term stability of compact multiplanet systems.

We combine analytical understanding of resonant dynamics in two-planet systems with machine-learning techniques to train a model capable of robustly classifying stability in compact multiplanet systems over long timescales of [Formula: see text] orbits. Our Stability of Planetary Orbital Configurations Klassifier (SPOCK) predicts stability using physically motivated summary statistics measured in integrations of the first [Formula: see text] orbits, thus achieving speed-ups of up to [Formula: see text] over full simulations. This computationally opens up the stability-constrained characterization of multiplanet systems.

Oxidative DNA Damage Modulates DNA Methylation Pattern in Human Breast Cancer 1 (BRCA1) Gene via the Crosstalk between DNA Polymerase β and a DNA Methyltransferase.

DNA damage and base excision repair (BER) are actively involved in the modulation of DNA methylation and demethylation. However, the underlying molecular mechanisms remain unclear. In this study, we seek to understand the mechanisms by exploring the effects of oxidative DNA damage on the DNA methylation pattern of the tumor suppressor breast cancer 1 (BRCA1) gene in the human embryonic kidney (HEK) HEK293H cells.

A Noninvasive, Economical, and Instant-Result Method to Diagnose and Monitor Type 2 Diabetes Using Pulse Wave: Case-Control Study.

Background: We should pay more attention to the long-term monitoring and early warning of type 2 diabetes and its complications. The traditional blood glucose tests are traumatic and cannot effectively monitor the development of diabetic complications. The development of mobile health is changing rapidly.

Determination of surface energies of hot-melt extruded sugar-starch pellets.

Hot-melt extruded sugar-starch pellets are an alternative for commercial sugar spheres, but their coating properties remain to be studied. Both the European Pharmcopoeia 8.6 and the United States Pharmacopoeia 40 specify the composition of sugar-starch pellets without giving requirements for the manufacturing process.

Modulation of trinucleotide repeat instability by DNA polymerase β polymorphic variant R137Q.

Trinucleotide repeat (TNR) instability is associated with human neurodegenerative diseases and cancer. Recent studies have pointed out that DNA base excision repair (BER) mediated by DNA polymerase β (pol β) plays a crucial role in governing somatic TNR instability in a damage-location dependent manner. It has been shown that the activities and function of BER enzymes and cofactors can be modulated by their polymorphic variations.

Coagulative safety of epidural catheters after major upper gastrointestinal surgery: advanced and routine coagulation analysis in 38 patients.

Background: The risk of spinal haematoma in patients receiving epidural catheters is estimated using routine coagulation tests, but guidelines are inconsistent in their recommendations on what to do when results indicate slight hypocoagulation. Postoperative patients are prone to thrombosis, and thromboelastometry has previously shown hypercoagulation in this setting. We aimed to better understand perioperative haemostasis by comparing results from routine and advanced tests, hypothesizing that patients undergoing major upper gastrointestinal surgery would be deficient in vitamin K-dependent coagulation factors because of malnutrition, or hypocoagulative because of accumulation of low molecular weight heparin (LMWH).

Continuous production of controlled release dosage forms based on hot-melt extruded gum arabic: Formulation development, in vitro characterization and evaluation of potential application fields.

Controlled release matrices based on gum arabic are prepared by applying a continuous hot-melt extrusion technology: the pre-mixture consisting of gum arabic and the incorporated API is plasticized by a co-rotating twin-screw extruder, an intermediate strand is formed by a round nozzle. Single dosed matrices are prepared by cutting the semi elastic strand with a rotary fly cutter. Paracetamol and phenazone are used as model drug substances.

Hot-melt extrusion of sugar-starch-pellets.

Sugar-starch-pellets (syn. sugar spheres) are usually manufactured through fluidized bed granulation or wet extrusion techniques. This paper introduces hot-melt extrusion (HME) as an alternative method to manufacture sugar-starch-pellets.

Some inconvenient truths about biosignatures involving two chemical species on Earth-like exoplanets.

The detection of strong thermochemical disequilibrium in the atmosphere of an extrasolar planet is thought to be a potential biosignature. In this article we present a previously unidentified kind of false positive that can mimic a disequilibrium or any other biosignature that involves two chemical species. We consider a scenario where the exoplanet hosts a moon that has its own atmosphere and neither of the atmospheres is in chemical disequilibrium.

A new method for the continuous production of single dosed controlled release matrix systems based on hot-melt extruded starch: analysis of relevant process parameters and implementation of an in-process control.

Purpose: In the present study, we evaluated a novel processing technique for the continuous production of hot-melt extruded controlled release matrix systems. A cutting technique derived from plastics industry, where it is widely used for cutting of cables and wires was adapted into the production line. Extruded strands were shaped by a rotary fly cutter.

Preparation of starch-based pellets by hot-melt extrusion.

Spherical starch pellets were directly and continuously produced using hot-melt extrusion and die-face pelletisation. In contrast to conventional pelletisation procedures, a discontinuous spheronisation step can be dropped. Pellets were produced based on four different starches (corn starch, pea starch, potato starch and waxy corn starch), four different active ingredients (ibuprofen, paracetamol, phenazon and tramadol-HCl) and various additives.

Complications and litigation in gynecologic endoscopy.

Most medical malpractice lawsuits that involve gynecologic endoscopy and laparoscopy result from either improper prevention, inadequate recognition, or delayed intervention. Continuing recognition of this will prevent many and mitigate most such cases. We can learn much from the events and rapid progress of the past decade.

Luminol-and lucigenin-amplified chemiluminescence with rat liver microsomes. Kinetics and influence of ascorbic acid, glutathione, dimethylsulfoxide, N-t-butyl-a-phenyl-nitrone, copper-ions and a copper complex, catalase, superoxide dismutase, hexobarbital and aniline.

For the investigation of luminol (LM)-and lucigenin (LC)-amplified chemiluminescence (CL) in rat liver microsomes using both a liquid-scintillation counter (LKB/Wallac 1219 Rackbeta) and a Berthold luminometer (AutoLumat LB 953) optimal incubation mixtures and conditions and basic kinetics have been established. Whereas calibration curves for both LM- and LC-CL are performed with hydrogenperoxide (LC quantum yield is 6.25 fold higher as that of LM), distinct differences were revealed with microsomes, indicating that different reactive oxygen species (ROS) are determined: Both LM- and LC-CL follow the kinetics of enzymatic reactions in terms of dependence on protein and NADPH or NADH concentration, time course, temperature etc.

The high-spin/low-spin equilibrium in cytochrome P-450--a new method for determination of the high-spin content.

A new method for determination of the population of the high-spin state (high-spin content) in ferric cytochrome P-450 is presented. Based on curve fitting the electronic absorption spectra with a linear combination of gaussian bands analytical functions for the pure high-spin and pure low-spin states were constructed. These functions were used to fit the high-spin/low-spin mixed spectra.

Cytochrome P-450 spin state and leakiness of the monooxygenase pathway.

1. The monooxygenase and oxidase activities of liver microsomes from phenobarbital (PB)-treated rabbits were investigated for their dependence on the high spin shift (delta alpha) of the ferric cytochrome P-450 induced by a series of benzphetamine analogues. 2.

Demethylation of tertiary amines by a reconstituted cytochrome P-450 enzyme system: kinetics of oxygen consumption and hydrogen peroxide formation.

Initial reaction rates of oxygen consumption and hydrogen peroxide formation in a cytochrome P-450 catalyzed reaction are practically independent of the nature of tertiary amines that were used as substrates. From the kinetic studies and the substrate conversion results that the amount of water formed in a side reaction is determined by the substrate specificity. Both hydrogen peroxide and water formation lower the efficiency of the monooxygenatic activity of cytochrome P-450.