Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer.

Background: Resistance to therapies that target homologous recombination deficiency (HRD) in breast cancer limits their overall effectiveness. Multiple, preclinically validated, mechanisms of resistance have been proposed, but their existence and relative frequency in clinical disease are unclear, as is how to target resistance.

Patients And Methods: Longitudinal mutation and methylation profiling of circulating tumour (ct)DNA was carried out in 47 patients with metastatic BRCA1-, BRCA2- or PALB2-mutant breast cancer treated with HRD-targeted therapy who developed progressive disease-18 patients had primary resistance and 29 exhibited response followed by resistance.

MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells.

The PSMC3IP-MND1 heterodimer promotes meiotic D loop formation before DNA strand exchange. In genome-scale CRISPR-Cas9 mutagenesis and interference screens in mitotic cells, depletion of PSMC3IP or MND1 causes sensitivity to poly (ADP-Ribose) polymerase inhibitors (PARPi) used in cancer treatment. PSMC3IP or MND1 depletion also causes ionizing radiation sensitivity.

Thermal and Mechanical Properties of Concrete Incorporating Silica Fume and Waste Rubber Powder.

Using waste rubber tires for concrete production will reduce the demand for natural aggregate and help to reduce environmental pollution. The main challenge of using waste rubber tires in concrete is the deterioration of mechanical properties, due to poor bonding between rubber and cement matrix. This research aims to evaluate the mechanical and thermal properties of rubberised concrete produced by using different proportions of rubber powder and silica fume.

Potential application of spent mushroom compost (SMC) biochar as low-cost filtration media in heavy metal removal from abandoned mining water: a review.

Overpopulation and rapid development have put an increasing burden on the environment, leading to various water crisis. Importing water from abandoned mines as an alternative raw water source could be the next answer to alleviate water scarcity problems globally. However, due to its high heavy metals content, there is a need to find an economical and effective method to remove heavy metals before reusing it as potable water source.

The multifaceted hTR telomerase RNA from a structural perspective: Distinct domains of hTR differentially interact with protein partners to orchestrate its telomerase-independent functions.

Human telomerase progressively emerged as a multifaceted ribonucleoprotein complex with additional functions beyond telomeric repeat synthesis. Both the hTERT catalytic subunit and the hTR long non-coding RNA (lncRNA) subunit are engaged in highly regulated cellular pathways that, together, contribute to cell fitness and protection against apoptosis. We recently described a new role for hTR in regulating the abundance of replication protein A at telomeres, adding to the growing repertoire of hTR's functions.

NHP2 downregulation counteracts hTR-mediated activation of the DNA damage response at ALT telomeres.

About 10% of cancer cells employ the "alternative lengthening of telomeres" (ALT) pathway instead of re-activating the hTERT subunit of human telomerase. The hTR RNA subunit is also abnormally silenced in some ALT cells not expressing hTERT, suggesting a possible negative non-canonical impact of hTR on ALT. Indeed, we show that ectopically expressed hTR reduces phosphorylation of ssDNA-binding protein RPA (p-RPA ) at ALT telomeres by promoting the hnRNPA1- and DNA-PK-dependent depletion of RPA.

Initialization of quantum simulators by sympathetic cooling.

Simulating computationally intractable many-body problems on a quantum simulator holds great potential to deliver insights into physical, chemical, and biological systems. While the implementation of Hamiltonian dynamics within a quantum simulator has already been demonstrated in many experiments, the problem of initialization of quantum simulators to a suitable quantum state has hitherto remained mostly unsolved. Here, we show that already a single dissipatively driven auxiliary particle can efficiently prepare the quantum simulator in a low-energy state of largely arbitrary Hamiltonians.

Numerical and Experimental Investigation of Oil Palm Shell Reinforced Rubber Composites.

This paper presents a pioneering effort to ascertain the suitability of hyperelastic modelling in simulating the stress-strain response of oil palm shell reinforced rubber (ROPS) composites. ROPS composites with different oil palm shell contents (0%, 5%, 10% and 20% by volume) were cast in the laboratory for the experimental investigation. ROPS specimens with circular, square, hexagon, and octagon shapes (loading surface) were considered to evaluate the accuracy of finite element simulation considering the shape effect of composites.

Functional cross talk between the Fanconi anemia and ATRX/DAXX histone chaperone pathways promotes replication fork recovery.

Fanconi anemia (FA) is a chromosome instability syndrome characterized by increased cancer predisposition. Specifically, the FA pathway functions to protect genome stability during DNA replication. The central FA pathway protein, FANCD2, locates to stalled replication forks and recruits homologous recombination (HR) factors such as CtBP interacting protein (CtIP) to promote replication fork restart while suppressing new origin firing.

A facile water-induced complexation of lycopene and pectin from pink guava byproduct: Extraction, characterization and kinetic studies.

The redfleshed pulp discarded from pink guava puree industry is a rich source of lycopene and pectin. In this study, we developed a facile extraction process employing water as the primary extraction medium to isolate the lycopene and pectin from pink guava decanter. When the decanter was suspended in water, the complexation of lycopene and pectin formed the cloudy solution, where the colloidal complexes were recovered through centrifugation.

High-Density Quantum Sensing with Dissipative First Order Transitions.

The sensing of external fields using quantum systems is a prime example of an emergent quantum technology. Generically, the sensitivity of a quantum sensor consisting of N independent particles is proportional to sqrt[N]. However, interactions invariably occurring at high densities lead to a breakdown of the assumption of independence between the particles, posing a severe challenge for quantum sensors operating at the nanoscale.

FANCI and FANCD2 have common as well as independent functions during the cellular replication stress response.

Fanconi anemia (FA) is an inherited cancer predisposition syndrome characterized by cellular hypersensitivity to DNA interstrand crosslinks (ICLs). To repair these lesions, the FA proteins act in a linear hierarchy: following ICL detection on chromatin, the FA core complex monoubiquitinates and recruits the central FANCI and FANCD2 proteins that subsequently coordinate ICL removal and repair of the ensuing DNA double-stranded break by homology-dependent repair (HDR). FANCD2 also functions during the replication stress response by mediating the restart of temporarily stalled replication forks thereby suppressing the firing of new replication origins.

Isolation, characterization and the potential use of starch from jackfruit seed wastes as a coagulant aid for treatment of turbid water.

Fruit wastes constituting up to half of total fruit weight represent a large pool of untapped resources for isolation of starch with diverse applications. In this work, the possibility of isolating starch from tropical fruit wastes and its extended application as a natural coagulant was elucidated. Amongst the 12 various parts of fruit wastes selected, only jackfruit seeds contained more than 50% of total starch content.

FANCD2, FANCJ and BRCA2 cooperate to promote replication fork recovery independently of the Fanconi Anemia core complex.

Fanconi Anemia (FA) is an inherited multi-gene cancer predisposition syndrome that is characterized on the cellular level by a hypersensitivity to DNA interstrand crosslinks (ICLs). To repair these lesions, the FA pathway proteins are thought to act in a linear hierarchy: Following ICL detection, an upstream FA core complex monoubiquitinates the central FA pathway members FANCD2 and FANCI, followed by their recruitment to chromatin. Chromatin-bound monoubiquitinated FANCD2 and FANCI subsequently coordinate DNA repair factors including the downstream FA pathway members FANCJ and FANCD1/BRCA2 to repair the DNA ICL.

Utilization of plant-based natural coagulants as future alternatives towards sustainable water clarification.

Rapid industrial developments coupled with surging population growth have complicated issues dealing with water scarcity as the quest for clean and sanitized water intensifies globally. Existing fresh water supplies could be contaminated with organic, inorganic and biological matters that have potential harm to the society. Turbidity in general is a measure of water cloudiness induced by such colloidal and suspended matters and is also one of the major criteria in raw water monitoring to meet the stipulated water quality guidelines.

FANCD2 regulates BLM complex functions independently of FANCI to promote replication fork recovery.

Fanconi Anemia (FA) and Bloom Syndrome share overlapping phenotypes including spontaneous chromosomal abnormalities and increased cancer predisposition. The FA protein pathway comprises an upstream core complex that mediates recruitment of two central players, FANCD2 and FANCI, to sites of stalled replication forks. Successful fork recovery depends on the Bloom's helicase BLM that participates in a larger protein complex ('BLMcx') containing topoisomerase III alpha, RMI1, RMI2 and replication protein A.

Laparoscopic remodeling of abdominal aortic aneurysms after endovascular exclusion: a technical description.

We report our experience with a novel combined laparoscopic-endovascular procedure to treat endoleaks and graft migration. The operative procedure consisted of the following steps: laparoscopic exposure of the aorta, clipping of lumbar arteries and of the inferior mesenteric artery, incision of the sac of the aneurysm without clamping the aorta, and removal of thrombus material. Laparoscopic sutures were placed externally to attach the endograft to the aortic neck.