Fabrication tolerant multi-layer integrated photonic topology optimization.

Optimal multi-layer device design requires consideration of fabrication uncertainties associated with inter-layer alignment and conformal layering. We present layer-restricted topology optimization (TO), which we believe to be a novel technique which mitigates the effects of unwanted conformal layering for multi-layer structures and enables TO in multi-etch material platforms. We explore several approaches to achieve this result compatible with density-based TO projection techniques and geometric constraints.

Use of Renewable Alcohols in Autocatalytic Production of Aspen Organosolv Lignins.

This study aimed to investigate the intrinsic efficiency of renewable alcohols, applied under autocatalytic conditions, for removing lignin from aspen and hot-water-extracted aspen while substantially preserving the lignin structure so as to facilitate various valorization strategies. Ethylene glycol (EG), propylene glycol (PG), 1,4-butanediol (BDO), ethanol (EtOH), and tetrahydrofurfuryl alcohol (THFA) were evaluated based on their lignin solubilization ability, expressed as the relative energy difference (RED) following the principles of the Hansen solubility theory. The findings indicate that alcohols with a higher lignin solubilization potential lead to increased delignification, almost 90%, and produce a lignin with a higher content of β-O-4 bonds, up to 68% of those found in aspen milled wood lignin, thereby indicating their potential for valorization through depolymerization.

Apicoplast-derived isoprenoids are essential for biosynthesis of GPI protein anchors, and consequently for egress and invasion in Plasmodium falciparum.

Glycophosphatidylinositol (GPI) anchors are the predominant glycoconjugate in Plasmodium parasites, enabling modified proteins to associate with biological membranes. GPI biosynthesis commences with donation of a mannose residue held by dolichol-phosphate at the endoplasmic reticulum membrane. In Plasmodium dolichols are derived from isoprenoid precursors synthesised in the Plasmodium apicoplast, a relict plastid organelle of prokaryotic origin.

Effect of substituents on the ability of nickel Schiff base complexes with four pendant groups to bind to G-quadruplexes.

The synthesis of eleven new nickel Schiff base complexes each bearing four pendant groups is reported. The structures of the complexes differ in the identity of the pendant groups and/or diamine moiety. All complexes were characterised by microanalysis, Nuclear Magnetic Resonance (NMR) spectroscopy and Electrospray Ionisation Mass Spectrometry (ESI-MS), while the solid-state structures of two of the molecules were also determined using X-ray crystallographic methods.

DNA N-glycosylases Ogg1 and EndoIII as components of base excision repair in Plasmodium falciparum organelles.

The integrity of genomes of the two crucial organelles of the malaria parasite - an apicoplast and mitochondrion in each cell - must be maintained by DNA repair mediated by proteins targeted to these compartments. We explored the localisation and function of Plasmodium falciparum base excision repair (BER) DNA N-glycosylase homologs PfEndoIII and PfOgg1. These N-glycosylases would putatively recognise DNA lesions prior to the action of apurinic/apyrimidinic (AP)-endonucleases.

G-quadruplex DNA binding properties of novel nickel Schiff base complexes with four pendant groups.

Three new nickel Schiff base complexes were prepared using a two-step procedure that involves initial selective dialkylation of 2,4,6-trihydroxybenzaldehyde, followed by reaction with 1,2-phenylenediamine and nickel(II) acetate. Each of the complexes possessed the same Schiff base core but differed in the identity of the four pendant groups. All complexes were characterised by microanalysis, NMR spectroscopy and ESI mass spectrometry.

Therapeutic Targeting of Mitochondrial Plasticity and Redox Control to Overcome Cancer Chemoresistance.

Mitochondria are subcellular organelles performing essential metabolic functions contributing to cellular bioenergetics and regulation of cell growth or death. The basic mitochondrial function in fulfilling the need for cell growth and vitality is evidenced whereby cancer cells with depleted mitochondrial DNA (rho zero, p cells) no longer form tumors until newly recruited mitochondria are internalized into the rho zero cells. Herein lies the absolute dependency on mitochondria for tumor growth.

Nonsense-mediated decay machinery in is inefficient and non-essential.

Nonsense-mediated decay (NMD) is a conserved mRNA quality control process that eliminates transcripts bearing a premature termination codon. In addition to its role in removing erroneous transcripts, NMD is involved in post-transcriptional regulation of gene expression via programmed intron retention in metazoans. The apicomplexan parasite shows relatively high levels of intron retention, but it is unclear whether these variant transcripts are functional targets of NMD.

Understanding G-Quadruplex Biology and Stability Using Single-Molecule Techniques.

The link between the chemical stability of G-quadruplex (qDNA) structures and their roles in eukaryotic genomic maintenance processes has been an area of interest now for several decades. This Review seeks to demonstrate how single-molecule force-based techniques can provide insight into the mechanical stabilities of a variety of qDNA structures as well as their ability to interconvert between different conformations under conditions of stress. Atomic force microscopy (AFM) and magnetic and optical tweezers have been the primary tools used in these investigations and have been used to examine both free and ligand-stabilized G-quadruplex structures.

Mitoribosome sensitivity to HSP70 inhibition uncovers metabolic liabilities of castration-resistant prostate cancer.

The androgen receptor is a key regulator of prostate cancer and the principal target of current prostate cancer therapies collectively termed androgen deprivation therapies. Insensitivity to these drugs is a hallmark of progression to a terminal disease state termed castration-resistant prostate cancer. Therefore, novel therapeutic options that slow progression of castration-resistant prostate cancer and combine effectively with existing agents are in urgent need.

Conservation, abundance, glycosylation profile, and localization of the TSP protein family in Cryptosporidium parvum.

Cryptosporidium parvum is a zoonotic apicomplexan parasite and a common cause of diarrheal disease worldwide. The development of vaccines to prevent or limit infection remains an important goal for tackling cryptosporidiosis. At present, the only approved vaccine against any apicomplexan parasite targets a conserved adhesin possessing a thrombospondin repeat domain.

Multi-layer inverse design of vertical grating couplers for high-density, commercial foundry interconnects.

Density-based topology optimization is used to design large-scale, multi-layer grating couplers that comply with commercial foundry fabrication constraints while simultaneously providing beam profiles that efficiently couple to a single-mode optical fiber without additional optics. Specifically, we describe the design process and experimentally demonstrate both single- and dual-polarization grating couplers that couple at normal incidence (0° from the normal) with low backreflections (-13.7 dB and -15.

Intratumoral pro-oxidants promote cancer immunotherapy by recruiting and reprogramming neutrophils to eliminate tumors.

Neutrophils have recently gained recognition for their potential in the fight against cancer. Neutrophil plasticity between the N1 anti-tumor and N2 pro-tumor subtypes is now apparent, as is the ability to polarize these individual subtypes by interventions such as intratumoral injection of various agents including bacterial products or pro-oxidants. Metabolic responses and the production of reactive oxygen species (ROS) such as hydrogen peroxide act as potent chemoattractants and activators of N1 neutrophils that facilitates their recruitment and ensuing activation of a toxic respiratory burst in tumors.

3, 2, 1, go! Cryptosporidium counts down to sex.

Cryptosporidium is a leading cause of death from childhood diarrhea, but its biology is poorly understood. A recent study in PLOS Biology reveals hitherto unknown aspects of the parasite's life cycle that may lead to improvements in ex vivo culture.

The AAA+ ATPase p97 as a novel parasite and tuberculosis drug target.

The multifunctional AAA+ ATPase p97 is an unfoldase/segregase involved in various cellular processes and present in all kingdoms of life. In mammals and yeast, p97 functions upstream of the proteasome. Interestingly, proteasome inhibitors targeting pathogenic microorganisms display efficacy in overcoming drug-resistant strains.

High-performance hybrid time/frequency-domain topology optimization for large-scale photonics inverse design.

We present a photonics topology optimization (TO) package capable of addressing a wide range of practical photonics design problems, incorporating robustness and manufacturing constraints, which can scale to large devices and massive parallelism. We employ a hybrid algorithm that builds on a mature time-domain (FDTD) package Meep to simultaneously solve multiple frequency-domain TO problems over a broad bandwidth. This time/frequency-domain approach is enhanced by new filter-design sources for the gradient calculation and new material-interpolation methods for optimizing dispersive media, as well as by multiple forms of computational parallelism.

Constellation-based identification of linear and nonlinear OSNR using machine learning: a study of link-agnostic performance.

We demonstrate accurate estimation of generalized optical signal to noise ratio (GOSNR) for wavelength division multiplexed fiber communication systems using an experimentally trained multi-tasking convolutional neural network while simultaneously estimating linear and nonlinear noise contributions. Using dual-polarized 32-GBaud 16QAM DWDM links we extract learnable features from constellation density matrices and accurately estimate GOSNR while simultaneously estimating linear and nonlinear contributions. Estimation of the OSNR, OSNR and GOSNR are demonstrated with < 0.

Chromosome-level genome of Schistosoma haematobium underpins genome-wide explorations of molecular variation.

Urogenital schistosomiasis is caused by the blood fluke Schistosoma haematobium and is one of the most neglected tropical diseases worldwide, afflicting > 100 million people. It is characterised by granulomata, fibrosis and calcification in urogenital tissues, and can lead to increased susceptibility to HIV/AIDS and squamous cell carcinoma of the bladder. To complement available treatment programs and break the transmission of disease, sound knowledge and understanding of the biology and ecology of S.

Is the AT-rich DNA of malaria parasites a drug target?

A recent antimalarial screen by Alder and colleagues has uncovered a natural product, PDE-I, with DNA-binding and schizonticidal activity against Plasmodium falciparum. Parasite specificity is likely conferred by the extremely high A+T content of the P. falciparum genome.

Targeting the redox imbalance in mitochondria: A novel mode for cancer therapy.

Changes in reactive oxygen species (ROS) levels affect many aspects of cell behavior. During carcinogenesis, moderate ROS production modifies gene expression to alter cell function, elevating metabolic activity and ROS. To avoid extreme ROS-activated death, cancer cells increase antioxidative capacity, regulating sustained ROS levels that promote growth.

Photonic topology optimization with semiconductor-foundry design-rule constraints.

We present a unified density-based topology-optimization framework that yields integrated photonic designs optimized for manufacturing constraints including all those of commercial semiconductor foundries. We introduce a new method to impose minimum-area and minimum-enclosed-area constraints, and simultaneously adapt previous techniques for minimum linewidth, linespacing, and curvature, all of which are implemented without any additional re-parameterizations. Furthermore, we show how differentiable morphological transforms can be used to produce devices that are robust to over/under-etching while also satisfying manufacturing constraints.

The Novel bis-1,2,4-Triazine MIPS-0004373 Demonstrates Rapid and Potent Activity against All Blood Stages of the Malaria Parasite.

Novel bis-1,2,4-triazine compounds with potent activity against Plasmodium falciparum parasites were recently identified. The bis-1,2,4-triazines represent a unique antimalarial pharmacophore and are proposed to act by a novel but as-yet-unknown mechanism of action. This study investigated the activity of the bis-1,2,4-triazine MIPS-0004373 across the mammalian life cycle stages of the parasite and profiled the kinetics of activity against blood and transmission stage parasites and .

Tea tree oil extract causes mitochondrial superoxide production and apoptosis as an anticancer agent, promoting tumor infiltrating neutrophils cytotoxic for breast cancer to induce tumor regression.

The antitumor activity of the tea tree oil (TTO) derived product, Melaleuca Alternifolia Concentrate (MAC) was characterized mechanistically at the molecular and cellular level. MAC was analyzed for its anticancer activity against human prostate (LNCaP) and breast (MCF-7) cancer cell lines growing in vitro. MAC (0.