Determinants of severity in sickle cell disease.

Sickle cell disease is a very variable condition, with outcomes ranging from death in childhood to living relatively symptom free into the 8 decade. Much of this variability is unexplained. The co-inheritance of α thalassaemia and factors determining HbF levels significantly modify the phenotype, but few other significant genetic variants have been identified, despite extensive studies.

HOTTIP-dependent R-loop formation regulates CTCF boundary activity and TAD integrity in leukemia.

HOTTIP lncRNA is highly expressed in acute myeloid leukemia (AML) driven by MLL rearrangements or NPM1 mutations to mediate HOXA topologically associated domain (TAD) formation and drive aberrant transcription. However, the mechanism through which HOTTIP accesses CCCTC-binding factor (CTCF) chromatin boundaries and regulates CTCF-mediated genome topology remains unknown. Here, we show that HOTTIP directly interacts with and regulates a fraction of CTCF-binding sites (CBSs) in the AML genome by recruiting CTCF/cohesin complex and R-loop-associated regulators to form R-loops.

Inexpensive Portable Infrared Device to Detect and Quantify Alcohols in Hand Sanitizers for Public Health and Safety.

The onset of Covid-19 pandemic has resulted in the exponential growth of alcohol-based hand rub (ABHR)/hand sanitizer use. Reports have emerged of ABHR products containing methanol, a highly toxic compound to humans, exposing users to acute and chronic medical illnesses. While gas chromatography-mass spectrometry (GC-MS) remains the gold-standard method for the detection and identification of impurities in ABHRs, there exist limitations at widespread volume testing.

Polyelectrolyte Multi-Layered Griseofulvin Nanoparticles: Conventional versus Continuous Layer-by-Layer Fabrication.

Polyelectrolyte multilayers are promising drug carriers with potential applications in the delivery of poorly soluble drugs. Furthermore, the polyelectrolyte multilayer contributes towards electrostatic interactions, which enhances the physical and chemical stability of colloids when compared to those prepared by other approaches. The aim of this work was to generate a polyelectrolyte multilayer on well characterised nanoparticles of the poorly water-soluble drug, griseofulvin.

Integron gene cassettes harboring novel variants of D-alanine-D-alanine ligase confer high-level resistance to D-cycloserine.

Antibiotic resistance poses an increasing threat to global health. To tackle this problem, the identification of principal reservoirs of antibiotic resistance genes (ARGs) plus an understanding of drivers for their evolutionary selection are important. During a PCR-based screen of ARGs associated with integrons in saliva-derived metagenomic DNA of healthy human volunteers, two novel variants of genes encoding a D-alanine-D-alanine ligase (ddl6 and ddl7) located within gene cassettes in the first position of a reverse integron were identified.

Writing Your Next Medicinal Chemistry Article: Journal Bibliometrics and Guiding Principles for Industrial Authors.

Writing scientific articles is immensely rewarding but challenging. This Perspective provides the medicinal chemist with background and advice on the art and process of writing manuscripts and complements the instructions to authors provided by journals. Included are many tips that we wish we had known when we first started writing.

Optimizing hepcidin measurement with a proficiency test framework and standardization improvement.

Objectives: Hepcidin measurement advances insights in pathophysiology, diagnosis, and treatment of iron disorders, but requires analytically sound and standardized measurement procedures (MPs). Recent development of a two-level secondary reference material (sRM) for hepcidin assays allows worldwide standardization. However, no proficiency testing (PT) schemes to ensure external quality assurance (EQA) exist and the absence of a high calibrator in the sRM set precludes optimal standardization.

Rethinking animal models of sepsis - working towards improved clinical translation whilst integrating the 3Rs.

Sepsis is a major worldwide healthcare issue with unmet clinical need. Despite extensive animal research in this area, successful clinical translation has been largely unsuccessful. We propose one reason for this is that, sometimes, the experimental question is misdirected or unrealistic expectations are being made of the animal model.

Synchrotron Photothermal Infrared Nanospectroscopy of Drug-Induced Phospholipidosis in Macrophages.

Synchrotron resonance-enhanced infrared atomic force microscopy (RE-AFM-IR) is a near-field photothermal vibrational nanoprobe developed at Diamond Light Source (DLS), capable of measuring mid-infrared absorption spectra with spatial resolution around 100 nm. The present study reports a first application of synchrotron RE-AFM-IR to interrogate biological soft matter at the subcellular level, in this case, on a cellular model of drug-induced phospholipidosis (DIPL). J774A-1 macrophages were exposed to amiodarone (10 μM) or medium for 24 h and chemically fixed.

Novel pyrrolobenzodiazepine benzofused hybrid molecules inhibit NF-κB activity and synergise with bortezomib and ibrutinib in hematological cancers.

Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are incurable hematological malignancies that are pathologically linked with aberrant NF-κB activation. In this study, we identified a group of novel C8-linked benzofused Pyrrolo[2,1-c][1,4]benzodiazepines (PBD) monomeric hybrids capable of sequence-selective inhibition of NF-κB with low nanomolar LD50 values in CLL (n=46) and MM cell lines (n=5). The lead compound, DC-1-192, significantly inhibited NF-κB DNA binding after just 4h exposure and demonstrating inhibitory effects on both canonical and non-canonical NF-κB subunits.

Noncytotoxic Pyrrolobenzodiazepine-Ciprofloxacin Conjugate with Activity against .

The development of new antitubercular agents for the treatment of infections caused by multidrug-resistant (MDR) is an urgent priority. Pyrrolobenzodiazepines (PBDs) are a promising class of antibacterial agents that were initially discovered and isolated from a range of species. Recently, C8-linked PBD monomers have been shown to work by inhibiting DNA gyrase and have demonstrated activity against .

Nanoparticle modification in biological media: implications for oral nanomedicines.

Nanomedicine has shown potential in enabling oral administration of poorly absorbable drugs, such as biologics. As part of the process related to optimisation of the safety and efficacy of nanomedicines, it is imperative that the interaction of nanoparticles with the biological systems - including the gut - is fully characterised. In this article, we provide an overview of the major mechanisms by which nanoparticles may transform upon introduction in biological media.

HOTTIP lncRNA Promotes Hematopoietic Stem Cell Self-Renewal Leading to AML-like Disease in Mice.

Long non-coding RNAs (lncRNAs) are critical for regulating HOX genes, aberration of which is a dominant mechanism for leukemic transformation. How HOX gene-associated lncRNAs regulate hematopoietic stem cell (HSC) function and contribute to leukemogenesis remains elusive. We found that HOTTIP is aberrantly activated in acute myeloid leukemia (AML) to alter HOXA-driven topologically associated domain (TAD) and gene expression.

Author Correction: Mapping the Dynamic Functions and Structural Features of AcrB Efflux Pump Transporter Using Accelerated Molecular Dynamics Simulations.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Nitric Oxide Modulates Metabolic Remodeling in Inflammatory Macrophages through TCA Cycle Regulation and Itaconate Accumulation.

Classical activation of macrophages (M(LPS+IFNγ)) elicits the expression of inducible nitric oxide synthase (iNOS), generating large amounts of NO and inhibiting mitochondrial respiration. Upregulation of glycolysis and a disrupted tricarboxylic acid (TCA) cycle underpin this switch to a pro-inflammatory phenotype. We show that the NOS cofactor tetrahydrobiopterin (BH) modulates IL-1β production and key aspects of metabolic remodeling in activated murine macrophages via NO production.

Towards identifying the mode of action of drugs using live-cell FTIR spectroscopy.

Fourier transform infrared spectroscopy (FTIR) has been shown to be a promising tool for identifying the mode of action of drugs. However, most previous studies have focused on the analysis of fixed or dried cells. The measurement of living cells has the advantage of obtaining time series data, and the in situ approach eliminates the need for fixing or drying the cells.

SmvA is an important efflux pump for cationic biocides in Klebsiella pneumoniae and other Enterobacteriaceae.

The multidrug resistant (MDR) opportunistic pathogen Klebsiella pneumoniae has previously been shown to adapt to chlorhexidine by increasing expression of the MFS efflux pump smvA. Here we show that loss of the regulator SmvR, through adaptation to chlorhexidine, results in increased resistance to a number of cationic biocides in K. pneumoniae and other members of the Enterobacteriaceae.

Application of carbon nanotubes in cancer vaccines: Achievements, challenges and chances.

Tumour-specific, immuno-based therapeutic interventions can be considered as safe and effective approaches for cancer therapy. Exploitation of nano-vaccinology to intensify the cancer vaccine potency may overcome the need for administration of high vaccine doses or additional adjuvants and therefore could be a more efficient approach. Carbon nanotube (CNT) can be described as carbon sheet(s) rolled up into a cylinder that is nanometers wide and nanometers to micrometers long.