The lives of cells, recorded.

A paradigm for biology is emerging in which cells can be genetically programmed to write their histories into their own genomes. These records can subsequently be read, and the cellular histories reconstructed, which for each cell could include a record of its lineage relationships, extrinsic influences, internal states and physical locations, over time. DNA recording has the potential to transform the way that we study developmental and disease processes.

Lineage motifs as developmental modules for control of cell type proportions.

In multicellular organisms, cell types must be produced and maintained in appropriate proportions. One way this is achieved is through committed progenitor cells or extrinsic interactions that produce specific patterns of descendant cell types on lineage trees. However, cell fate commitment is probabilistic in most contexts, making it difficult to infer these dynamics and understand how they establish overall cell type proportions.

Digital remote monitoring for screening and early detection of urinary tract infections.

Urinary Tract Infections (UTIs) are one of the most prevalent bacterial infections in older adults and a significant contributor to unplanned hospital admissions in People Living with Dementia (PLWD), with early detection being crucial due to the predicament of reporting symptoms and limited help-seeking behaviour. The most common diagnostic tool is urine sample analysis, which can be time-consuming and is only employed where UTI clinical suspicion exists. In this method development and proof-of-concept study, participants living with dementia were monitored via low-cost devices in the home that passively measure activity, sleep, and nocturnal physiology.

Lineage motifs: developmental modules for control of cell type proportions.

In multicellular organisms, cell types must be produced and maintained in appropriate proportions. One way this is achieved is through committed progenitor cells that produce specific sets of descendant cell types. However, cell fate commitment is probabilistic in most contexts, making it difficult to infer progenitor states and understand how they establish overall cell type proportions.

Distinct genomic routes underlie transitions to specialised symbiotic lifestyles in deep-sea annelid worms.

Bacterial symbioses allow annelids to colonise extreme ecological niches, such as hydrothermal vents and whale falls. Yet, the genetic principles sustaining these symbioses remain unclear. Here, we show that different genomic adaptations underpin the symbioses of phylogenetically related annelids with distinct nutritional strategies.

New ways of using old antibiotics in pediatrics: Focus on fosfomycin.

Fosfomycin, originally named phosphonomycin when it was first isolated from fermentation broth of Streptomyces species and synthesized at Merck in 1969. The phosphonic acid containing a structurally strained and reactive epoxide ring confers broad spectrum, bactericidal activity against gram-positive and gram-negative bacteria. Fosfomycin's small size and hydrophilicity permits broad tissues penetration.

Annelid functional genomics reveal the origins of bilaterian life cycles.

Indirect development with an intermediate larva exists in all major animal lineages, which makes larvae central to most scenarios of animal evolution. Yet how larvae evolved remains disputed. Here we show that temporal shifts (that is, heterochronies) in trunk formation underpin the diversification of larvae and bilaterian life cycles.

Embryo model completes gastrulation to neurulation and organogenesis.

Embryonic stem (ES) cells can undergo many aspects of mammalian embryogenesis in vitro, but their developmental potential is substantially extended by interactions with extraembryonic stem cells, including trophoblast stem (TS) cells, extraembryonic endoderm stem (XEN) cells and inducible XEN (iXEN) cells. Here we assembled stem cell-derived embryos in vitro from mouse ES cells, TS cells and iXEN cells and showed that they recapitulate the development of whole natural mouse embryo in utero up to day 8.5 post-fertilization.

Appropriateness of imaging decisions for low back pain presenting to the emergency department: a retrospective chart review study.

Background: Imaging for low back pain is widely regarded as a target for efforts to reduce low-value care.

Objective: We aimed to estimate the prevalence of the overuse and underuse of lumbar imaging in patients presenting with low back pain to the emergency department (ED).

Methods: This was a retrospective chart review study of five public hospital EDs in Sydney, Australia, in 2019-20.

Implementation of Vancomycin Therapeutic Monitoring Guidelines: Focus on Bayesian Estimation Tools in Neonatal and Pediatric Patients.

Background: The 2020 consensus guidelines for vancomycin therapeutic monitoring recommend using Bayesian estimation targeting the ratio of the area under the curve over 24 hours to minimum inhibitory concentration as an optimal approach to individualize therapy in pediatric patients. To support institutional guideline implementation in children, the objective of this study was to comprehensively assess and compare published population-based pharmacokinetic (PK) vancomycin models and available Bayesian estimation tools, specific to neonatal and pediatric patients.

Methods: PubMed and Embase databases were searched from January 1994 to December 2020 for studies in which a vancomycin population PK model was developed to determine clearance and volume of distribution in neonatal and pediatric populations.

The economic burden of poor glycemic control associated with therapeutic inertia in patients with type 2 diabetes in Denmark.

Objective: To evaluate the economic burden associated with therapeutic inertia in patients with type 2 diabetes mellitus (T2D) in Denmark.

Methods: The economic burden for a newly diagnosed Danish T2D population was estimated using a validated diabetes model (The Swedish Institute for Health Economics (IHE) Cohort model), based on achieving varying levels of glycemic control. The analyses were based on clinical data from the Danish Centre for Strategic Research (DD2) and supplemented with relevant Swedish data where variables were missing.

Multifunctional Nitroso--acetylpenicillamine-Incorporated Medical-Grade Polymer with Selenium Interface for Biomedical Applications.

Modern crises in implantable or indwelling blood-contacting medical devices are mainly due to the dual problems of infection and thrombogenicity. There is a paucity of biomaterials that can address both problems simultaneously through a singular platform. Taking cues from the body's own defense mechanism against infection and blood clotting (thrombosis) via the endogenous gasotransmitter nitric oxide (NO), both of these issues are addressed through the development of a layered nitroso--acetylpenicillamine (SNAP)-doped polymer with a blended selenium (Se)-polymer interface.

Fast and Efficient Expression of Multiple Proteins in Avian Embryos Using mRNA Electroporation.

We report that mRNA electroporation permits fluorescent proteins to label cells in living quail embryos more quickly and broadly than DNA electroporation. The high transfection efficiency permits at least 4 distinct mRNAs to be co-transfected with ~87% efficiency. Most of the electroporated mRNAs are degraded during the first 2 h post-electroporation, permitting time-sensitive experiments to be carried out in the developing embryo.

Correlative SICM-FCM reveals changes in morphology and kinetics of endocytic pits induced by disease-associated mutations in dynamin.

Dynamin 2 (DNM2) is a GTP-binding protein that controls endocytic vesicle scission and defines a whole class of dynamin-dependent endocytosis, including clathrin-mediated endocytosis by caveoli. It has been suggested that mutations in the gene, associated with 3 inherited diseases, disrupt endocytosis. However, how exactly mutations affect the nanoscale morphology of endocytic machinery has never been studied.

The frequency of testing for glycated haemoglobin, HbA1c, is linked to the probability of achieving target levels in patients with suboptimally controlled diabetes mellitus.

Background We previously showed, in patients with diabetes, that >50% of monitoring tests for glycated haemoglobin (HbA1c) are outside recommended intervals and that this is linked to diabetes control. Here, we examined the effect of tests/year on achievement of commonly utilised HbA1c targets and on HbA1c changes over time. Methods Data on 20,690 adults with diabetes with a baseline HbA1c of >53 mmol/mol (7%) were extracted from Clinical Biochemistry Laboratory records at three UK hospitals.

Asymmetric Sensory-Motor Regeneration of Transected Peripheral Nerves Using Molecular Guidance Cues.

Neural interfaces are designed to decode motor intent and evoke sensory precepts in amputees. In peripheral nerves, recording movement intent is challenging because motor axons are only a small fraction compared to sensory fibers and are heterogeneously mixed particularly at proximal levels. We previously reported that pain and myelinated axons regenerating through a Y-shaped nerve guide with sealed ends, can be modulated by luminar release of nerve growth factor (NGF) and neurotrophin-3 (NT-3), respectively.

Early development of Drosophila embryos requires Smc5/6 function during oogenesis.

Mutations in structural maintenance of chromosomes (Smc) proteins are frequently associated with chromosomal abnormalities commonly observed in developmental disorders. However, the role of Smc proteins in development still remains elusive. To investigate Smc5/6 function during early embryogenesis we examined smc5 and smc6 mutants of the fruit fly Drosophila melanogaster using a combination of reverse genetics and microscopy approaches.

Reduced testing frequency for glycated hemoglobin, HbA1c, is associated with deteriorating diabetes control.

Objective: We previously showed that in patients with diabetes mellitus, glycated hemoglobin (HbA1c) monitoring outside international guidance on testing frequency is widespread. Here we examined the relationship between testing frequency and diabetes control to test the hypothesis that retest interval is linked to change in HbA1c level.

Research Design And Methods: We examined repeat HbA1c tests (400,497 tests in 79,409 patients, 2008-2011) processed by three U.

Role of MXD3 in proliferation of DAOY human medulloblastoma cells.

A subset of medulloblastomas, the most common brain tumor in children, is hypothesized to originate from granule neuron precursors (GNPs) in which the sonic hedgehog (SHH) pathway is over-activated. MXD3, a basic helix-look-helix zipper transcription factor of the MAD family, has been reported to be upregulated during postnatal cerebellar development and to promote GNP proliferation and MYCN expression. Mxd3 is upregulated in mouse models of medulloblastoma as well as in human medulloblastomas.

Inappropriate requesting of glycated hemoglobin (Hb A1c) is widespread: assessment of prevalence, impact of national guidance, and practice-to-practice variability.

Background: Estimates suggest that approximately 25% of requests for pathology tests are unnecessary. Even in diabetes, for which international guidance provides recommended testing frequency, considerable variability in requesting practice exists. Using the diabetes marker, Hb A(1c), we examined (a) the prevalence of under- and overrequesting, (b) the impact of international guidance on prevalence, and (c) practice-to-practice variability.

Illuminator: increasing synergies between medicinal and computational chemists.

We present Illuminator, a user-friendly web front end to computational models such as docking and 3D shape similarity calculations. Illuminator was specifically created to allow non-experts to design and submit molecules to computational chemistry programs. As such it provides a simple user interface allowing users to submit jobs starting from a 2D structure.

5,6-Dihydro-1H-pyridin-2-ones as potent inhibitors of HCV NS5B polymerase.

5,6-Dihydro-1H-pyridin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4ad displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; IC(50) (1a)<25nM, EC(50) (1b)=16nM), good in vitro DMPK properties, as well as moderate oral bioavailability in monkeys (F=24%).

Structure-based design, synthesis, and biological evaluation of 1,1-dioxoisothiazole and benzo[b]thiophene-1,1-dioxide derivatives as novel inhibitors of hepatitis C virus NS5B polymerase.

A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC(50) values. The most potent compound exhibited IC(50) less than 10nM against the genotype 1b HCV polymerase and EC(50) of 70 nM against a genotype 1b replicon in cell culture.

Pyrrolo[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase.

Pyrrolo[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Structure-based design led to the discovery of compound 3 k, which displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; EC(50) (1b)=12 nM) as well as good stability towards human liver microsomes (HLM t(1/2)>60 min).