Enzymatic Cascades for Stereoselective and Regioselective Amide Bond Assembly.

Amide bond formation is fundamental in nature and is widely used in the synthesis of pharmaceuticals and other valuable products. Current methods for amide synthesis are often step and atom inefficient, requiring the use of protecting groups, deleterious reagents and organic solvents that create significant waste. The development of cleaner and more efficient catalytic methods for amide synthesis remains an urgent unmet need.

Tracking Nongenetic Evolution from Primary to Metastatic ccRCC: TRACERx Renal.

Using joint genomic-transcriptomic analysis of 243 samples, we reveal recurrent patterns of nongenetic evolution in ccRCC not exclusively governed by genetic factors, including T-cell depletion, tumor T-cell receptor coevolution, potential cGAS-STING repression, and increased cell proliferation. These patterns can aid clinical management and guide novel treatment approaches.

Tracking non-genetic evolution from primary to metastatic ccRCC: TRACERx Renal.

While the key aspects of genetic evolution and their clinical implications in clear cell renal-cell carcinoma (ccRCC) are well-documented, how genetic features co-evolve with the phenotype and tumor microenvironment (TME) remains elusive. Here, through joint genomic-transcriptomic analysis of 243 samples from 79 patients recruited to the TRACERx Renal study, we identify pervasive non-genetic intratumor heterogeneity, with over 40% not attributable to genetic alterations. By integrating tumor transcriptomes and phylogenetic structures, we observe convergent evolution to specific phenotypic traits, including cell proliferation, metabolic reprogramming and overexpression of putative cGAS-STING repressors amid high aneuploidy.

Solution biophysics identifies lipid nanoparticle non-sphericity, polydispersity, and dependence on internal ordering for efficacious mRNA delivery.

Lipid nanoparticles (LNPs) are the most advanced delivery system currently available for RNA therapeutics. Their development has accelerated since the success of Patisiran, the first siRNA-LNP therapeutic, and the mRNA vaccines that emerged during the COVID-19 pandemic. Designing LNPs with specific targeting, high potency, and minimal side effects is crucial for their successful clinical use.

Robust, Scalable Microfluidic Manufacturing of RNA-Lipid Nanoparticles Using Immobilized Antifouling Lubricant Coating.

Despite the numerous advantages demonstrated by microfluidic mixing for RNA-loaded lipid nanoparticle (RNA-LNP) production over bulk methods, such as precise size control, homogeneous distributions, higher encapsulation efficiencies, and improved reproducibility, their translation from research to commercial manufacturing remains elusive. A persistent challenge hindering the adoption of microfluidics for LNP production is the fouling of device surfaces during prolonged operation, which significantly diminishes performance and reliability. The complexity of LNP constituents, including lipids, cholesterol, RNA, and solvent mixtures, makes it difficult to find a single coating that can prevent fouling.

Pharmacological and structural understanding of the Trypanosoma cruzi proteasome provides key insights for developing site-specific inhibitors.

The proteasome is considered an excellent drug target for many infectious diseases as well as cancer. Challenges with robust and safe supply of proteasomes from infectious agents, lack of structural information, and complex pharmacology due to multiple active sites have hampered progress in the infectious disease space. We recombinantly expressed the proteasome of the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease, and demonstrate pharmacological equivalence to the native T.

Bioinspired designer DNA NanoGripper for virus sensing and potential inhibition.

DNA has shown great biocompatibility, programmable mechanical properties, and precise structural addressability at the nanometer scale, rendering it a material for constructing versatile nanorobots for biomedical applications. Here, we present the design principle, synthesis, and characterization of a DNA nanorobotic hand, called DNA NanoGripper, that contains a palm and four bendable fingers as inspired by naturally evolved human hands, bird claws, and bacteriophages. Each NanoGripper finger consists of three phalanges connected by three rotatable joints that are bendable in response to the binding of other entities.

A free-living, walking-based, exercise programme, with exercise timed relative to breakfast, to improve metabolic health in people living with overweight and obesity: A feasibility study.

Optimising the timing of food intake relative to exercise may maximise the effectiveness of free-living exercise programmes on improvements in glycaemic control and cardio-metabolic health. This study aimed to assess the feasibility of a free-living, walking-based exercise programme and determine whether undertaking each exercise session before or after breakfast would most benefit longer-term metabolic health. Thirty-four people living with obesity (43±12 y, BMI 35.

Generation of TWO iPSC lines (CRICKi009-A; CRICKi010-A) from patients with type 1 von Hippel-Lindau (VHL) and histopathologically confirmed renal cell carcinoma (RCC).

VHL disease is an inherited and autosomal dominant disorder affecting 1 in 36,0000 individuals worldwide. It is caused by von Hippel-Lindau (VHL) gene mutations and can affect both genders and all ethnic backgrounds (Nordstrom-O'Brien et al., 2009; Maher, 2004).

Towards the clinical translation of a silver sulfide nanoparticle contrast agent: large scale production with a highly parallelized microfluidic chip.

Purpose: Ultrasmall silver sulfide nanoparticles (AgS-NP) have been identified as promising contrast agents for a number of modalities and in particular for dual-energy mammography. These AgS-NP have demonstrated marked advantages over clinically available agents with the ability to generate higher contrast with high biocompatibility. However, current synthesis methods for inorganic nanoparticles are low-throughput and highly time-intensive, limiting the possibility of large animal studies or eventual clinical use of this potential imaging agent.

Cost- effectiveness of a simplified acute malnutrition program: a secondary analysis of the OptiMA randomized clinical trial in the Democratic Republic of the Congo.

Acute malnutrition (AM) causes large loss of life and disability in children in Africa. Researchers are testing innovative approaches to increase efficiency of treatment programs. This paper presents results of a cost-effectiveness analysis of one such program in the Democratic Republic of the Congo (DRC) based on a secondary analysis of a randomized controlled trial Optimizing Treatment for Acute Malnutrition (OptiMA), conducted in DRC in 2018-20.

MANDI-Code: A Coding System for the human mandible.

Background: The mandible provides valuable insights into its biological identity. However, the existence of several terminologies for mandibular measurements and inconsistent language can lead to misinterpretation, confusion, and miscommunication.

Highlight: A standardised set of anatomical points, planes, and measurements would assist with these issues and ensure reproducibility and comparability.

Portable, smartphone-linked, and miniaturized photonic resonator absorption microscope (PRAM Mini) for point-of-care diagnostics.

We report the design, development, and characterization of a miniaturized version of the photonic resonator absorption microscope (PRAM Mini), whose cost, size, and functionality are compatible with point-of-care (POC) diagnostic assay applications. Compared to previously reported versions of the PRAM instrument, the PRAM Mini components are integrated within an optical framework comprised of an acrylic breadboard and plastic alignment fixtures. The instrument incorporates a Raspberry Pi microprocessor and Bluetooth communication circuit board for wireless control and data connection to a linked smartphone.

Examining trends in the incidence of HIV infection among people with a history of drug use to inform an outbreak investigation and response: A retrospective cohort study.

Background: In the context of an outbreak of HIV among people who inject drugs in Glasgow, Scotland, identified in 2015, our objectives were to: (1) develop epidemiological methods to estimate HIV incidence using data linkage, and (2) examine temporal changes in HIV incidence to inform public health responses.

Methods: This was a retrospective cohort study involving data linkage of laboratory HIV testing data to identify individuals with a history of drug use. Person-years (PY) and Poisson regression were used to estimate incidence by time period (pre-outbreak: 2000-2010 and 2011-2013; early outbreak: 2014-2016; ongoing outbreak: 2017-2019).

Combinatorial design of siloxane-incorporated lipid nanoparticles augments intracellular processing for tissue-specific mRNA therapeutic delivery.

Systemic delivery of messenger RNA (mRNA) for tissue-specific targeting using lipid nanoparticles (LNPs) holds great therapeutic potential. Nevertheless, how the structural characteristics of ionizable lipids (lipidoids) impact their capability to target cells and organs remains unclear. Here we engineered a class of siloxane-based ionizable lipids with varying structures and formulated siloxane-incorporated LNPs (SiLNPs) to control in vivo mRNA delivery to the liver, lung and spleen in mice.

Fast-twitch myofibrils grow in proportion to Mylpf dosage in the zebrafish embryo.

Muscle cells become stronger by expanding myofibrils, the chains of sarcomeres that produce contraction. Here we investigate how Mylpf (Myosin Light Chain Phosphorylatable Fast) abundance impacts myofibril assembly in fast-twitch muscle. The two zebrafish Mylpf genes ( and ) are exclusively expressed in fast-twitch muscle.

Factors associated with non-response and nutrional status of non-responders at 6-month post-discharge: a cohort study nested in a MUAC-based nutrition programme for acutely malnourished children in Mirriah, Niger.

Background: In the treatment of acute malnutrition (AM), non-response is considered a treatment failure for not meeting recovery criteria within a therapeutic window of 12-16 weeks, but this category of children is misunderstood. As current research emphasizes ways to simplify and optimize treatment protocols, non-response emerges as a new issue to enhance program efficiency.

Methods: A prospective cohort study was conducted from 2019 to 2020 at two health centres in Mirriah, Niger among children aged 6-59 months with uncomplicated AM treated under the Optimising treatment for Acute MAlnutrition (OptiMA) protocol.

Effect of Mifepristone on Migration and Proliferation of Oral Cancer Cells.

Glucocorticoid receptor (GR) overexpression has been linked to increased tumour aggressiveness and treatment resistance. GR antagonists have been shown to enhance treatment effectiveness. Emerging research has investigated mifepristone, a GR antagonist, as an anticancer agent with limited research in the context of oral cancer.

Dicobalt(ii) helices kill colon cancer cells enantiomer-specific mechanisms; DNA damage or microtubule disruption.

Highly diastereoselective self-assembly reactions give both enantiomers (Λ and Δ) of anti-parallel triple-stranded bimetallic Co(ii) and Co(iii) cationic helices, without the need for resolution; the first such reaction for Co. The complexes are water soluble and stable, even in the case of Co(ii). Studies in a range of cancer and healthy cell lines indicate high activity and selectivity, and substantial differences between enantiomers.

Newborn and infant hearing screening for early detection of hearing loss in Nairobi, Kenya.

Background: Early detection of hearing loss and subsequent intervention leads to better speech, language and educational outcomes giving way to improved social economic prospects in adult life. This can be achieved through establishing newborn and infant hearing screening programs.

Objective: To determine the prevalence of hearing loss in newborns and infants in Nairobi, Kenya.