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Chronic wounds represent a large and growing disease burden. Infection and biofilm formation are two of the leading impediments of wound healing, suggesting an important role for the microbiome of these wounds. Debridement is a common and effective treatment for chronic wounds. We analyzed the bacterial content of the wound surface from 20 outpatients with chronic wounds before and immediately after debridement, as well as healthy skin. Given the large variation observed among different wounds, we introduce a Bayesian statistical method that models patient-to-patient variability and identify several genera that were significantly enriched in wounds vs. healthy skin. We found no difference between the microbiome of the original wound surface and that exposed by a single episode of sharp debridement, suggesting that this debridement did not directly alter the wound microbiome. However, we found that aerobes and especially facultative anaerobes were significantly associated with wounds that did not heal within 6 months. The facultative anaerobic genus Enterobacter was significantly associated with lack of healing. The results suggest that an abundance of facultative anaerobes is a negative prognostic factor in the chronic wound microbiome, possibly due to the increased robustness of such communities to different metabolic environments.

High-throughput experimentation (HTE) is an increasingly important tool in reaction discovery. While the hardware for running HTE in the chemical laboratory has evolved significantly in recent years, there remains a need for software solutions to navigate data-rich experiments. Here we have developed phactor™, a software that facilitates the performance and analysis of HTE in a chemical laboratory. phactor™ allows experimentalists to rapidly design arrays of chemical reactions or direct-to-biology experiments in 24, 96, 384, or 1,536 wellplates. Users can access online reagent data, such as a chemical inventory, to virtually populate wells with experiments and produce instructions to perform the reaction array manually, or with the assistance of a liquid handling robot. After completion of the reaction array, analytical results can be uploaded for facile evaluation, and to guide the next series of experiments. All chemical data, metadata, and results are stored in machine-readable formats that are readily translatable to various software. We also demonstrate the use of phactor™ in the discovery of several chemistries, including the identification of a low micromolar inhibitor of the SARS-CoV-2 main protease. Furthermore, phactor™ has been made available for free academic use in 24- and 96-well formats via an online interface. High-throughput experimentation is an increasingly important tool in reaction discovery, while there remains a need for software solutions to navigate data-rich experiments. Here the authors report phactor™, a software that facilitates the performance and analysis of high-throughput experimentation in a chemical laboratory.

The global disruption caused by the 2020 coronavirus pandemic stressed the supply chain of many products, including pharmaceuticals. Multiple drug repurposing studies for COVID-19 are now underway. If a winning therapeutic emerges, it is unlikely that the existing inventory of the medicine, or even the chemical raw materials needed to synthesize it, will be available in the quantities required. Here, we utilize retrosynthetic software to arrive at alternate chemical supply chains for the antiviral drug umifenovir, as well as eleven other antiviral and anti-inflammatory drugs. We have experimentally validated four routes to umifenovir and one route to bromhexine. In one route to umifenovir the software invokes conversion of six C–H bonds into C–C bonds or functional groups. The strategy we apply of excluding known starting materials from search results can be used to identify distinct starting materials, for instance to relieve stress on existing supply chains. COVID-19 has exposed the fragility of supply chains, particularly for goods that are essential or may suddenly become essential, such as repurposed pharmaceuticals. Here the authors develop a methodology to provide routes to pharmaceutical targets that allow low-supply starting materials or intermediates to be avoided, with representative pathways validated experimentally.

The molecules of today — the medicines that cure diseases, the agrochemicals that protect our crops, the materials that make life convenient — are becoming increasingly sophisticated thanks to advancements in chemical synthesis. As tools for synthesis improve, molecular architects can be bold and creative in the way they design and produce molecules. Several emerging tools at the interface of chemical synthesis and data science have come to the forefront in recent years, including algorithms for retrosynthesis and reaction prediction, and robotics for autonomous or high-throughput synthesis. This Primer covers recent additions to the toolbox of the data-savvy organic chemist. There is a new movement in retrosynthetic logic, predictive models of reactivity and chemistry automata, with considerable recent engagement from contributors in diverse fields. The promise of chemical synthesis in the information age is to improve the quality of the molecules of tomorrow through data-harnessing and automation. This Primer is written for organic chemists and data scientists looking to understand the software, hardware, data sets and tactics that are commonly used as well as the capabilities and limitations of the field. The Primer is split into three main components covering retrosynthetic logic, reaction prediction and automated synthesis. The former of these topics is about distilling the strategy of multistep synthesis to a logic that can be taught to a computer. The section on reaction prediction details modern tools and models for developing reaction conditions, catalysts and even new transformations based on information-rich data sets and statistical tools such as machine learning. Finally, we cover recent advances in the use of liquid handling robotics and autonomous systems that can physically perform experiments in the chemistry laboratory.This Primer summarizes the most relevant aspects of chemical synthesis in this information age for those looking to understand the software, hardware and data and how these are used to enable retrosynthetic logic, reaction prediction and automation.

Systems of catalytic RNAs presumably gave rise to important evolutionary innovations, such as the genetic code. Such systems may exhibit particular tolerance to errors (error minimization) as well as coding specificity. While often assumed to result from natural selection, error minimization may instead be an emergent by-product. In an RNA world, a system of self-aminoacylating ribozymes could enforce the mapping of amino acids to anticodons. We measured the activity of thousands of ribozyme mutants on alternative substrates (activated analogs for tryptophan, phenylalanine, leucine, isoleucine, valine, and methionine). Related ribozymes exhibited shared preferences for substrates, indicating that adoption of additional amino acids by existing ribozymes would itself lead to error minimization. Furthermore, ribozyme activity was positively correlated with specificity, indicating that selection for increased activity would also lead to increased specificity. These results demonstrate that by-products of ribozyme evolution could lead to adaptive value in specificity and error tolerance. Complex biochemical systems exhibit traits that appear to be highly adapted. Studies of catalytic RNA demonstrate that adaptive traits, such as increased specificity and error tolerance, could originate as evolutionary by-products.

Repurposing of amine and carboxylic acid building blocks provides an enormous opportunity to expand the accessible chemical space, because amine and acid feedstocks are typically low cost and available in high diversity. Herein, we report a copper-catalyzed deaminative esterification based on C–N activation of aryl amines via diazonium salt formation. The reaction was specifically designed to complement the popular amide coupling reaction. A chemoinformatic analysis of commercial building blocks demonstrates that by utilizing aryl amines, our method nearly doubles the available esterification chemical space compared to classic Fischer esterification with phenols. High-throughput experimentation in microliter reaction droplets was used to develop the reaction, along with classic scope studies, both of which demonstrated robust performance against hundreds of substrate pairs. Furthermore, we have demonstrated that this new esterification is suitable for late-stage diversification and for building-block repurposing to expand chemical space. Given their low cost and diverse nature, coupling of amine and carboxylic acid building blocks provides an opportunity to expand the accessible chemical space. Here, a copper-catalyzed deaminative esterification of aryl amines with carboxylic acids is developed and its use in library synthesis with high-throughput experimentation is demonstrated.

Background Falls are a major public safety issue, and improving the posture control ability of elderly people is highly important for preventing falls. Transcranial direct current stimulation (tDCS) and virtual reality-based balance training (VRBT) have been proven to be effective in improving postural stability and balance ability. The combination of these two methods may achieve better therapeutic effects. At present, there is a lack of research on the effects of tDCS combined with VRBT on postural stability and fall prevention in elderly individuals. Methods This 4-week single-blind, parallel-group randomized controlled trial will allocate 64 participants into the experimental or control group at a 1:1 ratio. The experimental group will undergo cerebellar tDCS combined with VRBT, whereas the control group will receive sham cerebellar tDCS paired with conventional exercise guidance. The outcome measures will be single leg stance with eyes closed, timed up and go, activities-specific balance confidence scale, modified falls efficacy scale, center of pressure measurements, and functional near-infrared spectroscopy. Assessments will be conducted at 0, 4, 8 and 12 weeks. Discussion Studies examining the effects of cerebellar tDCS combined with VRBT on postural stability and fall risk among older adults are lacking. This study aims to comprehensively assess the effects of cerebellar tDCS combined with VRBT on postural stability and balance function through clinical scales and objective instrumental assessments. The findings of this study are anticipated to enhance existing intervention strategies for fall prevention and inspire researchers to develop innovative treatment methods for older adults. Trial registration Chinese Clinical Trial Registry, ChiCTR2300078998, Registered on 22 December 2023.

Chemical transformations determine the structure of a product, and therefore its properties, which in turn affect complex macroscopic functions such as the metabolic stability of pharmaceuticals or the volatility of perfumes. Therefore, reaction selection can influence the success or failure of a candidate molecule to meet a functional objective. The coupling of an amine with a carboxylic acid to form an amide bond is the most popular chemical reaction used for drug discovery 1 . However, there are many other ways to connect these two common functional groups together. Here we show computationally that amines and acids can couple via hundreds of hypothetical yet plausible transformations, and we demonstrate experimentally the application of a dozen such reactions. To investigate the contribution of chemical transformations to properties, we developed a string-based notation and used an enumerative combinatorics approach to produce a map of conceivable amine–acid coupling transformations, which can be charted using chemoinformatic techniques. We find that critical physicochemical parameters of the products, such as partition coefficient and polar surface area, vary considerably depending on the transformation chosen. Data mining the amine–acid coupling system produced here should enable reaction discovery, which we demonstrate by developing an esterification reaction found within the mapped space. Complex molecules with distinct property profiles can also be discovered within the amine–acid coupling system, as we show here via the late-stage diversification of drugs and natural products. All possible chemical transformations between amine and carboxylic acid groups are mapped using an automated string-based combinatorics method, showing that the properties and functions of the products vary considerably over all plausible reactions.

Comedy shows are an acute barometer of social contexts as they are embedded in power relations and often constructed as a space of resistance. With the increasing presence of China in Kenya, China has been a recurring theme in one of the most popular Kenyan stand-up comedies, the Churchill Comedy Show. In 2018, a clip circulated widely of a Chinese female comedian on stage with Churchill and Sleepy. In the clip they discuss the debt issue between Kenya and China through romantic metaphors of an \"engagement\" ceremony before the wedding, including both expressions of love and bargaining about bride price. This article argues that humour and laughter help in carving out a space for open discussions and critical reflections on the debt issue within Kenya-China relations. It inserts agency and expresses resistance and moral critique of Chinese engagements in Kenya, especially from socio-economically marginalised publics. At the same time, the humour jointly generated through a reiteration of tropes of nationhood, separation of languages and gendered expressions runs the risk of taking interpersonal relations back to rigidly divided national, ethnic and gendered categorisations and representations.