bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatiotemporal dynamics of sensory neuron and Merkel-cell remodeling are decoupled during epidermal homeostasis
Authors: Clary Rachel C. , Jenkins Blair A. , Lumpkin Ellen A.
Published: May 2023

As the juncture between the body and environment, epithelia are both protective barriers and sensory interfaces that continually renew. To determine whether sensory neurons remodel to maintain homeostasis, we used
in vivo
two-photon imaging of somatosensory axons innervating Merkel cells in adult mouse skin. These touch receptors were highly plastic: 63% of Merkel cells and 89% of branches appeared, disappeared, grew, regressed and/or relocated over a month. Interestingly, Merkel-cell plasticity was synchronized across arbors during rapid epithelial turnover. When Merkel cells remodeled, the degree of plasticity between Merkel-cell clusters and their axons was well correlated. Moreover, branches were stabilized by Merkel-cell contacts. These findings highlight the role of epithelial-neural crosstalk in homeostatic remodeling. Conversely, axons were also dynamic when Merkel cells were stable, indicating that intrinsic neural mechanisms drive branch plasticity. Two terminal morphologies innervated Merkel cells: transient swellings called boutons, and stable cups termed kylikes. In
Atoh1
knockout mice that lack Merkel cells, axons showed higher complexity than control mice, with exuberant branching and no kylikes. Thus, Merkel cells limit axonal branching and promote branch maturation. Together, these results reveal a previously unsuspected high degree of plasticity in somatosensory axons that is biased, but not solely dictated, by plasticity of target epithelial cells. This system provides a platform to identify intrinsic and extrinsic mechanisms that govern axonal patterning in epithelial homeostasis.
Bactabolize: A tool for high-throughput generation of bacterial strain-specific metabolic models
Authors: Vezina Ben , Watts Stephen C. , Hawkey Jane , Cooper Helena B. , Judd Louise M. , Jenney Adam , Monk Jonathan M. , Holt Kathryn E. , Wyres Kelly L.
Published: May 2023

Metabolic capacity can vary substantially within a bacterial species, leading to ecological niche separation, as well as differences in virulence and antimicrobial susceptibility. Genome-scale metabolic models are useful tools for studying the metabolic potential of individuals, and with the rapid expansion of genomic sequencing there is a wealth of data that can be leveraged for comparative analysis. However, there exist few tools to construct strain-specific metabolic models at scale.Here we describe Bactabolize (github.com/kelwyres/Bactabolize), a reference-based tool which rapidly produces strain-specific metabolic models and growth phenotype predictions. We describe a pan reference model for the priority antimicrobial-resistant pathogen,
Klebsiella pneumoniae
(github.com/kelwyres/KpSC-pan-metabolic-model), and a quality control framework for using draft genome assemblies as input for Bactabolize.The Bactabolize-derived model for
K. pneumoniae
reference strain KPPR1 outperformed the CarveMe-derived model across ≥201 substrate and ≥1220 knockout mutant growth predictions. Novel draft genomes passing our systematically-defined quality control criteria resulted in models with a high degree of completeness (≥99% genes and reactions captured) and high accuracy (mean 0.97, n=10).We anticipate the tools and framework described herein will facilitate large-scale metabolic modelling analyses that broaden our understanding of diversity within bacterial species and inform novel control strategies for priority pathogens.
Decoding the mechanisms of allostery
Authors: Khan Saif , Gati Cornelius
Published: June 2023

A complex interplay between structure, conformational dynamics and pharmacology defines distant regulation of G protein-coupled receptors.
Uncertainty in projections of future lake thermal dynamics is differentially driven by lake and global climate models
Authors: Wynne Jacob H. , Woelmer Whitney , Moore Tadhg N. , Thomas R. Quinn , Weathers Kathleen C. , Carey Cayelan C.
Published: June 2023

Freshwater ecosystems provide vital services, yet are facing increasing risks from global change. In particular, lake thermal dynamics have been altered around the world as a result of climate change, necessitating a predictive understanding of how climate will continue to alter lakes in the future as well as the associated uncertainty in these predictions. Numerous sources of uncertainty affect projections of future lake conditions but few are quantified, limiting the use of lake modeling projections as management tools. To quantify and evaluate the effects of two potentially important sources of uncertainty, lake model selection uncertainty and climate model selection uncertainty, we developed ensemble projections of lake thermal dynamics for a dimictic lake in New Hampshire, USA (Lake Sunapee). Our ensemble projections used four different climate models as inputs to five vertical one-dimensional (1-D) hydrodynamic lake models under three different climate change scenarios to simulate thermal metrics from 2006 to 2099. We found that almost all the lake thermal metrics modeled (surface water temperature, bottom water temperature, Schmidt stability, stratification duration, and ice cover, but not thermocline depth) are projected to change over the next century. Importantly, we found that the dominant source of uncertainty varied among the thermal metrics, as thermal metrics associated with the surface waters (surface water temperature, total ice duration) were driven primarily by climate model selection uncertainty, while metrics associated with deeper depths (bottom water temperature, stratification duration) were dominated by lake model selection uncertainty. Consequently, our results indicate that researchers generating projections of lake bottom water metrics should prioritize including multiple lake models for best capturing projection uncertainty, while those focusing on lake surface metrics should prioritize including multiple climate models. Overall, our ensemble modeling study reveals important information on how climate change will affect lake thermal properties, and also provides some of the first analyses on how climate model selection uncertainty and lake model selection uncertainty interact to affect projections of future lake dynamics.
An Overview and Discussion of Azido Impurities and their Risk Assessments in Drug Substances and Drug Products
Authors: Shaikh Tabrez , Gosar Amit
Published: May 2023

Azido impurities are known to be mutagenic and carcinogenic. A small exposure to these impurities may lead to cancer. These impurities may be formed and get incorporated into drug substances or drug products through reagents, catalysts, solvents, or raw materials used in the process of manufacturing drug substances. Various regulatory authorities have published press releases and notices regarding the control of these impurities with the interim limit. Azido impurities can be avoided by taking precautions during the manufacturing of drug substances and products. The methods used to identify and quantify these impurities require highly sensitive instruments such as LCMS/MS or GCMS, which can detect these impurities to a trace level within the given interim limit. These methods are validated according to various regulatory guidelines. Liquid chromatography, along with a mass detector, is mostly used for their determination.
Effectiveness of WhatsApp Messages on Knowledge Gain of Sugarcane Cultivation Practices among the Farmers
Authors: Pawar Rahul , Devendrappa S. , Shree D. A. Nithya
Published: May 2023

Information and communication technology in agriculture provides solutions to agricultural challenges. The present study was conducted in Athani taluk of Belagavi District in Karnataka state. ‘Before-After’ without control group experimental design was used to determine the effectiveness of WhatsApp messages on knowledge gain of sugarcane cultivation practices among farmers. WhatsApp messages on “Sugarcane cultivation practices” was the subject matter selected for the study and tested for their effectiveness. WhatsApp messages acted as treatment for the study. 50 Sugarcane growers were selected for the treatment on the basis of random sampling. The effectiveness was studied in terms of knowledge gain for WhatsApp messages. The results revealed that highest mean differences 2.50 was observed in case of integrated disease management followed by weed management (2.38), micronutrients and inter cultivation (2.10). The mean knowledge score of WhatsApp messages of the respondents before exposure was 20.52 and after exposure it was 50.52, thus there was mean knowledge gain of 30.00. Farming experience, land holding, extension contact, Innovative proneness achievement motivation and Management orientation were found to be positive and significant relationship with knowledge gain. Hence, WhatsApp messages are effective to disseminate the information among the farmers.
Carbon and Zeolite Based Slow Release Fertilizer Formulations Enhances Nutrient Use Efficiency and Yield in Chilli
Authors: Farha M. K. , Gladis R. , Rani B. , Aparna B. , Sarada S. , Joseph Biju
Published: May 2023

Aims: To develop slow release fertilizer formulations using humic acid, charcoal and zeolite and to evaluate nutrient availability, nutrient use efficiency and yield in chilli.

Study Design: This experiment was conducted through completely randomized design with 14 treatments and 3 replications.

Place and Duration of Study: The research was appraised at the Department of Soil Science, College of Agriculture, Vellayani between September 2022- December 2022.

Methods: Carbon and zeolite based slow release fertilizer formulations (SRF) containing all the major, secondary and micronutrients were prepared using compatible fertilizer materials (urea, rajphos, muriate of potash, phosphogypsum, magnesium sulphate, zinc sulphate and borax), carrier materials (zeolite, humic acid and charcoal) and the binding agent (carboxy methyl cellulose) in the ratio of 1:1 and 1: 0.5 in the form of pellets. These formulations were applied to chilli and evaluated nutrient use efficiency and yield.

Results: The pellets were highly stable and weight ranged between 4.0 and 4.5 g. The highest fruit yield of chilli observed was 581.2 g/ plant. The available nitrogen (320.86 kg ha-1), phosphorus (87.15 kg ha-1), potassium (214.35 kg ha-1), calcium (351.13 mg kg-1), magnesium (106.54 mg kg-1), sulphur (9.32 mg kg- 1), boron (0.46 mg kg-1) and zinc (4.25 mg kg-1) was found to be highest in treatment receiving 75% recommended dose of fertilizers (RDF) as humic acid based slow release formulation applied in two splits (basal and 1 MAP). The apparent recovery percentage of nitrogen 78.2%, phosphorus 86.33% and potassium 98.70% and partial factor productivity of 25.98 g g-1 were recorded due to the application of pellets.

Conclusion: Carbon and zeolite based slow release fertilizer formulations in the form of pellets are very effective compared to conventional fertilizers due to their gradual pattern of nutrient release which better meets plant demand, minimizes leaching and therefore nutrient use efficiency and ultimately crop yield. Application of slow release formulations significantly increases the nutrient availability in soil, nutrient use efficiency, growth and yield of chilli.
Clinical Outcomes of Intensive Inpatient Blood Pressure Management in Hospitalized Older Adults
Authors: Anderson Timothy S. , Herzig Shoshana J. , Jing Bocheng , Boscardin W. John , Fung Kathy , Marcantonio Edward R. , Steinman Michael A.
Published: May 2023

Importance

Asymptomatic blood pressure (BP) elevations are common in hospitalized older adults, and widespread heterogeneity in the clinical management of elevated inpatient BPs exists.

Objective

To examine the association of intensive treatment of elevated inpatient BPs with in-hospital clinical outcomes of older adults hospitalized for noncardiac conditions.

Design, Setting, and Participants

This retrospective cohort study examined Veterans Health Administration data between October 1, 2015, and December 31, 2017, for patients aged 65 years or older hospitalized for noncardiovascular diagnoses and who experienced elevated BPs in the first 48 hours of hospitalization.

Interventions

Intensive BP treatment following the first 48 hours of hospitalization, defined as receipt of intravenous antihypertensives or oral classes not used prior to admission.

Main Outcome and Measures

The primary outcome was a composite of inpatient mortality, intensive care unit transfer, stroke, acute kidney injury, B-type natriuretic peptide elevation, and troponin elevation. Data were analyzed between October 1, 2021, and January 10, 2023, with propensity score overlap weighting used to adjust for confounding between those who did and did not receive early intensive treatment.

Results

Among 66 140 included patients (mean [SD] age, 74.4 [8.1] years; 97.5% male and 2.6% female; 17.4% Black, 1.7% Hispanic, and 75.9% White), 14 084 (21.3%) received intensive BP treatment in the first 48 hours of hospitalization. Patients who received early intensive treatment vs those who did not continued to receive a greater number of additional antihypertensives during the remainder of their hospitalization (mean additional doses, 6.1 [95% CI, 5.8-6.4] vs 1.6 [95% CI, 1.5-1.8], respectively). Intensive treatment was associated with a greater risk of the primary composite outcome (1220 [8.7%] vs 3570 [6.9%]; weighted odds ratio [OR], 1.28; 95% CI, 1.18-1.39), with the highest risk among patients receiving intravenous antihypertensives (weighted OR, 1.90; 95% CI, 1.65-2.19). Intensively treated patients were more likely to experience each component of the composite outcome except for stroke and mortality. Findings were consistent across subgroups stratified by age, frailty, preadmission BP, early hospitalization BP, and cardiovascular disease history.

Conclusions and Relevance

The study’s findings indicate that among hospitalized older adults with elevated BPs, intensive pharmacologic antihypertensive treatment was associated with a greater risk of adverse events. These findings do not support the treatment of elevated inpatient BPs without evidence of end organ damage, and they highlight the need for randomized clinical trials of inpatient BP treatment targets.
The formation of “form” and the “decoration” of space in Charlotte Perriand, part 1: Theory and practice of “en Forme (in shape)”
Authors: Sendai Shoichiro
Published: May 2023

This paper aims to clarify the formation process of the concept of “form” from the 1920s to the 1930s by chronologically tracing the creation of Perriand's furniture. That is, by analyzing the key terms “equipment,” “art brut” and “en forme (in shape),” this paper examines how the generation and transformation of steel pipe furniture as “form,” which was considered “new decoration.” When Perriand pursued the possibilities of “form,” the dualisms of industrial and natural materials were not at issue. When she sought in form to induce and “control” a gesture, the geometrical form limited and inhibited it. “En forme” was to liberate the threshold of gesture that form defines. Being “controlled” by the matter, rather than “controlled” by humans, could give rise to unexpected uses. It was the practice of her “new decoration,” a development of Le Corbusier's concept of “equipment” as the kind of interior “decoration” to regulate the typological gestures of humans.
The Creation of DNA Origami‐Based Supramolecular Nanostructures for Cancer Therapy
Authors: Zhang Siyuan , Lou Xin‐Yue , Liu Linlin , Yang Ying‐Wei
Published: May 2023

DNA origami technology, a unique type of DNA nanotechnology, has attracted much attention from researchers and is applied in various fields. Through exquisite design and precise self‐assembly of four kinds of deoxyribonucleotides, DNA origami nanostructures are endowed with excellent programmability and addressability and show outstanding biocompatibility in bio‐related applications, especially in cancer treatment. In this review, nanomaterials based on DNA origami for cancer therapy are concluded, whereby chemotherapy and photo‐assisted therapy are the main focus. Furthermore, the working mechanisms of the functional materials attached to the rigid DNA structures to enable targeted delivery and circumvent drug resistance are also discussed. DNA origami nanostructures are valuable carriers for delivering multifunctional therapeutic agents and demonstrate great potential in cancer treatment both in vitro and in vivo. It is undoubted that DNA origami technology is a promising strategy for constructing versatile nanodevices in biological fields and will excel in human healthcare.
Ultrafast Electrical Pulse Synthesis of Highly Active Electrocatalysts for Beyond‐Industrial‐Level Hydrogen Gas Batteries
Authors: Jiang Taoli , Liu Zaichun , Yuan Yuan , Zheng Xinhua , Park Sunhyeong , Wei Shuyang , Li Linxiang , Ma Yirui , Liu Shuang , Chen Jinghao , Zhu Zhengxin , Meng Yahan , Li Ke , Sun Jifei , Peng Qia , Chen Wei
Published: May 2023

The high reliability and proven ultra‐longevity make aqueous hydrogen gas (H2) batteries ideal for large‐scale energy storage. However, the low alkaline hydrogen evolution and oxidation reaction (HER/HOR) activities of expensive platinum catalysts severely hamper their widespread applications in H2 batteries. Here, cost‐effective, highly active electrocatalysts, with a model of ruthenium‐nickel alloy nanoparticles in ≈3 nm anchored on carbon black (RuNi/C) as an example, are developed by an ultrafast electrical pulse approach for nickel‐hydrogen gas (NiH2) batteries. Having a competitive low cost of about one fifth of Pt/C benckmark, this ultrafine RuNi/C catalyst displays an ultrahigh HOR mass activity of 2.34 A mg−1 at 50 mV (vs RHE) and an ultralow HER overpotential of 19.5 mV at a current density of 10 mA cm−2. As a result, the advanced NiH2 battery can efficiently operate under all‐climate conditions (from −25 to +50 °C) with excellent durability. Notably, the NiH2 cell stack achieves an energy density up to 183 Wh kg−1 and an estimated cost of ≈49 $ kWh−1 under an ultrahigh cathode Ni(OH)2 loading of 280 mg cm−2 and a low anode Ru loading of ≈62.5 µg cm−2. The advanced beyond‐industrial‐level hydrogen gas batteries provide great opportunities for practical grid‐scale energy storage applications.
High‐Valence Oxides for High Performance Oxygen Evolution Electrocatalysis
Authors: Wang Hao , Zhai Tingting , Wu Yifan , Zhou Tao , Zhou Binbin , Shang Congxiao , Guo Zhengxiao
Published: May 2023

Valence tuning of transition metal oxides is an effective approach to design high‐performance catalysts, particularly for the oxygen evolution reaction (OER) that underpins solar/electric water splitting and metal‐air batteries. Recently, high‐valence oxides (HVOs) are reported to show superior OER performance, in association with the fundamental dynamics of charge transfer and the evolution of the intermediates. Particularly considered are the adsorbate evolution mechanism (AEM) and the lattice oxygen‐mediated mechanism (LOM). High‐valence states enhance the OER performance mainly by optimizing the eg‐orbital filling, promoting the charge transfer between the metal d band and oxygen p band. Moreover, HVOs usually show an elevated O 2p band, which triggers the lattice oxygen as the redox center and enacts the efficient LOM pathway to break the “scaling” limitation of AEM. In addition, oxygen vacancies, induced by the overall charge‐neutrality, also promote the direct oxygen coupling in LOM. However, the synthesis of HVOs suffers from relatively large thermodynamic barrier, which makes their preparation difficult. Hence, the synthesis strategies of the HVOs are discussed to guide further design of the HVO electrocatalysts. Finally, further challenges and perspectives are outlined for potential applications in energy conversion and storage.
Mapping publications using the Japan Trauma Data Bank: Scoping review of the international literature
Authors: Nakao Shunichiro , Ito Hiroshi , Katayama Yusuke , Kitamura Tetsuhisa , Hirose Tomoya , Tachino Jotaro , Ogura Hiroshi , Oda Jun
Published: May 2023

The purpose of this study was to describe the characteristics of published international literature using the Japan Trauma Data Bank (JTDB). We undertook a scoping review of studies using data from JTDB. We carried out a systematic search of the following databases on November 21, 2022, using search terms that covers trauma registries in Japan: MEDLINE, Web of Science, CINAHL, and Cochrane Library. Two authors independently abstracted the data. We included all original articles written in English. We identified 166 studies from the 456 included articles. From 2010 to 2016, the annual number of published articles was less than 10. In 2017, there were 10 articles published (6.0%). This increased to 18 (10.8%) in 2018, 21 (12.7%) in 2019, 28 (16.9%) in 2020, 33 (19.9%) in 2021, and 37 (22.3%) in 2022. Most articles (n = 138, 83.1%) reported in‐hospital mortality as the primary outcome. There were more articles on the adult population (n = 86, 51.8%) than those on the pediatric population (n = 21, 12.7%). Twenty‐one articles (12.7%) specified a mechanism of injury for the study population, and three articles (1.8%) focused on burns. Most articles did not specify injury sites for the study population (n = 108, 65.1%) and the most common injury site described in publications was the head (n = 21, 12.7%), followed by the abdomen (n = 13, 7.8%). We observed an increase in international publications using the JTDB and highlighted the major topics and knowledge gaps. Our findings could encourage studies to explore less studied areas in research using the JTDB.
Versatile Production of Multivariate, Hyperdimensional End Group and Main Chain Functionalized Polyolefins
Authors: Fischbach Danyon M. , Krstic Katharina A. , Sita Lawrence R.
Published: May 2023

The (stereoselective) living coordinative copolymerization of 1‐alkenes with 4‐aryl‐1,6‐heptadienes, in both the absence and presence of multiple equivalents of a reversible chain transfer agent, is established as a highly versatile strategy for production of multivariate hyperdimensional functionalized semi‐crystalline or amorphous polyolefins that optionally possess either mono‐ or difunctionalized (telechelic) end‐groups in combination with a programmable level of incorporation of orthogonal functional groups within the main‐chain. The non‐conjugated diene comonomers are readily obtained from a diverse range of aryl carboxaldehyde precursors through a one‐step bis‐allylation process. These results serve to provide a new platform for exploring the science and technology of a vast new landscape of functionalized classes of polyolefins that are now accessible in practical and scalable quantities.
Stabilizing Solid‐state Lithium Metal Batteries through In Situ Generated Janus‐heterarchical LiF‐rich SEI in Ionic Liquid Confined 3D MOF/Polymer Membranes
Authors: Zhang Xingxing , Su Qingmei , Du Gaohui , Xu Bingshe , Wang Shun , Chen Zhuo , Wang Liming , Huang Wenhuan , Pang Huan
Published: May 2023

Pursuing high power density lithium metal battery with high safety is essential for developing next‐generation energy‐storage devices, but uncontrollable electrolyte degradation and the consequence formed unstable solid‐electrolyte interface (SEI) make the task really challenging. Herein, an ionic liquid (IL) confined MOF/Polymer 3D‐porous membrane was constructed for boosting in situ electrochemical transformations of Janus‐heterarchical LiF/Li3N‐rich SEI films on the nanofibers. Such a 3D‐Janus SEI‐incorporated into the separator offers fast Li+ transport routes, showing superior room‐temperature ionic conductivity of 8.17×10−4 S cm−1 and Li+ transfer number of 0.82. The cryo‐TEM was employed to visually monitor the in situ formed LiF and Li3N nanocrystals in SEI and the deposition of Li dendrites, which is greatly benefit to the theoretical simulation and kinetic analysis of the structural evolution during the battery charge and discharge process. In particular, this membrane with high thermal stability and mechanical strength used in solid‐state Li||LiFePO4 and Li||NCM‐811 full cells and even in pouch cells showed enhanced rate‐performance and ultra‐long life spans.
Enabling the Operation of Highly Compatible LiI‐3‐Hydroxypropionitrile Small‐Molecule Solid‐State Electrolytes in Lithium Metal Batteries via Stepped‐Amorphization Strategy
Authors: Song Tao , Wang Da , Wang Hongxia , Yu Jia , Shi Siqi
Published: May 2023

Integrating the advantages of both inorganic ceramic and organic polymer solid‐state electrolytes, small‐molecule solid‐state electrolytes represented by LiI‐3‐hydroxypropionitrile (LiI‐HPN) inorganic–organic hybrid systems possess good interfacial compatibility and high modulus. However, their lack of intrinsic Li+ conduction ability hinders potential application in lithium metal batteries until now, despite containing LiI phase composition. Herein, inspired by evolution tendency of ionic conduction behaviors together with first‐principles molecular dynamics simulations, we propose a stepped‐amorphization strategy to break the Li+ conduction bottleneck of LiI‐HPN. It involves three progressive steps of composition (LiI‐content increasing), time (long‐time standing), and temperature (high‐temperature melting) regulations, to essentially construct a small‐molecule‐based composite solid‐state electrolyte with intensified amorphous degree, which realizes efficient conversion from an I− to Li+ conductor and improved conductivity. As a proof, the stepped‐optimized LiI‐HPN is successfully operated in lithium metal batteries cooperated with Li4Ti5O12 cathode to deliver considerable compatibility and stability over 250 cycles. This work not only clarifies the ionic conduction mechanisms of LiI‐HPN inorganic–organic hybrid systems, but also provides a reasonable strategy to broaden the application scenarios of highly compatible small‐molecule solid‐state electrolytes.
Dissection of the Catalytic Mechanisms of Transmembrane Terpene Cyclases Involved in Fungal Meroterpenoid Biosynthesis
Authors: Tang Jia , Matsuda Yudai
Published: May 2023

Pyr4‐family terpene cyclases are noncanonical transmembrane terpene cyclases involved in the biosynthesis of microbial meroterpenoids and catalyze diverse cyclization reactions. Despite the ubiquity of Pyr4‐family terpene cyclases in microorganisms, their three‐dimensional structures have never been experimentally determined. Herein, we focused on AdrI, the Pyr4‐family enzyme for the andrastin A pathway, and its homologues, and performed a series of mutational experiments using their AlphaFold2‐generated structures. Intriguingly, we found that AdrI and InsA7, which both accept the same substrate, use different amino acid residues for the initiation of the cyclization cascade. Furthermore, we obtained several AdrI variants with altered product selectivity, one of which dominantly yielded a new meroterpenoid species. Collectively, our study provides important insights into the catalytic functions of Pyr4‐family terpene cyclases and will facilitate the engineering of these enzymes.
A Chemical Proteomic Strategy Reveals Inhibitors of Lipoate Salvage in Bacteria and Parasites
Authors: Dienemann Jan‐Niklas , Chen Shu‐Yu , Hitzenberger Manuel , Sievert Montana L. , Hacker Stephan M. , Prigge Sean T. , Zacharias Martin , Groll Michael , Sieber Stephan A.
Published: May 2023

The development of novel anti‐infectives requires unprecedented strategies targeting pathways which are solely present in pathogens but absent in humans. Following this principle, we developed inhibitors of lipoic acid (LA) salvage, a crucial pathway for the survival of LA auxotrophic bacteria and parasites but non‐essential in human cells. An LA‐based probe was selectively transferred onto substrate proteins via lipoate protein ligase (LPL) in intact cells, and their binding sites were determined by mass spectrometry. Probe labeling served as a proxy of LPL activity, enabling in situ screenings for cell‐permeable LPL inhibitors. Profiling a focused compound library revealed two substrate analogs (LAMe and C3) as inhibitors, which were further validated by binding studies and co‐crystallography. Importantly, LAMe exhibited low toxicity in human cells and achieved killing of Plasmodium falciparum in erythrocytes with an EC50 value of 15 μM, making it the most effective LPL inhibitor reported to date.
Synthesis and SARs study of novel spiro‐oxindoles as potent antiproliferative agents with CDK‐2 inhibitory activities
Authors: Al‐Jassas Refaah Mousa , Islam Mohammad Shahidul , Al‐Majid Abdullah Mohammed , Nafie Mohamed S. , Haukka Matti , Rahman A.F.M. Motiur , Alayyaf Abdul Majeed Abdullah , Barakat Assem
Published: May 2023

A series of 16 novel spirooxindole analogs 8a–p were designed and constructed via cost‐effective single‐step multicomponent [3+2] cycloaddition reaction of azomethine ylide (AY) generated in situ from substituted isatin (6a–d) with suitable amino acids (7a–c) and ethylene‐engrafted pyrazole derivatives (5a,b). The potency of all compounds was assayed against a human breast cancer cell line (MCF‐7) and a human liver cell line (HepG2). Spiro compound 8c was the most active member among the synthesized candidates, with exceptional cytotoxicity against the MCF‐7 and HepG2 cell lines, with IC50 values of 0.189 ± 0.01 and 1.04 ± 0.21 µM, respectively. The candidate 8c exhibited more potent activity (10.10‐ and 2.27‐fold) than the standard drug roscovitine (IC50 = 1.91 ± 0.17 µM (MCF‐7) and 2.36 ± 0.21 µM (HepG2)). Compound 8c was investigated for epidermal growth factor receptor (EGFR) inhibition; it exhibited promising IC50 values of 96.6 nM compared with 67.3 nM for erlotinib. The IC50 value of 8c (34.98 nM) exhibited cyclin‐dependent kinase 2 (CDK‐2) inhibition, being more active than roscovitine the (IC50 = 140 nM) in targeting the CDK‐2 kinase enzyme. Additionally, for apoptosis induction of compound 8c in MCF‐7, it upregulated the expression levels of proapoptotic genes for P53, Bax, caspases‐3, 8, and 9 at up to 6.18, 4.8, 9.8, 4.6, 11.3 fold‐change, respectively, and downregualted the level of the antiapoptotic gene for Bcl‐2 by 0.14‐fold. Finally, a molecular docking study of the most active compound 8c highlighted a good binding affinity with Lys89 as the key amino acid for CDK‐2 inhibition.
24‐hour movement guidelines and weight status among preschool‐aged children in Bangladesh: A community‐level cross‐sectional study
Authors: Hossain Mohammad Sorowar , Raheem Enayetur , Okely Anthony D
Published: May 2023

Background

Increasing levels of urbanization and digitization in Bangladesh may be adversely associated with children's weight status and related movement behaviors. This study examined the prevalence of obesity, physical activity (PA), sedentary behavior, and sleep among young children from a district town in northern Bangladesh and identified factors associated with unhealthy weight status.

Methods

Population‐based cross‐sectional study involving all kindergarten schools in Jamalpur District town. Schools and children aged 4–7 years were randomly selected and had their weight and height measured. Mothers completed a questionnaire on their child's PA, recreational screen time, and sleep and sociodemographic factors. Children's weight status was based on World Health Organization (WHO) categories. Meeting the PA recommendation was based on the WHO guidelines for children and adolescents, and meeting the sedentary behavior and sleep recommendations was based on the Canadian/Australian 24‐hour movement guidelines for children and young people.

Results

A total of 585 children and their parents were included in the study. Overall, 15% of children were overweight or obese. Three‐quarters of children met the sleep guideline, and 50% met the PA guideline. Less than one third of children (31%) met the recreational screen time guideline, whereas 15% met all three guidelines. However, when adjusted for all predictors in the model, maternal education, family income, and child's age were significantly associated with overweight/obesity. Children with higher maternal education level were 2.3 times (AOR = 2.33, 95% CI: 1.19–4.78) more likely to be overweight/obese. Children in families with a higher monthly income had 1.9 times (AOR = 1.95, 95% CI: 1.14, 3.35) higher risk of being overweight/obese.

Conclusions

Prioritizing maternal education (mother‐centric interventions) can help address the high levels of childhood obesity in Bangladesh.
Advances in experimental animal models of hepatocellular carcinoma
Authors: Li Jing , Wang Xin , Ren Mudan , He Shuixiang , Zhao Yan
Published: May 2023

Hepatocellular carcinoma (HCC) is a common malignant tumor with insidious early symptoms, easy metastasis, postoperative recurrence, poor drug efficacy, and a high drug resistance rate when surgery is missed, leading to a low 5‐year survival rate. Research on the pathogenesis and drugs is particularly important for clinical treatment. Animal models are crucial for basic research, which is conducive to studying pathogenesis and drug screening more conveniently and effectively. An appropriate animal model can better reflect disease occurrence and development, and the process of anti‐tumor immune response in the human body. This review summarizes the classification, characteristics, and advances in experimental animal models of HCC to provide a reference for researchers on model selection.
Molecular risk factors for locoregional recurrence in resected non‐small cell lung cancer
Authors: Guo Wei , Zhang Tao , Li Runze , Chen Xiaoxi , Pang Jiaohui , Bao Hua , Wu Xue , Shao Yang , Qiu Bin , Gao Shugeng , He Jie
Published: May 2023

Background

Locoregional recurrence is of high risk and is associated with a poor prognosis in terms of OS for non‐small cell lung cancer (NSCLC). Local control is essential for radical cure of NSCLC. Previous studies have investigated the clinicopathological risk factors for locoregional recurrence, but the genomic biomarkers associated with locoregional recurrence have been inadequately studied.

Methods

A total of 118 patients who underwent tumor resection with mutation‐detected tumor specimens were included. Tumor samples at surgery and pretreatment/postoperative blood samples were collected for mutational profiling.

Results

Among 48 patients with disease recurrence, 46% developed locoregional recurrence (LR) and 75% developed distant metastasis (DM). The 3‐year actuarial risk of LR and DM was 25% and 43%, respectively. The first sites of failure were locoregional only (29%), locoregional and distant (10%), and distant only (61%). Patients with LR showed significantly higher ctDNA level than those with only DM at the time of initial recurrence. On multivariate analysis of baseline risk factors, the presence of allele frequency heterogeneity and baseline ctDNA shedding were found to be independently associated with a higher risk of LR. Patients with disruptive TP53 mutations had significantly lower LR‐free survival as compared to patients with wild‐type TP53 or nondisruptive mutations. EGFR mutations showed a favorable prognostic value for LR and is not induced by EGFR tyrosine kinase inhibitor therapy. Both disruptive TP53 mutation and EGFR mutation remained the significant prognostic factor after adjustment for histological type, pathologic nodal stage and adjuvant therapy.

Conclusions

Nearly half of disease recurrences after surgery for NSCC involved locoregional sites. We identified genomic biomarkers from baseline tumor and ctDNA samples which showed promising prognostic value for LR only. This can help identify patients who had a higher risk of locoregional recurrence regardless of the risk of distant metastasis.
Metabolomic Profile by GC/MS and Antioxidant, Antidiabetic and Anti‐Inflammatory Activities of Green Solvent Extracts of Heterospathe elata Leaves
Authors: Dubey Supriya , Shukla Abha , Kumar Shukla Rishi
Published: May 2023

Plants are the prime source of phytoconstituents that can act as potent agents for the prevention and treatment of various diseases. Heterospathe elata is a plant belonging to the Arecaceae family having numerous medicinal properties. The present study was undertaken to prepare crude extracts of Heterospathe elata leaves with solvents of different polarity dimethyl carbonate (DMC), isopropyl alcohol (IPA), hydro alcohol (HYA) and water (WTR) by using successive Soxhlet extraction method. Further, the antioxidant, antidiabetic, and anti‐inflammatory activities were assessed by the spectrophotometric method and possible bioactive phytoconstituents from the hydro alcohol extract of Heterospathe elata leaves using GC/MS. In our study, it was found that the GC/MS analysis revealed the presence of nineteen bioactive phytoconstituents. The highest antioxidant activity was found in the water extract. In antidiabetic and anti‐inflammatory activity highest potential was shown by hydro alcohol extract and the lowest was in the dimethyl carbonate extract. These findings support the Heterospathe elata leaves showed the high biological potential attributed to a high amount of bioactive phytoconstituents and could be utilized as value‐added functional food and medicine.
Hydroxy Acid Activation in Fungal Non‐Ribosomal Peptide Synthesis Assessed by Site‐Directed Mutagenesis
Authors: Hoffmann Sylvester , Damm Maik , Roth Leonard , Süssmuth Roderich D.
Published: May 2023

The fungal cyclodepsipeptides (CDPs) enniatin, beauvericin, bassianolide, and PF1022 consist of alternating N‐methylated l‐amino and d‐hydroxy acids. They are synthesized by non‐ribosomal peptide synthetases (NRPS). The amino acid and hydroxy acid substrates are activated by adenylation (A) domains. Although various A domains have been characterized thus giving insights into the mechanism of substrate conversion, little is known about the utilization of hydroxy acids in NRPSs. Therefore, we used homology modelling and molecular docking of the A1 domain of enniatin synthetase (EnSyn) to gain insights into the mechanism of hydroxy acid activation. We introduced point mutations into the active site and used a photometric assay to study the substrate activation. The results suggest that the hydroxy acid is selected by interaction with backbone carbonyls rather than by a specific side chain. These insights enhance the understanding of non‐amino acid substrate activation and could contribute to the engineering of depsipeptide synthetases.
Chemoenzymatic Catalysis: Cooperativity Enables Opportunity
Authors: Hessefort Logan Z. , Harstad Lauren J. , Merker Kayla R. , Ramos Lauren P. T. , Biegasiewicz Kyle F.
Published: May 2023

The application of enzymes in synthetic organic chemistry has emerged as a powerful means to generate molecular complexity in a highly selective, efficient, and sustainable manner. While enzymes have increasingly been incorporated into synthetic sequences for numerous academic and industrial applications on their own and in sequential processes, their utility in cooperative catalysis with small molecule catalytic platforms has recently drawn increased attention across the field of organic synthesis. In this review, we present a selection of notable accomplishments in cooperative chemoenzymatic catalysis and provide a perspective on its future directions.
Conserved Active Site Architecture Between Bacterial Cellulose and Chitin Synthases
Authors: Shamshoum Melina , Natalio Filipe
Published: May 2023

Glycosyltransferases (GTs) are a large and diverse group of enzymes responsible for catalyzing the formation of a glycosidic bond between a donor molecule, usually a monosaccharide, and a wide range of acceptor molecules, thus, playing critical roles in various essential biological processes. Chitin and cellulose synthases are two inverting processive integral membrane GTs, belonging to the type‐2 family involved in the biosynthesis of chitin and cellulose, respectively. Herein, we report that bacterial cellulose and chitin synthases share an E‐D‐D‐ED‐QRW‐TK active site common motif that is spatially co‐localized. This motif is conserved among distant bacterial evolutionary species despite their low amino acid sequence and structural similarities between them. This theoretical framework offers a new perspective to the current view that bacterial cellulose and chitin synthases are substrate specific and that chitin and cellulose are organism specific. It lays the ground for future in vivo and in silico experimental assessment of cellulose synthase catalytic promiscuity against uridine diphosphate N‐acetylglucosamine and chitin synthase against uridine diphosphate glucose, respectively.
Design of multifunctional polymeric binders in silicon anodes for lithium‐ion batteries
Authors: Ramdhiny Masytha Nuzula , Jeon Ju‐Won
Published: May 2023

Silicon (Si) is a promising anode material for lithium‐ion batteries (LIBs) owing to its tremendously high theoretical storage capacity (4200 mAh g−1), which has the potential to elevate the energy of LIBs. However, Si anodes exhibit severe volume change during lithiation/delithiation processes, resulting in anode pulverization and delamination with detrimental growth of solid electrolyte interface layers. As a result, the cycling stability of Si anodes is insufficient for commercialization in LIBs. Polymeric binders can play critical roles in Si anodes by affecting their cycling stability, although they occupy a small portion of the electrodes. This review introduces crucial factors influencing polymeric binders' properties and the electrochemical performance of Si anodes. In particular, we emphasize the structure–property relationships of binders in the context of molecular design strategy, functional groups, types of interactions, and functionalities of binders. Furthermore, binders with additional functionalities, such as electrical conductivity and self‐healability, are extensively discussed, with an emphasis on the binder design principle.
Capture and Stabilization of the Hydroxyl Radical in a Uranyl Peroxide Cluster**
Authors: Lottes Brett , Carter Korey P.
Published: May 2023

Here we describe the synthesis and characterization of a new uranyl peroxide cluster (UPC), U60Ox30*, which captures and stabilizes oxygen‐based free radicals for more than one week. These radical species were first detected with a nitroblue tetrazolium colorimetric assay and U60Ox30* was characterized by single crystal X‐ray diffraction as well as infrared (IR), Raman, UV‐Vis‐NIR, and electron paramagnetic resonance (EPR) spectroscopies. Identification of the free radicals present in U60Ox30* was done via room temperature solid and solution state X‐band EPR studies using spin trapping methods. The spin trapping agent 5,5‐dimethyl‐1‐pyrroline N‐oxide (DMPO) was definitive for identifying the free radicals in U60Ox30*, which are hydroxyl radicals (⋅OH) that are stable for up to ten days that also persist upon addition of the metalloenzymes catalase and superoxide dismutase. Addition of the spin trapping agent α‐(4‐pyridyl N‐oxide)‐N‐tert‐butylnitrone (POBN) further confirmed the radicals were oxygen based, and deuteration experiments showed that the origin of the free radicals was from the decomposition of H2O2 in water. These results demonstrate that highly oxidizing species such as the ⋅OH radical can be stabilized in UPCs, which alters our understanding of the role of free radicals present in spent nuclear fuel.
Hexalacunary [α‐H2P2W12O48]12− Wells‐Dawson Anion: X‐ray Crystal Structural Evidence and Oligomerization to WO(OH2)4+‐Bridged Dimer and Trimers
Authors: Sugiarto  , Sadakane Masahiro
Published: May 2023

We report the first single‐crystal X‐ray structural evidence of the potassium salt of the hexalacunary [α‐H2P2W12O48]12− (abbreviated as {P2W12}) anion after its discovery by Contant and Ciabrini in 1977. In addition, we observed oligomerization of {P2W12} into a {WO(OH2)}4+‐bridged Pacman‐shaped [{WO(OH2)}(α‐HP2W12O48)2]22− ({P4W25}) dimer and a cyclic [{WO(OH2)}3(P2W12O48)3]30− ({P6W39}) trimer. The three phosphotungstate anions were synthesized through recrystallization of (NH4)12[α‐H2P2W12O48] from slightly alkaline (HOCH2)3CNH2/KCl, CH3NH3Cl/KCl, and CH3NH3Cl/NH4Cl solutions. The structure of {P2W12} is derived from [α‐P2W18O62]6− that has six tungsten atoms one from each polar group and four from the belt–removed, and the center of the lacunary site is capped by a potassium cation. Structures of {P4W25} and {P6W39} are constructed by connecting two and three {P2W12} units with {WO(OH2)}4+, respectively. The isolation of a pure {P6W39} phosphotungstate framework without coordination with transition metal cations is unprecedented. Powder X‐ray diffraction confirmed the bulk purity of these compounds, indicating that selective crystallization was achieved through the selection of countercations and pH.
The Bulk Breast Cancer Cell and Breast Cancer Stem Cell Activity of Binuclear Copper(II)‐Phenanthroline Complexes
Authors: Osei Priscilla B. , Northcote‐Smith Joshua , Fang Jiaxin , Singh Kuldip , Ortu Fabrizio , Suntharalingam Kogularamanan
Published: May 2023

Mononuclear copper(II)‐phenanthroline complexes have been widely investigated as anticancer agents whereas multinuclear copper(II)‐phenanthroline complexes are underexplored. Here the synthesis and characterisation of two new binuclear copper(II)‐phenanthroline complexes 1 and 2 is reported, comprising of 2,9‐dimethyl‐1,10‐phenanthroline or 2,9‐dimethyl‐4,7‐diphenyl‐1,10‐phenanthroline, terminal chloride ligands, and bridging chloride or hydroxide ligands. The binuclear copper(II) complex containing 2,9‐dimethyl‐1,10‐phenanthroline 1 displays nanomolar toxicity towards bulk breast cancer cells and breast cancer stem cells (CSCs) grown in monolayers, >50‐fold greater than cisplatin (an anticancer metallodrug) and salinomycin (a gold‐standard anti‐CSC agent). Spectacularly, 1 exhibits >100‐fold greater potency toward three‐dimensionally cultured mammospheres than cisplatin and salinomycin. Mechanistic studies show that 1 evokes breast CSC apoptosis by elevating intracellular reactive oxygen species levels and damaging genomic DNA (possibly by an oxidative mechanism). To the best of our knowledge, this is the first study to probe the anti‐breast CSC properties of binuclear copper(II)‐phenanthroline complexes.
Energy‐Dissipative Hydrogels: A Promising Material for Tissue Regeneration†
Authors: Li Mingrui , Lin Youshi , Zhang Yuxiao , Bian Liming , Zhang Kunyu
Published: May 2023

Comprehensive Summary

Hydrogels are promising candidates for mimicking native extracellular matrix (ECM) and are therefore widely adopted as scaffolds in tissue engineering. However, conventional hydrogels composed of static networks are prone to permanent structural damages and lack the ability to provide the time‐dependent mechanical cues, which are essential for cell development, ECM remodeling, and tissue regeneration. The recent substantial development in the structurally dynamic hydrogels with energy‐dissipative ability has demonstrated the unique capability of such viscoelastic hydrogels to withstand extreme biomechanical loads and regulate cellular behaviors not present in classical hydrogels. This review starts with the general design principles for energy‐dissipative hydrogels, followed by recent advancements in fabrication approaches for energy‐dissipative hydrogels. We then highlight some applications of energy‐dissipative hydrogels in tissue engineering, including bone and cartilage regeneration, vessel regeneration, nerve regeneration, and wound healing. Finally, we discuss about the key current challenges and future development of energy‐dissipative hydrogels for biomedical applications.