bluuebunny/crossref_metadata_2025 huggingface dataset:
Highly‐Efficiency Far‐Red Emission in Cr3+ Activated Ca1.8Mg1.2Al2Ge3O12 toward Plant Precise Lighting
Authors: Yang Chaowei , Zheng Dongwei , Zou Xikun , Dai Xiangyi , Tang Baoling , Molokeev Maxim S. , Zhang Xuejie , Zhang Haoran , Liu Yingliang , Lei Bingfu
Published: February 2024

Far‐red (FR) region (beyond 700 nm) lighting sources possess special potential for plant lighting. However, it remains a challenge to obtain high‐performance Cr3+‐doped FR phosphors. This study developed a FR phosphor, Ca1.8Mg1.2Al2Ge3O12:Cr3+ (CMAGG: Cr3+), using the cation substitution strategy. Under 438 nm blue light excitation, the phosphors display FR emission centered at 720 nm with a full width at half maximum (FWHM) of 91 nm. Benefit from the favorable match with the FR phytochrome (Pfr), the phosphor is combined with InGaN blue light chips to create a FR phosphor‐converted light‐emitting diode (pc‐LED), which is used in Italian lettuce growth experiments and it results shown in a 15% increase in fresh weight and a 6.5% increase in dry weight. Notably, supplemental FR light modulated its growth morphology. The results of this study will be useful for further research on novel Cr3+‐doped FR phosphors to meet the precise spectral requirements for plant growth.
Enabling C7 Methylation and Arylation of the Indolyl Core via P(III)‐Directed C−H Functionalization
Authors: Kelly Christopher B. , Padilla‐Salinas Rosaura , Chen Wenyong , Muuronen Mikko , Balsells Jaume
Published: February 2024

Peripheral editing of complex molecules via C−H functionalization removes the pervasive retrosynthetic bias toward pre‐functionalization and taps into the innate, often subtle, stereoelectronic differences between C−H linkages. Using this approach, bioactive molecules and residues can be modified without being beholden to lengthy sequences, thus allowing biochemical hypotheses to be interrogated on accelerated timelines. Herein, the C−H functionalization paradigm is leveraged to tackle C7 C−H functionalization of the biologically important tryptophan core. The devised process, which was expanded to indolyl (and related) systems, utilizes an N‐bound unsymmetrical “designer” phosphine to direct C−H functionalization to the desired position while maintaining operational ease of directing group installation/removal. Quantum mechanically calculated steric properties and activation free energies suggest that this phosphine is hindered enough for favoring C−H functionalization over deactivation pathways but is still easily cleaved by nucleophiles. In addition, the process enables the direct C−H methylation, cyclopropanation, and arylation of tryptophan to yield unnatural amino acid (UAA) building blocks. As a testament to the versatility of this method, a solid phase peptide synthesis (SPPS)‐ready phosphinated tryptophan was incorporated into a pentapeptide and the C−H functionalization/dephosphination sequence was executed with ease. The utility of “on‐peptide” editing was exhibited through the late‐stage functionalization of several pentapeptides with a diverse set of C7 substituents on‐ and off‐resin.
Recent Advances in Superhydrophobic Materials Development for Maritime Applications
Authors: Tang Zhao Qing , Tian Tongfei , Molino Paul J. , Skvortsov Alex , Ruan Dong , Ding Jie , Li Yali
Published: February 2024

Underwater superhydrophobic surfaces stand as a promising frontier in materials science, holding immense potential for applications in underwater infrastructure, vehicles, pipelines, robots, and sensors. Despite this potential, widespread commercial adoption of these surfaces faces limitations, primarily rooted in challenges related to material durability and the stability of the air plastron during prolonged submersion. Factors such as pressure, flow, and temperature further complicate the operational viability of underwater superhydrophobic technology. This comprehensive review navigates the evolving landscape of underwater superhydrophobic technology, providing a deep dive into the introduction, advancements, and innovations in design, fabrication, and testing techniques. Recent breakthroughs in nanotechnology, magnetic‐responsive coatings, additive manufacturing, and machine learning are highlighted, showcasing the diverse avenues of progress. Notable research endeavors concentrate on enhancing the longevity of plastrons, the fundamental element governing superhydrophobic behavior. The review explores the multifaceted applications of superhydrophobic coatings in the underwater environment, encompassing areas such as drag reduction, anti‐biofouling, and corrosion resistance. A critical examination of commercial offerings in the superhydrophobic coating landscape offers a current perspective on available solutions. In conclusion, the review provides valuable insights and forward‐looking recommendations to propel the field of underwater superhydrophobicity toward new dimensions of innovation and practical utility.
Differential taxation in agricultural credit market
Authors: Regmi Madhav , Featherstone Allen M.
Published: February 2024

This study examines whether the market competitiveness of farm loan suppliers is affected by the US tax policy for the farm credit system (FCS) and its potential spillover on the farmers' cost of borrowing. We exploit the variation in the corporate income tax rate to estimate its relationship with the farm debt share of the FCS and the potential spillover effect on the estimated cost of borrowing for agricultural loans. Results suggest that a 10% rise in the state (federal) tax rate is associated with an increase in FCS's total farm debt market share by 1.76% (3.76%). A 10% rise in the FCS total farm debt market share tends to increase the cost of borrowing on agricultural loans by 0.06%. Overall, the findings imply that favorable tax treatment could increase FCS' competitiveness in the agricultural lending market. Also, an increase in the interest rate on farm debt is correlated with the increasing market share of FCS in the agricultural credit market. [EconLit Citations: Q14, N22, H2, H7, G21].
A new method to quantify droplet size distribution based on Monte Carlo simulation in liquid–liquid solvent extraction
Authors: Cheng Quanzhong , Tan Boren , Duan Xiaofei , Dong Zhipeng , Xu Feng , Wang Yong , Qi Tao
Published: February 2024

The diameter of a dispersed‐phase droplet determines the interfacial area in liquid–liquid solvent extraction. Capturing the polydispersity of a liquid–liquid flow is crucial in computational fluid dynamics. In this study, a droplet size probability (DSP) model applied to the Eulerian–Eulerian (E–E) framework is proposed to characterize the droplet size distribution (DSD) at mesoscale. The physical characteristic of the DSP model demonstrates size similarity between the computational cells and droplets. Following the single‐droplet hypothesis, two sub‐models are investigated. The first model is the distribution function of the droplet size, and the second model is Monte Carlo simulation in the computational domain. By sampling randomly from the probability density function of the DSD, the loss of physical information caused by the averaging procedure is avoided. Simulation results of the pulsed disc and doughnut column (PDDC) showed that the CFD‐DSP coupled model accurately predicted the dispersed‐phase holdup and DSD under various conditions.
Melatonin alleviated splanchnic hyperdynamic circulation and portosystemic collaterals in cirrhotic rats
Authors: Pun Chon Kit , Chang Ching‐Chih , Chuang Chiao‐Lin , Hsu Shao‐Jung , Huang Hui‐Chun , Hou Ming‐Chih , Lee Fa‐Yauh
Published: February 2024

Chronic liver damages may end up with cirrhosis and portal hypertension, featured by splanchnic hyperdynamic circulation, angiogenesis, and collaterals formation. Melatonin is used to improve sleep quality, which exerts anti‐inflammatory, anti‐angiogenesis, and vascular actions without significant side effects. However, the relevant impacts on aforementioned derangements are unclear. Liver cirrhosis was induced by bile duct ligation in Sprague‐Dawley rats. The rats received melatonin (40 mg/kg/day, i.p.) or vehicle for 28 days. Experiments were performed on the 28th day when cirrhosis developed. In cirrhotic rats, melatonin treatment significantly increased superior mesenteric artery resistance and reduced the blood flow. Melatonin enhanced the portosystemic collateral responsiveness to arginine vasopressin, reduced mesenteric vascular area, shunting degree, and down‐regulated mesenteric MMP‐2 protein expression. Melatonin improved the splanchnic hyperdynamic circulation, portosystemic collateral shunting, and mesenteric angiogenesis in cirrhotic rats. These beneficial effects make melatonin potentially feasible in clinical setting, but further investigation is required.
Synthesis of 9,10‐Bis(organochalcogenyl)phenanthrenes by Cyclization of (Biphenyl‐2‐alkyne)chalcogenides
Authors: Hellwig Paola S. , Goulart Helen A. , Guedes Jonatan S. , Jorge Emily G. , Barcellos Angelita M. , Lenardão Eder J. , Perin Gelson
Published: February 2024

A regioselective, operationally simple and scalable protocol was developed for the synthesis of 9,10‐bis(organochalcogenyl)phenanthrenes and seleno‐spiro[cyclohexane‐1,1′‐indene]‐2,5‐dien‐4‐ones through the cyclization of (biphenyl‐2‐alkyne)chalcogenides. The reaction occurs in the presence of diorganyl diselenides, Oxone® as a green oxidizing agent, and acetonitrile at 80 °C. In this study, 20 compounds were obtained in yields of up to 97 % and in short reaction times (1–4 h).
Modulating Inorganic Dimensionality of Ultrastable Lead Halide Coordination Polymers for Photocatalytic CO2 Reduction to Ethanol
Authors: Yin Jinlin , Song Xueling , Sun Chen , Jiang Yilin , He Yani , Fei Honghan
Published: February 2024

Lead halide hybrids have shown great potentials in CO2 photoreduction, but challenging to afford C2+ reduced products, especially using H2O as the reductant. This is largely due to the trade‐off problem between instability of the benchmark 3D structures and low carrier mobility of quasi‐2D analogues. Herein, the lead halide dimensionality of robust coordination polymers (CP) was modulated by organic ligands differing in a single‐atom change (NH vs. CH2), in which the NH groups coordinate with interlamellar [PbI2] clusters to achieve the important 2D→3D transition. This first CP based on 3D cationic lead iodide sublattice possesses both high aqueous stability and a low exciton binding energy of 25 meV that is on the level of ambient thermal energy, achieving artificial photosynthesis of C2H5OH. Photophysical studies combined with theoretical calculations suggest the bridging [PbI2] clusters in the 3D structure not only results in enhanced carrier transport, but also promotes the intrinsic charge polarization to facilitate the C−C coupling. With trace loading of Rh cocatalyst, the apparent quantum efficiency of the 3D CP reaches 1.4 % at 400 nm with a high C2H5OH selectivity of 89.4 % (product basis), which presents one of the best photocatalysts for C2 products to date.
Rationalizing the Influence of the Binding Affinity on the Activity of Phosphoserine Phosphatases
Authors: Chiba Yoko , Ooka Hideshi , Wintzer Marie E. , Tsunematsu Nao , Nogawa Toshihiko , Suzuki Takehiro , Dohmae Naoshi , Nakamura Ryuhei
Published: February 2024

The Sabatier principle states that catalytic activity can be maximized when the substrate binding affinity is neither too strong nor too weak. Recent studies have shown that the activity of several hydrolases is maximized at intermediate values of the binding affinity (Michaelis–Menten constant: Km). However, it remains unclear whether this concept of artificial catalysis is applicable to enzymes in general, especially for those which have evolved under different reaction environments. Herein, we show that the activity of phosphoserine phosphatase is also enhanced at an intermediate Km value of approximately 0.5 mM. Within our dataset, the variation of Km by three orders of magnitude accounted for a roughly 18‐fold variation in the activity. Owing to the high phylogenetic and physiological diversity of our dataset, our results support the importance of optimizing Km for enzymes in general. On the other hand, a 77‐fold variation in the activity was attributed to other physicochemical parameters, such as the Arrhenius prefactor of kcat, and could not be explained by the Sabatier principle. Therefore, while tuning the binding affinity according to the Sabatier principle is an important consideration, the Km value is only one of many physicochemical parameters which must be optimized to maximize enzymatic activity.
Engineering Anti‐CRISPR Proteins to Create CRISPR‐Cas Protein Switches for Activatable Genome Editing and Viral Protease Detection
Authors: Kang Wenyuan , Xiao Fei , Zhu Xi , Ling Xinyu , Xie Shiyi , Li Ruimiao , Yu Peihang , Cao Linxin , Lei Chunyang , Qiu Ye , Liu Tao , Nie Zhou
Published: February 2024

Proteins capable of switching between distinct active states in response to biochemical cues are ideal for sensing and controlling biological processes. Activatable CRISPR‐Cas systems are significant in precise genetic manipulation and sensitive molecular diagnostics, yet directly controlling Cas protein function remains challenging. Herein, we explore anti‐CRISPR (Acr) proteins as modules to create synthetic Cas protein switches (CasPSs) based on computational chemistry‐directed rational protein interface engineering. Guided by molecular fingerprint analysis, electrostatic potential mapping, and binding free energy calculations, we rationally engineer the molecular interaction interface between Cas12a and its cognate Acr proteins (AcrVA4 and AcrVA5) to generate a series of orthogonal protease‐responsive CasPSs. These CasPSs enable the conversion of specific proteolytic events into activation of Cas12a function with high switching ratios (up to 34.3‐fold). These advancements enable specific proteolysis‐inducible genome editing in mammalian cells and sensitive detection of viral protease activities during virus infection. This work provides a promising strategy for developing CRISPR‐Cas tools for controllable gene manipulation and regulation and clinical diagnostics.
A Vitrimer Acts as a Compatibilizer for Polyethylene and Polypropylene Blends
Authors: Yokoyama Kosuke , Guan Zhibin
Published: February 2024

Polymer compatibilization plays a critical role in achieving polymer blends with favorable mechanical properties and enabling efficient recycling of mixed plastic wastes. Nonetheless, traditional compatibilization methods often require tailored designs based on the specific chemical compositions of the blends. In this study, we propose a new approach for compatibilizing polymer blends using a dynamically crosslinked polymer network, known as vitrimers. By adding a relatively small amount (1–5 w/w%) of a vitrimer made of siloxane‐crosslinked high‐density polyethylene (HDPE), we successfully compatibilized unmodified HDPE and isotactic polypropylene (iPP). The vitrimer‐compatibilized blend exhibited enhanced elongation at break (120 %) and smaller iPP domain sizes (0.4 μm) compared to the control blend (22 % elongation at break, 0.9 μm iPP droplet size). Moreover, the vitrimer‐compatibilized blend showed significantly improved microphase stability during annealing at 180 °C. This straightforward method shows promise for applications across various polymer blend systems.
RNA‐Templated Peptide Bond Formation Promotes L‐Homochirality
Authors: Węgrzyn Ewa , Mejdrová Ivana , Müller Felix M. , Nainytė Milda , Escobar Luis , Carell Thomas
Published: February 2024

The world in which we live is homochiral. The ribose units that form the backbone of DNA and RNA are all D‐configured and the encoded amino acids that comprise the proteins of all living species feature an all‐L‐configuration at the α‐carbon atoms. The homochirality of α‐amino acids is essential for folding of the peptides into well‐defined and functional 3D structures and the homochirality of D‐ribose is crucial for helix formation and base‐pairing. The question of why nature uses only encoded L‐α‐amino acids is not understood. Herein, we show that an RNA‐peptide world, in which peptides grow on RNAs constructed from D‐ribose, leads to the self‐selection of homo‐L‐peptides, which provides a possible explanation for the homo‐D‐ribose and homo‐L‐amino acid combination seen in nature.
Breaking Global Diatropic Current to Tame Diradicaloid Character: Thiele's Hydrocarbon Under Macrocyclic Constraints
Authors: Banachowicz Piotr , Das Mainak , Kruczała Krzysztof , Siczek Miłosz , Sojka Zbigniew , Kijewska Monika , Pawlicki Miłosz
Published: February 2024

A diradical/biradical character of organic derivatives is one of the key aspects of contemporary research focusing on the fundamental studies followed by potential applicability relying on the unique optical, electronic, or magnetic properties assigned to unpaired electrons. A precise involvement of two p‐phenylenes into a cyclophane‐like conjugated, diatropic system creates a flexible molecule with the two different characters of both subunits (benzene and quinone) imprinting into the structure a Kekulé delocalized system. A dynamic of both carbocyclic subunits, and their mutual interaction generates a singlet open‐shell state (J=−1.25 kcal/mol) as documented spectroscopically (NMR and EPR). The extended theoretical analysis has proved a correlation between dihedral angle and the diradicaloid character that shifts from a closed‐shell singlet to an open‐shell state, eventually showing the y0=0.86 for 78 degrees and ΔEST=−0.34 kcal/mol.
Redox‐Regulated Synthetic Channels: Enabling Reversible Ion Transport by Modulating the Ion‐Permeation Pathway
Authors: Shi Linlin , Zhao Wen , Jiu Zhihui , Guo Jingjing , Zhu Qiuhui , Sun Yonghui , Zhu Bo , Chang Junbiao , Xin Pengyang
Published: February 2024

Natural redox‐regulated channel proteins often utilize disulfide bonds as redox sensors for adaptive regulation of channel conformations in response to diverse physiological environments. In this study, we developed novel synthetic ion channels capable of reversibly switching their ion‐transport capabilities by incorporating multiple disulfide bonds into artificial systems. X‐ray structural analysis and electrophysiological experiments demonstrated that these disulfide‐bridged molecules possess well‐defined tubular cavities and can be efficiently inserted into lipid bilayers to form artificial ion channels. More importantly, the disulfide bonds in these molecules serve as redox‐tunable switches to regulate the formation and disruption of ion‐permeation pathways, thereby achieving a transition in the transmembrane transport process between the ON and OFF states.
Impact of water absorption on the creep performance of epoxy/microcrystalline cellulose composites
Authors: Lavoratti Alessandra , Bianchi Otávio , Cruz Joziel A. , Al‐Maqdasi Zainab , Varna Janis , Amico Sandro Campos , Joffe Roberts
Published: February 2024

Recently, considerable effort has been made to study cellulose/epoxy composites. However, there is a gap when it comes to understanding the post‐conditioning anomalous effect of moisture uptake on their mechanical and dynamic‐mechanical properties, and on their creep behavior. In this work, up to 10.0 wt% microcrystalline cellulose (MCC) was incorporated into epoxy resin by simple mixing and sonication. Epoxy/MCC composites were fabricated by casting in rubber silicone molds, and rectangular and dog‐bone test specimens were produced. The moisture uptake, dynamic mechanical, chemical, tensile, and creep behavior were evaluated. The incorporation of MCC increased the water diffusion coefficient. The changes in storage modulus and glass transition temperature, combined with Fourier‐transform infrared spectroscopy analysis, evidenced that water sorption in epoxies causes both plasticization and additional resin crosslinking, although the latter is prevented by the addition of MCC. The creep strain of the composites increased by 60% after conditioning, indicating that plasticization induced by water sorption plays an important role in the long‐term properties of the composites.
CFD evaluation of hydrophobic feedstock bench‐scale fermenters for efficient high agitation volumetric mass transfer
Authors: Marx Richard , Liu Huolong , Yoon Seongkyu , Xie Dongming
Published: February 2024

A new biomanufacturing platform combining intracellular metabolic engineering of the oleaginous yeast Yarrowia lipolytica and extracellular bioreaction engineering provides efficient bioconversion of plant oils/animal fats into high‐value products. However, predicting the hydrodynamics and mass transfer parameters is difficult due to the high agitation and sparging required to create dispersed oil droplets in an aqueous medium for efficient yeast fermentation. In the current study, commercial computational fluid dynamic (CFD) solver Ansys CFX coupled with the MUSIG model first predicts two‐phase system (oil/water and air/water) mixing dynamics and their particle size distributions. Then, a three‐phase model (oil, air, and water) utilizing dispersed air bubbles and a polydispersed oil phase was implemented to explore fermenter mixing, gas dispersion efficiency, and volumetric mass transfer coefficient estimations (kLa). The study analyzed the effect of the impeller type, agitation speed, and power input on the tank's flow field and revealed that upward‐pumping pitched blade impellers (PBI) in the top two positions (compared to Rushton‐type) provided advantageous oil phase homogeneity and similar estimated kLa values with reduced power. These results show good agreement with the experimental mixing and kLa data.
Engineering CREB‐activated promoters for adenosine‐induced gene expression
Authors: Cox John Robert , Fox Andrea , Lenahan Conor , Pivnik Liza , Manion Matthew , Blazeck John
Published: February 2024

Accumulation of the ribonucleoside, adenosine (ADO), triggers a cAMP response element binding protein (CREB)‐mediated signaling pathway to suppress the function of immune cells in tumors. Here, we describe a collection of CREB‐activated promoters that allow for strong and tunable ADO‐induced gene expression in human cells. By optimizing number of CREB transcription factor binding sites and altering the core promoter region of CREB‐based hybrid promoters, we created synthetic constructs that drive gene expression to higher levels than strong, endogenous mammalian promoters in the presence of ADO. These synthetic promoters are induced up to 47‐fold by ADO, with minimal expression in their “off” state. We further determine that our CREB‐based promoters are activated by other compounds that act as signaling analogs, and that combinatorial addition of ADO and these compounds has a synergistic impact on gene expression. Surprisingly, we also detail how background ADO degradation caused by the common cell culture media additive, fetal bovine serum (FBS), confounds experiments designed to determine ADO dose‐responsiveness. We show that only after long‐term heat deactivation of FBS can our synthetic promoters enable gene expression induction at physiologically relevant levels of ADO. Finally, we demonstrate that the strength of a CREB‐based promoter is enhanced by incorporating other transcription factor binding sites.
Filtration of a multi‐serotype glycoconjugate vaccine drug product through sterilizing grade 0.2/0.22 µm pore size filters
Authors: Du Zhuoshi , Qiu Siyi , Gill Kanwal , Toprani Vishal , Zydney Andrew L.
Published: February 2024

Glycoconjugate vaccines containing multiple serotypes of a bacterial capsular polysaccharide can provide strong immune protection against pathogenic infections. Sterile filtration is an important component of the fill and finish operations in the preparation of these vaccines, with the capacity of the sterile filter limited by membrane fouling. The objective of this study was to examine the performance of a range of commercial 0.2/0.22 µm nominal pore size sterilizing grade filters with both single‐layer and dual‐layer structures during filtration of a glycoconjugate vaccine drug product consisting of four polysaccharide serotypes. The highly asymmetric Millipore Express showed much higher capacity than the more homogeneous filters, with the support structure of the Express acting as a prefilter that was able to remove foulants thereby protecting the small pores in the size‐selective skin layer. This behavior was confirmed by performing experiments with different batch prefilters and by examining the location of foulant deposition within the sterile filters using confocal microscopy. These results provide important insights into the factors controlling fouling by these multiserotype vaccines as well as a framework for increasing the capacity of the sterile filter.
Removal of phenolic compounds from sugarcane syrup and impact on Saccharomyces cerevisiae fermentation for β‐farnesene production
Authors: Carvalho Luís Carlos , Oliveira Ana L. S. , Carsanba Erdem , Lopes Ana , Leal Tânia , Ribeiro Mónica , Fernandes Sara , Pintado Manuela , Oliveira Carla
Published: February 2024

This work aimed to study for the first time the effects of phenolic compounds from sugarcane syrup on Saccharomyces cerevisiae β‐farnesene fermentation by removing them from this feedstock. Syrup purification was optimized through a central composite design using five types of activated charcoal: three contact times (1–24 h) and three adsorbent concentrations (10–150 g L−1). The optimal purification condition—charcoal pellets at 115 g L−1 and contact time of 12.5 h—led to 96.7% of phenolic compounds removal and 43.7% of syrup recovery. The effects of reducing phenolic content from approximately 7.0–0.3 mg L−1 in sugarcane syrup on yeast fermentation varied with the scale. An increase in biomolecule productivity was only observed in shake‐flasks (11%) and in biomass productivity only in the 2 L bioreactor (12%). Thus, phenolic compounds from sugarcane syrup do not influence β‐farnesene production at a large scale under the conditions tested.
MCM2 is involved in subtyping and tamoxifen resistance of ERα‐positive breast cancer by acting as the downstream factor of ERα
Authors: Liu Sainan , Liang Zhuoshuai , Wang Yujian , Ren Yaxuan , Gu Yulu , Qiao Yichun , He Huan , Li Yong , Cheng Yi , Liu Yawen
Published: February 2024

Tamoxifen (TAM) resistance is finally developed in over 40% of patients with estrogen receptor α‐positive breast cancer (ERα+‐BC), documenting that discovering new molecular subtype is needed to confer perception to the heterogeneity of ERα+‐BC. We obtained representative gene sets subtyping ERα+‐BC using gene set variation analysis (GSVA), non‐negative matrix factorization (NMF), and COX regression methods on the basis of METABRIC, TCGA, and GEO databases. Furthermore, the risk score of ERα+‐BC subtyping was established using least absolute shrinkage and selection operator (LASSO) regression on the basis of genes in the representative gene sets, thereby generating the two subtypes of ERα+‐BC. We further found that minichromosome maintenance complex component 2 (MCM2) functioned as the hub gene subtyping ERα+‐BC using GO, KEGG, and MCODE. MCM2 expression was capable for specifically predicting 1‐year overall survival (OS) of ERα+‐BC and correlated with T stage, AJCC stage, and tamoxifen (TAM) sensitivity of ERα+‐BC. The downregulation of MCM2 expression inhibited proliferation, migration, and invasion of TAM‐resistant cells and promoted G0/G1 arrest. Altogether, tamoxifen resistance entails that MCM2 is a hub gene subtyping ERα+‐BC, providing a novel dimension for discovering a potential target of TAM‐resistant BC.
Targeting autophagy overcomes cancer‐intrinsic resistance to CAR‐T immunotherapy in B‐cell malignancies
Authors: Tang Lu , Zhang Huan , Zhou Fen , Wei Qiuzhe , Du Mengyi , Wu Jianghua , Li Chenggong , Luo Wenjing , Zhou Jie , Wang Xindi , Chen Zhaozhao , Zhang Yinqiang , Huang Zhongpei , Wu Zhuolin , Wen Yuxi , Jiang Huiwen , Liao Danying , Kou Haiming , Xiong Wei , Mei Heng , Hu Yu
Published: February 2024

Background

Chimeric antigen receptor T (CAR‐T) therapy has substantially revolutionized the clinical outcomes of patients with hematologic malignancies, but the cancer‐intrinsic mechanisms underlying resistance to CAR‐T cells remain yet to be fully understood. This study aims to explore the molecular determinants of cancer cell sensitivity to CAR‐T cell‐mediated killing and to provide a better understanding of the underlying mechanisms and potential modulation to improve clinical efficacy.

Methods

The human whole‐genome CRISPR/Cas9‐based knockout screening was conducted to identify key genes that enable cancer cells to evade CD19 CAR‐T‐cell‐mediated killing. The in vitro cytotoxicity assays and evaluation of tumor tissue and bone marrow specimens were further conducted to confirm the role of the key genes in cancer cell susceptibility to CAR‐T cells. In addition, the specific mechanisms influencing CAR‐T cell‐mediated cancer clearance were elucidated in mouse and cellular models.

Results

The CRISPR/Cas9‐based knockout screening showed that the enrichment of autophagy‐related genes (ATG3, BECN1, and RB1CC1) provided protection of cancer cells from CD19 CAR‐T cell‐mediated cytotoxicity. These findings were further validated by in vitro cytotoxicity assays in cells with genetic and pharmacological inhibition of autophagy. Notably, higher expression of the three autophagy‐related proteins in tumor samples was correlated with poorer responsiveness and worse survival in patients with relapsed/refractory B‐cell lymphoma after CD19 CAR‐T therapy. Bulk RNA sequencing analysis of bone marrow samples from B‐cell leukemia patients also suggested the clinical relevance of autophagy to the therapeutic response and relapse after CD19 CAR‐T cell therapy. Pharmacological inhibition of autophagy and knockout of RB1CC1 could dramatically sensitize tumor cells to CD19 CAR‐T cell‐mediated killing in mouse models of both B‐cell leukemia and lymphoma. Moreover, our study revealed that cancer‐intrinsic autophagy mediates evasion of CAR‐T cells via the TNF‐α‐TNFR1 axis‐mediated apoptosis and STAT1/IRF1‐induced chemokine signaling activation.

Conclusions

These findings confirm that autophagy signaling in B‐cell malignancies is essential for the effective cytotoxic function of CAR‐T cells and thereby pave the way for the development of autophagy‐targeting strategies to improve the clinical efficacy of CAR‐T cell immunotherapy.
LiDAR point clouds analysis computer tools for teaching autonomous vehicles perception algorithms
Authors: Jiménez Felipe , Clavijo Miguel
Published: February 2024

The technological developments behind autonomous vehicles cover several areas and engineers training in this field represents a challenge. The main layers include perception, decision making, and acting. In the first one, different technologies can be used. The processing of the information provided by the sensors must allow successive modules to understand the environment and Laser imaging Detection and Ranging (LiDAR) technology is one of the most promising ones nowadays for this task. It offers great robustness in detection, but the extraction of information from the point cloud involves the development of complex algorithms that could be very time‐consuming if an experimental teaching is intended. This article presents two educational solutions for deepening in perception algorithms using LiDAR for autonomous driving: a closed ad‐hoc computer application for two‐dimensional (2D) LiDAR point cloud processing and an oriented set of commands for three‐dimensional (3D) LiDARs in Matlab. Their use allows main concept exploration in practical sessions with little time consumption and provides students a general overview of the tasks that must be performed by the perception layer in the autonomous vehicles. Furthermore, these tools provide the possibility of organizing different activities in the classroom related to theoretical and experimental issues, and understanding of results because the most tedious tasks are eased.
Funny things are everywhere: Combatting geographic disparities in aortic stenosis care
Authors: Hashem Anas , Goldsweig Andrew M.
Published: February 2024

Key points

Only 25%–35% of geographic variation in the use of surgical and transcatheter aortic valve replacement can be attributed to differing patient and hospital characteristics.

To address geographic disparities, the cardiovascular community must address modifiable cardiovascular risk factors, social determinants of health, and healthcare delivery models.

Governmental and professional organizations must study and actively address geographic disparities in access to care for aortic valve disease.
Patient‐specific computer simulation of transcatheter aortic valve replacement in patients with previous mechanical mitral prosthesis: A case series
Authors: Maiani Silvia , Nardi Giulia , Di Mario Carlo , Meucci Francesco
Published: February 2024

Transcatheter aortic valve replacement performed in patients with previously implanted mechanical mitral prosthesis represents a high risk procedure with several potential complications. We report a systematic use of a prediction model based on artificial intelligence to plan the interventional strategy in this challenging scenario.
An Overview of Syntheses of Salvinorin A and its Analogues
Authors: Tibouti Soufian , Barriault Louis
Published: February 2024

Salvinorin A is a powerful hallucinogen in humans, and a selective, high efficacy agonist of the kappa‐opioid receptor (κ‐OR). Salvinorin A is the first plant‐derived ligand with high selectivity for κ‐OR over other receptors, its structure is unrelated to any known opioid receptor ligands, even lacking any nitrogenous moieties. Mechanistically and pharmacologically, salvinorin A is distinct from other known hallucinogens in humans, making it the only selective κ‐OR ligand to gain wide‐spread interest outside of research. Structurally, salvinorin A bares a highly functionalized trans‐decalin core, containing two quaternary centers, and is fused to a δ‐lactone baring a furan moiety. Synthetic access of salvinorin A has been elusive due to a highly sensitive epimerizable center at carbon 8 (C8). All these features make salvinorin A a highly challenging synthetic target. With multiple synthetic efforts from around the world, only nine completed syntheses have been achieved to date. This review is intended to provide a look at the key strategies used to achieve the syntheses reported to date. We will summarize the efforts towards the syntheses of salvinorin A starting from Evans in 2007 to Barriault in 2023.
Glutathione Protects other Cellular Thiols against Oxidation by CuII‐Dp44mT
Authors: Doumi Iman , Lang Lukas , Vileno Bertrand , Deponte Marcel , Faller Peter
Published: February 2024

Cu‐thiosemicarbazones have been intensively investigated for their application in cancer therapy or as antimicrobials. Copper(II)‐di‐2‐pyridylketone‐4,4‐dimethyl‐thiosemicarbazone (CuII‐Dp44mT) showed anticancer activity in the submicromolar concentration range in cell culture. The interaction of CuII‐Dp44mT with thiols leading to their depletion or inhibition was proposed to be involved in this activity. Indeed, CuII‐Dp44mT can catalyze the oxidation of thiols although with slow kinetics. The present work aims to obtain insights into the catalytic activity and selectivity of CuII‐Dp44mT toward the oxidation of different biologically relevant thiols. Reduced glutathione (GSH), L‐cysteine (Cys), N‐acetylcysteine (NAC), D‐penicillamine (D‐Pen), and the two model proteins glutaredoxin (Grx) and thioredoxin (Trx) were investigated. CuII‐Dp44mT catalyzed the oxidation of these thiols with different kinetics, with rates in the following order D‐Pen>Cys≫NAC>GSH and Trx>Grx. CuII‐Dp44mT was more efficient than CuII chloride for the oxidation of NAC and GSH, but not D‐Pen and Cys. In mixtures of biologically relevant concentrations of GSH and either Cys, Trx, or Grx, the oxidation kinetics and spectral properties were similar to that of GSH alone, indicating that the interaction of these thiols with CuII‐Dp44mT is dominated by GSH. Hence GSH could protect other thiols against potential deleterious oxidation by CuII‐Dp44mT.
Synthesis of Pyridazino[4,5‐b]indoles by [3+3] Annulation of 2‐Alkenylindoles and Hydrazonyl Chlorides
Authors: Zhang Shuting , Zhang Xinyu , Li Lesong , Shi Zhenyu , Wang Yang
Published: February 2024

A novel [3+3] annulation reaction of 2‐alkenylindoles with hydrazonyl chlorides in the presence of base for the formation of pyridazino[4,5‐b]indoles was developed. This approach provided a convenient and efficient way to synthesize a series of functionalized pyridazino[4,5‐b]indoles derivatives. The method exhibited a broad substrate scope and provided the corresponding pyridazino[4,5‐b]indoles products with excellent yields.
From Stilbenes to carbo‐Stilbenes: an Encouraging Prospect
Authors: Zhu Chongwei , Saquet Alix , Maraval Valérie , Bijani Christian , Cui Xiuling , Poater Albert , Chauvin Remi
Published: February 2024

Beyond previously described carbo‐naphthalene and carbo‐biphenyl, a novel type of bis‐carbo‐benzenic molecules is envisaged from the stilbene parent. The synthesis, structure, spectroscopic and electrochemical properties of two such carbo‐stilbenes are described at complementary experimental and computational DFT levels. In the selected targets, the bare skeletal carbo‐mer of carbo‐stilbene is decorated by 8 or 10 phenyl groups, 0 or 2 tert‐butyl groups, and 2 n‐octyl chains, the later substituents being introduced to compensate anticipated solubility issues. As in the parent stilbene series, isomers of the phenylated carbo‐stilbenes are characterized. The cis‐ and trans‐isomers are, however, formed in almost equal amounts and could not be separated by either chromatography or crystallization. Nevertheless, due to a slow interconversion at the NMR time scale (up to 55 °C) the 1H NMR signals of both isomers of the two carbo‐stilbenes could be tentatively assigned. The calculated structure of the cis‐isomer exhibits a helical shape, consistent with the observed magnetic shielding of phenyl p‐CH nuclei residing inside the shielding cone of the facing C18 ring. The presence of the two isomers in solution also gives rise to quite broad UV‐vis absorption spectra with main bands at ca 460, 560 and 710 nm, and a significant bathochromic shift for the decaphenylated carbo‐stilbene vs the di‐tert‐butyl‐octaphenylated counterpart. Square wave voltammograms do not show any resolution of the two isomers, giving a reversible reduction wave at −0.65 or −0.58 V/SCE, and an irreversible oxidation peak at 1.11 V/SCE, those values being classical for most carbo‐benzene derivatives. Calculated NICS values (NICS(1)=−12.5±0.2 ppm) also indicate that the aromatic nature of the C18 rings is not markedly affected by the dialkynylbutatriene (DAB) connector between them.
Fractionation of Glycans from Hot‐Water Extracts with Ceramic Ultrafiltration Membranes
Authors: Wolf Marius , Hanstein Stefan
Published: February 2024

Extraction of hemicelluloses from biomass with pressurized hot‐water employs the mechanism of autohydrolysis for molecular weight reduction. In a pilot‐scale extraction of depectinized apple pomace, molecular weight was 30 kDa with a broad mass distribution including monomers and their degradation products. Ultrafiltration with sequential use of ceramic membranes with decreasing cut‐off yielded a suitable fraction with molecular weight of 9 kDa representing 10 % of the extracted hemicelluloses. Further autohydrolytic treatment of the extracted hemicellulose decreases molecular weight while increasing the mass of degradation products. For a series of hydrolysates sequential filtration through ceramic membranes was further tested for fractionation and purification. The efficiency of this fractionation was analyzed by size exclusion chromatography and a total mass balance of the ultrafiltration process is given as an evaluation for suitability of purifying and fraction glycans.
The Interplay of Spacer Chirality and Parity in Mesogenic Dimers
Authors: Ožegović Antonija , Knežević Anamarija , Novak Jurica , Šegota Suzana , Davidson Patrick , Lesac Andreja
Published: February 2024

Introducing chirality into soft materials, including liquid crystals (LCs), profoundly impacts their self‐organization and physical properties. In this study, we synthesized a novel series of LC dimers with a chiral center as part of their flexible spacer. The dimers were prepared in racemic and enantiomerically pure forms. Their spacer length and parity were varied to investigate the effect of spacer chirality and parity on mesomorphic behavior and on chiral induction in the nematic phase of achiral mesogens. Our results show that the even‐membered chiral dimers only have chiral nematic phases. In contrast, the odd‐membered dimers display rich mesomorphism, including the intriguing blue phase (BP) and chiral form of the twist‐bend nematic phase (N*TB). The observed significant difference in the 3D surface morphology between the racemic and chiral forms of the N*TB phase suggests that the chiral moiety in the spacer promotes a chiral hierarchy. Furthermore, the chiral dimers show a prominent odd‐even effect in the helical twisting power in nematic hosts. These findings highlight the importance of the position of the chiral group within the dimeric molecule and provide new insights into how intrinsic chirality in the spacer affects the overall structural chirality.
Mechanistic Determinants of Daprodustat Drug–Drug Interactions and Pharmacokinetics in Hepatic Dysfunction and Chronic Kidney Disease: Significance of OATP1B‐CYP2C8 Interplay
Authors: Bi Yi‐An , Jordan Samantha , King‐Ahmad Amanda , West Mark A. , Varma Manthena V. S.
Published: February 2024

Daprodustat is the first oral hypoxia‐inducible factor prolyl hydroxylase inhibitor approved recently for the treatment of anemia caused by chronic kidney disease (CKD) in adults receiving dialysis. We evaluated the role of organic anion transporting polypeptide (OATP)1B‐mediated hepatic uptake transport in the pharmacokinetics (PKs) of daprodustat using in vitro and in vivo studies, and physiologically‐based PK (PBPK) modeling of its drug–drug interactions (DDIs) with inhibitor drugs. In vitro, daprodustat showed specific transport by OATP1B1/1B3 in the transfected cell systems and primary human and monkey hepatocytes. A single‐dose oral rifampin (OATP1B inhibitor) reduced daprodustat intravenous clearance by a notable 9.9 ± 1.2‐fold (P < 0.05) in cynomolgus monkeys. Correspondingly, volume of distribution at steady‐state was also reduced by 5.0 ± 1.1‐fold, whereas the half‐life change was minimal (1.5‐fold), corroborating daprodustat hepatic uptake inhibition by rifampin. A PBPK model accounting for OATP1B‐CYP2C8 interplay was developed, which well described daprodustat PK and DDIs with gemfibrozil (CYP2C8 and OATP1B inhibitor) and trimethoprim (weak CYP2C8 inhibitor) within 25% error of the observed data in healthy subjects. About 18‐fold increase in daprodustat area under the curve (AUC) following gemfibrozil treatment was found to be associated with strong CYP2C8 inhibition and moderate OATP1B inhibition. Moreover, PK modulation in hepatic dysfunction and subjects with CKD, in comparison to healthy control, was well‐captured by the model. CYP2C8 and/or OATP1B inhibitor drugs (e.g., gemfibrozil, clopidogrel, rifampin, and cyclosporine) were predicted to perpetrate moderate‐to‐strong DDIs in healthy subjects, as well as, in target CKD population. Daprodustat can be used as a sensitive CYP2C8 index substrate in the absence of OATP1B modulation.
Insulin requirements during pregnancy in women with type 1 diabetes treated with insulin pump
Authors: Dori‐Dayan Nimrod , Cukierman‐Yaffe Tali , Zemet Roni , Cohen Ohad , Levi Keren , Mazaki‐Tovi Shali , Yoeli‐Ullman Rakefet
Published: February 2024

Introduction

Insulin requirement in women with Type 1 diabetes (T1DM) changes throughout pregnancy. The aim of this study was to determine the total change in insulin requirements and the effect of gestational weight gain (GWG) and pre‐gestational BMI on insulin requirements during pregnancy in women with T1DM treated with continuous subcutaneous insulin infusion and continuous glucose monitoring.

Methods

This historical cohort study included all consecutive women with T1DM who were monitored during pregnancy at the high‐risk pregnancy clinic at a tertiary medical center during April 2011–April 2019. One Way Repeated Measures ANOVA with Bonferroni adjustment was conducted to compare the effects of gestational age on insulin requirements and a Two Way Repeated Measures ANOVA was employed to test for the interaction between gestational age intervals and maternal BMI and GWG.

Results

Data regarding insulin requirements of 185 pregnancies were included in the analyses. There was a significant effect of gestational age on total insulin (Wilks' Lambda = 0.34, F(6,14) = 4.52, p = 0.009), basal insulin (Wilks' Lambda = 0.41, F(6,14) = 3.30, p = 0.031) and bolus insulin (Wilks' Lambda = 0.43, F(6,14) = 3.02, p = 0.041). Total insulin/kg requirements increased by 5.5% from 13–20 weeks to 20–26 weeks, 19% from 20–26 weeks to 26–33 weeks, and 17.4% from 26 to 33 weeks to delivery (p for trend = 0.009). Overall, insulin requirements increased by 42.1% from conception to delivery (p < 0.01).

There was no significant main effect of maternal BMI or GWG on insulin requirements.

Conclusions

There is a significant increase in insulin requirements per kg during pregnancy in women with T1DM who were treated with an insulin pump.
Natural vegetation biomass and the dimension of forest quality in tropical agricultural landscapes
Authors: de Toledo Renato Miazaki , Pivello Vania Regina , Perring Michael Philip , Verdade Luciano Martins
Published: February 2024

Forest cover has been a pivotal indicator of biological conservation and carrying capacity for wildlife in forest ecoregions. Such a relationship underpins policies focused on the extension of protected lands. Here, we estimate aboveground biomass (AGB) as a proxy for habitat quality in seminatural rural patches and provide a comparison with approaches that only consider forest cover. We hypothesize that recommendations for biological conservation in agricultural landscapes are substantially improved if habitat quality is also taken into account, and thus consider the possibility of forest quality being modulated by land‐use amount, type, and age. We assessed AGB in a densely farmed Brazilian region using a straightforward approach designed to be affordable at large scales, focusing on two expanding and contrasting land uses: sugarcane, and eucalyptus plantations. At a detailed scale, we confirmed through field surveys and AGB estimation using 3D‐multispectral imagery (i.e., AGB = 0.842 × vegetation heightNDVI+1) that AGB variation could be predicted with forest degradation classes that are visually distinguishable with high‐resolution images: 9.33 t ha−1 (90% predictive intervals [PI] = [3.23, 26.97]) in regenerating fields (RF), 31.12 t ha−1 (90% PI = [10.77, 89.90]) in pioneer woods (PW), and 149.04 t ha−1 (90% PI = [51.59, 430.58]) in dense forests (DF). Applying these values to land units sampled across the study region, we found an average land use of 88.5%, together with 11.5% of land set aside for conservation, which reduced AGB to less than 4.2% of its potential (averages of 5.85 t ha−1 in sugarcane‐dominated areas and 6.56 t ha−1 in eucalyptus‐dominated areas, with secondary forests averaging 149.04 t ha−1). This imbalance between forest cover and AGB resulted from forest quality decay, which was similarly severe among land‐use types, ages, and extensions. Therefore, the shortage of trophic resources is likely more critical to wildlife than spatial limitations in vastly deforested tropical ecoregions, where AGB and carbon sinks can be more than doubled just by restoring forests in lands currently spared by agriculture.