bluuebunny/crossref_metadata_2025 huggingface dataset:
Organocatalytic Stereoselective Decarboxylative Addition of α‐Amido Malonic Acid Half Oxyesters to Isatins
Authors: Fujita Kazuki , Kumazawa Ibuki , Yokoi Jyunpei , Abe Kazuki , Takehara Tsunayoshi , Suzuki Takeyuki , Yasukawa Naoki , Nakamura Shuichi
Published: January 2024

The stereoselective reaction of α‐amido‐substituted malonic acid half oxyesters (α‐amido‐MAHOs) with isatins was developed. A cinchona alkaloid thiourea catalyst gave products bearing a tetrasubstituted stereogenic centre in high yields with high diastereo‐ and enantioselectivities (75–99% yield, 83:17–97:3 dr, 92:8–99:1 er). The obtained products can be converted into some chiral compounds without loss of enantiopurity. Density functional theory (DFT) calculations were conducted to clarify the origin of stereoselectivities, and suggested that the first stereogenic centre is set in the decarboxylation, the second in the protonation.
Continuous Manufacturing of Active Pharmaceutical Ingredients: Current Trends and Perspectives
Authors: Hyer Andres , Gregory Daniel , Kay Kaitlin , Le Quang , Turnage Justin , Gupton Frank , Ferri James K.
Published: January 2024

The pharmaceutical industry has traditionally employed batch processing as a means of synthesizing active pharmaceutical ingredients (APIs) on a commercial scale. Batch manufacturing enables API synthesis in large quantities in order to meet regulations. Yet, this strategy remains cumbersome, is labor‐intensive, and creates complex logistical networks. In recent decades, batch API processing has gradually eroded American economic competitiveness and has led to the offshoring of API manufacturing from the United States. Today it is estimated that +80% of APIs are manufactured overseas.[1] Meanwhile, disruptions from the Coronavirus Disease (SARS‐CoV‐2) have exacerbated weaknesses in the global supply chain, culminating with widespread shortages of critical life‐saving drugs.[2] These shortages have emphasized the importance of reshoring drug manufacturing to the U.S. and fostered a regulatory landscape that seeks advanced methods of API manufacturing in order to bolster America's supply chain resiliency.[3] Recently, increased attention has been directed towards continuous drug manufacturing to enable nonstop API production within modular stand‐alone flow systems. Continuous manufacturing (CM) facilitates modular automation, offers new avenues towards process intensification, and even enables in‐line analytical monitoring from raw materials to packaged products. This strategy offers better conversion, increased safety, reduced waste, and overall cost savings versus traditional batch‐style processing. The rise of advanced API manufacturing, coupled with the current regulatory landscape, offers a rare window of opportunity to convert traditional batch pharmaceutical processes into continuous, streamlined production systems to on‐shore API manufacturing and eliminate drug shortages. This review will outline the current state‐of‐the‐art in the CM of APIs and will highlight the translation of chemistry and unit operations from batch processes to modular CM systems.
Copper‐Catalyzed Diazidation of Allenes: Access to 3‐(Azidomethyl)‐2H‐Azirines
Authors: Zhang Shen‐Yuan , Hu Li‐Yan , Li Yang , Li Yuan , Luo Kai , Wu Lei
Published: January 2024

A class of 3‐(azidomethyl)‐2H‐azirine has been obtained through a copper‐catalyzed diazidation of allenes and a subsequent azirination involving vinyl azides. A variety of functional groups in the allenes are well tolerated, providing a series of 3‐(azidomethyl)‐2H‐azirine motifs in 51%‐93% yields (26 examples).
Calculation of Melting Temperature Using Nonequilibrium Thermodynamic Integration Methods
Authors: Nguyen Cao Thang , Ho Duc Tam , Ho Viet Hung , Kim Sung Youb
Published: January 2024

Melting temperature is a fundamental material property and is defined as the temperature at which the solid and liquid phases have the same free energy. However, there is no systematic study employing atomic simulations to calculate melting temperature using this definition. Here, molecular dynamics simulations and nonequilibrium thermodynamic integration methods are combined to calculate the melting temperature of Al and Cu. Results show that to accurately obtain the melting temperature, the model size should be considered carefully because the free energies of both solid and liquid phases are inversely proportional to the model size, causing a model size dependence on the calculated melting temperature. In addition, the melting temperature for various (semi‐) empirical potential models for Al and Cu is calculated and verified against experimental values to provide guidelines for the choice of potential models for simulation‐based problems relevant to the solid–liquid phase transformation.
Reprogrammable Metamaterial Processors for Soft Machines
Authors: Jiao Zhongdong , Hu Zhenhan , Dong Zeyu , Tang Wei , Yang Huayong , Zou Jun
Published: January 2024

Soft metamaterials have attracted extensive attention due to their remarkable properties. These materials hold the potential to program and control the morphing behavior of soft machines, however, their combination is limited by the poor reprogrammability of metamaterials and incompatible communication between them. Here, printable and recyclable soft metamaterials possessing reprogrammable embedded intelligence to regulate the morphing of soft machines are introduced. These metamaterials are constructed from interconnected and periodically arranged logic unit cells that are able to perform compound logic operations coupling multiplication and negation. The scalable computation capacity of the unit cell empowers it to simultaneously process multiple fluidic signals with different types and magnitudes, thereby allowing the execution of sophisticated and high‐level control operations. By establishing the laws of physical Boolean algebra and formulating a universal design route, soft metamaterials capable of diverse logic operations can be readily created and reprogrammed. Besides, the metamaterials' potential of directly serving as fluidic processors for soft machines is validated by constructing a soft latched demultiplexer, soft controllers capable of universal and customizable morphing programming, and a reprogrammable processor without reconnection. This work provides a facile way to create reprogrammable soft fluidic control systems to meet on‐demand requirements in dynamic situations.
Coupling of Perinuclear Actin Cap and Nuclear Mechanics in Regulating Flow‐Induced Yap Spatiotemporal Nucleocytoplasmic Transport
Authors: Ma Tianxiang , Liu Xiao , Su Haoran , Shi Qiusheng , He Yuan , Wu Fan , Gao Chenxing , Li Kexin , Liang Zhuqing , Zhang Dongrui , Zhang Xing , Hu Ke , Li Shangyu , Wang Li , Wang Min , Yue Shuhua , Hong Weili , Chen Xun , Zhang Jing , Zheng Lisha , Deng Xiaoyan , Wang Pu , Fan Yubo
Published: January 2024

Mechanical forces, including flow shear stress, govern fundamental cellular processes by modulating nucleocytoplasmic transport of transcription factors like Yes‐associated Protein (YAP). However, the underlying mechanical mechanism remains elusive. In this study, it is reported that unidirectional flow induces biphasic YAP transport with initial nuclear import, followed by nuclear export as actin cap formation and nuclear stiffening. Conversely, pathological oscillatory flow induces slight actin cap formation, nuclear softening, and sustained YAP nuclear localization. To elucidate the disparately YAP spatiotemporal distribution, a 3D mechanochemical model is developed, which integrates flow sensing, cytoskeleton organization, nucleus mechanotransduction, and YAP transport. The results unveiled that despite the significant localized nuclear stress imposed by the actin cap, its inherent stiffness counteracts the dispersed contractile stress exerted by conventional fibers on the nuclear membrane. Moreover, alterations in nuclear stiffness synergistically regulate nuclear deformation, thereby governing YAP transport. Furthermore, by expanding the single‐cell model to a collective vertex framework, it is revealed that the irregularities in actin cap formation within individual cells have the potential to induce topological defects and spatially heterogeneous YAP distribution in the cellular monolayer. This work unveils a unified mechanism of flow‐induced nucleocytoplasmic transport, providing a linkage between transcription factor localization and mechanical stimulation.
Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia
Authors: Jin Jie , Hou Shangyu , Yao Yiyi , Liu Miaomiao , Mao Liping , Yang Min , Tong Hongyan , Zeng Tao , Huang Jinyan , Zhu Yinghui , Wang Huafeng
Published: January 2024

Resistance to chemotherapy remains a formidable obstacle in acute myeloid leukemia (AML) therapeutic management, necessitating the exploration of optimal strategies to maximize therapeutic benefits. Venetoclax with 3+7 daunorubicin and cytarabine (DAV regimen) in young adult de novo AML patients is evaluated. 90% of treated patients achieved complete remission, underscoring the potential of this regimen as a compelling therapeutic intervention. To elucidate underlying mechanisms governing response to DAV in AML, quantitative phosphoproteomics to discern distinct molecular signatures characterizing a subset of DAV‐sensitive patients is used. Cluster analysis reveals an enrichment of phosphoproteins implicated in chromatin organization and RNA processing within DAV‐susceptible and DA‐resistant AML patients. Furthermore, kinase activity profiling identifies AURKB as a candidate indicator of DAV regimen efficacy in DA‐resistant AML due to AURKB activation. Intriguingly, AML cells overexpressing AURKB exhibit attenuated MCL‐1 expression, rendering them receptive to DAV treatment and maintaining them resistant to DA treatment. Moreover, the dataset delineates a shared kinase, AKT1, associated with DAV response. Notably, AKT1 inhibition augments the antileukemic efficacy of DAV treatment in AML. Overall, this phosphoproteomic study identifies the role of AURKB as a predictive biomarker for DA, but not DAV, resistance and proposes a promising strategy to counteract therapy resistance in AML.
Integrated Ink Printing Paper Based Self‐Powered Electrochemical Multimodal Biosensing (IFP−Multi) with ChatGPT–Bioelectronic Interface for Personalized Healthcare Management
Authors: Xiong Chuanyin , Dang Weihua , Yang Qi , Zhou Qiusheng , Shen Mengxia , Xiong Qiancheng , An Meng , Jiang Xue , Ni Yonghao , Ji Xianglin
Published: January 2024

Personalized healthcare management is an emerging field that requires the development of environment‐friendly, integrated, and electrochemical multimodal devices. In this study, the concept of integrated paper‐based biosensors (IFP−Multi) for personalized healthcare management is introduced. By leveraging ink printing technology and a ChatGPT–bioelectronic interface, these biosensors offer ultrahigh areal‐specific capacitance (74633 mF cm−2), excellent mechanical properties, and multifunctional sensing and humidity power generation capabilities. More importantly, the IFP−Multi devices have the potential to simulate deaf‐mute vocalization and can be integrated into wearable sensors to detect muscle contractions and bending motions. Moreover, they also enable monitoring of physiological signals from various body parts, such as the throat, nape, elbow, wrist, and knee, and successfully record sharp and repeatable signals generated by muscle contractions. In addition, the IFP−Multi devices demonstrate self‐powered handwriting sensing and moisture power generation for sweat‐sensing applications. As a proof‐of‐concept, a GPT 3.5 model‐based fine‐tuning and prediction pipeline that utilizes recorded physiological signals through IFP−Multi is showcased, enabling artificial intelligence with multimodal sensing capabilities for personalized healthcare management. This work presents a promising and ecofriendly approach to developing paper‐based electrochemical multimodal devices, paving the way for a new era of healthcare advancements.
A Bioorthogonal Antidote Against the Photosensitivity after Photodynamic Therapy
Authors: Xue Evelyn Y. , Yang Caixia , Zhou Yimin , Ng Dennis K. P.
Published: January 2024

As an effective and non‐invasive treatment modality for cancer, photodynamic therapy (PDT) has attracted considerable interest. With the recent advances in the photosensitizing agents, the fiber‐optic systems, and other aspects, its application is extended to a wide range of superficial and localized cancers. However, for the few clinically used photosensitizers, most of them suffer from the drawback of causing prolonged photosensitivity after the treatment. As a result, post‐PDT management is also a crucial issue. Herein, a facile bioorthogonal approach is reported that can effectively suppress this common side effect of PDT in nude mice. It involves the use of an antidote that contains a black‐hole quencher BHQ‐3 conjugated with a bicyclo[6.1.0]non‐4‐yne (BCN) moiety and a tetrazine‐substituted boron dipyrromethene‐based photosensitizer. By using tumor‐bearing nude mice as an animal model, it is demonstrated that after PDT with this photosensitizer, the administration of the antidote can effectively quench the photodynamic activity of the residual photosensitizer by bringing the BHQ‐3 quencher close to the photosensitizing unit through a rapid click reaction. It results in substantial reduction in skin damage upon light irradiation. The overall results demonstrate that this simple and facile strategy can provide an effective means for minimizing the photosensitivity after PDT.
Dock5 Deficiency Promotes Proteinuric Kidney Diseases via Modulating Podocyte Lipid Metabolism
Authors: Qu Hua , Liu Xiufei , Zhu Jiaran , Xiong Xin , Li Lu , He Qingshan , Wang Yuren , Yang Guojun , Zhang Linlin , Yang Qingwu , Luo Gang , Zheng Yi , Zheng Hongting
Published: January 2024

Podocytes are particularly sensitive to lipid accumulation, which has recently emerged as a crucial pathological process in the progression of proteinuric kidney diseases like diabetic kidney disease and focal segmental glomerulosclerosis. However, the underlying mechanism remains unclear. Here, podocytes predominantly expressed protein dedicator of cytokinesis 5 (Dock5) is screened to be critically related to podocyte lipid lipotoxicity. Its expression is reduced in both proteinuric kidney disease patients and mouse models. Podocyte‐specific deficiency of Dock5 exacerbated podocyte injury and glomeruli pathology in proteinuric kidney disease, which is mainly through modulating fatty acid uptake by the liver X receptor α  (LXRα)/scavenger receptor class B (CD36) signaling pathway. Specifically, Dock5 deficiency enhanced CD36‐mediated fatty acid uptake of podocytes via upregulating LXRα in an m6A‐dependent way. Moreover, the rescue of Dock5 expression ameliorated podocyte injury and proteinuric kidney disease. Thus, the findings suggest that Dock5 deficiency is a critical contributor to podocyte lipotoxicity and may serve as a promising therapeutic target in proteinuric kidney diseases.
SpyDirect: A Novel Biofunctionalization Method for High Stability and Longevity of Electronic Biosensors
Authors: Guo Keying , Grünberg Raik , Ren Yuxiang , Chang Tianrui , Wustoni Shofarul , Strnad Ondrej , Koklu Anil , Díaz‐Galicia Escarlet , Agudelo Jessica Parrado , Druet Victor , Castillo Tania Cecilia Hidalgo , Moser Maximilian , Ohayon David , Hama Adel , Dada Ashraf , McCulloch Iain , Viola Ivan , Arold Stefan T. , Inal Sahika
Published: January 2024

Electronic immunosensors are indispensable tools for diagnostics, particularly in scenarios demanding immediate results. Conventionally, these sensors rely on the chemical immobilization of antibodies onto electrodes. However, globular proteins tend to adsorb and unfold on these surfaces. Therefore, self‐assembled monolayers (SAMs) of thiolated alkyl molecules are commonly used for indirect gold–antibody coupling. Here, a limitation associated with SAMs is revealed, wherein they curtail the longevity of protein sensors, particularly when integrated into the state‐of‐the‐art transducer of organic bioelectronics—the organic electrochemical transistor. The SpyDirect method is introduced, generating an ultrahigh‐density array of oriented nanobody receptors stably linked to the gold electrode without any SAMs. It is accomplished by directly coupling cysteine‐terminated and orientation‐optimized spyTag peptides, onto which nanobody‐spyCatcher fusion proteins are autocatalytically attached, yielding a dense and uniform biorecognition layer. The structure‐guided design optimizes the conformation and packing of flexibly tethered nanobodies. This biolayer enhances shelf‐life and reduces background noise in various complex media. SpyDirect functionalization is faster and easier than SAM‐based methods and does not necessitate organic solvents, rendering the sensors eco‐friendly, accessible, and amenable to scalability. SpyDirect represents a broadly applicable biofunctionalization method for enhancing the cost‐effectiveness, sustainability, and longevity of electronic biosensors, all without compromising sensitivity.
Gradual Coordination and Reversible P–P Bond Activation of a P3‐Unit with Transition Metal Carbonyls
Authors: Franz Roman , Gál Dalma , Bruhn Clemens , Kelemen Zsolt , Pietschnig Rudolf
Published: January 2024

Coordination of a stereochemically defined P3‐chain to a series of transition metal carbonyls [M(CO)x]z− (M = Mn (x = 5, z = 1), Fe (x = 4, z = 2) or Co (x = 4, z = 1)) is explored using a [3]ferrocenophane scaffold. A gradual transition from η1‐, η2‐ to η3‐coordination is observed where in the η2‐mode the terminal positions of the phosphorus chain are bridged. With an excess of cobalt carbonyl successive P–P bond activation and gradual separation of the central phosphorus atoms from the phosphorus chain has been observed. This process is reversible and with suitable reagents such as methyl lithium, the P3‐unit is regenerated in stereospecific manner. The bonding situation and steps of the gradual P–P bond activation are investigated by DFT calculations as well as experimental methods (e.g., NMR spectroscopy, X‐ray crystallography).
Mind In Vitro Platforms: Versatile, Scalable, Robust, and Open Solutions to Interfacing with Living Neurons
Authors: Zhang Xiaotian , Dou Zhi , Kim Seung Hyun , Upadhyay Gaurav , Havert Daniel , Kang Sehong , Kazemi Kimia , Huang Kai‐Yu , Aydin Onur , Huang Raymond , Rahman Saeedur , Ellis‐Mohr Austin , Noblet Hayden A. , Lim Ki H. , Chung Hee Jung , Gritton Howard J. , Saif M. Taher A. , Kong Hyun Joon , Beggs John M. , Gazzola Mattia
Published: January 2024

Motivated by the unexplored potential of in vitro neural systems for computing and by the corresponding need of versatile, scalable interfaces for multimodal interaction, an accurate, modular, fully customizable, and portable recording/stimulation solution that can be easily fabricated, robustly operated, and broadly disseminated is presented. This approach entails a reconfigurable platform that works across multiple industry standards and that enables a complete signal chain, from neural substrates sampled through micro‐electrode arrays (MEAs) to data acquisition, downstream analysis, and cloud storage. Built‐in modularity supports the seamless integration of electrical/optical stimulation and fluidic interfaces. Custom MEA fabrication leverages maskless photolithography, favoring the rapid prototyping of a variety of configurations, spatial topologies, and constitutive materials. Through a dedicated analysis and management software suite, the utility and robustness of this system are demonstrated across neural cultures and applications, including embryonic stem cell‐derived and primary neurons, organotypic brain slices, 3D engineered tissue mimics, concurrent calcium imaging, and long‐term recording. Overall, this technology, termed “mind in vitro” to underscore the computing inspiration, provides an end‐to‐end solution that can be widely deployed due to its affordable (>10× cost reduction) and open‐source nature, catering to the expanding needs of both conventional and unconventional electrophysiology.
Inch‐Scale Freestanding Single‐Crystalline BiFeO3 Membranes for Multifunctional Flexible Electronics
Authors: Qiu Ruibin , Peng Bin , Zhang Jiaxuan , Guo Yunting , Liu Haixia , Wang Xianlei , Tang Haowen , Dong Guohua , Zhao Yanan , Jiang Zhuang‐De , Liu Ming , Hu Zhongqiang
Published: January 2024

Flexible electronics strongly demand the integration of flexible and large‐scale multifunctional oxides. BiFeO3 is one of the most essential multifunctional oxides that could be used in memories, logics, sensors, and actuators. Recently, freestanding single‐crystalline BiFeO3 membranes exhibited superior elasticity and flexibility. However, fabrication and integration of large‐scale freestanding BiFeO3 membranes into flexible electronics remain elusive. In this study, inch‐scale freestanding single‐crystalline BiFeO3 membranes are fabricated with assistance from a water‐soluble sacrificial layer. To transfer flat and crack‐free membranes, all the existing methods are first followed but fail. Then the study introduces a temporary supporting Cu layer on the surface of the as‐grown SiTiO3/Sr3Al2O6/(SrRuO3/)BiFeO3 heterostructure and successfully obtains full and crack‐free 5 mm × 5 mm freestanding membranes on various substrates. The residual strain within the heterostructure releases gradually under the protection of the Cu layer. The freestanding BiFeO3 membranes are relatively uniform among different regions and exhibit good dielectric, ferroelectric, and ferromagnetic properties. Finally, flexible ferroelectric photovoltaic devices are patterned based on those BiFeO3 membranes, and they have open circuit voltage and short circuit current density up to −0.25 ± 0.03 V and 0.82 ± 0.09 µA cm−2, respectively.
Hybrid 3D‐Ordered Membrane Electrode Assembly (MEA) with Highly Stable Structure, Enlarged Interface, and Ultralow Ir Loading by Doping Nano TiO2 Nanoparticles for Water Electrolyzer
Authors: Liu Yiyang , Tian Bin , Ning Fandi , Li Yali , Zhao Chengyan , He Can , Wen Qinglin , Dan Xiong , Chai Zhi , Li Wei , Shen Min , He Lei , Li Wenxian , Zhou Xiaochun
Published: January 2024

Proton exchange membrane water electrolysis (PEMWE) is a very promising and sustainable hydrogen production technology. Currently, there is a growing interest in achieving ordered structures within membrane electrode assembly (MEA) for PEMWE. However, both ordered electron conductor and ordered proton conductor structures are single component structure, which still have many shortcomings. In this work, a hybrid ordered membrane electrodes assembly based on cone‐shaped is constructed Nafion array with rough surface by introducing TiO2 nanoparticles to Nafion emulsion. As a result, this hybrid ordered MEA achieves a high surface roughness of 3.39 nm that is 2.64 times higher than that of ordered MEA without TiO2 nanoparticles doped and current density up to 2.48 A cm−2 at 2 V with 14.4 µg cm−2 (Ir) catalyst loading. This work provides a new hybrid ordered structure for MEA and exhibits the great potential of enhancing the interfacial contact between the catalyst layer and Nafion membrane to improve PEMWE performance.
Self‐Supported Earth‐Abundant Carbon‐Based Substrates in Electrocatalysis Landscape: Unleashing the Potentials Toward Paving the Way for Water Splitting and Alcohol Oxidation
Authors: Yap Feng Ming , Loh Jian Yiing , Ng Sue‐Faye , Ong Wee‐Jun
Published: January 2024

In the vast realm of scientific inquiry, the pursuit of hydrogen fuel production through electrochemical water splitting offers a promising gateway to green energy generation, alleviating the challenges posed by resource scarcity. However, conventional water splitting encounters hurdles like low efficiency and the sluggish oxygen evolution reaction (OER), which prompt searchers to seek for alternative oxidation process. Significant strides are made in conventional electrocatalytic research employing polymeric binders, resulting in commendable catalytic activity and minimal electron migration resistance. Yet, a pivotal breakthrough in this rapidly evolving field lies in the innovative conception of carbon‐based self‐supported electrocatalysts, heralding a promising trajectory ahead. This review delves into the essential electro‐activity parameters to establish the property‐activity nexus, emphasizing the benefits of self‐supported carbon‐based electrodes. Noteworthy advancements are demonstrated in electrochemical hydrogen evolution reaction (HER), OER, overall water splitting (OWS), and bifunctional HER and alcohol oxidation reaction (AOR), driven by a diverse range of self‐supported electrocatalysts. These include structure‐dependent materials such as metal oxides, hydroxides/oxyhydroxides, phosphides, sulfides, selenides, nitrides, and carbides, each meticulously tailored with nuanced modifications that shape their distinctive attributes. This field also acknowledges its challenges and opportunities, providing guidance for potential research directions and inspiring interdisciplinary collaboration among scientists.
Propagation of Electron Airy Tornado Waves in Free Space and in a Uniform Magnetic Field
Authors: Tang Huilin , Tu Zhifeng , Jiang Junjie , Huang Haoyu , Zhao Jiajia , Ouyang Shigen , Yang Xiangbo , Liu Hongzhan , Wang Guanghui , Deng Dongmei
Published: January 2024

In this paper, a new type of structured electron beam is introduced, which is the electron Airy tornado wave (eATW) with the characteristics of abrupt auto‐focusing and rotation property in free space. It is also found that the eATWs propagate periodically in a magnetic field, and their patterns of intensity distributions show the time‐like axial symmetry about a half‐period point in a period of time. Furthermore, the influence of the magnetic field's magnitude and direction on eATWs with different parameters has also been discussed.
Engineering Biocatalysts for the C−H Activation of Fatty Acids by Ancestral Sequence Reconstruction**
Authors: Jones Bethan S. , Ross Connie M. , Foley Gabriel , Pozhydaieva Nadiia , Sharratt Joseph W. , Kress Nico , Seibt Lisa S. , Thomson Raine E. S. , Gumulya Yosephine , Hayes Martin A. , Gillam Elizabeth M. J. , Flitsch Sabine L.
Published: January 2024

Selective, one‐step C−H activation of fatty acids from biomass is an attractive concept in sustainable chemistry. Biocatalysis has shown promise for generating high‐value hydroxy acids, but to date enzyme discovery has relied on laborious screening and produced limited hits, which predominantly oxidise the subterminal positions of fatty acids. Herein we show that ancestral sequence reconstruction (ASR) is an effective tool to explore the sequence‐activity landscape of a family of multidomain, self‐sufficient P450 monooxygenases. We resurrected 11 catalytically active CYP116B ancestors, each with a unique regioselectivity fingerprint that varied from subterminal in the older ancestors to mid‐chain in the lineage leading to the extant, P450‐TT. In lineages leading to extant enzymes in thermophiles, thermostability increased from ancestral to extant forms, as expected if thermophily had arisen de novo. Our studies show that ASR can be applied to multidomain enzymes to develop active, self‐sufficient monooxygenases as regioselective biocatalysts for fatty acid hydroxylation.
Supramolecular Hydrolase Mimics in Equilibrium and Kinetically Trapped States
Authors: Chen Jing , Shi Ke , Chen Rongjing , Zhai Zhaoyi , Song Peiyong , Chow Lesley W. , Chandrawati Rona , Pashuck E. Thomas , Jiao Fang , Lin Yiyang
Published: January 2024

The folding of proteins into intricate three‐dimensional structures to achieve biological functions, such as catalysis, is governed by both kinetic and thermodynamic controls. The quest to design artificial enzymes using minimalist peptides seeks to emulate supramolecular structures existing in a catalytically active state. Drawing inspiration from the nuanced process of protein folding, our study explores the enzyme‐like activity of amphiphilic peptide nanosystems in both equilibrium and non‐equilibrium states, featuring the formation of supramolecular nanofibrils and nanosheets. In contrast to thermodynamically stable nanosheets, the kinetically trapped nanofibrils exhibit dynamic characteristics (e.g., rapid molecular exchange and relatively weak intermolecular packing), resulting in a higher hydrolase‐mimicking activity. We emphasize that a supramolecular microenvironment characterized by an optimal local polarity, microviscosity, and β‐sheet hydrogen bonding is conducive to both substrate binding and ester bond hydrolysis. Our work underscores the pivotal role of both thermodynamic and kinetic control in impacting biomimetic catalysis and sheds a light on the development of artificial enzymes.
Tailoring on Rotational Symmetry of Liquid Crystal Domain Lattices
Authors: Wu Jin‐Bing , Hu Wei
Published: January 2024

Rotational symmetry is ubiquitous in nature. However, self‐assemblies of soft condensed matter such as liquid crystals (LCs) are entropy‐driven, making the tailoring of rotational symmetry challenging. Here, an approach is proposed to control the rotational symmetry of LC domain lattices based on the anchoring condition predesign and the orientational‐order inheritance during the nematic‐smectic phase transition. By this means, periodic and quasiperiodic LC textures with Ci symmetry (i = 2–6) determined by the preset alignment lattices are realized, and verified by symmetries of diffraction patterns. Topological analysis is carried out to disclose distinct evolutions of orders between disclination line textures and defect wall textures of different rotational symmetries. The influences of anchoring conditions, phase transitions, and mechanical stress on the self‐assembly of LCs, as well as the underlying mechanisms and dynamics, are investigated. This work realizes controllable rotational symmetry for large‐area self‐organized LCs and brings new insights to soft condensed matter.
Novel radioiodinated desvenlafaxine‐loaded lipid nanocapsule for brain delivery
Authors: Ayoub Veronia R. , Abdel‐Mottaleb Mona M. A. , Ibrahem Ismail T. , Motaleb Mohamed A. , Geneidi Ahmed S.
Published: January 2024

Lipid nanocapsules (LNCs) are lipid nanocarriers developed for drug delivery enhancement. The antidepressant drug desvenlafaxine (DSV) was entrapped in LNC to improve its brain delivery. Different DSV‐loaded LNCs formulae using different oils and surfactants were studied to obtain the optimum formula for further studies. In vivo biodistribution studies were done using Swiss albino mice by intravenous injection of DSV‐loaded LNCs by radioiodination technique. The optimum DSV‐loaded LNC formula was obtained by using Labrafil® M1944CS as the oil and Solutol® HS15 as the surfactant in the ratio of 1:1, with a particle size of 34.28 ± 0.41 nm, a polydispersity index of 0.032 ± 0.05, a zeta potential of −25.77 ± 1.41, and good stability for up to 6 months. The in vivo biodistribution and pharmacokinetics data ensure the bioavailability improvement for DSV brain delivery as Cmax and AUC(1–t) increased more than double for intravenously DSV‐loaded LNCs compared with the DSV solution. In conclusion, the results obtained from this study give an insight into the great potential of using DSV‐loaded LNC for the enhancement of brain delivery.
The role of secondary structures in the functioning of 3′ untranslated regions of mRNA
Authors: Zhukova Mariya , Schedl Paul , Shidlovskii Yulii V.
Published: January 2024

3′ untranslated regions (3′ UTRs) of mRNAs have many functions, including mRNA processing and transport, translational regulation, and mRNA degradation and stability. These different functions require cis‐elements in 3′ UTRs that can be either sequence motifs or RNA structures. Here we review the role of secondary structures in the functioning of 3′ UTRs and discuss some of the trans‐acting factors that interact with these secondary structures in eukaryotic organisms. We propose potential participation of 3′‐UTR secondary structures in cytoplasmic polyadenylation in the model organism Drosophila melanogaster. Because the secondary structures of 3′ UTRs are essential for post‐transcriptional regulation of gene expression, their disruption leads to a wide range of disorders, including cancer and cardiovascular diseases. Trans‐acting factors, such as STAU1 and nucleolin, which interact with 3′‐UTR secondary structures of target transcripts, influence the pathogenesis of neurodegenerative diseases and tumor metastasis, suggesting that they are possible therapeutic targets.
Assembling the thymus medulla: Development and function of epithelial cell heterogeneity
Authors: James Kieran D. , Cosway Emilie J. , Parnell Sonia M. , White Andrea J. , Jenkinson William E. , Anderson Graham
Published: January 2024

The thymus is a unique primary lymphoid organ that supports the production of self‐tolerant T‐cells essential for adaptive immunity. Intrathymic microenvironments are microanatomically compartmentalised, forming defined cortical, and medullary regions each differentially supporting critical aspects of thymus‐dependent T‐cell maturation. Importantly, the specific functional properties of thymic cortical and medullary compartments are defined by highly specialised thymic epithelial cells (TEC). For example, in the medulla heterogenous medullary TEC (mTEC) contribute to the enforcement of central tolerance by supporting deletion of autoreactive T‐cell clones, thereby counterbalancing the potential for random T‐cell receptor generation to contribute to autoimmune disease. Recent advances have further shed light on the pathways and mechanisms that control heterogeneous mTEC development and how differential mTEC functionality contributes to control self‐tolerant T‐cell development. Here we discuss recent findings in relation to mTEC development and highlight examples of how mTEC diversity contribute to thymus medulla function.
Endosteal stem cells at the bone‐blood interface: A double‐edged sword for rapid bone formation
Authors: Matsushita Yuki , Liu Jialin , Chu Angel Ka Yan , Ono Wanida , Welch Joshua D. , Ono Noriaki
Published: January 2024

Endosteal stem cells are a subclass of bone marrow skeletal stem cell populations that are particularly important for rapid bone formation occurring in growth and regeneration. These stem cells are strategically located near the bone surface in a specialized microenvironment of the endosteal niche. These stem cells are abundant in young stages but eventually depleted and replaced by other stem cell types residing in a non‐endosteal perisinusoidal niche. Single‐cell molecular profiling and in vivo cell lineage analyses play key roles in discovering endosteal stem cells. Importantly, endosteal stem cells can transform into bone tumor‐making cells when deleterious mutations occur in tumor suppressor genes. The emerging hypothesis is that osteoblast‐chondrocyte transitional identities confer a special subset of endosteal stromal cells with stem cell‐like properties, which may make them susceptible for tumorigenic transformation. Endosteal stem cells are likely to represent an important therapeutic target of bone diseases caused by aberrant bone formation.
Effect of cannabis use on blood levels of brain‐derived neurotrophic factor (BDNF) and nerve growth factor (NGF): A systematic review and meta‐analysis
Authors: Shafiee Arman , Rafiei Mohammad Ali , Jafarabady Kyana , Eskandari Alireza , Abhari Faeze Soltani , Sattari Mohammad Amin , Amini Mohammad Javad , Bakhtiyari Mahmood
Published: January 2024

Background

The impact of cannabis uses on blood levels of brain‐derived neurotrophic factor (BDNF) and nerve growth factor (NGF) remains uncertain, with conflicting findings reported in the literature. BDNF and NGF both are essential proteins for neuron's growth, and their dysregulation is seen in various mental disorders. This study aims to evaluate the relationship between cannabis usage and BDNF and NGF levels due to their potential implications for mental health.

Methods

A comprehensive search of electronic databases was performed using appropriate MeSH terms and keywords. Inclusion criteria comprised human studies investigating the relationship between cannabis use and BDNF and NGF levels.

Results

A total of 11 studies met the inclusion criteria and were included. The pooled analysis revealed a nonsignificant association between cannabis use and dysregulated blood levels of BDNF (random‐effects model, standardized mean differences [SMD] = .26, 95% CI −.34 to .76, p = .40). The results of our subgroup analysis based on BDNF source showed a nonsignificant between‐group difference. For NGF levels, four studies were included, the pooled analysis revealed a nonsignificant association between cannabis use and dysregulated blood levels of NGF (random‐effects model, SMD = −.60, 95% CI −1.43 to –.23, p = .16). In both analyses, high heterogeneity was observed among the included studies which is a notable limitation to current meta‐analysis.

Conclusion

This systematic review highlights the need for further research to elucidate the relationship between cannabis use and these neurotrophic factors. A better understanding of these associations can contribute to our knowledge of the neurobiological effects of cannabis and inform potential implications for mental health, cognitive function, and neurodegenerative disorders.
Turkish validity and reliability study on the quick aphasia battery
Authors: Parlak Mümüne Merve , Köse Ayşen
Published: January 2024

Introduction

The quick aphasia battery (QAB), which assesses all areas of language in detail and quickly, was developed in English. It has been shown to be suitable for bedside patients. There is a need for a Turkish bedside test that allows for a comprehensive yet rapid assessment of stroke patients in terms of aphasia. The aim of this study was to create a Turkish version of QAB (QAB‐TR) and to determine its validity and reliability in Turkish‐speaking patients after a stroke.

Materials and methods

The study was conducted with 188 people aged 41–88 years. Of these, 37 (19.7%) had aphasia (12 chronic, 25 acute), 53 (28.2%) were acute stroke patients without aphasia, and 98 (52.1%) were healthy controls. Internal consistency and criterion validity, test–retest reliability, and inter‐rater reliability of the QAB‐TR were performed. The language assessment test for aphasia was used for criterion validity. For the inter‐rater reliability of the test, two different speech language therapists (SLP) administered the QAB‐TR. For test–retest reliability, 2 weeks later, the same SLP who filled out the QAB‐TR the first time was administered the test again. To test the validity of the test, correlations between the items and subsections were determined. Receiver operating characteristic (ROC) analysis was performed to examine the sensitivity and selectivity of the QAB‐TR score, and a cut‐off value was determined to distinguish patients with aphasia.

Results

The inter‐rater Krippendorff's alpha value of the QAB‐TR total was 0.6754. There was no statistically significant difference (p > .05) between the first and second QAB‐TR total scores. The correlation analysis between the QAB‐TR subsection scores and the total QAB‐TR score (0.244–0.897) revealed statistically significant relationships. The area under the ROC curve was statistically significant and was found to be 0.853 (95% confidence interval: 0.799–0.906). The cut‐off point for the QAB score to discriminate between patients with aphasia and those without aphasia was found to be 8.825, with 0.767 sensitivity and 0.765 selectivity (1–0.235).

Conclusion

All the study results show that QAB‐TR has internal consistency, criterion validity, test–retest reliability, and inter‐rater reliability. It can be administered in as little as 15 min and provides information about the multidimensional linguistic profiles of individuals. QAB‐TR can be used for both clinical and study purposes as a language battery that allows for the measurement of the strengths and weaknesses of Turkish‐speaking individuals who have suffered a stroke in basic language areas in acute and chronic periods. It can be easily administered at the bedside for individuals who have just suffered an acute stroke and can facilitate early assessment of individuals in terms of aphasia and early initiation of therapy, if necessary.
No significant change of N6‐methyladenosine modification landscape in mouse brain after morphine exposure
Authors: Wu Xiaoli , Wu Cuiting , Zhou Tao
Published: January 2024

Objectives

N6‐methyladenosine (m6A) plays a crucial role in regulating neuroplasticity and different brain functions at the posttranscriptional level. However, it remains unknown whether m6A modification is involved in acute and chronic morphine exposure.

Materials and methods

In this study, we conducted a direct comparison of m6A levels and mRNA expression of m6A‐associated factors between morphine‐treated and nontreated C57BL/6 wild‐type mice. We established animal models of both acute and chronic morphine treatment and confirmed the rewarding effects of chronic morphine treatment using the conditioned place preference (CPP) assay. The activation status of different brain regions in response to morphine was assessed by c‐fos staining. To assess overall m6A modification levels, we employed the m6A dot blot assay, while mRNA levels of m6A‐associated proteins were measured using a quantitative polymerase chain reaction (qPCR) assay. These analyses were performed to investigate whether and how m6A modification and m6A‐associated protein expression will change following morphine exposure.

Results

The overall m6A methylation and mRNA levels of m6A‐associated proteins were not significantly altered in brain regions that were either activated or not activated during acute morphine stimulation. Similarly, the overall m6A modification and mRNA levels of m6A‐associated proteins remained unaffected in several key brain regions associated with reward following chronic morphine exposure.

Conclusion

This study showed that the overall m6A modification level and mRNA expression levels of m6A‐associated factors were not affected after acute and chronic morphine exposure in different brain regions, indicating m6A modification may not be involved in brain response to morphine exposure.
A lack of drebrin causes olfactory impairment
Authors: Kajita Yuki , Kojima Nobuhiko , Shirao Tomoaki
Published: January 2024

Introduction

Olfactory deficit often occurs during the prodromal stage of Alzheimer's disease (AD). Although olfactory deficit is a useful measure for screening AD‐related amnestic disorder, little is known about the cause of this deficit. Human and animal studies indicate that loss of the actin binding protein, drebrin, is closely related to cognitive dysfunction in AD. We hypothesized that the olfactory deficit in AD is caused by the loss of drebrin from the spine.

Methods

To verify this hypothesis, we performed the buried food test in two types of drebrin knockout mice, such as drebrin‐double (E and A) knockout (DXKO) mice, and drebrin A‐specific knockout (DAKO) mice.

Results

The DXKO mice spent a significantly longer time to find food compared with the wild‐type (WT) littermates. In contrast, the DAKO mice, in which drebrin E rather than drebrin A is expressed in the postsynaptic sites of mature neurons, spent an equivalent time trying to find food compared to that of the WT. The DXKO mice showed comparable food motivation and sensory functions other than olfaction, including visual and auditory functions.

Conclusion

These results indicate that drebrin is necessary for normal olfactory function. Further study is needed to determine whether it is necessary for normal olfaction to express drebrin E during the developmental stage or to have drebrin (whether E or A) present after maturation.
Nicorandil attenuates cognitive impairment after traumatic brain injury via inhibiting oxidative stress and inflammation: Involvement of BDNF and NGF
Authors: Tu Yaoyan , Han Desen , Liu Yanjun , Hong Dequan , Chen Rehua
Published: January 2024

Background and purpose

Cognitive impairment is a prevalent adverse consequence of traumatic brain injury (TBI). The neuroprotective effects of nicorandil (N‐(2‐hydroxyethyl)‐nicotinamide nitrate) has been previously documented, yet its protective effects against cognitive dysfunction post‐TBI remain unclear. Hence, the present study was aimed to evaluate whether nicorandil attenuates cognitive dysfunction in TBI rats and the underlying mechanism behind this process.

Methods

The TBI model was established with a controlled cortical impact (CCI). The effects of nicorandil on cognitive dysfunction of rats with TBI were examined through Novel object recognition (NOR) test, Y‐maze test, and Morris water maze (MWM) task. After behavioral tests, hippocampal tissue was collected for Quantitative real‐time PCR, Western blot analysis, and Enzyme‐linked immunosorbent assay (ELISA) assay.

Results

We observed that nicorandil administration effectively ameliorates learning and memory impairment in TBI rats. Alongside, nicorandil treatment attenuated oxidative stress in the hippocampus of TBI rats, characterized by the decreased reactive oxygen species generation, malondialdehyde, and protein carbonyls levels, and concurrent promotion of antioxidant‐related factors (including superoxide dismutase, glutathione peroxidase, and catalase) activities. Additionally, nicorandil treatment attenuated the inflammatory response in the hippocampus of TBI rat, as evidenced by the upregulated levels of interleukin (IL)‐1β, IL‐6, and tumor necrosis factor‐α (TNF‐α), as well as the downregulated level of IL‐10. Mechanistically, nicorandil treatment significantly enhanced the mRNA and protein levels of neurotrophic factors, brain‐derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus of TBI rats.

Conclusion

These findings suggest that nicorandil mitigates cognitive impairment after TBI by suppressing oxidative stress and inflammation, potentially through enhancing BDNF and NGF levels.