bluuebunny/crossref_metadata_2025 huggingface dataset:
The Structural Role of N170 in Substrate‐Assisted Deacylation in KPC‐2 β‐Lactamase
Authors: Parwana Diksha , Gu Jing , Chen Shuang , Bethel Christopher R. , Marshall Emma , Hujer Andrea M. , Bonomo Robert A. , Haider Shozeb
Published: January 2024

The amino acid substitutions in Klebsiella pneumoniae carbapenemase 2 (KPC‐2) that have arisen in the clinic are observed to lead to the development of resistance to ceftazidime‐avibactam, a preferred treatment for KPC bearing Gram‐negative bacteria. Specific substitutions in the omega loop (R164‐D179) result in changes in the structure and function of the enzyme, leading to alterations in substrate specificity, decreased stability, and more recently observed, increased resistance to ceftazidime/avibactam. Using accelerated rare‐event sampling well‐tempered metadynamics simulations, we explored in detail the structural role of R164 and D179 variants that are described to confer ceftazidime/avibactam resistance. The buried conformation of D179 substitutions produce a pronounced structural disorder in the omega loop ‐ more than R164 mutants, where the crystallographic omega loop structure remains mostly intact. Our findings also reveal that the conformation of N170 plays an underappreciated role impacting drug binding and restricting deacylation. The results further support the hypothesis that KPC‐2 D179 variants employ substrate‐assisted catalysis for ceftazidime hydrolysis, involving the ring amine of the aminothiazole group to promote deacylation and catalytic turnover. Moreover, the shift in the WT conformation of N170 contributes to reduced deacylation and an altered spectrum of enzymatic activity.
Nanoarchitectonics with a Membrane‐Embedded Electron Shuttle Mimics the Bioenergy Anabolism of Mitochondria
Authors: Wang Tonghui , Fei Jinbo , Dong Zhenzhen , Yu Fanchen , Li Junbai
Published: January 2024

Enhanced bioenergy anabolism through transmembrane redox reactions in artificial systems remains a great challenge. Here, we explore synthetic electron shuttle to activate transmembrane chemo‐enzymatic cascade reactions in a mitochondria‐like nanoarchitecture for augmenting bioenergy anabolism. In this nanoarchitecture, a dendritic mesoporous silica microparticle as inner compartment possesses higher load capacity of NADH as proton source and allows faster mass transfer. In addition, the outer compartment ATP synthase‐reconstituted proteoliposomes. Like natural enzymes in the mitochondrion respiratory chain, a small synthetic electron shuttle embedded in the lipid bilayer facilely mediates transmembrane redox reactions to convert NADH into NAD+ and a proton. These facilitate an enhanced outward proton gradient to drive ATP synthase to rotate for catalytic ATP synthesis with improved performance in a sustainable manner. This work opens a new avenue to achieve enhanced bioenergy anabolism by utilizing a synthetic electron shuttle and tuning inner nanostructures, holding great promise in wide‐range ATP‐powered bioapplications.
Radical Cation Salts of Hetera‐Buckybowls: Polar Crystals, Negative Thermal Expansion and Phase Transition
Authors: Wu Lingxi , Li Yecheng , Hua Xinqiang , Ye Lei , Yuan Chengshan , Liu Zitong , Zhang Hao‐Li , Shao Xiangfeng
Published: January 2024

Radical cation salts of π‐conjugated polycycles are rich in physical properties. Herein, two kinds of hetera‐buckybowls, ethoxy‐substituted trithiasumanene (3SEt) and triselenasumanene (3SeEt), are synthesized as electron donors. Galvanostatic oxidation of them affords radical cation salts (3SEt)5(TTFMPB)3, (3SeEt)5(TTFMPB)3, (3SEt)4PMA, and (3SeEt)4PMA, where PMA is Keggin‐type phosphomolybdate and TTFMPB is tetrakis[3,5‐bis(trifluoromethyl)‐phenyl]borate. In these salts, 3SEt/3SeEt are partially charged and show distinct conformation change with the site charge and counter anions. In TTFMPB salts, (TTFMPB)− forms hexagonal channels that accommodate the packing columns of 3SEt/3SeEt. In particular, (3SEt)5(TTFMPB)3 adopts the R3c space group and is a polar crystal with the columns of 3SEt all in the up‐bowl direction. The PMA salts of 3SEt/3SeEt are polar crystals (C2 space group) with 3SEt/3SeEt being planar and forming columnar stacks. (3SeEt)4PMA shows a structural modulation below 200 K, namely, negative thermal expansion (NTE) of the unit cell volume and enlargement of the intermolecular distances between neighboring 3SeEt molecules. The four salts are semiconductors with an activation energy of 0.18–0.38 eV. The conductivity of (3SeEt)4PMA shows a reversible transition upon cooling and heating, in accordance to the NTE structural modulation. This work paves the way toward conducting materials based on hetera‐buckybowls.
Polar X−H Bond (X=O, S, N) Activation at a Cage Silanide
Authors: Benzan Lantigua Pamela Adienes , Lutz Martin , Moret Marc‐Etienne
Published: January 2024

Low‐valent silicon compounds such as neutral silylenes display versatile reactivity for the activation of small molecules. In contrast, their anionic congeners silanides ([R3Si−]) have primarily been investigated for their nucleophilic reactivity. Here we show that incorporating a silanide center in a bicyclic cage structure allows for formal oxidative addition of polar element‐hydrogen bonds (RX−H, R=aromatic residue, X=O, S, NH). The resulting hydrosilicates were isolated and characterized structurally and spectroscopically. Density Functional Theory (DFT) calculations and experimental observations support an ionic mechanism for RX−H bond activation. Finally, the reactivity of the RS−H bond adduct was further investigated, revealing that it behaves as a Lewis pair upon facile heterolytic cleavage of the Si−S bond.
Channelrhodopsin‐2 Oligomerization in Cell Membrane Revealed by Photo‐Activated Localization Microscopy
Authors: Bestsennaia Ekaterina , Maslov Ivan , Balandin Taras , Alekseev Alexey , Yudenko Anna , Abu Shamseye Assalla , Zabelskii Dmitrii , Baumann Arnd , Catapano Claudia , Karathanasis Christos , Gordeliy Valentin , Heilemann Mike , Gensch Thomas , Borshchevskiy Valentin
Published: January 2024

Microbial rhodopsins are retinal membrane proteins that found a broad application in optogenetics. The oligomeric state of rhodopsins is important for their functionality and stability. Of particular interest is the oligomeric state in the cellular native membrane environment. Fluorescence microscopy provides powerful tools to determine the oligomeric state of membrane proteins directly in cells. Among these methods is quantitative photoactivated localization microscopy (qPALM) allowing the investigation of molecular organization at the level of single protein clusters. Here, we apply qPALM to investigate the oligomeric state of the first and most used optogenetic tool Channelrhodopsin‐2 (ChR2) in the plasma membrane of eukaryotic cells. ChR2 appeared predominantly as a dimer in the cell membrane and did not form higher oligomers. The disulfide bonds between Cys34 and Cys36 of adjacent ChR2 monomers were not required for dimer formation and mutations disrupting these bonds resulted in only partial monomerization of ChR2. The monomeric fraction increased when the total concentration of mutant ChR2 in the membrane was low. The dissociation constant was estimated for this partially monomerized mutant ChR2 as 2.2±0.9 proteins/μm2. Our findings are important for understanding the mechanistic basis of ChR2 activity as well as for improving existing and developing future optogenetic tools.
Nucleic Acid‐based Electrochemical Sensors Facilitate the Study of DNA Binding by Platinum (II)‐based Antineoplastics
Authors: Wu Yao , Arroyo‐Currás Netzahualcóyotl
Published: January 2024

DNA crosslinking agents such as cisplatin and related platinum(II) analogs are effective drugs to treat solid tumors. However, these therapeutics can cause high toxicity in the body, and tumors can develop resistance to them. To develop less toxic and more effective DNA crosslinkers, medicinal chemists have focused on tuning the ligands in square planar platinum(II) complexes to modulate their bioavailability, targeted cell penetration, and DNA binding rates. Unfortunately, linking in vitro DNA binding capacity of DNA crosslinkers with their in vivo efficacy has proven challenging. Here we report an electrochemical biosensor strategy that allows the study of platinum(II)‐DNA binding in real time. Our biosensors contain a purine‐rich deoxynucleotide sequence, T6(AG)10, modified with a 5’ hexylthiol linker for easy self‐assembly onto gold electrodes. The 3’ terminus is functionalized with the redox reporter methylene blue. Electron transfer from methylene blue to the sensor is a function of platinum(II) compound concentration and reaction time. Using these biosensors, we resolve DNA binding mechanisms including monovalent and bivalent binding, as well as base stacking. Our approach can measure DNA binding kinetics in buffers and in 50 % serum, offering a single‐step, real‐time approach to screen therapeutic compounds during drug development.
Heterogeneous Photocatalytic Strategies for C(sp3)−H Activation
Authors: Chai Zhigang
Published: January 2024

Activation of ubiquitous C(sp3)−H bonds is extremely attractive but remains a great challenge. Heterogeneous photocatalysis offers a promising and sustainable approach for C(sp3)−H activation and has been fast developing in the past decade. This Minireview focuses on mechanism and strategies for heterogeneous photocatalytic C(sp3)−H activation. After introducing mechanistic insights, heterogeneous photocatalytic strategies for C(sp3)−H activation including precise design of active sites, regulation of reactive radical species, improving charge separation and reactor innovations are discussed. In addition, recent advances in C(sp3)−H activation of hydrocarbons, alcohols, ethers, amines and amides by heterogeneous photocatalysis are summarized. Lastly, challenges and opportunities are outlined to encourage more efforts for the development of this exciting and promising field.
Artificial Homeostasis Systems Based on Feedback Reaction Networks: Design Principles and Future Promises
Authors: Ranganath Vinay Ambekar , Maity Indrajit
Published: January 2024

Feedback‐controlled chemical reaction networks (FCRNs) are indispensable for various biological processes, such as cellular mechanisms, patterns, and signaling pathways. Through the intricate interplay of many feedback loops (FLs), FCRNs maintain a stable internal cellular environment. Currently, creating minimalistic synthetic cells is the long‐term objective of systems chemistry, which is motivated by such natural integrity. The design, kinetic optimization, and analysis of FCRNs to exhibit functions akin to those of a cell still pose significant challenges. Indeed, reaching synthetic homeostasis is essential for engineering synthetic cell components. However, maintaining homeostasis in artificial systems against various agitations is a difficult task. Several biological events can provide us with guidelines for a conceptual understanding of homeostasis, which can be further applicable in designing artificial synthetic systems. In this regard, we organize our review with artificial homeostasis systems driven by FCRNs at different length scales, including homogeneous, compartmentalized, and soft material systems. First, we stretch a quick overview of FCRNs in different molecular and supramolecular systems, which are the essential toolbox for engineering different nonlinear functions and homeostatic systems. Moreover, the existing history of synthetic homeostasis in chemical and material systems and their advanced functions with self‐correcting, and regulating properties are also emphasized.
Act of faith versus voluntary reciprocation: Asymmetric commitments in exchange relationships
Authors: Liu Wendy
Published: January 2024

Financial payments take place in a wide variety of contexts. Expanding on a range of alternative forms of payments outside the common purchase of products and services at a price, this present article focuses on one dimension by which payments differ, namely, whether the payments take place in an exchange with mutual versus unilateral commitment between the buyer and the seller. This framework takes into account the timing and nature of commitments buyers and sellers make in an exchange, thereby further revealing the psychology underlying people's decisions to pay. In particular, the party that is unilaterally committed in an exchange relationship engages in “acts of faith”, whereas the party that is uncommitted engages in decisions of “voluntary reciprocation”.
Blended learning in biochemistry: The development of pre‐class and post‐class learning aids for electron transport chain and oxidative phosphorylation
Authors: Lee Rebecca K. Y. , Ng Bernard Y. N. , Chen Daisy M. H.
Published: January 2024

Electron transport chain and oxidative phosphorylation are always a challenging topic for students studying metabolism. We had adopted blended learning in metabolism teaching and evaluated the learning experiences of students. In this project, a pre‐class learning aid the Story Mode and a post‐class learning aid the Revision Mode in the Powerland was developed that facilitated students learning electron transport chain and oxidative phosphorylation. In the Story Mode, pathways were presented by short animations and simplified diagram that allowed students to understand basic concepts and recall simple facts of the topic. Students were asked to watch the animations before class to acquire lower level of cognitive learning first, and this facilitated students in understanding more complicated concepts later on during class. Another challenge that students faced was that they were especially weak at integrating metabolic pathways and understand the relationships between these pathways. A metro map was designed in the Revision Mode that aided students in knowledge integration, and the functions of biomolecules were summarized in flashcards that helped students in revising the concepts. This interactive self‐learning tool was packaged as a courseware using the Articulate Storyline.
Numerical Investigation of Cyclone Separators: Physical Mechanisms and Theoretical Algorithms
Authors: El‐Emam Mahmoud A. , Zhou Ling , Yasser Eman
Published: January 2024

Gas‐particle aero‐type cyclones have revolutionized biochemical processes, engineering industries, and environmental pollution protection by effectively separating particles from gas. These devices rely on gravitational energy and centrifugal force to dissipate particle phase energy, but achieving optimal energy efficiency while minimizing pressure drop remains challenging. This has led to the development of various cyclone designs in commercial industries, each with unique energy efficiency characteristics. The intricate gas‐particle flow inside cyclones is a critical issue impacted by cyclone geometry, operating conditions, and media parameters. Advanced numerical simulations have been employed to understand this complex flow pattern better, offering researchers valuable insights into the mechanisms of different cyclone separators. This comprehensive review explores the available numerical methods in the literature on cyclones and their corresponding validations. Computational numerical modeling is a promising technique for predicting cyclone energy efficiency, gas‐particle behavior, and overall performance. This investigation delves into the progress and numerical forms of gas‐particle flow cyclones, examining how different parameters impact cyclone performance and flow patterns within the two‐phase flow. The future developments and challenges that may further promote the development of aero‐type cyclone separators, providing theory and engineering support for future cyclone designs, are also covered. As a result, it can confidently be reported that aero‐type cyclone separators remain a critical component in various industrial sectors, offering energy‐efficient solutions for mitigating environmental pollutants and gas‐particle separation systems. With continued development and research, these devices will undoubtedly shape the future of energy processes and engineering industries, ushering in a new era of sustainability and efficiency.
Lipopolysaccharide‐mediated ATP signaling regulates interleukin‐6 mRNA expression via the P2‐purinoceptor in human dental pulp cells
Authors: Orimoto Ai , Kitamura Chiaki , Ono Kentaro
Published: January 2024

Dental pulp cells play a crucial role in maintaining the balance of the pulp tissue. They actively respond to bacterial inflammation by producing proinflammatory cytokines, particularly interleukin‐6 (IL‐6). While many cell types release adenosine triphosphate (ATP) in response to various stimuli, the mechanisms and significance of ATP release in dental pulp cells under inflammatory conditions are not well understood. This study aimed to investigate ATP release and its relationship with IL‐6 during the inflammatory response in immortalized human dental pulp stem cells (hDPSC‐K4DT) following lipopolysaccharide (LPS) stimulation. We found that hDPSC‐K4DT cells released ATP extracellularly when exposed to LPS concentrations above 10 μg/mL. ATP release was exclusively attenuated by N‐ethylmaleimide, whereas other inhibitors, including clodronic acid (a vesicular nucleotide transporter inhibitor), probenecid (a selective pannexin‐1 channel inhibitor), meclofenamic acid (a selective connexin 43 inhibitor), suramin (a nonspecific P2 receptor inhibitor), and KN‐62 (a specific P2X7 antagonist), did not exhibit any effect. Additionally, LPS increased IL‐6 mRNA expression, which was mitigated by the ATPase apyrase enzyme, N‐ethylmaleimide, and suramin, but not by KN‐62. Moreover, exogenous ATP induced IL‐6 mRNA expression, whereas ATPase apyrase, N‐ethylmaleimide, and suramin, but not KN‐62, diminished ATP‐induced IL‐6 mRNA expression. Overall, our findings suggest that LPS‐induced ATP release stimulates the IL‐6 pathway through P2‐purinoceptor, indicating that ATP may function as an anti‐inflammatory signal, contributing to the maintenance of dental pulp homeostasis.
The role of exo‐miRNA in diagnosis and treatment of cancers, focusing on effective miRNAs in colorectal cancer
Authors: Kzar Al‐Shukri Hamzah H. , Abdul‐Jabbar Ali Sana , Al‐Akkam Karam Akram , Hjazi Ahmed , Rasulova Irodakhon , Mustafa Yasser Fakri , Al‐Saidi Dahlia N. , Alasheqi Mohammed Qasim , Alawadi Ahmed , Alsaalamy Ali
Published: January 2024

Small extracellular (EV) particles known as exosomes are released by a variety of cell types, including immune system cells, stem cells, and tumor cells. They are regarded as a subgroup of EVs and have a diameter that ranges from 30 to 150 nm. Proteins, lipids, nucleic acids (including RNA and DNA), and different bioactive compounds are among the wide range of biomolecules that make up the cargo of exosomes. Exosomes are crucial for intercellular communication because they let cells share information and signaling chemicals. They are involved in various physiological and pathological processes, including immune responses, tissue regeneration, cancer progression, and neurodegenerative diseases. In conclusion, it is essential to continue research into exosome‐based cancer medicines to advance understanding, improve treatment plans, create personalized tactics, ensure safety, and speed up clinical translation.
A Procedure for Rational Probe Liquids Selection to Determine Hansen Solubility Parameters
Authors: Amin Amin Said , Lerche Dietmar , Odungat Ahammed Suhail , Boehm Sven Uwe , Koch Thomas , Özcan Fatih , Segets Doris
Published: January 2024

Hansen Solubility Parameters (HSP), viewed in the context of similarity whenever dispersion is focused, offer valuable insights into the surface characteristics of nanoparticles. However, existing methods for determining HSP via the sedimentation of nanoparticles require multiple probe liquids, resulting in time‐consuming, costly experiments with potential health risks. To address this, we developed a two‐step strategy that enables a systematic selection of liquids. The key element of the approach is to first identify the rough location of the Hansen sphere in the three‐dimensional Hansen space using a well‐chosen set of probe liquids of different polarities and chemical structures. Then, depending on the outcome of the first step, a particular choice of liquids is made for the final HSP determination. Taken together, the introduced procedure reduces the amount of required liquids for experiments from currently more than ten to a maximum of seven chosen based on a well‐defined, coherent methodology. Validation was performed on carbon black, non‐pigmentary nano‐scale titania, silicon/carbon composites, and lanthanum cobaltite particles, i. e., relevant materials that are commonly utilized in fuel cells, batteries, cyclohexene oxidation, catalytic combustion, photocatalysis, and heterogeneous Fenton reactions. The study showcases the potential to save time, costs, and efficiently determine HSP values in a comparable manner.
Experimental and Theoretical Studies on the Reactions of Aliphatic Imines with Isocyanates
Authors: Cotter Etienne , Pultar Felix , Riniker Sereina , Altmann Karl‐Heinz
Published: January 2024

In the context of a project aiming at the replacement of the 3‐substituted β‐lactam ring in classical β‐lactam antibiotics by an N(3)‐acyl‐1,3‐diazetidinone moiety, we have investigated the reaction of isocyanates with imines derived from allyl glycinate and differently substituted propionaldehydes. Imines of aromatic aldehydes with anilines have been reported to react with acyl isocyanates to give 1,3‐diazetidinones or 2,3‐dihydro‐4H‐1,3,5‐oxadiazin‐4‐ones, via [2+2] or [4+2] cycloaddition, respectively. However, neither of these products was formed with imines derived from allyl glycinate and 2‐(mono)methyl propionaldehydes. α,α‐Dimethylation of the imine enabled the [4+2] cycloaddition pathway, but the desired 1,3‐diazetidinone products were not observed. Surprisingly, the imines obtained from thioesters of 2,2‐dimethyl 3‐oxo propionic acid reacted with aryl isocyanates or with benzyl isocyanate to give 5,5‐dimethyl‐2,4‐dioxo‐6‐(aryl‐/alkylthio)tetrahydropyrimidines, via thiol displacement and re‐addition to a putative six‐membered iminium intermediate. These experimental results obtained for the reactions could be rationalized by DFT calculations. In addition, we have shown that N(3)‐acyl‐1,3‐diazetidinone and 2,3‐dihydro‐4H‐1,3,5‐oxadiazin‐4‐one products can be distinguished based on experimental IR data in combination with theoretical reference spectra employing the IR spectra alignment (IRSA) algorithm. This discrimination was not possible by means of 1H, 13C, or 15N NMR spectroscopy
Elevated uric acid/albumin ratio as a predictor of poor coronary collateral circulation development in patients with non‐ST segment elevation myocardial infarction
Authors: Yin Renlin , Ye Zongwei , You Hua , Wu Yanming , Chen Weixiang , Jiang Tingbo
Published: January 2024

Background

Uric acid/albumin ratio (UAR) is a novel composite biomarker with superior predictive value for cardiovascular disease.

Objective

To investigate the relationship between UAR and coronary collateral circulation (CCC) in patients with non‐ST segment elevation myocardial infarction (NSTEMI).

Methods

A total of 205 NSTEMI patients who underwent coronary arteriography with at least one major coronary stenosis, 95% were included. Patients were divided into two groups according to CCC development: poorly‐developed CCC group (Rentrop 0–1) and well‐developed CCC (Rentrop 2–3). Univariate analysis and logistic regression analysis were utilized to investigate the factors influencing adverse CCC formation in NSTEMI patients. The receiver operating characteristic (ROC) curve was plotted to evaluate the predictive value of UAR, C‐reactive protein (CRP), uric acid, and albumin for patients with poorly developed CCC, and the area under the curve (AUC) was compared.

Results

The UAR values of NSTEMI patients were significantly higher in the poorly developed CCC group than those in the well‐developed CCC group (10.19 [8.80–11.74] vs. 7.79 [6.28–9.55], p < .001). In the multiple logistic regression tests, UAR (odds ratio [OR]: 1.365, 95% confidence interval [CI]: 1.195–1.560, p < .001), CRP (OR: 1.149, 95% CI: 1.072–1.231, p < .001), and diabetes (OR: 2.924, 95% CI: 1.444–5.920, p = .003) were independent predictors of poorly developed CCC. The ROC curve analysis showed that the optimal cut‐off value of UAR was 8.78 in predicting poorly developed CCC with a sensitivity of 76.8% and specificity of 62.4%, with the AUC of 0.737 (95% Cl: 0.668–0.805, p < .001).

Conclusion

Elevated UAR may be an independent and effective biomarker for predicting poorly‐developed CCC development in NSTEMI patients.
Comparison of Structural, Water‐Retaining and Sorption Properties of Acrylamide‐Based Hydrogels Cross‐Linked by Physical and Chemical Methods
Authors: Siryk Olena , Goncharuk Olena , Samchenko Yurii , Kernosenko Liudmyla , Szewczuk‐Karpisz Katarzyna
Published: January 2024

Two series of hydrogels based on acrylamide and its copolymers with acrylonitrile and acrylic acid were synthesized by two cross‐linking methods – chemical (using N,N′‐methylene bis‐acrylamide) and physical (using montmorillonite (MMT)) ones. The structure of the gels was characterized by Fourier Transform Infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The swelling and sorption properties were analyzed as a function of both the monomer composition and the cross‐linking method. The shift of the band corresponding to Si−O (995–1030 cm−1) confirmed the formation of intercalation structures for MMT‐cross‐linked gels. Moreover, physically cross‐linked gels demonstrated a non‐monotonic dependence of the swelling degree on the MMT concentration, and acrylamide‐acrylic acid copolymer MMT‐cross‐linked gels showed pH sensitivity and the highest swelling degree of 150 g/g. The highest sorption capacity towards cadmium(II) ions was demonstrated by acrylamide‐acrylic acid copolymer gels, both covalently cross‐linked (30 mg/g) and MMT‐cross‐linked (8.9 mg/g).
Model‐Based Benefit/Risk Analysis for the Copanlisib Intermittent Dosing Regimen
Authors: Morcos Peter N. , Moss Jonathan , Veasy Josh , Hiemeyer Florian , Childs Barrett H. , Garmann Dirk
Published: January 2024

Copanlisib is an intravenously administered phosphatidylinositol 3‐kinase (PI3K) inhibitor, which is approved as monotherapy for relapsed follicular lymphoma in adult patients who have received at least two systemic therapies. In an April 2022 US Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC), the benefit–risk profile of the class PI3K inhibitors were scrutinized for use in hematological malignancies. Specifically, their unique toxicities may contribute to the high incidences in reported serious and high‐grade treatment emergent adverse events (TEAEs), thereby reducing their overall tolerability and potentially limiting their successful use. These tolerability concerns may be contributed by or compounded by inadequate dose optimization. The recommended dosing regimen of copanlisib 60 mg administered on days 1, 8, and 15 of a 28‐day cycle was selected as the maximal tolerated dose (MTD) during phase I. Thus, this analysis sought to justify the copanlisib dose regimen selection. Copanlisib exposure‐efficacy relationships were considered from its large phase III trial, CHRONOS‐3, whereas copanlisib safety was investigated by pooling data across its two large clinical trials to comprehensively assess its exposure‐safety relationships. Results demonstrated a statistically significant positive linear exposure‐efficacy relationship at the MTD. Exposure‐safety analyses revealed a borderline significant linear relationship for grade ≥3 TEAEs and no significant exposure‐safety relationships for other investigated safety end points. The model‐based benefit/risk framework considered the established exposure‐response models and defined clinical utility function which confirmed the appropriateness of the copanlisib dosing regimen across the range of its achieved exposures.
Towards Durable and High‐Rate Rechargeable Aluminum Dual‐ion Batteries via a Crosslinked Diphenylphenazine‐based Conjugated Polymer Cathode
Authors: Ma Wenyan , Zhang Pengchao , Tang Linting , Ge Mantang , Qi Yunpeng , Chen Yu , Zhang Chong , Jiang Jia‐Xing
Published: January 2024

Rechargeable aluminum battery (RAB) is expected to be a promising energy storage technique for grid‐scale energy storage. However, the development of RABs is seriously plagued by the lack of suitable cathode materials. Herein, we report two p‐type conjugated polymers of L‐PBPz and C‐PBPz with the same building blocks of diphenylphenazine but different linkage patterns of linear and crosslinked structures as the cathode materials for Al dual‐ion batteries. Compared to the linear polymer skeleton in L‐PBPz, the crosslinked structure endows C‐PBPz with amorphous nature and low dihedral angles of the polymer chains, which severally contribute to the fast diffusion of AlCl4− with large size and the electron transfer during the redox reaction of diphenylphenazine. As a result, C‐PBPz delivers a much better rate performance than L‐PBPz. The crosslinked structure also leads to a stable cyclability with over 80000 cycles for C‐PBPz. Benefiting from the fast kinetics, meanwhile, the C‐PBPz cathode could realize a high redox activity of 117 mAh g−1, corresponding to an areal capacity of 2.30 mAh cm−2, even under a high mass loading of 19.7 mg cm−2 and a low content of 10 wt% conductive agent. These results might boost the development of polymer cathodes for RABs.
Body composition and plasma total‐tau, neurofilament light chain, and amyloid‐β: A population‐based study
Authors: de Crom Tosca O. E. , Ghanbari Mohsen , Voortman Trudy , Ikram M. Arfan
Published: January 2024

A higher body mass at older age has been linked to a lower risk of dementia. This unexpected trend may be explained by age‐related lean mass depletion, or methodological issues such as the long preclinical phase of dementia or competing risks. Focusing on preclinical markers of dementia may overcome these issues.

Between 2002 and 2005, body composition and plasma total‐tau, neurofilament light chain (NfL), amyloid‐β40, and amyloid‐β42 were measured in 3408 dementia‐free participants from the population‐based Rotterdam Study. The cross‐sectional associations between body composition and plasma markers were determined using linear regression models.

Whole body and fat mass, but not lean mass, were positively associated with total‐tau, while all these measures were inversely associated with NfL. Apart from an inverse association between lean mass and amyloid‐β40, body composition measures were not associated with plasma amyloid‐β.

Our findings suggest distinct effects of body composition on neurodegeneration.
Impact of rapid sequential combination therapy on distinct haemodynamic measures in newly diagnosed pulmonary arterial hypertension
Authors: Kramer Tilmann , Nattmann Phillip , Gerhardt Felix , Stafiej Patrycja , Dumitrescu Daniel , ten Freyhaus Henrik , Wißmüller Max , Hohmann Christopher , Baldus Stephan , Rosenkranz Stephan
Published: January 2024

Aims

In pulmonary arterial hypertension (PAH), upfront combination therapy with ERA and PDE5i is associated with a reduction in morbidity and mortality events and improves standard haemodynamics, but data remain limited. Aims of this study were (i) to capture detailed haemodynamic effects of rapid sequential dual combination therapy in patients with newly diagnosed PAH; (ii) to monitor the impact of treatment initiation on clinical variables and patients' risk status, and (iii) to compare the treatment effect in patients with ‘classical PAH’ and ‘PAH with co‐morbidities’.

Methods

Fifty patients (median age 57 [42–71] years, 66% female) with newly diagnosed PAH (76% idiopathic) were treated with a PD5i/sGC‐S or ERA, followed by addition of the respective other drug class within 4 weeks. All patients underwent repeat right heart catheterization (RHC) during early follow‐up.

Results

At early repeat RHC (7 ± 2 months), there were substantial reductions in mean pulmonary artery pressure (mPAP: 52.2 ± 13.5 to 39.0 ± 10.6 mmHg; −25.3%), and pulmonary vascular resistance (PVR: 12.1 ± 5.7 to 5.8 ± 3.1 WU; −52.1%), and an increase in cardiac index (2.1 ± 0.4 to 2.7 ± 0.7 mL/min/m2; +32.2%) (all P < 0.05). Haemodynamic improvements correlated with improved clinical parameters including 6‐min walking distance (336 ± 315 to 389 ± 120 m), NTproBNP levels (1.712 ± 2.024 to 506 ± 550 ng/L, both P < 0.05) and WHO‐FC at 12 months, resulting in improved risk status, and were found in patients with few (n = 37) or multiple cardiovascular co‐morbidities (BMI > 30 kg/m2, hypertension, diabetes, coronary artery disease [≥3]; n = 13), albeit baseline PVR in PAH patients with multiple co‐morbidities was lower (9.3 ± 4.4 vs. 13.1 ± 5.9 WU) and PVR reduction less pronounced compared with those with few co‐morbidities (−42.7% vs. −54.7%). However, comprehensive haemodynamic assessment considering further variables of prognostic relevance such as stroke volume index and pulmonary artery compliance showed similar improvements among the two groups (SVI: +50.0% vs. +49.2%; PAC: 91.7% vs. 100.0%). Finally, the 4‐strata risk assessment approach was better able to capture treatment response as compared with other approaches, particularly in patients with co‐morbidities.

Conclusions

Rapid sequential combination therapy with PDE5i/sGC‐S and ERA substantially ameliorates cardiopulmonary haemodynamics at early follow‐up in patients without, and to a lesser extent, with cardiovascular co‐morbidities. This occurs in line with improvements of clinical parameters and risk status.
Fun With Unusual Functional Groups: Sulfamates, Phosphoramidates, and Di‐tert‐butyl Silanols
Authors: Sathyamoorthi Shyam
Published: January 2024

Compared to ubiquitous functional groups such as alcohols, carboxylic acids, amines, and amides, which serve as central “actors” in most organic reactions, sulfamates, phosphoramidates, and di‐tert‐butyl silanols have historically been viewed as “extras”. Largely considered functional group curiosities rather than launch‐points of vital reactivity, the chemistry of these moieties is under‐developed. Our research program has uncovered new facets of reactivity of each of these functional groups, and we are optimistic that the chemistry of these fascinating molecules can be developed into truly general transformations, useful for chemists across multiple disciplines. In the ensuing sections, I will describe our efforts to develop new reactions with these “unusual” functional groups, namely sulfamates, phosphoramidates, and di‐tert‐butyl silanols.
TransHyDE‐Sys: An Integrated Systemic Approach for Analyzing and Supporting the Transformation of Energy Systems and Hydrogen Infrastructure Development
Authors: Kigle Stephan , Mohr Stephan , Kneiske Tanja , Clees Tanja , Ebner Michael , Harper Ryan , Jahn Matthias , Klaassen Bernhard , Köppel Wolfgang , Ausfelder Florian , Neitz‐Regett Anika , Ragwitz Mario
Published: January 2024

In addition to the long‐term goal of mitigating climate change, the current geopolitical upheavals heighten the urgency to transform Europe's energy system. This involves expanding renewable energies while managing intermittent electricity generation. Hydrogen is a promising solution to balance generation and demand, simultaneously decarbonizing complex applications. To model the energy system's transformation, the project TransHyDE‐Sys, funded by the German Federal Ministry of Education and Research, takes an integrated approach beyond traditional energy system analysis, incorporating a diverse range of more detailed methods and tools. Herein, TransHyDE‐Sys is situated within the recent policy discussion. It addresses the requirements for energy system modeling to gain insights into transforming the European hydrogen and energy infrastructure. It identifies knowledge gaps in the existing literature on hydrogen infrastructure‐oriented energy system modeling and presents the research approach of TransHyDE‐Sys. TransHyDE‐Sys analyzes the development of hydrogen and energy infrastructures from “the system” and “the stakeholder” perspectives. The integrated modeling landscape captures temporal and spatial interactions among hydrogen, electricity, and natural gas infrastructure, providing comprehensive insights for systemic infrastructure planning. This allows a more accurate representation of the energy system's dynamics and aids in decision‐making for achieving sustainable and efficient hydrogen network development integration.
Aflatoxins in food: Prevalence, health effects, and emerging trends in its mitigation—An updated review
Authors: Balan Biji , Dhaulaniya Amit S. , Kumar Munendra , Kumar Mohit , Kumar Prateek
Published: January 2024

Mycotoxins are secondary metabolites produced by a variety of fungal and mold species. One of the mycotoxin families that is often regarded as the most concerned one in human and animal feeds, is aflatoxin. Aflatoxins produced by Aspergillus species are very toxic and cause significant contamination of food supplies, resulting in serious health repercussions including carcinogenicity. To date, several regulations on aflatoxin permissible level limits have been established in a number of nations. Based on government guidelines and restrictions, consumers and food producers anticipate that aflatoxin contamination in food should not negatively impact human and animal health. Aflatoxin contamination of food commodities poses a consequential risk to humans and is also associated with substantial financial losses. Conventional mycotoxin reduction strategies involve both preventative and decontamination approaches. The present review gives an update on recent research on conventional approaches, including pre‐ and post‐harvest procedures that could potentially be used to decontaminate aflatoxin. Additionally, the current study delves into the source of contamination, global occurrence, impact on human health, and management strategies to assure food security and safety.
The effect of turmeric and black pepper powder incorporated in breakfast on postprandial glycemia, appetite, palatability, and gastrointestinal well‐being in normal‐weight adults
Authors: Khan Safarat , Arif Muhammad , Laraib Hafza , Naqvi Syeda Nimra , Shah Omair Ali , Farooq Umar , Sami‐Ullah Muhammad , Khan Gul Asghar
Published: January 2024

Culinary herbs and spices are primarily known as flavor enhancers, research suggests that black pepper (Piper nigrum) and turmeric (Curcuma longa) have now been proven to prevent many non‐communicable chronic diseases such as diabetes. Bioactive components of black pepper and turmeric ameliorate glucose metabolism and appetite regulation. The present research was designed to investigate the impact of turmeric and black pepper on blood glycemia, gastrointestinal well‐being, appetite, and palatability. In a randomized crossover study, four iso‐caloric experimental meals each having 50 g of available carbohydrates were subjected to healthy human participants (N = 20). Turmeric and black pepper were incorporated in the breakfast meal, 1 g black pepper (BP), 1 g turmeric (TR), and combination of the (BP + TR) was added in the breakfast. Standard questionnaires were used to evaluate palatability, subjective appetite, and gastrointestinal well‐being. Blood glycemia, subjective gastrointestinal well‐being, and appetite were measured at 0, 30, 60, 120, and 180 min. Experimental meals BP and BP + TR resulted in lower blood glycemia (p < .05) significantly compared to control meal. A decrease in perceived eating ability and hunger, and an increase in satiety after BP + TR and BP meal was observed. No significant changes were observed after consuming test meals on gastrointestinal well‐being. Compared to control and BP + TR meals, BP and TR meals had considerably lower palatability. Results showed that compared to the control intake of starchy meals supplemented with black pepper and turmeric reduced postprandial glycemia, hunger, and perceived eating ability without affecting gastrointestinal well‐being.
Enhancement the solar box cooker performance using steel fibers
Authors: Ibrahim Osama Abd Al‐Munaf , Kadhim Saif Ali , Ali Hayder Mohsin
Published: January 2024

The use of fossil fuel and wood for cooking poses health, environmental, and economic challenges, especially with the growing population. This has led to an increase in the trend towards the use of clean and sustainable cooking sources, including solar cookers. This experimental study aims to contribute by enhancing the performance of a solar box cooker (SBC) according to the concept of porous media via adding steel fibers inside the box as a modified SBC and comparing it with a conventional SBC. The stagnation test to determine the first figure of merit and the load test to determine the second figure of merit, standard boiling time, and cooker optothermal ratio were conducted under the outdoor conditions of Baghdad city. Also, an energy and exergy efficiency analysis, and calculating the rate of heat loss by three water loads heating and cooling tests. The results revealed that the modified SBC has a higher thermal performance than the conventional SBC.
The relational change mechanisms of child‐centered play therapy with children exposed to adverse childhood experiences
Authors: Frawley Caitlin , Dillman Taylor Dalena
Published: January 2024

The researchers examined the relational mechanisms and coregulatory change mechanisms of child‐centered play therapy (CCPT) with children (ages 5–8) who endured multiple adverse childhood experiences (ACEs). The researchers computed surrogate synchrony analyses to measure heart rate synchrony between counselor and child participants during CCPT treatment. Child participants received between 10 and 14 CCPT sessions in the elementary school setting. Participants and counselor wore Empatica© E4 wristbands during sessions to collect heart rate data continuously during play therapy sessions. The researchers found consistent, large child‐counselor heart rate synchrony levels across play therapy sessions. The researchers discuss the implications of this research for counselors and play therapists working with children impacted by ACEs.
The BCKDH kinase inhibitor BT2 promotes BCAA disposal and mitochondrial proton leak in both insulin‐sensitive and insulin‐resistant C2C12 myotubes
Authors: Rivera Caroline N. , Smith Carly E. , Draper Lillian V. , Kee Madison E. , Cook Norah E. , McGovern Macey R. , Watne Rachel M. , Wommack Andrew J. , Vaughan Roger A.
Published: January 2024

Elevated circulating branched‐chain amino acids (BCAAs) have been correlated with the severity of insulin resistance, leading to recent investigations that stimulate BCAA metabolism for the potential benefit of metabolic diseases. BT2 (3,6‐dichlorobenzo[b]thiophene‐2‐carboxylic acid), an inhibitor of branched‐chain ketoacid dehydrogenase kinase, promotes BCAA metabolism by enhancing BCKDH complex activity. The purpose of this report was to investigate the effects of BT2 on mitochondrial and glycolytic metabolism, insulin sensitivity, and de novo lipogenesis both with and without insulin resistance. C2C12 myotubes were treated with or without low or moderate levels of BT2 with or without insulin resistance. Western blot and quantitative real‐time polymerase chain reaction were used to assess protein and gene expression, respectively. Mitochondrial, nuclei, and lipid content were measured using fluorescent staining and microscopy. Cell metabolism was assessed via oxygen consumption and extracellular acidification rate. Liquid chromatography‐mass spectrometry was used to quantify BCAA media content. BT2 treatment consistently promoted mitochondrial uncoupling following 24‐h treatment, which occurred largely independent of changes in expressional profiles associated with mitochondrial biogenesis, mitochondrial dynamics, BCAA catabolism, insulin sensitivity, or lipogenesis. Acute metabolic studies revealed a significant and dose‐dependent effect of BT2 on mitochondrial proton leak, suggesting BT2 functions as a small‐molecule uncoupler. Additionally, BT2 treatment consistently and dose‐dependently reduced extracellular BCAA levels without altering expression of BCAA catabolic enzymes or pBCKDHa activation. BT2 appears to act as a small‐molecule mitochondrial uncoupler that promotes BCAA utilization, though the interplay between these two observations requires further investigation.
Pyruvate maintains and enhances the pro‐inflammatory response of microglia caused by glucose deficiency in early stroke
Authors: Zhou Peng , Yu Zhe‐Cheng , Cao Cong , Cui Huai‐Rui , Ding Mao‐Chao , Yang Chao‐Xian , Liao Min
Published: January 2024

Pro‐inflammatory microglia mainly rely on glycolysis to maintain cytokine production during ischemia, accompanied by an increase in inducible nitric oxide synthase (iNOS) and monocarboxylate transporter 1 (MCT1). The role of energy metabolism in the pro‐inflammatory response of microglia is currently unclear. In this study, we tested the response of microglia in mice after cerebral ischemia and simulated an energy environment in vitro using low glucose culture medium. The research results indicate that the expression levels of iNOS and arginase 1 (ARG1) increase in the ischemic mouse brain, but the upregulation of MCT1 expression is mainly present in iNOS positive microglia. In microglia exposed to low glucose conditions, iNOS and MCT1 levels increased, while ARG1 levels decreased. Under the same conditions, knocking down MCT1 in microglia leads to a decrease in iNOS levels, while overexpression of MCT1 leads to the opposite result. The use of NF‐κB inhibitors reduced the expression levels of iNOS and MCT1 in microglia. In summary, our data indicate that pyruvate maintains and enhances the NF‐κB regulated pro‐inflammatory response of microglia induced by low glucose.
Manipulating sensitivities of planar oxadiazole‐based high performing energetic materials
Authors: Chinnam Ajay Kumar , Singh Jatinder , Staples Richard J. , Shreeve Jean'ne M.
Published: January 2024

Nitrogen‐rich energetic materials based on five‐membered azoles, such as tetrazoles, triazoles, oxadiazoles, pyrazoles, and imidazoles, have garnered significant attention in recent years due to their environmental compatibility while maintaining high performance. These materials, including explosives, propellants, and pyrotechnics, are designed to release energy rapidly and efficiently while minimizing the release of toxic or hazardous byproducts and have attracted potential applications in the defense and space industries. The presence of extensive NC, NN, and NN high energy bonds in azoles provides high enthalpies of formation and facilitates intermolecular interactions through π‐stacking which may help with reducing sensitivity to external stimuli. Now, we report on the synthesis and energetic properties of N‐(5‐(1H‐tetrazol‐5‐yl)‐1,3,4‐oxadiazol‐2‐yl)nitramide (5) and its energetic salts. These new high nitrogen–oxygen‐containing materials have attractive feature applications of insensitivity and increased performance.