bluuebunny/crossref_metadata_2025 huggingface dataset:
Gilteritinib clinical activity in relapsed/refractory FLT3 mutated acute myeloid leukemia previously treated with FLT3 inhibitors
Authors: Numan Yazan , Abdel Rahman Zaid , Grenet Justin , Boisclair Stephanie , Bewersdorf Jan Philipp , Collins Cailin , Barth Dylan , Fraga Martina , Bixby Dale L. , Zeidan Amer M. , Yilmaz Musa , Desai Pankil , Mannis Gabriel , Deutsch Yehuda E. , Abaza Yasmin , Dinner Shira , Frankfurt Olga , Litzow Mark , Al‐Kali Aref , Foran James M. , Sproat Lisa Z. , Jovanovic Borko , Daver Naval , Perl Alexander E. , Altman Jessica K.
Published: January 2022

Gilteritinib is approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with an FLT3‐mutation (FLT3mut+). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) was conducted prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or posttransplant FLT3 inhibitor maintenance. We performed a retrospective analysis using data from 11 US centers and where we identified 113 patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. The composite complete remission (CR) rate (CRc, defined as CR + CRi + CR with incomplete platelet recovery [CRp]) was 48.7% (n = 55). The CRc rate after treatment with gilteritinib in patients who were treated with only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. Survival was longest in patients who obtained a CR, particularly a cMRD (clinical minimal or measurable residual disease) negative response; this remained significant after censoring at the time of stem cell transplant. The mitogen‐activated protein kinase pathway activating mutations that are known for gilteritinib resistance (NRAS, KRAS, and PTPN11) had lower CRc (35% vs. 60.5%) and lower median overall survival than patients' whose leukemia did not express these mutations (4.9 months vs. 7.8 months) (HR 2.4; 95% CI 1. 5.4) p value <.01.
Improved outcomes among newly diagnosed patients with FMS‐like tyrosine kinase 3 internal tandem duplication mutated acute myeloid leukemia treated with contemporary therapy: Revisiting the European LeukemiaNet adverse risk classification
Authors: Reville Patrick K. , Sasaki Koji , Kantarjian Hagop M. , Daver Naval G. , Yilmaz Musa , Dinardo Courtney D. , Short Nicholas J. , Borthakur Gautam , Pemmaraju Naveen , Mehta Rohtesh S. , Pierce Sherry , Konoplev Sergej N. , Khoury Joseph D. , Garcia‐Manero Guillermo , Konopleva Marina Y. , Jabbour Elias , Ravandi Farhad , Kadia Tapan M.
Published: January 2022

Mutations in fms‐like tyrosine kinase 3 (FLT3) gene are common genomic alterations in acute myeloid leukemia (AML). FLT3 internal tandem duplication mutations (FLT3‐ITD) have consistently been shown to be adversely prognostic, particularly those with high allelic ratio (AR). Current AML treatment strategies, including high dose cytarabine, purine analogs, FLT3 inhibitors (FLT3i), and with or without allogeneic stem cell transplant (SCT) have been shown to improve the outcomes in patients with FLT3 mutations. We analyzed a consecutive cohort of newly diagnosed patients with AML treated at a large academic medical center from January 2012 to January 2020. A total of 1576 patients with a new diagnosis of AML were reviewed. Among these, 1438 (91%) had molecular testing for FLT3 mutations and 21% (304/1438) had an FLT3 mutation, including 17% with an FLT3‐ITD mutation. We show that FLT3‐ITD high AR with NPM1 wild‐type have significantly improved survival compared with other European LeukemiaNet (ELN) adverse risk disease. In multivariable cox proportional hazards model of patients receiving intensive or low‐intensity induction regimens, FLT3 mutations did not have prognostic significance. The use of allogeneic SCT in CR1 for patients with FLT3 mutations appears to improve survival, particularly in those with ELN adverse risk disease. Overall, this data highlights the changing prognostic impact of FLT3 mutations in a contemporary era with appropriate use of induction therapy combined with targeted agents and allogenic SCT.
Reduced Numbers of Corticotropin‐Releasing Hormone Neurons in Narcolepsy Type 1
Authors: Shan Ling , Balesar Rawien , Swaab Dick F. , Lammers Gert Jan , Fronczek Rolf
Published: January 2022

Narcolepsy type 1 (NT1) is a chronic sleep disorder correlated with loss of hypocretin(orexin). In NT1 post‐mortem brains, we observed 88% reduction in corticotropin‐releasing hormone (CRH)‐positive neurons in the paraventricular nucleus (PVN) and significantly less CRH‐positive fibers in the median eminence, whereas CRH‐neurons in the locus coeruleus and thalamus, and other PVN neuronal populations were spared: that is, vasopressin, oxytocin, tyrosine hydroxylase, and thyrotropin releasing hormone‐expressing neurons. Other hypothalamic cell groups, that is, the suprachiasmatic, ventrolateral preoptic, infundibular, and supraoptic nuclei and nucleus basalis of Meynert, were unaffected. The surprising selective decrease in CRH‐neurons provide novel targets for diagnostics and therapeutic interventions. ANN NEUROL 2022;91:282–288
Fluorinated Sulfinates as Source of Alkyl Radicals in the Photo‐Enantiocontrolled β‐Functionalization of Enals
Authors: Rodríguez Ricardo I. , Sicignano Marina , Alemán José
Published: January 2022

The generation of sulfonyl radicals has long been known as a flexible strategy in a wide range of different sulfonylative transformations. Meanwhile their use in alkylation processes has been somehow limited due to their inherent difficulty in evolving to less‐stable radicals after sulfur dioxide extrusion. Herein we report a convenient strategy that involvesgem‐difluorinated sulfinates as an “upgrading‐mask”, allowing these precursors to decompose into their corresponding alkyl radicals. The electron–donor character of sulfinates in the formation of an electron donor–acceptor (EDA) complex with transient iminium ions is displayed, achieving the first example of a stereocontrolled light‐driven insertion ofgem‐difluoro derivatives into unsaturated aldehydes. This methodology is compatible with flow conditions, maintaining identical levels of enantiocontrol.
Electropolymerization of Metal Clusters Establishing a Versatile Platform for Enhanced Catalysis Performance
Authors: Wang Yi‐Man , Cai Jinmeng , Wang Qian‐You , Li Yao , Han Zhen , Li Si , Gong Chun‐Hua , Wang Shan , Zang Shuang‐Quan , Mak Thomas C. W.
Published: January 2022

Atomically precise metal clusters are attractive as highly efficient catalysts, but suffer from continuous efficiency deactivation in the catalytic process. Here, we report the development of an efficient strategy that enhances catalytic performance by electropolymerization (EP) of metal clusters into hybrid materials. Based on carbazole ligand protection, three polymerized metal‐cluster hybrid materials, namely Poly‐Cu14cba, Poly‐Cu6Au6cbz and Poly‐Cu6Ag4cbz, were prepared. Compared with isolated metal clusters, metal clusters immobilizing on a biscarbazole network after EP significantly improved their electron‐transfer ability and long‐term recyclability, resulting in higher catalytic performance. As a proof‐of‐concept, Poly‐Cu14cba was evaluated as an electrocatalyst for reducing nitrate (NO3−) to ammonia (NH3), which exhibited ≈4‐fold NH3 yield rate and ≈2‐fold Faraday efficiency enhancement compared to that of Cu14cba with good durability. Similarly, Poly‐Cu6Au6cbz showed 10 times higher photocatalytic efficiency towards chemical warfare simulants degradation than the cluster counterpart.
Chirality Inversion in Self‐Assembled Nanocomposites Directed by Curvature‐Mediated Interactions
Authors: Gong Yanjun , Cao Zhaozhen , Zhang Zongze , Liu Rongjuan , Zhang Fenghua , Wei Jingjing , Yang Zhijie
Published: January 2022

Nanoscale curvature‐dependent interactions are of paramount importance in biological systems. Here, we report that nanoscale curvature plays an important role in regulating the chirality of self‐assembled nanocomposites from chiral organic molecules and achiral nanoparticles. Specifically, we show that the supramolecular chirality of the nanocomposites markedly depends on the nanoparticle curvature, where small‐sized nanoparticles of high curvature and large‐sized nanoparticles of low curvature lead to nanocomposites with opposite chirality. Quantitative kinetic experiments and molecular dynamics simulations reveal that nanoparticle curvature plays a key role in promoting the pre‐nucleation oligomerization of chiral molecules, which consequently regulates the supramolecular chirality of the nanocomposites. We anticipate that this study will aid in rational design of an artificial cooperative system giving rise to emergent assembling phenomena that can be surprisingly rich and often cannot be understood by studying the conventional noncooperative systems.
Chiral 1,2,3‐Triazolium Salt Catalyzed Asymmetric Mono‐ and Dialkylation of 2,5‐Diketopiperazines with the Construction of Tetrasubstituted Carbon Centers
Authors: Yang Ju‐Song , Lu Ka , Li Chen‐Xiao , Zhao Zu‐Hang , Zhang Xiao‐Ming , Zhang Fu‐Min , Tu Yong‐Qiang
Published: January 2022

Novel asymmetric mono‐ and dialkylation reactions of α‐substituted 2,5‐diketopiperazines catalyzed by new chiral spirocyclic‐amide‐derived triazolium organocatalysts have been developed, resulting in a range of enantioenriched 2,5‐diketopiperazine derivatives containing one or two tetrasubstituted carbon stereocenters. The reactions feature high yields (up to 98%), and excellent cis‐diastereo‐ and enantioselectivities (up to >20:1 dr, >99 % ee), and they provide a new asymmetric synthetic approach to important functionalized 2,5‐diketopiperazine skeletons. Furthermore, a possible reaction mechanism was proposed based on both control experiments and extensive DFT calculations.
Robust Luminescent Molecules with High‐Level Reverse Intersystem Crossing for Efficient Near Ultraviolet Organic Light‐Emitting Diodes
Authors: Chen Jinke , Liu Hao , Guo Jingjing , Wang Jianghui , Qiu Nuoling , Xiao Shu , Chi Jiajin , Yang Dezhi , Ma Dongge , Zhao Zujin , Tang Ben Zhong
Published: January 2022

Organic light‐emitting diodes (OLEDs) radiating near ultraviolet (NUV) light are of high importance but rarely reported due to the lack of robust organic short‐wavelength emitters. Here, we report a short π‐conjugated molecule (POPCN‐2CP) with high thermal and morphological stabilities and strong NUV photoluminescence. Its neat film exhibits an electroluminescence (EL) peak at 404 nm with a maximum external quantum efficiency (ηext,max) of 7.5 % and small efficiency roll‐off. The doped films of POPCN‐2CP in both non‐polar and polar hosts at a wide doping concentration range (10–80 wt%) achieve high‐purity NUV light (388–404 nm) and excellentηext,maxs of up to 8.2 %. The high‐level reverse intersystem crossing improves exciton utilization and accounts for the superbηext,maxs. POPCN‐2CP can also serve as an efficient host for blue fluorescence, thermally activated delayed fluorescence and phosphorescence emitters, providing excellent EL performance via Förster energy transfer.
Synthesis, structure, X‐ray photoelectron spectroscopy (XPS), and antimicrobial, anticancer, and antioxidant activities of Co (III) complexes based on the antihypertensive hydralazine
Authors: Khalil Tarek E. , Soliman Saied M. , Khalil Nessma A. , El‐Faham Ayman , Foro Sabine , El‐Dissouky Ali
Published: January 2022

The antimicrobial, anticancer, and antioxidant activities of four cobalt (III) complexes, [CoL2]X (X = ClO4¯ (1); OAc¯ (2), Cl¯ (3), or NO3¯ (4) with hydralazine Schiff base derivative (HL), were presented. The structure of the newly synthesized complexes 1 and 2 was confirmed utilizing FTIR, UV‐Vis, and NMR (1H and 13C) spectroscopy. In addition, single crystal X‐ray diffraction was used to approve the structure of complex 1. Based on Hirshfeld analysis, the molecular packing of 1 is controlled by short HH, OH, NH, and HC(π) interactions. The results of the X‐ray photoelectron spectroscopy (XPS) for the Co (III) complexes revealed the characteristic peaks of Co2p3/2 and Co2p1/2 with binding energy differences of 14.85–14.96 which greatly approved that the Co (III) complexes have been assembled successfully. Complex 4 (IC50 = 14.97 ± 0.59 μg/ml) has the highest cytotoxicity against lung carcinoma A‐549 cell line compared to the rest of the Co (III) complexes and the free ligand as well. Also, complex 4 has the best antioxidant activity with IC50 of 283.4 ± 12.3 μg/ml. The free ligand has broad spectrum of antibacterial and antifungal actions, while the studied Co (III) complexes have good antibacterial activity especially the chloride complex 3.
Homogeneous and heterogeneous reactions in the mixed convection flow of hybrid nanofluid over a slender cylinder
Authors: Patil Prabhugouda M. , Benawadi Sunil , Tonannavar Jagdish R. , Shanker Bandari
Published: January 2022

This article is about the study of homogeneous and heterogeneous reactions in the mixed convection flow of hybrid nanofluid over a moving vertical slender cylinder. It is based on the considerations of unequal diffusivity of chemical species and the numerical solutions from the nonsimilar approach. This study has found applications in many chemically reacting processes, including the processes in the biochemical systems, combustion, and catalysis. Numerically approximate solutions to a set of equations, which govern the flow, temperature, and concentrations of the chemical species with prescribed boundary constraints, are obtained by utilizing the implicit finite‐difference scheme aided by the quasi‐linearization technique. The impacts of several relevant parameters on various profiles and gradients are discussed with the aid of graphs and tables. From the results, the skin friction coefficient and rate of heat transport are pronounced to be more for hybrid nanofluid than nanofluid. The strength of homogeneous reaction on species concentration is found to be fewer than the heterogeneous reaction. The streamwise coordinate (nonsimilar variable) is more favorable to the concentration of autocatalyst than to the reactant concentration.
Phosphoglyceride‐coated polylactic acid porous microspheres and its regulation of curcumin release behavior
Authors: Shen Wen , Ning Yuanlan , Ge Xuemei , Fan Guodong , Ao Fen , Wu Shang , Mao Yueyang
Published: January 2022

Polymer microspheres are widely used as carriers in delivering of hydrophobic or hydrophilic drugs. Surface coating of microspheres could be one of the attractive strategies to improve their properties. In this study, biodegradable polymer polylactic acid was dissolved in chloroform and non‐solvent to electrospray porous polymer microspheres. The properties of the microspheres were improved by phosphoglyceride (P‐P‐Gly) coating, and its behavior was investigated by loading with curcumin as a model drug. The morphologies of different microspheres were observed by scanning electron microscope. The results indicated that the microspheres obtained by dimethyl sulfoxide as non‐solvent could form the structure with porous characteristics. X‐ray diffraction, X‐ray photoelectron spectroscopy, and Fourier transform infrared spectroscopy analysis revealed that P‐P‐Gly was successfully coated on the surface of the microspheres. In addition, the thermal behavior of the coated microspheres was investigated by differential scanning calorimetry. In vitro release experiments indicated that the drug‐loaded microspheres showed a very gentle release trend, which was mainly due to the P‐P‐Gly coating could not completely cover the pores of the microspheres. The P‐P‐Gly‐coated microspheres prepared in this work can be used as controlled release drug carriers with special needs.
Injection molding and shear‐induced stress simulation of poly (styrene‐ethylene‐butylene‐styrene) and polypropylene blends
Authors: Chen Yaowei , Yang Jian , He Wenjun , Liu Lilan , Niu Xinsheng , Li Chao , Xiong Mengyuan , Li Xiaoyan
Published: January 2022

In this article, the structure and rheological properties of poly (styrene‐ethylene‐butylene‐styrene) (SEBS) triblock copolymer blends are analyzed. The influence of polypropylene content on the three SEBS blends was discussed, the viscoelastic response and phase structure evolution during injection molding were studied. According to the capillary flow test data, the least square method is used to fit the viscosity parameters of the cross‐WLF model. The filling length of the spline was tested by adjusting the injection molding process parameters, and its accuracy was verified by comparing the filling simulation with the experimental results. Numerical simulation is used to predict the shear rate distribution of injection‐molded samples, and the shear sensitivity and residual stress of SEBS blends with different phase structures are analyzed. Based on the phase structure analysis and rheological properties, this article predicts the filling properties of triblock copolymer composites, which can be used to construct the flow‐induced structure–property relationship of complex polymer blends.
Suitably Band‐aligned MOF‐Derived Ni2P/MnO2 Heterostructure with Ni(I) Coordination Surface Sites for Self‐Coupling of Aryl Halides to Biaryls
Authors: Bhat Sajad , Wahid Malik , Banday Javid
Published: January 2022

An efficient photo‐redox strategy for the aryl‐aryl self‐coupling of aryl halides through a heterogeneous catalysis route has been demonstrated. A coordinatively unsaturated Ni2P surface with the enhanced photochemical property upon hetero‐structuring with δ‐MnO2 affects the organic transformation to biaryls with impressive yield and photo‐conversion efficiency. The dual‐role of the Ni2P catalyst with its participation as the catalytic active surface and the photo‐redox center distinguishes the organic transformation achieved herein with other catalytic and photocatalytic aryl‐aryl self‐coupling.
Using an intervention package with percentile schedules to increase on‐task behavior
Authors: Kwak Daniel , Najdowski Adel C. , Danielyan Svetlana
Published: January 2022

Improving on‐task behavior can allow individuals to access more learning opportunities and is especially relevant for individuals with developmental disabilities. The current study examined the efficacy of an intervention package that used percentile schedule of reinforcement, feedback, and application of lower limits to changes in criteria to increase on‐task behaviors in children with developmental disabilities. Using a nonconcurrent multiple baseline across participants design, data revealed a functional relationship between the implementation of the intervention and an increase in the percentage of intervals that participants were on task. Overall, the participants' on‐task behavior improved from a mean of 32% during baseline to 68% during intervention, with a proportionate percentage change of 118%. Although there is no widely accepted method for shaping, using percentile schedules as part of an intervention package appears to be a promising way to shape behavior.
Rapid determination of acyclovir, its main metabolite 9‐carboxymethoxymethylguanine, ganciclovir, and penciclovir in human serum using LC–MS/MS
Authors: Ärlemalm Andreas , Helldén Anders , Karlsson Louise , Carlsson Björn
Published: January 2022

A novel MS‐based analytical method for simultaneous analysis of the antiviral drugs acyclovir, its metabolite 9‐carboxymethoxymethylguanine, ganciclovir, and penciclovir in human serum is described. These antiviral drugs are active against herpes virus infections. Acyclovir and penciclovir are regarded as safe and effective medicines with mild side effects such as headache and gastrointestinal discomfort, and ganciclovir is regarded as more toxic and is known to cause, for example, bone marrow suppression. Acyclovir’s main metabolite 9‐carboxymethoxymethylguanine is a presumptive neurotoxin and should be monitored in patients with impaired renal function or in cases with neurotoxic symptoms. A sample was prepared using protein precipitation with 1% formic acid in methanol containing isotopically labeled internal standard. Chromatographic separation on a biphenyl column and mass spectrometric detection were performed in multiple reaction monitoring (MRM) mode on a Xevo TQ‐S micro with ESI in positive ion mode, within 3 min. Inter‐day assay accuracies for the quality controls varied between 95 and 104% and intra‐day assay between 93 and 105%. Inter‐day and intra‐day assay imprecision for the quality controls ranged between 1.4 and 4.2% and 1.7 and 6.5% respectively. The lower limit of quantification for all four substances was 0.156 μmol/L. It is an accurate and reproducible method for therapeutic drug monitoring.
Anti‐PD‐L1/TGF‐βR fusion protein (SHR‐1701) overcomes disrupted lymphocyte recovery‐induced resistance to PD‐1/PD‐L1 inhibitors in lung cancer
Authors: Cheng Bo , Ding Kaikai , Chen Pengxiang , Ji Jianxiong , Luo Tao , Guo Xiaofan , Qiu Wei , Ma Chunhong , Meng Xue , Wang Jian , Yu Jinming , Liu Yuan
Published: January 2022

Background

Second‐generation programmed cell death‐protein 1/programmed death‐ligand 1 (PD‐1/PD‐L1) inhibitors, such as bintrafusp alfa (M7824), SHR‐1701, and YM101, have been developed to simultaneously block PD‐1/PD‐L1 and transforming growth factor‐beta/transforming growth factor‐beta receptor (TGF‐β/TGF‐βR). Consequently, it is necessary to identify predictive factors of lung cancer patients who are not only resistant to PD‐1/PD‐L1 inhibitors but also sensitive to bifunctional drugs. The purpose of this study was to search for such predictors.

Methods

Multivariable Cox regression was used to study the association between the clinical outcome of treatment with PD‐1/PD‐L1 inhibitors and lymphocyte recovery after lymphopenia in lung cancer patients. Murine CMT167 lung cancer cells were engineered to express the firefly luciferase gene and implanted orthotopically in the lung of syngeneic mice. Bioluminescence imaging, flow cytometry, and immunohistochemistry were employed to determine response to immunotherapy and function of tumor‐infiltrating immune cells.

Results

For lung cancer patients treated with anti‐PD‐1/PD‐L1 antibodies, poor lymphocyte recovery was associated with a shorter progression‐free survival (PFS; P < 0.001), an accumulation of regulatory T cells (Tregs), and an elimination of CD8+ T cells in the peripheral blood. Levels of CD8+ T cells and Treg cells were also imbalanced in the tumors and peripheral immune organs of mice with poor lymphocyte recovery after chemotherapy. Moreover, these mice failed to respond to anti‐PD‐1 antibodies but remained sensitive to the anti‐PD‐L1/TGF‐βR fusion protein (SHR‐1701). Consistently, SHR‐1701 but not anti‐PD‐1 antibodies, markedly enhanced IFN‐γ production and Ki‐67 expression in peripheral CD8+ T cells from patients with impaired lymphocyte recovery.

Conclusions

Lung cancer patients with poor lymphocyte recovery and suffering from persistent lymphopenia after previous chemotherapy are resistant to anti‐PD‐1/PD‐L1 antibodies but might be sensitive to second‐generation agents such as SHR‐1701.
The role of mesenchymal stem cells in the occurrence, development, and therapy of hepatocellular carcinoma
Authors: Zhang Xiaoli , Li Na , Zhu Ying , Wen Wei
Published: January 2022

Hepatocellular carcinoma (HCC) is the most common type of liver malignant tumor, with high recurrence and mortality rates. Mesenchymal stem cells (MSCs) are multipotent cells that can be recruited into the tumor microenvironment (TME). What is known, TME plays a vital part in tumor progression. In recent years, accumulating studies have found that MSCs have a dual role of promotion and inhibition in the occurrence and development of HCC. In this review, we analyzed the role of MSCs in TME and summarized the relationship between MSCs and liver cancer stem cells, the molecular signaling pathway mechanisms of MSCs promoting and inhibiting HCC, and the latest research progress of MSCs in the treatment of HCC.
An Allosteric Inhibitory Potential of Triterpenes from Combretum racemosum on the Structural and Functional Dynamics of Plasmodium falciparum Lactate Dehydrogenase Binding Landscape
Authors: Oluyemi Wande M. , Samuel Babatunde B. , Adewumi Adeniyi T. , Adekunle Yemi A. , Soliman Mahmoud E. S. , Krenn Liselotte
Published: January 2022

Multidrug resistance is a significant drawback in malaria treatment, and mutations in the active sites of the many critical antimalarial drug targets have remained challenging. Therefore, this has necessitated the global search for new drugs with new mechanisms of action. Plasmodium falciparum lactate dehydrogenase (pfLHD), a glycolytic enzyme, has emerged as a potential target for developing new drugs due to the parasite reliance on glycolysis for energy. Strong substrate‐binding is required in pfLDH enzymatic catalysis; however, there is a lack of information on small molecules’ inhibitory mechanism bound to the substrate‐binding pocket. Therefore, this study investigated a potential allosteric inhibition of pfLDH by targeting the substrate‐binding site. The structural and functional behaviour of madecassic acid (MA), the most promising among the six triterpenes bound to pfLDH, were unravelled using molecular dynamic simulations at 300 ns to gain insights into its mechanism of binding and inhibition and chloroquine as a standard drug. The docking studies identified that the substrate site has the preferred position for the compounds even in the absence of a co‐factor. The bound ligands showed comparably higher binding affinity at the substrate site than at the co‐factor site. Mechanistically, a characteristic loop implicated in the enzyme catalytic activity was identified at the substrate site. This loop accommodates key interacting residues (LYS174, MET175, LEU177 and LYS179) pivotal in the MA binding and inhibitory action. The MA‐bound pfLHD average RMSD (1.60 Å) relative to chloroquine‐bound pfLHD RMSD (2.00 Å) showed higher stability for the substrate pocket, explaining the higher binding affinity (−33.40 kcal/mol) observed in the energy calculations, indicating that MA exhibited profound inhibitory activity. The significant pfLDH loop conformational changes and the allostery substrate‐binding landscape suggested inhibiting the enzyme function, which provides an avenue for designing antimalarial compounds in the future studies of pfLDH protein as a target.
Combined effect of polyacrylic acid and vitamin E in preventing calcium oxalate crystal deposition in the kidneys of experimental hyperoxaluric rats
Authors: Sridharan Badrinathan , Jagannathan Venkataseshan , Rajesh Nachiappa Ganesh , Viswanathan Pragasam
Published: January 2022

Our study explores the combined effect of polyacrylic acid and vitamin E as prophylactic and curative agent against ethylene glycol (EG) induced calcium oxalate stone formation in Wistar rats. Male Wistar rats (54) were divided into nine groups, including control. The experimental groups were equally segregated into two for preventive study (4) and curative study (4). Urolithiasis was induced with 0.75% (v/v) EG in drinking water. Polyacrylic acid (10 mg/kg) and vitamin E (300 IU/day) were supplemented from day 1 for preventive and day 30 for curative studies. Restoration of urinary lithogenic factors (calcium, oxalate, phosphate, citrate and magnesium) and renal function (urea and creatinine in serum) by intervening agents were accomplished compared to urolithic rats (P < .001). Abnormal localization and increased expression of Tamm–Horsfall Protein, osteopontin and transferrin were observed in the kidneys of urolithic rats (P < .001) from immunohistochemistry and immunoblotting analysis. Polyacrylic acid and vitamin E supplementation have regulated the expression of the urinary macromolecules. Pro‐inflammatory cytokines in kidney were significantly reduced (P < .001) by the intervening agents compared to urolithic rats. Therefore, polyacrylic acid and vitamin E in combination could be a potential formulation for better management of urolithiasis.
Hollow Covalent Organic Framework Cages with Zn Ion‐Implantation Promoting Photocatalytic H2 Evolution
Authors: Liu Guoyu , Pan Guodong , Dang Qiang , Li Rui , Li Liuyi , Yang Chengkai , Yu Yan
Published: January 2022

Abstract: Covalent organic frameworks (COFs) are emerging as a class of photocatalyst for solar energy utilization. The separation of photogenerated excitons in COFs is crucial for their photocatalytic performance. Herein, we report a strategy to tune the electronic structure of COFs by implanting Zn ions within the framework to facilitate the separation and utilization of the photoinduced charges. Zn ions are incorporated within the shell of hollow COF cages (Zn@H‐TpPa) by a sacrificial template method with a formation of hollow cages. The implantation of Zn ions within the framework results in a redistribution of electron density and an increment of the polarity of the COF, as evidenced by experimental and computational analyses, and thus contributes to the separation and transport of charge carries. The Zn@H‐TpPa shows enhanced photocatalytic H2 production efficiency as compared to TpPa. The results demonstrate a new way to optimize the electronic structure of COFs for photocatalysis.
Structural Insights into Pixatimod (PG545) Inhibition of Heparanase, a Key Enzyme in Cancer and Viral Infections
Authors: Chhabra Mohit , Wilson Jennifer C. , Wu Liang , Davies Gideon J. , Gandhi Neha S. , Ferro Vito
Published: January 2022

Pixatimod (PG545), a heparan sulfate (HS) mimetic and anticancer agent currently in clinical trials, is a potent inhibitor of heparanase. Heparanase is an endo‐β‐glucuronidase that degrades HS in the extracellular matrix and basement membranes and is implicated in numerous pathological processes such as cancer and viral infections, including SARS−CoV‐2. To understand how PG545 interacts with heparanase, we firstly carried out a conformational analysis through a combination of NMR experiments and molecular modelling which showed that the reducing end β‐D‐glucose residue of PG545 adopts a distorted conformation. This was followed by docking and molecular dynamics simulations to study the interactions of PG545 with heparanase, revealing that PG545 is able to block the active site by binding in different conformations, with the cholestanol side‐chain making important hydrophobic interactions. While PG545 blocks its natural substrate HS from binding to the active site, small synthetic heparanase substrates are only partially excluded, and thus pentasaccharide or larger substrates are preferred for assaying this class of inhibitor. This study provides new insights for the design of next‐generation heparanase inhibitors and substrates.
The Effect of Fluorinated Solvents on the Physicochemical Properties, Ionic Association, and Free Volume of a Prototypical Solvate Ionic Liquid
Authors: Burba Christopher M. , Feightner Kylie , Liu Ming , Hawari Ayman
Published: January 2022

Solvate ionic liquid (SIL) synthesis and properties depend on a delicate balancing of cation‐solvent and cation‐anion interactions to produce materials containing only cation‐solvent complexes and solvent‐separated anions. Most SILs meeting these characteristics fall within the paradigm of oligomeric ethylene oxides (e.g. glymes and glycols) and lithium salts. Targeted functionalization of solvent molecules to achieve desired properties is a relatively unexplored avenue of research. Fluorinated solvents have significantly different electric charge distributions compared to their nonfluorinated analogs. We test the impact of solvent fluorination for a SIL created from equimolar mixtures of lithium bis(trifluoromethylsulfonyl)imide (LiNTf2) and triethylene glycol (TEG), hereafter [(TEG)1Li]NTf2. In the first experiment, TEG is partially substituted with 2,2,4,4,5,5,7,7‐octafluoro‐3,6‐dioxaoctane‐1,8‐diol (FTEG). This leads to a precipitous decrease in ionic conductivity and larger quantities of ionically‐associated Li(NTf2)2− species, as detected with vibrational spectroscopy. These observations suggest FTEG does not readily coordinate Li+ ions in a manner analogous to TEG. Computational studies reinforce this conclusion. Relative complex cation stabilities are ranked as [(FTEG)1Li]+>[(TEG)1Li]+. A second experiment adds FTEG as a diluent to [(TEG)1Li]NTf2. This places FTEG and TEG in competition to coordinate a limited number of Li+ ions. The resulting mixtures exhibit conductivity enhancement over the parent SIL and minimal changes in ion speciation due to the poor Li+ binding by FTEG compared to TEG. Positron annihilation lifetime spectroscopic studies point to increased amounts of free volume upon dilution of FTEG. This likely explains the origin of the conductivity and viscosity enhancements.
Mechanistic Insights into the Selectivity of Norcarane Oxidation by Oxo‐Manganese(V) Porphyrin Complexes
Authors: Ma Zhifeng , Nakatani Naoki , Hada Masahiko
Published: January 2022

Oxo‐Mn(V) porphyrin complexes perform competitive hydroxylation, desaturation, and radical rearrangement reactions using diagnostic substrate norcarane. Initial C−H cleavage proceeds through the two hydrogen abstraction steps from the two adjacent carbon on the norcarane and then through selective reactions various products are generated. Using density functional theory calculations, we show that the hydroxylation and desaturation reactions are triggered by a rate‐determining H‐abstraction step, whereas the rate‐determining step for the radical rearrangement is located at the rebound step (TS2). We find that the endo‐2 reaction is favorable over other reactions, which is consistent with the experimental result. Furthermore, the competitive pathways for norcarane oxidation depend on the non‐covalent interaction between norcarane and the porphyrin‐ring, and orbital energy gaps between donor and acceptor orbitals because of stable or unstable acceptor orbital. The stereo‐ and regio‐selectivities of norcarane oxidation are hardly sensitive to the zero‐point energy and thermal free energy corrections.
First experience of magnetically levitated extracorporeal left ventricular assist device for cardiogenic shock in China
Authors: Li Ping , Wu Long , Dong Nianguo
Published: January 2022

We report the first case of an investigational maglev extracorporeal ventricular assist device (extra‐VAD) use in China for a patient with cardiogenic shock post‐coronary artery bypass surgery. There were no extra‐VAD devices available for clinical use in China. The patient was successfully supported for 9 days and recovered to hospital discharge. Throughout the support, the patient's haemodynamic and haematologic parameters demonstrated good patient recovery and no device‐related complications were observed. Our results encourage extra‐VAD use in short‐term to mid‐term bridging the cardiogenic shock patients in China and potentially other developing countries for both clinical and health economic benefits.
Repurposing face mask waste to construct floating photothermal evaporator for autonomous solar ocean farming
Authors: Guo Shuai , Zhang Yaoxin , Qu Hao , Li Meng , Zhang Songlin , Yang Jiachen , Zhang Xueping , Tan Swee Ching
Published: January 2022

Plastic waste caused by the extensive usage of face masks during COVID‐19 pandemic has become a severe threat to natural environment and ecosystem. Herein, an eco‐friendly approach to repurpose face mask waste for clean water production via solar thermal evaporation is proposed. By taking advantage of its interwind structure, face mask holds the promise to be an ideal candidate material for constructing photothermal evaporator. In‐situ surface modifications are performed successively with polyvinyl alcohol and polypyrrole to improve its wettability and solar absorption (97%). The obtained face mask‐based evaporator achieves significantly enhanced solar efficiency (91.5%) and long‐term salt‐rejection stability. The harvested clean water befits plant growing to enable farming on sea surface. A floating photothermal evaporation prototype is then developed to demonstrate autonomous solar ocean farming, with plants successfully cultivated over time. As such, the proposed strategy provides a promising solution towards ecological sustainability by tapping multiple benefits.

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Optimal stochastic energy management of electrical railway systems considering renewable energy resources' uncertainties and interactions with utility grid
Authors: Ehteshami Hossein , Hashemi‐Dezaki Hamed , Javadi Saeid
Published: January 2022

Several studies have been reported for optimal operation of electrical railway systems (ERSs). However, the stochastic energy management of ERSs, including renewable energy resources (RERs), has received less attention. The RERs’ uncertainties might affect the ERSs. On the other hand, the calculation time of the Monte Carlo simulation (MCS)‐based approaches is an essential challenge, which should be solved, particularly in real‐time decisions and recursive optimization problems. Thus, it is crucial to study the ERSs' stochastic behaviors and uncertainties, including RERs. This paper tries to overcome the discussed concerns and challenges by proposing a novel ERS’s optimal stochastic energy management using clustering algorithms. In this paper, the backward scenario reduction algorithm has been used. In addition, regenerative braking energy (RBE) and energy management systems (ESSs) have been studied. Studying the impacts of changes in the number of passengers on the optimized operation of ERSs and investigating the interaction between the utility grid and the ERS are other contributions of this research. The proposed method is applied to an actual test system of Tehran Urban and Suburban Railway Operation Company (TUSROC). Test results are validated by comparing with available MCS‐based methods. Simulation results illustrate the accuracy and computation time advantages of the proposed method. Simulation results illustrate that <0.6% inaccuracy appears in the proposed method, while it would be 500 times faster than MCS‐based ones. The comparative test results show the advantages of the introduced method.
The effect and mechanism of four drying methods on the quality of tilapia fillet products
Authors: Cao Jun , Feng Aiguo , He Yanfu , Wang Jiamei , Liu Zhongyuan , Xia Guanghua , Lin Xiangdong , Shen Xuanri , Zhou Dayong , Li Chuan
Published: January 2022

Tilapia (Oreochromis niloticus) holds a major position in the fishery market worldwide. This study aimed to investigate the effect of four drying methods, namely vacuum freeze (VFD), vacuum microwave (VMD), hot air (HAD) and microwave (MD), on texture, amino acids, microstructure, lipid oxidation and protein degradation of tilapia fillets. The results showed that vacuum combined with refrigeration (VFD) or VMD had better color, chromatic aberration, shrinkage ratio and microstructure. The total essential amino acid content (31.16%), α‐helical (28.06%) structure and protein denaturation temperature of nonthermal VFD were higher than the VMD, HAD and MD methods. In thermal drying processing, VMD had some advantages in protein stability, microstructure, lipid oxidation and flavor compared with HAD and MD products. Therefore, a combined drying method was discovered to have prospects for use in tilapia processing. VFD was considered the appropriate nonthermal drying method of fillets with high product quality and protein stability. Meanwhile, considering the advantages of its efficiency, quality and energy consumption, the VMD had the best potential of the four methods employed to dry tilapia fillets.
High‐resolution terrestrial record of orbital climate forcing in the coal‐bearing Middle Jurassic Yan'an Formation, Ordos Basin, North China
Authors: Chen Zheng'an , Li Fengjie , Zhang Pengfei
Published: January 2022

The coal‐bearing Yan'an Formation in the Ordos Basin of the Middle Jurassic was deposited in a river delta–lacustrine sedimentary environment with relatively stable accumulation rates. Spectral analysis and wavelet transform analysis of the natural gamma‐ray (GR) curves from several boreholes through the Yan'an Formation yielded five main sedimentary cycles with wavelengths of 34–57, 10–18, 8–14, 2.9–4.1, and 2–3 m. These cycles were controlled by orbital cycles of eccentricity (405, 128, and 97 kyr), obliquity (35 kyr), and precession (22 kyr), and the long‐eccentricity period of 405 kyr was the most significant cycle. Filtering the sedimentary records for the long‐wavelength cycle and short‐wavelength cycle implies that there are 11 long‐eccentricity cycles and 35 short‐eccentricity cycles preserved in the Yan'an Formation. Assigning the 405 kyr long‐eccentricity cycle to the filtered 11 primary long‐wavelength cycles implies that the Yan'an Formation spanned 4.4 Myr. The orbital–climate cycles were critical factors in the sediment facies changes and episodes of coal formation within the basin. The long‐eccentricity cycles of the Milankovitch cycle are the predominant control factors of the coal seams deposited in the Middle Jurassic Yan'an Formation.
The effects of a hypertension diagnosis on health behaviors: A two‐dimensional regression discontinuity analysis
Authors: Dai Tiantian , Jiang Shenyi , Liu Xiangbo , Sun Ang
Published: January 2022

This paper explores how a diagnosis of hypertension might affect a person's health‐related behaviors. The analysis uses a two‐dimensional regression discontinuity design because hypertension is diagnosed when a person's systolic or diastolic blood pressure (SBP or DBP) surpasses a pre‐established threshold. We find that those closely above the SBP threshold significantly adjusted their lifestyle, such as reducing daily fat intake and quitting smoking, while those just surpassing the DBP cutoff did not. Further mechanism analysis suggests that the possibility of constraints, rather than education and income gradients, does more to explain the disparate behaviors of subjects near the SBP and DBP thresholds. Those around the DBP threshold generally have tighter work schedules and undertake more competitive jobs, which hinder them from improving their lifestyle. Overall, our findings complement the existing literature by posing a new perspective for understanding people's potential reluctance to adjust their behavior.
A three‐wave study on the development of prosocial behaviours across toddlerhood: The role of socialization
Authors: Song Yue , Broekhuizen Martine , Dubas Judith Semon
Published: January 2022

This 3‐wave longitudinal study investigated the developmental trajectories of instrumental helping, sharing and empathic helping across toddlerhood, and how socialisation processes (i.e., parents' and teachers' practices) contribute to these developments. Participants were 50 18‐months‐olds and 62 24‐months‐olds, their parents, and daycare teachers, who were followed 6 months and 12 months later. At each wave, toddlers' prosocial behaviours were observed through three laboratory tasks, and socialisation processes were examined through parents' and teachers' self‐report at the first and second waves. Instrumental helping increased from 18 to 36 months. Sharing increased from 18 to 30 months. Empathic helping increased from 24 to 36 months. Both parental and teachers' practices predicted prosocial behaviours at the ages when they are still emerging, but the relationship varied by types of behaviour examined. These findings confirm the developmental trajectories proposed in cross‐sectional studies and add evidence to the role of socialisation processes in the early development of prosocial behaviour.
Glycosylation of FGFR4 in cholangiocarcinoma regulates receptor processing and cancer signaling
Authors: Phillips Andrew J. , Lobl Marissa B. , Hafeji Yamnah A. , Safranek Hannah R. , Mohr Ashley M. , Mott Justin L.
Published: January 2022

Recent advances in targeted treatment for cholangiocarcinoma have focused on fibroblast growth factor (FGF) signaling. There are four receptor tyrosine kinases that respond to FGFs, and posttranslational processing has been demonstrated for each FGF receptor. Here, we investigated the role of N‐linked glycosylation on the processing and function of FGFR4. We altered glycosylation through enzymatic deglycosylation, small molecule inhibition of glycosyltransferases, or through site‐directed mutagenesis of selected asparagine residues in FGFR4. Signaling was tested through caspase activation, migration, and subcellular localization of FGFR4. Our data demonstrate that FGFR4 has multiple glycoforms, with predominant bands relating to the full‐length receptor that has a high mannose‐ or hybrid‐type form and a complex‐type glycan form. We further identified a set of faster migrating FGFR4 bands that correspond to the intracellular kinase domain, termed FGFR4 intracellular domain (R4‐ICD). These glycoforms and R4‐ICD were detected in human cholangiocarcinoma tumor samples, where R4‐ICD was predominant. Removal of glycans in intact cells by enzymatic deglycosylation resulted in increased processing to R4‐ICD. Inhibition of glycosylation using NGI‐1, an oligosaccharyltransferase inhibitor, reduced both high mannose‐ or hybrid‐ and complex‐type glycan forms of FGFR4, increased processing and sensitized to apoptosis. Mutation of Asn‐112, Asn‐258, Asn‐290, or Asn‐311 to glutamine modestly reduced apoptosis resistance, while mutation of Asn‐322 or simultaneous mutation of the other four asparagine residues caused a loss of cytoprotection by FGFR4. None of the glycomutants altered the migration of cancer cells. Finally, mutation of Asn‐112 caused a partial localization of FGFR4 to the Golgi. Overall, preventing glycosylation at individual residues reduced the cell survival function of FGFR4 and receptor glycosylation may regulate access to an extracellular protease or proteolytic susceptibility of FGFR4.
Interaction with mammalian enteric viruses alters outer membrane vesicle production and content by commensal bacteria
Authors: Mosby Chanel A. , Bhar Sutonuka , Phillips Matthew B. , Edelmann Mariola J. , Jones Melissa K.
Published: January 2022

Intestinal commensal bacteria contribute to maintaining gut homeostasis. Disruptions to the commensal flora are linked to the development and persistence of disease. The importance of these organisms is further demonstrated by the widespread ability of enteric viruses to exploit commensal bacteria to enhance viral infection. These viruses interact directly with commensal bacteria, and while the impact of this interaction on viral infection is well described for several viruses, the impact on the commensal bacteria has yet to be explored. In this article, we demonstrate, for the first time, that enteric viruses alter the gene expression and phenotype of individual commensal bacteria. Human and murine norovirus interaction with bacteria resulted in genome‐wide differential gene expression and marked changes in the surface architecture of the bacterial cells. Furthermore, the interaction of the virus with bacteria led to increased production of smaller outer membrane vesicles (OMVs). Enhanced production of smaller vesicles was also observed when noroviruses were incubated with other commensal bacteria, indicating a potentially broad impact of norovirus interaction. The vesicle production observed in the in vivo model followed a similar trend where an increased quantity of smaller bacterial vesicles was observed in stool collected from virus‐infected mice compared to mock‐infected mice. Furthermore, changes in vesicle size were linked to changes in protein content and abundance, indicating that viral binding induced a shift in the mechanism of the OMV biogenesis. Collectively, these data demonstrate that enteric viruses induce specific changes in bacterial gene expression, leading to changes in bacterial extracellular vesicle production that can potentially impact host responses to infection.