bluuebunny/crossref_metadata_2025 huggingface dataset:
Teriflunomide shifts the astrocytic bioenergetic profile from oxidative metabolism to glycolysis and attenuates TNFα-induced inflammatory responses
Authors: Kabiraj Parijat , Grund Ethan M. , Clarkson Benjamin D. S. , Johnson Renee K. , LaFrance-Corey Reghann G. , Lucchinetti Claudia F. , Howe Charles L.
Published: February 2022

Astrocytes utilize both glycolytic and mitochondrial pathways to power cellular processes that are vital to maintaining normal CNS functions. These cells also mount inflammatory and acute phase reactive programs in response to diverse stimuli. While the metabolic functions of astrocytes under homeostatic conditions are well-studied, the role of cellular bioenergetics in astrocyte reactivity is poorly understood. Teriflunomide exerts immunomodulatory effects in diseases such as multiple sclerosis by metabolically reprogramming lymphocytes and myeloid cells. We hypothesized that teriflunomide would constrain astrocytic inflammatory responses. Purified murine astrocytes were grown under serum-free conditions to prevent acquisition of a spontaneous reactive state. Stimulation with TNFα activated NFκB and increased secretion of Lcn2. TNFα stimulation increased basal respiration, maximal respiration, and ATP production in astrocytes, as assessed by oxygen consumption rate. TNFα also increased glycolytic reserve and glycolytic capacity of astrocytes but did not change the basal glycolytic rate, as assessed by measuring the extracellular acidification rate. TNFα specifically increased mitochondrial ATP production and secretion of Lcn2 required ATP generated by oxidative phosphorylation. Inhibition of dihydroorotate dehydrogenase via teriflunomide transiently increased both oxidative phosphorylation and glycolysis in quiescent astrocytes, but only the increased glycolytic ATP production was sustained over time, resulting in a bias away from mitochondrial ATP production even at doses down to 1 μM. Preconditioning with teriflunomide prevented the TNFα-induced skew toward oxidative phosphorylation, reduced mitochondrial ATP production, and reduced astrocytic inflammatory responses, suggesting that this drug may limit neuroinflammation by acting as a metabolomodulator.
Internalization and trafficking of CSPG-bound recombinant VAR2CSA lectins in cancer cells
Authors: Wang Chris Kedong , Nelepcu Irina , Hui Desmond , Oo Htoo Zarni , Truong Sarah , Zhao Sarah , Tahiry Zakir , Esfandnia Shaghayegh , Ghaidi Fariba , Adomat Hans , Dagil Robert , Gustavsson Tobias , Choudhary Swati , Salanti Ali , Sorensen Poul H. , Al Nakouzi Nader , Daugaard Mads
Published: February 2022

Proteoglycans are proteins that are modified with glycosaminoglycan chains. Chondroitin sulfate proteoglycans (CSPGs) are currently being exploited as targets for drug-delivery in various cancer indications, however basic knowledge on how CSPGs are internalized in tumor cells is lacking. In this study we took advantage of a recombinant CSPG-binding lectin VAR2CSA (rVAR2) to track internalization and cell fate of CSPGs in tumor cells. We found that rVAR2 is internalized into cancer cells via multiple internalization mechanisms after initial docking on cell surface CSPGs. Regardless of the internalization pathway used, CSPG-bound rVAR2 was trafficked to the early endosomes in an energy-dependent manner but not further transported to the lysosomal compartment. Instead, internalized CSPG-bound rVAR2 proteins were secreted with exosomes to the extracellular environment in a strictly chondroitin sulfate-dependent manner. In summary, our work describes the cell fate of rVAR2 proteins in tumor cells after initial binding to CSPGs, which can be further used to inform development of rVAR2-drug conjugates and other therapeutics targeting CSPGs.
Prediction of lymph node metastasis in early colorectal cancer based on histologic images by artificial intelligence
Authors: Takamatsu Manabu , Yamamoto Noriko , Kawachi Hiroshi , Nakano Kaoru , Saito Shoichi , Fukunaga Yosuke , Takeuchi Kengo
Published: February 2022

Risk evaluation of lymph node metastasis (LNM) for endoscopically resected submucosal invasive (T1) colorectal cancers (CRC) is critical for determining therapeutic strategies, but interobserver variability for histologic evaluation remains a major problem. To address this issue, we developed a machine-learning model for predicting LNM of T1 CRC without histologic assessment. A total of 783 consecutive T1 CRC cases were randomly split into 548 training and 235 validation cases. First, we trained convolutional neural networks (CNN) to extract cancer tile images from whole-slide images, then re-labeled these cancer tiles with LNM status for re-training. Statistical parameters of the tile images based on the probability of primary endpoints were assembled to predict LNM in cases with a random forest algorithm, and defined its predictive value as random forest score. We evaluated the performance of case-based prediction models for both training and validation datasets with area under the receiver operating characteristic curves (AUC). The accuracy for classifying cancer tiles was 0.980. Among cancer tiles, the accuracy for classifying tiles that were LNM-positive or LNM-negative was 0.740. The AUCs of the prediction models in the training and validation sets were 0.971 and 0.760, respectively. CNN judged the LNM probability by considering histologic tumor grade.
Simulating COVID19 transmission from observed movement
Authors: Zhang Yi , Tao Yudong , Shyu Mei-Ling , Perry Lynn K. , Warde Prem R. , Messinger Daniel S. , Song Chaoming
Published: February 2022

Current models of COVID-19 transmission predict infection from reported or assumed interactions. Here we leverage high-resolution observations of interaction to simulate infectious processes. Ultra-Wide Radio Frequency Identification (RFID) systems were employed to track the real-time physical movements and directional orientation of children and their teachers in 4 preschool classes over a total of 34 observations. An agent-based transmission model combined observed interaction patterns (individual distance and orientation) with CDC-published risk guidelines to estimate the transmission impact of an infected patient zero attending class on the proportion of overall infections, the average transmission rate, and the time lag to the appearance of symptomatic individuals. These metrics highlighted the prophylactic role of decreased classroom density and teacher vaccinations. Reduction of classroom density to half capacity was associated with an 18.2% drop in overall infection proportion while teacher vaccination receipt was associated with a 25.3% drop. Simulation results of classroom transmission dynamics may inform public policy in the face of COVID-19 and similar infectious threats.
PD-L1 mediates lung fibroblast to myofibroblast transition through Smad3 and β-catenin signaling pathways
Authors: Guo Xia , Sunil Christudas , Adeyanju Oluwaseun , Parker Andrew , Huang Steven , Ikebe Mitsuo , Tucker Torry A. , Idell Steven , Qian Guoqing
Published: February 2022

Programmed death ligand-1 (PD-L1) is an immune checkpoint protein that has been linked with idiopathic pulmonary fibrosis (IPF) and fibroblast to myofibroblast transition (FMT). However, it remains largely unclear how PD-L1 mediates this process. We found significantly increased PD-L1 in the lungs of idiopathic pulmonary fibrosis patients and mice with pulmonary fibrosis induced by bleomycin and TGF-β. In primary human lung fibroblasts (HLFs), TGF-β induced PD-L1 expression that is dependent on both Smad3 and p38 pathways. PD-L1 knockdown using siRNA significantly attenuated TGF-β-induced expression of myofibroblast markers α-SMA, collagen-1, and fibronectin in normal and IPF HLFs. Further, we found that PD-L1 interacts with Smad3, and TGF-β induces their interaction. Interestingly, PD-L1 knockdown reduced α-SMA reporter activity induced by TGF-β in HLFs, suggesting that PD-L1 might act as a co-factor of Smad3 to promote target gene expression. TGF-β treatment also phosphorylates GSK3β and upregulates β-catenin protein levels. Inhibiting β-catenin signaling with the pharmaceutical inhibitor ICG001 significantly attenuated TGF-β-induced FMT. PD-L1 knockdown also attenuated TGF-β-induced GSK3β phosphorylation/inhibition and β-catenin upregulation, implicating GSK3β/β-catenin signaling in PD-L1-mediated FMT. Collectively, our findings demonstrate that fibroblast PD-L1 may promote pulmonary fibrosis through both Smad3 and β-catenin signaling and may represent a novel interventional target for IPF.
Towards optimal thermal distribution in magnetic hyperthermia
Authors: Rytov R. A. , Bautin V. A. , Usov N. A.
Published: February 2022

A linear combination of spherically symmetric heat sources is shown to provide optimal stationary thermal distribution in magnetic hyperthermia. Furthermore, such spatial location of heat sources produces suitable temperature distribution in biological medium even for assemblies of magnetic nanoparticles with a moderate value of specific absorption rate (SAR), of the order of 100–150 W/g. We also demonstrate the advantage of using assemblies of spherical magnetic nanocapsules consisting of metallic iron nanoparticles covered with non magnetic shells of sufficient thickness in magnetic hyperthermia. Based on numerical simulation we optimize the size and geometric structure of biocompatible spherical capsules in order to minimize the influence of strong magneto-dipole interaction between closely spaced nanoparticles. It is shown that assembly of capsules can provide sufficiently high SAR values of the order of 250–400 W/g at moderate amplitudes H0 = 50–100 Oe and frequencies f = 100–200 kHz of alternating magnetic field, being appropriate for application in clinics.
Integrated bioinformatics analysis identifies established and novel TGFβ1-regulated genes modulated by anti-fibrotic drugs
Authors: Wilson Ava C. , Chiles Joe , Ashish Shah , Chanda Diptiman , Kumar Preeti L. , Mobley James A. , Neptune Enid R. , Thannickal Victor J. , McDonald Merry-Lynn N.
Published: February 2022

Fibrosis is a leading cause of morbidity and mortality worldwide. Although fibrosis may involve different organ systems, transforming growth factor-β (TGFβ) has been established as a master regulator of fibrosis across organs. Pirfenidone and Nintedanib are the only currently-approved drugs to treat fibrosis, specifically idiopathic pulmonary fibrosis, but their mechanisms of action remain poorly understood. To identify novel drug targets and uncover potential mechanisms by which these drugs attenuate fibrosis, we performed an integrative ‘omics analysis of transcriptomic and proteomic responses to TGFβ1-stimulated lung fibroblasts. Significant findings were annotated as associated with pirfenidone and nintedanib treatment in silico via Coremine. Integrative ‘omics identified a co-expressed transcriptomic and proteomic module significantly correlated with TGFβ1 treatment that was enriched (FDR-p = 0.04) with genes associated with pirfenidone and nintedanib treatment. While a subset of genes in this module have been implicated in fibrogenesis, several novel TGFβ1 signaling targets were identified. Specifically, four genes (BASP1, HSD17B6, CDH11, and TNS1) have been associated with pirfenidone, while five genes (CLINT1, CADM1, MTDH, SYDE1, and MCTS1) have been associated with nintedanib, and MYDGF has been implicated with treatment using both drugs. Using the Clue Drug Repurposing Hub, succinic acid was highlighted as a metabolite regulated by the protein encoded by HSD17B6. This study provides new insights into the anti-fibrotic actions of pirfenidone and nintedanib and identifies novel targets for future mechanistic studies.
Data-driven design of targeted gene panels for estimating immunotherapy biomarkers
Authors: Bradley Jacob R. , Cannings Timothy I.
Published: February 2022

Tumour mutation burden and other exome-wide biomarkers are used to determine which patients will benefit from immunotherapy. However, the cost of whole exome sequencing limits the widespread use of such biomarkers. Here, we introduce a data-driven framework for the design of targeted gene panels for estimating a broad class of biomarkers including tumour mutation burden and tumour indel burden. Our first goal is to develop a generative model for the profile of mutation across the exome, which allows for gene- and variant type-dependent mutation rates. Based on this model, we then propose a procedure for constructing biomarker estimators. Our approach allows the practitioner to select a targeted gene panel of prespecified size and construct an estimator that only depends on the selected genes. Alternatively, our method may be applied to make predictions based on an existing gene panel, or to augment a gene panel to a given size. We demonstrate the excellent performance of our proposal using data from three non small-cell lung cancer studies, as well as data from six other cancer types.
Combination of antiviral drugs inhibits SARS-CoV-2 polymerase and exonuclease and demonstrates COVID-19 therapeutic potential in viral cell culture
Authors: Wang Xuanting , Sacramento Carolina Q. , Jockusch Steffen , Chaves Otávio Augusto , Tao Chuanjuan , Fintelman-Rodrigues Natalia , Chien Minchen , Temerozo Jairo R. , Li Xiaoxu , Kumar Shiv , Xie Wei , Patel Dinshaw J. , Meyer Cindy , Garzia Aitor , Tuschl Thomas , Bozza Patrícia T. , Russo James J. , Souza Thiago Moreno L. , Ju Jingyue
Published: February 2022

SARS-CoV-2 has an exonuclease-based proofreader, which removes nucleotide inhibitors such as Remdesivir that are incorporated into the viral RNA during replication, reducing the efficacy of these drugs for treating COVID-19. Combinations of inhibitors of both the viral RNA-dependent RNA polymerase and the exonuclease could overcome this deficiency. Here we report the identification of hepatitis C virus NS5A inhibitors Pibrentasvir and Ombitasvir as SARS-CoV-2 exonuclease inhibitors. In the presence of Pibrentasvir, RNAs terminated with the active forms of the prodrugs Sofosbuvir, Remdesivir, Favipiravir, Molnupiravir and AT-527 were largely protected from excision by the exonuclease, while in the absence of Pibrentasvir, there was rapid excision. Due to its unique structure, Tenofovir-terminated RNA was highly resistant to exonuclease excision even in the absence of Pibrentasvir. Viral cell culture studies also demonstrate significant synergy using this combination strategy. This study supports the use of combination drugs that inhibit both the SARS-CoV-2 polymerase and exonuclease for effective COVID-19 treatment.
A novel screening strategy to identify histone methyltransferase inhibitors reveals a crosstalk between DOT1L and CARM1
Authors: Si Yang , Bon Corentin , Barbachowska Magdalena , Cadet-Daniel Veronique , Jallet Corinne , Soresinetti Laura , Boullé Mikaël , Duchateau Magalie , Matondo Mariette , Agou Fabrice , Halby Ludovic , Arimondo Paola B.
Published: February 2022

By a novel screening strategy, we identified Compound 4, a published CARM1 inhibitor, inhibits both histone mark H3R2me2a, regulated also by CARM1, and H3K79me2, regulated only by DOT1L, pointing out a crosstalk between CARM1 and DOT1L.
First principles assessment of the phase stability and transition mechanisms of designated crystal structures of pristine and Janus transition metal dichalcogenides
Authors: Demirkol Öznur , Sevik Cem , Demiroğlu İlker
Published: February 2022

Coexistence of lateral hybrid structures are strongly stable against phase transitions for both pristine and Janus type two-dimensional transition metal dichalcogenides.
Photo-chemical/catalytic oxidative/reductive decomposition of per- and poly-fluoroalkyl substances (PFAS), decomposition mechanisms and effects of key factors: a review
Authors: Banayan Esfahani Ehsan , Asadi Zeidabadi Fatemeh , Zhang Shengyang , Mohseni Madjid
Published: February 2022

Mechanisms of photodegradation of PFAS with different chain lengths and structures using a wide range of photo-oxidative/reductive agents, effects of key parameters on these processes, and synergistic effects of other treatments are reviewed.
The polysaccharide–peptide complex from mushroom Cordyceps militaris ameliorates atherosclerosis by modulating the lncRNA–miRNA–mRNA axis
Authors: Li Yuan , Miao Miao , Yin Fan , Shen Nuo , Yu Wen-Qian , Guo Shou-Dong
Published: February 2022

An N-glycosidic polysaccharide-peptide complex CMPS-80 from the fruiting body of C. militaris modulates ceRNA network in the liver of apoE(−/−) mice.
A binuclear Fe(iii)/quinizarin complex as a structural model for anthracycline drugs binding to iron
Authors: do Nascimento Juliana S. , de Sousa Aurideia P. , Gondim Ana C. S. , Sousa Eduardo H. S. , Teixeira Edson H. , do Nascimento Neto Luiz Gonzaga , Bezerra Beatriz Pinheiro , Ayala Alejandro Pedro , Batista Alzir A. , Vasconcelos Igor F. , Oliveira Francisco G. S. , Holanda Alda K. M.
Published: February 2022

Quinizarin, an anthracyclin-like compound, was used to prepare a binuclear complex, [(Fe(cyclam))2Qz]Cl(PF6)3, which showed damage to DNA with glutathione. This mimic of anthracyclin drugs might explain undesired side effects of these compounds.
Fabrication of g-C3N4/Bi2WO6 as a direct Z-scheme excellent photocatalyst
Authors: Zhao Ping , Jin Bo , Zhang Qingchun , Peng Rufang
Published: February 2022

To improve the photocatalytic efficiency of Bi2WO6, two types of g-C3N4 nanomaterial, g-C3N4 quantum dots and nanosheets, were incorporated with Bi2WO6 to construct two kinds of g-C3N4/Bi2WO6 photocatalysts with excellent photocatalytic activity.
Bimetallic Co–Mo sulfide/carbon composites derived from polyoxometalate encapsulated polydopamine-decorated ZIF nanocubes for efficient hydrogen and oxygen evolution
Authors: Huang Zheng , Yang Zhuxian , Jia Quanli , Wang Nannan , Zhu Yanqiu , Xia Yongde
Published: February 2022

Defect-rich bimetallic Co–Mo sulfide/carbon composites derived from polyoxometalate encapsulated polydopamine-decorated ZIF nanocubes exhibit a remarkable improvement in electrocatalyic performance towards both hydrogen and oxygen evolution.
Diels–Alder adducts of a labdane diterpenoid from the Chinese liverwort Pallavicinia subciliata
Authors: Liu Shu-Gong , Zhang Chun-Yang , Zhou Jin-Chuan , Han Jing-Jing , Zhu Ming-Zhu , Zhang Jiao-Zhen , Li Yi , Xu Ze-Jun , Meng Hui , Wang Xue , Zong Yan , Yuan Shuang-Zhi , Qiao Ya-Nan , Tang Ya-Jie , Lou Hong-Xiang
Published: February 2022

A 7,8-seco-2,8-cyclolabdane diterpenoid, pallasubcin A (1), and three pallasubcin A-derived dimers, pallasubcins B–D (2–4), formed via a Diels–Alder reaction, were isolated from the Chinese liverwort Pallavicinia subciliata.
Comparative investigation of bioflavonoid electrocatalysis in 1D, 2D, and 3D carbon nanomaterials for simultaneous detection of naringin and hesperidin in fruits
Authors: Xia Hong-qi , Gu Tingting , Fan Ruiyi , Zeng Jiwu
Published: February 2022

Electrocatalysis of bioflavonoids at 1D, 2D and 3D carbon nanomaterials was investigated for simultaneous detection of naringin and hesperidin in fruits.
Structure and absolute configuration of liquid molecules based on adamantane derivative cocrystallization
Authors: Ou Guang-Chuan , Chen Hai-Yang , Wang Qiong , Zhou Qiang , Zeng Fei
Published: February 2022

Liquid molecules are difficult to crystallize, and their structures and absolute configurations cannot be directly determined by X-ray crystallography.
Effect of pore diameter and length on electrochemical CO2 reduction reaction at nanoporous gold catalysts
Authors: Goyal Akansha , Bondue Christoph J. , Graf Matthias , Koper Marc T. M.
Published: February 2022

In this work, we employ differential electrochemical mass spectrometry (DEMS) to track the real-time evolution of CO at nanoporous gold (NpAu) catalysts with varying pore parameters (diameter and length) during the electrochemical CO2 reduction reaction (CO2RR).
Design and characterization of fibroblast activation protein targeted pan-cancer imaging agent for fluorescence-guided surgery of solid tumors
Authors: Mukkamala Ramesh , Lindeman Spencer D. , Kragness Kate A. , Shahriar Imrul , Srinivasarao Madduri , Low Philip S.
Published: February 2022

Tumor-targeted fluorescent dyes have been shown to significantly improve a surgeon's ability to locate and resect occult malignant lesions, thereby enhancing a patient's chances of long term survival.
Cross-conjugated isothianaphthene quinoids: a versatile strategy for controlling electronic structures
Authors: Yamamoto Keitaro , Quintero Sergio Moles , Jinnai Seihou , Jeong Eunjeong , Matsuo Kyohei , Suzuki Mitsuharu , Yamada Hiroko , Casado Juan , Ie Yutaka
Published: February 2022

The elucidation of new structure–property relationships in π-conjugated molecules bearing quinoidal moieties is of relevance in organic electronics applications and as models of doped conducting polymers.
Efficient semi-transparent organic solar cells enabled by a quasi-heterojunction active layer structure
Authors: Tang Hao , Li Youzhan , Liu He , Wu Jiang , Chen Liang , Fu Yingying , Xie Zhiyuan
Published: February 2022

A type of ternary ST-OSC based on a PTB7-Th:10%PCDTBT/IEICO-4Cl quasi-heterojunction prepared by sequential processing was fabricated. The prepared ST-OSC achieves a PCE of 6.30% with an AVT of 43.93%, leading to a LUE of 2.77%.
Sustainable catalysis with fluxional acridine-based PNP pincer complexes
Authors: Kar Sayan , Milstein David
Published: February 2022

The recent developments of sustainable catalytic reactions catalyzed by fluxional acridine-based PNP pincer complexes are explored, focusing on their unique structural features and reactivities compared to other traditional pincer complexes.
Mechanochemically synthesised dicyanamide hybrid organic–inorganic perovskites, and their melt-quenched glasses
Authors: McHugh Lauren N. , Thorne Michael F. , Chester Ashleigh M. , Etter Martin , Užarević Krunoslav , Bennett Thomas D.
Published: February 2022

Dicyanamide hybrid organic–inorganic perovskites were synthesised mechanochemically and their properties, along with those of their bulk melt-quenched glasses were investigated.
Pairing nanoarchitectonics of oligodeoxyribonucleotides with complex diversity: concatemers and self-limited complexes
Authors: Zamoskovtseva Anastasia A. , Golyshev Victor M. , Kizilova Valeria A. , Shevelev Georgiy Yu. , Pyshnyi Dmitrii V. , Lomzov Alexander A.
Published: February 2022

The development of approaches to the design of two- and three-dimensional self-assembled DNA-based nanostructures with a controlled shape and size is an essential task for applied nanotechnology, therapy, biosensing, and bioimaging.
Synthetic studies with the brevicidine and laterocidine lipopeptide antibiotics including analogues with enhanced properties and in vivo efficacy
Authors: Al Ayed Karol , Ballantine Ross D. , Hoekstra Michael , Bann Samantha J. , Wesseling Charlotte M. J. , Bakker Alexander T. , Zhong Zheng , Li Yong-Xin , Brüchle Nora C. , van der Stelt Mario , Cochrane Stephen A. , Martin Nathaniel I.
Published: February 2022

Convenient solid-phase approaches are described for the synthesis of brevicidine and laterocidine. Also reported are novel analogues including a laterocidine variant with enhanced hydrolytic stability and potent in vivo antibacterial activity.
Hydridotetrylene [Ar*EH] (E = Ge, Sn, Pb) coordination at tantalum, tungsten, and zirconium
Authors: Widemann Max , Jeggle Sebastian , Auer Maximilian , Eichele Klaus , Schubert Hartmut , Sindlinger Christian P. , Wesemann Lars
Published: February 2022

Low valent cations of tin and lead were used to form hydridotetrylene coordination compounds. The mobility of the hydrogen substituent was investigated in deprotonation equilibria as well as in 1,2-H-shift reactions.
Efficient solid-state photoswitching of methoxyazobenzene in a metal–organic framework for thermal energy storage
Authors: Griffiths Kieran , Halcovitch Nathan R. , Griffin John M.
Published: February 2022

4-Methoxyazobenzene can be occluded into the pores of a MOF and show near-quantitative E → Z photoisomerization under irradiation with 365 nm light. The energy density of the composite is 101 J g−1 and the half-life of the Z-isomer is 6 days.
Design of 3D topological nodal-net porous carbon for sodium-ion battery anodes
Authors: Ni Dongyuan , Shen Yiheng , Sun Wei , Wang Qian
Published: February 2022

A new nodal net carbon allotrope, oC46, is proposed, which can be used as an anode material for SIBs; the effective k·p models are applied for elucidating the symmetry-protection mechanisms of oC46.
FoxO transcription factors in mitochondrial homeostasis
Authors: Cheng Zhiyong
Published: February 2022

Mitochondria play essential roles in cellular energetics, biosynthesis, and signaling transduction. Dysfunctional mitochondria have been implicated in different diseases such as obesity, diabetes, cardiovascular disease, nonalcoholic fatty liver disease, neurodegenerative disease, and cancer. Mitochondrial homeostasis is controlled by a triad of mitochondrial biogenesis, dynamics (fusion and fission), and autophagy (mitophagy). Studies have underscored FoxO transcription factors as key mitochondrial regulators. Specifically, FoxOs regulate mitochondrial biogenesis by dampening NRF1-Tfam and c-Myc-Tfam cascades directly, and inhibiting NAD-Sirt1-Pgc1α cascade indirectly by inducing Hmox1 or repressing Fxn and Urod. In addition, FoxOs mediate mitochondrial fusion (via Mfn1 and Mfn2) and fission (via Drp1, Fis1, and MIEF2), during which FoxOs elicit regulatory mechanisms at transcriptional, posttranscriptional (e.g. via miR-484/Fis1), and posttranslational (e.g. via Bnip3-calcineurin mediated Drp1 dephosphorylation) levels. Furthermore, FoxOs control mitochondrial autophagy in the stages of autophagosome formation and maturation (e.g. initiation, nucleation, and elongation), mitochondria connected to and engulfed by autophagosome (e.g. via PINK1 and Bnip3 pathways), and autophagosome-lysosome fusion to form autolysosome for cargo degradation (e.g. via Tfeb and cathepsin proteins). This article provides an up-to-date view of FoxOs regulating mitochondrial homeostasis and discusses the potential of targeting FoxOs for therapeutics.
The benefits of joining a learned society
Authors: Morris Ryan Daniel
Published: February 2022

Throughout my time as a student I have been fortunate enough to be involved in learned societies. A learned society is an organization (typically not for profit) which aims to promote the scholarly work of a particular discipline. This can take the form of running conferences, publishing literature and offering training and educational resources to society members. Whilst membership to a learned society is often a small fee (often discounted for students) the benefits that can be obtained from membership are extremely rewarding.
A comprehensive design approach for a three‐winding planar transformer
Authors: Zou Shenli , Singhabahu Chanaka , Chen Jianfei , Khaligh Alireza
Published: February 2022

In this paper, a new three‐winding planar transformer design with the integrated leakage inductor is proposed for a triple‐active‐bridge converter. It enables two output voltage levels: a high voltage (HV) output port and a low voltage (LV) output port. The primary and secondary windings are split unevenly in both side legs while the tertiary winding is connected in parallel. The unique winding configuration enables: (i) enhanced efficiency with low volume; and (ii) suppressed parasitic capacitances. Detailed transformer reluctance and loss models are developed in the design process. The core geometry is optimized using a reluctance‐model‐based mathematical computation. Moreover, comprehensive high‐fidelity simulations are conducted to analyse the trade‐offs among parasitic capacitances, losses, and inductances. The customized core and the non‐overlapping winding boards are assembled, characterized, and tested under various power flow conditions.
The central deformation calculation and analysis of the heavy steel plate for the gradient temperature rolling
Authors: Jiang Lian-Yun , Li Heng , Wei Yao-Yu , Li Zhen-Lei , Huang Zhi-Quan
Published: February 2022

The traditional symmetrical rolling process may result in the insufficient central deformation of the heavy steel plate. The gradient temperature rolling (GTR) based on the ultra-fast cooling was adopted in order to improve the central deformation and keep the deformation along the thickness to be well distributed. The temperature and strain field of the gradient temperature rolling were obtained by the thermo-mechanical coupling finite element method combined with different surface heat transfer coefficient, plate thickness, work roll diameters and so on. The calculated results showed that the deformation was more likely to penetrate into the core compared with uniform temperature rolling (UTR). The central equivalent strain with GTR was increased by 44.3% maximum compared with UTR in the same case. The deformation along the thickness was well distributed compared to the UTR. The central deformation gradually increases with the increase of reduction rate, surface heat transfer coefficient, work roll diameters and speed ratio, while the central deformation almost unchanged with linear velocity. Furthermore, industrial application showed the deformation can penetrate into the core compared with the UTR and it can help to eliminate the band structure. In this study, the influencing law of equivalent strain along the thickness with different parameters was summarized. The fitting model to calculate the central equivalent strain after GTR was established according to the numerical results. It can provide reliable theory and technology support for the setting of various parameters for GTR.
A common weight credibility data envelopment analysis model for evaluating decision making units with an application in airline performance
Authors: Omrani Hashem , Fahimi Pegah , Emrouznejad Ali
Published: February 2022

Data envelopment analysis (DEA) model has been widely applied for estimating efficiency scores of decision making units (DMUs) and is especially used in many applications in transportation. In this paper, a novel common weight credibility DEA (CWCDEA) model is proposed to evaluate DMUs considering uncertain inputs and outputs. To develop a credibility DEA model, a credibility counterpart constraint is suggested for each constraint of DEA model. Then, the weights generated by the credibility DEA (CDEA) model are considered as ideal solution in a multi-objective DEA model. To solve the multi-objective DEA model, a goal programming model is proposed. The goal programming model minimized deviations from the ideal solutions and found the common weights of inputs and outputs. Using the common weights generated by goal programming model, the final efficiency scores for decision making are calculated. The usefulness and applicability of the proposed approach have been shown using a data set in the airline industry.
Responding trends of ionosphericF2-layer to weaker geomagnetic activities
Authors: Chen Yiding , Liu Libo , Le Huijun , Zhang Hui , Zhang Ruilong
Published: February 2022

Geomagnetic activities frequently occur in varying degrees. Strong geomagnetic activities, which have been widely investigated, occur occasionally; they can cause distinguishable and significant disturbances in the ionosphere. Weaker geomagnetic activities frequently appear, whereas their effects are generally difficult to be distinguished from complex ionospheric variations. Weaker geomagnetic activities play important roles in ionospheric day-to-day variability thus should deserve further attention. In this study, long-term (longer than one solar cycle) measurements of theF2-layer critical frequency (foF2) were collected to statistically investigate ionospheric responses to weaker geomagnetic activities (Ap < 60). The responding trends of low- to high-latitudefoF2to increasing geomagnetic activity are presented for the first time; they are statistically evident. Both increasing and decreasing trends can occur, depending on latitudes and seasons. The trend gradually transits from high-latitude decreasing trends to equatorial increasing trends with decreasing latitude, and this transition is seasonally dependent. As a result, the trend has a seasonal difference at mid-latitudes. The responding trend is generally more distinct at higher latitudes and in the equatorial region than at mid-latitudes, and the responding intensity is largest at higher latitudes. Although theoretically, geomagnetic activities can disturb the ionosphere through multiple mechanisms, the morphology of the trend suggests that the frequent weaker geomagnetic activities modulate the high- to low-latitude ionosphere mainly through disturbing high-latitude thermospheric composition and further altering the thermospheric background circulation.
Akute Schwellung im Halsbereich nach iodhaltigem Kontrastmittel – der oft unerkannte Iodmumps anhand von drei Fallbeispielen
Authors: Bircher Andreas J. , Hofmeier Kathrin Scherer
Published: February 2022

Es werden drei Patientinnen vorgestellt, die zur Abklärung einer akuten Halsschwellung nach einer Untersuchung mit iodierten Kontrastmitteln zugewiesen wurden. Bei allen drei war ein akutes Angioödem vermutet worden, das allerdings nicht ausreichend auf Antihistaminika und Kortikosteroide ansprach. Es wurde schließlich ein sog. „Iodmumps“ oder Iod-assoziierte Sialoadenopathie diagnostiziert. Sonografisch und histologisch finden sich lediglich ein Ödem der Speicheldrüsen, hingegen keine Hinweise für eine ausgeprägte entzündliche Reaktion. Diese Komplikation ist nicht so selten und wird von Iod selbst ausgelöst, wie mit einer Provokation mit Iod-Kaliumiodid (Lugolʼscher Lösung) nachgewiesen werden konnte. Die pathophysiologisch ungeklärte Iod-assoziierte Sialoadenopathie wird somit als idiosynkratische Reaktion klassifiziert.
An Update on Safe Anticoagulation
Authors: Mailer Reiner K. , Kuta Piotr , Renné Thomas
Published: February 2022

Blood coagulation is essential to maintain the integrity of a closed circulatory system (hemostasis), but also contributes to thromboembolic occlusion of vessels (thrombosis). Thrombosis may cause deep vein thrombosis, pulmonary embolism, myocardial infarction, peripheral artery disease, and ischemic stroke, collectively the most common causes of death and disability in the developed world. Treatment for the prevention of thromboembolic diseases using anticoagulants such as heparin, coumarins, thrombin inhibitors, or antiplatelet drugs increase the risk of bleeding and are associated with an increase in potentially life-threatening hemorrhage, partially offsetting the benefits of reduced coagulation. Thus, drug development aiming at novel targets is needed to provide efficient and safe anticoagulation. Within the last decade, experimental and preclinical data have shown that some coagulation mechanisms principally differ in thrombosis and hemostasis. The plasma contact system protein factors XII and XI, high-molecular-weight kininogen, and plasma kallikrein specifically contribute to thrombosis, however, have minor, if any, role in hemostatic coagulation mechanisms. Inherited deficiency in contact system proteins is not associated with increased bleeding in humans and animal models. Therefore, targeting contact system proteins provides the exciting opportunity to interfere specifically with thromboembolic diseases without increasing the bleeding risk. Recent studies that investigated pharmacologic inhibition of contact system proteins have shown that this approach provides efficient and safe thrombo-protection that in contrast to classical anticoagulants is not associated with increased bleeding risk. This review summarizes therapeutic and conceptual developments for selective interference with pathological thrombus formation, while sparing physiologic hemostasis, that enables safe anticoagulation treatment.
Verkürzte Therapiekonzepte im Maßregelvollzug
gemäß §64 StGB: Ein maßgeschneiderter
Behandlungspfad?
Authors: Praus Peter , Biebinger Eva , Bepler Ralf , Kubath-Heimann Sylvia , Funk Beate , Dreßing Harald
Published: February 2022

Die forensische Therapie gemäß §64 StGB zeichnet sich
aktuell durch hohe Abbruch- bzw. Erledigungsquoten aus. Das hier vorgestellte
verkürzte Therapiekonzept der Klinik für Forensische Psychiatrie
des Pfalzklinikums für Patienten mit günstigen Prognosemerkmalen
soll durch Förderung von Eigeninitiative, Verantwortung und Motivation
sowie eine möglichst individualisierte, störungsorientierte,
strafzeit- und tatangemessene Behandlung mit intensiver Erprobung unter
Alltagsbedingungen zu einer Verkürzung der stationären
Unterbringung führen. Empirische Belege hierfür fehlen jedoch
bislang. Erstmals werden hier Pilotdaten aus dem Zeitraum April 2016 bis Mai
2021 vorgestellt. Zusammenfassend hat sich das o.g. Konzept als umsetzbar
erwiesen. Die erhobenen Daten weisen darauf hin, dass die im verkürzten
Therapieprogramm behandelten Patienten eine geringere Erledigungsquote als der
Durchschnitt aller gemäß §64 StGB untergebrachter
Patienten aufweist. Eine deutliche Verkürzung der durchschnittlichen
Behandlungsdauer ließ sich demgegenüber jedoch nicht belegen.
Die vorliegende Arbeit will einen ersten Beitrag zur Diskussion und
Weiterentwicklung derartiger Behandlungsoptionen leisten. Mögliche
Nachteile derartiger Therapieangebote bei für ungeeignet befundenen
Patienten, z. B. eine Abnahme der Therapiemotivation, werden
diskutiert.
Rescue Extracranial–Intracranial Bypass for Ischemic Stroke Secondary to Progressive Human Immunodeficiency Virus–Associated Vasculopathy
Authors: Mizushima Makoto , Sugiyama Taku , Eguchi Katsuki , Tarisawa Monami , Tokairin Kikutaro , Ito Masaki , Hashimoto Daigo , Yabe Ichiro , Fujimura Miki
Published: February 2022

Background Human immunodeficiency virus (HIV) associated vasculopathy can cause ischemic cerebral stroke; however, there is limited evidence on optimal management. Herein, we report a case of acute ischemic stroke due to progressive internal carotid artery (ICA) stenosis in an HIV-positive patient. Superficial temporal artery to middle cerebral artery (STA-MCA) bypass, in addition to the best medical treatments, prevented stroke progression.

Clinical Description A 39-year-old man with HIV infection presented with a sudden onset of aphasia and right hemiparesis. Magnetic resonance imaging revealed an ischemic lesion in the left basal ganglia and concentric thickening of the vessel wall in the terminal portion of the bilateral ICAs. Despite maximal medical treatments for HIV-associated vasculopathy and possible opportunistic infections, bilateral ICA stenoses progressed, leading to a second hemodynamic stroke event. Because tissue plasminogen activator treatment failed, we performed STA-MCA bypass. A significant improvement in neurologic symptoms and cerebral blood flow was observed after surgery. No further stroke events occurred during the continuation of medical treatments.

Conclusion This is the first case of STA-MCA bypass performed in a patient with recurrent ischemic stroke caused by HIV-associated vasculopathy. Although further evidence is needed, such treatment options can shed new light on the management of progressive HIV-associated vasculopathy, which is refractory to maximal medical treatment.
Catalytic Enantioselective Synthesis of C–N Atropisomeric Heterobiaryls
Authors: Knipe Peter C. , Sweet Jamie S.
Published: February 2022

Molecules containing an atropisomeric C–N biaryl axis are gaining increasing attention in catalytic and medicinal chemistry. Despite this rising interest, relatively few approaches towards their catalytic enantioselective synthesis have been reported. Here we review these approaches, with a focus on the mechanism of asymmetric induction. Some common themes emerge: Brønsted acid catalysed cyclo-condensation and palladium-catalysed ring-closure are the most common and successful approaches. Meanwhile, the more direct but challenging axial C–N bond formation strategy remains in its infancy, with just two reports to-date. We hope this review will inform and inspire other researchers to develop new creative approaches to this important chemical motif.

1 Introduction

2 Cyclo-Condensation

3 Proximal C–N Bond Formation

4 Desymmetrisation of Intact Axes

5 ortho-C–H Functionalisation

6 Cycloaddition

7 Axial C–N Bond Formation

8 Atropisomeric N–N Axes: An Emerging Class of Heterobiaryls

9 Conclusion and Outlook
Cross-Cultural Adaptation, Validation, and Arabic Translation of the Eustachian Tube Dysfunction Questionnaire (ETDQ-7)
Authors: Alkholaiwi Feras , Alnatheer Abdullah M. , Theyab Rami Saud , Alyousef Meshal , Aldrees Turki , Dahmash Abdulmajeed Bin , Alghonaim Yazeed
Published: February 2022

Introduction The Eustachian Tube Dysfunction Patient Questionnaire (ETDQ-7) scale is used to assess the effectiveness of the treatment and to determine the severity of the eustachian tube dysfunction (ETD). There is currently no validated Arabic version of the ETDQ-7.

Objectives The aim of the present study is to test the validity and the reliability of a translated Arabic version of the ETDQ-7.

Methods A multicenter prospective validation study was conducted in Riyadh, Saudi Arabia. The ETDQ-7 was adapted and translated into Arabic using a standard validation methodology. Fifty-one patients diagnosed with Eustachian tube dysfunction and 45 healthy individuals were enrolled in the study. The known-groups method was used in the validity analysis. The test-retest method, item-total score correlation, and internal consistency analysis were used for the reliability analyses.

Result The overall internal consistency of the Arabic ETDQ items was measured using Cronbach α (Cronbach α = 0.803). The average and total ETDQ scores were significantly higher in the ETD group (17.6) than in the control group (9.87) (p < 0.001). The results indicate a good to excellent correlation (> 0.7). The area under the curve for the total ETDQ score was 88.6% (95% confidence interval [CI]: 80.3–96.8%)

Conclusion The Arabic version of the ETDQ-7 scale is a valid instrument for evaluating ETD. It can also be used as an important tool for diagnosis, patient follow-up, and treatment management.
Molecular Characterization of High-Level Aminoglycoside Resistance among Enterococcus Species
Authors: Manoharan Harish , Lalitha Aishwarya K.V. , Mariappan Shanthi , Sekar Uma , Venkataramana Geetha P.
Published: February 2022

Background Enterococci are nosocomial pathogen. They can develop high-level resistance to aminoglycoside by producing aminoglycoside modifying enzymes (AMEs). In enterococci, high level resistance to aminoglycosides is mediated by acquisition of plasmid mediated genes encoding for aminoglycoside modifying enzymes (AMEs). High level gentamicin resistance (MIC ≥ 500μg /mL) is predominantly mediated by aac(6′)-Ie-aph(2″)-Ia, encoding the bifunctional aminoglycoside modifying enzyme AAC(6′)-APH(2″). This enzyme eliminates the synergistic activity of gentamicin when combined with a cell wall active agent. Other AME genes such as aph(2″)-Ib, aph(2″)-Ic, aph(2″)-Id and ant(4′)-1a have also been detected in enterococci.

Objective This study was carried out to determine the diverse prevalence of AME and their pattern of occurrence in the clinical isolates of Enterococci.

Materials and Methods A total number of 150 clinical isolates were included in this study. Susceptibility to various antibiotics was determined by disc diffusion. Minimum Inhibitory Concentration (MIC) was ascertained by agar dilution method. Polymerase chain reaction was done to screen the following AMEs (aac(6′)-Ie-aph(2″)-Ia; aph(2″)-Ib; aph(2″)-Ic; aph(2″)-Id and aph(3′)- IIIa genes).

Results 51.3% of the study isolates exhibited high level gentamicin resistance. Polymerase chain reaction revealed that aph(3′)-111a is the most prevalent AME, followed by aac(6′)-1e-aph(2″)-1a. The combination of both the genes were detected in 44.1% of the study isolates. The rest of the AMEs and their combinations were not encountered in this study. 8.6% of the study isolates did not harbour any AME genes screened for, but was phenotypically resistant to gentamicin. In contrast 31.3% anchored the AME genes but phenotypically appeared susceptible to gentamicin.

Conclusion This study indicates the high- level aminoglycoside resistance disseminated among Enterococci in our geographical region. It also emphasizes the detection of AMEs by PCR is mandatory because strains that appear susceptible by disc diffusion and/or MIC method may harbour one or more AMEs genes leading to therapeutic failure.
DFT investigation of physical properties and electronic structure of metastable cubic CrC partially substituted with transitional metals
Authors: Liu R. L. , Zhang D. , Tang Y. Q. , Li D. Y.
Published: February 2022

Mechanical strength and wear resistance of chromium carbides are relatively low compared to other transition metal (TM) carbides, such as TiC or WC. However, carbides can be tailored by partially substituting their host metal elements with other TMs. In this computational study with first-principles calculations, we investigated the effects of TMs on the stability and properties of metastable CrC carbide having a face-centered cubic structure. It is demonstrated that most TMs in IV and V groups can improve the thermodynamic stability of CrC with negative formation energies, meaning that such TM-substituted CrC can be formed using equilibrium or near-equilibrium synthesis routes. Mechanisms for the improved stability and mechanical properties of CrC by TM substitution were investigated through analyzing corresponding changes in the density of states, charge density distribution, and Bader charge. It is shown that the improved stability and properties of TM-substituted CrC result from changes in the distributions of covalent, ionic, and metallic bonds. TM-substituted CrC carbides with different densities provide more alternatives or options for widened applications of the Cr carbide family.
A perspective on the use of light as a driving element for bio-hybrid actuation
Authors: Vurro V. , Venturino I. , Lanzani G.
Published: February 2022

Bio-hybrid actuators are devices based on muscle cells or tissues, designed to exploit the force generated by the biological element to execute an action or a movement. Typically, cells and tissue control are achieved electrically by using metal electrodes implanted in living elements. In this Perspective, we focus our attention on an alternative stimulation approach based on light. We highlight the potential of light stimulation in terms of performance and discuss the comparison with classical electrical stimulation. Finally, we discuss future challenges and possible applications of light-controlled actuators.