bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of maternal and perinatal factors on macronutrient content of very preterm human milk during the first weeks after birth
Authors: Borràs-Novell Cristina , Herranz Barbero Ana , Balcells Esponera Carla , López-Abad Miriam , Aldecoa Bilbao Victoria , Izquierdo Renau Montserrat , Iglesias Platas Isabel
Published: August 2022

Objective

To identify changes in macronutrient content of very preterm human milk associated with perinatal factors.

Study design

Milk macronutrients were measured on weeks 1, 2, 4 and 8 with mid-infrared transmission spectrometers.

Result

We assessed 625 samples (from 117 mothers and 130 very preterm infants). Average concentrations were: protein 1.3 ± 0.3 g/dl, carbohydrates 7.3 ± 0.6 g/dl, fat 3.7 ± 1.0 g/dl and energy 296.0 ± 41.0 kJ/dl (70.7 kcal/dl). Gestational age negatively correlated with protein (rho: −0.307, p < 0.001) and energy (r: −0.193, p = 0.003). Advanced maternal age, gestational age and intrauterine growth restriction were independently associated with milk protein content over the first 4 weeks (adjusted R2: 0.113, p = 0.002).

Conclusion

These findings may help neonatologists identify patients fed Mother´s Own Milk who are at increased risk of poor postnatal growth.
A novel circulating miRNA panel for non-invasive ovarian cancer diagnosis and prognosis
Authors: Gahlawat Aoife Ward , Witte Tania , Haarhuis Lisa , Schott Sarah
Published: August 2022

Background

Ovarian cancer (OC) is an aggressive disease, primarily diagnosed in late stages with only 20% of patients surviving more than 5 years after diagnosis. There is a pending need to improve current diagnostics and prognostics.

Methods

In this study, we investigated total circulating cell-free microRNA (cf-miRNA) levels as well as a panel of cf-miRNAs in the plasma of OC patients (n = 100), patients with benign lesions (n = 45) and healthy controls (n = 99).

Results

High levels of cf-miRNAs correlated with unfavourable clinical features and were an independent prognosticator of patient survival. By mining NGS data, we identified a signature panel of seven individual cf-miRNAs which could distinguish controls from benign cases with an AUC of 0.77 and controls from cancer cases with an AUC of 0.87. Importantly, in combination with the current gold-standard marker, CA-125, the panel could predict early OC with an AUC of 0.93.

Conclusion

Our findings highlight the potential of cf-miRNA levels as well as individual cf-miRNAs for OC diagnosis and prognosis that warrants further clinical evaluation.
Eukaryotic initiation factor 5A2 mediates hypoxia-induced autophagy and cisplatin resistance
Authors: Xu Guodong , Chen Hang , Wu Shibo , Chen Jiabin , Zhang Shufen , Shao Guofeng , Sun Lebo , Mu Yinyu , Liu Kaitai , Pan Qiaoling , Li Ni , An Xiaoxia , Lin Shuang , Chen Wei
Published: August 2022

Hypoxia-induced cisplatin resistance is a major challenge during non-small cell lung cancer (NSCLC) treatment. Based on previous studies, we further explored the effect of eukaryotic initiation factor 5A2 (eIF5A2) in hypoxia-induced cisplatin resistance. In this study, we found that autophagy and cisplatin resistance were increased under hypoxic conditions in three different NSCLC cell lines. Compared with that under normoxic conditions, dramatic upregulation of eIF5A2 and hypoxia inducible factor 1 subunit alpha (HIF-1α) levels were detected under hypoxia exposure. Small interfering RNA silencing of HIF-1α resulted in decreased expression of eIF5A2, indicating that eIF5A2 acts downstream of HIF-1α. In addition, the expression of eIF5A2 was significantly higher in NSCLC tumors compared with that in normal tissues. RNA silencing-mediated downregulation of eIF5A2 decreased hypoxia-induced autophagy, thereby reducing hypoxia-induced cisplatin resistance in NSCLC cells. The roles of eIF5A2 in cisplatin resistance were further validated in vivo. Combined treatment using eIF5A2-targeted downregulation together with cisplatin significantly inhibited tumor growth compared with cisplatin alone in the subcutaneous mouse model. In conclusions, eIF5A2 overexpression is involved in hypoxia-induced autophagy during cisplatin resistance. We suggest that a combination of eIF5A2 targeted therapy and cisplatin chemotherapy is probably an effective strategy to reverse hypoxia-induced cisplatin resistance and inhibit NSCLC development.
Gemcitabine resistance of pancreatic cancer cells is mediated by IGF1R dependent upregulation of CD44 expression and isoform switching
Authors: Chen Chen , Zhao Shujie , Zhao Xiangru , Cao Lin , Karnad Anand , Kumar Addanki P. , Freeman James W.
Published: August 2022

Chemoresistance in pancreatic cancer cells may be caused by the expansion of inherently resistant cancer cells or by the adaptive plasticity of initially sensitive cancer cells. We investigated how CD44 isoforms switching contributed to gemcitabine resistance. Treating CD44 null/low single-cell clones with increasing amounts of gemcitabine caused an increase in expression of CD44 and development of gemcitabine resistant (GR) cells. Drug sensitivity, invasiveness, and EMT process was evaluated by MTT, Matrigel invasion assays, and western blots. Genetic knockdown and pharmacological inhibitors were used to examine the roles of CD44 and IGF1R in mediating gemcitabine resistance. CD44 promoter activity and its interactive EMT-related transcription factors were evaluated by luciferase reporter assay and chromatin immunoprecipitation assay. Kaplan–Meier curve was created by log-rank test to reveal the clinical relevance of CD44 and IGF1R expression in patients. We found silence of CD44 in GR cells partially restored E-cadherin expression, reduced ZEB1 expression, and increased drug sensitivity. The gemcitabine-induced CD44 expressing and isoform switching were associated with an increase in nuclear accumulation of phosphor-cJun, Ets1, and Egr1 and binding of these transcription factors to the CD44 promoter. Gemcitabine treatment induced phosphorylation of IGF1R and increased the expression of phosphor-cJun, Ets1, and Egr1 within 72 h. Stimulation or suppression of IGF1R signaling or its downstream target promoted or blocked CD44 promoter activity. Clinically, patients whose tumors expressed high levels of CD44/IGF1R showed a poor prognosis. This study suggests that IGF1R-dependent CD44 isoform switching confers pancreatic cancer cells to undergo an adaptive change in response to gemcitabine and provides the basis for improved targeted therapy of pancreatic cancer.
Preclinical assessment of antigen-specific chimeric antigen receptor regulatory T cells for use in solid organ transplantation
Authors: Proics Emma , David Marion , Mojibian Majid , Speck Madeline , Lounnas-Mourey Nadia , Govehovitch Adeline , Baghdadi Wissam , Desnouveaux Justine , Bastian Hervé , Freschi Laura , Privat Geoffrey , Pouzet Cédric , Grossi Mauro , Heimendinger Pierre , Abel Tobias , Fenard David , Levings Megan K. , Meyer François , Dumont Céline
Published: August 2022

A primary goal in transplantation medicine is the induction of a tolerogenic environment for prevention of transplant rejection without the need for long-term pharmacological immunosuppression. Generation of alloantigen-specific regulatory T cells (Tregs) by transduction with chimeric antigen receptors (CARs) is a promising strategy to achieve this goal. This publication reports the preclinical characterization of Tregs (TR101) transduced with a human leukocyte antigen (HLA)-A*02 CAR lentiviral vector (TX200) designated to induce immunosuppression of allograft-specific effector T cells in HLA-A*02-negative recipients of HLA-A*02-positive transplants. In vitro results demonstrated specificity, immunosuppressive function, and safety of TX200-TR101. In NOD scid gamma (NSG) mice, TX200-TR101 prevented graft-versus-host disease (GvHD) in a xenogeneic GvHD model and TX200-TR101 Tregs localized to human HLA-A*02-positive skin transplants in a transplant model. TX200-TR101 persisted over the entire duration of a 3-month study in humanized HLA-A*02 NSG mice and remained stable, without switching to a proinflammatory phenotype. Concomitant tacrolimus did not impair TX200-TR101 Treg survival or their ability to inhibit peripheral blood mononuclear cell (PBMC) engraftment. These data demonstrate that TX200-TR101 is specific, stable, efficacious, and safe in preclinical models, and provide the basis for a first-in-human study.
Recursive Editing improves homology-directed repair through retargeting of undesired outcomes
Authors: Möller Lukas , Aird Eric J. , Schröder Markus S. , Kobel Lena , Kissling Lucas , van de Venn Lilly , Corn Jacob E.
Published: August 2022

CRISPR-Cas induced homology-directed repair (HDR) enables the installation of a broad range of precise genomic modifications from an exogenous donor template. However, applications of HDR in human cells are often hampered by poor efficiency, stemming from a preference for error-prone end joining pathways that yield short insertions and deletions. Here, we describe Recursive Editing, an HDR improvement strategy that selectively retargets undesired indel outcomes to create additional opportunities to produce the desired HDR allele. We introduce a software tool, named REtarget, that enables the rational design of Recursive Editing experiments. Using REtarget-designed guide RNAs in single editing reactions, Recursive Editing can simultaneously boost HDR efficiencies and reduce undesired indels. We also harness REtarget to generate databases for particularly effective Recursive Editing sites across the genome, to endogenously tag proteins, and to target pathogenic mutations. Recursive Editing constitutes an easy-to-use approach without potentially deleterious cell manipulations and little added experimental burden.
Club cells employ regeneration mechanisms during lung tumorigenesis
Authors: Chen Yuanyuan , Toth Reka , Chocarro Sara , Weichenhan Dieter , Hey Joschka , Lutsik Pavlo , Sawall Stefan , Stathopoulos Georgios T. , Plass Christoph , Sotillo Rocio
Published: August 2022

The high plasticity of lung epithelial cells, has for many years, confounded the correct identification of the cell-of-origin of lung adenocarcinoma (LUAD), one of the deadliest malignancies worldwide. Here, we employ lineage-tracing mouse models to investigate the cell of origin of Eml4-Alk LUAD, and show that Club and Alveolar type 2 (AT2) cells give rise to tumours. We focus on Club cell originated tumours and find that Club cells experience an epigenetic switch by which they lose their lineage fidelity and gain an AT2-like phenotype after oncogenic transformation. Single-cell transcriptomic analyses identified two trajectories of Club cell evolution which are similar to the ones used during lung regeneration, suggesting that lung epithelial cells leverage on their plasticity and intrinsic regeneration mechanisms to give rise to a tumour. Together, this study highlights the role of Club cells in LUAD initiation, identifies the mechanism of Club cell lineage infidelity, confirms the presence of these features in human tumours, and unveils key mechanisms conferring LUAD heterogeneity.
Intrinsically fluorescent polyureas toward conformation-assisted metamorphosis, discoloration and intracellular drug delivery
Authors: Zhou Yeqiang , Fan Fan , Zhao Jinling , Wang Zhaoding , Wang Rui , Zheng Yi , Liu Hang , Peng Chuan , Li Jianshu , Tan Hong , Fu Qiang , Ding Mingming
Published: August 2022

Peptidomimetic polymers have attracted increasing interest because of the advantages of facile synthesis, high molecular tunability, resistance to degradation, and low immunogenicity. However, the presence of non-native linkages compromises their ability to form higher ordered structures and protein-inspired functions. Here we report a class of amino acid-constructed polyureas with molecular weight- and solvent-dependent helical and sheet-like conformations as well as green fluorescent protein-mimic autofluorescence with aggregation-induced emission characteristics. The copolymers self-assemble into vesicles and nanotubes and exhibit H-bonding-mediated metamorphosis and discoloration behaviors. We show that these polymeric vehicles with ultrahigh stability, superfast responsivity and conformation-assisted cell internalization efficiency could act as an “on-off” switchable nanocarrier for specific intracellular drug delivery and effective cancer theranosis in vitro and in vivo. This work provides insights into the folding and hierarchical assembly of biomacromolecules, and a new generation of bioresponsive polymers and nonconventional luminescent aliphatic materials for diverse applications.
Reactive oxygen species-responsive and Raman-traceable hydrogel combining photodynamic and immune therapy for postsurgical cancer treatment
Authors: Zhang Yiyi , Tian Sidan , Huang Liping , Li Yanan , Lu Yuan , Li Hongyu , Chen Guiping , Meng Fanling , Liu Gang L. , Yang Xiangliang , Tu Jiasheng , Sun Chunmeng , Luo Liang
Published: August 2022

Combining immune checkpoint blockade (ICB) therapy with photodynamic therapy (PDT) holds great potential in treating immunologically “cold” tumors, but photo-generated reactive oxygen species (ROS) can inevitably damage co-administered ICB antibodies, hence hampering the therapeutic outcome. Here we create a ROS-responsive hydrogel to realize the sustained co-delivery of photosensitizers and ICB antibodies. During PDT, the hydrogel skeleton poly(deca-4,6-diynedioic acid) (PDDA) protects ICB antibodies by scavenging the harmful ROS, and at the same time, triggers the gradual degradation of the hydrogel to release the drugs in a controlled manner. More interestingly, we can visualize the ROS-responsive hydrogel degradation by Raman imaging, given the ultrastrong and degradation-correlative Raman signal of PDDA in the cellular silent window. A single administration of the hydrogel not only completely inhibits the long-term postoperative recurrence and metastasis of 4T1-tumor-bearing mice, but also effectively restrains the growth of re-challenged tumors. The PDDA-based ROS-responsive hydrogel herein paves a promising way for the durable synergy of PDT and ICB therapy.
Mettl3-mediated mRNA m6A modification controls postnatal liver development by modulating the transcription factor Hnf4a
Authors: Xu Yan , Zhou Zhuowei , Kang Xinmei , Pan Lijie , Liu Chang , Liang Xiaoqi , Chu Jiajie , Dong Shuai , Li Yanli , Liu Qiuli , Sun Yuetong , Yu Shanshan , Zhang Qi
Published: August 2022

Hepatic specification and functional maturation are tightly controlled throughout development. N6-methyladenosine (m6A) is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. However, the function of m6A in liver development remains elusive. Here we dissect the role of Mettl3-mediated m6A modification in postnatal liver development and homeostasis. Knocking out Mettl3 perinatally withAlb-Cre(Mettl3cKO) induces apoptosis and steatosis of hepatocytes, results in severe liver injury, and finally leads to postnatal lethality within 7 weeks. m6A-RIP sequencing and RNA-sequencing reveal that mRNAs of a series of crucial liver-enriched transcription factors are modified by m6A, includingHnf4a, a master regulator for hepatic parenchymal formation. Deleting Mettl3 reduces m6A modification onHnf4a, decreases its transcript stability in an Igf2bp1-dependent manner, and down-regulatesHnf4aexpression, while overexpressing Hnf4a with AAV8 alleviates the liver injury and prolongs the lifespan ofMettl3cKO mice. However, knocking out Mettl3 in adults usingAlb-CreERT2does not affect liver homeostasis. Our study identifies a dynamic role of Mettl3-mediated RNA m6A modification in liver development.
Tuning crystal-phase of bimetallic single-nanoparticle for catalytic hydrogenation
Authors: Liu Shuang , Li Yong , Yu Xiaojuan , Han Shaobo , Zhou Yan , Yang Yuqi , Zhang Hao , Jiang Zheng , Zhu Chuwei , Li Wei-Xue , Wöll Christof , Wang Yuemin , Shen Wenjie
Published: August 2022

Bimetallic nanoparticles afford geometric variation and electron redistribution via strong metal-metal interactions that substantially promote the activity and selectivity in catalysis. Quantitatively describing the atomic configuration of the catalytically active sites, however, is experimentally challenged by the averaging ensemble effect that is caused by the interplay between particle size and crystal-phase at elevated temperatures and under reactive gases. Here, we report that the intrinsic activity of the body-centered cubic PdCu nanoparticle, for acetylene hydrogenation, is one order of magnitude greater than that of the face-centered cubic one. This finding is based on precisely identifying the atomic structures of the active sites over the same-sized but crystal-phase-varied single-particles. The densely-populated Pd-Cu bond on the chemically ordered nanoparticle possesses isolated Pd site with a lower coordination number and a high-lying valenced-band center, and thus greatly expedites the dissociation of H2over Pd atom and efficiently accommodates the activated H atoms on the particle top/subsurfaces.
Detection of companion galaxies around hot dust-obscured hyper-luminous galaxy W0410-0913
Authors: Ginolfi M. , Piconcelli E. , Zappacosta L. , Jones G. C. , Pentericci L. , Maiolino R. , Travascio A. , Menci N. , Carniani S. , Rizzo F. , Arrigoni Battaia F. , Cantalupo S. , De Breuck C. , Graziani L. , Knudsen K. , Laursen P. , Mainieri V. , Schneider R. , Stanley F. , Valiante R. , Verhamme A.
Published: August 2022

The phase transition between galaxies and quasars is often identified with the rare population of hyper-luminous, hot dust-obscured galaxies. Galaxy formation models predict these systems to grow via mergers, that can deliver large amounts of gas toward their centers, induce intense bursts of star formation and feed their supermassive black holes. Here we report the detection of 24 galaxies emitting Lyman-α emission on projected physical scales of about 400 kpc around the hyper-luminous hot dust-obscured galaxy W0410-0913, at redshift z = 3.631, using Very Large Telescope observations. While this indicates that W0410-0913 evolves in a very dense environment, we do not find clear signs of mergers that could sustain its growth. Data suggest that if mergers occurred, as models expect, these would involve less massive satellites, with only a moderate impact on the internal interstellar medium of W0410-0913, which is sustained by a rotationally-supported fast-rotating molecular disk, as Atacama Large Millimeter Array observations suggest.
Disease-associated mutations within the yeast DNAJB6 homolog Sis1 slow conformer-specific substrate processing and can be corrected by the modulation of nucleotide exchange factors
Authors: Bhadra Ankan K. , Rau Michael J. , Daw Jil A. , Fitzpatrick James A. J. , Weihl Conrad C. , True Heather L.
Published: August 2022

Molecular chaperones, or heat shock proteins (HSPs), protect against the toxic misfolding and aggregation of proteins. As such, mutations or deficiencies within the chaperone network can lead to disease. Dominant mutations within DNAJB6 (Hsp40)—an Hsp70 co-chaperone—lead to a protein aggregation-linked myopathy termed Limb-Girdle Muscular Dystrophy Type D1 (LGMDD1). Here, we used the yeast prion model client in conjunction with in vitro chaperone activity assays to gain mechanistic insights into the molecular basis of LGMDD1. Here, we show how mutations analogous to those found in LGMDD1 affect Sis1 (a functional homolog of human DNAJB6) function by altering the structure of client protein aggregates, interfering with the Hsp70 ATPase cycle, dimerization and substrate processing; poisoning the function of wild-type protein. These results uncover the mechanisms through which LGMDD1-associated mutations alter chaperone activity, and provide insights relevant to potential therapeutic interventions.
Enantioselective construction of ortho-sulfur- or nitrogen-substituted axially chiral biaryls and asymmetric synthesis of isoplagiochin D
Authors: Yang He , Tang Wenjun
Published: August 2022

Axially chiral biaryl motifs possessing ortho-heteroatom-substituted functionalities exist widely in the structures of natural products and have served as foundation for constructing prominent chiral organocatalysts, ligands, functional materials, and even bioactive molecules. However, a general and enantioselective synthesis of such chiral structures with high synthetic value is rare. Taking advantage of the BaryPhos-facilitated asymmetric Suzuki-Miyaura cross-coupling, we have established a general, efficient and enantioselective construction of the ortho sulfur- or nitrogen-substituted axially chiral biaryls. The protocol shows excellent compatibility to various functional groups and structural features, delivering chiral biaryl structures with ortho-sulfonyl groups or with ortho-nitro groups at a broad range of molecular diversity and complexity. The immobilization of BaryPhos on polyethylene glycol (PEG) support has enabled homogeneous enantioselective cross-coupling in aqueous media and the palladium catalyst recycling for multiple times. The method has enabled a concise 10-step asymmetric synthesis of isoplagiochin D as well as the construction of chiroptical molecules with circularly polarized luminescence (CPL) properties.
Single-cell transcriptome and cell type-specific molecular pathways of human non-alcoholic steatohepatitis
Authors: Fred Rikard G. , Steen Pedersen Julie , Thompson Jonatan J. , Lee Julie , Timshel Pascal N. , Stender Stefan , Opseth Rygg Marte , Gluud Lise Lotte , Bjerregaard Kristiansen Viggo , Bendtsen Flemming , Hansen Torben , Pers Tune H.
Published: August 2022

The aim of this study is to characterize cell type-specific transcriptional signatures in non-alcoholic steatohepatitis (NASH) to improve our understanding of the disease. We performed single-cell RNA sequencing on liver biopsies from 10 patients with NASH. We applied weighted gene co-expression network analysis and validated our findings using a publicly available RNA sequencing data set derived from 160 patients with non-alcoholic fatty liver disease (NAFLD) and 24 controls with normal liver histology. Our study provides a comprehensive single-cell analysis of NASH pathology in humans, describing 19,627 single-cell transcriptomes from biopsy-proven NASH patients. Our data suggest that the previous notion of ”NASH-associated macrophages” can be explained by an up-regulation of normally existing subpopulations of liver macrophages. Similarly, we describe two distinct populations of activated hepatic stellate cells, associated with the level of fibrosis. Finally, we find that the expression of several circulating markers of NAFLD are co-regulated in hepatocytes together with predicted effector genes from NAFLD genome-wide association studies (GWAS), coupled to abnormalities in the complement system. In sum, our single-cell transcriptomic data set provides insights into novel cell type-specific and general biological processes associated with inflammation and fibrosis, emphasizing the importance of studying cell type-specific biological processes in human NASH.
The association of APOE genotype with COVID-19 disease severity
Authors: Safdari Lord Javad , Soltani Rezaiezadeh Javad , Yekaninejad Mir Saeed , Izadi Pantea
Published: August 2022

COVID-19 has caused the recent pandemic of respiratory infection, which threatened global health. The severity of the symptoms varies among affected individuals, from asymptotic or mild signs to severe or critical illness. Genetic predisposition explains the variation in disease severity among patients who suffer from severe symptoms without any known background risk factors. The present study was performed to show the association between APOE genotype and the severity of COVID-19 disease. The APOE genotype of 201 COVID-19 patients (101 patients with asymptomatic to mild form of the disease as the control group and 100 patients with severe to critical illness without any known background risk factors as the case group) were detected via multiplex tetra-primer ARMS-PCR method. Results showed that the e4 allele increased the risk of the COVID-19 infection severity more than five times and the e4/e4 genotype showed a 17-fold increase in the risk of severe disease. In conclusion, since our study design was based on the exclusion of patients with underlying diseases predisposing to severe form of COVID-19 and diseases related to the APOE gene in the study population, our results showed that the e4 genotype is independently associated with the severity of COVID-19 disease. However, further studies are needed to confirm these findings in other nations and to demonstrate the mechanisms behind the role of these alleles in disease severity.
Canal-Net for automatic and robust 3D segmentation of mandibular canals in CBCT images using a continuity-aware contextual network
Authors: Jeoun Bo-Soung , Yang Su , Lee Sang-Jeong , Kim Tae-Il , Kim Jun-Min , Kim Jo-Eun , Huh Kyung-Hoe , Lee Sam-Sun , Heo Min-Suk , Yi Won-Jin
Published: August 2022

The purpose of this study was to propose a continuity-aware contextual network (Canal-Net) for the automatic and robust 3D segmentation of the mandibular canal (MC) with high consistent accuracy throughout the entire MC volume in cone-beam CT (CBCT) images. The Canal-Net was designed based on a 3D U-Net with bidirectional convolutional long short-term memory (ConvLSTM) under a multi-task learning framework. Specifically, the Canal-Net learned the 3D anatomical context information of the MC by incorporating spatio-temporal features from ConvLSTM, and also the structural continuity of the overall MC volume under a multi-task learning framework using multi-planar projection losses complementally. The Canal-Net showed higher segmentation accuracies in 2D and 3D performance metrics (p < 0.05), and especially, a significant improvement in Dice similarity coefficient scores and mean curve distance (p < 0.05) throughout the entire MC volume compared to other popular deep learning networks. As a result, the Canal-Net achieved high consistent accuracy in 3D segmentations of the entire MC in spite of the areas of low visibility by the unclear and ambiguous cortical bone layer. Therefore, the Canal-Net demonstrated the automatic and robust 3D segmentation of the entire MC volume by improving structural continuity and boundary details of the MC in CBCT images.
Deep learning-based noise filtering toward millisecond order imaging by using scanning transmission electron microscopy
Authors: Ihara Shiro , Saito Hikaru , Yoshinaga Mizumo , Avala Lavakumar , Murayama Mitsuhiro
Published: August 2022

Application of scanning transmission electron microscopy (STEM) to in situ observation will be essential in the current and emerging data-driven materials science by taking STEM’s high affinity with various analytical options into account. As is well known, STEM’s image acquisition time needs to be further shortened to capture a targeted phenomenon in real-time as STEM’s current temporal resolution is far below the conventional TEM’s. However, rapid image acquisition in the millisecond per frame or faster generally causes image distortion, poor electron signals, and unidirectional blurring, which are obstacles for realizing video-rate STEM observation. Here we show an image correction framework integrating deep learning (DL)-based denoising and image distortion correction schemes optimized for STEM rapid image acquisition. By comparing a series of distortion corrected rapid scan images with corresponding regular scan speed images, the trained DL network is shown to remove not only the statistical noise but also the unidirectional blurring. This result demonstrates that rapid as well as high-quality image acquisition by STEM without hardware modification can be established by the DL. The DL-based noise filter could be applied to in-situ observation, such as dislocation activities under external stimuli, with high spatio-temporal resolution.
Assessment of potential exposure to As, Cd, Pb and Zn in vegetable garden soils and vegetables in a mining region
Authors: Vejvodová Kateřina , Ash Christopher , Dajčl Julie , Tejnecký Václav , Johanis Hana , Spasić Marko , Polák Filip , Praus Lukáš , Borůvka Luboš , Drábek Ondřej
Published: August 2022

Mining and smelting activities can contaminate soils and affect farming due to high emissions and input of potentially toxic elements (PTE) into the environment. Soils (sampled from two depths) and market vegetables from vegetable gardens located within the vicinity of unconfined slag deposits from decades of mining and smelting activities in Kutná Hora, Czechia were assessed to determine to what extent they pose a health hazard to communities that use these gardens. Pseudo-total As concentrations in the soils exceeded background levels (4.5 mg kg−1) 1.9–93 times, with higher concentrations in the deeper layer. The pseudo-total concentrations of PTE in soils ranked in the order As > Zn > Cd > Pb. Phyto-available concentrations of PTE in soils were relatively low, compared to pseudo-total concentrations. Concentration of As, Cd, Pb and Zn in the vegetables exceeded guideline values, with the highest concentrations found in the fruits of cucumber, peppers, and zucchini. Despite low phyto-available PTE concentrations in soils, all the PTE concentrations in the vegetables surpassed the guidelines set by the Czech Ministry of Health and EU directive, indicating a health hazard to consumers.
TGFβ-induced changes in membrane curvature influence Ras oncoprotein membrane localization
Authors: Damalas Alexandros , Vonkova Ivana , Tutkus Marijonas , Stamou Dimitrios
Published: August 2022

In the course of cancer progression tumor cells undergo morphological changes that lead to increased motility and invasiveness thus promoting formation of metastases. This process called epithelial to mesenchymal transition (EMT) is triggered by transforming growth factor (TGFβ) but for gaining the full invasive potential an interplay between signaling of TGFβ and Ras GTPases is required. Ras proteins possess a lipidated domain that mediates Ras association with the plasma membrane, which is essential for Ras biological functions. Type and number of the lipid anchors are the main difference among three Ras variants—H-ras, N-ras and K-ras. The lipid anchors determine membrane partitioning of lipidated proteins into membrane areas of specific physico-chemical properties and curvature. In this study, we investigated the effect of TGFβ treatment on the subcellular localization of H-ras and K-ras. We show that TGFβ increases positive plasma membrane curvature, which is subsequently sensed by H-ras, leading to its elevated plasma membrane localization and activation. This observation suggests the existence of a novel positive feedback loop whereby the increased level of plasma membrane curvature during TGFβ induced EMT attracts more Ras molecules to the plasma membrane resulting in increased Ras activity which in turn promotes further EMT and thus ultimately enables the acquisition of full invasive potential.
Functional human cell-based vascularised cardiac tissue model for biomedical research and testing
Authors: Koivisto Maria , Tolvanen Tuomas A. , Toimela Tarja , Miinalainen Ilkka , Kiviaho Antti , Kesseli Juha , Nykter Matti , Eklund Lauri , Heinonen Tuula
Published: August 2022

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) are widely used in in vitro biomedical research and testing. However, fully matured, adult cardiomyocyte characteristics have not been achieved. To improve the maturity and physiological relevance of hiPSC-derived cardiomyocytes, we co-cultured them with preconstructed vascular-like networks to form a functional, human cell-based cardiac tissue model. The morphology and gene expression profiles indicated advanced maturation in the cardiac tissue model compared to those of a cardiomyocyte monoculture. The cardiac tissue model’s functionality was confirmed by measuring the effects of 32 compounds with multielectrode array and comparing results to human data. Our model predicted the cardiac effects with a predictive accuracy of 91%, sensitivity of 90% and specificity of 100%. The correlation between the effective concentration (EC50) and the reported clinical plasma concentrations was 0.952 (R2 = 0.905). The developed advanced human cell-based cardiac tissue model showed characteristics and functionality of human cardiac tissue enabling accurate transferability of gained in vitro data to human settings. The model is standardized and thus, it would be highly useful in biomedical research and cardiotoxicity testing.
Transmission of gram-negative antibiotic-resistant bacteria following differing exposure to antibiotic-resistance reservoirs in a rural community: a modelling study for bloodstream infections
Authors: Allel Kasim , Goscé Lara , Araos Rafael , Toro Daniel , Ferreccio Catterina , Munita Jose M. , Undurraga Eduardo A. , Panovska-Griffiths Jasmina
Published: August 2022

Exposure to community reservoirs of gram-negative antibiotic-resistant bacteria (GN-ARB) genes poses substantial health risks to individuals, complicating potential infections. Transmission networks and population dynamics remain unclear, particularly in resource-poor communities. We use a dynamic compartment model to assess GN-ARB transmission quantitatively, including the susceptible, colonised, infected, and removed populations at the community-hospital interface. We used two side streams to distinguish between individuals at high- and low-risk exposure to community ARB reservoirs. The model was calibrated using data from a cross-sectional cohort study (N = 357) in Chile and supplemented by existing literature. Most individuals acquired ARB from the community reservoirs (98%) rather than the hospital. High exposure to GN-ARB reservoirs was associated with 17% and 16% greater prevalence for GN-ARB carriage in the hospital and community settings, respectively. The higher exposure has led to 16% more infections and attributed mortality. Our results highlight the need for early-stage identification and testing capability of bloodstream infections caused by GN-ARB through a faster response at the community level, where most GN-ARB are likely to be acquired. Increasing treatment rates for individuals colonised or infected by GN-ARB and controlling the exposure to antibiotic consumption and GN-ARB reservoirs, is crucial to curve GN-ABR transmission.
In vivo study of the immune response to bioengineered spider silk spheres
Authors: Deptuch Tomasz , Penderecka Karolina , Kaczmarek Mariusz , Molenda Sara , Dams-Kozlowska Hanna
Published: August 2022

Bioengineered MS1 silk is derived from major ampullate spidroin 1 (MaSp1) from the spider Nephila clavipes. The MS1 silk was functionalized with the H2.1 peptide to target Her2-overexpressing cancer cells. The immunogenic potential of drug carriers made from MS1-type silks was investigated. The silk spheres were administered to healthy mice, and then (i) the phenotypes of the immune cells that infiltrated the Matrigel plugs containing spheres (implanted subcutaneously), (ii) the presence of silk-specific antibodies (after two intravenous injections of the spheres), (iii) the splenocyte phenotypes and their activity after restimulation ex vivo in terms of proliferation and cytokine secretion (after single intravenous injection of the spheres) were analyzed. Although the immunogenicity of MS1 particles was minor, the H2.1MS1 spheres attracted higher levels of B lymphocytes, induced a higher anti-silk antibody titer, and, after ex vivo restimulation, caused the activation of splenocytes to proliferate and express more IFN-γ and IL-10 compared with the PBS and MS1 groups. Although the H2.1MS1 spheres triggered a certain degree of an immunological response, multiple injections (up to six times) neither hampered the carrier-dependent specific drug delivery nor induced toxicity, as previously indicated in a mouse breast cancer model. Both findings indicate that a drug delivery system based on MS1-type silk has great potential for the treatment of cancer and other conditions.
Schistosomes in the Persian Gulf: novel molecular data, host associations, and life-cycle elucidations
Authors: Khosravi Maral , Thieltges David W. , Shamseddin Jebreil , Georgieva Simona
Published: August 2022

Avian schistosomes, comprise a diverse and widespread group of trematodes known for their surprising ability to switch into new hosts and habitats. Despite the considerable research attention on avian schistosomes as causatives of the human cercarial dermatitis, less it is known about the diversity, geographical range and host associations of the marine representatives. Our molecular analyses inferred fromcox1 and 28S DNA sequence data revealed presence of two schistosome species,Ornithobilharzia canaliculata(Rudolphi, 1819) Odhner, 1912 and a putative new species ofAustrobilharziaJohnston, 1917. Molecular elucidation of the life-cycle ofO.canaliculatawas achieved for the first time via matching novel and published sequence data from adult and larval stages. This is the first record ofOrnithobilharziafrom the Persian Gulf and globally the first record of this genus in a potamidid snail host. Our study provides: (i) new host and distribution records for major etiological agents of cercarial dermatitis and contributes important information on host-parasite relationships; (ii) highlights the importance of the molecular systematics in the assessment of schistosome diversity; and (iii) calls for further surveys to reach a better understanding of the schistosome diversity and patterns of relationships among them, host associations, transmission strategies and distribution coverage.
Study of the factors influencing load displacement curve of energy absorbing device by area division simulation
Authors: An Dong , Liu Tianwang , Cui Hewei , Chen Zheng , Xu Hailiang , Song Yimin
Published: August 2022

A pre folded energy absorbing device, which is the key device of energy absorption anti impact for roadway support, is tested by quasi-static compression and simulated. The energy absorbing device is divided into zones, and the influence of the area on the load displacement curve of the energy absorbing device is studied according to the area. It is found that the error of numerical simulation is within 5%, indicating that the finite element modeling procedure is appropriate for the problem analyzed here. The device crushes following the pre folded origami pattern in a stable progressive. The device was divided into four areas: the upper and lower opening region of the concave surface four corner parts; the other areas of opening regions; the middle fold edge; the surrounding four sides edge. Each area has effect on the first drop stage and the second rise stage of the load displacement curve. The middle fold edge area has an effect on the peak load value of load displacement curve. Four indicators of peak load, average load, load efficiency, and specific energy absorption were generated from the results of numerical simulation. The strength enhancement of corner region can ensure the energy absorbing device with low peak load and high mean crushing load. The other areas of opening regions affect the first descending and second ascending of the curve. The first rising stage bears the load from the middle edge.
Dose-dependent toxicity profile and genotoxicity mechanism of lithium carbonate
Authors: Kuloğlu Selin Sipahi , Yalçin Emine , Çavuşoğlu Kültiğin , Acar Ali
Published: August 2022

The increasing widespread use of lithium, which is preferred as an energy source in batteries produced for electric vehicles and in many electronic vehicles such as computers and mobile phones, has made it an important environmental pollutant. In this study, the toxicity profile of lithium carbonate (Li2CO3) was investigated with the Allium test, which is a bio-indicator test. Dose-related toxic effects were investigated using Li2CO3 at doses of 25 mg/L, 50 mg/L, and 100 mg/L. The toxicity profile was determined by examining physiological, cytotoxic, genotoxic, biochemical and anatomical effects. Physiological effects of Li2CO3 were determined by root length, injury rate, germination percentage and weight gain while cytotoxic effects were determined by mitotic index (MI) ratio and genotoxic effects were determined by micronucleus (MN) and chromosomal aberrations (CAs). The effect of Li2CO3 on antioxidant and oxidant dynamics was determined by examining glutathione (GSH), malondialdehyde (MDA), catalase (CAT) and superoxide dismutase (SOD) levels, and anatomical changes were investigated in the sections of root meristematic tissues. As a result, Li2CO3 exhibited a dose-dependent regression in germination-related parameters. This regression is directly related to the MI and 100 mg/L Li2CO3 reduced MI by 38% compared to the control group. MN and CAs were observed at high rates in the groups treated with Li2CO3. Fragments were found with the highest rate among CAs. Other damages were bridge, unequal distribution of chromatin, sticky chromosome, vagrant chromosome, irregular mitosis, reverse polarization and multipolar anaphase. The genotoxic effects were associated with Li2CO3-DNA interactions determined by molecular docking. The toxic effects of Li2CO3 are directly related to the deterioration of the antioxidant/oxidant balance in the cells. While MDA, an indicator of lipid peroxidation, increased by 59.1% in the group administered 100 mg/L Li2CO3, GSH, which has an important role in cell defense, decreased by 60.8%. Significant changes were also detected in the activities of SOD and CAT, two important enzymes in antioxidant defense, compared to the control. These toxic effects, which developed in the cells belonging to the lithium-treated groups, were also reflected in the tissue anatomy, and anatomical changes such as epidermis cell damage, cortex cell damage, flattened cell nucleus, thickening of the cortex cell wall and unclear vascular tissue were observed in the anatomical sections. The frequency of these changes also increased depending on the Li2CO3 dose. As a result, Li2CO3, which is one of the lithium compounds, and has become an important contaminant in the environment with increasing technological developments, caused a combined and versatile toxicity in Allium cepa L. meristematic cells, especially by causing deterioration in antioxidant/oxidant dynamics.
Structure of human spermine oxidase in complex with a highly selective allosteric inhibitor
Authors: Diaz Elsie , Adhikary Suraj , Tepper Armand W. J. W. , Riley Daniel , Ortiz-Meoz Rodrigo , Krosky Daniel , Buyck Christophe , Lamenca Carolina Martinez , Llaveria Josep , Fang Lichao , Kalin Jay H. , Klaren Vincent N. A. , Fahmy Shorouk , Shaffer Paul L. , Kirkpatrick Robert , Carbajo Rodrigo J. , Thomsen Maren , Impagliazzo Antonietta
Published: August 2022

Human spermine oxidase (hSMOX) plays a central role in polyamine catabolism. Due to its association with several pathological processes, including inflammation and cancer, hSMOX has garnered interest as a possible therapeutic target. Therefore, determination of the structure of hSMOX is an important step to enable drug discovery and validate hSMOX as a drug target. Using insights from hydrogen/deuterium exchange mass spectrometry (HDX-MS), we engineered a hSMOX construct to obtain the first crystal structure of hSMOX bound to the known polyamine oxidase inhibitor MDL72527 at 2.4 Å resolution. While the overall fold of hSMOX is similar to its homolog, murine N1-acetylpolyamine oxidase (mPAOX), the two structures contain significant differences, notably in their substrate-binding domains and active site pockets. Subsequently, we employed a sensitive biochemical assay to conduct a high-throughput screen that identified a potent and selective hSMOX inhibitor, JNJ-1289. The co-crystal structure of hSMOX with JNJ-1289 was determined at 2.1 Å resolution, revealing that JNJ-1289 binds to an allosteric site, providing JNJ-1289 with a high degree of selectivity towards hSMOX. These results provide crucial insights into understanding the substrate specificity and enzymatic mechanism of hSMOX, and for the design of highly selective inhibitors.
Topological flat bands in a kagome lattice multiorbital system
Authors: Okamoto Satoshi , Mohanta Narayan , Dagotto Elbio , Sheng D. N.
Published: August 2022

Flat bands and dispersive Dirac bands are known to coexist in the electronic bands in a two-dimensional kagome lattice. Including the relativistic spin-orbit coupling, such systems often exhibit nontrivial band topology, allowing for gapless edge modes between flat bands at several locations in the band structure, and dispersive bands or at the Dirac band crossing. Here, we theoretically demonstrate that a multiorbital system on a kagome lattice is a versatile platform to explore the interplay between nontrivial band topology and electronic interaction. Specifically, here we report that the multiorbital kagome model with the atomic spin–orbit coupling naturally supports topological bands characterized by nonzero Chern numbers $${{{{{{{\mathcal{C}}}}}}}}$$
C
, including a flat band with $$| {{{{{{{\mathcal{C}}}}}}}}| =1$$
∣
C
∣
=
1
. When such a flat band is 1/3 filled, the non-local repulsive interactions induce a fractional Chern insulating state. We also discuss the possible realization of our findings in real kagome materials.
Understanding irradiation damage in high-temperature superconductors for fusion reactors using high resolution X-ray absorption spectroscopy
Authors: Nicholls Rebecca J. , Diaz-Moreno Sofia , Iliffe William , Linden Yatir , Mousavi Tayebeh , Aramini Matteo , Danaie Mohsen , Grovenor Chris R. M. , Speller Susannah C.
Published: August 2022

Understanding the effects of fast neutrons on high-temperature superconductors is of growing importance as new compact fusion reactors rely on these materials to generate the high magnetic fields needed to confine the plasma. The critical temperature of the most promising candidate material for small-scale fusion devices, rare-earth barium cuprate, is known to decrease monotonically with radiation dose, indicating the generation of lattice defects everywhere in the material. Here, we use high-energy-resolution X-ray absorption spectroscopy to probe how the local environment around the copper atoms is influenced by point defects induced by He+ ion irradiation in the oxygen sublattice. Density functional theory calculations are used to interpret spectral features and we find clear evidence that ion irradiation significantly disrupts the bonding environment around the copper atoms in the copper-oxygen planes responsible for superconductivity in this compound. We propose the generation of a specific Frenkel defect that is consistent with our experimental results. Our results challenge previous assumptions in the literature that irradiation produces point defects only in the chain sites. In addition, we show that partial recovery is possible by annealing at modest temperatures, which may have implications for the operation of superconducting fusion magnets.
High-performance miniature linear time-of-flight mass spectrometry as an advantageous tool in a high mass-to-charge range
Authors: Chang Ko-Keng , Cai Yi-Hong , Hsiao Chih-Hao , Hsu Cheng-Chih , Wang Yi-Sheng
Published: August 2022

A newly developed miniature MALDI-TOF mass spectrometer provides superior performance in a high m/z range.
Imitate to illuminate: labeling of bacterial peptidoglycan with fluorescent and bio-orthogonal stem peptide-mimicking probes
Authors: Lin Huibin , Yang Chaoyong , Wang Wei
Published: August 2022

By imitating the structures of stem peptide, many fluorescent and bio-orthogonal labeling probes have been designed and used in illuminating the peptidoglycan biosynthesis processes.
Correction: Catalytic (3 + 2) umpolung annulations of α-thioacyl carbenes with aryl isothiocyanates
Authors: Dong Ziyang , Ma Meng-Yao , Xu Jiaxi , Yang Zhanhui
Published: August 2022

Correction for ‘Catalytic (3 + 2) umpolung annulations of α-thioacyl carbenes with aryl isothiocyanates’ by Ziyang Dong et al., Chem. Commun., 2022, 58, 7980–7983, https://doi.org/10.1039/D2CC02882D.