bluuebunny/crossref_metadata_2025 huggingface dataset:
Water Film Thickness in Unsaturated Porous Media: Effect of Pore Size, Pore Solution Chemistry, and Mineral Type
Authors: Nishiyama Naoki , Yokoyama Tadashi
Published: May 2021

The thickness of the water film on minerals is key for a quantitative understanding of mass transport and reaction in porous media under air entrapment. How the film thickness changes with pore structure, ionic strength, pH, and type of mineral, however, is not fully understood. Here, we present a model to predict the film thickness in porous media under air entrapment. The model numerically solves the Poisson–Boltzmann equation combined with the electrical triple‐layer model to consider the overlapping of electric double layers (EDLs) in the film, where EDLs formed at the mineral/water and air/water interfaces interact with each other. Based on the model, we estimated the film thickness for silica, montmorillonite, calcite, and goethite for various ionic strengths and pH. With decreasing film thickness, the overlapping of EDLs reduces the surface charges but increases the electric potentials of silica/water and air/water interfaces. The predicted film thickness for silica generally agreed with the measured value. The film on calcite and goethite is significantly thinner than that on silica and montmorillonite because the surface charges for calcite and goethite have a sign opposite to that of the air/water interface. Our model shows that the pore radius, ionic strength, pH, and sign of surface charge are the primary factors controlling the film thickness. When the ionic strength and pH are similar to those of rainwater, river water, and groundwater, the typical film thicknesses for silica in silt, sand, and gravel were predicted to be <14 nm, 14–45 nm, and >23 nm, respectively.
A New Tool May Make Geological Microscopy Data More Accessible
Authors: Sima Richard
Published: May 2021

PiAutoStage can automatically digitize and send microscope samples to students and researchers on the cheap and from a distance.
Aurora kinase A, a synthetic lethal target for precision cancer medicine
Authors: Mou Pui Kei , Yang Eun Ju , Shi Changxiang , Ren Guowen , Tao Shishi , Shim Joong Sup
Published: May 2021

Recent advances in high-throughput sequencing technologies and data science have facilitated the development of precision medicine to treat cancer patients. Synthetic lethality is one of the core methodologies employed in precision cancer medicine. Synthetic lethality describes the phenomenon of the interplay between two genes in which deficiency of a single gene does not abolish cell viability but combined deficiency of two genes leads to cell death. In cancer treatment, synthetic lethality is leveraged to exploit the dependency of cancer cells on a pathway that is essential for cell survival when a tumor suppressor is mutated. This approach enables pharmacological targeting of mutant tumor suppressors that are theoretically undruggable. Successful clinical introduction of BRCA-PARP synthetic lethality in cancer treatment led to additional discoveries of novel synthetic lethal partners of other tumor suppressors, including p53, PTEN, and RB1, using high-throughput screening. Recent work has highlighted aurora kinase A (AURKA) as a synthetic lethal partner of multiple tumor suppressors. AURKA is a serine/threonine kinase involved in a number of central biological processes, such as the G2/M transition, mitotic spindle assembly, and DNA replication. This review introduces synthetic lethal interactions between AURKA and its tumor suppressor partners and discusses the potential of AURKA inhibitors in precision cancer medicine.
Efficacy and tolerability of repetitive transcranial magnetic stimulation for the treatment of obsessive-compulsive disorder in adults: a systematic review and network meta-analysis
Authors: Liang Kaili , Li Hailong , Bu Xuan , Li Xue , Cao Lingxiao , Liu Jing , Gao Yingxue , Li Bin , Qiu Changjian , Bao Weijie , Zhang Suming , Hu Xinyu , Xing Haoyang , Gong Qiyong , Huang Xiaoqi
Published: May 2021

Repetitive transcranial magnetic stimulation (rTMS) has been widely used as an alternative treatment for obsessive-compulsive disorder (OCD). However, the most effective rTMS parameters, such as the targets and stimulation frequencies, remain controversial. Therefore, we aimed to compare and rank the efficacy and tolerability of different rTMS strategies for OCD treatment. We searched five electronic databases from the date of their inception to March 25, 2020. Pairwise meta-analyses and network meta-analyses were performed to synthesize data. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Twenty-two eligible randomized controlled trials (RCTs) were included. For efficacy, low-frequency (LF) rTMS over the dorsolateral prefrontal cortex (DLPFC; mean difference (MD) 6.34, 95% credible interval (CrI) 2.12–10.42) and supplementary motor area (MD 4.18, 95% CrI 0.83–7.62), and high-frequency rTMS over the DLPFC (MD 3.75, 95% CrI 1.04–6.81) were more effective than sham rTMS. Regarding tolerability, all rTMS treatment strategies were similar to the sham rTMS. The estimated ranking probabilities of treatments showed that LF-rTMS over the DLPFC might be the most effective intervention among all rTMS strategies. However, the quality of evidence regarding efficacy was evaluated as very low. Current evidence suggested a marginal advantage for LF-rTMS over the DLPFC on OCD treatment. High-quality RCTs with low selection and performance bias are needed to further verify the efficacy of specific rTMS strategies for the OCD treatment.
Mindfulness practice for protecting mental health during the COVID-19 pandemic
Authors: Zhu Julie Lei , Schülke Rasmus , Vatansever Deniz , Xi Dayou , Yan Junjie , Zhao Hanqing , Xie Xiaohua , Feng Jianfeng , Chen Mark Yuting , Sahakian Barbara Jacquelyn , Wang Shouyan
Published: May 2021

Emerging evidence shows that the coronavirus disease 2019 (COVID-19) pandemic is negatively affecting mental health around the globe. Interventions to alleviate the psychological impact of the pandemic are urgently needed. Whether mindfulness practice may protect against the harmful emotional effects of a pandemic crisis remains hitherto unknown. We investigated the influence of mindfulness training on mental health during the COVID-19 outbreak in China. We hypothesized that mindfulness practitioners might manifest less pandemic-related distress, depression, anxiety, and stress than non-practitioners and that more frequent practice would be associated with an improvement in mental health during the pandemic. Therefore, we assessed pandemic-related distress and symptoms of depression, anxiety, and stress, as well as the frequency of meditation practice at the peak of new infections (Feb 4–5; N = 673) and three weeks later (Feb 29–30; N = 521) in mindfulness practitioners via online questionnaires. Self-reported symptoms were also collected from non-practitioners at peak time only (N = 1550). We found lower scores of pandemic-related distress in mindfulness practitioners compared to non-practitioners. In general, older participants showed fewer symptoms of depression and anxiety. In younger practitioners, pandemic-related distress decreased from peak to follow-up. Importantly, increased mindfulness training during the preceding two weeks was associated with lower scores of depression and anxiety at both assessments. Likewise, practice frequency predicted individual improvement in scores of depression, anxiety, and stress at follow-up. Our results indicate that mindfulness meditation might be a viable low-cost intervention to mitigate the psychological impact of the COVID-19 crisis and future pandemics.
LncRNA H19 governs mitophagy and restores mitochondrial respiration in the heart through Pink1/Parkin signaling during obesity
Authors: Wang Shao-Hua , Zhu Xiao-Lin , Wang Fei , Chen Si-Xu , Chen Zhi-Teng , Qiu Qiong , Liu Wen-Hao , Wu Mao-Xiong , Deng Bing-Qing , Xie Yong , Mai Jing-Ting , Yang Ying , Wang Jing-Feng , Zhang Hai-Feng , Chen Yang-Xin
Published: May 2021

Maintaining proper mitochondrial respiratory function is crucial for alleviating cardiac metabolic disorders during obesity, and mitophagy is critically involved in this process. Long non-coding RNA H19 (H19) is crucial for metabolic regulation, but its roles in cardiac disorders, mitochondrial respiratory function, and mitophagy during obesity are largely unknown. In this study, palmitic acid (PA)-treated H9c2 cell and Lep−/− mice were used to investigate cardiac metabolic disorders in vitro and in vivo, respectively. The effects of H19 on metabolic disorders, mitochondrial respiratory function, and mitophagy were investigated. Moreover, the regulatory mechanisms of PA, H19, mitophagy, and respiratory function were examined. The models tested displayed a reduction in H19 expression, respiratory function and mitochondrial number and volume, while the expression of mitophagy- and Pink1/Parkin signaling-related proteins was upregulated, as indicated using quantitative real-time PCR, Seahorse mitochondrial stress test analyzer, transmission electron microscopy, fluorescence indicators and western blotting. Forced expression of H19 helped to the recoveries of respiratory capacity and mitochondrial number while inhibited the levels of mitophagy- and Pink1/Parkin signaling-related proteins. Pink1 knockdown also attenuated PA-induced mitophagy and increased respiratory capacity. Mechanistically, RNA pull-down, mass spectrometry, and RNA-binding protein immunoprecipitation assays showed that H19 could hinder the binding of eukaryotic translation initiation factor 4A, isoform 2 (eIF4A2) with Pink1 mRNA, thus inhibiting the translation of Pink1 and attenuation of mitophagy. PA significantly increased the methylation levels of the H19 promoter region by upregulation Dnmt3b methylase levels, thereby inhibiting H19 transcription. Collectively, these findings suggest that DNA methylation-mediated the downregulation of H19 expression plays a crucial role in cardiomyocyte or H9c2 cells metabolic disorders and induces cardiac respiratory dysfunction by promoting mitophagy. H19 inhibits excessive mitophagy by limiting Pink1 mRNA translation, thus alleviating this cardiac defect that occurs during obesity.
Anti-miR-518d-5p overcomes liver tumor cell death resistance through mitochondrial activity
Authors: Fernández-Tussy Pablo , Rodríguez-Agudo Rubén , Fernández-Ramos David , Barbier-Torres Lucía , Zubiete-Franco Imanol , Davalillo Sergio López de , Herraez Elisa , Goikoetxea-Usandizaga Naroa , Lachiondo-Ortega Sofia , Simón Jorge , Lopitz-Otsoa Fernando , Juan Virginia Gutiérrez-de , McCain Misti V. , Perugorria Maria J. , Mabe Jon , Navasa Nicolás , Rodrigues Cecilia M. P. , Fabregat Isabel , Boix Loreto , Sapena Victor , Anguita Juan , Lu Shelly C. , Mato José M. , Banales Jesus M. , Villa Erica , Reeves Helen L. , Bruix Jordi , Reig Maria , Marin Jose J. G. , Delgado Teresa C. , Martínez-Chantar María L.
Published: May 2021

Dysregulation of miRNAs is a hallmark of cancer, modulating oncogenes, tumor suppressors, and drug responsiveness. The multi-kinase inhibitor sorafenib is one of the first-line drugs for advanced hepatocellular carcinoma (HCC), although the outcome for treated patients is heterogeneous. The identification of predictive biomarkers and targets of sorafenib efficacy are sorely needed. Thus, selected top upregulated miRNAs from the C19MC cluster were analyzed in different hepatoma cell lines compared to immortalized liver human cells, THLE-2 as control. MiR-518d-5p showed the most consistent upregulation among them. Thus, miR-518d-5p was measured in liver tumor/non-tumor samples of two distinct cohorts of HCC patients (n = 16 andn = 20, respectively). Circulating miR-518d-5p was measured in an independent cohort of HCC patients receiving sorafenib treatment (n = 100), where miR-518d-5p was analyzed in relation to treatment duration and patient’s overall survival. In vitro and in vivo studies were performed in human hepatoma BCLC3 and Huh7 cells to analyze the effect of miR-518d-5p inhibition/overexpression during the response to sorafenib. Compared with healthy individuals, miR-518d-5p levels were higher in hepatic and serum samples from HCC patients (n = 16) and in an additional cohort of tumor/non-tumor paired samples (n = 20). MiR-518d-5p, through the inhibition of c-Jun and its mitochondrial target PUMA, desensitized human hepatoma cells and mouse xenograft to sorafenib-induced apoptosis. Finally, serum miR-518d-5p was assessed in 100 patients with HCC of different etiologies and BCLC-stage treated with sorafenib. In BCLC-C patients, higher serum miR-518d-5p at diagnosis was associated with shorter sorafenib treatment duration and survival. Hence, hepatic miR-518d-5p modulates sorafenib resistance in HCC through inhibition of c-Jun/PUMA-induced apoptosis. Circulating miR-518d-5p emerges as a potential lack of response biomarker to sorafenib in BCLC-C HCC patients.
KLHL38 involvement in non-small cell lung cancer progression via activation of the Akt signaling pathway
Authors: Xu Yitong , Wang Chenglong , Jiang Xizi , Zhang Yao , Su Hongbo , Jiang Jun , Ren Hongjiu , Qiu Xueshan
Published: May 2021

Lung cancer is the leading cause of cancer-related death worldwide. KLHL38 has been reported to be upregulated during diapause but downregulated after androgen treatment during the reversal of androgen-dependent skeletal muscle atrophy. This study aimed to clarify the role of KLHL38 in non-small cell lung cancer (NSCLC). KLHL38 expression was evaluated in tumor and adjacent normal tissues from 241 patients with NSCLC using immunohistochemistry and real-time PCR, and its association with clinicopathological parameters was analyzed. KLHL38 levels positively correlated with tumor size, lymph node metastasis, and pathological tumor-node-metastasis stage (all P < 0.001). In NSCLC cell lines, KLHL38 overexpression promoted PTEN ubiquitination, thereby activating Akt signaling. It also promoted cell proliferation, migration, and invasion by upregulating the expression of genes encoding cyclin D1, cyclin B, c-myc, RhoA, and MMP9, while downregulating the expression of p21 and E-cadherin. In vivo experiments in nude mice further confirmed that KLHL38 promotes NSCLC progression through Akt signaling pathway activation. Together, these results indicate that KLHL38 is a valuable candidate prognostic biomarker and potential therapeutic target for NSCLC.
Neocortex- and hippocampus-specific deletion of Gabrg2 causes temperature-dependent seizures in mice
Authors: Li Xinxiao , Guo Shengnan , Xu Siying , Chen Zhangping , Wang Lei , Ding Jiangwei , Huo Junming , Xiao Lifei , He Zhenquan , Jin Zhe , Wang Feng , Sun Tao
Published: May 2021

Mutations in the GABRG2 gene encoding the γ-aminobutyric acid (GABA) A receptor gamma 2 subunit are associated with genetic epilepsy with febrile seizures plus, febrile seizures plus, febrile seizures, and other symptoms of epilepsy. However, the mechanisms underlying Gabrg2-mediated febrile seizures are poorly understood. Here, we used the Cre/loxP system to generate conditional knockout (CKO) mice with deficient Gabrg2 in the hippocampus and neocortex. Heterozygous CKO mice (Gabrg2fl/wtCre+) exhibited temperature-dependent myoclonic jerks, generalised tonic-clonic seizures, increased anxiety-like symptoms, and a predisposition to induce seizures. Cortical electroencephalography showed the hyperexcitability in response to temperature elevation in Gabrg2fl/wtCre+ mice, but not in wild-type mice. Gabrg2fl/wtCre+ mice exhibited spontaneous seizures and susceptibility to temperature-induced seizures. Loss of neurons were observed in cortical layers V–VI and hippocampus of Gabrg2fl/wtCre+ mice. Furthermore, the latency of temperature- or pentylenetetrazol-induced seizures were significantly decreased in Gabrg2fl/wtCre+ mice compared with wild-type mice. In summary, Gabrg2fl/wtCre+ mice with Gabrg2 deletion in the neocortex and hippocampus reproduce many features of febrile seizures and therefore provide a novel model to further understand this syndrome at the cellular and molecular level.
Nanonet: Low-temperature-processed tellurium nanowire network for scalable p-type field-effect transistors and a highly sensitive phototransistor array
Authors: Naqi Muhammad , Choi Kyung Hwan , Yoo Hocheon , Chae Sudong , Kim Bum Jun , Oh Seungbae , Jeon Jiho , Wang Cong , Liu Na , Kim Sunkook , Choi Jae-Young
Published: May 2021

Low-temperature-processed semiconductors are an emerging need for next-generation scalable electronics, and these semiconductors need to feature large-area fabrication, solution processability, high electrical performance, and wide spectral optical absorption properties. Although various strategies of low-temperature-processed n-type semiconductors have been achieved, the development of high-performance p-type semiconductors at low temperature is still limited. Here, we report a unique low-temperature-processed method to synthesize tellurium nanowire networks (Te-nanonets) over a scalable area for the fabrication of high-performance large-area p-type field-effect transistors (FETs) with uniform and stable electrical and optical properties. Maximum mobility of 4.7 cm2/Vs, an on/off current ratio of 1 × 104, and a maximum transconductance of 2.18 µS are achieved. To further demonstrate the applicability of the proposed semiconductor, the electrical performance of a Te-nanonet-based transistor array of 42 devices is also measured, revealing stable and uniform results. Finally, to broaden the applicability of p-type Te-nanonet-based FETs, optical measurements are demonstrated over a wide spectral range, revealing an exceptionally uniform optical performance.
A sand fly salivary protein acts as a neutrophil chemoattractant
Authors: Guimaraes-Costa Anderson B. , Shannon John P. , Waclawiak Ingrid , Oliveira Jullyanna , Meneses Claudio , de Castro Waldione , Wen Xi , Brzostowski Joseph , Serafim Tiago D. , Andersen John F. , Hickman Heather D. , Kamhawi Shaden , Valenzuela Jesus G. , Oliveira Fabiano
Published: May 2021

Apart from bacterial formyl peptides or viral chemokine mimicry, a non-vertebrate or insect protein that directly attracts mammalian innate cells such as neutrophils has not been molecularly characterized. Here, we show that members of sand fly yellow salivary proteins induce in vitro chemotaxis of mouse, canine and human neutrophils in transwell migration or EZ-TAXIScan assays. We demonstrate murine neutrophil recruitment in vivo using flow cytometry and two-photon intravital microscopy in Lysozyme-M-eGFP transgenic mice. We establish that the structure of this ~ 45 kDa neutrophil chemotactic protein does not resemble that of known chemokines. This chemoattractant acts through a G-protein-coupled receptor and is dependent on calcium influx. Of significance, this chemoattractant protein enhances lesion pathology (P < 0.0001) and increases parasite burden (P < 0.001) in mice upon co-injection with Leishmania parasites, underlining the impact of the sand fly salivary yellow proteins on disease outcome. These findings show that some arthropod vector-derived factors, such as this chemotactic salivary protein, activate rather than inhibit the host innate immune response, and that pathogens take advantage of these inflammatory responses to establish in the host.
Bell-state tomography in a silicon many-electron artificial molecule
Authors: Leon Ross C. C. , Yang Chih Hwan , Hwang Jason C. C. , Camirand Lemyre Julien , Tanttu Tuomo , Huang Wei , Huang Jonathan Y. , Hudson Fay E. , Itoh Kohei M. , Laucht Arne , Pioro-Ladrière Michel , Saraiva Andre , Dzurak Andrew S.
Published: May 2021

An error-corrected quantum processor will require millions of qubits, accentuating the advantage of nanoscale devices with small footprints, such as silicon quantum dots. However, as for every device with nanoscale dimensions, disorder at the atomic level is detrimental to quantum dot uniformity. Here we investigate two spin qubits confined in a silicon double quantum dot artificial molecule. Each quantum dot has a robust shell structure and, when operated at an occupancy of 5 or 13 electrons, has single spin-$$\frac{1}{2}$$

1

2

valence electron in its p- or d-orbital, respectively. These higher electron occupancies screen static electric fields arising from atomic-level disorder. The larger multielectron wavefunctions also enable significant overlap between neighbouring qubit electrons, while making space for an interstitial exchange-gate electrode. We implement a universal gate set using the magnetic field gradient of a micromagnet for electrically driven single qubit gates, and a gate-voltage-controlled inter-dot barrier to perform two-qubit gates by pulsed exchange coupling. We use this gate set to demonstrate a Bell state preparation between multielectron qubits with fidelity 90.3%, confirmed by two-qubit state tomography using spin parity measurements.
Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden
Authors: Peneder Peter , Stütz Adrian M. , Surdez Didier , Krumbholz Manuela , Semper Sabine , Chicard Mathieu , Sheffield Nathan C. , Pierron Gaelle , Lapouble Eve , Tötzl Marcus , Ergüner Bekir , Barreca Daniele , Rendeiro André F. , Agaimy Abbas , Boztug Heidrun , Engstler Gernot , Dworzak Michael , Bernkopf Marie , Taschner-Mandl Sabine , Ambros Inge M. , Myklebost Ola , Marec-Bérard Perrine , Burchill Susan Ann , Brennan Bernadette , Strauss Sandra J. , Whelan Jeremy , Schleiermacher Gudrun , Schaefer Christiane , Dirksen Uta , Hutter Caroline , Boye Kjetil , Ambros Peter F. , Delattre Olivier , Metzler Markus , Bock Christoph , Tomazou Eleni M.
Published: May 2021

Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. Moreover, we benchmark different metrics for cell-free DNA fragmentation analysis, and we introduce the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. Finally, we combine several fragmentation-based metrics into an integrated machine learning classifier for liquid biopsy analysis that exploits widespread epigenetic deregulation and is tailored to cancers with low mutation rates. Clinical associations highlight the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent genetic aberrations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers.
Rationally designed bacterial consortia to treat chronic immune-mediated colitis and restore intestinal homeostasis
Authors: van der Lelie Daniel , Oka Akihiko , Taghavi Safiyh , Umeno Junji , Fan Ting-Jia , Merrell Katherine E. , Watson Sarah D. , Ouellette Lisa , Liu Bo , Awoniyi Muyiwa , Lai Yunjia , Chi Liang , Lu Kun , Henry Christopher S. , Sartor R. Balfour
Published: May 2021

Environmental factors, mucosal permeability and defective immunoregulation drive overactive immunity to a subset of resident intestinal bacteria that mediate multiple inflammatory conditions. GUT-103 and GUT-108, live biotherapeutic products rationally designed to complement missing or underrepresented functions in the dysbiotic microbiome of IBD patients, address upstream targets, rather than targeting a single cytokine to block downstream inflammation responses. GUT-103, composed of 17 strains that synergistically provide protective and sustained engraftment in the IBD inflammatory environment, prevented and treated chronic immune-mediated colitis. Therapeutic application of GUT-108 reversed established colitis in a humanized chronic T cell-mediated mouse model. It decreased pathobionts while expanding resident protective bacteria; produced metabolites promoting mucosal healing and immunoregulatory responses; decreased inflammatory cytokines and Th-1 and Th-17 cells; and induced interleukin-10-producing colonic regulatory cells, and IL-10-independent homeostatic pathways. We propose GUT-108 for treating and preventing relapse for IBD and other inflammatory conditions characterized by unbalanced microbiota and mucosal permeability.
Robust coherent control of solid-state spin qubits using anti-Stokes excitation
Authors: Wang Jun-Feng , Yan Fei-Fei , Li Qiang , Liu Zheng-Hao , Cui Jin-Ming , Liu Zhao-Di , Gali Adam , Xu Jin-Shi , Li Chuan-Feng , Guo Guang-Can
Published: May 2021

Optically addressable solid-state color center spin qubits have become important platforms for quantum information processing, quantum networks and quantum sensing. The readout of color center spin states with optically detected magnetic resonance (ODMR) technology is traditionally based on Stokes excitation, where the energy of the exciting laser is higher than that of the emission photons. Here, we investigate an unconventional approach using anti-Stokes excitation to detect the ODMR signal of silicon vacancy defect spin in silicon carbide, where the exciting laser has lower energy than the emitted photons. Laser power, microwave power and temperature dependence of the anti-Stokes excited ODMR are systematically studied, in which the behavior of ODMR contrast and linewidth is shown to be similar to that of Stokes excitation. However, the ODMR contrast is several times that of the Stokes excitation. Coherent control of silicon vacancy spin under anti-Stokes excitation is then realized at room temperature. The spin coherence properties are the same as those of Stokes excitation, but with a signal contrast that is around three times greater. To illustrate the enhanced spin readout contrast under anti-Stokes excitation, we also provide a theoretical model. The experiments demonstrate that the current anti-Stokes excitation ODMR approach has promising applications in quantum information processing and quantum sensing.
Dynamic methylation of histone H3K18 in differentiating Theileria parasites
Authors: Cheeseman Kevin , Jannot Guillaume , Lourenço Nelly , Villares Marie , Berthelet Jérémy , Calegari-Silva Teresa , Hamroune Juliette , Letourneur Franck , Rodrigues-Lima Fernando , Weitzman Jonathan B.
Published: May 2021

Lysine methylation on histone tails impacts genome regulation and cell fate determination in many developmental processes. Apicomplexa intracellular parasites cause major diseases and they have developed complex life cycles with fine-tuned differentiation events. Yet, apicomplexa genomes have few transcription factors and little is known about their epigenetic control systems. Tick-borne Theileria apicomplexa species have relatively small, compact genomes and a remarkable ability to transform leucocytes in their bovine hosts. Here we report enriched H3 lysine 18 monomethylation (H3K18me1) on the gene bodies of repressed genes in Theileria macroschizonts. Differentiation to merozoites (merogony) leads to decreased H3K18me1 in parasite nuclei. Pharmacological manipulation of H3K18 acetylation or methylation impacted parasite differentiation and expression of stage-specific genes. Finally, we identify a parasite SET-domain methyltransferase (TaSETup1) that can methylate H3K18 and represses gene expression. Thus, H3K18me1 emerges as an important epigenetic mark which controls gene expression and stage differentiation in Theileria parasites.
Magnetic charge propagation upon a 3D artificial spin-ice
Authors: May A. , Saccone M. , van den Berg A. , Askey J. , Hunt M. , Ladak S.
Published: May 2021

Magnetic charge propagation in spin-ice materials has yielded a paradigm-shift in science, allowing the symmetry between electricity and magnetism to be studied. Recent work is now suggesting the spin-ice surface may be important in mediating the ordering and associated phase space in such materials. Here, we detail a 3D artificial spin-ice, which captures the exact geometry of bulk systems, allowing magnetic charge dynamics to be directly visualized upon the surface. Using magnetic force microscopy, we observe vastly different magnetic charge dynamics along two principal directions. For a field applied along the surface termination, local energetics force magnetic charges to nucleate over a larger characteristic distance, reducing their magnetic Coulomb interaction and producing uncorrelated monopoles. In contrast, applying a field transverse to the surface termination yields highly correlated monopole-antimonopole pairs. Detailed simulations suggest it is the difference in effective chemical potential as well as the energy landscape experienced during dynamics that yields the striking differences in monopole transport.
Photon bubble turbulence in cold atom gases
Authors: Giampaoli R. , Rodrigues João D. , Rodrigues José-António , Mendonça J. T.
Published: May 2021

Turbulent radiation flow is commonplace in systems with strong, incoherent, light-matter interactions. In astrophysical contexts, photon bubble turbulence is considered a key mechanism behind enhanced radiation transport, and its importance has been widely asserted for a variety of high energy objects such as accretion disks and massive stars. Here, we show that analogous conditions to those of dense astrophysical objects can be obtained in large clouds of cold atoms, prepared in a laser-cooling experiment, driven close to a sharp electronic resonance. By accessing the spatially-resolved atom density, we are able to identify a photon bubble instability and the resulting regime of photon bubble turbulence. We also develop a theoretical model describing the coupled dynamics of both photon and atom gases, which accurately describes the statistical properties of the turbulent regime. This study thus opens the possibility of simulating radiation-dominated astrophysical systems in cold atom experiments.
Structures of the human LONP1 protease reveal regulatory steps involved in protease activation
Authors: Shin Mia , Watson Edmond R. , Song Albert S. , Mindrebo Jeffrey T. , Novick Scott J. , Griffin Patrick R. , Wiseman R. Luke , Lander Gabriel C.
Published: May 2021

The human mitochondrial AAA+ protein LONP1 is a critical quality control protease involved in regulating diverse aspects of mitochondrial biology including proteostasis, electron transport chain activity, and mitochondrial transcription. As such, genetic or aging-associated imbalances in LONP1 activity are implicated in pathologic mitochondrial dysfunction associated with numerous human diseases. Despite this importance, the molecular basis for LONP1-dependent proteolytic activity remains poorly defined. Here, we solved cryo-electron microscopy structures of human LONP1 to reveal the underlying molecular mechanisms governing substrate proteolysis. We show that, like bacterial Lon, human LONP1 adopts both an open and closed spiral staircase orientation dictated by the presence of substrate and nucleotide. Unlike bacterial Lon, human LONP1 contains a second spiral staircase within its ATPase domain that engages substrate as it is translocated toward the proteolytic chamber. Intriguingly, and in contrast to its bacterial ortholog, substrate binding within the central ATPase channel of LONP1 alone is insufficient to induce the activated conformation of the protease domains. To successfully induce the active protease conformation in substrate-bound LONP1, substrate binding within the protease active site is necessary, which we demonstrate by adding bortezomib, a peptidomimetic active site inhibitor of LONP1. These results suggest LONP1 can decouple ATPase and protease activities depending on whether AAA+ or both AAA+ and protease domains bind substrate. Importantly, our structures provide a molecular framework to define the critical importance of LONP1 in regulating mitochondrial proteostasis in health and disease.
Cooperative stator assembly of bacterial flagellar motor mediated by rotation
Authors: Ito Kenta I. , Nakamura Shuichi , Toyabe Shoichi
Published: May 2021

Cooperativity has a central place in biological regulation, providing robust and highly-sensitive regulation. The bacterial flagellar motor implements autonomous torque regulation based on the stator’s dynamic structure; the stator units bind to and dissociate from the motor dynamically in response to environmental changes. However, the mechanism of this dynamic assembly is not fully understood. Here, we demonstrate the cooperativity in the stator assembly dynamics. The binding is slow at the stalled state, but externally forced rotation as well as driving by motor torque in either direction boosts the stator binding. Hence, once a stator unit binds, it drives the rotor and triggers the avalanche of succeeding bindings. This cooperative mechanism based on nonequilibrium allostery accords with the recently-proposed gear-type coupling between the rotor and stator.
Electrosynthesis of 1,4-bis(diphenylphosphanyl) tetrasulfide via sulfur radical addition as cathode material for rechargeable lithium battery
Authors: Wang Dan-Yang , Si Yubing , Guo Wei , Fu Yongzhu
Published: May 2021

Organic electrodes are promising as next generation energy storage materials originating from their enormous chemical diversity and electrochemical specificity. Although organic synthesis methods have been extended to a broad range, facile and selective methods are still needed to expose the corners of chemical space. Herein, we report the organopolysulfide, 1,4-bis(diphenylphosphanyl)tetrasulfide, which is synthesized by electrochemical oxidation of diphenyl dithiophosphinic acid featuring the cleavage of a P–S single bond and a sulfur radical addition reaction. Density functional theory proves that the external electric field triggers the intramolecular rearrangement of diphenyl dithiophosphinic acid through dehydrogenation and sulfur migration along the P–S bond axis. Impressively, the Li/bis(diphenylphosphanyl)tetrasulfide cell exhibits the high discharge voltage of 2.9 V and stable cycling performance of 500 cycles with the capacity retention of 74.8%. Detailed characterizations confirm the reversible lithiation/delithiation process. This work demonstrates that electrochemical synthesis offers the approach for the preparation of advanced functional materials.
Pareto optimality between growth-rate and lag-time couples metabolic noise to phenotypic heterogeneity in Escherichia coli
Authors: Fuentes Diego Antonio Fernandez , Manfredi Pablo , Jenal Urs , Zampieri Mattia
Published: May 2021

Despite mounting evidence that in clonal bacterial populations, phenotypic variability originates from stochasticity in gene expression, little is known about noise-shaping evolutionary forces and how expression noise translates to phenotypic differences. Here we developed a high-throughput assay that uses a redox-sensitive dye to couple growth of thousands of bacterial colonies to their respiratory activity and show that in Escherichia coli, noisy regulation of lower glycolysis and citric acid cycle is responsible for large variations in respiratory metabolism. We found that these variations are Pareto optimal to maximization of growth rate and minimization of lag time, two objectives competing between fermentative and respiratory metabolism. Metabolome-based analysis revealed the role of respiratory metabolism in preventing the accumulation of toxic intermediates of branched chain amino acid biosynthesis, thereby supporting early onset of cell growth after carbon starvation. We propose that optimal metabolic tradeoffs play a key role in shaping and preserving phenotypic heterogeneity and adaptation to fluctuating environments.
Restoration of energy homeostasis by SIRT6 extends healthy lifespan
Authors: Roichman A. , Elhanati S. , Aon M. A. , Abramovich I. , Di Francesco A. , Shahar Y. , Avivi M. Y. , Shurgi M. , Rubinstein A. , Wiesner Y. , Shuchami A. , Petrover Z. , Lebenthal-Loinger I. , Yaron O. , Lyashkov A. , Ubaida-Mohien C. , Kanfi Y. , Lerrer B. , Fernández-Marcos P. J. , Serrano M. , Gottlieb E. , de Cabo R. , Cohen H. Y.
Published: May 2021

Aging leads to a gradual decline in physical activity and disrupted energy homeostasis. The NAD+-dependent SIRT6 deacylase regulates aging and metabolism through mechanisms that largely remain unknown. Here, we show that SIRT6 overexpression leads to a reduction in frailty and lifespan extension in both male and female B6 mice. A combination of physiological assays, in vivo multi-omics analyses and 13C lactate tracing identified an age-dependent decline in glucose homeostasis and hepatic glucose output in wild type mice. In contrast, aged SIRT6-transgenic mice preserve hepatic glucose output and glucose homeostasis through an improvement in the utilization of two major gluconeogenic precursors, lactate and glycerol. To mediate these changes, mechanistically, SIRT6 increases hepatic gluconeogenic gene expression, de novo NAD+ synthesis, and systemically enhances glycerol release from adipose tissue. These findings show that SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging.
Enhancing CRISPR-Cas9 gRNA efficiency prediction by data integration and deep learning
Authors: Xiang Xi , Corsi Giulia I. , Anthon Christian , Qu Kunli , Pan Xiaoguang , Liang Xue , Han Peng , Dong Zhanying , Liu Lijun , Zhong Jiayan , Ma Tao , Wang Jinbao , Zhang Xiuqing , Jiang Hui , Xu Fengping , Liu Xin , Xu Xun , Wang Jian , Yang Huanming , Bolund Lars , Church George M. , Lin Lin , Gorodkin Jan , Luo Yonglun
Published: May 2021

The design of CRISPR gRNAs requires accurate on-target efficiency predictions, which demand high-quality gRNA activity data and efficient modeling. To advance, we here report on the generation of on-target gRNA activity data for 10,592 SpCas9 gRNAs. Integrating these with complementary published data, we train a deep learning model, CRISPRon, on 23,902 gRNAs. Compared to existing tools, CRISPRon exhibits significantly higher prediction performances on four test datasets not overlapping with training data used for the development of these tools. Furthermore, we present an interactive gRNA design webserver based on the CRISPRon standalone software, both available via https://rth.dk/resources/crispr/. CRISPRon advances CRISPR applications by providing more accurate gRNA efficiency predictions than the existing tools.
Heparanase: a potential marker of worse prognosis in estrogen receptor-positive breast cancer
Authors: Zahavi Tamar , Salmon-Divon Mali , Salgado Roberto , Elkin Michael , Hermano Esther , Rubinstein Ariel M. , Francis Prudence A. , Di Leo Angelo , Viale Giuseppe , de Azambuja Evandro , Ameye Lieveke , Sotiriou Christos , Salmon Asher , Kravchenko-Balasha Nataly , Sonnenblick Amir
Published: May 2021

Heparanase promotes tumor growth in breast tumors. We now evaluated heparanase protein and gene-expression status and investigated its impact on disease-free survival in order to gain better insight into the role of heparanase in ER-positive (ER+) breast cancer prognosis and to clarify its role in cell survival following chemotherapy. Using pooled analysis of gene-expression data, we found that heparanase was associated with a worse prognosis in estrogen receptor-positive (ER+) tumors (log-rankp < 10−10) and predictive to chemotherapy resistance (interactionp = 0.0001) but not hormonal therapy (Interactionp = 0.62). These results were confirmed by analysis of data from a phase III, prospective randomized trial which showed that heparanase protein expression is associated with increased risk of recurrence in ER+ breast tumors (log-rankp = 0.004). In vitro experiments showed that heparanase promoted tumor progression and increased cell viability via epithelial–mesenchymal transition, stemness, and anti-apoptosis pathways in luminal breast cancer. Taken together, our results demonstrated that heparanase is associated with worse outcomes and increased cell viability in ER+ BC.
Machine learning for deep elastic strain engineering of semiconductor electronic band structure and effective mass
Authors: Tsymbalov Evgenii , Shi Zhe , Dao Ming , Suresh Subra , Li Ju , Shapeev Alexander
Published: May 2021

The controlled introduction of elastic strains is an appealing strategy for modulating the physical properties of semiconductor materials. With the recent discovery of large elastic deformation in nanoscale specimens as diverse as silicon and diamond, employing this strategy to improve device performance necessitates first-principles computations of the fundamental electronic band structure and target figures-of-merit, through the design of an optimal straining pathway. Such simulations, however, call for approaches that combine deep learning algorithms and physics of deformation with band structure calculations to custom-design electronic and optical properties. Motivated by this challenge, we present here details of a machine learning framework involving convolutional neural networks to represent the topology and curvature of band structures in k-space. These calculations enable us to identify ways in which the physical properties can be altered through “deep” elastic strain engineering up to a large fraction of the ideal strain. Algorithms capable of active learning and informed by the underlying physics were presented here for predicting the bandgap and the band structure. By training a surrogate model with ab initio computational data, our method can identify the most efficient strain energy pathway to realize physical property changes. The power of this method is further demonstrated with results from the prediction of strain states that influence the effective electron mass. We illustrate the applications of the method with specific results for diamonds, although the general deep learning technique presented here is potentially useful for optimizing the physical properties of a wide variety of semiconductor materials.
Compositionally restricted attention-based network for materials property predictions
Authors: Wang Anthony Yu-Tung , Kauwe Steven K. , Murdock Ryan J. , Sparks Taylor D.
Published: May 2021

In this paper, we demonstrate an application of the Transformer self-attention mechanism in the context of materials science. Our network, the Compositionally Restricted Attention-Based network (), explores the area of structure-agnostic materials property predictions when only a chemical formula is provided. Our results show that ’s performance matches or exceeds current best-practice methods on nearly all of 28 total benchmark datasets. We also demonstrate how ’s architecture lends itself towards model interpretability by showing different visualization approaches that are made possible by its design. We feel confident that and its attention-based framework will be of keen interest to future materials informatics researchers.
High-content siRNA 3D co-cultures to identify myoepithelial cell-derived breast cancer suppressor proteins
Authors: Duivenvoorden Hendrika M. , Brockwell Natasha K. , Nowell Cameron J. , Simpson Kaylene J. , Parker Belinda S.
Published: May 2021

Understanding how cancer cells interact with the surrounding microenvironment early in breast cancer development can provide insight into the initiation and progression of invasive breast cancers. The myoepithelial cell layer surrounding breast ducts acts as a physical barrier in early breast cancer, preventing cancer cells from invading the surrounding stroma. Changes to the expression profile and properties of myoepithelial cells have been implicated in progression to invasive carcinoma. Identifying the molecular drivers of myoepithelial cell-mediated tumour suppression may offer new approaches to predict and block the earliest stages of cancer invasion. We employed a high-content approach to knock down 87 different genes using siRNA in an immortalised myoepithelial cell line, prior to co-culture with invasive breast cancer cells in 3D. Combined with high-content imaging and a customised analysis pipeline, this system was used to identify myoepithelial proteins that are necessary to control cancer cell invasion. This dataset has identified prospective myoepithelial suppressors of early breast cancer invasion which may be used by researchers to investigate their clinical validity and utility.
Genetically determined hypoalbuminemia as a risk factor for hypertension: instrumental variable analysis
Authors: Choi Jong Wook , Park Joon-Sung , Lee Chang Hwa
Published: May 2021

Hypoalbuminemia is associated with vascular endothelial dysfunction and the development of chronic cardiovascular diseases. However, the relationship between serum albumin concentration and blood pressure changes remains controversial. Community-based longitudinal cohort data collected from Korean Genome and Epidemiology Study were used in this study. Hypoalbuminemia was defined as a serum albumin concentration of ≤ 4.0 g/dL. A total of 4325 participants were categorized into control (n = 3157) and hypoalbuminemia (n = 1168) groups. Serum albumin had a non-linear relationship with the risk of hypertension development. A genome-wide association study revealed 71 susceptibility loci associated with hypoalbuminemia. Among susceptibility loci, genetic variations at rs2894536 inLOC107986598and rs10972486 inATP8B5Pwere related to elevated blood pressure. Serum albumin (HR = 0.654, 95% CI 0.521–0.820) and polymorphisms of rs2894536 (HR = 1.176, 95% CI 1.015–1.361) and rs10972486 (HR = 1.152, 95% CI 1.009–1.316) were significant predictors of hypertension development. Increased albumin concentration instrumented by 2 hypoalbuminemia-associated SNPs (rs2894536 and rs10972486) was associated with decreased HRs for hypertension development (HR = 0.762, 95% CI 0.659–0.882 and HR = 0.759, 95% CI 0.656–0.878). Our study demonstrated that genetically determined hypoalbuminemia is a significant predictor of incipient hypertension.
Ultraviolet radiation protection potentials of Methylene Blue for human skin and coral reef health
Authors: Xiong Zheng-Mei , Mao Xiaojing , Trappio Mason , Arya Chanda , Kordi Jasmin el , Cao Kan
Published: May 2021

Methylene blue (MB) is a century-old medicine, a laboratory dye, and recently shown as a premier antioxidant that combats ROS-induced cellular aging in human skins. Given MB’s molecular structure and light absorption properties, we hypothesize that MB has the potential to be considered as a sunscreen active for UV radiation protection. In this study, we tested the effects of MB on UVB ray-induced DNA double-strand breaks in primary human keratinocytes. We found that MB treatment reduced DNA damages caused by UVB irradiation and subsequent cell death. Next, we compared MB with Oxybenzone, which is the most commonly used chemical active ingredient in sunscreens but recently proven to be hazardous to aquatic ecosystems, in particular to coral reefs. At the same concentrations, MB showed more effective UVB absorption ability than Oxybenzone and significantly outperformed Oxybenzone in the prevention of UVB-induced DNA damage and the clearance of UVA-induced cellular ROS. Furthermore, unlike Oxybenzone, MB-containing seawater did not affect the growth of the coral species Xenia umbellata. Altogether, our study suggests that MB has the potential to be a coral reef-friendly sunscreen active ingredient that can provide broad-spectrum protection against UVA and UVB.