bluuebunny/crossref_metadata_2025 huggingface dataset:
VARIATION ON A THEME BY KISELEV AND NAZAROV: HÖLDER ESTIMATES FOR NONLOCAL TRANSPORT-DIFFUSION, ALONG A NON-DIVERGENCE-FREE BMO FIELD
Authors: Vasilyev Ioann , Vigneron François
Published: January 2021

We prove uniform Hölder regularity estimates for a transport-diffusion equation with a fractional diffusion operator and a general advection field in of bounded mean oscillation, as long as the order of the diffusion dominates the transport term at small scales; our only requirement is the smallness of the negative part of the divergence in some critical Lebesgue space. In comparison to a celebrated result by Silvestre, our advection field does not need to be bounded. A similar result can be obtained in the supercritical case if the advection field is Hölder continuous. Our proof is inspired by Kiselev and Nazarov and is based on the dual evolution technique. The idea is to propagate an atom property (i.e., localisation and integrability in Lebesgue spaces) under the dual conservation law, when it is coupled with the fractional diffusion operator.
A call for greater conceptual clarity in the field of mental health and psychosocial support in humanitarian settings
Authors: Miller K. E. , Jordans M. J. D. , Tol W. A. , Galappatti A.
Published: January 2021

Aims

When the Interagency Standing Committee (IASC) adopted the composite term mental health and psychosocial support (MHPSS) and published its guidelines for MHPSS in emergency settings in 2007, it aimed to build consensus and strengthen coordination among relevant humanitarian actors. The term MHPSS offered an inclusive tent by welcoming the different terminologies, explanatory models and intervention methods of diverse actors across several humanitarian sectors (e.g., health, protection, education, nutrition). Since its introduction, the term has become well-established within the global humanitarian system. However, it has also been critiqued for papering over substantive differences in the intervention priorities and conceptual frameworks that inform the wide range of interventions described as MHPSS. Our aims are to clarify those conceptual frameworks, to argue for their essential complementarity and to illustrate the perils of failing to adequately consider the causal models and theories of change that underlie our interventions.

Methods

We describe the historical backdrop against which the term MHPSS and the IASC guidelines were developed, as well as their impact on improving relations and coordination among different aid sectors. We consider the conceptual fuzziness in the field of MHPSS and the lack of clear articulation of the different conceptual frameworks that guide interventions. We describe the explanatory models and intervention approaches of two primary frameworks within MHPSS, which we labelclinicalandsocial-environmental. Using the examples of intimate partner violence and compromised parenting in humanitarian settings, we illustrate the complementarity of these two frameworks, as well as the challenges that can arise when either framework is inappropriately applied.

Results

Clinical interventions prioritise the role of intrapersonal variables, biological and/or psychological, as mediators of change in the treatment of distress. Social-environmental interventions emphasise the role of social determinants of distress and target factors in the social and material environments in order to lower distress and increase resilience in the face of adversity. Both approaches play a critical role in humanitarian settings; however, the rationale for adopting one or the other approach is commonly insufficiently articulated and should be based on a thorough assessment of causal processes at multiple levels of the social ecology.

Conclusions

Greater attention to the ‘why’ of our intervention choices and more explicit articulation of the causal models and theories of change that underlie those decisions (i.e., the ‘how’), may strengthen intervention effects and minimise the risk of applying the inappropriate framework and actions to a particular problem.
Very Good Space Boys: Robotic Dogs May Dig Into Martian Caves
Authors: Backman Isabella
Published: January 2021

Four-legged, autonomous robots known as “Mars Dogs” will explore previously inaccessible caves to look for signs of life and potential locations for future human colonies.
C1GALT1 high expression is associated with poor survival of patients with pancreatic ductal adenocarcinoma and promotes cell invasiveness through integrin αv
Authors: Kuo Ting-Chun , Wu Ming-Hsun , Yang Shih-Hung , Chen Syue-Ting , Hsu Tzu-Wen , Jhuang Jie-Yang , Liao Ying-Yu , Tien Yu-Wen , Huang Min-Chuan
Published: January 2021

Pancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related death. Altered glycosylation contributes to tumor progression and chemoresistance in many cancers. C1GALT1 is the key enzyme controlling the elongation of GalNAc-type O-glycosylation. Here we showed that C1GALT1 was overexpressed in 85% (107/126) of PDAC tumors compared with adjacent non-tumor tissues. High expression of C1GALT1 was associated with poor disease-free and overall survival (n = 99). C1GALT1 knockdown using siRNA suppressed cell viability, migration, and invasion as well as increased gemcitabine sensitivity in PDAC cells. In contrast, C1GALT1 overexpression enhanced cell migration and invasion. In subcutaneous and pancreatic orthotopic injection models, C1GALT1 knockdown decreased tumor growth and metastasis of PDAC cells in NOD/SCID mice. Mechanistically, C1GALT1 knockdown dramatically suppressed cell-extracellular matrix (ECM) adhesion, which was associated with decreased phosphorylation of FAK at Y397/Y925 and changes in O-glycans on integrins including the β1, αv, and α5 subunits. Using functional blocking antibodies, we identified integrin αv as a critical factor in C1GALT1-mediated invasiveness of PDAC cells. In conclusion, this study not only reveals that C1GALT1 could be a potential therapeutic target for PDAC but also provides novel insights into the role of O-glycosylation in the α subunits of integrins.
A feed-forward loop between SorLA and HER3 determines heregulin response and neratinib resistance
Authors: Al-Akhrass Hussein , Conway James R. W. , Poulsen Annemarie Svane Aavild , Paatero Ilkka , Kaivola Jasmin , Padzik Artur , Andersen Olav M. , Ivaska Johanna
Published: January 2021

Current evidence indicates that resistance to the tyrosine kinase-type cell surface receptor (HER2)-targeted therapies is frequently associated with HER3 and active signaling via HER2-HER3 dimers, particularly in the context of breast cancer. Thus, understanding the response to HER2-HER3 signaling and the regulation of the dimer is essential to decipher therapy relapse mechanisms. Here, we investigate a bidirectional relationship between HER2-HER3 signaling and a type-1 transmembrane sorting receptor, sortilin-related receptor (SorLA; SORL1). We demonstrate that heregulin-mediated signaling supports SorLA transcription downstream of the mitogen-activated protein kinase pathway. In addition, we demonstrate that SorLA interacts directly with HER3, forming a trimeric complex with HER2 and HER3 to attenuate lysosomal degradation of the dimer in a Ras-related protein Rab4-dependent manner. In line with a role for SorLA in supporting the stability of the HER2 and HER3 receptors, loss of SorLA compromised heregulin-induced cell proliferation and sensitized metastatic anti-HER2 therapy-resistant breast cancer cells to neratinib in cancer spheroids in vitro and in vivo in a zebrafish brain xenograft model.
Comprehensive characterisation of intronic mis-splicing mutations in human cancers
Authors: Jung Hyunchul , Lee Kang Seon , Choi Jung Kyoon
Published: January 2021

Previous studies studying mis-splicing mutations were based on exome data and thus our current knowledge is largely limited to exons and the canonical splice sites. To comprehensively characterise intronic mis-splicing mutations, we analysed 1134 pan-cancer whole genomes and transcriptomes together with 3022 normal control samples. The ratio-based splicing analysis resulted in 678 somatic intronic mutations, with 46% residing in deep introns. Among the 309 deep intronic single nucleotide variants, 245 altered core splicing codes, with 38% activating cryptic splice sites, 12% activating cryptic polypyrimidine tracts, and 36% and 12% disrupting authentic polypyrimidine tracts and branchpoints, respectively. All the intronic cryptic splice sites were created at pre-existing GT/AG dinucleotides or by GC-to-GT conversion. Notably, 85 deep intronic mutations indicated gain of splicing enhancers or loss of splicing silencers. We found that 64 tumour suppressors were affected by intronic mutations and blood cancers showed higher proportion of deep intronic mutations. In particular, a telomere maintenance gene, POT1, was recurrently mis-spliced by deep intronic mutations in blood cancers. We validated a pseudoexon activation involving a splicing silencer in POT1 by CRISPR/Cas9. Our results shed light on previously unappreciated mechanisms by which noncoding mutations acting on splicing codes in deep introns contribute to tumourigenesis.
Inhibition of PFKFB3 induces cell death and synergistically enhances chemosensitivity in endometrial cancer
Authors: Xiao Yinan , Jin Ling , Deng Chaolin , Guan Ye , Kalogera Eleftheria , Ray Upasana , Thirusangu Prabhu , Staub Julie , Sarkar Bhattacharya Sayantani , Xu Haotian , Fang Xiaoling , Shridhar Viji
Published: January 2021

The advanced or recurrent endometrial cancer (EC) has a poor prognosis because of chemoresistance. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a glycolytic enzyme, is overexpressed in a variety of human cancers and plays important roles in promoting tumor cell growth. Here, we showed that high expression of PFKFB3 in EC cell lines is associated with chemoresistance. Pharmacological inhibition of PFKFB3 with PFK158 and or genetic downregulation of PFKFB3 dramatically suppressed cell proliferation and enhanced the sensitivity of EC cells to carboplatin (CBPt) and cisplatin (Cis). Moreover, PFKFB3 inhibition resulted in reduced glucose uptake, ATP production, and lactate release. Notably, we found that PFK158 with CBPt or Cis exerted strong synergistic antitumor activity in chemoresistant EC cell lines, HEC-1B and ARK-2 cells. We also found that the combination of PFK158 and CBPt/Cis induced apoptosis- and autophagy-mediated cell death through inhibition of the Akt/mTOR signaling pathway. Mechanistically, we found that PFK158 downregulated the CBPt/Cis-induced upregulation of RAD51 expression and enhanced CBPt/Cis-induced DNA damage as demonstrated by an increase in γ-H2AX levels in HEC-1B and ARK-2 cells, potentially revealing a means to enhance PFK158-induced chemosensitivity. More importantly, PFK158 treatment, either as monotherapy or in combination with CBPt, led to a marked reduction in tumor growth in two chemoresistant EC mouse xenograft models. These data suggest that PFKFB3 inhibition alone or in combination with standard chemotherapy may be used as a novel therapeutic strategy for improved therapeutic efficacy and outcomes of advanced and recurrent EC patients.
Loss of COPZ1 induces NCOA4 mediated autophagy and ferroptosis in glioblastoma cell lines
Authors: Zhang Yulin , Kong Yang , Ma Yuan , Ni Shilei , Wikerholmen Tobias , Xi Kaiyan , Zhao Feihu , Zhao Zhimin , Wang Junpeng , Huang Bin , Chen Anjing , Yao Zhong , Han Mingzhi , Feng Zichao , Hu Yaotian , Thorsen Frits , Wang Jian , Li Xingang
Published: January 2021

Dysregulated iron metabolism is a hallmark of many cancers, including glioblastoma (GBM). However, its role in tumor progression remains unclear. Herein, we identified coatomer protein complex subunit zeta 1 (COPZ1) as a therapeutic target candidate which significantly dysregulated iron metabolism in GBM cells. Overexpression of COPZ1 was associated with increasing tumor grade and poor prognosis in glioma patients based on analysis of expression data from the publicly available database The Cancer Genome Atlas (P < 0.001). Protein levels of COPZ1 were significantly increased in GBM compared to non-neoplastic brain tissue samples in immunohistochemistry and western blot analysis. SiRNA knockdown of COPZ1 suppressed proliferation of U87MG, U251 and P3#GBM in vitro. Stable expression of a COPZ1 shRNA construct in U87MG inhibited tumor growth in vivo by ~60% relative to controls at day 21 after implantation (P < 0.001). Kaplan–Meier analysis of the survival data demonstrated that the overall survival of tumor bearing animals increased from 20.8 days (control) to 27.8 days (knockdown, P < 0.05). COPZ1 knockdown also led to the increase in nuclear receptor coactivator 4 (NCOA4), resulting in the degradation of ferritin, and a subsequent increase in the intracellular levels of ferrous iron and ultimately ferroptosis. These data demonstrate that COPZ1 is a critical mediator in iron metabolism. The COPZ1/NCOA4/FTH1 axis is therefore a novel therapeutic target for the treatment of human GBM.
Targeting STAT3 by a small molecule suppresses pancreatic cancer progression
Authors: Chen Huang , Bian Aiwu , Yang Lian-fang , Yin Xuan , Wang Jie , Ti Chaowen , Miao Ying , Peng Shihong , Xu Shifen , Liu Mingyao , Qiu Wen-Wei , Yi Zhengfang
Published: January 2021

Pancreatic cancer is lethal in over 90% of cases since it is resistant to current therapeutic strategies. The key role of STAT3 in promoting pancreatic cancer progression has been proven, but effective interventions that suppress STAT3 activities are limited. The development of novel anticancer agents that directly target STAT3 may have potential clinical benefits for pancreatic cancer treatment. Here, we report a new small-molecule inhibitor (N4) with potent antitumor bioactivity, which inhibits multiple oncogenic processes in pancreatic cancer. N4 blocked STAT3 and phospho-tyrosine (pTyr) peptide interactions in fluorescence polarization (FP) assay, specifically abolished phosphor-STAT3 (Tyr705), and suppressed expression of STAT3 downstream genes. The mechanism involved the direct binding of N4 to the STAT3 SH2 domain, thereby, the STAT3 dimerization, STAT3-EGFR, and STAT3-NF-κB cross-talk were efficiently inhibited. In animal models of pancreatic cancer, N4 was well tolerated, suppressed tumor growth and metastasis, and significantly prolonged survival of tumor-bearing mice. Our results offer a preclinical proof of concept for N4 as a candidate therapeutic compound for pancreatic cancer.
YAP/TAZ inhibition reduces metastatic potential of Ewing sarcoma cells
Authors: Bierbaumer Lisa , Katschnig Anna M. , Radic-Sarikas Branka , Kauer Maximilian O. , Petro Jeffrey A. , Högler Sandra , Gurnhofer Elisabeth , Pedot Gloria , Schäfer Beat W. , Schwentner Raphaela , Mühlbacher Karin , Kromp Florian , Aryee Dave N. T. , Kenner Lukas , Uren Aykut , Kovar Heinrich
Published: January 2021

Ewing sarcoma (EwS) is a highly metastatic bone cancer characterized by the ETS fusion oncoprotein EWS-FLI1. EwS cells are phenotypically highly plastic and switch between functionally distinct cell states dependent on EWS-FLI1 fluctuations. Whereas EWS-FLI1high cells proliferate, EWS-FLI1low cells are migratory and invasive. Recently, we reported activation of MRTFB and TEAD, effectors of RhoA and Hippo signalling, upon low EWS-FLI1, orchestrating key steps of the EwS migratory gene expression program. TEAD and its co-activators YAP and TAZ are commonly overexpressed in cancer, providing attractive therapeutic targets. We find TAZ levels to increase in the migratory EWS-FLI1low state and to associate with adverse prognosis in EwS patients. We tested the effects of the potent YAP/TAZ/TEAD complex inhibitor verteporfin on EwS cell migration in vitro and on metastasis in vivo. Verteporfin suppressed expression of EWS-FLI1 regulated cytoskeletal genes involved in actin signalling to the extracellular matrix, effectively blocked F-actin and focal-adhesion assembly and inhibited EwS cell migration at submicromolar concentrations. In a mouse EwS xenograft model, verteporfin treatment reduced relapses at the surgical site and delayed lung metastasis. These data suggest that YAP/TAZ pathway inhibition may prevent EwS cell dissemination and metastasis, justifying further preclinical development of YAP/TAZ inhibitors for EwS treatment.
G protein-coupled receptors: structure- and function-based drug discovery
Authors: Yang Dehua , Zhou Qingtong , Labroska Viktorija , Qin Shanshan , Darbalaei Sanaz , Wu Yiran , Yuliantie Elita , Xie Linshan , Tao Houchao , Cheng Jianjun , Liu Qing , Zhao Suwen , Shui Wenqing , Jiang Yi , Wang Ming-Wei
Published: January 2021

As one of the most successful therapeutic target families, G protein-coupled receptors (GPCRs) have experienced a transformation from random ligand screening to knowledge-driven drug design. We are eye-witnessing tremendous progresses made recently in the understanding of their structure–function relationships that facilitated drug development at an unprecedented pace. This article intends to provide a comprehensive overview of this important field to a broader readership that shares some common interests in drug discovery.
Potentiation of NETs release is novel characteristic of TREM-1 activation and the pharmacological inhibition of TREM-1 could prevent from the deleterious consequences of NETs release in sepsis
Authors: Boufenzer Amir , Carrasco Kevin , Jolly Lucie , Brustolin Benjamin , Di-Pillo Elisa , Derive Marc , Gibot Sébastien
Published: January 2021

During sepsis, neutrophil activation induces endothelial cell (EC) dysfunction partly through neutrophil extracellular trap (NET) release. The triggering receptor expressed on myeloid cell-1 (TREM-1) is an orphan immune receptor that amplifies the inflammatory response mediated by Toll-like receptor-4 (TLR4) engagement. Although the key role of TLR4 signaling in NETosis is known, the role of TREM-1 in this process has not yet been investigated. Here, we report that TREM-1 potentiates NET release by human and murine neutrophils and is a component of the NET structure. In contrast, pharmacologic inhibition or genetic ablation of TREM-1 decreased NETosis in vitro and during experimental septic shock in vivo. Moreover, isolated NETs were able to activate ECs and impair vascular reactivity, and these deleterious effects were dampened by TREM-1 inhibition. TREM-1 may, therefore, constitute a new therapeutic target to prevent NETosis and associated endothelial dysfunction.
Artificial synapses with a sponge-like double-layer porous oxide memristor
Authors: Gao Qin , Huang Anping , Zhang Jing , Ji Yuhang , Zhang Jingjing , Chen Xueliang , Geng Xueli , Hu Qi , Wang Mei , Xiao Zhisong , Chu Paul K.
Published: January 2021

Closely following the rapid development of artificial intelligence, studies of the human brain and neurobiology are focusing on the biological mechanisms of neurons and synapses. Herein, a memory system employing a nanoporous double-layer structure for simulation of synaptic functions is described. The sponge-like double-layer porous (SLDLP) oxide stack of Pt/porous LiCoO2/porous SiO2/Si is designed as presynaptic and postsynaptic membranes. This bionic structure exhibits high ON–OFF ratios up to 108 during the stability test, and data can be maintained for 105 s despite a small read voltage of 0.5 V. Typical synaptic functions, such as nonlinear transmission characteristics, spike-timing-dependent plasticity, and learning-experience behaviors, are achieved simultaneously with this device. Based on the hydrodynamic transport mechanism of water molecules in porous sponges and the principle of water storage, the synaptic behavior of the device is discussed. The SLDLP oxide memristor is very promising due to its excellent synaptic performance and potential in neuromorphic computing.
Pushing the limits of high-resolution polymer microscopy using antioxidants
Authors: Kuei Brooke , Gomez Enrique D.
Published: January 2021

High-resolution transmission electron microscopy (HRTEM) has been transformative to the field of polymer science, enabling the direct imaging of molecular structures. Although some materials have remarkable stability under electron beams, most HRTEM studies are limited by the electron dose the sample can handle. Beam damage of conjugated polymers is not yet fully understood, but it has been suggested that the diffusion of secondary reacting species may play a role. As such, we examine the effect of the addition of antioxidants to a series of solution-processable conjugated polymers as an approach to mitigating beam damage. Characterizing the effects of beam damage by calculating critical dose DC values from the decay of electron diffraction peaks shows that beam damage of conjugated polymers in the TEM can be minimized by using antioxidants at room temperature, even if the antioxidant does not alter or incorporate into polymer crystals. As a consequence, the addition of antioxidants pushes the resolution limit of polymer microscopy, enabling imaging of a 3.6 Å lattice spacing in poly[(5,6-difluoro-2,1,3-benzothiadiazol-4,7-diyl)-alt-(3,3″′-di(2-octyldodecyl)-2,2′;5′,2″;5″,2″′-quaterthiophene-5,5″′-diyl)] (PffBT4T-2OD).
Hydride-based antiperovskites with soft anionic sublattices as fast alkali ionic conductors
Authors: Gao Shenghan , Broux Thibault , Fujii Susumu , Tassel Cédric , Yamamoto Kentaro , Xiao Yao , Oikawa Itaru , Takamura Hitoshi , Ubukata Hiroki , Watanabe Yuki , Fujii Kotaro , Yashima Masatomo , Kuwabara Akihide , Uchimoto Yoshiharu , Kageyama Hiroshi
Published: January 2021

Most solid-state materials are composed of p-block anions, only in recent years the introduction of hydride anions (1s2) in oxides (e.g., SrVO2H, BaTi(O,H)3) has allowed the discovery of various interesting properties. Here we exploit the large polarizability of hydride anions (H–) together with chalcogenide (Ch2–) anions to construct a family of antiperovskites with soft anionic sublattices. The M3HCh antiperovskites (M = Li, Na) adopt the ideal cubic structure except orthorhombic Na3HS, despite the large variation in sizes of M and Ch. This unconventional robustness of cubic phase mainly originates from the large size-flexibility of the H– anion. Theoretical and experimental studies reveal low migration barriers for Li+/Na+ transport and high ionic conductivity, possibly promoted by a soft phonon mode associated with the rotational motion of HM6 octahedra in their cubic forms. Aliovalent substitution to create vacancies has further enhanced ionic conductivities of this series of antiperovskites, resulting in Na2.9H(Se0.9I0.1) achieving a high conductivity of ~1 × 10–4 S/cm (100 °C).
Enhancing carbon dioxide gas-diffusion electrolysis by creating a hydrophobic catalyst microenvironment
Authors: Xing Zhuo , Hu Lin , Ripatti Donald S. , Hu Xun , Feng Xiaofeng
Published: January 2021

Electroreduction of carbon dioxide (CO2) over copper-based catalysts provides an attractive approach for sustainable fuel production. While efforts are focused on developing catalytic materials, it is also critical to understand and control the microenvironment around catalytic sites, which can mediate the transport of reaction species and influence reaction pathways. Here, we show that a hydrophobic microenvironment can significantly enhance CO2 gas-diffusion electrolysis. For proof-of-concept, we use commercial copper nanoparticles and disperse hydrophobic polytetrafluoroethylene (PTFE) nanoparticles inside the catalyst layer. Consequently, the PTFE-added electrode achieves a greatly improved activity and Faradaic efficiency for CO2 reduction, with a partial current density >250 mA cm−2 and a single-pass conversion of 14% at moderate potentials, which are around twice that of a regular electrode without added PTFE. The improvement is attributed to a balanced gas/liquid microenvironment that reduces the diffusion layer thickness, accelerates CO2 mass transport, and increases CO2 local concentration for the electrolysis.
Slowing down DNA translocation through solid-state nanopores by edge-field leakage
Authors: Wang Ceming , Sensale Sebastian , Pan Zehao , Senapati Satyajyoti , Chang Hsueh-Chia
Published: January 2021

Solid-state nanopores allow high-throughput single-molecule detection but identifying and even registering all translocating small molecules remain key challenges due to their high translocation speeds. We show here the same electric field that drives the molecules into the pore can be redirected to selectively pin and delay their transport. A thin high-permittivity dielectric coating on bullet-shaped polymer nanopores permits electric field leakage at the pore tip to produce a voltage-dependent surface field on the entry side that can reversibly edge-pin molecules. This mechanism renders molecular entry an activated process with sensitive exponential dependence on the bias voltage and molecular rigidity. This sensitivity allows us to selectively prolong the translocation time of short single-stranded DNA molecules by up to 5 orders of magnitude, to as long as minutes, allowing discrimination against their double-stranded duplexes with 97% confidence.
High performance tandem organic solar cells via a strongly infrared-absorbing narrow bandgap acceptor
Authors: Jia Zhenrong , Qin Shucheng , Meng Lei , Ma Qing , Angunawela Indunil , Zhang Jinyuan , Li Xiaojun , He Yakun , Lai Wenbin , Li Ning , Ade Harald , Brabec Christoph J. , Li Yongfang
Published: January 2021

Tandem organic solar cells are based on the device structure monolithically connecting two solar cells to broaden overall absorption spectrum and utilize the photon energy more efficiently. Herein, we demonstrate a simple strategy of inserting a double bond between the central core and end groups of the small molecule acceptor Y6 to extend its conjugation length and absorption range. As a result, a new narrow bandgap acceptor BTPV-4F was synthesized with an optical bandgap of 1.21 eV. The single-junction devices based on BTPV-4F as acceptor achieved a power conversion efficiency of over 13.4% with a high short-circuit current density of 28.9 mA cm−2. With adopting BTPV-4F as the rear cell acceptor material, the resulting tandem devices reached a high power conversion efficiency of over 16.4% with good photostability. The results indicate that BTPV-4F is an efficient infrared-absorbing narrow bandgap acceptor and has great potential to be applied into tandem organic solar cells.
Cross-scale interaction of host tree size and climatic water deficit governs bark beetle-induced tree mortality
Authors: Koontz Michael J. , Latimer Andrew M. , Mortenson Leif A. , Fettig Christopher J. , North Malcolm P.
Published: January 2021

The recent Californian hot drought (2012–2016) precipitated unprecedented ponderosa pine (Pinus ponderosa) mortality, largely attributable to the western pine beetle (Dendroctonus brevicomis; WPB). Broad-scale climate conditions can directly shape tree mortality patterns, but mortality rates respond non-linearly to climate when local-scale forest characteristics influence the behavior of tree-killing bark beetles (e.g., WPB). To test for these cross-scale interactions, we conduct aerial drone surveys at 32 sites along a gradient of climatic water deficit (CWD) spanning 350 km of latitude and 1000 m of elevation in WPB-impacted Sierra Nevada forests. We map, measure, and classify over 450,000 trees within 9 km2, validating measurements with coincident field plots. We find greater size, proportion, and density of ponderosa pine (the WPB host) increase host mortality rates, as does greater CWD. Critically, we find a CWD/host size interaction such that larger trees amplify host mortality rates in hot/dry sites. Management strategies for climate change adaptation should consider how bark beetle disturbances can depend on cross-scale interactions, which challenge our ability to predict and understand patterns of tree mortality.
Exploring the effect of network topology, mRNA and protein dynamics on gene regulatory network stability
Authors: Guo Yipei , Amir Ariel
Published: January 2021

Homeostasis of protein concentrations in cells is crucial for their proper functioning, requiring steady-state concentrations to be stable to fluctuations. Since gene expression is regulated by proteins such as transcription factors (TFs), the full set of proteins within the cell constitutes a large system of interacting components, which can become unstable. We explore factors affecting stability by coupling the dynamics of mRNAs and proteins in a growing cell. We find that mRNA degradation rate does not affect stability, contrary to previous claims. However, global structural features of the network can dramatically enhance stability. Importantly, a network resembling a bipartite graph with a lower fraction of interactions that target TFs has a higher chance of being stable. Scrambling the E. coli transcription network, we find that the biological network is significantly more stable than its randomized counterpart, suggesting that stability constraints may have shaped network structure during the course of evolution.
Properties and dynamics of meron topological spin textures in the two-dimensional magnet CrCl3
Authors: Augustin Mathias , Jenkins Sarah , Evans Richard F. L. , Novoselov Kostya S. , Santos Elton J. G.
Published: January 2021

Merons are nontrivial topological spin textures highly relevant for many phenomena in solid state physics. Despite their importance, direct observation of such vortex quasiparticles is scarce and has been limited to a few complex materials. Here, we show the emergence of merons and antimerons in recently discovered two-dimensional (2D) CrCl3 at zero magnetic field. We show their entire evolution from pair creation, their diffusion over metastable domain walls, and collision leading to large magnetic monodomains. Both quasiparticles are stabilized spontaneously during cooling at regions where in-plane magnetic frustration takes place. Their dynamics is determined by the interplay between the strong in-plane dipolar interactions and the weak out-of-plane magnetic anisotropy stabilising a vortex core within a radius of 8–10 nm. Our results push the boundary to what is currently known about non-trivial spin structures in 2D magnets and open exciting opportunities to control magnetic domains via topological quasiparticles.
Distinct populations of cortical pyramidal neurons mediate drug reward and aversion
Authors: Garcia A. F. , Crummy E. A. , Webb I. G. , Nooney M. N. , Ferguson S. M.
Published: January 2021

Processing within the anterior cingulate cortex (ACC) is crucial for the patterning of appropriate behavior, and ACC dysfunction following chronic drug use is thought to play a major role in drug addiction. However, cortical pyramidal projection neurons can be subdivided into two major types (intratelencephalic (IT) and pyramidal tract (PT)), with distinct inputs and projection targets, molecular and receptor profiles, morphologies and electrophysiological properties. Yet, how each of these cell populations modulate behavior related to addiction is unknown. We demonstrate that PT neurons regulate the positive features of a drug experience whereas IT neurons regulate the negative features. These findings support a revised theory of cortical function in addiction, with distinct cells and circuits mediating reward and aversion.
Exploring structure-property relationships in magnesium dissolution modulators
Authors: Würger Tim , Mei Di , Vaghefinazari Bahram , Winkler David A. , Lamaka Sviatlana V. , Zheludkevich Mikhail L. , Meißner Robert H. , Feiler Christian
Published: January 2021

Small organic molecules that modulate the degradation behavior of Mg constitute benign and useful materials to modify the service environment of light metal materials for specific applications. The vast chemical space of potentially effective compounds can be explored by machine learning-based quantitative structure-property relationship models, accelerating the discovery of potent dissolution modulators. Here, we demonstrate how unsupervised clustering of a large number of potential Mg dissolution modulators by structural similarities and sketch-maps can predict their experimental performance using a kernel ridge regression model. We compare the prediction accuracy of this approach to that of a prior artificial neural networks study. We confirm the robustness of our data-driven model by blind prediction of the dissolution modulating performance of 10 untested compounds. Finally, a workflow is presented that facilitates the automated discovery of chemicals with desired dissolution modulating properties from a commercial database. We subsequently prove this concept by blind validation of five chemicals.
Topological superconductivity in skyrmion lattices
Authors: Mascot Eric , Bedow Jasmin , Graham Martin , Rachel Stephan , Morr Dirk K.
Published: January 2021

Atomic manipulation and interface engineering techniques have provided an intriguing approach to custom-designing topological superconductors and the ensuing Majorana zero modes, representing a paradigm for the realization of topological quantum computing and topology-based devices. Magnet-superconductor hybrid (MSH) systems have proven to be experimentally suitable to engineer topological superconductivity through the control of both the complex structure of its magnetic layer and the interface properties of the superconducting surface. Here, we demonstrate that two-dimensional MSH systems containing a magnetic skyrmion lattice provide an unprecedented ability to control the emergence of topological phases. By changing the skyrmion radius, which can be achieved experimentally through an external magnetic field, one can tune between different topological superconducting phases, allowing one to explore their unique properties and the transitions between them. In these MSH systems, Josephson scanning tunneling spectroscopy spatially visualizes one of the most crucial aspects underlying the emergence of topological superconductivity, the spatial structure of the induced spin–triplet correlations.
Mammalian expression of virus-like particles as a proof of principle for next generation polio vaccines
Authors: Bahar Mohammad W. , Porta Claudine , Fox Helen , Macadam Andrew J. , Fry Elizabeth E. , Stuart David I.
Published: January 2021

Global vaccination programs using live-attenuated oral and inactivated polio vaccine (OPV and IPV) have almost eradicated poliovirus (PV) but these vaccines or their production pose significant risk in a polio-free world. Recombinant PV virus-like particles (VLPs), lacking the viral genome, represent safe next-generation vaccines, however their production requires optimisation. Here we present an efficient mammalian expression strategy producing good yields of wild-type PV VLPs for all three serotypes and a thermostabilised variant for PV3. Whilst the wild-type VLPs were predominantly in the non-native C-antigenic form, the thermostabilised PV3 VLPs adopted the native D-antigenic conformation eliciting neutralising antibody titres equivalent to the current IPV and were indistinguishable from natural empty particles by cryo-electron microscopy with a similar stabilising lipidic pocket-factor in the VP1 β-barrel. This factor may not be available in alternative expression systems, which may require synthetic pocket-binding factors. VLPs equivalent to these mammalian expressed thermostabilized particles, represent safer non-infectious vaccine candidates for the post-eradication era.
Development of a structural epitope mimic: an idiotypic approach to HCV vaccine design
Authors: Cowton Vanessa M. , Owsianka Ania M. , Fadda Valeria , Ortega-Prieto Ana Maria , Cole Sarah J. , Potter Jane A. , Skelton Jessica K. , Jeffrey Nathan , Di Lorenzo Caterina , Dorner Marcus , Taylor Garry L. , Patel Arvind H.
Published: January 2021

HCV vaccine development is stymied by the high genetic diversity of the virus and the variability of the envelope glycoproteins. One strategy to overcome this is to identify conserved, functionally important regions—such as the epitopes of broadly neutralizing antibodies (bNAbs)—and use these as a basis for structure-based vaccine design. Here, we report an anti-idiotype approach that has generated an antibody that mimics a highly conserved neutralizing epitope on HCV E2. Crucially, a mutagenesis screen was used to identify the antibody, designated B2.1 A, whose binding characteristics to the bNAb AP33 closely resemble those of the original antigen. Protein crystallography confirmed that B2.1 A is a structural mimic of the AP33 epitope. When used as an immunogen B2.1 A induced antibodies that recognized the same epitope and E2 residues as AP33 and most importantly protected against HCV challenge in a mouse model.
Ginkgo biloba extract (GbE) attenuates obesity and anxious/depressive-like behaviours induced by ovariectomy
Authors: Banin Renata Mancini , Machado Meira Maria Forcelini , de Andrade Iracema Senna , Carvalho Lorenza Oliveira Testa , Hirata Bruna Kelly Sousa , de Andrade Heider Mendonça , Júlio Viviane da Silva , Ribeiro Jéssica de Souza Figueiredo Borges , Cerutti Suzete Maria , Oyama Lila Missae , Ribeiro Eliane Beraldi , Telles Mônica Marques
Published: January 2021

While several pieces of evidence link obesity and mood disorders in menopause, the mechanisms involved are not yet fully understood. We have previously demonstrated that Ginkgo biloba extract (GbE) both attenuated diet-induced obesity of male rats and restored serotonin-induced hypophagia in ovariectomized female rats. The present study aimed at exploring whether GbE treatment ameliorates ovariectomy-related obesity and anxious/depressive-like behaviours. Wistar female rats were either ovariectomized (OVX) or sham-operated (Sham). After 2 months, either 500 mg/kg of GbE or vehicle were administered daily by gavage for 14 days. Anxious/depressive-like behaviours were assessed by the Elevated Plus Maze and the Forced Swim Tests, respectively. Ovariectomy caused high visceral adiposity, hyperleptinemia, and hypercholesterolemia, and increased the anxiety index (p = 0.048 vs. Sham + GbE) while it decreased the latency to immobility (p = 0.004 vs. Sham). GbE treatment in OVX rats improved body composition, adiponectin levels and blood lipid profile. It also reduced the anxiety index (p = 0.004) and increased the latency to immobility (p = 0.003) of OVX rats. Linear regression analysis demonstrated that leptin (p = 0.047) and total cholesterol levels (p = 0.022) were associated with anxious-like behaviours while body adiposity (p = 0.00005) was strongly associated with depressive-like behaviours. The results showed that GbE therapy was effective in attenuating the deleterious effects of ovariectomy on body composition, lipid profile, and anxious/depressive-like behaviours. Further studies are warranted to better understand the therapeutic potential of GbE in menopause.
Reconstructing hotspots of genetic diversity from glacial refugia and subsequent dispersal in Italian common toads (Bufo bufo)
Authors: Chiocchio Andrea , Arntzen Jan. W. , Martínez-Solano Iñigo , de Vries Wouter , Bisconti Roberta , Pezzarossa Alice , Maiorano Luigi , Canestrelli Daniele
Published: January 2021

Genetic diversity feeds the evolutionary process and allows populations to adapt to environmental changes. However, we still lack a thorough understanding of why hotspots of genetic diversity are so 'hot'. Here, we analysed the relative contribution of bioclimatic stability and genetic admixture between divergent lineages in shaping spatial patterns of genetic diversity in the common toad Bufo bufo along the Italian peninsula. We combined population genetic, phylogeographic and species distribution modelling (SDM) approaches to map ancestral areas, glacial refugia, and secondary contact zones. We consistently identified three phylogeographic lineages, distributed in northern, central and southern Italy. These lineages expanded from their ancestral areas and established secondary contact zones, before the last interglacial. SDM identified widespread glacial refugia in peninsular Italy, sometimes located under the present-day sea-level. Generalized linear models indicated genetic admixture as the only significant predictor of the levels of population genetic diversity. Our results show that glacial refugia contributed to preserving both levels and patterns of genetic diversity across glacial-interglacial cycles, but not to their formation, and highlight a general principle emerging in Mediterranean species: higher levels of genetic diversity mark populations with substantial contributions from multiple genetic lineages, irrespective of the location of glacial refugia.
The spreading of the invasive sacred ibis in Italy
Authors: Cucco Marco , Alessandria Gianfranco , Bissacco Marta , Carpegna Franco , Fasola Mauro , Gagliardi Alessandra , Gola Laura , Volponi Stefano , Pellegrino Irene
Published: January 2021

The spreading of invasive species in new continents can vary from slow and limited diffusion to fast colonisations over vast new areas. We studied the sacred ibisThreskiornis aethiopicusalong a 31-year period, from 1989 to 2019, with particular attention to the first area of release in NW Italy. We collected data on species distribution through observations by citizen science projects, population density by transects with distance method, breeding censuses at colonies, and post breeding censuses at roosts. The birds counted at winter roosts in NW Italy increased from a few tens up to 10,880 individuals in 2019. Sacred ibises started breeding in 1989, with a single nest in north-western Italy. The number of breeders remained very low until 2006, when both overwintering and breeding sacred ibises started to increase exponentially and expand their range throughout northern Italy with isolated breeding cases in central Italy. In 2019, the number of nests had increased to 1249 nests in 31 colonies. In NW Italy, the density of foraging birds averaged 3.9 ind./km2in winter and 1.5 ind./km2in the breeding period, with a mean size of the foraging groups of 8.9 and 2.1 birds respectively. Direct field observations and species distribution models (SDM) showed that foraging habitats were mainly rice fields and wetlands. A SDM applied to the whole Italian peninsula plus Sardinia and Sicily showed that the variables best related to the SDM were land class (rice fields and wetlands), altitude, and the temperature seasonality. The areas favourable for species expansion encompass all the plains of Northern Italy, and several areas of Tuscany, Latium, Sardinia, and Apulia.
Efficacy of compressed sodium chloride (CSC) against E. coli and Candida auris in minutes and methods improvement for testing
Authors: Truong Lan N. , Whitlock Brayden D.
Published: January 2021

Controlling infections has become one of the biggest problems in the world, whether measured in lives lost or money spent. This is worsening as pathogens continue becoming resistant to therapeutics. Antimicrobial surfaces are one strategy being investigated in an attempt to decrease the spread of infections through the most common route of transmission: surfaces, including hands. Regulators have chosen two hours as the time point at which efficacy should be measured. The objectives of this study were to characterize the new antimicrobial surface compressed sodium chloride (CSC) so that its action may be understood at timepoints more relevant to real-time infection control, under two minutes; to develop a sensitive method to test efficacy at short time points; and to investigate antifungal properties for the first time. E. coli and Candida auris are added to surfaces, and the surfaces are monitored by contact plate, or by washing into collection vats. An improved method of testing antimicrobial efficacy is reported. Antimicrobial CSC achieves at least 99.9% reduction of E. coli in the first two minutes of contact, and at least 99% reduction of C. auris in one minute.
Subglottal pressure oscillations in anechoic and resonant conditions and their influence on excised larynx phonations
Authors: Lehoux Sarah , Hampala Vít , Švec Jan G.
Published: January 2021

Excised larynges serve as natural models for studying behavior of the voice source. Acoustic resonances inside the air-supplying tubes below the larynx (i.e., subglottal space), however, interact with the vibratory behavior of the larynges and obscure their inherent vibration properties. Here, we explore a newly designed anechoic subglottal space which allows removing its acoustic resonances. We performed excised larynx experiments using both anechoic and resonant subglottal spaces in order to analyze and compare, for the very first time, the corresponding subglottal pressures, electroglottographic and radiated acoustic waveforms. In contrast to the resonant conditions, the anechoic subglottal pressure waveforms showed negligible oscillations during the vocal fold contact phase, as expected. When inverted, these waveforms closely matched the inverse filtered radiated sound waveforms. Subglottal resonances modified also the radiated sound pressures (Level 1 interactions). Furthermore, they changed the fundamental frequency (fo) of the vocal fold oscillations and offset phonation threshold pressures (Level 2 interactions), even for subglottal resonance frequencies 4–10 times higher than fo. The obtained data offer the basis for better understanding the inherent vibratory properties of the vocal folds, for studying the impact of structure-acoustic interactions on voice, and for validation of computational models of voice production.
Metabolic changes and anti-tumor effects of a ketogenic diet combined with anti-angiogenic therapy in a glioblastoma mouse model
Authors: Maeyama Masahiro , Tanaka Kazuhiro , Nishihara Masamitsu , Irino Yasuhiro , Shinohara Masakazu , Nagashima Hiroaki , Tanaka Hirotomo , Nakamizo Satoshi , Hashiguchi Mitsuru , Fujita Yuichi , Kohta Masaaki , Kohmura Eiji , Sasayama Takashi
Published: January 2021

The ketogenic diet (KD) is a high fat and low carbohydrate diet that produces ketone bodies through imitation of starvation. The combination of KD and Bevacizumab (Bev), a VEGF inhibitor, is considered to further reduce the supply of glucose to the tumor. The metabolite changes in U87 glioblastoma mouse models treated with KD and/or Bev were examined using gas chromatography-mass spectrometry. The combination therapy of KD and Bev showed a decrease in the rate of tumor growth and an increase in the survival time of mice, although KD alone did not have survival benefit. In the metabolome analysis, the pattern of changes for most amino acids are similar between tumor and brain tissues, however, some amino acids such as aspartic acid and glutamic acid were different between tumors and brain tissues. The KD enhanced the anti-tumor efficacy of Bev in a glioblastoma intracranial implantation mouse model, based on lowest levels of microvascular density (CD31) and cellular proliferation markers (Ki-67 and CCND1) in KD + Bev tumors compared to the other groups. These results suggested that KD combined with Bev may be a useful treatment strategy for patients with GBM.