bluuebunny/crossref_metadata_2025 huggingface dataset:
Blockade of VLA4 sensitizes leukemic and myeloma tumor cells to CD3 redirection in the bone marrow microenvironment
Authors: Nair-Gupta Priyanka , Rudnick Stephen I. , Luistro Leopoldo , Smith Melissa , McDaid Ronan , Li Yingzhe , Pillarisetti Kodandaram , Joseph Jocelin , Heidrich Bradley , Packman Kathryn , Attar Ricardo , Gaudet François
Published: June 2020

Redirecting T cells to specifically kill malignant cells has been validated as an effective anti-cancer strategy in the clinic with the approval of blinatumomab for acute lymphoblastic leukemia. However, the immunosuppressive nature of the tumor microenvironment potentially poses a significant hurdle to T cell therapies. In hematological malignancies, the bone marrow (BM) niche is protective to leukemic stem cells and has minimized the efficacy of several anti-cancer drugs. In this study, we investigated the impact of the BM microenvironment on T cell redirection. Using bispecific antibodies targeting specific tumor antigens (CD123 and BCMA) and CD3, we observed that co-culture of acute myeloid leukemia or multiple myeloma cells with BM stromal cells protected tumor cells from bispecific antibody-T cell-mediated lysis in vitro and in vivo. Impaired CD3 redirection cytotoxicity was correlated with reduced T cell effector responses and cell–cell contact with stromal cells was implicated in reducing T cell activation and conferring protection of cancer cells. Finally, blocking the VLA4 adhesion pathway in combination with CD3 redirection reduced the stromal-mediated inhibition of cytotoxicity and T cell activation. Our results lend support to inhibiting VLA4 interactions along with administering CD3 redirection therapeutics as a novel combinatorial regimen for robust anti-cancer responses.
The MAO inhibitors phenelzine and clorgyline revert enzalutamide resistance in castration resistant prostate cancer
Authors: Wang Keliang , Luo Jie , Yeh Shuyuan , You Bosen , Meng Jialin , Chang Philip , Niu Yuanjie , Li Gonghui , Lu Changxue , Zhu Yezi , Antonarakis Emmanuel S. , Luo Jun , Huang Chi-Ping , Xu Wanhai , Chang Chawnshang
Published: June 2020

The antiandrogen enzalutamide (Enz) has improved survival in castration resistant prostate cancer (CRPC) patients. However, most patients eventually develop Enz resistance that may involve inducing the androgen receptor (AR) splicing variant 7 (ARv7). Here we report that high expression of monoamine oxidase-A (MAO-A) is associated with positive ARv7 detection in CRPC patients following Enz treatment. Targeting MAO-A with phenelzine or clorgyline, the FDA-approved drugs for antidepression, resensitize the Enz resistant (EnzR) cells to Enz treatment and further suppress EnzR cell growth in vitro and in vivo. Our findings suggest that Enz-increased ARv7 expression can transcriptionally enhance MAO-A expression resulting in Enz resistance via altering the hypoxia HIF-1α signals. Together, our results show that targeting the Enz/ARv7/MAO-A signaling with the antidepressants phenelzine or clorgyline can restore Enz sensitivity to suppress EnzR cell growth, which may indicate that these antidepression drugs can overcome the Enz resistance to further suppress the EnzR CRPC.
Urbanization and agricultural intensification destabilize animal communities differently than diversity loss
Authors: Olivier Théophile , Thébault Elisa , Elias Marianne , Fontaine Benoit , Fontaine Colin
Published: June 2020

Despite growing concern over consequences of global changes, we still know little about potential interactive effects of anthropogenic perturbations and diversity loss on the stability of local communities, especially for taxa other than plants. Here we analyse the relationships among landscape composition, biodiversity and community stability looking at time series of three types of communities, i.e., bats, birds and butterflies, monitored over the years by citizen science programs in France. We show that urban and intensive agricultural landscapes as well as diversity loss destabilize these communities but in different ways: while diversity loss translates into greater population synchrony, urban and intensive agricultural landscapes mainly decrease mean population stability. In addition to highlight the stabilizing effects of diversity on ecologically important but overlooked taxa, our results further reveal new pathways linking anthropogenic activities to diversity and stability.
Co-evolution of primitive methane-cycling ecosystems and early Earth’s atmosphere and climate
Authors: Sauterey Boris , Charnay Benjamin , Affholder Antonin , Mazevet Stéphane , Ferrière Régis
Published: June 2020

The history of the Earth has been marked by major ecological transitions, driven by metabolic innovation, that radically reshaped the composition of the oceans and atmosphere. The nature and magnitude of the earliest transitions, hundreds of million years before photosynthesis evolved, remain poorly understood. Using a novel ecosystem-planetary model, we find that pre-photosynthetic methane-cycling microbial ecosystems are much less productive than previously thought. In spite of their low productivity, the evolution of methanogenic metabolisms strongly modifies the atmospheric composition, leading to a warmer but less resilient climate. As the abiotic carbon cycle responds, further metabolic evolution (anaerobic methanotrophy) may feed back to the atmosphere and destabilize the climate, triggering a transient global glaciation. Although early metabolic evolution may cause strong climatic instability, a low CO:CH4 atmospheric ratio emerges as a robust signature of simple methane-cycling ecosystems on a globally reduced planet such as the late Hadean/early Archean Earth.
Hot carriers perspective on the nature of traps in perovskites
Authors: Righetto Marcello , Lim Swee Sien , Giovanni David , Lim Jia Wei Melvin , Zhang Qiannan , Ramesh Sankaran , Tay Yong Kang Eugene , Sum Tze Chien
Published: June 2020

Amongst the many spectacular properties of hybrid lead halide perovskites, their defect tolerance is regarded as the key enabler for a spectrum of high-performance optoelectronic devices that propel perovskites to prominence. However, the plateauing efficiency enhancement of perovskite devices calls into question the extent of this defect tolerance in perovskite systems; an opportunity for perovskite nanocrystals to fill. Through optical spectroscopy and phenomenological modeling based on the Marcus theory of charge transfer, we uncover the detrimental effect of hot carriers trapping in methylammonium lead iodide and bromide nanocrystals. Higher excess energies induce faster carrier trapping rates, ascribed to interactions with shallow traps and ligands, turning these into potent defects. Passivating these traps with the introduction of phosphine oxide ligands can help mitigate hot carrier trapping. Importantly, our findings extend beyond photovoltaics and are relevant for low threshold lasers, light-emitting devices and multi-exciton generation devices.
Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation
Authors: Azazmeh Narmen , Assouline Benjamin , Winter Eitan , Ruppo Shmuel , Nevo Yuval , Maly Alexander , Meir Karen , Witkiewicz Agnieszka K. , Cohen Jonathan , Rizou Sophia V. , Pikarsky Eli , Luxenburg Chen , Gorgoulis Vassilis G. , Ben-Porath Ittai
Published: June 2020

p16INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16INK4a accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16INK4a in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16INK4a expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16INK4a expression, and Wnt inhibition suppresses p16INK4a-induced hyperplasia. Senolytic treatment reduces p16INK4a-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16INK4a-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16INK4a expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.
Electrode interface optimization advances conversion efficiency and stability of thermoelectric devices
Authors: Chu Jing , Huang Jian , Liu Ruiheng , Liao Jincheng , Xia Xugui , Zhang Qihao , Wang Chao , Gu Ming , Bai Shengqiang , Shi Xun , Chen Lidong
Published: June 2020

Although the CoSb3-based skutterudite thermoelectric devices have been highly expected for wide uses such as waste heat recovery and space power supply, the limited long-term service stability majorly determined by the degradation of electrode interface obstructs its applications. Here, we built up an effective criterion for screening barrier layer based on the combination of negative interfacial reaction energy and high activation energy barrier of Sb migration through the formed interfacial reaction layer. Accordingly, we predicted niobium as a promising barrier layer. The experimental results show the skutterudite/Nb joint has the slowest interfacial reaction layer growth rate and smallest interfacial electrical resistivity. The fabricated 8-pair skutterudite module using Nb as barrier layer achieves a recorded conversion efficiency of 10.2% at hot-side temperature of 872 K and shows excellent stability during long-time aging. This simple criterion provides an effective guidance on screening barrier layer with bonding-blocking-conducting synergetic functions for thermoelectric device integration.
Cathode engineering with perylene-diimide interlayer enabling over 17% efficiency single-junction organic solar cells
Authors: Yao Jia , Qiu Beibei , Zhang Zhi-Guo , Xue Lingwei , Wang Rui , Zhang Chunfeng , Chen Shanshan , Zhou Qiuju , Sun Chenkai , Yang Changduk , Xiao Min , Meng Lei , Li Yongfang
Published: June 2020

In organic solar cells (OSCs), cathode interfacial materials are generally designed with highly polar groups to increase the capability of lowering the work function of cathode. However, the strong polar group could result in a high surface energy and poor physical contact at the active layer surface, posing a challenge for interlayer engineering to address the trade-off between device stability and efficiency. Herein, we report a hydrogen-bonding interfacial material, aliphatic amine-functionalized perylene-diimide (PDINN), which simultaneously down-shifts the work function of the air stable cathodes (silver and copper), and maintains good interfacial contact with the active layer. The OSCs based on PDINN engineered silver-cathode demonstrate a high power conversion efficiency of 17.23% (certified value 16.77% by NREL) and high stability. Our results indicate that PDINN is an effective cathode interfacial material and interlayer engineering via suitable intermolecular interactions is a feasible approach to improve device performance of OSCs.
Multi-site-mediated entwining of the linear WIR-motif around WIPI β-propellers for autophagy
Authors: Ren Jinqi , Liang Ruobing , Wang Wenjuan , Zhang Dachuan , Yu Li , Feng Wei
Published: June 2020

WIPI proteins (WIPI1-4) are mammalian PROPPIN family phosphoinositide effectors essential for autophagosome biogenesis. In addition to phosphoinositides, WIPI proteins can recognize a linear WIPI-interacting-region (WIR)-motif, but the underlying mechanism is poorly understood. Here, we determine the structure of WIPI3 in complex with the WIR-peptide from ATG2A. Unexpectedly, the WIR-peptide entwines around the WIPI3 seven-bladed β-propeller and binds to three sites in blades 1–3. The N-terminal part of the WIR-peptide forms a short strand that augments the periphery of blade 2, the middle segment anchors into an inter-blade hydrophobic pocket between blades 2–3, and the C-terminal aromatic tail wedges into another tailored pocket between blades 1–2. Mutations in three peptide-binding sites disrupt the interactions between WIPI3/4 and ATG2A and impair the ATG2A-mediated autophagic process. Thus, WIPI proteins recognize the WIR-motif by multi-sites in multi-blades and this multi-site-mediated peptide-recognition mechanism could be applicable to other PROPPIN proteins.
Four-dimensional metal-organic frameworks
Authors: Evans Jack D. , Bon Volodymyr , Senkovska Irena , Lee Hui-Chun , Kaskel Stefan
Published: June 2020

Recognising timescale as an adjustable dimension in porous solids provides a new perspective to develop novel four-dimensional framework materials. The deliberate design of three-dimensional porous framework architectures is a developed field; however, the understanding of dynamics in open frameworks leaves a number of key questions unanswered: What factors determine the spatiotemporal evolution of deformable networks? Can we deliberately engineer the response of dynamic materials along a time-axis? How can we engineer energy barriers for the selective recognition of molecules? Answering these questions will require significant methodological development to understand structural dynamics across a range of time and length scales.
Imaging the node-linker coordination in the bulk and local structures of metal-organic frameworks
Authors: Shen Boyuan , Chen Xiao , Shen Kui , Xiong Hao , Wei Fei
Published: June 2020

Porous metal-organic frameworks (MOFs) have shown wide applications in catalysis, gas storage and separation due to their highly tunable porosity, connectivity and local structures. However, the electron-beam sensitivity of MOFs makes it difficult to achieve the atomic imaging of their bulk and local structures under (scanning) transmission electron microscopy ((S)TEM) to study their structure-property relations. Here, we report the low-dose imaging of a beam-sensitive MOF, MIL-101, under a Cs-corrected STEM based on the integrated differential phase contrast (iDPC) technique. The images resolve the coordination of Cr nodes and organic linkers inside the frameworks with an information transfer of ~1.8Å. The local structures in MIL-101 are also revealed under iDPC-STEM, including the surfaces, interfaces and defects. These results provide an extensible method to image various beam-sensitive materials with ultrahigh resolution, and unravel the whole framework architectures for further defect and surface engineering of MOFs towards tailored functions.
Evolution of the Chinese guarantee network under financial crisis and stimulus program
Authors: Wang Yingli , Zhang Qingpeng , Yang Xiaoguang
Published: June 2020

Our knowledge about the evolution of guarantee network in downturn period is limited due to the lack of comprehensive data of the whole credit system. Here we analyze the dynamic Chinese guarantee network constructed from a comprehensive bank loan dataset that accounts for nearly 80% total loans in China, during 01/2007-03/2012. The results show that, first, during the 2007-2008 global financial crisis, the guarantee network became smaller, less connected and more stable because of many bankruptcies; second, the stimulus program encouraged mutual guarantee behaviors, resulting in highly reciprocal and fragile network structure; third, the following monetary policy adjustment enhanced the resilience of the guarantee network by reducing mutual guarantees. Interestingly, our work reveals that the financial crisis made the network more resilient, and conversely, the government bailout degenerated network resilience. These counterintuitive findings can provide new insight into the resilience of real-world credit system under external shocks or rescues.
Polymorphism of feldspars above 10 GPa
Authors: Pakhomova Anna , Simonova Dariia , Koemets Iuliia , Koemets Egor , Aprilis Georgios , Bykov Maxim , Gorelova Liudmila , Fedotenko Timofey , Prakapenka Vitali , Dubrovinsky Leonid
Published: June 2020

Feldspars are rock-forming minerals that make up most of the Earth’s crust. Along the mantle geotherm, feldspars are stable at pressures up to 3 GPa and may persist metastably at higher pressures under cold conditions. Previous structural studies of feldspars are limited to ~10 GPa, and have shown that the dominant mechanism of pressure-induced deformation is the tilting of AlO4and SiO4tetrahedra in a tetrahedral framework. Herein, based on results of in situ single-crystal X-ray diffraction studies up to 27 GPa, we report the discovery of new high-pressure polymorphs of the feldspars anorthite (CaSi2Al2O8), albite (NaAlSi3O8),and microcline (KAlSi3O8). The phase transitions are induced by severe tetrahedral distortions, resulting in an increase in the Al and/or Si coordination number. High-pressure phases derived from feldspars could persist at depths corresponding to the Earth upper mantle and could possibly influence the dynamics and fate of cold subducting slabs.
Thin-film transistor-driven vertically stacked full-color organic light-emitting diodes for high-resolution active-matrix displays
Authors: Choi Sukyung , Kang Chan-mo , Byun Chun-Won , Cho Hyunsu , Kwon Byoung-Hwa , Han Jun-Han , Yang Jong-Heon , Shin Jin-Wook , Hwang Chi-Sun , Cho Nam Sung , Lee Kang Me , Kim Hee-Ok , Kim Eungjun , Yoo Seunghyup , Lee Hyunkoo
Published: June 2020

Thin-film transistor (TFT)-driven full-color organic light-emitting diodes (OLEDs) with vertically stacked structures are developed herein using photolithography processes, which allow for high-resolution displays of over 2,000 pixels per inch. Vertical stacking of OLEDs by the photolithography process is technically challenging, as OLEDs are vulnerable to moisture, oxygen, solutions for photolithography processes, and temperatures over 100 °C. In this study, we develop a low-temperature processed Al2O3/SiNx bilayered protection layer, which stably protects the OLEDs from photolithography process solutions, as well as from moisture and oxygen. As a result, transparent intermediate electrodes are patterned on top of the OLED elements without degrading the OLED, thereby enabling to fabricate the vertically stacked OLED. The aperture ratio of the full-color-driven OLED pixel is approximately twice as large as conventional sub-pixel structures, due to geometric advantage, despite the TFT integration. To the best of our knowledge, we first demonstrate the TFT-driven vertically stacked full-color OLED.
Ancient genomes from northern China suggest links between subsistence changes and human migration
Authors: Ning Chao , Li Tianjiao , Wang Ke , Zhang Fan , Li Tao , Wu Xiyan , Gao Shizhu , Zhang Quanchao , Zhang Hai , Hudson Mark J. , Dong Guanghui , Wu Sihao , Fang Yanming , Liu Chen , Feng Chunyan , Li Wei , Han Tao , Li Ruo , Wei Jian , Zhu Yonggang , Zhou Yawei , Wang Chuan-Chao , Fan Shengying , Xiong Zenglong , Sun Zhouyong , Ye Maolin , Sun Lei , Wu Xiaohong , Liang Fawei , Cao Yanpeng , Wei Xingtao , Zhu Hong , Zhou Hui , Krause Johannes , Robbeets Martine , Jeong Choongwon , Cui Yinqiu
Published: June 2020

Northern China harbored the world’s earliest complex societies based on millet farming, in two major centers in the Yellow (YR) and West Liao (WLR) River basins. Until now, their genetic histories have remained largely unknown. Here we present 55 ancient genomes dating to 7500-1700 BP from the YR, WLR, and Amur River (AR) regions. Contrary to the genetic stability in the AR, the YR and WLR genetic profiles substantially changed over time. The YR populations show a monotonic increase over time in their genetic affinity with present-day southern Chinese and Southeast Asians. In the WLR, intensification of farming in the Late Neolithic is correlated with increased YR affinity while the inclusion of a pastoral economy in the Bronze Age was correlated with increased AR affinity. Our results suggest a link between changes in subsistence strategy and human migration, and fuel the debate about archaeolinguistic signatures of past human migration.
A nanobody-based fluorescent reporter reveals human α-synuclein in the cell cytosol
Authors: Gerdes Christoph , Waal Natalia , Offner Thomas , Fornasiero Eugenio F. , Wender Nora , Verbarg Hannes , Manzini Ivan , Trenkwalder Claudia , Mollenhauer Brit , Strohäker Timo , Zweckstetter Markus , Becker Stefan , Rizzoli Silvio O. , Basmanav Fitnat Buket , Opazo Felipe
Published: June 2020

Aggregation and spreading of α-Synuclein (αSyn) are hallmarks of several neurodegenerative diseases, thus monitoring human αSyn (hαSyn) in animal models or cell cultures is vital for the field. However, the detection of native hαSyn in such systems is challenging. We show that the nanobody NbSyn87, previously-described to bind hαSyn, also shows cross-reactivity for the proteasomal subunit Rpn10. As such, when the NbSyn87 is expressed in the absence of hαSyn, it is continuously degraded by the proteasome, while it is stabilized when it binds to hαSyn. Here, we exploit this feature to design a new Fluorescent Reporter for hαSyn (FluoReSyn) by fusing NbSyn87 to fluorescent proteins, which results in fluorescence signal fluctuations depending on the presence and amounts of intracellular hαSyn. We characterize this biosensor in cells and tissues to finally reveal the presence of transmittable αSyn in human cerebrospinal fluid, demonstrating the potential of FluoReSyn for clinical research and diagnostics.
Closing the gap towards super-long suspension bridges using computational morphogenesis
Authors: Baandrup Mads , Sigmund Ole , Polk Henrik , Aage Niels
Published: June 2020

Girder design for suspension bridges has remained largely unchanged for the past 60 years. However, for future super-long bridges, aiming at record-breaking spans beyond 3 km, the girder weight is a limiting factor. Here we report on a design concept, inspired by computational morphogenesis procedures, demonstrating possible weight savings in excess of 28 percent while maintaining manufacturability. Although morphogenesis procedures are rarely used in civil engineering, often due to complicated designs, we demonstrate that even a crude extraction of the main features of the optimized design, followed by a simple parametric optimization, results in hitherto unseen weight reductions. We expect that further studies of the proposed design, as well as applications to other structures, will lead to even greater weight savings and reductions in carbon footprint in a construction industry, currently responsible for 39 percent of the world’s CO2 emissions.
A tunable and unidirectional one-dimensional electronic system Nb2n+1SinTe4n+2
Authors: Zhu Zhen , Li Si , Yang Meng , Nie Xiao-Ang , Xu Hao-Ke , Yang Xu , Guan Dan-Dan , Wang Shiyong , Li Yao-Yi , Liu Canhua , Mao Zhi-Qiang , Xu Nan , Yao Yugui , Yang Shengyuan A. , Shi You-Guo , Zheng Hao , Jia Jin-Feng
Published: June 2020

One dimensional (1D) electronic system is a versatile platform hosting novel physics, such as charge density wave, Su-Schrieffer-Heeger (SSH) topological state and solitons, Tomonaga-Luttinger Liquid etc. Here, we systematically study the surface electronic properties on layered composition-tunable compounds Nb2n+1SinTe4n+2 (n = 1–5), which is predicted to be a nodal-line semimetal when n = 1 (Nb3SiTe6). Via scanning tunneling microscopy/spectroscopy, we observe 1D chains formed on the surface of the compounds. We uncover that with the increasing of n, the distance between the chains becomes larger, and the 1D electronic state is developed in the compounds with n ≥ 3. Our first-principle calculations reveal that the nodal-line in Nb3SiTe6 and the 1D electronic state in the crystals with higher n in fact arise from the same bands, which are protected by the same nonsymmorphic symmetry. Furthermore, we can understand the evolution of the electronic states on these series of compounds with such complicated structures and compositions based on a simple SSH type picture. Our experiment demonstrates a tunable and unidirectional 1D electronic system, which offers a concrete platform for the exploration of intriguing 1D electron physics and will enrich the opportunity for future condensed matter physics, material science and nanotechnology researches.
The Visual Word Form Area compensates for auditory working memory dysfunction in schizophrenia
Authors: Herman Alexander B. , Brown Ethan G. , Dale Corby L. , Hinkley Leighton B. , Subramaniam Karuna , Houde John F. , Fisher Melissa , Vinogradov Sophia , Nagarajan Srikantan S.
Published: June 2020

Auditory working memory impairments feature prominently in schizophrenia. However, the existence of altered and perhaps compensatory neural dynamics, sub-serving auditory working memory, remains largely unexplored. We compared the dynamics of induced high gamma power (iHGP) across cortex in humans during speech-sound working memory in individuals with schizophrenia (SZ) and healthy comparison subjects (HC) using magnetoencephalography (MEG). SZ showed similar task performance to HC while utilizing different brain regions. During encoding of speech sounds, SZ lacked the correlation of iHGP with task performance in posterior superior temporal gyrus (STGp) that was observed in healthy subjects. Instead, SZ recruited the visual word form area (VWFA) during both stimulus encoding and response preparation. Importantly, VWFA activity during encoding correlated with the magnitude of SZ hallucinations, task performance and an independent measure of verbal working memory. These findings suggest that VWFA plasticity is harnessed to compensate for STGp dysfunction in schizophrenia patients with hallucinations.
Expression of a Barhl1a reporter in subsets of retinal ganglion cells and commissural neurons of the developing zebrafish brain
Authors: Albadri Shahad , Armant Olivier , Aljand-Geschwill Tairi , Del Bene Filippo , Carl Matthias , Strähle Uwe , Poggi Lucia
Published: June 2020

Promoting the regeneration or survival of retinal ganglion cells (RGCs) is one focus of regenerative medicine. Homeobox Barhl transcription factors might be instrumental in these processes. In mammals, only barhl2 is expressed in the retina and is required for both subtype identity acquisition of amacrine cells and for the survival of RGCs downstream of Atoh7, a transcription factor necessary for RGC genesis. The underlying mechanisms of this dual role of Barhl2 in mammals have remained elusive. Whole genome duplication in the teleost lineage generated the barhl1a and barhl2 paralogues. In the Zebrafish retina, Barhl2 functions as a determinant of subsets of amacrine cells lineally related to RGCs independently of Atoh7. In contrast, barhl1a expression depends on Atoh7 but its expression dynamics and function have not been studied. Here we describe for the first time a Barhl1a reporter line in vivo showing that barhl1a turns on exclusively in subsets of RGCs and their post-mitotic precursors. We also show transient expression of barhl1a:GFP in diencephalic neurons extending their axonal projections as part of the post-optic commissure, at the time of optic chiasm formation. This work sets the ground for future studies on RGC subtype identity, axonal projections and genetic specification of Barhl1a-positive RGCs and commissural neurons.
Efficacy and safety of artemisinin-based combination therapy and the implications of Pfkelch13 and Pfcoronin molecular markers in treatment failure in Senegal
Authors: Diallo Mamadou Alpha , Yade Mamadou Samb , Ndiaye Yaye Die , Diallo Ibrahima , Diongue Khadim , Sy Saidou Abdoul , Sy Mouhamad , Seck Mame Cheikh , Ndiaye Mouhamadou , Dieye Baba , Gomis Jules François , Sow Djiby , Dème Awa Bineta , Badiane Aida Sadikh , Ndiaye Daouda
Published: June 2020

In 2006, Senegal adopted artemisinin-based combination therapy (ACT) as first-line treatment in the management of uncomplicated malaria. This study aimed to update the status of antimalarial efficacy more than ten years after their first introduction. This was a randomized, three-arm, open-label study to evaluate the efficacy and safety of artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ) and dihydroartemisinin-piperaquine (DP) in Senegal. Malaria suspected patients were screened, enrolled, treated, and followed for 28 days for AL and ASAQ arms or 42 days for DP arm. Clinical and parasitological responses were assessed following antimalarial treatment. Genotyping (msp1, msp2 and 24 SNP-based barcode) were done to differentiate recrudescence from re-infection; in case of PCR-confirmed treatment failure, Pfk13 propeller and Pfcoronin genes were sequenced. Data was entered and analyzed using the WHO Excel-based application. A total of 496 patients were enrolled. In Diourbel, PCR non-corrected/corrected adequate clinical and parasitological responses (ACPR) was 100.0% in both the AL and ASAQ arms. In Kedougou, PCR corrected ACPR values were 98.8%, 100% and 97.6% in AL, ASAQ and DP arms respectively. No Pfk13 or Pfcoronin mutations associated with artemisinin resistance were found. This study showed that AL, ASAQ and DP remain efficacious and well-tolerated in the treatment of uncomplicated P. falciparum malaria in Senegal.
Detector clothes for MRI: A wearable array receiver based on liquid metal in elastic tubes
Authors: Port Andreas , Luechinger Roger , Albisetti Loris , Varga Matija , Marjanovic Josip , Reber Jonas , Brunner David Otto , Pruessmann Klaas Paul
Published: June 2020

In modern magnetic resonance imaging, signal detection is performed by dense arrays of radiofrequency resonators. Tight-fitting arrays boost the sensitivity and speed of imaging. However, current devices are rigid and cage-like at the expense of patient comfort. They also constrain posture, limiting the examination of joints. For better ergonomics and versatility, detectors should be flexible, adapt to individual anatomy, and follow posture. Towards this goal, the present work proposes a novel design based on resonators formed by liquid metal in polymer tubes. Textile integration creates lightweight, elastic devices that are worn like pieces of clothing. A liquid-metal array tailored to the human knee is shown to deliver competitive image quality while self-adapting to individual anatomy and adding the ability to image flexion of the joint. Relative to other options for stretchable conductors, liquid metal in elastic tubes stands out by reconciling excellent electrical and mechanical properties with ease of manufacturing.
A computational drug repositioning method applied to rare diseases: Adrenocortical carcinoma
Authors: Lotfi Shahreza Maryam , Ghadiri Nasser , Green James R.
Published: June 2020

Rare or orphan diseases affect only small populations, thereby limiting the economic incentive for the drug development process, often resulting in a lack of progress towards treatment. Drug repositioning is a promising approach in these cases, due to its low cost. In this approach, one attempts to identify new purposes for existing drugs that have already been developed and approved for use. By applying the process of drug repositioning to identify novel treatments for rare diseases, we can overcome the lack of economic incentives and make concrete progress towards new therapies. Adrenocortical Carcinoma (ACC) is a rare disease with no practical and definitive therapeutic approach. We apply Heter-LP, a new method of drug repositioning, to suggest novel therapeutic avenues for ACC. Our analysis identifies innovative putative drug-disease, drug-target, and disease-target relationships for ACC, which include Cosyntropin (drug) and DHCR7, IGF1R, MC1R, MAP3K3, TOP2A (protein targets). When results are analyzed using all available information, a number of novel predicted associations related to ACC appear to be valid according to current knowledge. We expect the predicted relations will be useful for drug repositioning in ACC since the resulting ranked lists of drugs and protein targets can be used to expedite the necessary clinical processes.
Carbohydrate antigen 19-9 elevation without evidence of malignant or pancreatobiliary diseases
Authors: Kim Sunyoung , Park Byung Kyu , Seo Jeong Hun , Choi Jinyoung , Choi Jong Won , Lee Chun Kyon , Chung Jae Bock , Park Yongjung , Kim Dong Wook
Published: June 2020

Although carbohydrate antigen 19-9 (CA 19-9) may be elevated in benign diseases, elevated CA 19-9 may cause a fear of cancer and unnecessary follow-up studies. Research on how to approach systematically in this case is very limited. The purpose of this study was to analyze the clinical features and the causes of CA 19-9 elevation without evidence of malignant or pancreatobiliary diseases. We retrospectively reviewed the medical records of patients who had CA 19-9 elevation (≥80 U/mL) and were found to be unrelated to cancer after follow-up. After exclusion, 192 patients were included in this study. The median level of CA 19-9 was 136.5 U/mL. The causes of CA 19-9 elevation were determined in 147 (76.6%) patients, and that was unknown in 45 (23.4%). The estimated causative diseases were hepatic diseases in 63 patients, pulmonary diseases in 32, gynecologic diseases in 38, endocrine diseases in 13, and spleen disease in 1. Of 45 patients with unknown cause, 35 had normalization of CA 19-9 and 10 had persistently elevated CA 19-9. In conclusion, CA 19-9 elevation without malignancies or pancreatobiliary diseases should be systematically evaluated and followed up. We suggest an algorithm to investigate the causes and follow up these patients.
The atypical E2F transcription factor DEL1 modulates growth–defense tradeoffs of host plants during root-knot nematode infection
Authors: Nakagami Satoru , Saeki Kentaro , Toda Kei , Ishida Takashi , Sawa Shinichiro
Published: June 2020

In plants, growth–defense tradeoffs are essential for optimizing plant performance and adaptation under stress conditions, such as pathogen attack. Root-knot nematodes (RKNs) cause severe economic losses in many crops worldwide, although little is known about the mechanisms that control plant growth and defense responses during nematode attack. Upon investigation of Arabidopsis thaliana infected with RKN (Meloidogyne incognita), we observed that the atypical transcription factor DP-E2F-like 1 (DEL1) repressed salicylic acid (SA) accumulation in RKN-induced galls. The DEL1-deficient Arabidopsis mutant (del1-1) exhibited excessive SA accumulation in galls and is more resistant to RKN infection. In addition, excessive lignification was observed in galls of del1-1. On the other hand, the root growth of del1-1 is reduced after RKN infection. Taken together, these findings suggest that DEL1 plays an important role in the balance between plant growth and defense responses to RKN infection by controlling SA accumulation and lignification.
Preparation of high drug-loading celastrol nanosuspensions and their anti-breast cancer activities in vitro and in vivo
Authors: Huang Tiantian , Wang Yian , Shen Yiping , Ao Hui , Guo Yifei , Han Meihua , Wang Xiangtao
Published: June 2020

As one of the main components of Tripterygium wilfordii Hook F, celastrol (CSL) has significant antitumor activity, but its clinical application has been limited by its poor solubility, low oral bioavailability and systemic toxicity. In this study, celastrol nanosuspensions (CSL-NSps) were prepared using an antisolvent precipitation method with poloxamer 188 (P-188) as a stabilizer at a high CSL/P-188 feeding ratio of 8:1. The resultant CSL was spherical in shape with an average particle size of 147.9 nm, a polydispersity index (PDI) of 0.12 and zeta potential of -19.2 mV. The encapsulation efficiency and drug loading content were 98.18% and 86.83%, respectively, and the X-ray diffraction (XRD) pattern showed that CSL existed in an amorphous state in the nanosuspensions. CSL-NSps were quite stable in various physiological media and plasma and were both suitable for oral and intravenous administration. Nanosuspensions greatly enhanced the in vitro dissolution, and the cumulative drug release reached approximately 69.20% within 48 h. In vivo, CSL-NSps (3 mg/kg, i.g.) displayed a significantly enhanced tumor inhibition rate (TIR) in comparison with that of CSL suspension when administered orally (TIR, 50.39%, vs. 41.16%, p < 0.05),  similar to that of PTX injection (8 mg/kg, i.v. TIR, 50.88%). CSL-NSps showed even better therapeutic efficacy than PTX injection (TIR, 64.18%, p < 0.01) when intravenously injected. This has demonstrated that, with the help of nanosuspensions, CSL is likely to be an effective and promising antitumor agent in clinic practice for the treatment of breast cancer.
On the Aggregation and Nucleation Mechanism of the Monoclonal Antibody Anti-CD20 Near Liquid-Liquid Phase Separation (LLPS)
Authors: Pantuso Elvira , Mastropietro Teresa F. , Briuglia Maria L. , Gerard Charline J. J. , Curcio Efrem , ter Horst Joop H. , Nicoletta Fiore P. , Di Profio Gianluca
Published: June 2020

The crystallization of Anti-CD20, a full-length monoclonal antibody, has been studied in the PEG400/Na2SO4/Water system near Liquid-Liquid Phase Separation (LLPS) conditions by both sitting-drop vapour diffusion and batch methods. In order to understand the Anti-CD20 crystallization propensity in the solvent system of different compositions, we investigated some measurable parameters, normally used to assess protein conformational and colloidal stability in solution, with the aim to understand the aggregation mechanism of this complex biomacromolecule. We propose that under crystallization conditions a minor population of specifically aggregated protein molecules are present. While this minor species hardly contributes to the measured average solution behaviour, it induces and promotes crystal formation. The existence of this minor species is the result of the LLPS occurring concomitantly under crystallization conditions.
Study on influencing factors and mechanism of removal of Cr(VI) from soil suspended liquid by bentonite-supported nanoscale zero-valent iron
Authors: Liu Shichao , Gao Hongjun , Cheng Rui , Wang Yujun , Ma Xiulan , Peng Chang , Xie Zhonglei
Published: June 2020

In order to clarify the mechanism and effect of bentonite-supported nanoscale zero-valent iron (nZVI@Bent) on Cr(VI) removal in soil suspended liquid, nZVI@Bent was prepared by liquid-phase reduction method in this research. A number of factors, including the mass ratio of Fe2+ to bentonite during preparation of nZVI@Bent, nZVI@Bent dosage, soil suspended liquid pH value and reaction temperature were assessed to determine their impact on the reduction of Cr(VI) in soil suspended liquid. The nZVI@Bent was characterized by scanning electron microscope (SEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) to analyze the mechanism of removal of Cr(VI) from the soil. The results showed that the temperature of soil suspended liquid had a significant effect on the removal efficiency. Calculated by the Arrhenius formula, nZVI@Bent removes Cr(VI) from the soil suspended liquid as an endothermic reaction with a reaction activation energy of 47.02 kJ/mol, showed that the reaction occurred easily. The removal of mechanism Cr(VI) from the soil by nZVI@Bent included adsorption and reduction, moreover, the reduction process can be divided into direct reduction and indirect reduction. According to XPS spectrogram analysis, the content of Cr(III) in the reaction product was 2.1 times of Cr(VI), indicated that the reduction effect was greater than the adsorption effect in the process of Cr(VI) removal. The experiment proved that nZVI@Bent can effectively remove Cr(VI) from soil suspension, and can provide technical support for repairing Cr(VI)-polluted paddy fields.
Role of DNA-LL37 complexes in the activation of plasmacytoid dendritic cells and monocytes in subjects with type 1 diabetes
Authors: Badal Darshan , Dayal Devi , Singh Gunjan , Sachdeva Naresh
Published: June 2020

Initiation of type 1 diabetes (T1D) is marked by the infiltration of plasmacytoid dendritic cells (pDCs) and monocytes in pancreatic islets. Dying beta cells release self-DNA, which forms complexes with antimicrobial peptide, LL37, and its delayed clearance can activate pDCs and monocytes. Here, we studied the phenotypic effects of DNA-LL37 complexes on pDCs and monocytes in 55 recently diagnosed T1D and 25 healthy control (HC) subjects. Following in vitro stimulation with DNA-LL37 complexes, T1D group demonstrated higher frequency and mean fluorescence intensity (MFI) of pDCs expressing IFN-α. Similarly, the monocytes in T1D group showed an increase in MFI of IFN-α. Post-stimulation, an increase in the antigen presentation and co-stimulatory ability of pDCs and monocytes was observed in T1D group, as indicated by higher expression of HLA-DR, CD80 and CD86. Upon co-culture, the stimulated monocytes and pDCs, particularly in the T1D group were able to further activate autologous CD4 + T cells, with increase in expression of CD69 and CD71. Finally, in a transwell assay, the stimulated pDCs and monocytes induced an increase in apoptosis of 1.1B4 beta cells. Additionally, we observed reduced expression of indoleamine 2,3-dioxygenase 1 (IDO1) in pDCs and monocytes of T1D subjects. Our results suggest that DNA-LL37 complexes activate pDCs and monocytes towards a proinflammatory phenotype during pathogenesis of T1D.
Rapid conjugation of antibodies to toxins to select candidates for the development of anticancer Antibody-Drug Conjugates (ADCs)
Authors: Hoffmann Ricarda M. , Mele Silvia , Cheung Anthony , Larcombe-Young Daniel , Bucaite Gintare , Sachouli Eirini , Zlatareva Iva , Morad Hassan O. J. , Marlow Rebecca , McDonnell James M. , Figini Mariangela , Lacy Katie E. , Tutt Andrew J. N. , Spicer James F. , Thurston David E. , Karagiannis Sophia N. , Crescioli Silvia
Published: June 2020

Antibody-Drug Conjugates (ADCs) developed as a targeted treatment approach to deliver toxins directly to cancer cells are one of the fastest growing classes of oncology therapeutics, with eight ADCs and two immunotoxins approved for clinical use. However, selection of an optimum target and payload combination, to achieve maximal therapeutic efficacy without excessive toxicity, presents a significant challenge. We have developed a platform to facilitate rapid and cost-effective screening of antibody and toxin combinations for activity and safety, based on streptavidin-biotin conjugation. For antibody selection, we evaluated internalization by target cells using streptavidin-linked antibodies conjugated to biotinylated saporin, a toxin unable to cross cell membranes. For payload selection, we biotinylated toxins and conjugated them to antibodies linked to streptavidin to evaluate antitumour activity and pre-clinical safety. As proof of principle, we compared trastuzumab conjugated to emtansine via streptavidin-biotin (Trastuzumab-SB-DM1) to the clinically approved trastuzumab emtansine (T-DM1). We showed comparable potency in reduction of breast cancer cell survival in vitro and in growth restriction of orthotopic breast cancer xenografts in vivo. Our findings indicate efficient generation of functionally active ADCs. This approach can facilitate the study of antibody and payload combinations for selection of promising candidates for future ADC development.
Structural, mechanical and electronic properties and hardness of ionic vanadium dihydrides under pressure from first-principles computations
Authors: Wang Wenjie , Zhang Chuanzhao , Jin Yuanyuan , Li Song , Zhang Weibin , Kong Panlong , Xie Chengwu , Du Chengzhuo , Liu Qian , Zhang Caihong
Published: June 2020

Based on a combination of the CALYPSO method for crystal structure prediction and first-principles calculations, we explore the crystal structures of VH2 under the pressure range of 0−300 GPa. The cubic Fm-3m phase with regular VH8 cubes is predicted to transform into orthorhombic Pnma structure with fascinating distorted VH9 tetrakaidecahedrons at 47.36 GPa. Both the Fm-3m phase at 0 GPa and the Pnma phase at 100 GPa are mechanically and dynamically stable, as verified with the calculations of elastic constants and phonon dispersions, respectively. Moreover, the calculated electronic band structure and density of states indicate both stable phases are metallic. Remarkably, the analyses of the Poisson’s ratio, electron localization function (ELF) and Bader charge substantiate that both stable phases are ionic crystals on account of effective charges transferring from V atom to H. On the basis of the microscopic hardness model, the Fm-3m and Pnma crystals of VH2 are potentially incompressible and hard materials with the hardness values of 17.83 and 17.68 GPa, respectively.
PTH(1–34) treatment and/or mechanical loading have different osteogenic effects on the trabecular and cortical bone in the ovariectomized C57BL/6 mouse
Authors: Roberts Bryant C. , Arredondo Carrera Hector M. , Zanjani-pour Sahand , Boudiffa Maya , Wang Ning , Gartland Alison , Dall’Ara Enrico
Published: June 2020

In preclinical mouse models, a synergistic anabolic response to PTH(1–34) and tibia loading was shown. Whether combined treatment improves bone properties with oestrogen deficiency, a cardinal feature of osteoporosis, remains unknown. This study quantified the individual and combined longitudinal effects of PTH(1–34) and loading on the bone morphometric and densitometric properties in ovariectomised mice. C57BL/6 mice were ovariectomised at 14-weeks-old and treated either with injections of PTH(1–34); compressive loading of the right tibia; both interventions concurrently; or both interventions on alternating weeks. Right tibiae were microCT-scanned from 14 until 24-weeks-old. Trabecular metaphyseal and cortical midshaft morphometric properties, and bone mineral content (BMC) in 40 different regions of the tibia were measured. Mice treated only with loading showed the highest trabecular bone volume fraction at week 22. Cortical thickness was higher with co-treatment than in the mice treated with PTH alone. In the mid-diaphysis, increases in BMC were significantly higher with loading than PTH. In ovariectomised mice, the osteogenic benefits of co-treatment on the trabecular bone were lower than loading alone. However, combined interventions had increased, albeit regionally-dependent, benefits to cortical bone. Increased benefits were largest in the mid-diaphysis and postero-laterally, regions subjected to higher strains under compressive loads.
Trace amines produced by skin bacteria accelerate wound healing in mice
Authors: Luqman Arif , Muttaqin Muhammad Zainul , Yulaipi Sumah , Ebner Patrick , Matsuo Miki , Zabel Susanne , Tribelli Paula Maria , Nieselt Kay , Hidayati Dewi , Götz Friedrich
Published: June 2020

Certain skin bacteria are able to convert aromatic amino acids (AAA) into trace amines (TA) that act as neuromodulators. Since the human skin and sweat contain a comparatively high content of AAA one can expect that such bacteria are able to produce TA on our skin. Here we show that TA-producingStaphylococcus epidermidisstrains expressing SadA are predominant on human skin and that TA accelerate wound healing. In wounded skin, keratinocytes produce epinephrine (EPI) that leads to cell motility inhibition by β2-adrenergic receptor (β2-AR) activation thus delay wound healing. As β2-AR antagonists, TA and dopamine (DOP) abrogate the effect of EPI thus accelerating wound healing both in vitro and in a mouse model. In the mouse model, theS. epidermidiswild type strain accelerates wound healing compared to its ΔsadAmutant. Our study demonstrates that TA-producingS. epidermidisstrains present on our skin might be beneficial for wound healing.
Exploring direct and hydrogen-assisted CO activation on iridium surfaces – surface dependent activity
Authors: Liu Chunli , Zhu Ling , Wen Xiaodong , Yang Yong , Li Yong-Wang , Jiao Haijun
Published: June 2020

To understand CO activation on iridium surfaces, direct dissociation, H-assisted activation and hydrogenation to methanol were computed on the flat Ir(111) and Ir(100), corrugated Ir(110) and Ir(210), and stepped Ir(311) and Ir(221) surfaces.
Enzyme immobilization inside the porous wood structure: a natural scaffold for continuous-flow biocatalysis
Authors: Goldhahn Christian , Taut Josef A. , Schubert Mark , Burgert Ingo , Chanana Munish
Published: June 2020

Green biocatalytic systems for continuous-flow cascade reactions are realized by enzyme immobilization inside the porous wood structure.