bluuebunny/crossref_metadata_2025 huggingface dataset:
LIF/LIFR oncogenic signaling is a novel therapeutic target in endometrial cancer
Authors: Tang Weiwei , Ramasamy Kumaraguruparan , Pillai Sureshkumar M. A. , Santhamma Bindu , Konda Swapna , Pitta Venkata Prabhakar , Blankenship Logan , Liu Junhao , Liu Zexuan , Altwegg Kristin A. , Ebrahimi Behnam , Pratap Uday P. , Li Xiaonan , Valente Philip T. , Kost Edward , Sareddy Gangadhara R. , Vadlamudi Ratna K. , Nair Hareesh B. , Tekmal Rajeshwar R. , Viswanadhapalli Suryavathi
Published: August 2021

Endometrial cancer (EC) is the fourth most common cancer in women. Advanced-stage EC has limited treatment options with a poor prognosis. There is an unmet need for the identification of actionable drivers for the development of targeted therapies in EC. Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a major role in cancer progression, metastasis, stemness, and therapy resistance. However, little is known about the functional significance of the LIF/LIFR axis in EC progression. In this study using endometrial tumor tissue arrays, we identified that expression of LIF, LIFR is upregulated in EC. Knockout of LIFR using CRISPR/Cas9 in two different EC cells resulted in a significant reduction of their cell viability and cell survival. In vivo studies demonstrated that LIFR-KO significantly reduced EC xenograft tumor growth. Treatment of established and primary patient-derived EC cells with a novel LIFR inhibitor, EC359 resulted in the reduction of cell viability with an IC50in the range of 20–100 nM and induction of apoptosis. Further, treatment with EC359 reduced the spheroid formation of EC cancer stem cells and reduced the levels of cancer stem cell markers SOX2, OCT4, NANOG, and Axin2. Mechanistic studies demonstrated that EC359 treatment attenuated the activation of LIF-LIFR driven pathways, including STAT3 and AKT/mTOR signaling in EC cells. Importantly, EC359 treatment resulted in a significant reduction of the growth of EC patient-derived explants ex vivo, EC cell line-derived xenografts, and patient-derived xenografts in vivo. Collectively, our work revealed the oncogenic potential of the LIF/LIFR axis in EC and support the utility of LIFR inhibitor, EC359, as a novel targeted therapy for EC via the inhibition of LIF/LIFR oncogenic signaling.
Tunable exciton-polaritons emerging from WS2 monolayer excitons in a photonic lattice at room temperature
Authors: Lackner L. , Dusel M. , Egorov O. A. , Han B. , Knopf H. , Eilenberger F. , Schröder S. , Watanabe K. , Taniguchi T. , Tongay S. , Anton-Solanas C. , Höfling S. , Schneider C.
Published: August 2021

Engineering non-linear hybrid light-matter states in tailored lattices is a central research strategy for the simulation of complex Hamiltonians. Excitons in atomically thin crystals are an ideal active medium for such purposes, since they couple strongly with light and bear the potential to harness giant non-linearities and interactions while presenting a simple sample-processing and room temperature operability. We demonstrate lattice polaritons, based on an open, high-quality optical cavity, with an imprinted photonic lattice strongly coupled to excitons in a WS2 monolayer. We experimentally observe the emergence of the canonical band-structure of particles in a one-dimensional lattice at room temperature, and demonstrate frequency reconfigurability over a spectral window exceeding 85 meV, as well as the systematic variation of the nearest-neighbour coupling, reflected by a tunability in the bandwidth of the p-band polaritons by 7 meV. The technology presented in this work is a critical demonstration towards reconfigurable photonic emulators operated with non-linear photonic fluids, offering a simple experimental implementation and working at ambient conditions.
Efficiency and selectivity of CO2 reduction to CO on gold gas diffusion electrodes in acidic media
Authors: Monteiro Mariana C. O. , Philips Matthew F. , Schouten Klaas Jan P. , Koper Marc T. M.
Published: August 2021

The electrochemical reduction of CO2 to CO is a promising technology for replacing production processes employing fossil fuels. Still, low energy efficiencies hinder the production of CO at commercial scale. CO2 electrolysis has mainly been performed in neutral or alkaline media, but recent fundamental work shows that high selectivities for CO can also be achieved in acidic media. Therefore, we investigate the feasibility of CO2 electrolysis at pH 2–4 at indrustrially relevant conditions, using 10 cm2 gold gas diffusion electrodes. Operating at current densities up to 200 mA cm−2, we obtain CO faradaic efficiencies between 80–90% in sulfate electrolyte, with a 30% improvement of the overall process energy efficiency, in comparison with neutral media. Additionally, we find that weakly hydrated cations are crucial for accomplishing high reaction rates and enabling CO2 electrolysis in acidic media. This study represents a step towards the application of acidic electrolyzers for CO2 electroreduction.
Toward scalable biocatalytic conversion of 5-hydroxymethylfurfural by galactose oxidase using coordinated reaction and enzyme engineering
Authors: Birmingham William R. , Toftgaard Pedersen Asbjørn , Dias Gomes Mafalda , Bøje Madsen Mathias , Breuer Michael , Woodley John M. , Turner Nicholas J.
Published: August 2021

5-Hydroxymethylfurfural (HMF) has emerged as a crucial bio-based chemical building block in the drive towards developing materials from renewable resources, due to its direct preparation from sugars and its readily diversifiable scaffold. A key obstacle in transitioning to bio-based plastic production lies in meeting the necessary industrial production efficiency, particularly in the cost-effective conversion of HMF to valuable intermediates. Toward addressing the challenge of developing scalable technology for oxidizing crude HMF to more valuable chemicals, here we report coordinated reaction and enzyme engineering to provide a galactose oxidase (GOase) variant with remarkably high activity toward HMF, improved O2 binding and excellent productivity (>1,000,000 TTN). The biocatalyst and reaction conditions presented here for GOase catalysed selective oxidation of HMF to 2,5-diformylfuran offers a productive blueprint for further development, giving hope for the creation of a biocatalytic route to scalable production of furan-based chemical building blocks from sustainable feedstocks.
NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma
Authors: Lee Seungyong , Hwang Charles , Marini Simone , Tower Robert J. , Qin Qizhi , Negri Stefano , Pagani Chase A. , Sun Yuxiao , Stepien David M. , Sorkin Michael , Kubiak Carrie A. , Visser Noelle D. , Meyers Carolyn A. , Wang Yiyun , Rasheed Husain A. , Xu Jiajia , Miller Sarah , Huber Amanda K. , Minichiello Liliana , Cederna Paul S. , Kemp Stephen W. P. , Clemens Thomas L. , James Aaron W. , Levi Benjamin
Published: August 2021

Pain is a central feature of soft tissue trauma, which under certain contexts, results in aberrant osteochondral differentiation of tissue-specific stem cells. Here, the role of sensory nerve fibers in this abnormal cell fate decision is investigated using a severe extremity injury model in mice. Soft tissue trauma results in NGF (Nerve growth factor) expression, particularly within perivascular cell types. Consequently, NGF-responsive axonal invasion occurs which precedes osteocartilaginous differentiation. Surgical denervation impedes axonal ingrowth, with significant delays in cartilage and bone formation. Likewise, either deletion ofNgfor two complementary methods to inhibit its receptor TrkA (Tropomyosin receptor kinase A) lead to similar delays in axonal invasion and osteochondral differentiation. Mechanistically, single-cell sequencing suggests a shift from TGFβ to FGF signaling activation among pre-chondrogenic cells after denervation. Finally, analysis of human pathologic specimens and databases confirms the relevance of NGF-TrkA signaling in human disease. In sum, NGF-mediated TrkA-expressing axonal ingrowth drives abnormal osteochondral differentiation after soft tissue trauma. NGF-TrkA signaling inhibition may have dual therapeutic use in soft tissue trauma, both as an analgesic and negative regulator of aberrant stem cell differentiation.
Lagrangian betweenness as a measure of bottlenecks in dynamical systems with oceanographic examples
Authors: Ser-Giacomi Enrico , Baudena Alberto , Rossi Vincent , Follows Mick , Clayton Sophie , Vasile Ruggero , López Cristóbal , Hernández-García Emilio
Published: August 2021

The study of connectivity patterns in networks has brought novel insights across diverse fields ranging from neurosciences to epidemic spreading or climate. In this context, betweenness centrality has demonstrated to be a very effective measure to identify nodes that act as focus of congestion, or bottlenecks, in the network. However, there is not a way to define betweenness outside the network framework. By analytically linking dynamical systems and network theory, we provide a trajectory-based formulation of betweenness, called Lagrangian betweenness, as a function of Lyapunov exponents. This extends the concept of betweenness beyond the context of network theory relating hyperbolic points and heteroclinic connections in any dynamical system to the structural bottlenecks of the network associated with it. Using modeled and observational velocity fields, we show that such bottlenecks are present and surprisingly persistent in the oceanic circulation across different spatio-temporal scales and we illustrate the role of these areas in driving fluid transport over vast oceanic regions. Analyzing plankton abundance data from the Kuroshio region of the Pacific Ocean, we find significant spatial correlations between measures of diversity and betweenness, suggesting promise for ecological applications.
An amphiphilic dendrimer as a light-activable immunological adjuvant for in situ cancer vaccination
Authors: Wang Yongchao , Gong Ningqiang , Ma Chi , Zhang Yuxuan , Tan Hong , Qing Guangchao , Zhang Jimei , Wang Yufei , Wang Jinjin , Chen Shizhu , Li Xianlei , Ni Qiankun , Yuan Yuan , Gan Yaling , Chen Junge , Li Fangzhou , Zhang Jinchao , Ou Caiwen , Zhao Yongxiang , Liu Xiaoxuan , Liang Xing-Jie
Published: August 2021

Immunological adjuvants are essential for successful cancer vaccination. However, traditional adjuvants have some limitations, such as lack of controllability and induction of systemic toxicity, which restrict their broad application. Here, we present a light-activable immunological adjuvant (LIA), which is composed of a hypoxia-responsive amphiphilic dendrimer nanoparticle loaded with chlorin e6. Under irradiation with near-infrared light, the LIA not only induces tumour cell lysis and tumour antigen release, but also promotes the structural transformation of 2-nitroimidazole containing dendrimer to 2-aminoimidazole containing dendrimer which can activate dendritic cells via the Toll-like receptor 7-mediated signaling pathway. The LIA efficiently inhibits both primary and abscopal tumour growth and induces strong antigen-specific immune memory effect to prevent tumour metastasis and recurrence in vivo. Furthermore, LIA localizes the immunological adjuvant effect at the tumour site. We demonstrate this light-activable immunological adjuvant offers a safe and potent platform for in situ cancer vaccination.
Biomimetic approach to the catalytic enantioselective synthesis of tetracyclic isochroman
Authors: Lin Xiangfeng , Liu Xianghui , Wang Kai , Li Qian , Liu Yan , Li Can
Published: August 2021

Polyketide oligomers containing the structure of tetracyclic isochroman comprise a large class of natural products with diverse activity. However, a general and stereoselective method towards the rapid construction of this structure remains challenging due to the inherent instability and complex stereochemistry of polyketide. By mimicking the biosynthetic pathway of this structurally diverse set of natural products, we herein develop an asymmetric hetero-Diels–Alder reaction of in-situ generated isochromene and ortho-quinonemethide. A broad range of tetracyclic isochroman frameworks are prepared in good yields and excellent stereoinduction (up to 95% ee) from readily available α-propargyl benzyl alcohols and 2-(hydroxylmethyl) phenols under mild conditions. This direct enantioselective cascade reaction is achieved by a Au(I)/chiral Sc(III) bimetallic catalytic system. Experimental studies indicate that the key hetero-Diels-Alder reaction involves a stepwise pathway, and the steric hindrance between in-situ generated isochromene and t-Bu group of Sc(III)/N,N’-dioxide complex is responsible for the enantioselectivity in the hetero-Diels–Alder reaction step.
Offspring born to influenza A virus infected pregnant mice have increased susceptibility to viral and bacterial infections in early life
Authors: Jacobsen Henning , Walendy-Gnirß Kerstin , Tekin-Bubenheim Nilgün , Kouassi Nancy Mounogou , Ben-Batalla Isabel , Berenbrok Nikolaus , Wolff Martin , dos Reis Vinicius Pinho , Zickler Martin , Scholl Lucas , Gries Annette , Jania Hanna , Kloetgen Andreas , Düsedau Arne , Pilnitz-Stolze Gundula , Jeridi Aicha , Yildirim Ali Önder , Fuchs Helmut , Gailus-Durner Valerie , Stoeger Claudia , de Angelis Martin Hrabe , Manuylova Tatjana , Klingel Karin , Culley Fiona J. , Behrends Jochen , Loges Sonja , Schneider Bianca , Krauss-Etschmann Susanne , Openshaw Peter , Gabriel Gülsah
Published: August 2021

Influenza during pregnancy can affect the health of offspring in later life, among which neurocognitive disorders are among the best described. Here, we investigate whether maternal influenza infection has adverse effects on immune responses in offspring. We establish a two-hit mouse model to study the effect of maternal influenza A virus infection (first hit) on vulnerability of offspring to heterologous infections (second hit) in later life. Offspring born to influenza A virus infected mothers are stunted in growth and more vulnerable to heterologous infections (influenza B virus and MRSA) than those born to PBS- or poly(I:C)-treated mothers. Enhanced vulnerability to infection in neonates is associated with reduced haematopoetic development and immune responses. In particular, alveolar macrophages of offspring exposed to maternal influenza have reduced capacity to clear second hit pathogens. This impaired pathogen clearance is partially reversed by adoptive transfer of alveolar macrophages from healthy offspring born to uninfected dams. These findings suggest that maternal influenza infection may impair immune ontogeny and increase susceptibility to early life infections of offspring.
On the molecular origins of the ferroelectric splay nematic phase
Authors: Mandle Richard J. , Sebastián Nerea , Martinez-Perdiguero Josu , Mertelj Alenka
Published: August 2021

Nematic liquid crystals have been known for more than a century, but it was not until the 60s–70s that, with the development of room temperature nematics, they became widely used in applications. Polar nematic phases have been long-time predicted, but have only been experimentally realized recently. Synthesis of materials with nematic polar ordering at room temperature is certainly challenging and requires a deep understanding of its formation mechanisms, presently lacking. Here, we compare two materials of similar chemical structure and demonstrate that just a subtle change in the molecular structure enables denser packing of the molecules when they exhibit polar order, which shows that reduction of excluded volume is in the origin of the polar nematic phase. Additionally, we propose that molecular dynamics simulations are potent tools for molecular design in order to predict, identify and design materials showing the polar nematic phase and its precursor nematic phases.
Decline in plankton diversity and carbon flux with reduced sea ice extent along the Western Antarctic Peninsula
Authors: Lin Yajuan , Moreno Carly , Marchetti Adrian , Ducklow Hugh , Schofield Oscar , Delage Erwan , Meredith Michael , Li Zuchuan , Eveillard Damien , Chaffron Samuel , Cassar Nicolas
Published: August 2021

Since the middle of the past century, the Western Antarctic Peninsula has warmed rapidly with a significant loss of sea ice but the impacts on plankton biodiversity and carbon cycling remain an open question. Here, using a 5-year dataset of eukaryotic plankton DNA metabarcoding, we assess changes in biodiversity and net community production in this region. Our results show that sea-ice extent is a dominant factor influencing eukaryotic plankton community composition, biodiversity, and net community production. Species richness and evenness decline with an increase in sea surface temperature (SST). In regions with low SST and shallow mixed layers, the community was dominated by a diverse assemblage of diatoms and dinoflagellates. Conversely, less diverse plankton assemblages were observed in waters with higher SST and/or deep mixed layers when sea ice extent was lower. A genetic programming machine-learning model explained up to 80% of the net community production variability at the Western Antarctic Peninsula. Among the biological explanatory variables, the sea-ice environment associated plankton assemblage is the best predictor of net community production. We conclude that eukaryotic plankton diversity and carbon cycling at the Western Antarctic Peninsula are strongly linked to sea-ice conditions.
C. elegans colony formation as a condensation phenomenon
Authors: Chen Yuping , Ferrell James E.
Published: August 2021

Phase separation at the molecular scale affects many biological processes. The theoretical requirements for phase separation are fairly minimal, and there is growing evidence that analogous phenomena occur at other scales in biology. Here we examine colony formation in the nematode C. elegans as a possible example of phase separation by a population of organisms. The population density of worms determines whether a colony will form in a thresholded fashion, and a simple two-compartment ordinary differential equation model correctly predicts the threshold. Furthermore, small, round colonies sometimes fuse to form larger, round colonies, and a phenomenon akin to Ostwald ripening – a coarsening process seen in many systems that undergo phase separation – also occurs. These findings support the emerging view that the principles of microscopic phase separation can also apply to collective behaviors of living organisms.
Survival of itinerant excitations and quantum spin state transitions in YbMgGaO4 with chemical disorder
Authors: Rao X. , Hussain G. , Huang Q. , Chu W. J. , Li N. , Zhao X. , Dun Z. , Choi E. S. , Asaba T. , Chen L. , Li L. , Yue X. Y. , Wang N. N. , Cheng J.-G. , Gao Y. H. , Shen Y. , Zhao J. , Chen G. , Zhou H. D. , Sun X. F.
Published: August 2021

A recent focus of quantum spin liquid (QSL) studies is how disorder/randomness in a QSL candidate affects its true magnetic ground state. The ultimate question is whether the QSL survives disorder or the disorder leads to a “spin-liquid-like” state, such as the proposed random-singlet (RS) state. Since disorder is a standard feature of most QSL candidates, this question represents a major challenge for QSL candidates. YbMgGaO4, a triangular lattice antiferromagnet with effective spin-1/2 Yb3+ions, is an ideal system to address this question, since it shows no long-range magnetic ordering with Mg/Ga site disorder. Despite the intensive study, it remains unresolved as to whether YbMgGaO4 is a QSL or in the RS state. Here, through ultralow-temperature thermal conductivity and magnetic torque measurements, plus specific heat and DC magnetization data, we observed a residual κ0/T term and series of quantum spin state transitions in the zero temperature limit for YbMgGaO4. These observations strongly suggest that a QSL state with itinerant excitations and quantum spin fluctuations survives disorder in YbMgGaO4.
Anion-exchange-mediated internal electric field for boosting photogenerated carrier separation and utilization
Authors: Han Tong , Cao Xing , Sun Kaian , Peng Qing , Ye Chenliang , Huang Aijian , Cheong Weng-Chon , Chen Zheng , Lin Rui , Zhao Di , Tan Xin , Zhuang Zewen , Chen Chen , Wang Dingsheng , Li Yadong
Published: August 2021

Heterojunctions modulated internal electric field (IEF) usually result in suboptimal efficiencies in carrier separation and utilization because of the narrow IEF distribution and long migration paths of photocarriers. In this work, we report distinctive bismuth oxyhydroxide compound nanorods (denoted as BOH NRs) featuring surface-exposed open channels and a simple chemical composition; by simply modifying the bulk anion layers to overcome the limitations of heterojunctions, the bulk IEF could be readily modulated. Benefiting from the unique crystal structure and the localization of valence electrons, the bulk IEF intensity increases with the atomic number of introduced halide anions. Therefore, A low exchange ratio (~10%) with halide anions (I–, Br–, Cl–) gives rise to a prominent elevation in carrier separation efficiency and better photocatalytic performance for benzylamine coupling oxidation. Here, our work offers new insights into the design and optimization of semiconductor photocatalysts.
Simultaneously enhancing the ultimate strength and ductility of high-entropy alloys via short-range ordering
Authors: Chen Shuai , Aitken Zachary H. , Pattamatta Subrahmanyam , Wu Zhaoxuan , Yu Zhi Gen , Srolovitz David J. , Liaw Peter K. , Zhang Yong-Wei
Published: August 2021

Simultaneously enhancing strength and ductility of metals and alloys has been a tremendous challenge. Here, we investigate a CoCuFeNiPd high-entropy alloy (HEA), using a combination of Monte Carlo method, molecular dynamic simulation, and density-functional theory calculation. Our results show that this HEA is energetically favorable to undergo short-range ordering (SRO), and the SRO leads to a pseudo-composite microstructure, which surprisingly enhances both the ultimate strength and ductility. The SRO-induced composite microstructure consists of three categories of clusters: face-center-cubic-preferred (FCCP) clusters, indifferent clusters, and body-center-cubic-preferred (BCCP) clusters, with the indifferent clusters playing the role of the matrix, the FCCP clusters serving as hard fillers to enhance the strength, while the BCCP clusters acting as soft fillers to increase the ductility. Our work highlights the importance of SRO in influencing the mechanical properties of HEAs and presents a fascinating route for designing HEAs to achieve superior mechanical properties.
Metadynamics sampling in atomic environment space for collecting training data for machine learning potentials
Authors: Yoo Dongsun , Jung Jisu , Jeong Wonseok , Han Seungwu
Published: August 2021

The universal mathematical form of machine-learning potentials (MLPs) shifts the core of development of interatomic potentials to collecting proper training data. Ideally, the training set should encompass diverse local atomic environments but conventional approaches are prone to sampling similar configurations repeatedly, mainly due to the Boltzmann statistics. As such, practitioners handpick a large pool of distinct configurations manually, stretching the development period significantly. To overcome this hurdle, methods are being proposed that automatically generate training data. Herein, we suggest a sampling method optimized for gathering diverse yet relevant configurations semi-automatically. This is achieved by applying the metadynamics with the descriptor for the local atomic environment as a collective variable. As a result, the simulation is automatically steered toward unvisited local environment space such that each atom experiences diverse chemical environments without redundancy. We apply the proposed metadynamics sampling to H:Pt(111), GeTe, and Si systems. Throughout these examples, a small number of metadynamics trajectories can provide reference structures necessary for training high-fidelity MLPs. By proposing a semi-automatic sampling method tuned for MLPs, the present work paves the way to wider applications of MLPs to many challenging applications.
Giant room temperature elastocaloric effect in metal-free thin-film perovskites
Authors: Li Cheng , Huang Yu Hui , Wang Jian-Jun , Wang Bo , Wu Yong Jun , Tian He , Chen Long-Qing , Hong Zijian
Published: August 2021

Solid-state refrigeration which is environmentally benign has attracted considerable attention. Mechanocaloric (mC) materials, in which the phase transitions can be induced by mechanical stresses, represent one of the most promising types of solid-state caloric materials. Herein, we have developed a thermodynamic phenomenological model and predicted extraordinarily large elastocaloric (eC) strengths for the (111)-oriented metal-free perovskite ferroelectric [MDABCO](NH4)I3 thin-films. The predicted room temperature isothermal eC ΔSeC/Δσ (eC entropy change under unit stress change) and adiabatic eC ΔTeC/Δσ (eC temperature change under unit stress change) for [MDABCO](NH4)I3 are −60.0 J K−1 kg−1 GPa−1 and 17.9 K GPa−1, respectively, which are 20 times higher than the traditional ferroelectric oxides such as BaTiO3 thin films. We have also demonstrated that the eC performance can be improved by reducing the Young’s modulus or enhancing the thermal expansion coefficient (which could be realized through chemical doping, etc.). We expect these discoveries to spur further interest in the potential applications of metal-free organic ferroelectrics materials towards next-generation eC refrigeration devices.
Distinguishing features of current COVID-19 vaccines: knowns and unknowns of antigen presentation and modes of action
Authors: Heinz Franz X. , Stiasny Karin
Published: August 2021

COVID-19 vaccines were developed with an unprecedented pace since the beginning of the pandemic. Several of them have reached market authorization and mass production, leading to their global application on a large scale. This enormous progress was achieved with fundamentally different vaccine technologies used in parallel. mRNA, adenoviral vector as well as inactivated whole-virus vaccines are now in widespread use, and a subunit vaccine is in a final stage of authorization. They all rely on the native viral spike protein (S) of SARS-CoV-2 for inducing potently neutralizing antibodies, but the presentation of this key antigen to the immune system differs substantially between the different categories of vaccines. In this article, we review the relevance of structural modifications of S in different vaccines and the different modes of antigen expression after vaccination with genetic adenovirus-vector and mRNA vaccines. Distinguishing characteristics and unknown features are highlighted in the context of protective antibody responses and reactogenicity of vaccines.
Placental endocrine function shapes cerebellar development and social behavior
Authors: Vacher Claire-Marie , Lacaille Helene , O’Reilly Jiaqi J. , Salzbank Jacquelyn , Bakalar Dana , Sebaoui Sonia , Liere Philippe , Clarkson-Paredes Cheryl , Sasaki Toru , Sathyanesan Aaron , Kratimenos Panagiotis , Ellegood Jacob , Lerch Jason P. , Imamura Yuka , Popratiloff Anastas , Hashimoto-Torii Kazue , Gallo Vittorio , Schumacher Michael , Penn Anna A.
Published: August 2021

Compromised placental function or premature loss has been linked to diverse neurodevelopmental disorders. Here we show that placenta allopregnanolone (ALLO), a progesterone-derived GABA-A receptor (GABAAR) modulator, reduction alters neurodevelopment in a sex-linked manner. A new conditional mouse model, in which the gene encoding ALLO’s synthetic enzyme (akr1c14) is specifically deleted in trophoblasts, directly demonstrated that placental ALLO insufficiency led to cerebellar white matter abnormalities that correlated with autistic-like behavior only in male offspring. A single injection of ALLO or muscimol, a GABAAR agonist, during late gestation abolished these alterations. Comparison of male and female human preterm infant cerebellum also showed sex-linked myelination marker alteration, suggesting similarities between mouse placental ALLO insufficiency and human preterm brain development. This study reveals a new role for a placental hormone in shaping brain regions and behaviors in a sex-linked manner. Placental hormone replacement might offer novel therapeutic opportunities to prevent later neurobehavioral disorders.
Exposure to continuous or fluid theories of sexual orientation leads some heterosexuals to embrace less-exclusive heterosexual orientations
Authors: Morandini James S. , Dacosta Liam , Dar-Nimrod Ilan
Published: August 2021

We examined whether heterosexual individuals’ self-reported sexual orientation could be influenced experimentally by manipulating their knowledge of the nature of sexual orientation. In Study 1 (180 university students, 66% female) participants read summaries describing evidence for sexual orientation existing on a continuum versus discrete categories or a control manipulation, and in Study 2 (460 participants in a nationally representative Qualtrics panel, 50% female) additionally read summaries describing sexual orientation as fluid versus stable across the life-course. After reading summaries, participants answered various questions about their sexual orientation. In Study 1, political moderates and progressives (but not conservatives) who read the continuous manipulation subsequently reported being less exclusively heterosexual, and regardless of political alignment, participants reported less certainty about their sexual orientation, relative to controls. In Study 2, after exposure to fluid or continuous manipulations heterosexual participants were up to five times more likely than controls to rate themselves as non-exclusively heterosexual. Additionally, those in the continuous condition reported less certainty about their sexual orientation and were more willing to engage in future same-sex sexual experiences, than those in the control condition. These results suggest that non-traditional theories of sexual orientation can lead heterosexuals to embrace less exclusive heterosexual orientations.
Dayara bugyal restoration model in the alpine and subalpine region of the Central Himalaya: a step toward minimizing the impacts
Authors: Kuniyal Jagdish Chandra , Maiti Priyanka , Kumar Sandeep , Kumar Anand , Bisht Nisha , Sekar K. Chandra , Arya Satish Chandra , Rai Sumit , Nand Mahesha
Published: August 2021

Eco-restoration initiative work in the high altitude Dayara pastureland (3501 m) from the Indian Himalayan Region has been considered to be one of the successful field demonstration against both natural and anthropogenic degradation. The present study therefore attempts to assess the implications of entire eco-restoration model as practiced by Department of Forest, Government of Uttarakhand in 2019. Its assessment was done by calculating restoration success index by way of considering three categories, viz., direct management measure (M), environmental desirability (E) and socio-economic feasibility (SE) considering 22 individual variables. ‘M’ comprised both biotic and abiotic pressures. Grazing and tourism were biotic, while abiotic pressure was considered mainly soil erosion in alpine area due to topographic fragility. Above ground vegetation profile and below ground soil nutrient profile (N, P, K, pH and water holding capacity) were analyzed in ‘E’ component. In the last but not least, ‘SE’ was analyzed to assess the social acceptability of the local communities and stakeholders who are supposed to be ultimate beneficiary of alike interventions. Direct management measure was found with the variable index score of 0.8 indicating the higher score as compared to environmental desirability (0.56). Under direct management measure, grazing and tourists’ carrying capacity of the area was analyzed with high management needs to call the region sustainable in terms of availability of bio-resources. The ecosystem index score was evaluated for the reference (81.94), treated (64.5) and untreated zones (52.03), wherein increasing profile of these values were found. The outcomes like improved vegetation profile in terms of total herb density, soil nutrient profile of the restored area along with soil pH (4.96) and water holding capacity (49.85%) were found to be restored significantly along with controlling 169.64 tonne year-1 soil erosion from draining. The assessment of grazing pattern of 118 migratory Cow Unit (CU) (76 horse/mule and 18 sheep/goat, already controlled), 318 local CU (30 horse/mule and 187 sheep/goat) were calculated and recommended to be controlled. Tourists’ carrying capacity of 274 tourists per day and manual removal of Rumex nepalensis at the shepherd camping site were found to be worth to apply in the area. Use of biodegradable but locally sourced material and engaging local villagers in this endeavor were also found to be in harmony with SDG Goal 1 (no poverty). Therefore, the restoration and its evaluation model could have its future prospects to prove as a successful restoration practice. This restoration practice could not only be worth in high altitude degraded alpine pastures of the Indian Himalayan Region but also to other mountain alpine and sub-alpine ecosystems.
The full phase space dynamics of a magnetically levitated electromagnetic vibration harvester
Authors: Jensen Tobias Willemoes , Insinga Andrea R. , Ehlers Johan Christian , Bjørk Rasmus
Published: August 2021

We consider the motion of an electromagnetic vibrational energy harvester (EMVEH) as function of the initial position and velocity and show that this displays a classical chaotic dynamical behavior. The EMVEH considered consists of three coaxial cylindrical permanent magnets and two coaxial coils. The polarities of the three magnets are chosen in such a way that the central magnet floats, with its lateral motion being prevented by enclosion in a hollow plastic tube. The motion of the floating magnet, caused by e.g. environmental vibrations, induces a current in the coils allowing electrical energy to be harvested. We analyze the behavior of the system using a numerical model employing experimentally verified expressions of the force between the magnets and the damping force between the floating magnet and the coils. We map out the phase space of the motion of the system with and without gravity, and show that this displays a fractal-like behavior and that certain driving frequencies and initial conditions allow a large power to be harvested, and that more stable states than two exists. Finally, we show that at leasts fifth order polynomial approximation is necessary to approximate the magnet-magnet force and correctly predict the system behavior.
PEG-modified gadolinium nanoparticles as contrast agents for in vivo micro-CT
Authors: Cruje Charmainne , Dunmore-Buyze P. Joy , Grolman Eric , Holdsworth David W. , Gillies Elizabeth R. , Drangova Maria
Published: August 2021

Vascular research is largely performed in rodents with the goal of developing treatments for human disease. Micro-computed tomography (micro-CT) provides non-destructive three-dimensional imaging that can be used to study the vasculature of rodents. However, to distinguish vasculature from other soft tissues, long-circulating contrast agents are required. In this study, we demonstrated that poly(ethylene glycol) (PEG)-coated gadolinium nanoparticles can be used as a vascular contrast agent in micro-CT. The coated particles could be lyophilized and then redispersed in an aqueous solution to achieve 100 mg/mL of gadolinium. After an intravenous injection of the contrast agent into mice, micro-CT scans showed blood pool contrast enhancements of at least 200 HU for 30 min. Imaging and quantitative analysis of gadolinium in tissues showed the presence of contrast agent in clearance organs including the liver and spleen and very low amounts in other organs. In vitro cell culture experiments, subcutaneous injections, and analysis of mouse body weight suggested that the agents exhibited low toxicity. Histological analysis of tissues 5 days after injection of the contrast agent showed cytotoxicity in the spleen, but no abnormalities were observed in the liver, lungs, kidneys, and bladder.
Combined effect of mineralogical and chemical parameters on swelling behaviour of expansive soils
Authors: Rao Bendadi Hanumantha , Reddy Peddireddy Sreekanth , Mohanty Bijayananda , Reddy Krishna R.
Published: August 2021

Microlevel properties such as mineralogical and chemical compositions greatly control the macro behaviour of expansive soils. In this paper, the combined effect of mineral (i.e. montmorillonite, MMC) and chemical contents (i.e. Ca and Na in their total (T), leachable (L) and exchangeable form (CEC)) on swelling behaviour is investigated in a comprehensive way. Several 3-dimensional (3D) graphs correlating MMC and Ca/Na ratio, together, with swelling property (swelling potential, Sa, and swelling pressure, Sp) are developed. 3D plots, in general, portrayed a non-linear relationship of Sa and Sp with MMC and Ca/Na ratio, together. It is hypothesized that swelling initially is triggered by chemical parameters due to their quick and rapid ionization capability, but the overall swelling phenomenon is largely controlled by MMC. It is importantly found that expansive soils are dominant with divalent Ca++ ions up to MMC of 67% and beyond this percentage, monovalent Na+ ions are prevalent. From the interpretation of results, the maximum Sa of 18% and Sp of 93 kPa is measured at MMC of 43%, (Ca/Na)T of 10–14 and (Ca/Na)L of 2–7. It is concluded from study that total CEC + MMC for determining Sa and (Ca/Na)T + MMC for determining Sp are superior parameters to be considered. The findings of the study also excellently endorsed the results of Foster32, who stated that ionization of Na or Ca depends on the constituent mineral contents. The findings presented herein are unique, interesting and bear very practical significance, as no earlier research work reported such findings by accounting for chemical and mineralogical parameters impact, in tandem, on swelling properties.
Comparative analysis of machine learning approaches to classify tumor mutation burden in lung adenocarcinoma using histopathology images
Authors: Sadhwani Apaar , Chang Huang-Wei , Behrooz Ali , Brown Trissia , Auvigne-Flament Isabelle , Patel Hardik , Findlater Robert , Velez Vanessa , Tan Fraser , Tekiela Kamilla , Wulczyn Ellery , Yi Eunhee S. , Mermel Craig H. , Hanks Debra , Chen Po-Hsuan Cameron , Kulig Kimary , Batenchuk Cory , Steiner David F. , Cimermancic Peter
Published: August 2021

Both histologic subtypes and tumor mutation burden (TMB) represent important biomarkers in lung cancer, with implications for patient prognosis and treatment decisions. Typically, TMB is evaluated by comprehensive genomic profiling but this requires use of finite tissue specimens and costly, time-consuming laboratory processes. Histologic subtype classification represents an established component of lung adenocarcinoma histopathology, but can be challenging and is associated with substantial inter-pathologist variability. Here we developed a deep learning system to both classify histologic patterns in lung adenocarcinoma and predict TMB status using de-identified Hematoxylin and Eosin (H&E) stained whole slide images. We first trained a convolutional neural network to map histologic features across whole slide images of lung cancer resection specimens. On evaluation using an external data source, this model achieved patch-level area under the receiver operating characteristic curve (AUC) of 0.78–0.98 across nine histologic features. We then integrated the output of this model with clinico-demographic data to develop an interpretable model for TMB classification. The resulting end-to-end system was evaluated on 172 held out cases from TCGA, achieving an AUC of 0.71 (95% CI 0.63–0.80). The benefit of using histologic features in predicting TMB is highlighted by the significant improvement this approach offers over using the clinical features alone (AUC of 0.63 [95% CI 0.53–0.72], p = 0.002). Furthermore, we found that our histologic subtype-based approach achieved performance similar to that of a weakly supervised approach (AUC of 0.72 [95% CI 0.64–0.80]). Together these results underscore that incorporating histologic patterns in biomarker prediction for lung cancer provides informative signals, and that interpretable approaches utilizing these patterns perform comparably with less interpretable, weakly supervised approaches.
Novel somatic variants involved in biochemical activity of pure growth hormone-secreting pituitary adenoma without GNAS variant
Authors: Ku Cheol Ryong , Lim Hyeonseob , Lee Yang Jong , Kim Sun Ho , Kim Daham , Kim Se Hoon , Lee Mi Kyung , Bang Duhee , Lee Eun Jig
Published: August 2021

We aimed to identify somatic genetic alterations in pure growth hormone (GH)-secreting pituitary adenomas without GNAS variants. Patients with GH-secreting pituitary adenoma who underwent transsphenoidal adenomectomy at Severance Hospital, Yonsei University College of Medicine were recruited. Somatic genetic alterations were profiled by whole-exome sequencing (WES) and targeted resequencing. WES was performed using DNA from nine GH-secreting pituitary tumors and corresponding blood samples. Absence of GNAS variant was confirmed by Sanger sequencing. For targeted resequencing of 140 fixed tissues, 48 WES-derived candidate genes and 7 GH-secreting pituitary adenoma-associated genes were included. Forty-eight genes with 59 somatic variants were identified by WES. In targeted resequencing, variants in 26 recurrent genes, including MAST4, PRIM2, TNN, STARD9, DNAH11, DOCK4, GPR98, BCHE, DARS, CUBN, NGDN, PLXND1, UNC5B, and COL22A1, were identified, but variants in previously reported genes were not detected. BCHE, DARS, NGDN, and UNC5B variants were associated with increased GH-secreting pituitary tumor biochemical activity, which was confirmed in vitro. Although recurrent point variants were rare, several somatic variants were identified in sporadic pure GH-secreting pituitary adenomas. Several somatic variants may affect pathways involved in the tumorigenesis and biochemical activities of GH-secreting pituitary adenomas.
Chimeric virus-like particles (VLPs) designed from shrimp nodavirus (MrNV) capsid protein specifically target EGFR-positive human colorectal cancer cells
Authors: Grataitong Khwanthana , Huault Sébastien , Chotwiwatthanakun Charoonroj , Jariyapong Pitchanee , Thongsum Orawan , Chawiwithaya Chidchanok , Chakrabandhu Krittalak , Hueber Anne-Odile , Weerachatyanukul Wattana
Published: August 2021

Recombinant MrNV capsid protein has been shown to effectively deliver plasmid DNA and dsRNA into Sf9 insect cells and shrimp tissues. To extend its application to cancer cell-targeting drug delivery, we created three different types of chimeric MrNV virus-like particles (VLPs) (R-MrNV, I-MrNV, and E-MrNV) that have specificity toward the epidermal growth factor receptor (EGFR), a cancer cell biomarker, by incorporating the EGFR-specific GE11 peptide at 3 different locations within the host cell recognition site of the capsid. All three chimeric MrNV-VLPs preserved the ability to form a mulberry-like VLP structure and to encapsulate EGFP DNA plasmid with an efficiency comparable to that previously reported for normal MrNV (N-MrNV). Compared to N-MrNV, the chimeric R-MrNV and E-MrNV carrying the exposed GE-11 peptide showed a significantly enhanced binding and internalization abilities that were specific towards EGFR expression in colorectal cancer cells (SW480). Specific targeting of chimeric MrNV to EGFR was proven by both EGFR silencing with siRNA vector and a competition with excess GE-11 peptide as well as the use of EGFR-negative colorectal cells (SW620) and breast cancer cells (MCF7). We demonstrated here that both chimeric R-MrNV and E-MrNV could be used to encapsulate cargo such as exogenous DNA and deliver it specifically to EGFR-positive cells. Our study presents the potential use of surface-modified VLPs of shrimp virus origin as nanocontainers for targeted cancer drug delivery.
Maternal high-fat diet during pregnancy with concurrent phthalate exposure leads to abnormal placentation
Authors: Kannan Athilakshmi , Davila Juanmahel , Gao Liying , Rattan Saniya , Flaws Jodi A. , Bagchi Milan K. , Bagchi Indrani C.
Published: August 2021

Di(2-ethylhexyl) phthalate (DEHP) is a synthetic chemical commonly used for its plasticizing capabilities. Because of the extensive production and use of DEHP, humans are exposed to this chemical daily. Diet is a significant exposure pathway and fatty food contain the highest level of phthalates. The impact on pregnancy following DEHP exposure and the associated interaction of high fat (HF) diet remains unknown. Here we report that exposure of pregnant mice to an environmentally relevant level of DEHP did not affect pregnancy. In contrast, mice fed a HF diet during gestation and exposed to the same level of DEHP display marked impairment in placental development, resulting in poor pregnancy outcomes. Our study further reveals that DEHP exposure combined with a HF diet interfere with the signaling pathway controlled by nuclear receptor PPARγ to adversely affect differentiation of trophoblast cells, leading to compromised vascularization and glucose transport in the placenta. Collectively, these findings demonstrate that maternal diet during pregnancy is a critical factor that determines whether exposure to an environmental toxicant results in impaired placental and fetal development, causing intrauterine growth restriction, fetal morbidity, and mortality.
High taxonomic resolution surveys and trait-based analyses reveal multiple benthic regimes in North Sulawesi (Indonesia)
Authors: Reverter Miriam , Jackson Matthew , Rohde Sven , Moeller Mareen , Bara Robert , Lasut Markus T. , Segre Reinach Marco , Schupp Peter J.
Published: August 2021

As coral reef communities change and reorganise in response to increasing disturbances, there is a growing need for understanding species regimes and their contribution to ecosystem processes. Using a case study on coral reefs at the epicentre of tropical marine biodiversity (North Sulawesi, Indonesia), we explored how application of different biodiversity approaches (i.e., use of major taxonomic categories, high taxonomic resolution categories and trait-based approaches) affects the detection of distinct fish and benthic communities. Our results show that using major categories fails to identify distinct coral reef regimes. We also show that monitoring of only scleractinian coral communities is insufficient to detect different benthic regimes, especially communities dominated by non-coral organisms, and that all types of benthic organisms need to be considered. We have implemented the use of a trait-based approach to study the functional diversity of whole coral reef benthic assemblages, which allowed us to detect five different community regimes, only one of which was dominated by scleractinian corals. Furthermore, by the parallel study of benthic and fish communities we provide new insights into key processes and functions that might dominate or be compromised in the different community regimes.