bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing Quaternary Shortening Rates at an Andean Frontal Thrust (32°30′S), Argentina
Authors: Costa Carlos H. , Schoenbohm Lindsay M. , Brooks Benjamin A. , Gardini Carlos E. , Richard Andrés D.
Published: July 2019

At the latitude of 32–33°S, the orogenic front of the eastern flank of the Andes is located in the Southern Precordillera, where two major thrusts concentrate Quaternary deformation at the surface. We estimate the shortening rate for one of these, the Las Peñas thrust, for the last ~200 ka, at the site of one of the best exposures of Quaternary thrusting along the Andes. Shortening was estimated across two prominent splays of the deformation zone at the mouth of the Las Peñas River through balanced cross‐sections by using a terrace surface as a marker of cumulative deformation. Terrace ages were constrained through cosmogenic isotopes (10Be) analysis on quartz cobbles collected from the surface and three depth profiles. Results indicate a mean shortening rate across the Las Peñas thrust of 0.27 + 0.11 mm/a. Our results are lower than Holocene shortening rates (1.9–2.4 mm/a) obtained for individual splays of the Las Peñas thrust nearby. We discuss these discrepancies and implications for thrust evolution since the Late Pleistocene, in particular regarding along‐strike rate variations that highlight the complexity of the Quaternary‐active thrust deformation zone. We argue that ongoing stream incision rates largely prevail with respect to thrust activity at the study site. This observation might be connected with a recent (Holocene?) basinward shift of blind thrust activity.
Detection of anti-correlation of hot and cold baryons in galaxy clusters
Authors: Farahi Arya , Mulroy Sarah L. , Evrard August E. , Smith Graham P. , Finoguenov Alexis , Bourdin Hervé , Carlstrom John E. , Haines Chris P. , Marrone Daniel P. , Martino Rossella , Mazzotta Pasquale , O’Donnell Christine , Okabe Nobuhiro
Published: July 2019

The largest clusters of galaxies in the Universe contain vast amounts of dark matter, plus baryonic matter in two principal phases, a majority hot gas component and a minority cold stellar phase comprising stars, compact objects, and low-temperature gas. Hydrodynamic simulations indicate that the highest-mass systems retain the cosmic fraction of baryons, a natural consequence of which is anti-correlation between the masses of hot gas and stars within dark matter halos of fixed total mass. We report observational detection of this anti-correlation based on 4 elements of a 9 × 9-element covariance matrix for nine cluster properties, measured from multi-wavelength observations of 41 clusters from the Local Cluster Substructure Survey. These clusters were selected using explicit and quantitative selection rules that were then encoded in our hierarchical Bayesian model. Our detection of anti-correlation is consistent with predictions from contemporary hydrodynamic cosmological simulations that were not tuned to reproduce this signal.
Multi-functional soft-bodied jellyfish-like swimming
Authors: Ren Ziyu , Hu Wenqi , Dong Xiaoguang , Sitti Metin
Published: July 2019

The functionalities of the untethered miniature swimming robots significantly decrease as the robot size becomes smaller, due to limitations of feasible miniaturized on-board components. Here we propose an untethered jellyfish-inspired soft millirobot that could realize multiple functionalities in moderate Reynolds number by producing diverse controlled fluidic flows around its body using its magnetic composite elastomer lappets, which are actuated by an external oscillating magnetic field. We particularly investigate the interaction between the robot’s soft body and incurred fluidic flows due to the robot’s body motion, and utilize such physical interaction to achieve different predation-inspired object manipulation tasks. The proposed lappet kinematics can inspire other existing jellyfish-like robots to achieve similar functionalities at the same length and time scale. Moreover, the robotic platform could be used to study the impacts of the morphology and kinematics changing in ephyra jellyfish.
Spatial suppression promotes rapid figure-ground segmentation of moving objects
Authors: Tadin Duje , Park Woon Ju , Dieter Kevin C. , Melnick Michael D. , Lappin Joseph S. , Blake Randolph
Published: July 2019

Segregation of objects from their backgrounds is a fundamental visual function and one that is particularly effective when objects are in motion. Theoretically, suppressive center-surround mechanisms are well suited for accomplishing motion segregation. This longstanding hypothesis, however, has received limited empirical support. We report converging correlational and causal evidence that spatial suppression of background motion signals is critical for rapid segmentation of moving objects. Motion segregation ability is strongly predicted by both individual and stimulus-driven variations in spatial suppression strength. Moreover, aging-related superiority in perceiving background motion is associated with profound impairments in motion segregation. This segregation deficit is alleviated via perceptual learning, but only when motion segregation training also causes decreased sensitivity to background motion. We argue that perceptual insensitivity to large moving stimuli effectively implements background subtraction, which, in turn, enhances the visibility of moving objects and accounts for the observed link between spatial suppression and motion segregation.
The deubiquitylase OTUD3 stabilizes GRP78 and promotes lung tumorigenesis
Authors: Du Tongde , Li Hongchang , Fan Yongsheng , Yuan Lin , Guo Xiaodan , Zhu Qiong , Yao Yuying , Li Xin , Liu Chunlei , Yu Xinhe , Liu Zhaofei , Cui Chun-Ping , Han Chuanchun , Zhang Lingqiang
Published: July 2019

The deubiquitylase OTUD3 plays a suppressive role in breast tumorigenesis through stabilizing PTEN protein, but its role in lung cancer remains unclear. Here, we demonstrate that in vivo deletion of OTUD3 indeed promotes breast cancer development in mice, but by contrast, it slows down KrasG12D-driven lung adenocarcinoma (ADC) initiation and progression and markedly increases survival in mice. Moreover, OTUD3 is highly expressed in human lung cancer tissues and its higher expression correlates with poorer survival of patients. Further mechanistic studies reveal that OTUD3 interacts with, deubiquitylates and stabilizes the glucose-regulated protein GRP78. Knockdown of OTUD3 results in a decrease in the level of GRP78 protein, suppression of cell growth and migration, and tumorigenesis in lung cancer. Collectively, our results reveal a previously unappreciated pro-oncogenic role of OTUD3 in lung cancer and indicate that deubiquitylases could elicit tumor-suppressing or tumor-promoting activities in a cell- and tissue-dependent context.
An anionic human protein mediates cationic liposome delivery of genome editing proteins into mammalian cells
Authors: Kim Y. Bill , Zhao Kevin T. , Thompson David B. , Liu David R.
Published: July 2019

Delivery into mammalian cells remains a significant challenge for many applications of proteins as research tools and therapeutics. We recently reported that the fusion of cargo proteins to a supernegatively charged (–30)GFP enhances encapsulation by cationic lipids and delivery into mammalian cells. To discover polyanionic proteins with optimal delivery properties, we evaluate negatively charged natural human proteins for their ability to deliver proteins into cultured mammalian cells and human primary fibroblasts. Here we discover that ProTα, a small, widely expressed, intrinsically disordered human protein, enables up to ~10-fold more efficient cationic lipid-mediated protein delivery compared to (–30)GFP. ProTα enables efficient delivery at low- to mid-nM concentrations of two unrelated genome editing proteins, Cre recombinase and zinc-finger nucleases, under conditions in which (–30)GFP fusion or cationic lipid alone does not result in substantial activity. ProTα may enable mammalian cell protein delivery applications when delivery potency is limiting.
Mechanically strong MXene/Kevlar nanofiber composite membranes as high-performance nanofluidic osmotic power generators
Authors: Zhang Zhen , Yang Sheng , Zhang Panpan , Zhang Jian , Chen Guangbo , Feng Xinliang
Published: July 2019

Two-dimensional nanofluidic channels are emerging candidates for capturing osmotic energy from salinity gradients. However, present two-dimensional nanofluidic architectures are generally constructed by simple stacking of pristine nanosheets with insufficient charge densities, and exhibit low-efficiency transport dynamics, consequently resulting in undesirable power densities (<1 W m−2). Here we demonstrate MXene/Kevlar nanofiber composite membranes as high-performance nanofluidic osmotic power generators. By mixing river water and sea water, the power density can achieve a value of approximately 4.1 W m−2, outperforming the state-of-art membranes to the best of our knowledge. Experiments and theoretical calculations reveal that the correlation between surface charge of MXene and space charge brought by nanofibers plays a key role in modulating ion diffusion and can synergistically contribute to such a considerable energy conversion performance. This work highlights the promise in the coupling of surface charge and space charge in nanoconfinement for energy conversion driven by chemical potential gradients.
Fas signaling-mediated TH9 cell differentiation favors bowel inflammation and antitumor functions
Authors: Shen Yingying , Song Zhengbo , Lu Xinliang , Ma Zeyu , Lu Chaojie , Zhang Bei , Chen Yinghu , Duan Meng , Apetoh Lionel , Li Xu , Guo Jufeng , Miao Ying , Zhang Gensheng , Yang Diya , Cai Zhijian , Wang Jianli
Published: July 2019

Fas induces apoptosis in activated T cell to maintain immune homeostasis, but the effects of non-apoptotic Fas signaling on T cells remain unclear. Here we show that Fas promotes TH9 cell differentiation by activating NF-κB via Ca2+-dependent PKC-β activation. In addition, PKC-β also phosphorylates p38 to inactivate NFAT1 and reduce NFAT1-NF-κB synergy to promote the Fas-induced TH9 transcription program. Fas ligation exacerbates inflammatory bowel disease by increasing TH9 cell differentiation, and promotes antitumor activity in p38 inhibitor-treated TH9 cells. Furthermore, low-dose p38 inhibitor suppresses tumor growth without inducing systemic adverse effects. In patients with tumor, relatively high TH9 cell numbers are associated with good prognosis. Our study thus implicates Fas in CD4+ T cells as a target for inflammatory bowel disease therapy. Furthermore, simultaneous Fas ligation and low-dose p38 inhibition may be an effective approach for TH9 cell induction and cancer therapy.
Cell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium
Authors: Brandt Raphael , Sell Thomas , Lüthen Mareen , Uhlitz Florian , Klinger Bertram , Riemer Pamela , Giesecke-Thiel Claudia , Schulze Silvia , El-Shimy Ismail Amr , Kunkel Desiree , Fauler Beatrix , Mielke Thorsten , Mages Norbert , Herrmann Bernhard G. , Sers Christine , Blüthgen Nils , Morkel Markus
Published: July 2019

Oncogenic mutations in KRAS or BRAF are frequent in colorectal cancer and activate the ERK kinase. Here, we find graded ERK phosphorylation correlating with cell differentiation in patient-derived colorectal cancer organoids with and without KRAS mutations. Using reporters, single cell transcriptomics and mass cytometry, we observe cell type-specific phosphorylation of ERK in response to transgenic KRASG12Vin mouse intestinal organoids, while transgenic BRAFV600Eactivates ERK in all cells. Quantitative network modelling from perturbation data reveals that activation of ERK is shaped by cell type-specific MEK to ERK feed forward and negative feedback signalling. We identify dual-specificity phosphatases as candidate modulators of ERK in the intestine. Furthermore, we find that oncogenic KRAS, together with β-Catenin, favours expansion of crypt cells with high ERK activity. Our experiments highlight key differences between oncogenic BRAF and KRAS in colorectal cancer and find unexpected heterogeneity in a signalling pathway with fundamental relevance for cancer therapy.
Chemical logic of MraY inhibition by antibacterial nucleoside natural products
Authors: Mashalidis Ellene H. , Kaeser Benjamin , Terasawa Yuma , Katsuyama Akira , Kwon Do-Yeon , Lee Kiyoun , Hong Jiyong , Ichikawa Satoshi , Lee Seok-Yong
Published: July 2019

Novel antibacterial agents are needed to address the emergence of global antibiotic resistance. MraY is a promising candidate for antibiotic development because it is the target of five classes of naturally occurring nucleoside inhibitors with potent antibacterial activity. Although these natural products share a common uridine moiety, their core structures vary substantially and they exhibit different activity profiles. An incomplete understanding of the structural and mechanistic basis of MraY inhibition has hindered the translation of these compounds to the clinic. Here we present crystal structures of MraY in complex with representative members of the liposidomycin/caprazamycin, capuramycin, and mureidomycin classes of nucleoside inhibitors. Our structures reveal cryptic druggable hot spots in the shallow inhibitor binding site of MraY that were not previously appreciated. Structural analyses of nucleoside inhibitor binding provide insights into the chemical logic of MraY inhibition, which can guide novel approaches to MraY-targeted antibiotic design.
Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma
Authors: Ning Jian-Fang , Stanciu Monica , Humphrey Melissa R. , Gorham Joshua , Wakimoto Hiroko , Nishihara Reiko , Lees Jacqueline , Zou Lee , Martuza Robert L. , Wakimoto Hiroaki , Rabkin Samuel D.
Published: July 2019

PARP inhibitors (PARPis) have clinical efficacy in BRCA-deficient cancers, but not BRCA-intact tumors, including glioblastoma (GBM). We show that MYC or MYCN amplification in patient-derived glioblastoma stem-like cells (GSCs) generates sensitivity to PARPi via Myc-mediated transcriptional repression of CDK18, while most tumors without amplification are not sensitive. In response to PARPi, CDK18 facilitates ATR activation by interacting with ATR and regulating ATR-Rad9/ATR-ETAA1 interactions; thereby promoting homologous recombination (HR) and PARPi resistance. CDK18 knockdown or ATR inhibition in GSCs suppressed HR and conferred PARPi sensitivity, with ATR inhibitors synergizing with PARPis or sensitizing GSCs. ATR inhibitor VE822 combined with PARPi extended survival of mice bearing GSC-derived orthotopic tumors, irrespective of PARPi-sensitivity. These studies identify a role of CDK18 in ATR-regulated HR. We propose that combined blockade of ATR and PARP is an effective strategy for GBM, even for low-Myc GSCs that do not respond to PARPi alone, and potentially other PARPi-refractory tumors.
Two-gap superconductivity in CaFe0.88Co0.12AsF revealed by temperature dependence of the lower critical field Hc1c (T)
Authors: Wang Teng , Ma Yonghui , Li Wei , Chu Jianan , Wang Lingling , Feng Jiaxin , Xiao Hong , Li Zhuojun , Hu Tao , Liu Xiaosong , Mu Gang
Published: July 2019

Gap symmetry and structure are crucial issues in understanding the superconducting mechanism of unconventional superconductors. Here, we report an in-depth investigation on the out-of-plane lower critical field $$H_{c1}^c$$

H

c
1

c

of fluorine-based 1111 system superconductor CaFe0.88Co0.12AsF with Tc = 21 K. A pronounced two-gap feature is revealed by the kink in the temperature-dependent $$H_{c1}^c(T)$$

H

c
1

c

(

T

)

curve. The magnitudes of the two gaps are determined to be Δ1 = 0.86 meV and Δ2 = 4.48 meV, which account for 74% and 26% of the total superfluid density, respectively. Our results suggest that the local antiferromagnetic exchange pairing picture is favored compared to the Fermi surface nesting scenario.
Sex differences in respiratory and circulatory cost during hypoxic walking: potential impact on oxygen saturation
Authors: Horiuchi Masahiro , Kirihara Yoko , Fukuoka Yoshiyuki , Pontzer Herman
Published: July 2019

Energy expenditure (EE) during treadmill walking under normal conditions (normobaric normoxia, 21% O2) and moderate hypoxia (13% O2) was measured. Ten healthy young men and ten healthy young women walked on a level (0°) gradient a range of speeds (0.67–1.67 m s−1). During walking, there were no significant differences in reductions in arterial oxygen saturation (SpO2) between the sexes. The hypoxia-induced increase in EE, heart rate (HR [bpm]) and ventilation ($${\dot{{\rm{V}}}}_{{\rm{E}}}$$

V
̇

E

[L min−1]) were calculated. Using a multivariate model that combined EE, $${\dot{{\rm{V}}}}_{{\rm{E}}}$$

V
̇

E

, and HR to predict ΔSpO2 (hypoxia-induced reduction), a very strong fit model both for men (r2 = 0.900, P < 0.001) and for women was obtained (r2 = 0.957, P < 0.001). The contributions of EE, VE, and HR to ΔSpO2 were markedly different between men and women. $${\dot{{\rm{V}}}}_{{\rm{E}}}$$

V
̇

E

and EE had a stronger effect on ΔSpO2 in women ($${\dot{{\rm{V}}}}_{{\rm{E}}}$$

V
̇

E

: 4.1% in women vs. 1.7% in men; EE: 28.1% in women vs. 15.8% in men), while HR had a greater effect in men (82.5% in men and 67.9% in women). These findings suggested that high-altitude adaptation in response to hypoxemia has different underlying mechanisms between men and women. These results can help to explain how to adapt high-altitude for men and women, respectively.
Making stratigraphy in the Anthropocene: climate change impacts and economic conditions controlling the supply of sediment to Lake Geneva
Authors: Lane S. N. , Bakker M. , Costa A. , Girardclos S. , Loizeau J.-L. , Molnar P. , Silva T. , Stutenbecker L. , Schlunegger F.
Published: July 2019

The Anthropocene has been proposed as a profound, globally synchronous rupture in the history of the Earth System with its current state fundamentally different to that of the Holocene and driven by the geological force of human activity. Here, we show how stratigraphy is being made in a lake that is heavily impacted upon by climate change and human activities. For one of the largest inner-Alpine catchments in the European Alps, we draw attention to how sedimentation rates are a product of non-stationary, reflexive, human actions. In Lake Geneva, we identify both a human-induced climate change (HCC) signature and the effects of a recent economic shock on sediment extraction upon sediment loading to and sedimentation rates in the lake. The HCC signature thus reflects the nature of climate change impacts in this basin, where sediment accumulation rates evolve with climate, but where economic conditions contribute to shifts in the supply of sediment to the lake. Following social theory, we call this glocalization because of the combined importance and inseparability of human impacts across different spatial scales. The nature of human impacts on sediment delivery to the lake mean that the influence of humans is unlikely to be captured in the long-term depositional record.
Tomato plants rather than fertilizers drive microbial community structure in horticultural growing media
Authors: Grunert Oliver , Robles-Aguilar Ana A. , Hernandez-Sanabria Emma , Schrey Silvia D. , Reheul Dirk , Van Labeke Marie-Christine , Vlaeminck Siegfried E. , Vandekerckhove Tom G. L. , Mysara Mohamed , Monsieurs Pieter , Temperton Vicky M. , Boon Nico , Jablonowski Nicolai D.
Published: July 2019

Synthetic fertilizer production is associated with a high environmental footprint, as compounds typically dissolve rapidly leaching emissions to the atmosphere or surface waters. We tested two recovered nutrients with slower release patterns, as promising alternatives for synthetic fertilizers: struvite and a commercially available organic fertilizer. Using these fertilizers as nitrogen source, we conducted a rhizotron experiment to test their effect on plant performance and nutrient recovery in juvenile tomato plants. Plant performance was significantly improved when organic fertilizer was provided, promoting higher shoot biomass. Since the microbial community influences plant nitrogen availability, we characterized the root-associated microbial community structure and functionality. Analyses revealed distinct root microbial community structure when different fertilizers were supplied. However, plant presence significantly increased the similarity of the microbial community over time, regardless of fertilization. Additionally, the presence of the plant significantly reduced the potential ammonia oxidation rates, implying a possible role of the rhizosheath microbiome or nitrification inhibition by the plant. Our results indicate that nitrifying community members are impacted by the type of fertilizer used, while tomato plants influenced the potential ammonia-oxidizing activity of nitrogen-related rhizospheric microbial communities. These novel insights on interactions between recovered fertilizers, plant and associated microbes can contribute to develop sustainable crop production systems.
Extracellular matrix stiffness regulates human airway smooth muscle contraction by altering the cell-cell coupling
Authors: Polio Samuel R. , Stasiak Suzanne E. , Jamieson Ryan R. , Balestrini Jenna L. , Krishnan Ramaswamy , Parameswaran Harikrishnan
Published: July 2019

For an airway or a blood vessel to narrow, there must be a connected path that links the smooth muscle (SM) cells with each other, and transmits forces around the organ, causing it to constrict. Currently, we know very little about the mechanisms that regulate force transmission pathways in a multicellular SM ensemble. Here, we used extracellular matrix (ECM) micropatterning to study force transmission in a two-cell ensemble of SM cells. Using the two-SM cell ensemble, we demonstrate (a) that ECM stiffness acts as a switch that regulates whether SM force is transmitted through the ECM or through cell-cell connections. (b) Fluorescent imaging for adherens junctions and focal adhesions show the progressive loss of cell-cell borders and the appearance of focal adhesions with the increase in ECM stiffness (confirming our mechanical measurements). (c) At the same ECM stiffness, we show that the presence of a cell-cell border substantially decreases the overall contractility of the SM cell ensemble. Our results demonstrate that connectivity among SM cells is a critical factor to consider in the development of diseases such as asthma and hypertension.
The Epstein-Barr Virus Oncoprotein, LMP1, Regulates the Function of SENP2, a SUMO-protease
Authors: Selby Thomas L. , Biel Natalie , Varn Matthew , Patel Sheetal , Patel Akash , Hilding Leslie , Ray Ashley , Ross Tabithia , Cramblet Wyatt T. , Moss C. Randall , Lowrey Angela J. , Bentz Gretchen L.
Published: July 2019

Epstein-Barr virus (EBV) latent membrane protein-1 (LMP1) activates numerous signal transduction pathways using its C-terminal activating regions. We reported that LMP1 increased global levels of sumoylated proteins, which aided the oncogenic nature of LMP1. Because increased protein sumoylation is detected in numerous cancers, we wanted to elucidate additional mechanisms by which LMP1 modulates the sumoylation machinery. Results indicated that SUMO-protease activity decreased in a LMP1-dependent manner, so we hypothesized that LMP1 inhibits SUMO-protease activity, resulting in reduced de-sumoylation of cellular proteins, which contributes to the detected accumulation of sumoylated proteins in EBV-positive lymphomas. Focusing on SENP2, findings revealed that LMP1 expression corresponded with increased sumoylation of SENP2 at K48 and K447 in a CTAR-dependent manner. Interestingly, independent of LMP1-induced sumoylation of SENP2, LMP1 also decreased SENP2 activity, decreased SENP2 turnover, and altered the localization of SENP2, which led us to investigate if LMP1 regulated the biology of SENP2 by a different post-translational modification, specifically ubiquitination. Data showed that expression of LMP1 inhibited the ubiquitination of SENP2, and inhibition of ubiquitination was sufficient to mimic LMP1-induced changes in SENP2 activity and trafficking. Together, these findings suggest that LMP1 modulates different post-translational modifications of SENP2 in order to modulate its biology and identify a third member of the sumoylation machinery that is manipulated by LMP1 during latent EBV infections, which can affect oncogenesis.
Protective effects of delayed intraventricular TLR7 agonist administration on cerebral white and gray matter following asphyxia in the preterm fetal sheep
Authors: Cho Kenta H. T. , Wassink Guido , Galinsky Robert , Xu Bing , Mathai Sam , Dhillon Simerdeep K. , van den Heuij Lotte G. , Davidson Joanne O. , Weaver-Mikaere Luke , Bennet Laura , Gunn Alistair J. , Fraser Mhoyra
Published: July 2019

Preterm brain injury is highly associated with inflammation, which is likely related in part to sterile responses to hypoxia-ischemia. We have recently shown that neuroprotection with inflammatory pre-conditioning in the immature brain is associated with induction of toll-like receptor 7 (TLR7). We therefore tested the hypothesis that central administration of a synthetic TLR7 agonist, gardiquimod (GDQ), after severe hypoxia-ischemia in preterm-equivalent fetal sheep would improve white and gray matter recovery. Fetal sheep at 0.7 of gestation received sham asphyxia or asphyxia induced by umbilical cord occlusion for 25 minutes, followed by a continuous intracerebroventricular infusion of GDQ or vehicle from 1 to 4 hours (total dose 1.8 mg/kg). Sheep were killed 72 hours after asphyxia for histology. GDQ significantly improved survival of immature and mature oligodendrocytes (2′,3′-cyclic-nucleotide 3′-phosphodiesterase, CNPase) and total oligodendrocytes (oligodendrocyte transcription factor 2, Olig-2) within the periventricular and intragyral white matter. There were reduced numbers of cells showing cleaved caspase-3 positive apoptosis and astrogliosis (glial fibrillary acidic protein, GFAP) in both white matter regions. Neuronal survival was increased in the dentate gyrus, caudate and medial thalamic nucleus. Central infusion of GDQ was associated with a robust increase in fetal plasma concentrations of the anti-inflammatory cytokines, interferon-β (IFN-β) and interleukin-10 (IL-10), with no significant change in the concentration of the pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α). In conclusion, delayed administration of the TLR7 agonist, GDQ, after severe hypoxia-ischemia in the developing brain markedly ameliorated white and gray matter damage, in association with upregulation of anti-inflammatory cytokines. These data strongly support the hypothesis that modulation of secondary inflammation may be a viable therapeutic target for injury of the preterm brain.
Improving the SERS signals of biomolecules using a stacked biochip containing Fe2O3/Au nanoparticles and a DC magnetic field
Authors: Deng Zu-Yin , Chen Kuen-Lin , Wu Chiu-Hsien
Published: July 2019

This study proposes a magnetic biochip that uses surface-enhanced Raman scattering (SERS) for antigen detection. The biochip was a sandwich structure containing alternating layers of gold and magnetic Fe2O3 nanoparticles. Both single (Au/Fe2O3/Au) and multilayer (Au/Fe2O3/Au/Fe2O3/Au) chips containing Fe2O3 nanoparticles were fabricated to detect bovine serum albumin (BSA). The single-layer chip detected the BSA antigen at a signal-to-noise ratio (SNR) of 5.0. Peaks detected between 1000 and 1500 cm−1 corresponded to various carbon chains. With more Fe2O3 layers, bond resonance was enhanced via the Hall effect. The distribution of electromagnetic field enhancement was determined via SERS. The signal from the single-layer chip containing Au nanoparticles was measured in an external magnetic field. Maximum signal strength was recorded in a field strength of 12.5 gauss. We observed peaks due to other carbon–hydrogen molecules in a 62.5-gauss field. The magnetic field could improve the resolution and selectivity of sample observations.
Optical fibre Fabry-Pérot interferometer based on inline microcavities for salinity and temperature sensing
Authors: Flores Raquel , Janeiro Ricardo , Viegas Jaime
Published: July 2019

This work explores the development of highly sensitive salinity sensors. The demonstrated sensors are based on optical fibres and consist on Fabry-Pérot optical cavities formed by optimized processes that include chemical etching and fusion splicing, on which microfluidic channels are milled by focused ion beam. Two configurations are presented and their performance compared, including a design that makes use of Vernier-effect for the simultaneous measurement of salinity and temperature with high sensitivity. The interrogation of the devices is carried out by spectral measurements using a broadband light source yielding sensitivities to salinity up to 82.61 nm/M, or 6830.0 nm/RIU.
Compensated pathogenic variants in coagulation factors VIII and IX present complex mapping between molecular impact and hemophilia severity
Authors: Marín Òscar , Aguirre Josu , de la Cruz Xavier
Published: July 2019

Compensated pathogenic deviations (CPDs) are sequence variants that are pathogenic in humans but neutral in other species. In recent years, our molecular understanding of CPDs has advanced substantially. For example, it is known that their impact on human proteins is generally milder than that of average pathogenic mutations and that their impact is suppressed in non-human carriers by compensatory mutations. However, prior studies have ignored the evolutionarily relevant relationship between molecular impact and organismal phenotype. Here, we explore this topic using CPDs from FVIII and FIX and data concerning carriers’ hemophilia severity. We find that, regardless of their molecular impact, these mutations can be associated with either mild or severe disease phenotypes. Only a weak relationship is found between protein stability changes and severity. We also characterize the population variability of hemostasis proteins, which constitute the genetic background of FVIII and FIX, using data from the 1000 Genome project. We observe that genetic background can vary substantially between individuals in terms of both the amount and nature of genetic variants. Finally, we discuss how these results highlight the need to include new terms in present models of protein evolution to explain the origin of CPDs.
Critical Limb Ischemia Induces Remodeling of Skeletal Muscle Motor Unit, Myonuclear-, and Mitochondrial-Domains
Authors: Mohiuddin Mahir , Lee Nan Hee , Moon June Young , Han Woojin M. , Anderson Shannon E. , Choi Jeongmoon J. , Shin Eunjung , Nakhai Shadi A. , Tran Thu , Aliya Berna , Kim Do Young , Gerold Aimee , Hansen Laura M. , Taylor W. Robert , Jang Young C.
Published: July 2019

Critical limb ischemia, the most severe form of peripheral artery disease, leads to extensive damage and alterations to skeletal muscle homeostasis. Although recent research has investigated the tissue-specific responses to ischemia, the role of the muscle stem cell in the regeneration of its niche components within skeletal muscle has been limited. To elucidate the regenerative mechanism of the muscle stem cell in response to ischemic insults, we explored cellular interactions between the vasculature, neural network, and muscle fiber within the muscle stem cell niche. Using a surgical murine hindlimb ischemia model, we first discovered a significant increase in subsynaptic nuclei and remodeling of the neuromuscular junction following ischemia-induced denervation. In addition, ischemic injury causes significant alterations to the myofiber through a muscle stem cell-mediated accumulation of total myonuclei and a concomitant decrease in myonuclear domain size, possibly to enhance the transcriptional and translation output and restore muscle mass. Results also revealed an accumulation of total mitochondrial content per myonucleus in ischemic myofibers to compensate for impaired mitochondrial function and high turnover rate. Taken together, the findings from this study suggest that the muscle stem cell plays a role in motor neuron reinnervation, myonuclear accretion, and mitochondrial biogenesis for skeletal muscle regeneration following ischemic injury.
Single-cell RNA-seq variant analysis for exploration of genetic heterogeneity in cancer
Authors: Fasterius Erik , Uhlén Mathias , Al-Khalili Szigyarto Cristina
Published: July 2019

Inter- and intra-tumour heterogeneity is caused by genetic and non-genetic factors, leading to severe clinical implications. High-throughput sequencing technologies provide unprecedented tools to analyse DNA and RNA in single cells and explore both genetic heterogeneity and phenotypic variation between cells in tissues and tumours. Simultaneous analysis of both DNA and RNA in the same cell is, however, still in its infancy. We have thus developed a method to extract and analyse information regarding genetic heterogeneity that affects cellular biology from single-cell RNA-seq data. The method enables both comparisons and clustering of cells based on genetic variation in single nucleotide variants, revealing cellular subpopulations corroborated by gene expression-based methods. Furthermore, the results show that lymph node metastases have lower levels of genetic heterogeneity compared to their original tumours with respect to variants affecting protein function. The analysis also revealed three previously unknown variants common across cancer cells in glioblastoma patients. These results demonstrate the power and versatility of scRNA-seq variant analysis and highlight it as a useful complement to already existing methods, enabling simultaneous investigations of both gene expression and genetic variation.
Influence of the spatial confinement on the self-focusing of ultrashort pulses in hollow-core fibers
Authors: Crego Aurora , Conejero Jarque Enrique , San Roman Julio
Published: July 2019

The collapse of a laser beam propagating inside a hollow-core fiber is investigated by numerically solving different nonlinear propagation models. We have identified that the fiber confinement favors the spatial collapse, especially in case of pulses with the input peak power close to the critical value. We have also observed that when using pulses in the femtosecond range, the temporal dynamics plays an important role, activating the spatial collapse even for pulses with input peak powers below the critical value. The complex self-focusing dynamics observed in the region below the critical power depends on the temporal evolution of the pulse and, also, on the interaction between the different spatial modes of the hollow-core fiber.
Forming individual magnetic biskyrmions by merging two skyrmions in a centrosymmetric nanodisk
Authors: Göbel Börge , Henk Jürgen , Mertig Ingrid
Published: July 2019

When two magnetic skyrmions – whirl-like, topologically protected quasiparticles – form a bound pair, a biskyrmion state with a topological charge ofNSk = ±2 is constituted. Recently, especially the case of two partially overlapping skyrmions has brought about great research interest. Since for its formation the individual skyrmions need to posses opposite in-plane magnetizations, such a biskyrmion cannot be stabilized by the Dzyaloshinskii-Moriya-interaction (DMI), which is the interaction that typically stabilizes skyrmions in non-centrosymmetric materials and at interfaces. Here, we show that these biskyrmions can be stabilized by the dipole-dipole interaction in centrosymmetric materials in which the DMI is forbidden. Analytical considerations indicate that the bound state of a biskyrmion is energetically preferable over two individual skyrmions. As a result, when starting from two skyrmions in a micromagnetic simulation, a biskyrmion is formed upon relaxation. We propose a scheme that allows to control this biskyrmion formation in nanodisks and analyze the individual steps.
Inhibition of Cathepsin S Reduces Lacrimal Gland Inflammation and Increases Tear Flow in a Mouse Model of Sjögren’s Syndrome
Authors: Klinngam Wannita , Janga Srikanth R. , Lee Changrim , Ju Yaping , Yarber Frances , Shah Mihir , Guo Hao , Wang Dandan , MacKay J. Andrew , Edman Maria C. , Hamm-Alvarez Sarah F.
Published: July 2019

Cathepsin S (CTSS) is highly increased in Sjögren’s syndrome (SS) patients tears and in tears and lacrimal glands (LG) of male non-obese diabetic (NOD) mice, a murine model of SS. To explore CTSS’s utility as a therapeutic target for mitigating ocular manifestations of SS in sites where CTSS is increased in disease, the tears and the LG (systemically), the peptide-based inhibitor, Z-FL-COCHO (Z-FL), was administered to 14–15 week male NOD mice. Systemic intraperitoneal (i.p.) injection for 2 weeks significantly reduced CTSS activity in tears, LG and spleen, significantly reduced total lymphocytic infiltration into LG, reduced CD3+ and CD68+ cell abundance within lymphocytic infiltrates, and significantly increased stimulated tear secretion. Topical administration of Z-FL to a different cohort of 14–15 week male NOD mice for 6 weeks significantly reduced only tear CTSS while not affecting LG and spleen CTSS and attenuated the disease-progression related reduction of basal tear secretion, while not significantly impacting lymphocytic infiltration of the LG. These findings suggest that CTSS inhibitors administered either topically or systemically can mitigate aspects of the ocular manifestations of SS.
Tunnel magnetoresistance angular and bias dependence enabling tuneable wireless communication
Authors: Kowalska Ewa , Fukushima Akio , Sluka Volker , Fowley Ciarán , Kákay Attila , Aleksandrov Yuriy , Lindner Jürgen , Fassbender Jürgen , Yuasa Shinji , Deac Alina M.
Published: July 2019

Spin-transfer torques (STTs) can be exploited in order to manipulate the magnetic moments of nanomagnets, thus allowing for new consumer-oriented devices to be designed. Of particular interest here are tuneable radio-frequency (RF) oscillators for wireless communication. Currently, the structure that maximizes the output power is an Fe/MgO/Fe-type magnetic tunnel junction (MTJ) with a fixed layer magnetized in the plane of the layers and a free layer magnetized perpendicular to the plane. This structure allows for most of the tunnel magnetoresistance (TMR) to be converted into output power. Here, we experimentally and theoretically demonstrate that the main mechanism sustaining steady-state precession in such structures is the angular dependence of the magnetoresistance. The TMR of such devices is known to exhibit a broken-linear dependence versus the applied bias. Our results show that the TMR bias dependence effectively quenches spin-transfer-driven precession and introduces a non-monotonic frequency dependence at high applied currents. This has an impact on devices seeking to work in the ‘THz gap’ due to their non-trivial TMR bias dependences.
Diffraction-limited axial scanning in thick biological tissue with an aberration-correcting adaptive lens
Authors: Philipp Katrin , Lemke Florian , Scholz Stefan , Wallrabe Ulrike , Wapler Matthias C. , Koukourakis Nektarios , Czarske Jürgen W.
Published: July 2019

Diffraction-limited deep focusing into biological tissue is challenging due to aberrations that lead to a broadening of the focal spot. The diffraction limit can be restored by employing aberration correction for example with a deformable mirror. However, this results in a bulky setup due to the required beam folding. We propose a bi-actuator adaptive lens that simultaneously enables axial scanning and the correction of specimen-induced spherical aberrations with a compact setup. Using the bi-actuator lens in a confocal microscope, we show diffraction-limited axial scanning up to 340 μm deep inside a phantom specimen. The application of this technique to in vivo measurements of zebrafish embryos with reporter-gene-driven fluorescence in a thyroid gland reveals substructures of the thyroid follicles, indicating that the bi-actuator adaptive lens is a meaningful supplement to the existing adaptive optics toolset.
Identification of dominant gas transport frequencies during barometric pumping of fractured rock
Authors: Harp Dylan R. , Ortiz John P. , Stauffer Philip H.
Published: July 2019

We demonstrate that although barometric pressures are complicated signals comprised of numerous frequencies, it is a subset of these frequencies that drive the overwhelming majority of gas transport in fractured rock. Using an inverse numerical analysis, we demonstrate that a single barometric component with seasonally modulated amplitude approximates gas transport due to a measured barometric signal. If past barometric tendencies are expected to continue at a location, the identification of this frequency can facilitate accurate long term predictions of barometrically induced gas transport negating the need to consider stochastic realizations of future barometric variations. Additionally, we perform an analytical analysis that indicates that there is a set of barometric frequencies, consistent with the inverse numerical analysis, with high production efficiency. Based on the corroborating inverse numerical and analytical analyses, we conclude that there is a set of dominant gas transport frequencies in barometric records.
Wheat and barley can increase grain yield in shade through acclimation of physiological and morphological traits in Mediterranean conditions
Authors: Arenas-Corraliza M. G. , Rolo V. , López-Díaz M. L. , Moreno G.
Published: July 2019

Major cereal yields are expected to decline significantly in coming years due to the effects of climate change temperature rise. Agroforestry systems have been recognized as a useful land management strategy that could mitigate these effects through the shelter provided by trees, but it is unclear how shade affects cereal production. Most cereal species and cultivars have been selected for full light conditions, making it necessary to determine those able to acclimate to low irradiance environments and the traits that drive this acclimation. A greenhouse experiment was conducted in central Spain to assess the photosynthetic response, leaf morphology and grain yield of nine cultivars of winter wheat (Triticum aestivum L.) and barley (Hordeum vulgare L.) at three levels of photosynthetic active radiation (100%, 90% and 50%). Cultivars were selected according to three different precocity categories and were widely used in the studied area. The main objective was to assess whether the species and cultivars could acclimate to partial shade through physiological and morphological acclimations and thus increase their grain yield for cultivation in agroforestry systems. Both species increased grain yield by 19% in shade conditions. However, they used different acclimation strategies. Barley mostly performed a physiological acclimation, while wheat had a major morphological adjustment under shaded environment. Barley had lower dark respiration (42%), lower light compensation point (73%) and higher maximum quantum yield (48%) than wheat in full light conditions, revealing that it was a more shade-tolerant species than wheat. In addition, to acclimate to low irradiance conditions, barley showed a 21% reduction of the carotenoids/chlorophyll ratio in the lowest irradiance level compared to 100% light availability and adjusted the chlorophyll a/b ratio, photosystem II quantum efficiency, electron transport rate and non-photochemical quenching to shade conditions. On the other hand, wheat showed a 48% increase in single leaf area in the 50% irradiance level than in full light to maximize light capture. Our results showed that current commercialized wheat and barley cultivars had sufficient plasticity for adaptation to shade, supporting tree presence as a tool to reduce the negative effects of climate change.
Nasal delivery of donepezil HCl-loaded hydrogels for the treatment of Alzheimer’s disease
Authors: Al Harthi Sitah , Alavi Seyed Ebrahim , Radwan Mahasen Ali , El Khatib Mona Mohamed , AlSarra Ibrahim Abdullah
Published: July 2019

This study aims to prepare, characterize and evaluate the pharmacokinetics of liposomal donepezil HCl (LDH) dispersed into thiolated chitosan hydrogel (TCH) in rabbits. Various hydrogels including TCH were prepared, and after characterization, TCH was selected for subsequent evaluations, due to the promising results. TCH was then incorporated with LDH prepared by reverse phase evaporation method. The hydrogel was characterized using scanning electron microscope, dialysis membrane technique, and ultra-performance liquid chromatography methods. The optimized resultant was then evaluated in terms of pharmacokinetics in an in vivo environment. The mean size of LDH and drug entrapment efficiency were 438.7 ± 28.3 nm and 62.5% ± 0.6, respectively. The controlled drug release pattern results showed that the half-life of the loaded drug was approximately 3.5 h. Liposomal hydrogel and free liposomes were more stable at 4 °C compared to those in 20 °C. The pharmacokinetics study in the rabbit showed that the optimized hydrogel increased the mean peak drug concentration and area under the curve by 46% and 39%, respectively, through nasal route compared to the oral tablets of DH. Moreover, intranasal delivery of DH through liposomal hydrogel increased the mean brain content of the drug by 107% compared to the oral DH tablets. The results suggested that liposomes dispersed into TCH is a promising device for the nasal delivery of DH and can be considered for the treatment of Alzheimer’s disease.
Impact of weight variability on mortality among Korean men and women: a population based study
Authors: Choi Daein , Choi Seulggie , Park Sang Min
Published: July 2019

The health consequences of weight fluctuation have been controversial and little-studied within Asian populations. We aimed to determine the effect of weight variability on mortality using Korean National Health Insurance Service – National Health Screening Cohort. Weight variability was defined as the average successive variability of body mass index (BMI) of the first (2002 and 2003), second (2004 and 2005), and third (2006 and 2007) health examinations. Then, we used Cox regression models to estimate the effect of weight variability on mortality. Compared to participants within the first quintile (lowest) of weight variability, those within the fifth quintile (highest) had increased the risk of death from all causes (hazard ratio, HR 1.33, 95% confidence interval, CI 1.26–1.41), cardiovascular disease (HR 1.31, 95% CI 1.12–1.53), cancer (HR 1.11, 95% CI 1.02–1.22), and other causes (HR 1.58, 95% CI 1.45–1.73). The risk-increasing effect of weight variability on mortality was preserved after excluding past and current smokers as well as those with pre-existing cardiovascular disease or cancer. In conclusion, high weight variability may lead to elevated risk of death even among healthy never smokers. Therefore, maintaining a steady weight should be recommended to benefit from reduced risk of death.