bluuebunny/crossref_metadata_2025 huggingface dataset:
Constraining Central Himalayan (Nepal) Fault Geometry Through Integrated Thermochronology and Thermokinematic Modeling
Authors: Ghoshal Suryodoy , McQuarrie Nadine , Robinson Delores M. , Adhikari D. P. , Morgan Leah E. , Ehlers Todd A.
Published: August 2020

Constraining the subsurface structural geometry of the central Himalaya continues to prove difficult, even after the 2015 Gorkha earthquake and the resulting insights into the trajectory of the Main Himalayan thrust (MHT). To this end, we apply a thermokinematic model to evaluate four possible balanced cross section geometries based on three estimates of the MHT in central Nepal. We compare the effect of different décollement and duplex geometries on predicted cooling ages and compare these to new and published ages. We find that the best‐fit geometry able to reproduce the cooling ages at the surface is a hinterland‐dipping duplex, which has been translated over a mid‐crustal ramp located ~110 km north of the Main Frontal thrust. We find that the temporal evolution of the duplex and MHT mid‐crustal ramp both play an integral role in producing the observed cooling ages, implying that the common assumption that the active décollement and ramp geometry solely control the distribution of cooling ages is incorrect. Furthermore, results indicate that the Ramgarh‐Munsiari thrust was emplaced between 17 and ~10 Ma, followed by the Trishuli thrust. Duplex growth occurs between 6.5 and 0.75 Ma, with its constituent thrust sheets moving at variable rates between 10 and 42 mm/yr. Young out‐of‐sequence thrusting (5 km of displacement) in the hinterland produces a slightly improved fit to the cooling ages. Finally, the resulting thermal field modeled from our best‐fit geometry suggests a possible basis for the nucleation and rupture characteristics of the Gorkha earthquake.
Effects of Time‐Dependent Contact Angle on Wettability of Subcritically Water‐Repellent Soils
Authors: Wang Zhongfu , Wallach Rony
Published: August 2020

Recent studies have indicated that under certain conditions, most soils are water repellent to some degree, which impacts agricultural fields, pastures, forests, grasslands, and turf areas. Soil water repellency originates from amphiphilic molecules that reorient during contact with water. However, models to describe the flow in soils affected by time‐dependent contact angle (CA(t)) are still lacking. The current study aims to close this gap. The measured CA(t) for an oleic acid‐coated glass surface and a uniform capillary tube indicated that the initial CA was substantially higher for the latter. However, the rate of CA decrease was similar for both cases in spite of the fact that the contact area between the water and the tube wall continuously increases by the capillary rise. This indicates that the amphiphilic molecules reorientation at the vicinity of the contact line rather than at the wetted tube area controls the CA dynamics. A mathematical model for flow in a uniform and sinusoidal capillary tube with CA(t) < 90° that includes model for the reorientation of the amphiphilic molecules was introduced. The model for uniform case was successfully verified by comparison with measured capillary rise in a coated uniform tube. The simulations indicated that nonuniform pore geometry amplifies the effect of CA(t) on the capillary rise dynamics. The stepwise meniscus propagation in the sinusoidal capillary tubes is driven by the time for the meniscus to reach the converging section of the tube. The retardation in capillary rise increases with tube waviness.
Real Time Control of Rainwater Harvesting Systems: The Benefits of Increasing Rainfall Forecast Window
Authors: Xu Wei D. , Fletcher Tim D. , Burns Matthew J. , Cherqui Frédéric
Published: August 2020

Use of real time control (RTC) technology in rainwater harvesting systems can improve performance across water supply, flood protection, and environmental flow provision. Such systems make the most of rainfall forecast information, to release water prior to storm events and thus minimize uncontrolled overflows. To date, most advanced applications have adopted 24‐hr forecast information, leaving longer‐term forecasts largely untested. In this study, we aimed to predict the performance of four different RTC strategies, based on different forecast lead time and preferred objectives. RTC systems were predicted to yield comparatively less harvested rainwater than conventional passive systems but delivered superior performance in terms of flood mitigation and delivery of environmental water for streamflow restoration. More importantly, using a 7‐day rainfall forecast was shown to enhance the ability of RTC in mitigating flood risks and delivering an outflow regime that is close to the natural (reference) streamflow. Such a finding suggests that RTC combined with 7‐day forecast can enhance the functionality of rainwater harvesting systems to restore and even mimic the entire natural flow regimes in receiving streams. This also opens up a new opportunity for practitioners to implement smart technology in managing urban stormwater in a range of contexts and for a range of stream health objectives.
Using Remote Sensing Data‐Based Hydrological Model Calibrations for Predicting Runoff in Ungauged or Poorly Gauged Catchments
Authors: Huang Qi , Qin Guanghua , Zhang Yongqiang , Tang Qiuhong , Liu Changming , Xia Jun , Chiew Francis H. S. , Post David
Published: August 2020

Because remote sensing (RS) data are spatially and temporally explicit and available across the globe, they have the potential to be used for predicting runoff in ungauged catchments and poorly gauged regions, a challenging area of research in hydrology. There is potential to use remotely sensed data for calibrating hydrological models in regions with limited streamflow gauges. This study conducts a comprehensive investigation on how to incorporate gridded remotely sensed evapotranspiration (AET) and water storage data for constraining hydrological model calibration in order to predict daily and monthly runoff in 30 catchments in the Yalong River basin in China. To this end, seven RS data calibration schemes are explored and compared to direct calibration against observed runoff and traditional regionalization using spatial proximity to predict runoff in ungauged catchments. The results show that using bias‐corrected remotely sensed AET (bias‐corrected PML‐AET data) for constraining model calibration performs much better than using the raw remotely sensed AET data (nonbias‐corrected AET obtained from PML model estimate). Using the bias‐corrected PML‐AET data in a gridded way is much better than using lumped data and outperforms the traditional regionalization approach especially in headwater and large catchments. Combining the bias‐corrected PML‐AET and GRACE water storage data performs similarly to using the bias‐corrected PML‐AET data only. This study demonstrates that there is great potential in using bias‐corrected RS‐AET data to calibrating hydrological models (without the need for gauged streamflow data) to estimate daily and monthly runoff time series in ungauged catchments and sparsely gauged regions.
Presenilin 1 phosphorylation regulates amyloid-β degradation by microglia
Authors: Ledo Jose Henrique , Liebmann Thomas , Zhang Ran , Chang Jerry C. , Azevedo Estefania P. , Wong Eitan , Silva Hernandez Moura , Troyanskaya Olga G. , Bustos Victor , Greengard Paul
Published: August 2020

Amyloid-β peptide (Aβ) accumulation in the brain is a hallmark of Alzheimer’s Disease. An important mechanism of Aβ clearance in the brain is uptake and degradation by microglia. Presenilin 1 (PS1) is the catalytic subunit of γ-secretase, an enzyme complex responsible for the maturation of multiple substrates, such as Aβ. Although PS1 has been extensively studied in neurons, the role of PS1 in microglia is incompletely understood. Here we report that microglia containing phospho-deficient mutant PS1 display a slower kinetic response to micro injury in the brain in vivo and the inability to degrade Aβ oligomers due to a phagolysosome dysfunction. An Alzheimer’s mouse model containing phospho-deficient PS1 show severe Aβ accumulation in microglia as well as the postsynaptic protein PSD95. Our results demonstrate a novel mechanism by which PS1 modulates microglial function and contributes to Alzheimer’s -associated phenotypes.
A novel N6-methyladenosine (m6A)-dependent fate decision for the lncRNA THOR
Authors: Liu Hongmei , Xu Yuxin , Yao Bing , Sui Tingting , Lai Liangxue , Li Zhanjun
Published: August 2020

Previous studies have revealed the critical roles of the N6-methyladenosine (m6A) modification of long non-coding RNAs (lncRNAs) in cancers, but the relationship between the oncogenic role of the lncRNATHOR(a representative of cancer/testis lncRNAs) and m6A modification remains unclear. Here, we show that the internal m6A modification of the lncRNATHORvia an m6A-reader-dependent modality regulates the proliferation of cancer cells. Our findings demonstrated that the loss of the lncRNATHORinhibits the proliferation, migration, and invasion of cancer cells in vitro and in vivo. In addition, m6A is highly enriched on lncRNATHORtranscripts, which contain GA (m6A) CA, GG (m6A) CU, and UG (m6A) CU sequence motifs. RIP-qRT-PCR and RNA pull-down assay results revealed that the specific m6A readers YTHDF1 and YTHDF2 can read the m6A motifs and regulate the stability of the lncRNATHOR(stabilization and decay). These m6A-dependent RNA-protein interactions can maintain the oncogenic role of the lncRNATHOR. Collectively, these findings highlight the critical role of the m6A modification in oncogenic lncRNATHORand reveal a novel long non-coding RNA regulatory mechanism, providing a new way to explore RNA epigenetic regulatory patterns in the future.
The circular RNA circ-GRB10 participates in the molecular circuitry inhibiting human intervertebral disc degeneration
Authors: Guo Wei , Mu Kun , Zhang Bin , Sun Chao , Zhao Ling , Li Hao-Ran , Dong Zhan-Yin , Cui Qing
Published: August 2020

Intervertebral disc degeneration (IDD) is the most common degenerative disease all over the word. Our previous study confirmed that the downregulated circ-GRB10 directly interacts with miR-328-5p, which modulate ERBB2 and leads to the degeneration of intervertebral disc; however, the underpinning mechanism of circ-GRB10 dysregulation remains unclear. We identified that FUS and demonstrated that circ-GBR10 biosynthesis in nucleus pulposus (NP) cells was promoted by FUS, whose expression was controlled by miR-141-3p. In addition, ERBB2 downregulation led to decreased Erk1/2 phosphorylation which enhanced miR-141-3p production in NP cells. In vivo data indicated that circ-GRB10 inhibited IDD in rat model. The present study revealed that miR-141-3p and FUS are key factors that regulate circ-GRB10 synthesis in NP cells. In addition, circ-GBR10 participates in the molecular circuitry that controls human IDD development. These findings provide a basis for further functional, diagnostic and therapeutic studies of circ-GRB10 in IDD.
Turn-on chemiluminescence probes and dual-amplification of signal for detection of amyloid beta species in vivo
Authors: Yang Jing , Yin Wei , Van Richard , Yin Keyi , Wang Peng , Zheng Chao , Zhu Biyue , Ran Kathleen , Zhang Can , Kumar Mohanraja , Shao Yihan , Ran Chongzhao
Published: August 2020

Turn-on fluorescence imaging is routinely studied; however, turn-on chemiluminescence has been rarely explored for in vivo imaging. Herein, we report the design and validation of chemiluminescence probe ADLumin-1 as a turn-on probe for amyloid beta (Aβ) species. Two-photon imaging indicates that ADLumin-1 can efficiently cross the blood–brain barrier and provides excellent contrast for Aβ plaques and cerebral amyloid angiopathy. In vivo brain imaging shows that the chemiluminescence signal of ADLumin-1 from 5-month-old transgenic 5xFAD mice is 1.80-fold higher than that from the age-matched wild-type mice. Moreover, we demonstrate that it is feasible to further dually-amplify signal via chemiluminescence resonance energy transfer (DAS-CRET) using two non-conjugated smart probes (ADLumin-1 and CRANAD-3) in solutions, brain homogenates, and in vivo whole brain imaging. Our results show that DAS-CRET can provide a 2.25-fold margin between 5-month-old 5xFAD mice and wild type mice. We believe that our strategy could be extended to other aggregating-prone proteins.
Deep neural networks enable quantitative movement analysis using single-camera videos
Authors: Kidziński Łukasz , Yang Bryan , Hicks Jennifer L. , Rajagopal Apoorva , Delp Scott L. , Schwartz Michael H.
Published: August 2020

Many neurological and musculoskeletal diseases impair movement, which limits people’s function and social participation. Quantitative assessment of motion is critical to medical decision-making but is currently possible only with expensive motion capture systems and highly trained personnel. Here, we present a method for predicting clinically relevant motion parameters from an ordinary video of a patient. Our machine learning models predict parameters include walking speed (r = 0.73), cadence (r = 0.79), knee flexion angle at maximum extension (r = 0.83), and Gait Deviation Index (GDI), a comprehensive metric of gait impairment (r = 0.75). These correlation values approach the theoretical limits for accuracy imposed by natural variability in these metrics within our patient population. Our methods for quantifying gait pathology with commodity cameras increase access to quantitative motion analysis in clinics and at home and enable researchers to conduct large-scale studies of neurological and musculoskeletal disorders.
Pancreatic cancers suppress negative feedback of glucose transport to reprogram chromatin for metastasis
Authors: Bechard Matthew E. , Smalling Rana , Hayashi Akimasa , Zhong Yi , Word Anna E. , Campbell Sydney L. , Tran Amanda V. , Weiss Vivian L. , Iacobuzio-Donahue Christine , Wellen Kathryn E. , McDonald Oliver G.
Published: August 2020

Although metastasis is the most common cause of cancer deaths, metastasis-intrinsic dependencies remain largely uncharacterized. We previously reported that metastatic pancreatic cancers were dependent on the glucose-metabolizing enzyme phosphogluconate dehydrogenase (PGD). Surprisingly, PGD catalysis was constitutively elevated without activating mutations, suggesting a non-genetic basis for enhanced activity. Here we report a metabolic adaptation that stably activates PGD to reprogram metastatic chromatin. High PGD catalysis prevents transcriptional up-regulation of thioredoxin-interacting protein (TXNIP), a gene that negatively regulates glucose import. This allows glucose consumption rates to rise in support of PGD, while simultaneously facilitating epigenetic reprogramming through a glucose-fueled histone hyperacetylation pathway. Restoring TXNIP normalizes glucose consumption, lowers PGD catalysis, reverses hyperacetylation, represses malignant transcripts, and impairs metastatic tumorigenesis. We propose that PGD-driven suppression of TXNIP allows pancreatic cancers to avidly consume glucose. This renders PGD constitutively activated and enables metaboloepigenetic selection of additional traits that increase fitness along glucose-replete metastatic routes.
ABHD11 maintains 2-oxoglutarate metabolism by preserving functional lipoylation of the 2-oxoglutarate dehydrogenase complex
Authors: Bailey Peter S. J. , Ortmann Brian M. , Martinelli Anthony W. , Houghton Jack W. , Costa Ana S. H. , Burr Stephen P. , Antrobus Robin , Frezza Christian , Nathan James A.
Published: August 2020

2-oxoglutarate (2-OG or α-ketoglutarate) relates mitochondrial metabolism to cell function by modulating the activity of 2-OG dependent dioxygenases involved in the hypoxia response and DNA/histone modifications. However, metabolic pathways that regulate these oxygen and 2-OG sensitive enzymes remain poorly understood. Here, using CRISPR Cas9 genome-wide mutagenesis to screen for genetic determinants of 2-OG levels, we uncover a redox sensitive mitochondrial lipoylation pathway, dependent on the mitochondrial hydrolase ABHD11, that signals changes in mitochondrial 2-OG metabolism to 2-OG dependent dioxygenase function. ABHD11 loss or inhibition drives a rapid increase in 2-OG levels by impairing lipoylation of the 2-OG dehydrogenase complex (OGDHc)—the rate limiting step for mitochondrial 2-OG metabolism. Rather than facilitating lipoate conjugation, ABHD11 associates with the OGDHc and maintains catalytic activity of lipoyl domain by preventing the formation of lipoyl adducts, highlighting ABHD11 as a regulator of functional lipoylation and 2-OG metabolism.
Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas-Casp8-Bid-axis
Authors: Carlström Karl E. , Zhu Keying , Ewing Ewoud , Krabbendam Inge E. , Harris Robert A. , Falcão Ana Mendanha , Jagodic Maja , Castelo-Branco Gonçalo , Piehl Fredrik
Published: August 2020

Arrest of oligodendrocyte (OL) differentiation and remyelination following myelin damage in multiple sclerosis (MS) is associated with neurodegeneration and clinical worsening. We show that Glutathione S-transferase 4α (Gsta4) is highly expressed during adult OL differentiation and that Gsta4 loss impairs differentiation into myelinating OLs in vitro. In addition, we identify Gsta4 as a target of both dimethyl fumarate, an existing MS therapy, and clemastine fumarate, a candidate remyelinating agent in MS. Overexpression of Gsta4 reduces expression of Fas and activity of the mitochondria-associated Casp8-Bid-axis in adult oligodendrocyte precursor cells, leading to improved OL survival during differentiation. The Gsta4 effect on apoptosis during adult OL differentiation was corroborated in vivo in both lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis models, where Casp8 activity was reduced in Gsta4-overexpressing OLs. Our results identify Gsta4 as an intrinsic regulator of OL differentiation, survival and remyelination, as well as a potential target for future reparative MS therapies.
The impact of transposable elements on tomato diversity
Authors: Domínguez Marisol , Dugas Elise , Benchouaia Médine , Leduque Basile , Jiménez-Gómez José M , Colot Vincent , Quadrana Leandro
Published: August 2020

Tomatoes come in a multitude of shapes and flavors despite a narrow genetic pool. Here, we leverage whole-genome resequencing data available for 602 cultivated and wild accessions to determine the contribution of transposable elements (TEs) to tomato diversity. We identify 6,906 TE insertions polymorphisms (TIPs), which result from the mobilization of 337 distinct TE families. Most TIPs are low frequency variants and TIPs are disproportionately located within or adjacent to genes involved in environmental responses. In addition, genic TE insertions tend to have strong transcriptional effects and they can notably lead to the generation of multiple transcript isoforms. Using genome-wide association studies (GWAS), we identify at least 40 TIPs robustly associated with extreme variation in major agronomic traits or secondary metabolites and in most cases, no SNP tags the TE insertion allele. Collectively, these findings highlight the unique role of TE mobilization in tomato diversification, with important implications for breeding.
Cellular and molecular properties of neural progenitors in the developing mammalian hypothalamus
Authors: Zhou Xin , Zhong Suijuan , Peng Honghai , Liu Jing , Ding Wenyu , Sun Le , Ma Qiang , Liu Zeyuan , Chen Ruiguo , Wu Qian , Wang Xiaoqun
Published: August 2020

The neuroendocrine hypothalamus is the central regulator of vital physiological homeostasis and behavior. However, the cellular and molecular properties of hypothalamic neural progenitors remain unexplored. Here, hypothalamic radial glial (hRG) and hypothalamic mantle zone radial glial (hmRG) cells are found to be neural progenitors in the developing mammalian hypothalamus. The hmRG cells originate from hRG cells and produce neurons. During the early development of hypothalamus, neurogenesis occurs in radial columns and is initiated from hRG cells. The radial glial fibers are oriented toward the locations of hypothalamic subregions which act as a scaffold for neuronal migration. Furthermore, we use single-cell RNA sequencing to reveal progenitor subtypes in human developing hypothalamus and characterize specific progenitor genes, such as TTYH1, HMGA2, and FAM107A. We also demonstrate that HMGA2 is involved in E2F1 pathway, regulating the proliferation of progenitor cells by targeting on the downstream MYBL2. Different neuronal subtypes start to differentiate and express specific genes of hypothalamic nucleus at gestational week 10. Finally, we reveal the developmental conservation of nuclear structures and marker genes in mouse and human hypothalamus. Our identification of cellular and molecular properties of neural progenitors provides a basic understanding of neurogenesis and regional formation of the non-laminated hypothalamus.
Lattice oxygen activation enabled by high-valence metal sites for enhanced water oxidation
Authors: Zhang Ning , Feng Xiaobin , Rao Dewei , Deng Xi , Cai Lejuan , Qiu Bocheng , Long Ran , Xiong Yujie , Lu Yang , Chai Yang
Published: August 2020

Anodic oxygen evolution reaction (OER) is recognized as kinetic bottleneck in water electrolysis. Transition metal sites with high valence states can accelerate the reaction kinetics to offer highly intrinsic activity, but suffer from thermodynamic formation barrier. Here, we show subtle engineering of highly oxidized Ni4+ species in surface reconstructed (oxy)hydroxides on multicomponent FeCoCrNi alloy film through interatomically electronic interplay. Our spectroscopic investigations with theoretical studies uncover that Fe component enables the formation of Ni4+ species, which is energetically favored by the multistep evolution of Ni2+→Ni3+→Ni4+. The dynamically constructed Ni4+ species drives holes into oxygen ligands to facilitate intramolecular oxygen coupling, triggering lattice oxygen activation to form Fe-Ni dual-sites as ultimate catalytic center with highly intrinsic activity. As a result, the surface reconstructed FeCoCrNi OER catalyst delivers outstanding mass activity and turnover frequency of 3601 A gmetal−1 and 0.483 s−1 at an overpotential of 300 mV in alkaline electrolyte, respectively.
Author Correction: Ex vivo editing of human hematopoietic stem cells for erythroid expression of therapeutic proteins
Authors: Pavani Giulia , Laurent Marine , Fabiano Anna , Cantelli Erika , Sakkal Aboud , Corre Guillaume , Lenting Peter J. , Concordet Jean-Paul , Toueille Magali , Miccio Annarita , Amendola Mario
Published: August 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Prognostic significance of residual nodal disease after neoadjuvant endocrine therapy for hormone receptor-positive breast cancer
Authors: Kantor Olga , Wong Stephanie , Weiss Anna , Metzger Otto , Mittendorf Elizabeth A. , King Tari A.
Published: August 2020

Axillary management after NET has not been well studied and the significance of residual axillary node disease after NET remains uncertain. We used the National Cancer Data Base to examine the prognostic significance of residual nodal disease after NET. From 2010–2016, 4,496 patients received NET for cT1–3N0–1M0 hormone receptor-positive, HER2-negative breast cancer. Among cN0 patients treated with NET, final node status was ypN0 in 65%, isolated tumor cells (ITCs) in 3%, ypN1mi in 6%, and ypN1 in 26%. In cN1 patients, nodal pathologic complete response was uncommon (10%), and residual nodal disease included ITCs in 1%, ypN1mi in 3%, and ypN1 in 86%. There were no differences in 5-year overall survival (OS) between patients with pathologic node-negative disease, ITCs, or micrometastases after NET. When compared to a matched cohort of upfront surgery patients, there were also no differences in 5-year OS between NET and upfront surgery patients for any residual nodal disease category. These findings suggest NET patient outcomes mirror those of upfront surgery patients and present an opportunity to consider de-escalation of axillary management strategies in NET patients.
Correlated states in magic angle twisted bilayer graphene under the optical conductivity scrutiny
Authors: Calderón María J. , Bascones Elena
Published: August 2020

Moiré systems displaying flat bands have emerged as novel platforms to study correlated electron phenomena. Insulating and superconducting states appear upon doping magic angle twisted bilayer graphene (TBG), and there is evidence of correlation induced effects at the charge neutrality point (CNP) which could originate from spontaneous symmetry breaking. Our theoretical calculations show how optical conductivity measurements can distinguish different symmetry breaking states, and reveal the nature of the correlated states. In the specific case of nematic order, which breaks the discrete rotational symmetry of the lattice, we find that the Dirac cones are displaced, not only in momentum space but also in energy, inducing finite Drude weight at the CNP. We also show that the sign of the Drude weight anisotropy induced by a nematic order depends on the degree of lattice relaxation, the doping and the nature of the symmetry breaking.
A candidate vaccine for human visceral leishmaniasis based on a specific T cell epitope-containing chimeric protein protects mice against Leishmania infantum infection
Authors: Lage Daniela P. , Ribeiro Patrícia A. F. , Dias Daniel S. , Mendonça Débora V. C. , Ramos Fernanda F. , Carvalho Lívia M. , de Oliveira Daysiane , Steiner Bethina T. , Martins Vívian T. , Perin Luísa , Machado Amanda S. , Santos Thaís T. O. , Tavares Grasiele S. V. , Oliveira-da-Silva João A. , Oliveira Jamil S. , Roatt Bruno M. , Machado-de-Ávila Ricardo A. , Teixeira Antônio L. , Humbert Maria V. , Coelho Eduardo A. F. , Christodoulides Myron
Published: August 2020

Leishmaniases are neglected diseases caused by infection with Leishmania parasites and there are currently no prophylactic vaccines. In this study, we designed in silico a synthetic recombinant vaccine against visceral leishmaniasis (VL) called ChimeraT, which contains specific T-cell epitopes from Leishmania Prohibitin, Eukaryotic Initiation Factor 5a and the hypothetical LiHyp1 and LiHyp2 proteins. Subcutaneous delivery of ChimeraT plus saponin stimulated a Th1 cell-mediated immune response and protected mice against L. infantum infection, significantly reducing the parasite load in distinct organs. ChimeraT/saponin vaccine stimulated significantly higher levels of IFN-γ, IL-12, and GM-CSF cytokines by both murine CD4+ and CD8+ T cells, with correspondingly low levels of IL-4 and IL-10. Induced antibodies were predominantly IgG2a isotype and homologous antigen-stimulated spleen cells produced significant nitrite as a proxy for nitric oxide. ChimeraT also induced lymphoproliferative responses in peripheral blood mononuclear cells from VL patients after treatment and healthy subjects, as well as higher IFN-γ and lower IL-10 secretion into cell supernatants. Thus, ChimeraT associated with a Th1 adjuvant could be considered as a potential vaccine candidate to protect against human disease.
Taxonomic identity best explains variation in body nutrient stoichiometry in a diverse marine animal community
Authors: Allgeier Jacob E. , Wenger Seth , Layman Craig A.
Published: August 2020

Animal-mediated nutrient dynamics are critical processes in ecosystems. Previous research has found animal-mediated nutrient supply (excretion) to be highly predictable based on allometric scaling, but similar efforts to find universal predictive relationships for an organism’s body nutrient content have been inconclusive. We use a large dataset from a diverse tropical marine community to test three frameworks for predicting body nutrient content. We show that body nutrient content does not follow allometric scaling laws and that it is not well explained by trophic status. Instead, we find strong support for taxonomic identity (particularly at the family level) as a predictor of body nutrient content, indicating that evolutionary history plays a crucial role in determining an organism’s composition. We further find that nutrients are “stoichiometrically linked” (e.g., %C predicts %N), but that the direction of these relationships does not always conform to expectations, especially for invertebrates. Our findings demonstrate that taxonomic identity, not trophic status or body size, is the best baseline from which to predict organismal body nutrient content.
Genome-wide identification and characterization of bHLH family genes from Ginkgo biloba
Authors: Zhou Xian , Liao Yongling , Kim Soo-Un , Chen Zexiong , Nie Gongping , Cheng Shuiyuan , Ye Jiabao , Xu Feng
Published: August 2020

Basic helix–loop–helix (bHLH) proteins, one of the most important and largest transcription factor family in plants, play important roles in regulating growth and development, stress response. In recent years, many bHLH family genes have been identified and characterized in woody plants. However, a systematic analysis of thebHLHgene family has not been reported inGinkgo biloba, the oldest relic plant species. In this study, we identifed a total of 85GbbHLHgenes from the genomic and transcriptomic databasesof G. biloba, which were classified into 17 subfamilies based on the phylogenetic analysis. Gene structures analysis indicated that the number of exon–intron range inGbbHLHsfrom 0 to 12. The MEME analysis showed that two conserved motifs, motif 1 and motif 2, distributed in most GbbHLH protein. Subcellular localization analysis exhibited that most GbbHLHs located in nucleus and a few GbbHLHs were distributed in chloroplast, plasma membrane and peroxisome. Promotercis-elementanalysis revealed that most of theGbbHLHgenes contained abundantcis-elementsthat involved in plant growth and development, secondary metabolism biosynthesis, various abiotic stresses response. In addition, correlation analysis between gene expression and flavonoid content screened seven candidateGbbHLHgenes involved in flavonoid biosynthesis, providing the targeted gene encoding transcript factor for increase the flavonoid production through genetic engineering inG. biloba.
Toxic metabolite profiling of Inocybe virosa
Authors: Sai Latha S. , Shivanna Naveen , Naika Mahadeva , Anilakumar K. R. , Kaul Ankur , Mittal Gaurav
Published: August 2020

Wild mushroom foraging involves a high risk of unintentional consumption of poisonous mushrooms which is a serious health concern. This problem arises due to the close morphological resemblances of toxic mushrooms with edible ones. The genus Inocybe comprises both edible and poisonous species and it is therefore important to differentiate them. Knowledge about their chemical nature will unambiguously determine their edibility and aid in an effective treatment in case of poisonings. In the present study, the presence of volatile toxic metabolites was verified in Inocybe virosa by gas chromatography. Methyl palmitate, phenol, 3,5-bis (1,1-dimethyl ethyl) and phytol were the identified compounds with suspected toxicity. The presence of the toxin muscarine was confirmed by liquid chromatography. The in vitro study showed that there was negligible effect of the digestion process on muscarine content or its toxicity. Therefore, the role of muscarine in the toxicity of Inocybe virosa was studied using a bioassay wherein metameters such as hypersalivation, immobility, excessive defecation, heart rate and micturition were measured. Administration of muscarine resulted in an earlier onset of symptoms and the extract showed a slightly stronger muscarinic effect in comparison to an equivalent dose of muscarine estimated in it. Further, the biological fate of muscarine was studied by pharmacokinetics and gamma scintigraphy in New Zealand white rabbits. Significant amount of the toxin was rapidly and effectively concentrated in the thorax and head region. This study closely explains the early muscarinic response such as miosis and salivation in mice. By the end of 24 h, a relatively major proportion of muscarine administered was accumulated in the liver which stands as an explanation to the hepatotoxicity of Inocybe virosa. This is one of the rare studies that has attempted to understand the toxic potential of muscarine which has previously been explored extensively for its pharmaceutical applications.
Switching behaviour of dSTORM dyes in glycerol-containing buffer
Authors: Goossen-Schmidt Nora C. , Schnieder Marco , Hüve Jana , Klingauf Jürgen
Published: August 2020

To suppress optical aberrations caused by refractive index mismatch, we employ glycerol-immersion objectives in conjunction with fused silica cover glasses and imaging buffers with a high glycerol content. Here we demonstrate that the addition of glycerol to the buffer does not degrade the switching behaviour of the dyes Alexa Fluor 647 and Alexa Fluor 568 in dSTORM measurements, which shows that this approach is suitable for dSTORM. Additionally, we report evidence that sealed sample geometries as used in our experiments reduce photobleaching due to the lower influx of oxygen into the imaging buffer.
Unprecedented enhancement of recombinant protein production in sugarcane culms using a combinatorial promoter stacking system
Authors: Damaj Mona B. , Jifon John L. , Woodard Susan L. , Vargas-Bautista Carol , Barros Georgia O. F. , Molina Joe , White Steven G. , Damaj Bassam B. , Nikolov Zivko L. , Mandadi Kranthi K.
Published: August 2020

Plants represent a safe and cost-effective platform for producing high-value proteins with pharmaceutical properties; however, the ability to accumulate these in commercially viable quantities is challenging. Ideal crops to serve as biofactories would include low-input, fast-growing, high-biomass species such as sugarcane. The objective of this study was to develop an efficient expression system to enable large-scale production of high-value recombinant proteins in sugarcane culms. Bovine lysozyme (BvLz) is a potent broad-spectrum antimicrobial enzyme used in the food, cosmetics and agricultural industries. Here, we report a novel strategy to achieve high-level expression of recombinant proteins using a combinatorial stacked promoter system. We demonstrate this by co-expressing BvLz under the control of multiple constitutive and culm-regulated promoters on separate expression vectors and combinatorial plant transformation. BvLz accumulation reached 1.4% of total soluble protein (TSP) (10.0 mg BvLz/kg culm mass) in stacked multiple promoter:BvLz lines, compared to 0.07% of TSP (0.56 mg/kg) in single promoter:BvLz lines. BvLz accumulation was further boosted to 11.5% of TSP (82.5 mg/kg) through event stacking by re-transforming the stacked promoter:BvLz lines with additional BvLz expression vectors. The protein accumulation achieved with the combinatorial promoter stacking expression system was stable in multiple vegetative propagations, demonstrating the feasibility of using sugarcane as a biofactory for producing high-value proteins and bioproducts.
Discovery of small molecules that normalize the transcriptome and enhance cysteine cathepsin activity in progranulin-deficient microglia
Authors: Telpoukhovskaia Maria A. , Liu Kai , Sayed Faten A. , Etchegaray Jon Iker , Xie Min , Zhan Lihong , Li Yaqiao , Zhou Yungui , Le David , Bahr Ben A. , Bogyo Matthew , Ding Sheng , Gan Li
Published: August 2020

Patients with frontotemporal dementia (FTD) resulting from granulin (GRN) haploinsufficiency have reduced levels of progranulin and exhibit dysregulation in inflammatory and lysosomal networks. Microglia produce high levels of progranulin, and reduction of progranulin in microglia alone is sufficient to recapitulate inflammation, lysosomal dysfunction, and hyperproliferation in a cell-autonomous manner. Therefore, targeting microglial dysfunction caused by progranulin insufficiency represents a potential therapeutic strategy to manage neurodegeneration in FTD. Limitations of current progranulin-enhancing strategies necessitate the discovery of new targets. To identify compounds that can reverse microglial defects in Grn-deficient mouse microglia, we performed a compound screen coupled with high throughput sequencing to assess key transcriptional changes in inflammatory and lysosomal pathways. Positive hits from this initial screen were then further narrowed down based on their ability to rescue cathepsin activity, a critical biochemical readout of lysosomal capacity. The screen identified nor-binaltorphimine dihydrochloride (nor-BNI) and dibutyryl-cAMP, sodium salt (DB-cAMP) as two phenotypic modulators of progranulin deficiency. In addition, nor-BNI and DB-cAMP also rescued cell cycle abnormalities in progranulin-deficient cells. These data highlight the potential of a transcription-based platform for drug screening, and advance two novel lead compounds for FTD.
CINENet: deep learning-based 3D cardiac CINE MRI reconstruction with multi-coil complex-valued 4D spatio-temporal convolutions
Authors: Küstner Thomas , Fuin Niccolo , Hammernik Kerstin , Bustin Aurelien , Qi Haikun , Hajhosseiny Reza , Masci Pier Giorgio , Neji Radhouene , Rueckert Daniel , Botnar René M. , Prieto Claudia
Published: August 2020

Cardiac CINE magnetic resonance imaging is the gold-standard for the assessment of cardiac function. Imaging accelerations have shown to enable 3D CINE with left ventricular (LV) coverage in a single breath-hold. However, 3D imaging remains limited to anisotropic resolution and long reconstruction times. Recently deep learning has shown promising results for computationally efficient reconstructions of highly accelerated 2D CINE imaging. In this work, we propose a novel 4D (3D + time) deep learning-based reconstruction network, termed 4D CINENet, for prospectively undersampled 3D Cartesian CINE imaging. CINENet is based on (3 + 1)D complex-valued spatio-temporal convolutions and multi-coil data processing. We trained and evaluated the proposed CINENet on in-house acquired 3D CINE data of 20 healthy subjects and 15 patients with suspected cardiovascular disease. The proposed CINENet network outperforms iterative reconstructions in visual image quality and contrast (+ 67% improvement). We found good agreement in LV function (bias ± 95% confidence) in terms of end-systolic volume (0 ± 3.3 ml), end-diastolic volume (− 0.4 ± 2.0 ml) and ejection fraction (0.1 ± 3.2%) compared to clinical gold-standard 2D CINE, enabling single breath-hold isotropic 3D CINE in less than 10 s scan and ~ 5 s reconstruction time.
Accelerated spin dynamics using deep learning corrections
Authors: Park Sojeong , Kwak Wooseop , Lee Hwee Kuan
Published: August 2020

Theoretical models capture very precisely the behaviour of magnetic materials at the microscopic level. This makes computer simulations of magnetic materials, such as spin dynamics simulations, accurately mimic experimental results. New approaches to efficient spin dynamics simulations are limited by integration time step barrier to solving the equations-of-motions of many-body problems. Using a short time step leads to an accurate but inefficient simulation regime whereas using a large time step leads to accumulation of numerical errors that render the whole simulation useless. In this paper, we use a Deep Learning method to compute the numerical errors of each large time step and use these computed errors to make corrections to achieve higher accuracy in our spin dynamics. We validate our method on the 3D Ferromagnetic Heisenberg cubic lattice over a range of temperatures. Here we show that the Deep Learning method can accelerate the simulation speed by 10 times while maintaining simulation accuracy and overcome the limitations of requiring small time steps in spin dynamic simulations.
Early pregnancy-induced transcripts in peripheral blood immune cells in Bos indicus heifers
Authors: Rocha Cecilia Constantino , da Silva Andrade Sónia Cristina , de Melo Gabriela Dalmaso , Motta Igor Garcia , Coutinho Luiz Lehmann , Gonella-Diaza Angela Maria , Binelli Mario , Pugliesi Guilherme
Published: August 2020

Immune cells play a central role in early pregnancy establishment in cattle. We aimed to: (1) discover novel early-pregnancy-induced genes in peripheral blood mononuclear cells (PBMC); and (2) characterize the temporal pattern of early-pregnancy-induced transcription of select genes in PBMC and peripheral blood polymorphonuclear cells (PMN). Beef heifers were artificially inseminated on D0 and pregnancies were diagnosed on D28. On D10, 14, 16, 18, and 20, blood was collected for isolation of PBMC and PMN from heifers that were retrospectively classified as pregnant (P) or non-pregnant (NP). PBMC samples from D18 were submitted to RNAseq and 220 genes were differentially expressed between pregnant (P) and non-pregnant (NP) heifers. The temporal abundance of 20 transcripts was compared between P and NP, both in PBMC and PMN. In PBMC, pregnancy stimulated transcription of IFI6, RSAD2, IFI44, IFITM2, CLEC3B, OAS2, TNFSF13B, DMKN and LGALS3BP as early as D18. Expression of IFI44, RSAD2, OAS2, LGALS3BP, IFI6 and C1R in PMN was stimulated in the P group from D18. The novel early-pregnancy induced genes discovered in beef heifers will allow both the understanding of the role of immune cells during the pre-attachment period and the development of technologies to detect early pregnancies in beef cattle.
Recalibration and validation of the Charlson Comorbidity Index in an Asian population: the National Health Insurance Service-National Sample Cohort study
Authors: Choi Jae Shin , Kim Myoung-Hee , Kim Yong Chul , Lim Youn-Hee , Bae Hyun Joo , Kim Dong Ki , Park Jae Yoon , Noh Junhyug , Lee Jung Pyo
Published: August 2020

Weights assigned to comorbidities in predicting mortality may vary based on the type of index disease and advances in the management of comorbidities. We aimed to develop a modified version of the Charlson Comorbidity Index (CCI) using an Asian nationwide database (mCCI-A), enabling the precise prediction of mortality rates in this population. The main data source used in this study was the National Health Insurance Service-National Sample Cohort (NHIS-NSC) obtained from the National Health Insurance database, which includes health insurance claims filed between January 1, 2002, and December 31, 2013, in Korea. Of the 1,025,340 individuals included in the NHIS-NSC, 570,716 patients who were hospitalized at least once were analyzed in this study. In total, 399,502 patients, accounting for 70% of the cohort, were assigned to the development cohort, and the remaining patients (n = 171,214) were assigned to the validation cohort. The mCCI-A scores were calculated by summing the weights assigned to individual comorbidities according to their relative prognostic significance determined by a multivariate Cox proportional hazard model. The modified index was validated in the same cohort. The Cox proportional hazard model provided reassigned severity weights for 17 comorbidities that significantly predicted mortality. Both the CCI and mCCI-A were correlated with mortality. However, compared with the CCI, the mCCI-A showed modest but significant increases in the c statistics. According to the analyses using continuous net reclassification improvement, the mCCI-A improved the net mortality risk reclassification by 44.0% (95% confidence intervals (CI), 41.6–46.5; p < 0.001). The mCCI-A facilitates better risk stratification of mortality rates in Korean inpatients than the CCI, suggesting that the mCCI-A may be a preferable index for use in clinical practice and statistical analyses in epidemiological studies.
Time, space and social interactions: exit mechanisms for the Covid-19 epidemics
Authors: Scala Antonio , Flori Andrea , Spelta Alessandro , Brugnoli Emanuele , Cinelli Matteo , Quattrociocchi Walter , Pammolli Fabio
Published: August 2020

We develop a minimalist compartmental model to study the impact of mobility restrictions in Italy during the Covid-19 outbreak. We show that, while an early lockdown shifts the contagion in time, beyond a critical value of lockdown strength the epidemic tends to restart after lifting the restrictions. We characterize the relative importance of different lockdown lifting schemes by accounting for two fundamental sources of heterogeneity, i.e. geography and demography. First, we consider Italian Regions as separate administrative entities, in which social interactions between age classes occur. We show that, due to the sparsity of the inter-Regional mobility matrix, once started, the epidemic spreading tends to develop independently across areas, justifying the adoption of mobility restrictions targeted to individual Regions or clusters of Regions. Second, we show that social contacts between members of different age classes play a fundamental role and that interventions which target local behaviours and take into account the age structure of the population can provide a significant contribution to mitigate the epidemic spreading. Our model aims to provide a general framework, and it highlights the relevance of some key parameters on non-pharmaceutical interventions to contain the contagion.
Long non-coding RNA FENDRR regulates IFNγ-induced M1 phenotype in macrophages
Authors: Munteanu Maria Cristina , Huang Chaoqun , Liang Yurong , Sathiaseelan Roshini , Zeng Xiangming , Liu Lin
Published: August 2020

Macrophages play an essential role in host defense and display remarkable plasticity in switching between classically (pro-inflammatory—M1) and alternatively activated (anti-inflammatory—M2) phenotypes. The molecular mechanisms of macrophage polarization are not fully understood. Long non-coding RNAs (lncRNAs) with a length of > 200 nucleotides have been shown to play diverse roles in biological processes. Aberrant expression of lncRNAs is associated with a variety of pathophysiological conditions such as cancer, diabetes, cardiovascular, pulmonary diseases, and tissue fibrosis. In this study, we investigated the role of lncRNA FENDRR in human and mouse macrophage polarization. Human THP-1 monocytes were activated with phorbol-12-myristate-13-acetate (PMA) and differentiated into M1 macrophages with IFNγ or M2 macrophages with IL4. Real-time PCR analysis revealed that FENDRR was expressed 80-fold higher in M1 macrophages than that in M2 macrophages. Overexpression of FENDRR in PMA-activated THP-1 cells increased the IFNγ-induced expression of M1 markers, including IL1β and TNFα at both mRNA and protein levels. Knockdown of FENDRR had an opposite effect. Similarly, FENDRR overexpression in primary mouse bone marrow-derived macrophages increased mRNA expression of M1 markers. FENDRR overexpression increased, while FENDRR knock-down decreased, the IFNγ-induced phosphorylation of STAT1 in PMA-activated THP-1 cells. Our studies suggest that FENDRR enhances IFNγ-induced M1 macrophage polarization via the STAT1 pathway.