bluuebunny/crossref_metadata_2025_split huggingface dataset:
Restoration ecologists might not get what they want: Global change shifts trade-offs among ecosystem functions
Authors: Fiedler Sebastian , Monteiro José A.F. , Hulvey Kristin B. , Standish Rachel J. , Perring Michael P. , Tietjen Britta 
Published: December 2020

ABSTRACTEcological restoration increasingly aims at improving ecosystem multifunctionality and making landscapes resilient to future threats, especially in biodiversity hotspots such as Mediterranean-type ecosystems. Successful realisation of such a strategy requires a fundamental mechanistic understanding of the link between ecosystem plant composition, plant traits and related ecosystem functions and services, as well as how climate change affects these relationships. An integrated approach of empirical research and simulation modelling with focus on plant traits can allow this understanding.Based on empirical data from a large-scale restoration project in a Mediterranean-type climate in Western Australia, we developed and validated the spatially explicit simulation model ModEST, which calculates coupled dynamics of nutrients, water and individual plants characterised by traits. We then simulated all possible combinations of eight plant species with different levels of diversity to assess the role of plant diversity and traits on multifunctionality, the provision of six ecosystem functions (covering three ecosystem services), as well as trade-offs and synergies among the functions under current and future climatic conditions.Our results show that multifunctionality cannot fully be achieved because of trade-offs among functions that are attributable to sets of traits that affect functions differently. Our measure of multifunctionality was increased by higher levels of planted species richness under current, but not future climatic conditions. In contrast, single functions were differently impacted by increased plant diversity. In addition, we found that trade-offs and synergies among functions shifted with climate change.Synthesis and application. Our results imply that restoration ecologists will face a clear challenge to achieve their targets with respect to multifunctionality not only under current conditions, but also in the long-term. However, once ModEST is parameterized and validated for a specific restoration site, managers can assess which target goals can be achieved given the set of available plant species and site-specific conditions. It can also highlight which species combinations can best achieve long-term improved multifunctionality due to their trait diversity.
Repurposing Nintedanib for Pathological Cardiac Remodeling and Dysfunction
Authors: Umbarkar Prachi , Singh Anand P. , Tousif Sultan , Zhang Qinkun , Sethu Palaniappan , Lal Hind 
Published: December 2020

AbstractBackgroundHeart Failure (HF) is the leading cause of death worldwide. Myocardial fibrosis, one of the clinical manifestations implicated in almost every form of heart disease, contributes significantly to HF development. However, there is no approved drug specifically designed to target cardiac fibrosis. Nintedanib (NTB) is an FDA approved tyrosine kinase inhibitor for idiopathic pulmonary fibrosis (IPF) and chronic fibrosing interstitial lung diseases (ILD). The favorable clinical outcome of NTB in IPF patients is well established. Furthermore, NTB is well tolerated in IPF patients irrespective of cardiovascular comorbidities. However, there is a lack of direct evidence to support the therapeutic efficacy and safety of NTB in cardiac diseases.Methods and ResultsWe examined the effects of NTB treatment on cardiac fibrosis and dysfunction using a murine model of HF. Specifically, 10 weeks old C57BL/6J male mice were subjected to Transverse Aortic Constriction (TAC) surgery. NTB was administered once daily by oral gavage (50mg/kg) till 16 weeks post-TAC. Cardiac function was monitored by serial echocardiography. Histological analysis and morphometric studies were performed at 16 weeks post-TAC. In the control group, systolic dysfunction started developing from 4 weeks post-surgery and progressed till 16 weeks. However, NTB treatment prevented TAC-induced cardiac functional decline. In another experiment, NTB treatment was stopped at 8 weeks, and animals were followed till 16 weeks post-TAC. Surprisingly, NTB’s beneficial effect on cardiac function was maintained even after treatment interruption. NTB treatment remarkably reduced cardiac fibrosis as confirmed by Masson’s trichome staining and decreased expression of collagen genes (COL1A1, COL3A1). Compared to TAC group, NTB treated mice showed lower HW/TL ratio and cardiomyocyte cross-sectional area. Ourin vitrostudies demonstrated that NTB prevents myofibroblast transformation, TGFβ1-induced SMAD3 phosphorylation, and production of fibrogenic proteins (Fibronectin-1). However, NTB significantly altered vital signaling pathways in both, isolated fibroblast and cardiomyocytes, suggesting that its biological effect and underlying cardiac protection mechanisms are not limited to fibroblast and fibrosis alone.ConclusionOur findings provide a proof of concept for repurposing NTB to combat adverse myocardial fibrosis and encourage the need for further validation in large animal models and subsequent clinical development for HF patients.
Fast and memory-efficient mapping of short bisulfite sequencing reads using a two-letter alphabet
Authors: de Sena Brandine Guilherme , Smith Andrew D. 
Published: December 2020

AbstractDNA cytosine methylation is an important epigenomic mark with a wide range of functions across many organisms. Whole genome bisulfite sequencing (WGBS) is the gold standard to interrogate cyto-sine methylation genome-wide. Algorithms used to map WGBS reads often encode the four-base DNA alphabet with three letters by reducing two bases to a common letter. This encoding substantially reduces the entropy of nucleotide frequencies in the resulting reference genome. Within the paradigm of read mapping by first filtering possible candidate alignments, reduced entropy of the reference can increase the required computing effort. We introduce another bisulfite mapping algorithm (abismal), based on the idea of encoding a four-letter DNA sequence as only two letters, one for purines and one for pyrimidines. We show that this encoding has greater specificity when subsequences are selected from reads for filtration. Through the two-letter encoding, the abismal software tool maps reads in less time and using less memory than most WGBS read mapping software tools, while attaining similar accuracy. This allowsin silicomethylation analysis to be performed in a wider range of computing machines with limited hardware settings.
Combinatorial approach of binary colloidal crystals (BCCs) and CRISPR activation to improve induced pluripotent stem cell differentiation into neurons
Authors: Urrutia-Cabrera Daniel , Liou Roxanne Hsiang-Chi , Lin Jiao , Liu Kun , Hung Sandy S.C. , Hewitt Alex W. , Wang Peng-Yuan , Wong Raymond Ching-Bong 
Published: December 2020

AbstractConventional methods of neuronal differentiation for human induced pluripotent stem cells (iPSCs) are tedious and complicated, involving multi-stage protocols with complex cocktails of growth factors and small molecules. Artificial extracellular matrix with defined surface topography and chemistry represents a promising venue to improve the neuronal differentiationin vitro. In the present study, we test the impact of a type of colloidal self-assembled patterns called binary colloidal crystals (BCCs) in neuronal differentiation. We developed a CRISPR activation (CRISPRa) iPSC platform that constitutively expresses the dCas9-VPR system, which allows robust activation of the proneural transcription factorNEUROD1to rapidly induce neuronal differentiation within seven days. We showed that the combinatorial use of BCCs can further improve this neuronal differentiation system. In particular, our results indicate that fine tuning of silica and polystyrene size is critical to generate specific topographies to improve neuronal differentiation and branching. BCCs with 5 μm silica and 100 nm carboxylated polystyrene has the most prominent effect on increasing neurite outgrowth and more complex ramification, while BCCs with 2μm silica and 65nm carboxylated polystyrene is better in promoting neuronal enrichment. These results indicate that biophysical cues can support rapid differentiation and improve neuronal maturation. In summary, our combinatorial approach of CRISPRa and BCCs provides a robust and rapid pipeline forin vitroproduction of human neurons. Specific BCCs can be adapted to late stages of neuronal differentiation protocols to improve neuronal maturation, which have important implications in tissue engineering,in vitrobiological studies and disease modeling.
Genome-wide reversal of glial and neurovascular cell transcriptomic aging signatures by GLP-1R agonism
Authors: Li Zhongqi , Chen Xinyi , Vong Joaquim S. L. , Zhao Lei , Huang Junzhe , Yan Leo Y. C. , Ip Bonaventure , Wing Yun Kwok , Lai Hei-Ming , Mok Vincent C. T. , Ko Ho 
Published: December 2020

AbstractPharmacological reversal of brain aging is a long-sought yet challenging strategy for the prevention and treatment of age-related neurodegeneration, due to the diverse cell types and complex cellular pathways impacted by the aging process. Here, we report the genome-wide reversal of transcriptomic aging signatures in multiple major brain cell types, including glial and mural cells, by glucagon-like peptide-1 receptor (GLP-1R) agonist (GLP-1RA) treatment. The age-related expression changes reversed by GLP-1RA encompass both shared and cell type-specific functional pathways that are implicated in aging and neurodegeneration. Concomitantly, Alzheimer’s disease (AD)-associated transcriptomic signature in microglia that arises from aging is reduced. These results show the feasibility of reversing brain aging by pharmacological means, provide mechanistic insights into the neurological benefits of GLP-1RAs in diabetic patients, and imply that GLP-1R agonism may be a generally applicable pharmacological intervention for patients at risk of age-related neurodegeneration.
Social disparities in the first wave of COVID-19 infections in Germany: A county-scale explainable machine learning approach
Authors: Doblhammer Gabriele , Reinke Constantin , Kreft Daniel 
Published: December 2020

AbstractBackgroundLittle is known about factors correlated with this geographic spread of the first wave of COVID-19 infections in Germany. Given the lack of individual-level socioeconomic information on COVID-19 cases, we resorted to an ecological study design, exploring regional correlates of COVID-19 diagnoses.Data and MethodWe used data from the Robert-Koch-Institute on COVID-19 diagnoses by sex, age (age groups: 0-4, 5-14, 15-34, 35-59, 60-79, 80+), county (NUTS3 region) differentiating five periods (initial phase: through 15 March; 1st lockdown period: 16 March to 31 March; 2nd lockdown period: from 1 April to 15 April; easing period: 16 April to 30 April; post-lockdown period: 1 May through 23 July). For each period we calculated age-standardized incidence of COVID-19 diagnoses on the county level, using the German age distribution from the year 2018. We characterized the regions by macro variables in nine domains: “Demography”, “Employment”, “Politics, religion, and education”, “Income”, “Settlement structure and environment”, “Health care”, “(structural) Poverty”, “Interrelationship with other regions”, and “Geography”. We trained gradient boosting models to predict the age-standardized incidence rates with the macro structures of the counties, and used SHAP values to characterize the 20 most prominent features in terms of negative/positive correlations with the outcome variable.ResultsThe change in the age-standardized incidence rates over time is reflected in the changing importance of features as indicated by the mean SHAP values for the five periods. The first COVID-19 wave started as a disease in wealthy rural counties in southern Germany, and ventured into poorer urban and agricultural counties during the course of the first wave. The negative social gradient became more pronounced from the 2ndlockdown period onwards, when wealthy counties appeared to be better protected. Population density per se does not appear to be a risk factor, and only in the post-lockdown period did connectedness become an important regional characteristic correlated with higher infections. Features related to economic and educational characteristics of the young population in a county played an important role at the beginning of the pandemic up to the 2ndlockdown phase, as did features related to the population living in nursing homes; those related to international migration and a large proportion of foreigners living in a county became important in the post-lockdown period.DiscussionIn the absence of individual level data, explainable machine learning methods based on regional data may help to better understand the changing nature of the drivers of the pandemic. High mobility of high SES groups may drive the pandemic at the beginning of waves, while mitigation measures and beliefs about the seriousness of the pandemic as well as the compliance with mitigation measures put lower SES groups at higher risks later on.
The interplay between vaccination and social distancing strategies affects COVID19 population-level outcomes
Authors: Guerstein Sharon , Romeo-Aznar Victoria , Dekel Ma’ayan , Miron Oren , Davidovitch Nadav , Puzis Rami , Pilosof Shai 
Published: December 2020

AbstractSocial distancing is an effective population-level mitigation strategy to prevent COVID19 propagation but it does not reduce the number of susceptible individuals and bears severe social consequences—a dire situation that can be overcome with the recently developed vaccines. Although a combination of these interventions should provide greater benefits than their isolated deployment, a mechanistic understanding of the interplay between them is missing. To tackle this challenge we developed an age-structured deterministic model in which vaccines are deployed during the pandemic to individuals who, in the eye of public health, are susceptible (do not show symptoms). The model allows for flexible and dynamic prioritization strategies with shifts between target groups. We find a strong interaction between social distancing and vaccination in their effect on the proportion of hospitalizations. In particular, prioritizing vaccines to elderly (60+) before adults (20-59) is more effective when social distancing is applied to adults or uniformly. In addition, the temporal reproductive number Rt is only affected by vaccines when deployed at sufficiently high rates and in tandem with social distancing. Finally, the same reduction in hospitalization can be achieved via different combination of strategies, giving decision makers flexibility in choosing public health policies. Our study provides insights into the factors that affect vaccination success and provides methodology to test different intervention strategies in a way that will align with ethical guidelines.Author summaryA major question in epidemiology is how to combine intervention methods in an optimal way. With the recent deployment of COVID19 vaccine, this question is now particularly relevant. Using a data-driven model in which vaccines are deployed during the pandemic and their prioritization can shift between target groups we show that there is a strong interplay between these interventions. For example, prioritizing vaccines to elderly—the common strategy worldwide—results in a larger reduction in hospitalizations when social distancing is applied to adults than to elderly. Importantly, reduction in hospitalizations can be achieved via multiple combination of intervention strategies, allowing for flexible public health policies.
Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency
Authors: De la Rossa Andres , Laporte Marine H. , Astori Simone , Marissal Thomas , Montessuit Sylvie , Sheshadri Preethi , Ramos-Fernández Eva , Mendez Pablo , Khani Abbas , Quairiaux Charles , Taylor Eric , Rutter Jared , Nunes José Manuel , Carleton Alan , Duchen Michael R. , Sandi Carmen , Martinou Jean-Claude 
Published: December 2020

AbstractNeuronal excitation imposes a high demand of ATP in neurons. Most of the ATP derives primarily from pyruvate-mediated oxidative phosphorylation, a process that relies on import of pyruvate into mitochondria occuring exclusively via the mitochondrial pyruvate carrier (MPC). To investigate whether deficient oxidative phosphorylation impacts neuron excitability, we generated a mouse strain carrying a conditional deletion of MPC1, an essential subunit of the mitochondrial pyruvate carrier, specifically in adult glutamatergic neurons. We found that, despite decreased levels of oxidative phosphorylation in these excitatory neurons, mice were normal at rest. Paradoxically, in response to mild inhibition of GABA mediated synaptic activity, they rapidly developed severe seizures and died, whereas under similar conditions the behaviour of control mice remained unchanged. We show that neurons with a deficient MPC are intrinsically hyperexcitable as a consequence of impaired calcium homeostasis, which reduces M-type potassium channel activity. Provision of ketone bodies restores energy status, calcium homeostasis and M-channel activity and attenuates seizures in animals fed a ketogenic diet. Our results provide an explanation for the paradoxical seizures that frequently accompany a large number of neuropathologies, including cerebral ischemia and diverse mitochondriopathies, in which neurons experience an energy deficit.One Sentence SummaryDecreased OXPHOS and Ca2+-mediated neuronal hyperexcitability lead to seizure in a mouse model of mitochondrial pyruvate import deficiency.
Computational modeling of seizure spread on a cortical surface
Authors: Sip Viktor , Guye Maxime , Bartolomei Fabrice , Jirsa Viktor 
Published: December 2020

AbstractIn the field of computational epilepsy, neural field models helped to understand some large-scale features of seizure dynamics. These insights however remain on general levels, without translation to the clinical settings via personalization of the model with the patient-specific structure. In particular, a link was suggested between epileptic seizures spreading across the cortical surface and the so-called theta-alpha activity (TAA) pattern seen on intracranial electrographic signals, yet this link was not demonstrated on a patient-specific level. Here we present a single patient computational study linking the seizure spreading across the patient-specific cortical surface with a specific instance of the TAA pattern recorded in the patient. Using the realistic geometry of the cortical surface we perform the simulations of seizure dynamics in The Virtual Brain platform, and we show that the simulated electrographic signals qualitatively agree with the recorded signals. Furthermore, the comparison with the simulations performed on surrogate surfaces reveals that the best quantitative fit is obtained for the real surface. The work illustrates how the patient-specific cortical geometry can be utilized in The Virtual Brain for personalized model building, and the importance of such approach.
Single-pulse phase-contrast imaging at free-electron lasers in the hard X-ray regime
Authors: Hagemann Johannes , Vassholz Malte , Hoeppe Hannes , Osterhoff Markus , Rosselló Juan M. , Mettin Robert , Seiboth Frank , Schropp Andreas , Möller Johannes , Hallmann Jörg , Kim Chan , Scholz Markus , Boesenberg Ulrike , Schaffer Robert , Zozulya Alexey , Lu Wei , Shayduk Roman , Madsen Anders , Schroer Christian G. , Salditt Tim 
Published: December 2020

X-ray free-electron lasers (XFELs) have opened up unprecedented opportunities for time-resolved nano-scale imaging with X-rays. Near-field propagation-based imaging, and in particular near-field holography (NFH) in its high-resolution implementation in cone-beam geometry, can offer full-field views of a specimen's dynamics captured by single XFEL pulses. To exploit this capability, for example in optical-pump/X-ray-probe imaging schemes, the stochastic nature of the self-amplified spontaneous emission pulses, i.e. the dynamics of the beam itself, presents a major challenge. In this work, a concept is presented to address the fluctuating illumination wavefronts by sampling the configuration space of SASE pulses before an actual recording, followed by a principal component analysis. This scheme is implemented at the MID (Materials Imaging and Dynamics) instrument of the European XFEL and time-resolved NFH is performed using aberration-corrected nano-focusing compound refractive lenses. Specifically, the dynamics of a micro-fluidic water-jet, which is commonly used as sample delivery system at XFELs, is imaged. The jet exhibits rich dynamics of droplet formation in the break-up regime. Moreover, pump–probe imaging is demonstrated using an infrared pulsed laser to induce cavitation and explosion of the jet.
“Stay at home” for addressing COVID-19 protocol: learning from the traditional Balinese house
Authors: Putra I Dewa Gede Agung Diasana 
Published: December 2020

PurposeCOVID-19 caused dramatic changes in daily life, including the way people stay in a building. Since the virus's outbreak and the mandate of social distancing from WHO, a house has become an essential place for people to avoid the propagation of the virus. However, recent house configurations cannot satisfy people's needs when staying at home and have not provided complete protection from viruses. Therefore, architects are expected to create new configurations. In order to establish a new trend, this paper aimed to explore the ability of the traditional architectural concepts that discuss the efforts to produce suitable configurations.Design/methodology/approachTo investigate to what extent the traditional Balinese concepts are still relevant to counter infectious diseases, architectural examinations and spatial stories were used as a method of investigations.FindingsThis paper found that certain traditional knowledge elements are still relevant to produce suitable configurations to deal with possible virus attacks and introduce more security layers to the house.Research limitations/implicationsLearning from the COVID-19 pandemic, this paper provides a view of traditional concepts that are now still applicable to modifications and adaptations.Practical implicationsIn these modifications, the traditional hierarchy of entering the house and the function of open spaces for food production are traditional elements that address the protocol to face the virus.Social implicationsLocal knowledge has given good things as a precious heritage from the Balinese communities' ancestors to face this new challenge.Originality/valueThis pandemic has taught architects to combine modern technologies with local wisdom as an approach to develop innovative antivirus designs.