bluuebunny/crossref_metadata_2025 huggingface dataset:
Bacterial coinfection in influenza pneumonia: Rates, pathogens, and outcomes
Authors: Bartley Patricia S. , Deshpande Abhishek , Yu Pei-Chun , Klompas Michael , Haessler Sarah D. , Imrey Peter B. , Zilberberg Marya D. , Rothberg Michael B.
Published: April 2021

Background:

Evidence from pandemics suggests that influenza is often associated with bacterial coinfection. Among patients hospitalized for influenza pneumonia, we report the rate of coinfection and distribution of pathogens, and we compare outcomes of patients with and without bacterial coinfection.

Methods:

We included adults admitted with community-acquired pneumonia (CAP) and tested for influenza from 2010 to 2015 at 179 US hospitals participating in the Premier database. Pneumonia was identified using an International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) algorithm. We used multiple logistic and gamma-generalized linear mixed models to assess the relationships between coinfection and inpatient mortality, intensive care unit (ICU) admission, length of stay, and cost.

Results:

Among 38,665 patients hospitalized with CAP and tested for influenza, 4,313 (11.2%) were positive. In the first 3 hospital days, patients with influenza were less likely than those without to have a positive culture (10.3% vs 16.2%; P < .001), and cultures were more likely to contain Staphylococcus aureus (34.2% vs 28.2%; P = .007) and less likely to contain Streptococcus pneumoniae (24.9% vs 31.0%; P = .008). Of S. aureus isolates, 42.8% were methicillin resistant among influenza patients versus 53.2% among those without influenza (P = .01). After hospital day 3, pathogens for both groups were similar. Bacterial coinfection was associated with increased odds of in-hospital mortality (aOR, 3.00; 95% CI, 2.17–4.16), late ICU transfer (aOR, 2.83; 95% CI, 1.98–4.04), and higher cost (risk-adjusted mean multiplier, 1.77; 95% CI, 1.59–1.96).

Conclusions:

In a large US inpatient sample hospitalized with influenza and CAP, S. aureus was the most frequent cause of bacterial coinfection. Coinfection was associated with worse outcomes and higher costs.
A higher-protein nut-based snack product suppresses glycaemia and decreases glycaemic response to co-ingested carbohydrate in an overweight prediabetic Asian Chinese cohort: the Tū Ora postprandial RCT
Authors: Lu Louise W. , Silvestre Marta P. , Sequeira Ivana R. , Plank Lindsay D. , Foster Meika , Middleditch Nikki , Acevedo-Fani Alejandra , Hollingsworth Kieren G. , Poppitt Sally D.
Published: April 2021

Nut-based products may aid low-glycaemic dietary strategies that are important for diabetes prevention in populations at increased risk of dysglycaemia, such as Asian Chinese. This randomised cross-over trial assessed the postprandial glycaemic response (0–120 min) of a higher-protein nut-based (HP-NB) snack formulation, in bar format (1009 kJ, Nutrient Profiling Score, NPS, −2), when compared with an iso-energetic higher-carbohydrate (CHO) cereal-based bar (HC-CB, 985 kJ, NPS +3). It also assessed the ability to suppress glucose response to a typical CHO-rich food (white bread, WB), when co-ingested. Ten overweight prediabetic Chinese adults (mean, sd: age 47⋅9, 15⋅7 years; BMI 25⋅5, 1⋅6 kg/m2), with total body fat plus ectopic pancreas and liver fat quantified using dual-energy X-ray absorptiometry and magnetic resonance imaging and spectroscopy, received the five meal treatments in random order: HP-NB, HC-CB, HP-NB + WB (50 g available CHO), HC-CB + WB and WB only. Compared with HC-CB, HP-NB induced a significantly lower 30–120 min glucose response (P < 0⋅05), with an approximately 10-fold lower incremental area under the glucose curve (iAUC0–120; P < 0⋅001). HP-NB also attenuated glucose response by approximately 25 % when co-ingested with WB (P < 0⋅05). Half of the cohort had elevated pancreas and/or liver fat, with 13–21 % greater suppression of iAUC0–120 glucose in the low v. high organ fat subgroups across all five treatments. A nut-based snack product may be a healthier alternative to an energy equivalent cereal-based product with evidence of both a lower postprandial glycaemic response and modulation of CHO-induced hyperglycaemia even in high-risk, overweight, pre-diabetic adults.
Raja Shehadeh’s “Cartography of Refusal”: The Enduring Land Narrative Practice of Palestinian Walks
Authors: Batarseh Amanda
Published: April 2021

In the 1920s, the Palestinian ethnographer Tawfiq Kan‘an examined the physical and narrative construction of Palestinian space by cataloguing the living archive of Palestinian sanctuaries. His collection of narratives, imbued in the sacred space of the “shrine, tomb, tree, shrub, cave, spring, well, rock [or] stone” is suggestive of cultural anthropologist Keith Basso’s elaboration of “place-making” as learned from the Western Apache. Articulating two modes of disruption, place-making narratives preserve indigenous culture in the face of colonial conquest and unsettle colonial paradigms of spatial belonging and exclusion. Despite the efforts of settler colonial erasure, this interpolative practice has been carried through Palestinian narrative traditions into the present. Raja Shehadeh’s Palestinian Walks: Notes on a Vanishing Landscape (2007) illustrates an indigenous mode of seeing, creating, and contesting spatial narratives, disclosing the role of place-making in contemporary Palestinian literature.
Spinoza's Account of Blessedness Explored through an Aristotelian Lens
Authors: Soyarslan Sanem
Published: April 2021

In this article, I examine whether Spinoza's account of blessedness can be identified with a contemplative ideal in the Aristotelian tradition. I first introduce the main features of the Aristotelian life of contemplation and its difference from the life of practically oriented virtues — a difference that is grounded in Aristotle's distinction betweenpraxisandtheoria. In highlighting the commonalities between Spinoza's two kinds of adequate cognition — that is, intuitive knowledge and reason — I show that there is no room for a similar distinction in Spinoza, which will enable us to identify intuitive knowledge and its attendant blessedness exclusively with the theoretical activity.
Philosophical Advice
Authors: Archard David
Published: April 2021

Philosophers who publish articles that make practical ethical recommendations are thereby offering advice. I consider what obligations they incur in advising. I analyse the giving of advice as a communicative act whose defining and characteristic aim is to secure acceptance of what is advised. Such advice need not be solicited or taken up. I distinguish advice from incitement and threats and specify the scope of the adviser's responsibility for others acting upon the advice. I explore how advice can be bad in how it is given and what is given. I consider, and criticise, various pleas for exemption from the responsibilities of philosophical advising: that advice was not meant; that it wouldn't make any difference anyway; and that the writing was not for those who might act on it. I examine the offering of philosophical advice to policy makers, comparing the views on this of Mary Warnock and Dan Brock. I conclude by asking practical normative philosophers to consider what they should do inasmuch as they are advising.
Powder X-ray diffraction of pazopanib hydrochloride Form 1, C21H24N7O2SCl
Authors: Kaduk James A. , Gindhart Amy M. , Blanton Thomas N.
Published: April 2021

The crystal structure of pazopanib hydrochloride Form 1 has been refined using synchrotron X-ray powder diffraction data and optimized using density functional theory techniques. Pazopanib hydrochloride crystallizes in space group P-1 (#2) with a = 8.45008(6), b = 8.71310(12), c = 16.05489(35) Å, α = 79.5996(9), β = 86.4784(5), γ = 87.3764(3)°, V = 1159.724(9) Å3, and Z = 2. The crystal structure is essentially identical to that of CSD Refcode CEVYEK. There are four strong N–H⋯Cl hydrogen bonds to the chloride anion. Several additional weaker N–H⋯Cl and C–H⋯Cl hydrogen bonds are also present. A variety of C–H⋯O, C–H⋯N, and N–H⋯S hydrogen bonds also contribute to the lattice energy. The powder pattern has been submitted to ICDD® for inclusion in the Powder Diffraction File™.
Exit, Voice, Loyalty … or Deliberate Obstruction? Non-Collective Everyday Resistance under Oppression.
Authors: Dornschneider Stephanie
Published: April 2021

In highly oppressive environments, collective resistance is very costly. Non-collective resistance constitutes a less risky alternative. Focusing on a particular oppressed setting, the Occupied Palestinian Territories, I identify everyday forms of non-collective resistance: signaling, persevering, eschewing, and coping. Characterized by low visibility and targeting political goals indirectly, these activities have not yet been recognized as forms of resistance. However, they constitute important resistance efforts that deliberately obstruct oppressive regimes. These efforts show that individuals who are not visibly resisting their rulers cannot be assumed to be loyal or to suffer from a barrier of fear, as often suggested by theories in politics. They also offer an important addition to theories that identify violence as a common response to oppression, suggesting that peaceful non-collective activities constitute an everyday alternative.
Is sustainable development bad for global biodiversity conservation?
Authors: Clémençon Raymond
Published: April 2021

Non-technical summary

Global biodiversity is in dramatic decline. The general public appears to equate sustainable development with biodiversity conservation and environmental protection, whereas the international policy discourse treats sustainable development as little more than traditional economic development. This gap between public perception of what sustainable development entails and its translation into formal policy goals is an important barrier to mobilizing the public and critical financial support for meeting global biodiversity conservation objectives. This contribution argues that the goal of nature and biodiversity conservation must be much more clearly distinguished from the 2015 UN Sustainable Development Goals (SDGs) than is currently the case.

Technical summary

The term ‘sustainable development’ has become widely used since it was popularized through the 1992 Rio UN Conference on Environment and Development. The UN SDGs adopted in 2015 further reinforce the normative centrality of the concept. Yet, the extent to which sustainable development covers nature and biodiversity conservation depends on how it is defined. A better understanding of how the public in different countries assesses the value of local and global biodiversity is crucial for building support for financing the vision to live ‘in harmony with nature by 2050’ currently under negotiation in the Convention on Biodiversity. This review essay discusses four distinct definitions of sustainable development, and considers how these different conceptualizations are used by political actors to serve particular interests. It then describes how this discourse has unfolded in international agreements related to sustainable development and biodiversity. The analysis shows that the prevalent economic cost–benefit approach used to value ecosystem services to make a case for conservation cannot resolve trade-off decisions between short-term economic and long-term societal interests. What is needed is a broad discourse about the ethical and cultural dimensions of biodiversity as a global heritage at the highest political level.

Social media abstract

The goal of global biodiversity conservation must be more clearly distinguished from the 2015 SDGs economic objectives.
Lower‐Stage Plane Bed Topography Is an Outcome of Rarefied, Intermittent Sediment Transport
Authors: Ashley Thomas C. , Naqshband Suleyman , McElroy Brandon
Published: April 2021

Sedimentary bed configurations that are stable under weak fluid‐driven transport conditions can be divided into two groups: (1) mesoscale features that influence flow and sediment transport through roughness and drag partitioning effects (“mesoforms”) and (2) grain‐scale features that can effectively be ignored at the macroscopic scale (“microforms”). In practice, these groups delineate ripples and dunes from quasi‐planar bed configurations. They are thought to be separated by a transition in processes governing the relief of the bed; however, the physical mechanisms responsible for this transition are poorly understood. Previous studies suggest that planar topography is unstable when interactions between moving particles lead to stabilized bed disturbances that initiate morphodynamic pattern coarsening. This study presents a kinetic interpretation of this hypothesis in terms of parameters describing particle motion. We find that the microform/mesoform transition corresponds to a critical transition in particle behavior associated with increasing importance of particle collisions. This transition also corresponds to the point where continuum‐based morphodynamic models are permissible at the most unstable wavelength predicted from linear stability theory, providing a link between descriptive and mathematical theories of bedform initiation.
Assessing the Potential of Deep Learning for Emulating Cloud Superparameterization in Climate Models With Real‐Geography Boundary Conditions
Authors: Mooers Griffin , Pritchard Michael , Beucler Tom , Ott Jordan , Yacalis Galen , Baldi Pierre , Gentine Pierre
Published: April 2021

We explore the potential of feed‐forward deep neural networks (DNNs) for emulating cloud superparameterization in realistic geography, using offline fits to data from the superparameterized community atmospheric model. To identify the network architecture of greatest skill, we formally optimize hyperparameters using ∼250 trials. Our DNN explains over 70% of the temporal variance at the 15‐min sampling scale throughout the mid‐to‐upper troposphere. Autocorrelation timescale analysis compared against DNN skill suggests the less good fit in the tropical, marine boundary layer is driven by neural network difficulty emulating fast, stochastic signals in convection. However, spectral analysis in the temporal domain indicates skillful emulation of signals on diurnal to synoptic scales. A closer look at the diurnal cycle reveals correct emulation of land‐sea contrasts and vertical structure in the heating and moistening fields, but some distortion of precipitation. Sensitivity tests targeting precipitation skill reveal complementary effects of adding positive constraints versus hyperparameter tuning, motivating the use of both in the future. A first attempt to force an offline land model with DNN emulated atmospheric fields produces reassuring results further supporting neural network emulation viability in real‐geography settings. Overall, the fit skill is competitive with recent attempts by sophisticated Residual and Convolutional Neural Network architectures trained on added information, including memory of past states. Our results confirm the parameterizability of superparameterized convection with continents through machine learning and we highlight the advantages of casting this problem locally in space and time for accurate emulation and hopefully quick implementation of hybrid climate models.
Role of the Tropical Atlantic for the Interhemispheric Heat Transport During the Last Deglaciation
Authors: Meier Karl J. F. , Bahr André , Chiessi Cristiano M. , Albuquerque Ana Luiza , Raddatz Jacek , Friedrich Oliver
Published: April 2021

During the last deglaciation abrupt millennial‐scale perturbations of the Atlantic Meridional Overturning Circulation massively altered the interhemispheric heat distribution affecting, for example, continental ice volume and hydroclimate. If and how the related cross‐equatorial heat transport was controlled by the interplay between the southward‐flowing Brazil Current (BC) and northward‐flowing North Brazil Current (NBC) remains controversial. To assess the role of tropical heat transport during the last deglaciation, we obtained a high‐resolution foraminiferal Mg/Ca‐based sea surface temperature (SST) record from the BC domain at 21.5°S. The data reveal a yet undocumented warming of at least 4.6°C of the BC during Heinrich Stadial 1 at ∼16 ka indicating massive oceanic heat accumulation in the tropical South Atlantic. Simultaneously, a strongly diminished NBC prevented the release of this excess heat into the northern tropics. The observed magnitude of heat accumulation substantially exceeds numerical model simulations, stressing the need to further scrutinize atmospheric and oceanic heat transport during extreme climatic events.
How Much of the Earth's Surface is Underlain by Permafrost?
Authors: Obu J.
Published: April 2021

More than 80% of studies reporting the area on Earth underlain by permafrost refer to the extent of the permafrost region, which accounts for around 21 million km2 (22% of the Northern Hemisphere's exposed land surface). Since each permafrost zone (continuous, discontinuous, sporadic, and isolated, which combined represent the permafrost region) is not entirely underlain by permafrost, the actual area underlain by permafrost (permafrost area) accounts for approximately 14 million km2 (15% of the exposed land surface area in the Northern Hemisphere). Such overstatements create a general impression that there is 6 million km2 more permafrost than currently estimated. I highlight the known differences between the terms permafrost region and permafrost area, along with explaining the possible reasons leading to these overstatements. Recent studies estimating permafrost area extent are summarized to provide a baseline for the geoscientific community and general public about the actual area underlain by permafrost for different parts of the globe.
High‐Precision Carrier Tracking Algorithm for Extremely Weak and High‐Dynamic Signals
Authors: Deng Tao , Ma Maoli , Liu Qinghui , Wu Yajun
Published: April 2021

Obtaining high‐precision Doppler frequencies for very weak and high‐dynamic signals in deep space exploration is challenging. Such signals are commonly encountered, including in soft landing of lunar probes and the entry, descent, and landing (EDL) phase of Mars probes. Phase‐locked loop (PLL) is a widely used method for measuring high‐precision Doppler frequencies. In this study, two major improvements are applied to PLL. The first is that high precision estimation of initial frequency is achieved by open loop maximum amplitude search algorithm. Second, a novel denoising method is proposed and a new type of phase detector is designed based on this new denoising method. By replacing arctangent phase detector with the novel phase detector, the tracking accuracy and weak‐signal tracking abilities of the PLL are improved. The actual data processing results of soft landing process of lunar probe further verify the excellent performance of the improved PLL.
Astroglial tracer BU99008 detects multiple binding sites in Alzheimer’s disease brain
Authors: Kumar Amit , Koistinen Niina A. , Malarte Mona-Lisa , Nennesmo Inger , Ingelsson Martin , Ghetti Bernardino , Lemoine Laetitia , Nordberg Agneta
Published: April 2021

With reactive astrogliosis being established as one of the hallmarks of Alzheimer’s disease (AD), there is high interest in developing novel positron emission tomography (PET) tracers to detect early astrocyte reactivity. BU99008, a novel astrocytic PET ligand targeting imidazoline-2 binding sites (I2BS) on astrocytes, might be a suitable candidate. Here we demonstrate for the first time that BU99008 could visualise reactive astrogliosis in postmortem AD brains and propose a multiple binding site [Super-high-affinity (SH), High-affinity (HA) and Low-affinity (LA)] model for BU99008, I2BS specific ligands (2-BFI and BU224) and deprenyl in AD and control (CN) brains. The proportion (%) and affinities of these sites varied significantly between the BU99008, 2-BFI, BU224 and deprenyl in AD and CN brains. Regional binding studies demonstrated significantly higher 3H-BU99008 binding in AD brain regions compared to CN. Comparative autoradiography studies reinforced these findings, showing higher specific binding for 3H-BU99008 than 3H-Deprenyl in sporadic AD brain compared to CN, implying that they might have different targets. The data clearly shows that BU99008 could detect I2BS expressing reactive astrocytes with good selectivity and specificity and hence be a potential attractive clinical astrocytic PET tracer for gaining further insight into the role of reactive astrogliosis in AD.
Downregulation of miR-335 exhibited an oncogenic effect via promoting KDM3A/YAP1 networks in clear cell renal cell carcinoma
Authors: Zhang Wenqiang , Liu Ruiyu , Zhang Lin , Wang Chao , Dong Ziyan , Feng Jiasheng , Luo Mayao , Zhang Yifan , Xu Zhuofan , Lv Shidong , Wei Qiang
Published: April 2021

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer affecting many people worldwide. Although the 5-year survival rate is 65% in localized disease, after metastasis, the survival rate is <10%. Emerging evidence has shown that microRNAs (miRNAs) play a crucial regulatory role in the progression of ccRCC. Here, we show that miR-335, an anti-onco-miRNA, is downregulation in tumor tissue and inhibited ccRCC cell proliferation, invasion, and migration. Our studies further identify the H3K9me1/2 histone demethylase KDM3A as a new miR-335-regulated gene. We show that KDM3A is overexpressed in ccRCC, and its upregulation contributes to the carcinogenesis and metastasis of ccRCC. Moreover, with the overexpression of KDM3A, YAP1 was increased and identified as a direct downstream target of KDM3A. Enrichment of KDM3A demethylase on YAP1 promoter was confirmed by CHIP-qPCR and YAP1 was also found involved in the cell growth and metastasis inhibitory of miR-335. Together, our study establishes a new miR-335/KDM3A/YAP1 regulation axis, which provided new insight and potential targeting of the metastasized ccRCC.
Lead-halide Cs4PbBr6 single crystals for high-sensitivity radiation detection
Authors: Li Yang , Shao Wenyi , Chen Liang , Wang Juan , Nie Jing , Zhang Hang , Zhang Silong , Gao Runlong , Ouyang Xiao , Ouyang Xiaoping , Xu Qiang
Published: April 2021

Low-dimensional perovskite materials and their derivatives with excellent optical performance are promising candidates for light-emission applications. Herein, centimeter lead-halide Cs4PbBr6 single crystals (SCs), which have been used for radiation detection with the indirect conversion method, were synthesized by a facile solution process. The Cs4PbBr6 scintillator exhibits bright green emission peaking at 525 nm and a high photoluminescence quantum yield (up to 86.7%) under 375 nm laser excitation. The Cs4PbBr6 SCs exhibit high sensitivity to 40 keV X-rays, with a favorable linearity with the X-ray exposure dose rate, and the detection limit is as low as 64.4 nGyair/s. The scintillation time-response performance of the Cs4PbBr6 SCs was acquired by a time-correlated single-photon counting system under alpha-particle excitation. The Cs4PbBr6 SCs exhibit a very fast time response (τav = 1.46 ns) to alpha particles from a 241Am radiation source. This value is comparable to that of the commercial plastic scintillator EJ-228 (τav = 1.31 ns) and much faster than that of the LYSO(Ce) scintillator (τav = 36.17 ns). Conceptual X-ray imaging and alpha-particle pulse height spectroscopy experiments were also performed. These results demonstrated the potential of Cs4PbBr6 SCs for radiation detection applications, including X-ray imaging and charged particle detection with fast scintillation decay time and high sensitivity.
VPS39-deficiency observed in type 2 diabetes impairs muscle stem cell differentiation via altered autophagy and epigenetics
Authors: Davegårdh Cajsa , Säll Johanna , Benrick Anna , Broholm Christa , Volkov Petr , Perfilyev Alexander , Henriksen Tora Ida , Wu Yanling , Hjort Line , Brøns Charlotte , Hansson Ola , Pedersen Maria , Würthner Jens U. , Pfeffer Klaus , Nilsson Emma , Vaag Allan , Stener-Victorin Elisabet , Pircs Karolina , Scheele Camilla , Ling Charlotte
Published: April 2021

Insulin resistance and lower muscle quality (strength divided by mass) are hallmarks of type 2 diabetes (T2D). Here, we explore whether alterations in muscle stem cells (myoblasts) from individuals with T2D contribute to these phenotypes. We identify VPS39 as an important regulator of myoblast differentiation and muscle glucose uptake, andVPS39is downregulated in myoblasts and myotubes from individuals with T2D. We discover a pathway connecting VPS39-deficiency in human myoblasts to impaired autophagy, abnormal epigenetic reprogramming, dysregulation of myogenic regulators, and perturbed differentiation. VPS39 knockdown in human myoblasts has profound effects on autophagic flux, insulin signaling, epigenetic enzymes, DNA methylation and expression of myogenic regulators, and gene sets related to the cell cycle, muscle structure and apoptosis. These data mimic what is observed in myoblasts from individuals with T2D. Furthermore, the muscle ofVps39+/−mice display reduced glucose uptake and altered expression of genes regulating autophagy, epigenetic programming, and myogenesis. Overall, VPS39-deficiency contributes to impaired muscle differentiation and reduced glucose uptake. VPS39 thereby offers a therapeutic target for T2D.
Metrological complementarity reveals the Einstein-Podolsky-Rosen paradox
Authors: Yadin Benjamin , Fadel Matteo , Gessner Manuel
Published: April 2021

The Einstein-Podolsky-Rosen (EPR) paradox plays a fundamental role in our understanding of quantum mechanics, and is associated with the possibility of predicting the results of non-commuting measurements with a precision that seems to violate the uncertainty principle. This apparent contradiction to complementarity is made possible by nonclassical correlations stronger than entanglement, called steering. Quantum information recognises steering as an essential resource for a number of tasks but, contrary to entanglement, its role for metrology has so far remained unclear. Here, we formulate the EPR paradox in the framework of quantum metrology, showing that it enables the precise estimation of a local phase shift and of its generating observable. Employing a stricter formulation of quantum complementarity, we derive a criterion based on the quantum Fisher information that detects steering in a larger class of states than well-known uncertainty-based criteria. Our result identifies useful steering for quantum-enhanced precision measurements and allows one to uncover steering of non-Gaussian states in state-of-the-art experiments.
The VRNetzer platform enables interactive network analysis in Virtual Reality
Authors: Pirch Sebastian , Müller Felix , Iofinova Eugenia , Pazmandi Julia , Hütter Christiane V. R. , Chiettini Martin , Sin Celine , Boztug Kaan , Podkosova Iana , Kaufmann Hannes , Menche Jörg
Published: April 2021

Networks provide a powerful representation of interacting components within complex systems, making them ideal for visually and analytically exploring big data. However, the size and complexity of many networks render static visualizations on typically-sized paper or screens impractical, resulting in proverbial ‘hairballs’. Here, we introduce a Virtual Reality (VR) platform that overcomes these limitations by facilitating the thorough visual, and interactive, exploration of large networks. Our platform allows maximal customization and extendibility, through the import of custom code for data analysis, integration of external databases, and design of arbitrary user interface elements, among other features. As a proof of concept, we show how our platform can be used to interactively explore genome-scale molecular networks to identify genes associated with rare diseases and understand how they might contribute to disease development. Our platform represents a general purpose, VR-based data exploration platform for large and diverse data types by providing an interface that facilitates the interaction between human intuition and state-of-the-art analysis methods.
Imaging the response to DNA damage in heterochromatin domains reveals core principles of heterochromatin maintenance
Authors: Fortuny Anna , Chansard Audrey , Caron Pierre , Chevallier Odile , Leroy Olivier , Renaud Olivier , Polo Sophie E.
Published: April 2021

Heterochromatin is a critical chromatin compartment, whose integrity governs genome stability and cell fate transitions. How heterochromatin features, including higher-order chromatin folding and histone modifications associated with transcriptional silencing, are maintained following a genotoxic stress challenge is unknown. Here, we establish a system for targeting UV damage to pericentric heterochromatin in mammalian cells and for tracking the heterochromatin response to UV in real time. We uncover profound heterochromatin compaction changes during repair, orchestrated by the UV damage sensor DDB2, which stimulates linker histone displacement from chromatin. Despite massive heterochromatin unfolding, heterochromatin-specific histone modifications and transcriptional silencing are maintained. We unveil a central role for the methyltransferase SETDB1 in the maintenance of heterochromatic histone marks after UV. SETDB1 coordinates histone methylation with new histone deposition in damaged heterochromatin, thus protecting cells from genome instability. Our data shed light on fundamental molecular mechanisms safeguarding higher-order chromatin integrity following DNA damage.
Estimating the effect of social inequalities on the mitigation of COVID-19 across communities in Santiago de Chile
Authors: Gozzi Nicolò , Tizzoni Michele , Chinazzi Matteo , Ferres Leo , Vespignani Alessandro , Perra Nicola
Published: April 2021

We study the spatio-temporal spread of SARS-CoV-2 in Santiago de Chile using anonymized mobile phone data from 1.4 million users, 22% of the whole population in the area, characterizing the effects of non-pharmaceutical interventions (NPIs) on the epidemic dynamics. We integrate these data into a mechanistic epidemic model calibrated on surveillance data. As of August 1, 2020, we estimate a detection rate of 102 cases per 1000 infections (90% CI: [95–112 per 1000]). We show that the introduction of a full lockdown on May 15, 2020, while causing a modest additional decrease in mobility and contacts with respect to previous NPIs, was decisive in bringing the epidemic under control, highlighting the importance of a timely governmental response to COVID-19 outbreaks. We find that the impact of NPIs on individuals’ mobility correlates with the Human Development Index of comunas in the city. Indeed, more developed and wealthier areas became more isolated after government interventions and experienced a significantly lower burden of the pandemic. The heterogeneity of COVID-19 impact raises important issues in the implementation of NPIs and highlights the challenges that communities affected by systemic health and social inequalities face adapting their behaviors during an epidemic.
Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer’s disease-like pathology
Authors: Baglietto-Vargas David , Forner Stefania , Cai Lena , Martini Alessandra C. , Trujillo-Estrada Laura , Swarup Vivek , Nguyen Marie Minh Thu , Do Huynh Kelly , Javonillo Dominic I. , Tran Kristine Minh , Phan Jimmy , Jiang Shan , Kramár Enikö A. , Nuñez-Diaz Cristina , Balderrama-Gutierrez Gabriela , Garcia Franklin , Childs Jessica , Rodriguez-Ortiz Carlos J. , Garcia-Leon Juan Antonio , Kitazawa Masashi , Shahnawaz Mohammad , Matheos Dina P. , Ma Xinyi , Da Cunha Celia , Walls Ken C. , Ager Rahasson R. , Soto Claudio , Gutierrez Antonia , Moreno-Gonzalez Ines , Mortazavi Ali , Tenner Andrea J. , MacGregor Grant R. , Wood Marcelo , Green Kim N. , LaFerla Frank M.
Published: April 2021

The majority of Alzheimer’s disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aβ under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aβ sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression. In addition, when exon 14 encoding the Aβ sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAβ expression, rescues cognition and reduces the formation of PAS granules.
CRISPR-based genome editing in primary human pancreatic islet cells
Authors: Bevacqua Romina J. , Dai Xiaoqing , Lam Jonathan Y. , Gu Xueying , Friedlander Mollie S. H. , Tellez Krissie , Miguel-Escalada Irene , Bonàs-Guarch Silvia , Atla Goutham , Zhao Weichen , Kim Seung Hyun , Dominguez Antonia A. , Qi Lei S. , Ferrer Jorge , MacDonald Patrick E. , Kim Seung K.
Published: April 2021

Gene targeting studies in primary human islets could advance our understanding of mechanisms driving diabetes pathogenesis. Here, we demonstrate successful genome editing in primary human islets using clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9). CRISPR-based targeting efficiently mutated protein-coding exons, resulting in acute loss of islet β-cell regulators, like the transcription factor PDX1 and the KATP channel subunit KIR6.2, accompanied by impaired β-cell regulation and function. CRISPR targeting of non-coding DNA harboring type 2 diabetes (T2D) risk variants revealed changes in ABCC8, SIX2 and SIX3 expression, and impaired β-cell function, thereby linking regulatory elements in these target genes to T2D genetic susceptibility. Advances here establish a paradigm for genetic studies in human islet cells, and reveal regulatory and genetic mechanisms linking non-coding variants to human diabetes risk.
Arginine is an epigenetic regulator targeting TEAD4 to modulate OXPHOS in prostate cancer cells
Authors: Chen Chia-Lin , Hsu Sheng-Chieh , Chung Tan-Ya , Chu Cheng-Ying , Wang Hung-Jung , Hsiao Pei-Wen , Yeh Shauh-Der , Ann David K. , Yen Yun , Kung Hsing-Jien
Published: April 2021

Arginine plays diverse roles in cellular physiology. As a semi-essential amino acid, arginine deprivation has been used to target cancers with arginine synthesis deficiency. Arginine-deprived cancer cells exhibit mitochondrial dysfunction, transcriptional reprogramming and eventual cell death. In this study, we show in prostate cancer cells that arginine acts as an epigenetic regulator to modulate histone acetylation, leading to global upregulation of nuclear-encoded oxidative phosphorylation (OXPHOS) genes. TEAD4 is retained in the nucleus by arginine, enhancing its recruitment to the promoter/enhancer regions of OXPHOS genes and mediating coordinated upregulation in a YAP1-independent but mTOR-dependent manner. Arginine also activates the expression of lysine acetyl-transferases and increases overall levels of acetylated histones and acetyl-CoA, facilitating TEAD4 recruitment. Silencing of TEAD4 suppresses OXPHOS functions and prostate cancer cell growth in vitro and in vivo. Given the strong correlation of TEAD4 expression and prostate carcinogenesis, targeting TEAD4 may be beneficially used to enhance arginine-deprivation therapy and prostate cancer therapy.
Neural network based 3D tracking with a graphene transparent focal stack imaging system
Authors: Zhang Dehui , Xu Zhen , Huang Zhengyu , Gutierrez Audrey Rose , Blocker Cameron J. , Liu Che-Hung , Lien Miao-Bin , Cheng Gong , Liu Zhe , Chun Il Yong , Fessler Jeffrey A. , Zhong Zhaohui , Norris Theodore B.
Published: April 2021

Recent years have seen the rapid growth of new approaches to optical imaging, with an emphasis on extracting three-dimensional (3D) information from what is normally a two-dimensional (2D) image capture. Perhaps most importantly, the rise of computational imaging enables both new physical layouts of optical components and new algorithms to be implemented. This paper concerns the convergence of two advances: the development of a transparent focal stack imaging system using graphene photodetector arrays, and the rapid expansion of the capabilities of machine learning including the development of powerful neural networks. This paper demonstrates 3D tracking of point-like objects with multilayer feedforward neural networks and the extension to tracking positions of multi-point objects. Computer simulations further demonstrate how this optical system can track extended objects in 3D, highlighting the promise of combining nanophotonic devices, new optical system designs, and machine learning for new frontiers in 3D imaging.
Brockarchaeota, a novel archaeal phylum with unique and versatile carbon cycling pathways
Authors: De Anda Valerie , Chen Lin-Xing , Dombrowski Nina , Hua Zheng-Shuang , Jiang Hong-Chen , Banfield Jillian F. , Li Wen-Jun , Baker Brett J.
Published: April 2021

Geothermal environments, such as hot springs and hydrothermal vents, are hotspots for carbon cycling and contain many poorly described microbial taxa. Here, we reconstructed 15 archaeal metagenome-assembled genomes (MAGs) from terrestrial hot spring sediments in China and deep-sea hydrothermal vent sediments in Guaymas Basin, Gulf of California. Phylogenetic analyses of these MAGs indicate that they form a distinct group within the TACK superphylum, and thus we propose their classification as a new phylum, ‘Brockarchaeota’, named after Thomas Brock for his seminal research in hot springs. Based on the MAG sequence information, we infer that some Brockarchaeota are uniquely capable of mediating non-methanogenic anaerobic methylotrophy, via the tetrahydrofolate methyl branch of the Wood-Ljungdahl pathway and reductive glycine pathway. The hydrothermal vent genotypes appear to be obligate fermenters of plant-derived polysaccharides that rely mostly on substrate-level phosphorylation, as they seem to lack most respiratory complexes. In contrast, hot spring lineages have alternate pathways to increase their ATP yield, including anaerobic methylotrophy of methanol and trimethylamine, and potentially use geothermally derived mercury, arsenic, or hydrogen. Their broad distribution and their apparent anaerobic metabolic versatility indicate that Brockarchaeota may occupy previously overlooked roles in anaerobic carbon cycling.
Frustration-driven magnetic fluctuations as the origin of the low-temperature skyrmion phase in Co7Zn7Mn6
Authors: Ukleev V. , Karube K. , Derlet P. M. , Wang C. N. , Luetkens H. , Morikawa D. , Kikkawa A. , Mangin-Thro L. , Wildes A. R. , Yamasaki Y. , Yokoyama Y. , Yu L. , Piamonteze C. , Jaouen N. , Tokunaga Y. , Rønnow H. M. , Arima T. , Tokura Y. , Taguchi Y. , White J. S.
Published: April 2021

In chiral cubic helimagnets, phases of magnetic skyrmions—topologically protected spin whirls—are stabilized by thermal fluctuations over a narrow region directly below the magnetic ordering temperature Tc. Due to often being touted for use in applications, there is a high demand to identify new ways to stabilize equilibrium skyrmion phases far below Tc where they may display an enhanced robustness against external perturbation due to a larger magnetic order parameter. Here, from quantum beam experiments on the chiral magnet Co7Zn7Mn6, we unveil a direct correlation between the stability of its second skyrmion phase-stable far from Tc, and a concomitant enhancement of an underlying magnetic fluctuation rate that is driven by geometric magnetic frustration. The influences of other leading skyrmion stability mechanisms, such as those derived from thermal fluctuations and low T cubic anisotropies, are shown to be weak in this system. We therefore advance the existence of a fundamental mechanism for stabilizing topological skyrmions in Co7Zn7Mn6 chiral magnet that draws upon magnetic frustration as the key ingredient.
A multiple species, continent-wide, million-phenotype agronomic plant dataset
Authors: Newman Saul Justin , Furbank Robert T.
Published: April 2021

A critical shortage of ‘big’ agronomic data is placing an unnecessary constraint on the conduct of public agronomic research, imparting barriers to model development and testing. Here, we address this problem by providing a large non-relational database of agronomic trials, linked to intensive management and observational data, run under a unified experimental framework. The National Variety Trials (NVTs) represent a decade-long experimental trial network, conducted across thousands of Australian field sites using highly standardised randomised controlled designs. The NVTs contain over a million machine-measured phenotypic observations, aggregated from density-controlled populations containing hundreds of millions of plants and thousands of released plant varieties. These data are linked to hundreds of thousands of metadata observations including standardised soil tests, fertiliser and pesticide input data, crop rotation data, prior farm management practices, and in-field sensors. Finally, these data are linked to a suite of ground and remote sensing observations, arranged into interpolated daily- and ten-day aggregated time series, to capture the substantial diversity in vegetation and environmental patterns across the continent-spanning NVT network.
Elevated expression of the adhesion GPCR ADGRL4/ELTD1 promotes endothelial sprouting angiogenesis without activating canonical GPCR signalling
Authors: Favara David M. , Liebscher Ines , Jazayeri Ali , Nambiar Madhulika , Sheldon Helen , Banham Alison H. , Harris Adrian L.
Published: April 2021

ADGRL4/ELTD1 is an orphan adhesion GPCR (aGPCR) expressed in endothelial cells that regulates tumour angiogenesis. The majority of aGPCRs are orphan receptors. The Stachel Hypothesis proposes a mechanism for aGPCR activation, in which aGPCRs contain a tethered agonist (termed Stachel) C-terminal to the GPCR-proteolytic site (GPS) cleavage point which, when exposed, initiates canonical GPCR signalling. This has been shown in a growing number of aGPCRs. We tested this hypothesis on ADGRL4/ELTD1 by designing full length (FL) and C-terminal fragment (CTF) ADGRL4/ELTD1 constructs, and a range of potential Stachel peptides. Constructs were transfected into HEK293T cells and HTRF FRET, luciferase-reporter and Alphascreen GPCR signalling assays were performed. A stable ADGRL4/ELTD1 overexpressing HUVEC line was additionally generated and angiogenesis assays, signalling assays and transcriptional profiling were performed. ADGRL4/ELTD1 has the lowest GC content in the aGPCR family and codon optimisation significantly increased its expression. FL and CTF ADGRL4/ELTD1 constructs, as well as Stachel peptides, did not activate canonical GPCR signalling. Furthermore, stable overexpression of ADGRL4/ELTD1 in HUVECs induced sprouting angiogenesis, lowered in vitro anastomoses, and decreased proliferation, without activating canonical GPCR signalling or MAPK/ERK, PI3K/AKT, JNK, JAK/HIF-1α, beta catenin or STAT3 pathways. Overexpression upregulated ANTXR1, SLC39A6, HBB, CHRNA, ELMOD1, JAG1 and downregulated DLL4, KIT, CCL15, CYP26B1. ADGRL4/ELTD1 specifically regulates the endothelial tip-cell phenotype through yet undefined signalling pathways.
Effects of family planning on fertility behaviour across the demographic transition
Authors: Kramer Karen L. , Hackman Joe , Schacht Ryan , Davis Helen E.
Published: April 2021

The adoption of contraception often coincides with market integration and has transformative effects on fertility behavior. Yet many parents in small-scale societies make decisions about whether and when to adopt family planning in an environment where the payoffs to  have smaller families are uncertain. Here we track the fertility of Maya women across 90 years, spanning the transition from natural to contracepting fertility. We first situate the uncertainty in which fertility decisions are made and model how childbearing behaviors respond. We find that contraception, a key factor in cultural transmission models of fertility decline, initially has little effect on family size as women appear to hedge their bets and adopt fertility control only at the end of their reproductive careers. Family planning is, however, associated with the spread of lower fertility in later cohorts. Distinguishing influences on the origin versus spread of a behaviour provides valuable insight into causal factors shaping individual and normative changes in fertility.
Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden
Authors: Zhao Lue Ping , Papadopoulos George K. , Moustakas Antonis K. , Bondinas George P. , Carlsson Annelie , Larsson Helena Elding , Ludvigsson Johnny , Marcus Claude , Persson Martina , Samuelsson Ulf , Wang Ruihan , Pyo Chul-Woo , Geraghty Daniel E. , Lernmark Åke
Published: April 2021

HLA-DQ molecules account over 50% genetic risk of type 1 diabetes (T1D), but little is known about associated residues. Through next generation targeted sequencing technology and deep learning of DQ residue sequences, the aim was to uncover critical residues and their motifs associated with T1D. Our analysis uncovered (αa1, α44, α157, α196) and (β9, β30, β57, β70, β135) on the HLA-DQ molecule. Their motifs captured all known susceptibility and resistant T1D associations. Three motifs, “DCAA-YSARD” (OR = 2.10, p = 1.96*10−20), “DQAA-YYARD” (OR = 3.34, 2.69*10−72) and “DQDA-YYARD” (OR = 3.71, 1.53*10−6) corresponding to DQ2.5 and DQ8.1 (the latter two motifs) associated with susceptibility. Ten motifs were significantly associated with resistance to T1D. Collectively, homozygous DQ risk motifs accounted for 43% of DQ-T1D risk, while homozygous DQ resistant motifs accounted for 25% protection to DQ-T1D risk. Of the identified nine residues five were within or near anchoring pockets of the antigenic peptide (α44, β9, β30, β57 and β70), one was the N-terminal of the alpha chain (αa1), one in the CD4-binding region (β135), one in the putative cognate TCR-induced αβ homodimerization process (α157), and one in the intra-membrane domain of the alpha chain (α196). Finding these critical residues should allow investigations of fundamental properties of host immunity that underlie tolerance to self and organ-specific autoimmunity.
Liver fat scores do not reflect interventional changes in liver fat content induced by high-protein diets
Authors: Kabisch Stefan , Markova Mariya , Hornemann Silke , Sucher Stephanie , Pivovarova-Ramich Olga , Machann Jürgen , Hierholzer Johannes , Rohn Sascha , Pfeiffer Andreas F. H.
Published: April 2021

Non-alcoholic fatty liver disease (NAFLD) is common in Metabolic Syndrome and type 2 diabetes (T2DM), driven by energy imbalance, saturated fats and simple carbohydrates. NAFLD requires screening and monitoring for late complications. Liver fat indices may predict NAFLD avoiding expensive or invasive gold-standard methods, but they are poorly validated for use in interventional settings. Recent data indicate a particular insensitivity to weight-independent liver fat reduction. We evaluated 31 T2DM patients, completing a randomized intervention study on isocaloric high-protein diets. We assessed anthropometric measures, intrahepatic lipid (IHL) content and serum liver enzymes, allowing AUROC calculations as well as cross-sectional and longitudinal Spearman correlations between the fatty liver index, the NAFLD-liver fat score, the Hepatosteatosis Index, and IHL. At baseline, all indices predicted NAFLD with moderate accuracy (AUROC 0.731–0.770), supported by correlation analyses. Diet-induced IHL changes weakly correlated with changes of waist circumference, but no other index component or the indices themselves. Liver fat indices may help to easily detect NAFLD, allowing cost-effective allocation of further diagnostics to patients at high risk. IHL reduction by weight-independent diets is not reflected by a proportional change in liver fat scores. Further research on the development of treatment-sensitive indices is required.

Trial registration: The trial was registered at clinicaltrials.gov: NCT02402985.