bluuebunny/crossref_metadata_2025 huggingface dataset:
Regression discontinuity designs: a hands-on guide for practice
Authors: Valentim Vicente , Ruipérez Núñez Ana , Dinas Elias
Published: July 2021

Regression discontinuity (RD) designs have become increasingly popular in political science, due to their ability to showcase causal effects under weak assumptions. This paper provides an intuition-based guide for the use of the RD in applied research. After an intuitive explanation of how the method works, we provide a checklist that can help researchers understand the main robustness checks they should run, and a quick introduction to software implementing the design. We also provide a list of classic designs and examples of their application in political science. We hope this article can constitute a stepping stone from which researchers interested in RD can jump to more advanced literature; and which makes researchers not interested in implementing RDs better consumers of research employing this design.
Public Perceptions of Women’s Inclusion and Feelings of Political Efficacy
Authors: STAUFFER KATELYN E.
Published: July 2021

Theoretical work argues that citizens gain important symbolic benefits when they are represented by gender-inclusive institutions. Despite the centrality of this claim in the literature, empirical evidence is mixed. In this article, I argue that these mixed findings are—in part—because many Americans hold beliefs about women’s inclusion that are out of step with reality. Leveraging variation in survey respondents’ beliefs about women’s representation, I examine how these perceptions influence attitudes toward Congress and state legislatures. In both cases, I find that believing women are included is associated with higher levels of external efficacy among both men and women. Using panel data, I then show that when citizens’ underestimations (overestimations) are corrected, their levels of efficacy increase (decrease), shedding further light on this relationship. The findings presented in this research add new theoretical insights into when, and how, Americans consider descriptive representation when evaluating the institutions that represent them.
Advancing the RDoC initiative through the assessment of caregiver social processes
Authors: King Lucy S. , Salo Virginia C. , Kujawa Autumn , Humphreys Kathryn L.
Published: July 2021

The relationships infants and young children have with their caregivers are fundamental to their survival and well-being. Theorists and researchers across disciplines have attempted to describe and assess the variation in these relationships, leading to a general acceptance that caregiving is critical to understanding child functioning, including developmental psychopathology. At the same time, we lack consensus on how to assess these fundamental relationships. In the present paper, we first review research documenting the importance of the caregiver–child relationship in understanding environmental risk for psychopathology. Second, we propose that the National Institute of Mental Health's Research Domain Criteria (RDoC) initiative provides a useful framework for extending the study of children's risk for psychopathology by assessing their caregivers’social processes. Third, we describe the units of analysis for caregiversocial processes,documenting how the specific subconstructs in the domain ofsocial processesare relevant to the goal of enhancing knowledge of developmental psychopathology. Lastly, we highlight how past research can inform new directions in the study of caregiving and the parent–child relationship through this innovative extension of the RDoC initiative.
Impact of brain-derived neurotrophic factor Val66Met polymorphism and response to escitalopram or paroxetine in obsessive–compulsive disorder
Authors: Harika-Germaneau Ghina , Langbour Nicolas , Patri Sylvie , Solinas Marcello , Chatard Armand , Millet Bruno , Hashemian Farshad , Pérault-Pochat Marie-Christine , Jaafari Nematollah , Lafay-Chebassier Claire
Published: July 2021

Objective

Obsessive–compulsive disorder (OCD) is a severe psychiatric disorder characterized by its heterogeneous nature and by different dimensions of obsessive–compulsive (OC) symptoms. Serotonin reuptake inhibitors (SRIs) are used to treat OCD, but up to 40% to 60% of patients do not show a significant improvement with these medications. In this study, we aimed to test the impact of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on the efficacy of antidepressants in OCD overall, and in relation to the different OC dimensions.

Methods

In a 6-month prospective treatment study, 69 Caucasian OCD patients were treated with escitalopram for 24 weeks or with escitalopram for 12 weeks followed by paroxetine for an additional 12-week period. Patients were genotyped and assessed for treatment response. The main clinical outcomes were improvement of the Yale-Brown Obsessive–Compulsive Scale score and in different OC symptom dimension scores.

Results

The Val/Val group comprised 43 (62%) patients, the Val/Met and Met/Met group comprised 26 (38%) patients. Forty-two patients were classified as responders at 12 weeks and 38 at 24 weeks; no significant association was found between BDNF Val66Met and SRIs response at 12 and 24 weeks. In analyses of the different OC symptom dimensions, the Met allele was associated with a slightly reduced score in the aggressive/checking dimension at 6 months (P = .048).

Conclusions

Our findings do not support the usefulness of BDNF Val66Met genotyping to predict overall response to treatment with SRIs in OCD; they did however suggest a better outcome at 6 months for the aggressive/checking symptom dimension for patients carrying the Met allele.
Demolition traditions: Isozaki and Sakaguchi
Authors: Richards Simon
Published: July 2021

If ever an architect bit the hand that fed, it was the young Arata Isozaki, a mercurial and uncompromising architectural talent who would go on to secure establishment respectability with the Pritzker Prize of 2019. But he made his renown with designs and exhibitions exploring themes of death and destruction, not least his ‘Fractures’ pavilion for the 1996 Venice Biennale, which sought to stage the aftermath of the Kobe earthquake from a year earlier, while also being a leading proponent of a playful, almost saccharine postmodernism, with projects including the Team Disney HQ of 1991. Immersed in the leading currents of Japanese architecture from the 1960s onwards, his tendency to snipe at the motives of his collaborators was legendary. Commentators have tried to account for these professional shifts and antagonisms, his dour and contrarian thematic obsessions, as well as his critiques of architectural traditionalism and technological progressivism. Why did he conduct his professional life and art this way? The conclusion seems to be that he was a nihilistic maverick pushing at the outer limits of architectural culture and even taste.
Australia's Response to COVID-19
Authors: Stobart Anika , Duckett Stephen
Published: July 2021

Australia suffered two waves of the coronavirus disease 2019 pandemic in 2020: the first lasting from February to July 2020 was mainly caused by transmission from international arrivals, the second lasting from July to November was caused by breaches of hotel quarantine which allowed spreading into the community. From a second wave peak in early August of over 700 new cases a day, by November 2020 Australia had effectively eliminated community transmission. Effective elimination was largely maintained in the first half of 2021 using snap lockdowns, while a slow vaccination programme left Australia lagging behind comparable countries. This paper describes the interventions which led to Australia's relative success up to July 2021, and also some of the failures along the way.
Re‐Analysis of the Cassini RPWS/LP Data in Titan's Ionosphere: 2. Statistics on 57 Flybys
Authors: Chatain A. , Wahlund J.‐E. , Shebanits O. , Hadid L. Z. , Morooka M. , Edberg N. J. T. , Guaitella O. , Carrasco N.
Published: July 2021

The ionosphere of Titan hosts a complex ion chemistry leading to the formation of organic dust below 1,200 km. Current models cannot fully explain the observed electron temperature in this dusty environment. To achieve new insight, we have re‐analyzed the data taken in the ionosphere of Titan by the Cassini Langmuir probe (LP), part of the Radio and Plasma Wave Science package. A first paper (Chatain et al., 2021) introduces the new analysis method and discusses the identification of four electron populations produced by different ionization mechanisms. In this second paper, we present a statistical study of the whole LP dataset below 1,200 km which gives clues on the origin of the four populations. One small population is attributed to photo‐ or secondary electrons emitted from the surface of the probe boom. A second population is systematically observed, at a constant density (∼500 cm−3), and is attributed to background thermalized electrons from the ionization process of precipitating particles from the surrounding magnetosphere. The two last populations increase in density with pressure, solar illumination and Extreme ultraviolet flux. The third population is observed with varying densities at all altitudes and solar zenith angles (SZA) except on the far nightside (SZA > ∼140°), with a maximum density of 2,700 cm−3. It is therefore certainly related to the photo‐ionization of the atmospheric molecules. Finally, a fourth population detected only on the dayside and below 1,200 km reaching up to 2000 cm−3 could be photo‐ or thermo‐emitted from dust grains.
Investigating Axisymmetric and Asymmetric Signals of Secondary Eyewall Formation Using Observations‐Based Modeling of the Tropical Cyclone Boundary Layer
Authors: Yu Chau‐Lam , Didlake Anthony C. , Kepert Jeffrey D. , Zhang Fuqing
Published: July 2021

This study examines axisymmetric and asymmetric aspects of secondary eyewall formation (SEF) in tropical cyclones (TCs) by applying a nonlinear boundary layer model to tangential wind composites of observed TCs with and without SEF. SEF storms were further analyzed at times prior to and after SEF, as defined by the emergence of a secondary maximum in axisymmetric tangential wind. The model is used to investigate the steady‐state boundary layer response to the free‐tropospheric pressure forcing derived from observed tangential wind fields. The axisymmetric response to the Post‐SEF wind field displayed a secondary updraft maximum associated with a mature secondary eyewall; the model correctly produced no secondary updraft for non‐SEF storms. The Pre‐SEF response also exhibited a secondary updraft associated with an incipient secondary eyewall largely due to the broadened outer tangential wind field that commonly precedes SEF events. The asymmetric wind fields and model response were analyzed relative to the 850–200 hPa environmental wind shear vector. In Pre‐SEF storms, the tangential wind field displayed a broadened tangential wind structure in the downshear quadrants. The boundary layer response shows a downwind shift toward the left‐of‐shear quadrants, exhibiting the clearest secondary maxima in updrafts, tangential wind, and radial inflow. This left‐of‐shear response was the leading contributor to the secondary eyewall signals in the Pre‐SEF axisymmetric response. Sensitivity analyses confirmed the robustness of these asymmetric signals. These findings suggest that enhanced tangential wind and boundary layer updrafts in the left‐of‐shear sectors may be early indicators and critical features of SEF in sheared TCs.
Fault Planes, Fault Zone Structure and Detachment Fragmentation Resolved With High‐Precision Aftershock Locations of the 2016–2017 Central Italy Sequence
Authors: Waldhauser Felix , Michele Maddalena , Chiaraluce Lauro , Di Stefano Raffaele , Schaff David P.
Published: July 2021

Three devastating earthquakes of MW ≥ 5.9 activated a complex system of high‐angle normal, antithetic, and sub‐horizontal detachment faults during the 2016–2017 central Italy seismic sequence. Waveform cross‐correlation based double‐difference location of nearly 400,000 aftershocks illuminate complex, fine‐scale structures of interacting fault zones. The Mt. Vettore–Mt. Bove (VB) normal fault exhibits wide and complex damage zones, including a system of bookshelf faults that intersects the detachment zone. In the Laga domain, a comparatively narrow, shallow dipping segment of the deep Mt. Gorzano fault progressively ruptures through the detachment zone in four subsequent MW ∼ 5.4 events. Reconstructed fault planes show that the detachment zone is fragmented in four sub‐horizontal, partly overlaying shear planes that correlated with the extent of the mainshock ruptures. We find a new, deep reaching seismic barrier that coincides with a bend in the VB fault and may play a role in controlling rupture evolution.
Inter‐Basin Interaction Between Variability in the South Atlantic Ocean and the El Niño/Southern Oscillation
Authors: Ham Yoo‐Geun , Lee Hyun‐Jeong , Jo Hyun‐Su , Lee Se‐Gun , Cai Wenju , Rodrigues Regina R.
Published: July 2021

Oceanic variability that interacts with the El Niño/Southern Oscillation (ENSO) has been well identified in most ocean basins; however, the effect of variability over the South Atlantic (SA) on the ENSO is unknown. This study demonstrates that dominant mode of subtropical SA sea surface temperature (SST) variability during the boreal winter, referred to as the South Atlantic Subtropical Dipole (SASD), contributes to occurrence of an El Niño a year later. During a positive SASD, low‐tropospheric anticyclonic circulation anomalies over the mid‐latitude SA reduce convective activities over southeastern South America. The low‐tropospheric divergence anomalies associated with the reduced convection attenuate the occurrence of South American Low‐Level Jet, and moisture supply is directed along the South Atlantic Convergence Zone (SACZ). The increased precipitation over the SACZ leads to an anomalous surface easterly that lowers the SST over the equatorial Atlantic and eventually modulates the zonal Walker circulation, thereby favoring El Niño development.
Decadal Timescale Correlations Between Global Earthquake Activity and Volcanic Eruption Rates
Authors: Jenkins A. P. , Biggs J. , Rust A. C. , Rougier J. C.
Published: July 2021

At the global scale, large tectonic earthquakes and volcanic eruptions are believed to be random and independent events. Here, we compare global time‐series of large earthquakes ( 7) and explosive volcanic eruptions (VEI 2) spanning 1960–2019. Both time‐series exhibit decadal timescale trends, over which annual earthquake and eruption rates vary by a factor of 2. Moreover, global seismic moment release is positively correlated with global eruption rate, with Monte Carlo permutation tests showing that this correlation is significant with a ‐value of 0.05. Although large earthquakes can trigger eruptions at nearby volcanoes, the magnitude of this effect is insufficient to cause the observed global correlation. Other mechanisms, such as triggering of distant eruptions (>1000 km) by earthquake‐induced dynamic stress changes, modulation of global earthquake and eruption rates by variations in Earth's rotational velocity, or natural synchronization of events over repeating cycles, are therefore required to explain the correlation.
Antarctic Radiative and Temperature Responses to a Doubling of CO2
Authors: Freese Lyssa M. , Cronin Timothy W.
Published: July 2021

Greenhouse gases (GHGs), including carbon dioxide (), impact global and local outgoing longwave radiation (OLR). The Antarctic is known for its near‐surface temperature inversion, where the addition of GHGs can lead to increased OLR during all but the winter months. These changes in OLR, however, are unable to explain modeled surface warming due to changes in GHGs across central Antarctica. Here we develop a simple explanation showing why adding always warms the surface, and allowing an estimation of the change in surface temperature due to a change in concentration based on the initial surface temperature. We develop a radiative‐advective‐turbulent single‐column model based on observed temperatures for explicit comparisons between our estimations and model equilibrium behavior. We confirm that Antarctic surface temperatures warm as GHG concentrations increase, and find that this response is best explained through the surface greenhouse effect rather than that of the top of atmosphere (TOA).
Coupled Climate Responses to Recent Australian Wildfire and COVID‐19 Emissions Anomalies Estimated in CESM2
Authors: Fasullo J. T. , Rosenbloom N. , Buchholz R. R. , Danabasoglu G. , Lawrence D. M. , Lamarque J.‐F.
Published: July 2021

Multiple 50‐member ensemble simulations with the Community Earth System Model version 2 are performed to estimate the coupled climate responses to the 2019–2020 Australian wildfires and COVID‐19 pandemic policies. The climate response to the pandemic is found to be weak generally, with global‐mean net top‐of‐atmosphere radiative anomalies of +0.23 ± 0.14 W m−2 driving a gradual global warming of 0.05 ± 0.04 K by the end of 2022. While regional anomalies are detectable in aerosol burdens and clear‐sky radiation, few significant anomalies exist in other fields due to internal variability. In contrast, the simulated response to Australian wildfires is a strong and rapid cooling, peaking globally at −0.95 ± 0.15 W m−2 in late 2019 with a global cooling of 0.06 ± 0.04 K by mid‐2020. Transport of fire aerosols throughout the Southern Hemisphere increases albedo and drives a strong interhemispheric radiative contrast, with simulated responses that are consistent generally with those to a Southern Hemisphere volcanic eruption.
6,000‐Year Reconstruction of Modified Circumpolar Deep Water Intrusion and Its Effects on Sea Ice and Penguin in the Ross Sea
Authors: Xu Q. B. , Yang L. J. , Gao Y. S. , Sun L. G. , Xie Z. Q.
Published: July 2021

The Ross Sea has the world's largest marine protected area. Modified Circumpolar Deep Water (MCDW) has significant effects on physical and biological processes in the Ross Sea. Totally 13 penguin ornithogenic sediment profiles were collected from Inexpressible Island, Ross Sea, and the Cd/P ratios were used as a proxy of MCDW intrusion, enabling to reconstruct the variability of MCDW intrusion into the Ross Sea during the past 6,000 years. During the intervals of ∼0.7–1.6 and ∼2.8–6.0 kyr BP, enhanced MCDW intrusion increased the heat supply which warmed the surface water and reduced the coastal sea ice concentration. By contrast, reduced MCDW intrusion during ∼1.6–2.8 kyr BP caused a decrease in the penguin population via restricting food supply and/or increasing sea ice concentration. Thus, changes in MCDW were responsible for driving millennial changes in sea ice and penguin population in the Ross Sea.
ARTEMIS Observations of Lunar Nightside Surface Potentials in the Magnetotail Lobes: Evidence for Micrometeoroid Impact Charging
Authors: Poppe A. R. , Xu S. , Liuzzo L. , Halekas J. S. , Harada Y.
Published: July 2021

The Acceleration, Reconnection, Turbulence, and Electrodynamics of the Moon's Interaction with the Sun mission observes anomalously low lunar nightside surface potentials while in the terrestrial magnetotail lobes. Observed potential magnitudes are between 15% and 40% that expected from ambient tail‐plasma charging, are highly concentrated on the lunar dawn hemisphere, and are correlated with low ambient plasma densities. These characteristics suggest an additional, highly asymmetric source of cold current to the lunar surface. Given these characteristics, we identify micrometeoroid impact‐generated plasmas as the likely source of this additional current. Using laboratory measurements of impact charge yields and models of the micrometeoroid flux to the Moon constrained by in situ measurements, we show that currents due to micrometeoroid impact plasmas have the necessary magnitude and spatial distribution to explain the observed surface potential measurements. Micrometeoroid impact‐generated currents may contribute to surface charging at airless bodies with intense micrometeoroid bombardment and/or low ambient plasma densities.
Physical Origin of Recurrent Magnetic Dipolarization Events in Saturn’s Equatorial Plasma Sheet
Authors: Cowley S. W. H. , Provan G.
Published: July 2021

We consider the physical origin of reconnection‐related events in Saturn’s equatorial current sheet revealed by Cassini, specifically the dipolarization events discussed by Yao et al. (https://doi.org/10.1029/2018JA025837) that recur close to the ∼10.7 h planetary period oscillation (PPO) period. We argue that Yao et al.’s preferred recurrence explanation in terms of complete rotations of dipolarized field/current structures around the planet at close to the PPO period is highly implausible. All‐mission observations of ion flows at relevant radial ranges ∼20–30 Saturn radii are essentially invariably sub‐corotational, including reconnection‐related hot ion injections, thus requiring implausible structure propagation at significant speeds through the plasma. We further show their assertion that the nightside events occur at PPO phases unfavorable for reconnection is incorrect. These events instead occur under PPO conditions associated with outward radial plasma displacement and/or a thinning plasma sheet with falling colatitudinal field, shown previously to be optimal for modulated reconnection bursts leading to dipolarizations and plasmoids. We instead suggest these events are related to well‐documented Vasyliunas cycle disturbances, when two reconnection episodes happen to be triggered at similar favorable PPO phases on successive PPO cycles. Yao et al.’s dayside events do occur at phases unfavorable for recurrent reconnection, but may then simply be an effect of periodic field/plasma modulations during the regular PPO cycle combined with subcorotating small‐scale structures often present in the plasma sheet. Both dayside and nightside events can thus be understood within existing knowledge of PPO modulations of the structure and dynamics of Saturn’s equatorial current sheet.
Impacts of the Eruption of Mount Pinatubo on Surface Temperatures and Precipitation Forecasts With the NASA GEOS Subseasonal‐to‐Seasonal System
Authors: Aquila Valentina , Baldwin Colleen , Mukherjee Nikita , Hackert Eric , Li Feng , Marshak Jelena , Molod Andrea , Pawson Steven
Published: July 2021

A contemporary seasonal forecasting system is used to study the impacts of a volcanic sulfate injection into the stratosphere on the seasonal forecasts for surface temperatures, the El Niño Southern Oscillation (ENSO), and precipitation. The focus is a case study of the June 1991 eruption of Mt. Pinatubo, Philippines and the period from July 1991 to February 1992. Version 2 of the Goddard Earth Observing System (GEOS) subseasonal‐to‐seasonal (S2S) forecasting system is used in this study. GEOS‐S2S includes the GOddard Chemistry, Aerosols, Radiation and Transport (GOCART) aerosol module, which allows to prognostically simulate aerosol distributions. GOCART is coupled to the radiation and cloud modules to include the impact of the eruption on forecasted radiation and precipitation. The coupled GEOS‐S2S system was initialized in May 1991 with fields based on observations to produce ten‐member 9‐month forecasts with and without the volcanic sulfur injection. The results of these ensemble experiments demonstrate that including Mt. Pinatubo in seasonal forecasts would improve the forecasts of the 1991–1992 global mean temperature and precipitation but worsen the forecast of ENSO by strengthening of El Niño beyond what showed in observations. Most significant changes in the forecasts of temperatures and precipitation are limited to the tropics. The only land area where the inclusion of Pinatubo significantly lowered the forecasted precipitation is tropical Africa.
Experimental Investigation of Physical Leaky Barrier Design Implications on Juvenile Rainbow Trout (Oncorhynchus mykiss) Movement
Authors: Müller Stephanie , Wilson Catherine A. M. E. , Ouro Pablo , Cable Joanne
Published: July 2021

Rivers have been subject to the construction of numerous small‐scale anthropogenic structures, causing the alteration and fragmentation of habitats. Despite their impact on fish habitat selection, migration, and swimming performance, more hydraulic structures are being added to riverine systems. These mainly have the purpose of harnessing renewable energy or mitigating the impact of flooding, as in the case of leaky barriers that are widely used for natural flood management. By providing a sustainable and cost‐effective supplement to traditional hard engineering flood risk management methods, these channel‐spanning wooden barriers are constructed using sustainable, local materials, intended to slow down surface water and groundwater flow, reduce flood peaks, and attenuate the flow reaching downstream communities. Despite their increasing popularity, little is known about the design implications on fish movement or hydrodynamics. Using scaled laboratory flume experiments we investigate how the physical design of four leaky barriers varying in porosity, length, provision of overhead cover, and color, impact on fish movement and spatial usage, and the channel hydrodynamics. Our fish behavioral analysis reveals that juvenile rainbow trout (Oncorhynchus mykiss) movement reduces with barrier presence. Upstream passage increases with barrier color but not cover, for shorter rather than longer leaky barriers, and for a non‐porous barrier compared to its porous counterpart. Barrier‐specific flow alterations appear to play a secondary role compared to barrier color. Our study showed that physical barrier design and leaky barrier presence alter fish movement, and therefore care needs to be taken during the design of such natural flood management structures.
DiLFM: an artifact-suppressed and noise-robust light-field microscopy through dictionary learning
Authors: Zhang Yuanlong , Xiong Bo , Zhang Yi , Lu Zhi , Wu Jiamin , Dai Qionghai
Published: July 2021

Light field microscopy (LFM) has been widely used for recording 3D biological dynamics at camera frame rate. However, LFM suffers from artifact contaminations due to the illness of the reconstruction problem via naïve Richardson–Lucy (RL) deconvolution. Moreover, the performance of LFM significantly dropped in low-light conditions due to the absence of sample priors. In this paper, we thoroughly analyze different kinds of artifacts and present a new LFM technique termed dictionary LFM (DiLFM) that substantially suppresses various kinds of reconstruction artifacts and improves the noise robustness with an over-complete dictionary. We demonstrate artifact-suppressed reconstructions in scattering samples such as Drosophila embryos and brains. Furthermore, we show our DiLFM can achieve robust blood cell counting in noisy conditions by imaging blood cell dynamic at 100 Hz and unveil more neurons in whole-brain calcium recording of zebrafish with low illumination power in vivo.
Photonic-dispersion neural networks for inverse scattering problems
Authors: Li Tongyu , Chen Ang , Fan Lingjie , Zheng Minjia , Wang Jiajun , Lu Guopeng , Zhao Maoxiong , Cheng Xinbin , Li Wei , Liu Xiaohan , Yin Haiwei , Shi Lei , Zi Jian
Published: July 2021

Inferring the properties of a scattering objective by analyzing the optical far-field responses within the framework of inverse problems is of great practical significance. However, it still faces major challenges when the parameter range is growing and involves inevitable experimental noises. Here, we propose a solving strategy containing robust neural-networks-based algorithms and informative photonic dispersions to overcome such challenges for a sort of inverse scattering problem—reconstructing grating profiles. Using two typical neural networks, forward-mapping type and inverse-mapping type, we reconstruct grating profiles whose geometric features span hundreds of nanometers with nanometric sensitivity and several seconds of time consumption. A forward-mapping neural network with a parameters-to-point architecture especially stands out in generating analytical photonic dispersions accurately, featured by sharp Fano-shaped spectra. Meanwhile, to implement the strategy experimentally, a Fourier-optics-based angle-resolved imaging spectroscopy with an all-fixed light path is developed to measure the dispersions by a single shot, acquiring adequate information. Our forward-mapping algorithm can enable real-time comparisons between robust predictions and experimental data with actual noises, showing an excellent linear correlation (R2 > 0.982) with the measurements of atomic force microscopy. Our work provides a new strategy for reconstructing grating profiles in inverse scattering problems.
CRISPR screening identifies CDK12 as a conservative vulnerability of prostate cancer
Authors: Lei Hanqi , Wang Zifeng , Jiang Donggen , Liu Fang , Liu Meiling , Lei Xinxing , Yang Yafei , He Bin , Yan Min , Huang Hai , Liu Quentin , Pang Jun
Published: July 2021

Androgen receptor (AR) signaling inhibitors provide limited survival benefits to patients with prostate cancer (PCa), and worse, few feasible genomic lesions restrict targeted treatment to PCa. Thus, a better understanding of the critical dependencies of PCa may enable more feasible therapeutic approaches to the dilemma. We performed a kinome-scale CRISPR/Cas9 screen and identified cyclin-dependent kinase 12 (CDK12) as being conservatively required for PCa cell survival. Suppression of CDK12 by the covalent inhibitor THZ531 led to an obvious anti-PCa effect. Mechanistically, THZ531 downregulated AR signaling and preferentially repressed a distinct class of CDK12 inhibition-sensitive transcripts (CDK12-ISTs), including prostate lineage-specific genes, and contributed to cellular survival processes. Integration of the super-enhancer (SE) landscape and CDK12-ISTs indicated a group of potential PCa oncogenes, further conferring the sensitivity of PCa cells to CDK12 inhibition. Importantly, THZ531 strikingly synergized with multiple AR antagonists. The synergistic effect may be driven by attenuated H3K27ac signaling on AR targets and an intensive SE-associated apoptosis pathway. In conclusion, we highlight the validity of CDK12 as a druggable target in PCa. The synergy of THZ531 and AR antagonists suggests a potential combination therapy for PCa.
Dynamic BH3 profiling identifies active BH3 mimetic combinations in non-small cell lung cancer
Authors: Potter Danielle S. , Du Ruochen , Bhola Patrick , Bueno Raphael , Letai Anthony
Published: July 2021

Conventional chemotherapy is still of great utility in oncology and rationally constructing combinations with it remains a top priority. Drug-induced mitochondrial apoptotic priming, measured by dynamic BH3 profiling (DBP), has been shown in multiple cancers to identify drugs that promote apoptosis in vivo. We therefore hypothesized that we could use DBP to identify drugs that would render cancers more sensitive to conventional chemotherapy. We found that targeted agents that increased priming of non-small cell lung cancer (NSCLC) tumor cells resulted in increased sensitivity to chemotherapy in vitro. To assess whether targeted agents that increase priming might enhance the efficacy of cytotoxic agents in vivo as well, we carried out an efficacy study in a PC9 xenograft mouse model. The BH3 mimetic navitoclax, which antagonizes BCL-xL, BCL-w, and BCL-2, consistently primed NSCLC tumors in vitro and in vivo. The BH3 mimetic venetoclax, which electively antagonizes BCL-2, did not. Combining navitoclax with etoposide significantly reduced tumor burden compared to either single agent, while adding venetoclax to etoposide had no effect on tumor burden. Next, we assessed priming of primary patient NSCLC tumor cells on drugs from a clinically relevant oncology combination screen (CROCS). Results confirmed for the first time the utility of BCL-xL inhibition by navitoclax in priming primary NSCLC tumor cells and identified combinations that primed further. This is a demonstration of the principle that DBP can be used as a functional precision medicine tool to rationally construct combination drug regimens that include BH3 mimetics in solid tumors like NSCLC.
Retinoblastoma from human stem cell-derived retinal organoids
Authors: Norrie Jackie L. , Nityanandam Anjana , Lai Karen , Chen Xiang , Wilson Matthew , Stewart Elizabeth , Griffiths Lyra , Jin Hongjian , Wu Gang , Orr Brent , Tran Quynh , Allen Sariah , Reilly Colleen , Zhou Xin , Zhang Jiakun , Newman Kyle , Johnson Dianna , Brennan Rachel , Dyer Michael A.
Published: July 2021

Retinoblastoma is a childhood cancer of the developing retina that initiates with biallelic inactivation of the RB1 gene. Children with germline mutations in RB1 have a high likelihood of developing retinoblastoma and other malignancies later in life. Genetically engineered mouse models of retinoblastoma share some similarities with human retinoblastoma but there are differences in their cellular differentiation. To develop a laboratory model of human retinoblastoma formation, we make induced pluripotent stem cells (iPSCs) from 15 participants with germline RB1 mutations. Each of the stem cell lines is validated, characterized and then differentiated into retina using a 3-dimensional organoid culture system. After 45 days in culture, the retinal organoids are dissociated and injected into the vitreous of eyes of immunocompromised mice to support retinoblastoma tumor growth. Retinoblastomas formed from retinal organoids made from patient-derived iPSCs have molecular, cellular and genomic features indistinguishable from human retinoblastomas. This model of human cancer based on patient-derived iPSCs with germline cancer predisposing mutations provides valuable insights into the cellular origins of this debilitating childhood disease as well as the mechanism of tumorigenesis following RB1 gene inactivation.
Chloride sensing by WNK1 regulates NLRP3 inflammasome activation and pyroptosis
Authors: Mayes-Hopfinger Lindsey , Enache Aura , Xie Jian , Huang Chou-Long , Köchl Robert , Tybulewicz Victor L. J. , Fernandes-Alnemri Teresa , Alnemri Emad S.
Published: July 2021

The NLRP3 inflammasome mediates the production of proinflammatory cytokines and initiates inflammatory cell death. Although NLRP3 is essential for innate immunity, aberrant NLRP3 inflammasome activation contributes to a wide variety of inflammatory diseases. Understanding the pathways that control NLRP3 activation will help develop strategies to treat these diseases. Here we identify WNK1 as a negative regulator of the NLRP3 inflammasome. Macrophages deficient in WNK1 protein or kinase activity have increased NLRP3 activation and pyroptosis compared with control macrophages. Mice with conditional knockout of WNK1 in macrophages have increased IL-1β production in response to NLRP3 stimulation compared with control mice. Mechanistically, WNK1 tempers NLRP3 activation by balancing intracellular Cl– and K+ concentrations during NLRP3 activation. Collectively, this work shows that the WNK1 pathway has a critical function in suppressing NLRP3 activation and suggests that pharmacological inhibition of this pathway to treat hypertension might have negative clinical implications.
Extracellular vesicles and exosomes generated from cystic renal epithelial cells promote cyst growth in autosomal dominant polycystic kidney disease
Authors: Ding Hao , Li Linda Xiaoyan , Harris Peter C. , Yang Junwei , Li Xiaogang
Published: July 2021

Autosomal dominant polycystic kidney disease (ADPKD) is caused by germline mutations of PKD1 or PKD2 on one allele and a somatic mutation inactivating the remaining normal allele. However, if and how null ADPKD gene renal epithelial cells affect the biology and function of neighboring cells, including heterozygous renal epithelial cells, fibroblasts and macrophages during cyst initiation and expansion remains unknown. Here we address this question with a “cystic extracellular vesicles/exosomes theory”. We show that cystic cell derived extracellular vesicles and urinary exosomes derived from ADPKD patients promote cyst growth in Pkd1 mutant kidneys and in 3D cultures. This is achieved by: 1) downregulation of Pkd1 gene expression and upregulation of specific miRNAs, resulting in the activation of PKD associated signaling pathways in recipient renal epithelial cells and tissues; 2) the activation of fibroblasts; and 3) the induction of cytokine expression and the recruitment of macrophages to increase renal inflammation in cystic kidneys. Inhibition of exosome biogenesis/release with GW4869 significantly delays cyst growth in aggressive and milder ADPKD mouse models, suggesting that targeting exosome secretion has therapeutic potential for ADPKD.
Single-cell transcriptome of bronchoalveolar lavage fluid reveals sequential change of macrophages during SARS-CoV-2 infection in ferrets
Authors: Lee Jeong Seok , Koh June-Young , Yi Kijong , Kim Young-Il , Park Su-Jin , Kim Eun-Ha , Kim Se-Mi , Park Sung Ho , Ju Young Seok , Choi Young Ki , Park Su-Hyung
Published: July 2021

Few studies have used a longitudinal approach to describe the immune response to SARS-CoV-2 infection. Here, we perform single-cell RNA sequencing of bronchoalveolar lavage fluid cells longitudinally obtained from SARS-CoV-2-infected ferrets. Landscape analysis of the lung immune microenvironment shows distinct changes in cell proportions and characteristics compared to uninfected control, at 2 and 5 days post-infection (dpi). Macrophages are classified into 10 distinct subpopulations with transcriptome changes among monocyte-derived infiltrating macrophages and differentiated M1/M2 macrophages, notably at 2 dpi. Moreover, trajectory analysis reveals gene expression changes from monocyte-derived infiltrating macrophages toward M1 or M2 macrophages and identifies a macrophage subpopulation that has rapidly undergone SARS-CoV-2-mediated activation of inflammatory responses. Finally, we find that M1 or M2 macrophages show distinct patterns of gene modules downregulated by immune-modulatory drugs. Overall, these results elucidate fundamental aspects of the immune response dynamics provoked by SARS-CoV-2 infection.
Disruption of NIPBL/Scc2 in Cornelia de Lange Syndrome provokes cohesin genome-wide redistribution with an impact in the transcriptome
Authors: Garcia Patricia , Fernandez-Hernandez Rita , Cuadrado Ana , Coca Ignacio , Gomez Antonio , Maqueda Maria , Latorre-Pellicer Ana , Puisac Beatriz , Ramos Feliciano J. , Sandoval Juan , Esteller Manel , Mosquera Jose Luis , Rodriguez Jairo , Pié J. , Losada Ana , Queralt Ethel
Published: July 2021

Cornelia de Lange syndrome (CdLS) is a rare disease affecting multiple organs and systems during development. Mutations in the cohesin loader, NIPBL/Scc2, were first described and are the most frequent in clinically diagnosed CdLS patients. The molecular mechanisms driving CdLS phenotypes are not understood. In addition to its canonical role in sister chromatid cohesion, cohesin is implicated in the spatial organization of the genome. Here, we investigate the transcriptome of CdLS patient-derived primary fibroblasts and observe the downregulation of genes involved in development and system skeletal organization, providing a link to the developmental alterations and limb abnormalities characteristic of CdLS patients. Genome-wide distribution studies demonstrate a global reduction of NIPBL at the NIPBL-associated high GC content regions in CdLS-derived cells. In addition, cohesin accumulates at NIPBL-occupied sites at CpG islands potentially due to reduced cohesin translocation along chromosomes, and fewer cohesin peaks colocalize with CTCF.
A distinct assembly pathway of the human 39S late pre-mitoribosome
Authors: Cheng Jingdong , Berninghausen Otto , Beckmann Roland
Published: July 2021

Assembly of the mitoribosome is largely enigmatic and involves numerous assembly factors. Little is known about their function and the architectural transitions of the pre-ribosomal intermediates. Here, we solve cryo-EM structures of the human 39S large subunit pre-ribosomes, representing five distinct late states. Besides the MALSU1 complex used as bait for affinity purification, we identify several assembly factors, including the DDX28 helicase, MRM3, GTPBP10 and the NSUN4-mTERF4 complex, all of which keep the 16S rRNA in immature conformations. The late transitions mainly involve rRNA domains IV and V, which form the central protuberance, the intersubunit side and the peptidyltransferase center of the 39S subunit. Unexpectedly, we find deacylated tRNA in the ribosomal E-site, suggesting a role in 39S assembly. Taken together, our study provides an architectural inventory of the distinct late assembly phase of the human 39S mitoribosome.
In-situ nanospectroscopic imaging of plasmon-induced two-dimensional [4+4]-cycloaddition polymerization on Au(111)
Authors: Shao Feng , Wang Wei , Yang Weimin , Yang Zhilin , Zhang Yao , Lan Jinggang , Dieter Schlüter A. , Zenobi Renato
Published: July 2021

Plasmon-induced chemical reactions (PICRs) have recently become promising approaches for highly efficient light-chemical energy conversion. However, an in-depth understanding of their mechanisms at the nanoscale still remains challenging. Here, we present an in-situ investigation by tip-enhanced Raman spectroscopy (TERS) imaging of the plasmon-induced [4+4]-cycloaddition polymerization within anthracene-based monomer monolayers physisorbed on Au(111), and complement the experimental results with density functional theory (DFT) calculations. This two-dimensional (2D) polymerization can be flexibly triggered and manipulated by the hot carriers, and be monitored simultaneously by TERS in real time and space. TERS imaging provides direct evidence for covalent bond formation with ca. 3.7 nm spatial resolution under ambient conditions. Combined with DFT calculations, the TERS results demonstrate that the lateral polymerization on Au(111) occurs by a hot electron tunneling mechanism, and crosslinks form via a self-stimulating growth mechanism. We show that TERS is promising to be plasmon-induced nanolithography for organic 2D materials.
Unfolding the multiscale structure of networks with dynamical Ollivier-Ricci curvature
Authors: Gosztolai Adam , Arnaudon Alexis
Published: July 2021

Describing networks geometrically through low-dimensional latent metric spaces has helped design efficient learning algorithms, unveil network symmetries and study dynamical network processes. However, latent space embeddings are limited to specific classes of networks because incompatible metric spaces generally result in information loss. Here, we study arbitrary networks geometrically by defining a dynamic edge curvature measuring the similarity between pairs of dynamical network processes seeded at nearby nodes. We show that the evolution of the curvature distribution exhibits gaps at characteristic timescales indicating bottleneck-edges that limit information spreading. Importantly, curvature gaps are robust to large fluctuations in node degrees, encoding communities until the phase transition of detectability, where spectral and node-clustering methods fail. Using this insight, we derive geometric modularity to find multiscale communities based on deviations from constant network curvature in generative and real-world networks, significantly outperforming most previous methods. Our work suggests using network geometry for studying and controlling the structure of and information spreading on networks.
Vaccination as a preventative measure contributing to immune fitness
Authors: Laupèze Béatrice , Del Giudice Giuseppe , Doherty Mark T. , Van der Most Robbert
Published: July 2021

The primary goal of vaccination is the prevention of pathogen-specific infection. The indirect consequences may include maintenance of homeostasis through prevention of infection-induced complications; trained immunity that re-programs innate cells to respond more efficiently to later, unrelated threats; slowing or reversing immune senescence by altering the epigenetic clock, and leveraging the pool of memory B and T cells to improve responses to new infections. Vaccines may exploit the plasticity of the immune system to drive longer-term immune responses that promote health at a broader level than just the prevention of single, specific infections. In this perspective, we discuss the concept of “immune fitness” and how to potentially build a resilient immune system that could contribute to better health. We argue that vaccines may contribute positively to immune fitness in ways that are only beginning to be understood, and that life-course vaccination is a fundamental tool for achieving healthy aging.
Fast and scalable likelihood maximization for Exponential Random Graph Models with local constraints
Authors: Vallarano Nicolò , Bruno Matteo , Marchese Emiliano , Trapani Giuseppe , Saracco Fabio , Cimini Giulio , Zanon Mario , Squartini Tiziano
Published: July 2021

Exponential Random Graph Models (ERGMs) have gained increasing popularity over the years. Rooted into statistical physics, the ERGMs framework has been successfully employed for reconstructing networks, detecting statistically significant patterns in graphs, counting networked configurations with given properties. From a technical point of view, the ERGMs workflow is defined by two subsequent optimization steps: the first one concerns the maximization of Shannon entropy and leads to identify the functional form of the ensemble probability distribution that is maximally non-committal with respect to the missing information; the second one concerns the maximization of the likelihood function induced by this probability distribution and leads to its numerical determination. This second step translates into the resolution of a system of O(N) non-linear, coupled equations (with N being the total number of nodes of the network under analysis), a problem that is affected by three main issues, i.e. accuracy, speed and scalability. The present paper aims at addressing these problems by comparing the performance of three algorithms (i.e. Newton’s method, a quasi-Newton method and a recently-proposed fixed-point recipe) in solving several ERGMs, defined by binary and weighted constraints in both a directed and an undirected fashion. While Newton’s method performs best for relatively little networks, the fixed-point recipe is to be preferred when large configurations are considered, as it ensures convergence to the solution within seconds for networks with hundreds of thousands of nodes (e.g. the Internet, Bitcoin). We attach to the paper a Python code implementing the three aforementioned algorithms on all the ERGMs considered in the present work.
Anisotropic chemical expansion due to oxygen vacancies in perovskite films
Authors: Tyunina M. , Pacherova O. , Kocourek T. , Dejneka A.
Published: July 2021

In scientifically intriguing and technologically important multifunctional ABO3 perovskite oxides, oxygen vacancies are most common defects. They cause lattice expansion and can alter the key functional properties. Here, it is demonstrated that contrary to weak isotropic expansion in bulk samples, oxygen vacancies produce strong anisotropic strain in epitaxial thin films. This anisotropic chemical strain is explained by preferential orientation of elastic dipoles of the vacancies. Elastic interaction of the dipoles with substrate-imposed misfit strain is suggested to define the dipolar orientation. Such elastic behavior of oxygen vacancies is anticipated to be general for perovskite films and have critical impacts on the film synthesis and response functions.