bluuebunny/crossref_metadata_2025 huggingface dataset:
A Sandbox Approach to Regulating High-Risk Artificial Intelligence Applications
Authors: Truby Jon , Brown Rafael Dean , Ibrahim Imad Antoine , Parellada Oriol Caudevilla
Published: November 2021

This paper argues for a sandbox approach to regulating artificial intelligence (AI) to complement a strict liability regime. The authors argue that sandbox regulation is an appropriate complement to a strict liability approach, given the need to maintain a balance between a regulatory approach that aims to protect people and society on the one hand and to foster innovation due to the constant and rapid developments in the AI field on the other. The authors analyse the benefits of sandbox regulation when used as a supplement to a strict liability regime, which by itself creates a chilling effect on AI innovation, especially for small and medium-sized enterprises. The authors propose a regulatory safe space in the AI sector through sandbox regulation, an idea already embraced by European Union regulators and where AI products and services can be tested within safeguards.
Limit theorems for numbers of multiple returns in non-conventional arrays
Authors: KIFER YURI
Published: November 2021

For a
$\psi $
-mixing process

$\xi _0,\xi _1,\xi _2,\ldots $
we consider the number

${\mathcal N}_N$
of multiple returns

$\{\xi _{q_{i,N}(n)}\in {\Gamma }_N,\, i=1,\ldots ,\ell \}$
to a set

${\Gamma }_N$
for n until either a fixed number N or until the moment

$\tau _N$
when another multiple return

$\{\xi _{q_{i,N}(n)}\in {\Delta }_N,\, i=1,\ldots ,\ell \}$
, takes place for the first time where

${\Gamma }_N\cap {\Delta }_N=\emptyset $
and

$q_{i,N}$
,

$i=1,\ldots ,\ell $
are certain functions of n taking on non-negative integer values when n runs from 0 to N. The dependence of

$q_{i,N}(n)$
on both n and N is the main novelty of the paper. Under some restrictions on the functions

$q_{i,N}$
we obtain Poisson distributions limits of

${\mathcal N}_N$
when counting is until N as

$N\to \infty $
and geometric distributions limits when counting is until

$\tau _N$
as

$N\to \infty $
. We obtain also similar results in the dynamical systems setup considering a

$\psi $
-mixing shift T on a sequence space

${\Omega }$
and studying the number of multiple returns

$\{ T^{q_{i,N}(n)}{\omega }\in A^a_n,\, i=1,\ldots ,\ell \}$
until the first occurrence of another multiple return

$\{ T^{q_{i,N}(n)}{\omega }\in A^b_m,\, i=1,\ldots ,\ell \}$
where

$A^a_n,\, A_m^b$
are cylinder sets of length n and m constructed by sequences

$a,b\in {\Omega }$
, respectively, and chosen so that their probabilities have the same order.
Effects of the Dietary Approaches to Stop Hypertension (DASH) diet on clinical, quality of life and mental health outcomes in women with migraine: a randomised controlled trial
Authors: Arab Arman , Khorvash Fariborz , Kazemi Maryam , Heidari Zahra , Askari Gholamreza
Published: November 2021

The relationship between the Dietary Approaches to Stop Hypertension (DASH) diet and clinical, quality of life and mental health outcomes in migraine is unknown. To address this knowledge gap, we conducted a parallel-group, randomised controlled trial to evaluate the effect of the DASH diet on these health outcomes in women with migraine. Of 102 eligible women (20–50 years), fifty one randomised to the DASH and fifty one to the usual dietary advice (control) groups completed a 12-week intervention. The DASH diet was designed using a 7-d menu cycle to provide 15–20 % of total daily energy requirements from proteins, 25–30 % from fats and 55–60 % from carbohydrates. Dietary records and serum vitamin C levels were used to assess women’s compliance with the DASH diet. The clinical symptoms of migraine (i.e., frequency, duration and severity) and quality of life and mental health (i.e., depression, anxiety and stress) outcomes were assessed in groups pre-and post-intervention. We observed greater decreases in the frequency (–3·00 v. −1·40, P = 0·025) and severity (–1·76 v. −0·59, P < 0·001) of migraine in the DASH v. control group post-intervention. Similarly, the DASH group exhibited a tendency towards greater decreases in migraine duration (–0·58 v. −0·33 d, P = 0·053) and had lower scores of depression (–4·50 v. −2·73, P = 0·019) and stress (–5·84 v. −2·98, P = 0·011) v. controls. However, the quality of life and anxiety outcomes remained comparable in groups post-intervention. Together, evidence supports the benefits of the DASH diet on improving migraine health outcomes in reproductive-aged women. Further research is needed to confirm our findings.
Maternal energy-adjusted fatty acid intake during pregnancy and the development of cows’ milk allergy in the offspring
Authors: Lamminsalo Anni , Metsälä Johanna , Takkinen Hanna-Mari , Tapanainen Heli , Åkerlund Mari , Niinistö Sari , Toppari Jorma , Ilonen Jorma , Veijola Riitta , Knip Mikael , Kaila Minna , Virtanen Suvi M.
Published: November 2021

Cows’ milk allergy (CMA) is one of the earliest manifestations of allergic diseases. Early dietary factors, like maternal diet during pregnancy, may play a role in the development of allergic diseases in the offspring. We aimed to investigate the association between maternal intake of fatty acids during pregnancy and the risk of CMA in the offspring. Our study was conducted in a population-based cohort, the Finnish Type 1 Diabetes Prediction and Prevention study. We collected the maternal dietary data by a validated FFQ. We obtained the information on CMA in the study participants (n 448) from registers and from the parents. Dietary data and information on CMA were available for 4921 children. We used logistic regression in the analyses, and fatty acid intakes were energy adjusted. The maternal intake of SFA, MUFA, PUFA, n-3 PUFA, n-6 PUFA, trans fatty acids, ratio of n-3 PUFA to n-6 PUFA or ratio of linoleic acid to α-linolenic acid was not associated with the risk of CMA in the offspring when adjusted for perinatal factors, background factors, parental history of asthma or allergic rhinitis and infant animal contacts. The intake of α-linolenic acid was associated with a decreased risk (OR 0·72; 95 % CI 0·56, 0·93) of CMA in the offspring of mothers without a history of allergic rhinitis or asthma. In conclusion, the maternal intake of fatty acids during pregnancy is not associated with the risk of CMA in the offspring.
Heroines of Compassion and National Consolers: The Vietnam Women's Memorial Foundation and the Politics of Memory
Authors: ŻYCHLIŃSKA MONIKA
Published: November 2021

The article explores the politics of memory surrounding the Vietnam Women's Memorial Foundation (VWMF) – the grassroots organization that led the campaign to establish the Vietnam Women's Memorial in Washington, DC. Drawing on archival material, public statements, and interviews with members of the group, it demonstrates that the organization used the ambivalences and anxieties surrounding the Vietnam War's remembrance to argue for the commemoration of women who served during the war. The VWMF portrayed those women as heroines of compassion – similar to men in terms of courage and selflessness, but different because of their benignity and benevolence. However, the VWMF's depiction of women's compassion was informed by national loyalties and sentiments; it acknowledged Vietnamese civilians only as objects of American goodwill, and failed to engage with ethical questions concerning American intervention in Vietnam. By drawing attention to women's dedication and compassion, the organization carried out a symbolic rehabilitation of American actions in Vietnam. It contributed to solidifying the dominant mode of representing the Vietnam War through the lens of American military sacrifice and fostered an understanding of the Vietnam War as an American national event.
Social housing policy in the metropolitan area of Athens during the period 1922–2012
Authors: Myofa Nikolina
Published: November 2021

The aim of this survey is to present the Greek social housing model as a part of the southern European model through an Athenian case-study. Several characteristics of the Greek housing model are unique, and the analysis of the Athenian case provides an example that emphasizes those characteristics. Moreover, this survey intends to contribute to filling the gap in the relevant urban history and geography bibliography and, more specifically, to describe the Greek social housing model and the role of the city of Athens in the planning and distribution of social housing. This survey is based mainly on secondary data (literature review) but also on primary sources.
Characteristics of coronary flow velocity reserve on transthoracic Doppler echocardiography in patients with a history of Kawasaki disease
Authors: Tsuda Etsuko , Hashimoto Shuji
Published: November 2021

Whether the acute inflammation caused by Kawasaki disease will have an effect on the endothelial function of coronary arteries in the future is unknown.

Methods:

The coronary flow velocity reserve of the left anterior descending artery was examined by transthoracic Doppler echocardiography in 189 patients (male 125, female 64) with a history of Kawasaki disease and 10 volunteers (control). Their ages ranged from 6 to 40 years (median 22 years). The patients were divided into nine groups based on the left anterior descending artery lesions. The coronary flow velocity reserve was measured by intravenous administration of adenosine triphosphate (0.15 mg/kg/minute) while fasting. The coronary flow velocity reserve was calculated as the ratio of hyperaemic to basal mean diastolic flow velocities. The respective groups were as follows: control, no coronary artery lesions (n = 39), no coronary artery lesions in the right coronary artery (n = 29), regression (n = 11), aneurysm at the bifurcation of the left coronary artery (n = 26), aneurysm of the left anterior descending artery (n = 15), localised stenosis <75% (n = 12), localised stenosis ≥75% (n = 17), segmental stenosis (n = 5) and coronary artery bypass grafting (n = 36). One-factor ANOVA followed by Tukey’s test was used to compare the coronary flow velocity reserve among the groups.

Results:

The coronary flow velocity reserve was significantly lower in the localised stenosis ≥75%, segmental stenosis and coronary artery grafting groups than in the other groups (p < 0.05).

Conclusions:

The endothelial function in the epicoronary artery was preserved in patients with a history of Kawasaki disease and dilated coronary artery lesions.
Firms’ Employment Dynamics and the State of the Labor Market
Authors: Stadin Karolina
Published: November 2021

According to search and matching theory, a greater availability of unemployed workers should make it easier for a firm to fill a vacancy, but more vacancies at other firms should make recruitment more difficult. Simulating a theoretical model of a firm facing perfect competition in the product market and no convex adjustment costs (standard assumptions in the search and matching literature), I find that shocks to vacancies and unemployment lead to economically significant employment responses. Simulating a more realistic model with imperfect competition in the product market and convex adjustment costs, I find small employment effects of shocks to vacancies and unemployment. In particular, shocks to the number of unemployed seem to be unimportant. Estimating an employment equation on a panel of Swedish firms, I find that neither the number of unemployed workers nor the number of vacancies in the local labor market is important for firms’ employment decisions.
(How Much) Do Temporal Social Comparisons Matter?
Authors: Briker Roman , Walter Frank
Published: November 2021

Abstract. Moving beyond static perspectives in social comparison theory, Reh and colleagues (2018) provided initial evidence for the relevance of “temporal social comparisons” (i.e., comparing one’s own with others’ past development over time on a salient dimension). Although this research has received wide attention, the study illustrating the authors’ basic rationale (Study 1a) suffered from a small sample size, and its results did not reach conventional significance levels. Thus, we provide a direct, preregistered, and high-powered replication of this study. Our results corroborate the original conclusions, indicating that unfavorable temporal social comparisons evoke social undermining in more (but not less) competitive contexts. These findings reiterate the importance of a dynamic, temporal perspective for a complete understanding of social comparison processes.
Upper Troposphere Smoke Injection From Large Areal Fires
Authors: Redfern Stephanie , Lundquist Julie K. , Toon Owen B. , Muñoz‐Esparza Domingo , Bardeen Charles G. , Kosović Branko
Published: November 2021

Large areal fires, such as those ignited following a nuclear detonation, can inject smoke into the upper troposphere and lower stratosphere. Detailed fire simulations allow for assessment of how local weather interacts with these fires and affects smoke lofting. In this study, we employ the fire simulation package in the Weather Research and Forecasting (WRF‐Fire) model, Version 4.0.1, to explore how smoke lofting from a fire burning a homogeneous fuel bed changes with varying local winds, relative humidity, and atmospheric boundary‐layer stability for two different‐sized areal fires. The presence of moisture has the greatest influence on the results by raising the altitude of lofting, while faster wind speeds dampen lofting and lower the injection height. Stably stratified conditions inhibit plume propagation compared with neutrally stratified conditions, although the impact of stability is not as strong as that of moisture and winds. These findings highlight the importance of using an appropriate atmospheric profile when simulating large fires, as the local weather can have a meaningful influence on smoke lofting.
Assessing Net Growth of Phytoplankton Biomass on Hourly to Annual Time Scales Using the Geostationary Ocean Color Instrument
Authors: Salisbury Joseph E. , Jönsson Bror F. , Mannino Antonio , Kim Wonkook , Goes Joaquim I. , Choi Jin‐Yong , Concha Javier A.
Published: November 2021

Questions of whether diurnal changes in carbon fixation affect the global carbon budget cannot be answered using the present generation of polar orbiting ocean color sensors that can only retrieve one image daily. Here, we present novel satellite‐derived indices of chlorophyll‐based production based on the Geostationary Ocean Color Imager (GOCI), whose hourly imaging capability offer the potential for direct estimates of net phytoplankton growth over hourly to seasonal time scales. Our results reveal large variations in net chlorophyll growth in the GOCI study region, both over the day and between seasons. Hourly changes in chlorophyll concentration are highest during spring while growth rates show maxima during the winter. We show seasonal relationships between growth and photon flux. Our study suggests that Geostationary Ocean Color data can be used to constrain phytoplankton productivity on diurnal time scales and be an essential tool to better understand diurnal growth patterns over large spatial regions.
Understanding the Impact of Soil Moisture on Precipitation Under Different Climate and Meteorological Conditions: A Numerical Sensitivity Study Over the CONUS
Authors: Koukoula M. , Schwartz C. S. , Nikolopoulos E. I. , Anagnostou E. N.
Published: November 2021

Accurate quantitative precipitation forecasts are essential for water resources management, agriculture, and other applications. Soil moisture is among the most important boundary conditions affecting the overlying atmosphere. It can affect precipitation either directly via evapotranspiration, affecting the moisture supply to the atmosphere, or indirectly, changing sensible heat fluxes, which can affect the structure of storms and their associated distributions of precipitation. In this study we investigate the impact of soil moisture uncertainty on simulated precipitation over the conterminous United States (CONUS) with the Weather Research and Forecasting model. We selected two 30‐day periods to conduct simulation scenarios with 3‐km horizontal grid spacing over the CONUS, where the different simulations were identical except for their initial soil moisture and temperature states which were derived from three different products: Global Forecast System analyses, the National Center for Atmospheric Research (NCAR) continuously cycling ensemble Kalman filter (EnKF) data assimilation system, and the North American Land Data Assimilation System (NLDAS‐2). Results indicate different characteristics of the soil moisture–precipitation relationship during the cold and warm periods and under different climate and meteorological conditions. Better representation of initial soil moisture does not consistently provide an improvement in the simulation of precipitation. Our results suggest that soil moisture affects both the magnitude and spatial distribution of precipitation. The impact of soil moisture on precipitation is more pronounced under drier soil and strong thermal and weak synoptic forcing, while in areas with complex terrain the soil moisture‐precipitation coupling becomes weaker.
Tidal and Nontidal Marsh Restoration: A Trade‐Off Between Carbon Sequestration, Methane Emissions, and Soil Accretion
Authors: Arias‐Ortiz Ariane , Oikawa Patricia Y. , Carlin Joseph , Masqué Pere , Shahan Julie , Kanneg Sadie , Paytan Adina , Baldocchi Dennis D.
Published: November 2021

Support for coastal wetland restoration projects that consider carbon (C) storage as a climate mitigation benefit is growing as coastal wetlands are sites of substantial C sequestration. However, the climate footprint of wetland restoration remains controversial as wetlands can also be large sources of methane (CH4). We quantify the vertical fluxes of C in restored fresh and oligohaline nontidal wetlands with managed hydrology and a tidal euhaline marsh in California's San Francisco Bay‐Delta. We combine the use of eddy covariance atmospheric flux measurements with 210Pb‐derived soil C accumulation rates to quantify the C sequestration efficiency of restored wetlands and their associated climate mitigation service. Nontidal managed wetlands were the most efficient in burying C on‐site, with soil C accumulation rates as high as their net atmospheric C uptake (−280 ± 90 and −350 ± 150 g C m−2 yr−1). In contrast, the restored tidal wetland exhibited lower C burial rates over decadal timescales (70 ± 19 g C m−2 yr−1) that accounted for ∼13%–23% of its annual C uptake, suggesting that the remaining fraction is exported via lateral hydrologic flux. From an ecosystem radiative balance perspective, the restored tidal wetland showed a > 10 times higher CO2‐sequestration to CH4‐emission ratio than the nontidal managed wetlands. Thus overall, tidal wetland restoration resulted in a negative radiative forcing (cooling) through increased soil C accumulation, while nontidal wetland restoration led to an early positive forcing (warming) through increased CH4 emissions potentially lasting between 2.1 ± 2.0 to 8 ± 4 decades.
Explore Spatio‐Temporal Learning of Large Sample Hydrology Using Graph Neural Networks
Authors: Sun Alexander Y. , Jiang Peishi , Mudunuru Maruti K. , Chen Xingyuan
Published: November 2021

Streamflow forecasting over gauged and ungauged basins play a vital role in water resources planning, especially under the changing climate. Increased availability of large sample hydrology data sets, together with recent advances in deep learning techniques, has presented new opportunities to explore temporal and spatial patterns in hydrological signatures for improving streamflow forecasting. The purpose of this study is to adapt and benchmark several state‐of‐the‐art graph neural network (GNN) architectures, including ChebNet, Graph Convolutional Network (GCN), and GraphWaveNet, for end‐to‐end graph learning. We explicitly represent river basins as nodes in a graph, learn the spatiotemporal nodal dependencies, and then use the learned relations to predict streamflow simultaneously across all nodes in the graph. The efficacy of the developed GNN models is investigated using the Catchment Attributes and MEteorology for Large‐sample Studies (CAMELS) data set under two settings, fixed graph topology (transductive learning), and variable graph topology (inductive learning), with the latter applicable to prediction in ungauged basins (PUB). Results indicate that GNNs are generally robust and computationally efficient, achieving similar or better performance than a baseline model trained using the long short‐term memory (LSTM) network. Further analyses are conducted to interpret the graph learning process at the edge and node levels and to investigate the effect of different model configurations. We conclude that graph learning constitutes a viable machine learning‐based method for aggregating spatiotemporal information from a multitude of sources for streamflow forecasting
General dental practitioners' knowledge and opinions of snoring and sleep-related breathing disorders
Authors: Leigh Charlotte , Faigenblum Maurice , Fine Peter , Blizard Robert , Leung Albert
Published: November 2021

AimsThere is increasing recognition that sleep disturbances can affect lifestyle, economy and health. General dental practitioners (GDPs) can play a vital role in helping to identify at-risk patients through screening as well as aid in the management of these conditions. The aim of this study was to assess the knowledge of UK-based GDPs in relation to sleep-related breathing disorders (SRBDs).

Material and methodsA questionnaire was developed to assess GDPs' knowledge of SRBDs and their current practice in relation to the management of SRBDs, and identify the factors associated with improved knowledge and management. A volunteer sample was recruited from social media platforms and conference attendees.

ResultsIn total, 152 GDPs completed the questionnaire; 101 (66% [95% CI 59%,74%]) agreed that GDPs should ask their patients about sleep disorders, while only 82 (54% [95% CI 46%,62%]) confirmed that they actually asked their patients about the problem. On a 22-point knowledge scale, the mean score was 12.93 (95%CI 12.23, 13.63). Postgraduate education (F = 5.47; p = 0.001), increasing age (r = 0.23; p = 0.005) and GDP workplace (F = 4.98; p = 0.008) contributed to a higher knowledge score. GDPs were strongly in favour of having more information (N = 141; 93% [95% CI 87%,97%]).

ConclusionAlthough GDPs' knowledge of SRBDs was better than anticipated, they clearly felt a need for further information and training. There is a compelling case to include this subject in the undergraduate dental curriculum.
Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis
Authors: Mukherjee Amitava , Epperly Michael W. , Shields Donna , Hou Wen , Fisher Renee , Hamade Diala , Wang Hong , Saiful Huq M. , Bao Riyue , Tabib Tracy , Monier Daisy , Watkins Simon , Calderon Michael , Greenberger Joel S.
Published: November 2021

The role of cellular senescence in radiation-induced pulmonary fibrosis (RIPF) and the underlying mechanisms are unknown. We isolated radiation-induced senescent tdTOMp16 positive mesenchymal stem cells, established their absence of cell division, then measured levels of irradiation-induced expression of biomarkers of senescence by RNA-seq analysis. We identified a Log2 6.17-fold upregulation of tyrosine kinase Fgr, which was a potent inducer of biomarkers of fibrosis in target cells in non-contact co-cultures. Inhibition of Fgr by shRNA knockdown did not block radiation-induced senescence in vitro; however, both shRNA knockdown, or addition of a specific small-molecule inhibitor of Fgr, TL02-59, abrogated senescent cell induction of profibrotic genes in transwell-separated target cells. Single-cell RNA-seq (scRNAseq) analysis of mouse lungs at day 150 after 20 Gy thoracic irradiation revealed upregulation of Fgr in senescent neutrophils, and macrophages before detection of lung fibrosis. Thus, upregulated Fgr in radiation-induced senescent cells mediates RIPF and is a potential therapeutic target for the prevention of this radiation late effect.
Spectral analysis of climate dynamics with operator-theoretic approaches
Authors: Froyland Gary , Giannakis Dimitrios , Lintner Benjamin R. , Pike Maxwell , Slawinska Joanna
Published: November 2021

The Earth’s climate system is a classical example of a multiscale, multiphysics dynamical system with an extremely large number of active degrees of freedom, exhibiting variability on scales ranging from micrometers and seconds in cloud microphysics, to thousands of kilometers and centuries in ocean dynamics. Yet, despite this dynamical complexity, climate dynamics is known to exhibit coherent modes of variability. A primary example is the El Niño Southern Oscillation (ENSO), the dominant mode of interannual (3–5 yr) variability in the climate system. The objective and robust characterization of this and other important phenomena presents a long-standing challenge in Earth system science, the resolution of which would lead to improved scientific understanding and prediction of climate dynamics, as well as assessment of their impacts on human and natural systems. Here, we show that the spectral theory of dynamical systems, combined with techniques from data science, provides an effective means for extracting coherent modes of climate variability from high-dimensional model and observational data, requiring no frequency prefiltering, but recovering multiple timescales and their interactions. Lifecycle composites of ENSO are shown to improve upon results from conventional indices in terms of dynamical consistency and physical interpretability. In addition, the role of combination modes between ENSO and the annual cycle in ENSO diversity is elucidated.
Mesmerize is a dynamically adaptable user-friendly analysis platform for 2D and 3D calcium imaging data
Authors: Kolar Kushal , Dondorp Daniel , Zwiggelaar Jordi Cornelis , Høyer Jørgen , Chatzigeorgiou Marios
Published: November 2021

Calcium imaging is an increasingly valuable technique for understanding neural circuits, neuroethology, and cellular mechanisms. The analysis of calcium imaging data presents challenges in image processing, data organization, analysis, and accessibility. Tools have been created to address these problems independently, however a comprehensive user-friendly package does not exist. Here we present Mesmerize, an efficient, expandable and user-friendly analysis platform, which uses a Findable, Accessible, Interoperable and Reproducible (FAIR) system to encapsulate the entire analysis process, from raw data to interactive visualizations for publication. Mesmerize provides a user-friendly graphical interface to state-of-the-art analysis methods for signal extraction & downstream analysis. We demonstrate the broad scientific scope of Mesmerize’s applications by analyzing neuronal datasets from mouse and a volumetric zebrafish dataset. We also applied contemporary time-series analysis techniques to analyze a novel dataset comprising neuronal, epidermal, and migratory mesenchymal cells of the protochordate Ciona intestinalis.
Cell cycle arrest determines adult neural stem cell ontogeny by an embryonic Notch-nonoscillatory Hey1 module
Authors: Harada Yujin , Yamada Mayumi , Imayoshi Itaru , Kageyama Ryoichiro , Suzuki Yutaka , Kuniya Takaaki , Furutachi Shohei , Kawaguchi Daichi , Gotoh Yukiko
Published: November 2021

Quiescent neural stem cells (NSCs) in the adult mouse brain are the source of neurogenesis that regulates innate and adaptive behaviors. Adult NSCs in the subventricular zone are derived from a subpopulation of embryonic neural stem-progenitor cells (NPCs) that is characterized by a slower cell cycle relative to the more abundant rapid cycling NPCs that build the brain. Yet, how slow cell cycle can cause the establishment of adult NSCs remains largely unknown. Here, we demonstrate that Notch and an effector Hey1 form a module that is upregulated by cell cycle arrest in slowly dividing NPCs. In contrast to the oscillatory expression of the Notch effectors Hes1 and Hes5 in fast cycling progenitors, Hey1 displays a non-oscillatory stationary expression pattern and contributes to the long-term maintenance of NSCs. These findings reveal a novel division of labor in Notch effectors where cell cycle rate biases effector selection and cell fate.
Apoptotic stress-induced FGF signalling promotes non-cell autonomous resistance to cell death
Authors: Bock Florian J. , Sedov Egor , Koren Elle , Koessinger Anna L. , Cloix Catherine , Zerbst Désirée , Athineos Dimitris , Anand Jayanthi , Campbell Kirsteen J. , Blyth Karen , Fuchs Yaron , Tait Stephen W. G.
Published: November 2021

Damaged or superfluous cells are typically eliminated by apoptosis. Although apoptosis is a cell-autonomous process, apoptotic cells communicate with their environment in different ways. Here we describe a mechanism whereby cells under apoptotic stress can promote survival of neighbouring cells. We find that upon apoptotic stress, cells release the growth factor FGF2, leading to MEK-ERK-dependent transcriptional upregulation of pro-survival BCL-2 proteins in a non-cell autonomous manner. This transient upregulation of pro-survival BCL-2 proteins protects neighbouring cells from apoptosis. Accordingly, we find in certain cancer types a correlation between FGF-signalling, BCL-2 expression and worse prognosis. In vivo, upregulation of MCL-1 occurs in an FGF-dependent manner during skin repair, which regulates healing dynamics. Importantly, either co-treatment with FGF-receptor inhibitors or removal of apoptotic stress restores apoptotic sensitivity to cytotoxic therapy and delays wound healing. These data reveal a pathway by which cells under apoptotic stress can increase resistance to cell death in surrounding cells. Beyond mediating cytotoxic drug resistance, this process also provides a potential link between tissue damage and repair.
Zinc finger protein ZNF384 is an adaptor of Ku to DNA during classical non-homologous end-joining
Authors: Singh Jenny Kaur , Smith Rebecca , Rother Magdalena B. , de Groot Anton J. L. , Wiegant Wouter W. , Vreeken Kees , D’Augustin Ostiane , Kim Robbert Q. , Qian Haibin , Krawczyk Przemek M. , González-Prieto Román , Vertegaal Alfred C. O. , Lamers Meindert , Huet Sébastien , van Attikum Haico
Published: November 2021

DNA double-strand breaks (DSBs) are among the most deleterious types of DNA damage as they can lead to mutations and chromosomal rearrangements, which underlie cancer development. Classical non-homologous end-joining (cNHEJ) is the dominant pathway for DSB repair in human cells, involving the DNA-binding proteins XRCC6 (Ku70) and XRCC5 (Ku80). Other DNA-binding proteins such as Zinc Finger (ZnF) domain-containing proteins have also been implicated in DNA repair, but their role in cNHEJ remained elusive. Here we show that ZNF384, a member of the C2H2 family of ZnF proteins, binds DNA ends in vitro and is recruited to DSBs in vivo. ZNF384 recruitment requires the poly(ADP-ribosyl) polymerase 1 (PARP1)-dependent expansion of damaged chromatin, followed by binding of its C2H2 motifs to the exposed DNA. Moreover, ZNF384 interacts with Ku70/Ku80 via its N-terminus, thereby promoting Ku70/Ku80 assembly and the accrual of downstream cNHEJ factors, including APLF and XRCC4/LIG4, for efficient repair at DSBs. Altogether, our data suggest that ZNF384 acts as a ‘Ku-adaptor’ that binds damaged DNA and Ku70/Ku80 to facilitate the build-up of a cNHEJ repairosome, highlighting a role for ZNF384 in DSB repair and genome maintenance.
Precise visuomotor transformations underlying collective behavior in larval zebrafish
Authors: Harpaz Roy , Nguyen Minh Nguyet , Bahl Armin , Engert Florian
Published: November 2021

Complex schooling behaviors result from local interactions among individuals. Yet, how sensory signals from neighbors are analyzed in the visuomotor stream of animals is poorly understood. Here, we studied aggregation behavior in larval zebrafish and found that over development larvae transition from overdispersed groups to tight shoals. Using a virtual reality assay, we characterized the algorithms fish use to transform visual inputs from neighbors into movement decisions. We found that young larvae turn away from virtual neighbors by integrating and averaging retina-wide visual occupancy within each eye, and by using a winner-take-all strategy for binocular integration. As fish mature, their responses expand to include attraction to virtual neighbors, which is based on similar algorithms of visual integration. Using model simulations, we show that the observed algorithms accurately predict group structure over development. These findings allow us to make testable predictions regarding the neuronal circuits underlying collective behavior in zebrafish.
A Deep Gravity model for mobility flows generation
Authors: Simini Filippo , Barlacchi Gianni , Luca Massimilano , Pappalardo Luca
Published: November 2021

The movements of individuals within and among cities influence critical aspects of our society, such as well-being, the spreading of epidemics, and the quality of the environment. When information about mobility flows is not available for a particular region of interest, we must rely on mathematical models to generate them. In this work, we propose Deep Gravity, an effective model to generate flow probabilities that exploits many features (e.g., land use, road network, transport, food, health facilities) extracted from voluntary geographic data, and uses deep neural networks to discover non-linear relationships between those features and mobility flows. Our experiments, conducted on mobility flows in England, Italy, and New York State, show that Deep Gravity achieves a significant increase in performance, especially in densely populated regions of interest, with respect to the classic gravity model and models that do not use deep neural networks or geographic data. Deep Gravity has good generalization capability, generating realistic flows also for geographic areas for which there is no data availability for training. Finally, we show how flows generated by Deep Gravity may be explained in terms of the geographic features and highlight crucial differences among the three considered countries interpreting the model’s prediction with explainable AI techniques.
The phosphoinositide coincidence detector Phafin2 promotes macropinocytosis by coordinating actin organisation at forming macropinosomes
Authors: Schink Kay Oliver , Tan Kia Wee , Spangenberg Hélène , Martorana Domenica , Sneeggen Marte , Stévenin Virginie , Enninga Jost , Campsteijn Coen , Raiborg Camilla , Stenmark Harald
Published: November 2021

Uptake of large volumes of extracellular fluid by actin-dependent macropinocytosis has an important role in infection, immunity and cancer development. A key question is how actin assembly and disassembly are coordinated around macropinosomes to allow them to form and subsequently pass through the dense actin network underlying the plasma membrane to move towards the cell center for maturation. Here we show that the PH and FYVE domain protein Phafin2 is recruited transiently to newly-formed macropinosomes by a mechanism that involves coincidence detection of PtdIns3P and PtdIns4P. Phafin2 also interacts with actin via its PH domain, and recruitment of Phafin2 coincides with actin reorganization around nascent macropinosomes. Moreover, forced relocalization of Phafin2 to the plasma membrane causes rearrangement of the subcortical actin cytoskeleton. Depletion of Phafin2 inhibits macropinosome internalization and maturation and prevents KRAS-transformed cancer cells from utilizing extracellular protein as an amino acid source. We conclude that Phafin2 promotes macropinocytosis by controlling timely delamination of actin from nascent macropinosomes for their navigation through the dense subcortical actin network.
A viral genome packaging ring-ATPase is a flexibly coordinated pentamer
Authors: Dai Li , Singh Digvijay , Lu Suoang , Kottadiel Vishal I. , Vafabakhsh Reza , Mahalingam Marthandan , Chemla Yann R. , Ha Taekjip , Rao Venigalla B.
Published: November 2021

Multi-subunit ring-ATPases carry out a myriad of biological functions, including genome packaging in viruses. Though the basic structures and functions of these motors have been well-established, the mechanisms of ATPase firing and motor coordination are poorly understood. Here, using single-molecule fluorescence, we determine that the active bacteriophage T4 DNA packaging motor consists of five subunits of gp17. By systematically doping motors with an ATPase-defective subunit and selecting single motors containing a precise number of active or inactive subunits, we find that the packaging motor can tolerate an inactive subunit. However, motors containing one or more inactive subunits exhibit fewer DNA engagements, a higher failure rate in encapsidation, reduced packaging velocity, and increased pausing. These findings suggest a DNA packaging model in which the motor, by re-adjusting its grip on DNA, can skip an inactive subunit and resume DNA translocation, suggesting that strict coordination amongst motor subunits of packaging motors is not crucial for function.
SARS-CoV-2 B.1.1.7 (alpha) and B.1.351 (beta) variants induce pathogenic patterns in K18-hACE2 transgenic mice distinct from early strains
Authors: Radvak Peter , Kwon Hyung-Joon , Kosikova Martina , Ortega-Rodriguez Uriel , Xiang Ruoxuan , Phue Je-Nie , Shen Rong-Fong , Rozzelle James , Kapoor Neeraj , Rabara Taylor , Fairman Jeff , Xie Hang
Published: November 2021

SARS-CoV-2 variants of concern (VOC) B.1.1.7 (alpha) and B.1.351 (beta) show increased transmissibility and enhanced antibody neutralization resistance. Here we demonstrate in K18-hACE2 transgenic mice that B.1.1.7 and B.1.351 are 100-fold more lethal than the original SARS-CoV-2 bearing 614D. B.1.1.7 and B.1.351 cause more severe organ lesions in K18-hACE2 mice than early SARS-CoV-2 strains bearing 614D or 614G, with B.1.1.7 and B.1.351 infection resulting in distinct tissue-specific cytokine signatures, significant D-dimer depositions in vital organs and less pulmonary hypoxia signaling before death. However, K18-hACE2 mice with prior infection of early SARS-CoV-2 strains or intramuscular immunization of viral spike or receptor binding domain are resistant to the lethal reinfection of B.1.1.7 or B.1.351, despite having reduced neutralization titers against these VOC than early strains. Our results thus distinguish pathogenic patterns in K18-hACE2 mice caused by B.1.1.7 and B.1.351 infection from those induced by early SARS-CoV-2 strains, and help inform potential medical interventions for combating COVID-19.
Selective cobalt and nickel electrodeposition for lithium-ion battery recycling through integrated electrolyte and interface control
Authors: Kim Kwiyong , Raymond Darien , Candeago Riccardo , Su Xiao
Published: November 2021

Molecularly-selective metal separations are key to sustainable recycling of Li-ion battery electrodes. However, metals with close reduction potentials present a fundamental challenge for selective electrodeposition, especially for critical elements such as cobalt and nickel. Here, we demonstrate the synergistic combination of electrolyte control and interfacial design to achieve molecular selectivity for cobalt and nickel during potential-dependent electrodeposition. Concentrated chloride allows for the speciation control via distinct formation of anionic cobalt chloride complex (CoCl42-), while maintaining nickel in the cationic form ([Ni(H2O)5Cl]+). Furthermore, functionalizing electrodes with a positively charged polyelectrolyte (i.e., poly(diallyldimethylammonium) chloride) changes the mobility of CoCl42- by electrostatic stabilization, which tunes cobalt selectivity depending on the polyelectrolyte loading. This strategy is applied for the multicomponent metal recovery from commercially-sourced lithium nickel manganese cobalt oxide electrodes. We report a final purity of 96.4 ± 3.1% and 94.1 ± 2.3% for cobalt and nickel, respectively. Based on a technoeconomic analysis, we identify the limiting costs arising from the background electrolyte, and provide a promising outlook of selective electrodeposition as an efficient separation approach for battery recycling.
Mammalian SWI/SNF chromatin remodeler is essential for reductional meiosis in males
Authors: Menon Debashish U. , Kirsanov Oleksandr , Geyer Christopher B. , Magnuson Terry
Published: November 2021

The mammalian SWI/SNF nucleosome remodeler is essential for spermatogenesis. Here, we identify a role for ARID2, a PBAF (Polybromo - Brg1 Associated Factor)-specific subunit, in meiotic division. Arid2cKO spermatocytes arrest at metaphase-I and are deficient in spindle assembly, kinetochore-associated Polo-like kinase1 (PLK1), and centromeric targeting of Histone H3 threonine3 phosphorylation (H3T3P) and Histone H2A threonine120 phosphorylation (H2AT120P). By determining ARID2 and BRG1 genomic associations, we show that PBAF localizes to centromeres and promoters of genes known to govern spindle assembly and nuclear division in spermatocytes. Consistent with gene ontology of target genes, we also identify a role for ARID2 in centrosome stability. Additionally, misexpression of genes such as Aurkc and Ppp1cc (Pp1γ), known to govern chromosome segregation, potentially compromises the function of the chromosome passenger complex (CPC) and deposition of H3T3P, respectively. Our data support a model where-in PBAF activates genes essential for meiotic cell division.
Substantially enhanced plasticity of bulk metallic glasses by densifying local atomic packing
Authors: Wu Yuan , Cao Di , Yao Yilin , Zhang Guosheng , Wang Jinyue , Liu Leqing , Li Fengshou , Fan Huiyang , Liu Xiongjun , Wang Hui , Wang Xianzhen , Zhu Huihui , Jiang Suihe , Kontis Paraskevas , Raabe Dierk , Gault Baptiste , Lu Zhaoping
Published: November 2021

Introducing regions of looser atomic packing in bulk metallic glasses (BMGs) was reported to facilitate plastic deformation, rendering BMGs more ductile at room temperature. Here, we present a different alloy design approach, namely, doping the nonmetallic elements to form densely packed motifs. The enhanced structural fluctuations in Ti-, Zr- and Cu-based BMG systems leads to improved strength and renders these solutes’ atomic neighborhoods more prone to plastic deformation at an increased critical stress. As a result, we simultaneously increased the compressive plasticity (from ∼8% to unfractured), strength (from ∼1725 to 1925 MPa) and toughness (from 87 ± 10 to 165 ± 15 MPa√m), as exemplarily demonstrated for the Zr20Cu20Hf20Ti20Ni20 BMG. Our study advances the understanding of the atomic-scale origin of structure-property relationships in amorphous solids and provides a new strategy for ductilizing BMG without sacrificing strength.
Fast alignment and preprocessing of chromatin profiles with Chromap
Authors: Zhang Haowen , Song Li , Wang Xiaotao , Cheng Haoyu , Wang Chenfei , Meyer Clifford A. , Liu Tao , Tang Ming , Aluru Srinivas , Yue Feng , Liu X. Shirley , Li Heng
Published: November 2021

As sequencing depth of chromatin studies continually grows deeper for sensitive profiling of regulatory elements or chromatin spatial structures, aligning and preprocessing of these sequencing data have become the bottleneck for analysis. Here we present Chromap, an ultrafast method for aligning and preprocessing high throughput chromatin profiles. Chromap is comparable to BWA-MEM and Bowtie2 in alignment accuracy and is over 10 times faster than traditional workflows on bulk ChIP-seq/Hi-C profiles and than 10x Genomics’ CellRanger v2.0.0 pipeline on single-cell ATAC-seq profiles.
An integrative proteomics method identifies a regulator of translation during stem cell maintenance and differentiation
Authors: Sabatier Pierre , Beusch Christian M. , Saei Amir A. , Aoun Mike , Moruzzi Noah , Coelho Ana , Leijten Niels , Nordenskjöld Magnus , Micke Patrick , Maltseva Diana , Tonevitsky Alexander G. , Millischer Vincent , Carlos Villaescusa J. , Kadekar Sandeep , Gaetani Massimiliano , Altynbekova Kamilya , Kel Alexander , Berggren Per-Olof , Simonson Oscar , Grinnemo Karl-Henrik , Holmdahl Rikard , Rodin Sergey , Zubarev Roman A.
Published: November 2021

Detailed characterization of cell type transitions is essential for cell biology in general and particularly for the development of stem cell-based therapies in regenerative medicine. To systematically study such transitions, we introduce a method that simultaneously measures protein expression and thermal stability changes in cells and provide the web-based visualization tool ProteoTracker. We apply our method to study differences between human pluripotent stem cells and several cell types including their parental cell line and differentiated progeny. We detect alterations of protein properties in numerous cellular pathways and components including ribosome biogenesis and demonstrate that modulation of ribosome maturation through SBDS protein can be helpful for manipulating cell stemness in vitro. Using our integrative proteomics approach and the web-based tool, we uncover a molecular basis for the uncoupling of robust transcription from parsimonious translation in stem cells and propose a method for maintaining pluripotency in vitro.
Aborting meiosis allows recombination in sterile diploid yeast hybrids
Authors: Mozzachiodi Simone , Tattini Lorenzo , Llored Agnes , Irizar Agurtzane , Škofljanc Neža , D’Angiolo Melania , De Chiara Matteo , Barré Benjamin P. , Yue Jia-Xing , Lutazi Angela , Loeillet Sophie , Laureau Raphaelle , Marsit Souhir , Stenberg Simon , Albaud Benoit , Persson Karl , Legras Jean-Luc , Dequin Sylvie , Warringer Jonas , Nicolas Alain , Liti Gianni
Published: November 2021

Hybrids between diverged lineages contain novel genetic combinations but an impaired meiosis often makes them evolutionary dead ends. Here, we explore to what extent an aborted meiosis followed by a return-to-growth (RTG) promotes recombination across a panel of 20 Saccharomyces cerevisiae and S. paradoxus diploid hybrids with different genomic structures and levels of sterility. Genome analyses of 275 clones reveal that RTG promotes recombination and generates extensive regions of loss-of-heterozygosity in sterile hybrids with either a defective meiosis or a heavily rearranged karyotype, whereas RTG recombination is reduced by high sequence divergence between parental subgenomes. The RTG recombination preferentially arises in regions with low local heterozygosity and near meiotic recombination hotspots. The loss-of-heterozygosity has a profound impact on sexual and asexual fitness, and enables genetic mapping of phenotypic differences in sterile lineages where linkage analysis would fail. We propose that RTG gives sterile yeast hybrids access to a natural route for genome recombination and adaptation.