bluuebunny/crossref_metadata_2025 huggingface dataset:
Rethinking Childhood and War in the Twentieth Century
Authors: Kind-Kovács Friederike
Published: April 2023

On 7 March 2022, Catherine Russell, UNICEF executive director, and Filippo Grandi, the United Nations High Commissioner for Refugees, demanded that ‘unaccompanied and separated children fleeing escalating conflict in Ukraine must be protected’.1 They insisted that children should, once they crossed Ukraine's borders, be immediately registered, offered safe spaces, reunified with their families, and receive emergency care.2 Under no circumstances should children who came with their families be separated, and everything should be done to protect children from exploitation, trafficking and gender-based violence.3 However, since then, countless children from Ukraine who have crossed the borders unaccompanied have become victims of human trafficking and exploitation. Tens of thousands of children in Ukrainian state institutions or who had been orphaned prior to the war could not be protected. They were deported to Russia, many were interned in reeducation camps, and many were forcefully adopted by Russian families or moved into foster care.4 Since the war started, children have again become a means of warfare. The current war against Ukraine once more demonstrates how vulnerable children can become when they are separated from their families. Children have, once again, become targets of massive human rights violations and of crimes against humanity.
Emergency Medical Team Response during the Hokkaido Eastern Iburi Earthquake 2018: J-SPEED Data Analysis
Authors: Yumiya Yui , Chimed-Ochir Odgerel , Kayano Ryoma , Hitomi Yoshiaki , Akahoshi Kouki , Kondo Hisayoshi , Wakai Akinori , Mimura Seiji , Chishima Kayako , Toyokuni Yoshiki , Koido Yuichi , Kubo Tatsuhiko
Published: April 2023

Introduction:

In the last ten years, Japan has experienced several large-scale earthquakes with devastating social and health impacts. Earthquakes directly and indirectly cause a variety of health problems. Further investigation is required to increase preparedness and preventive efforts. In response to the Hokkaido Eastern Iburi Earthquake on September 6, 2018, 32 Emergency Medical Teams (EMTs) employed the Japanese version of Surveillance in Post-Extreme Emergencies and Disasters (J-SPEED) as a national standard daily reporting template, gathering data on the number and type of health problems treated.

Study Objective:

The purpose of the study is to conduct a descriptive epidemiology study using the J-SPEED data to better understand the health problems during the earthquake disaster.

Methods:

Reported items in J-SPEED (Ver 1.0) form were analyzed by age, gender, and time to better understand the health issues that have arisen from the earthquake.

Results:

Most consultations (721; 97.6%) occurred between Day 1 and Day 13 of the 32-day EMT response. During the response period, disaster stress-related symptoms were the most common health event (15.2%), followed by wounds (14.5%) and skin diseases (7.0%).

Conclusion:

The most often reported health event during the response period was stress-associated illnesses related to disasters, followed by wounds and skin conditions. The health consequences of natural disasters depend on diverse local environment and population. As a result, this initial study was hard to generalize; however, it is expected that data accumulated using the J-SPEED system in the future will strengthen and extend the conclusions.
What counts? Adding nuance to retail food environment measurement tools in a Canadian context
Authors: Ferdinands Alexa Rae , Brown Jennifer Ann , Nielsen Charlene C , Nykiforuk Candace IJ , Raine Kim D
Published: April 2023

Objective:

Limitations of traditional geospatial measures, like the modified Retail Food Environment Index (mRFEI), are well documented. In response, we aimed to: (1) extend existing food environment measures by inductively developing subcategories to increase the granularity of healthy v. less healthy food retailers; (2) establish replicable coding processes and procedures; and (3) demonstrate how a food retailer codebook and database can be used in healthy public policy advocacy.

Design:

We expanded the mRFEI measure such that ‘healthy’ food retailers included grocery stores, supermarkets, hypermarkets, wholesalers, bulk food stores, produce outlets, butchers, delis, fish and seafood shops, juice/smoothie bars, and fresh and healthy quick-service retailers; and ‘less healthy’ food retailers included fast-food restaurants, convenience stores, coffee shops, dollar stores, pharmacies, bubble tea restaurants, candy stores, frozen dessert restaurants, bakeries, and food trucks. Based on 2021 government food premise licences, we used geographic information systems software to evaluate spatial accessibility of healthy and less healthy food retailers across census tracts and in proximity to schools, calculating differences between the traditional v. expanded mRFEI.

Setting:

Calgary and Edmonton, Canada.

Participants:

N/A.

Results:

Of the 10 828 food retailers geocoded, 26 % were included using traditional mRFEI measures, while 53 % were included using our expanded categorisation. Changes in mean mRFEI across census tracts were minimal, but the healthfulness of food environments surrounding schools significantly decreased.

Conclusions:

Overall, we show how our mRFEI adaptation, and transparent reporting on its use, can promote more nuanced and comprehensive food environment assessments to better support local research, policy and practice innovations.
Modeling pH and Temperature Effects as Climatic Hazards in Vibrio Vulnificus and Vibrio Parahaemolyticus Planktonic Growth and Biofilm Formation
Authors: Velez K. E. Correa , Leighton R. E. , Decho A. W. , Pinckney J. L. , Norman R. S.
Published: April 2023

Climate‐induced stressors, such as changes in temperature, salinity, and pH, contribute to the emergence of infectious diseases. These changes alter geographical constraint, resulting in increased Vibrio spread, exposure, and infection rates, thus facilitating greater Vibrio‐human interactions. Multiple efforts have been developed to predict Vibrio exposure and raise awareness of health risks, but most models only use temperature and salinity as prediction factors. This study aimed to better understand the potential effects of temperature and pH on V. vulnificus and V. parahaemolyticus planktonic and biofilm growth. Vibrio strains were grown in triplicate at 25°, 30°, and 37°C in 96 well plates containing Modified Seawater Yeast Extract modified with CaCl2 at pH's ranging from 5 to 9.6. AMiGA software was used to model growth curves using Gaussian process regression. The effects of temperature and pH were evaluated using randomized complete block analysis of variance, and the growth rates of V. parahaemolyticus and V. vulnificus were modeled using the interpolation fit on the MatLab Curve Fitting Toolbox. Different optimal conditions involving temperature and pH were observed for planktonic and biofilm Vibrio growth within‐ and between‐species. This study showed that temperature and pH factors significantly affect Vibrio planktonic growth rates and V. parahaemolyticus biofilm formation. Therefore, pH effects must be added to the Vibrio growth modeling efforts to better predict Vibrio risk in estuarine and coastal zones that can potentially experience the cooccurrence of Vibrio and harmful algal bloom outbreak events.
Methanol Concentrations and Biological Methanol Consumption in the Northwest Pacific Ocean
Authors: Zhou Zhen , Zhuang Guang‐Chao , Mao Shi‐Hai , Liu Jiarui , Li Xiao‐Jun , Liu Qiao , Song Guo‐Dong , Zhang Hong‐Hai , Chen Zhaohui , Montgomery Andrew , Joye Samantha , Yang Gui‐Peng
Published: April 2023

Methanol metabolism can play an important role in marine carbon cycling. We made contemporaneous measurements of methanol concentration and consumption rates in the northwest Pacific Ocean to constrain the pathways and dynamics of methanol cycling. Methanol was detected in relatively low concentrations (<12–391 nM), likely due to rapid biological turnover. Rates of methanol oxidation to CO2 (0.9–130.5 nmol L−1 day−1) were much higher than those of assimilation into biomass (0.09–6.8 nmol L−1 day−1), suggesting that >89.7% of methanol was utilized as an energy source. Surface water acted as a net methanol sink at most sites, with an average flux of 9 μmol L−1 day−1. Atmospheric deposition accounted for 22.7% of microbial methanol consumption in the mixed layer, illustrating that the atmosphere is less important than internal processes for driving methanol cycling in these pelagic waters.
Parameterizing Submesoscale Vertical Buoyancy Flux by Simultaneously Considering Baroclinic Instability and Strain‐Induced Frontogenesis
Authors: Zhang Jinchao , Zhang Zhiwei , Qiu Bo
Published: April 2023

Oceanic submesoscale processes (submesoscales) with O(1–10) km horizontal scale can generate strong vertical buoyancy flux (VBF) that significantly modulate upper‐ocean stratification. Because submesoscales cannot be resolved by the prevailing ocean models, their VBFs have to be properly parameterized in order to improve model performance. Here, based on theoretical scaling analysis, we propose a new parameterization of submesoscale VBF by simultaneously considering mixed‐layer baroclinic instability (MLI) and strain‐induced frontogenesis, which are two leading generation mechanisms of submesoscales that typically co‐occur in open ocean. Compared with the parameterization of Fox‐Kemper et al. (2008, https://doi.org/10.1175/2007jpo3792.1; F08) that only considers the MLI, the new parameterization includes mesoscale strain rate and improves vertical structure function. Diagnostic validations based on submesoscale permitting simulation outputs suggest that the newly parameterized VBFs are more realistic than F08 in regard to three‐dimension distributions. How to incorporate this new parameterization into coarser‐grid ocean models, however, needs further studies.
Sub‐Auroral Ion Drifts (SAID) Developed Over the Northern Winter Hemisphere at Dawn During 2016–2017
Authors: Horvath Ildiko , Lovell Brian C.
Published: April 2023

We investigated the rare events of sunward (westward) sub‐auroral ion drifts (SAID) development in the dawn magnetic local time (MLT) sector by utilizing horizontal ion velocity measurements collected by the Defense Meteorological Satellite Program F16 spacecraft. We surveyed the 2‐year time period of 2016–2017 and found only 15 SAID detections made in the 3–6 MLT sector over the northern winter hemisphere: seven in 2016 and eight in 2017. Results show that the dawnside SAID developed poleward of the ring‐current‐related plasma density trough, called ring ionospheric trough (RIT). With a few inner‐magnetosphere observations, we demonstrated that the favorable conditions were created by (a) the proton/ring current injections occurring across the newly‐formed dawnside plasmapause where (b) the ring current ions became unstable. As a result of (a), the outward SAID electric (E) field developed via short‐circuiting, mapped down to the ionosphere as a poleward E field and drove the sunward (westward) SAID flow in the dawn MLT sector. As a result of (b), a localized heat source developed near the newly‐formed dawnside plasmapause in the hot zone and the resultant downward heat flux led to stable auroral red (SAR) arc development when the electron temperature was sufficiently high. Then, the dawnside SAID flow developed parallel with the RIT and SAR arc.
Shallow Volcano‐Tectonic Structures on the Island of Hawai'i Imaged by Multimode Rayleigh Wave Ambient Noise Tomography
Authors: Wei XiaoZhuo , Shen Yang , Morgan Julia K.
Published: April 2023

Seismic tomography of shield volcanoes can be used to better understand its structure, formation, and evolution. Previous tomographic studies on the Island of Hawai'i used body waves from earthquakes and active sources and had limited resolution in the shallow crust. In this study, we obtained the empirical Green Functions (EGFs) and empirical Green Tensors (EGTs) from cross‐correlating and stacking of multiyear seismic ambient noise recorded on the island. The EGFs/EGTs contained fundamental mode and first higher mode Rayleigh waves. The different modes were separated with a new algorithm and their group velocities were measured. Using the group arrival times, we inverted for two‐dimensional group velocity maps, which provide, for the first time, a full coverage of the Island of Hawai'i. From the group velocity maps, we inverted for a three‐dimensional shear wave velocity model, which shows strong lateral variations and yields new insights into the structure and growth of the volcanoes on the island: Kı̄lauea's East Rift Zone has prominent high velocities at all depths, whereas the current rift zones of Mauna Loa are characterized by intermediate to high velocities only at depths greater than 1 km below ground surface, which may be attributed to their relatively short history and less developed state. The flanks of the volcanoes, some cut by fault zones, displayed low velocities at over a range of depths, generally interpreted as consisting of extrusive rocks, which could be further shattered by faulting.
Atmospheric Turbulent Characteristics Under Summer Shamal in Coastal Qatar
Authors: Li Yuan , Sadr Reza
Published: April 2023

Summer Shamal, a strong low‐level northwesterly wind in the Middle Eastern, is the major trigger for dust storm activity with a broad impact on regional transport and human safety. However, near‐ground turbulent mixing analysis under Shamal is still rare due to the lack of available high frequency data. The present study explores the near‐surface turbulence characteristics under summer Shamal, compared with those of non‐Shamal, in the coastal region of Qatar (26.08°N, 51.36°E). The results show that Shamal prevents the development of summer sea breezes in the Persian Gulf. A “Shamal day” (SD) is commonly defined as a day with a strong, continuous, north‐northwesterly wind. Compared to non‐Shamal days (NSD), SDs are characterized by higher surface sensible heat flux and turbulent kinetic energy (TKE) with lower humidity, especially around noon time. At night, the wind turbulence energy is contained in smaller eddies for SD due to the more stable atmospheric conditions. The streamwise velocity spectra analysis displays a power‐law trend with a coefficient of −1.53 as compared to the traditional Kolmogorov −1.67 (−5/3) power law, indicating a higher TKE dissipation rate for SD. The smaller scatter of the normalized TKE dissipation rate observed for SD is related to lower streamwise turbulence intensity. A Weibull distribution is observed for probability distribution of TKE dissipation rate under SD in log scale for both stable and unstable conditions. This distribution for TKE dissipation rate is different than the results from other field measurements due to Shamal.
Depositional and Diagenetic Processes of Martian Lacustrine Sediments as Revealed at Pahrump Hills by the Mars Hand Lens Imager, Gale Crater, Mars
Authors: Yingst R. A. , Cowart A. C. , Kah L. C. , Gupta S. , Stack K. , Fey D. , Harker D. , Herkenhoff K. , Minitti M. E. , Rowland S.
Published: April 2023

The Murray formation represents fine‐grained sedimentary deposition in lacustrine environments within Gale crater, Mars. Both the overall thickness of the Murray formation and its broad uniformity in sedimentary character suggest the potential for a long‐lived, groundwater‐supported lake system. Rock textures were imaged by the Mars Hand Lens Imager camera at the Pahrump Hills location, which represents the lowermost Murray formation. We analyze data from Pahrump Hills to refine earlier estimates of grain size and grain size distribution, as well as to make detailed observations of diagenetic features and modification of primary sedimentological features. These observations and resulting interpretations provide a detailed look at the dynamic behavior of lake systems on Mars. The lower portions of this exposure are characterized by planar laminated, fine‐grained material; the predominant grain size in this region is smaller than that of very fine sand. Diagenetic mineral precipitation is also prominent in these lower layers, evidenced by likely in situ precipitation of lenticular crystals, preferential cementation of laminae in several layers, precipitation of late‐diagenetic crystal clusters, and secondary modification of previously deposited crystals. The upper portions of this locality are coarser‐grained, varicolored, and contain cross‐stratified features. The variation of these features over a relatively thin stratigraphic interval indicates rapid fluctuation in the hydrodynamic behavior of Gale crater lake, similar to that observed in the shallow‐water regions of terrestrial closed basin lakes.
Quantifying the Effects Sizes of Common Controls on Methane Emissions From an Ombrotrophic Peat Bog
Authors: Taylor M. A. , Bradford M. A. , Arnold W. , Takahashi D. , Colgan T. , Davis V. , Losos D. , Peccia J. , Raymond P. A.
Published: April 2023

Northern wetlands and bogs are a large source of biogenic methane (CH4) to the atmosphere and shape climate. There is then substantial interest in quantifying the effect sizes of controls on bog CH4 emissions. Yet quantification is complicated because wetland emissions are, like the controls that regulate them, spatially and temporarily heterogeneous within individual wetland systems. To account for this heterogeneity, we established 55 measurement plots in a sampling design that had extensive spatial, and repeated temporal, coverage over one ombrotrophic bog. This coverage allowed us to robustly estimate the effect sizes of known environmental controls on CH4 emissions such as temperature, water table depth (WTD), and plant functional composition. As expected, 89% of the cumulative measured flux came from 16% of the plots, with consistently high CH4 emissions over two consecutive growing seasons. Soil temperature exhibited the strongest control on emissions, while WTD and vegetation composition had much smaller relative effects compared to temperature. Interestingly, at high temperatures, WTD was a strong determinant of whether a plot had high versus lower emissions. Despite temperature's large effect size, the controls we measured only explained ∼29% of the variance in CH4 fluxes. Overall, our data confirm observations from other wetlands that CH4 emissions are highly variable at local scales, and yet our data also reveal that effect sizes can be quantified robustly within this heterogeneity. Highly‐replicated, local designs may therefore be useful for generating data that can serve to help refine wetland CH4 emissions uncertainties.
The Dynamics of Megafire Smoke Plumes in Climate Models: Why a Converged Solution Matters for Physical Interpretations
Authors: Guimond S. R. , Reisner J. , Dubey M.
Published: April 2023

As the climate system warms, megafires have become more frequent with devastating effects. A byproduct of these events is the creation of smoke plumes that can rise into the stratosphere and spread across the globe where they reside for many months. To gain a deeper understanding of the plume dynamics, global climate simulations of a megafire were performed at a wide range of grid spacings from 2.0° down to 7 km, including a 7 km nonhydrostatic experiment. The analysis focuses on how the resolved dynamics affects the specification of the plume characteristics such as injection height and black carbon (BC) mass. Prior studies initialize the smoke plume at one or a few grid points and this is shown here to produce severely dissipative dynamics. In order to validate such simulations with observations, enhancements of the plume characteristics to offset the dissipation is necessary. Using a numerically converged simulation, sensitivity tests show that to approximate the observed stratospheric lifetime, a reduction in BC fraction by 50% is necessary for external mixtures. The vorticity dynamics of the plume is also analyzed with a Lagrangian budget to understand the mechanisms responsible for the evolution of a collocated anticyclonic vortex. The results can be distilled down into a simple conceptual model. As the plume rises, the air diverges at the top of the updraft where the largest concentrations of smoke are found. This divergence induces a dilution of the background cyclonic absolute vorticity producing an anticyclonic vortex. Vortex decay occurs from opposite arguments.
Kinematic Response of Subaerial Salt Diapirs to Geomorphic, Tectonic and Climatic Regimes: Insights From Space‐Based Observations in the Western Kuqa Fold‐Thrust Belt, NW China
Authors: Chang Fengnian , Dong Shaochun , Yin Hongwei , Wu Zhenyun , Wang Wei
Published: April 2023

Ephemeral subaerial salt diapirs are gravitationally unstable and vulnerable to climate and tectonic activity due to the rheology and incompressibility of rock salt. Quantifying the kinematics of subaerial salt and clarifying the role of tectonics, surface processes, and climate in reshaping the surface salt morphology provides an invaluable opportunity to explore the interactions between Earth’s spheres on a much shorter timescale. With diverse exposed salt diapirs and potential motions, the Kuqa fold‐thrust belt (KFTB), NW China, represents an optimum natural laboratory to understand subaerial salt kinematics. Here, we integrated ascending and descending geometries of Sentinel‐1 synthetic aperture radar images with optical remote sensing data, seismic profiles, digital elevation models, and meteorological records to explore the potential correlation between subaerial salt motions and geomorphic, tectonic, and climatic factors. Using the interferometric synthetic aperture radar technique, we observed a maximum of 25 mm/yr in vertical and 40 mm/yr in horizontal surface salt deformation in the KFTB from 2014 to 2020. Our findings demonstrate a gravity spreading dominant system, where topography exerts a primary control on the surface displacement patterns of salt structures, while weather variables influence deformation mainly by softening salt and facilitating gravity‐driven salt flow.
A miniaturized transit-time ultrasonic flowmeter based on ScAlN piezoelectric micromachined ultrasonic transducers for small-diameter applications
Authors: Gao Yunfei , Chen Minkan , Wu Zhipeng , Yao Lei , Tong Zhihao , Zhang Songsong , Gu Yuandong Alex , Lou Liang
Published: April 2023

Transit-time ultrasonic flowmeters (TTUFs) are among the most widely used devices for flow measurements. However, traditional TTUFs are usually based on a bulk piezoelectric transducer, which limits their application in small-diameter channels. In this paper, we developed a miniaturized TTUF based on scandium-doped aluminum nitride (ScAlN) piezoelectric micromachined ultrasonic transducers (PMUTs). The proposed TTUF contains two PMUT-based transceivers and a π-type channel. The PMUTs contain 13 × 13 square cells with dimensions of 2.8 × 2.8 mm2. To compensate for the acoustic impedance mismatch with liquid, a layer of polyurethane is added to the surface of the PMUTs as a matching layer. The PMUT-based transceivers show good transmitting sensitivity (with 0.94 MPa/V surface pressure) and receiving sensitivity (1.79 mV/kPa) at a frequency of 1 MHz in water. Moreover, the dimensions of the π-type channel are optimized to achieve a measurement sensitivity of 82 ns/(m/s) and a signal-to-noise ratio (SNR) better than 15 dB. Finally, we integrate the fabricated PMUTs into the TDC-GP30 platform. The experimental results show that the developed TTUF provides a wide range of flow measurements from 2 to 300 L/h in a channel of 4 mm diameter, which is smaller than most reported channels. The accuracy and repeatability of the TTUF are within 0.2% and 1%, respectively. The proposed TTUF shows great application potential in industrial applications such as medical and chemical applications.
Neural complexity EEG biomarkers of rapid and post-rapid ketamine effects in late-life treatment-resistant depression: a randomized control trial
Authors: Murphy Nicholas , Tamman Amanda J. F. , Lijffijt Marijn , Amarneh Dania , Iqbal Sidra , Swann Alan , Averill Lynnette A. , O’Brien Brittany , Mathew Sanjay J.
Published: April 2023

Ketamine is an effective intervention for treatment-resistant depression (TRD), including late-in-life (LL-TRD). The proposed mechanism of antidepressant effects of ketamine is a glutamatergic surge, which can be measured by electroencephalogram (EEG) gamma oscillations. Yet, non-linear EEG biomarkers of ketamine effects such as neural complexity are needed to capture broader systemic effects, represent the level of organization of synaptic communication, and elucidate mechanisms of action for treatment responders. In a secondary analysis of a randomized control trial, we investigated two EEG neural complexity markers (Lempel-Ziv complexity [LZC] and multiscale entropy [MSE]) of rapid (baseline to 240 min) and post-rapid ketamine (24 h and 7 days) effects after one 40-min infusion of IV ketamine or midazolam (active control) in 33 military veterans with LL-TRD. We also studied the relationship between complexity and Montgomery-Åsberg Depression Rating Scale score change at 7 days post-infusion. We found that LZC and MSE both increased 30 min post-infusion, with effects not localized to a single timescale for MSE. Post-rapid effects of reduced complexity with ketamine were observed for MSE. No relationship was observed between complexity and reduction in depressive symptoms. Our findings support the hypothesis that a single sub-anesthetic ketamine infusion has time-varying effects on system-wide contributions to the evoked glutamatergic surge in LL-TRD. Further, changes to complexity were observable outside the time-window previously shown for effects on gamma oscillations. These preliminary results have clinical implications in providing a functional marker of ketamine that is non-linear, amplitude-independent, and represents larger dynamic properties, providing strong advantages over linear measures in highlighting ketamine’s effects.
The CDK7 inhibitor CT7001 (Samuraciclib) targets proliferation pathways to inhibit advanced prostate cancer
Authors: Constantin Theodora A. , Varela-Carver Anabel , Greenland Kyle K. , de Almeida Gilberto Serrano , Olden Ellen , Penfold Lucy , Ang Simon , Ormrod Alice , Leach Damien A. , Lai Chun-Fui , Ainscow Edward K. , Bahl Ash K. , Carling David , Fuchter Matthew J. , Ali Simak , Bevan Charlotte L.
Published: April 2023

Background

Current strategies to inhibit androgen receptor (AR) are circumvented in castration-resistant prostate cancer (CRPC). Cyclin-dependent kinase 7 (CDK7) promotes AR signalling, in addition to established roles in cell cycle and global transcription, providing a rationale for its therapeutic targeting in CRPC.

Methods

The antitumour activity of CT7001, an orally bioavailable CDK7 inhibitor, was investigated across CRPC models in vitro and in xenograft models in vivo. Cell-based assays and transcriptomic analyses of treated xenografts were employed to investigate the mechanisms driving CT7001 activity, alone and in combination with the antiandrogen enzalutamide.

Results

CT7001 selectively engages with CDK7 in prostate cancer cells, causing inhibition of proliferation and cell cycle arrest. Activation of p53, induction of apoptosis, and suppression of transcription mediated by full-length and constitutively active AR splice variants contribute to antitumour efficacy in vitro. Oral administration of CT7001 represses growth of CRPC xenografts and significantly augments growth inhibition achieved by enzalutamide. Transcriptome analyses of treated xenografts indicate cell cycle and AR inhibition as the mode of action of CT7001 in vivo.

Conclusions

This study supports CDK7 inhibition as a strategy to target deregulated cell proliferation and demonstrates CT7001 is a promising CRPC therapeutic, alone or in combination with AR-targeting compounds.
Active learning-assisted neutron spectroscopy with log-Gaussian processes
Authors: Teixeira Parente Mario , Brandl Georg , Franz Christian , Stuhr Uwe , Ganeva Marina , Schneidewind Astrid
Published: April 2023

Neutron scattering experiments at three-axes spectrometers (TAS) investigate magnetic and lattice excitations by measuring intensity distributions to understand the origins of materials properties. The high demand and limited availability of beam time for TAS experiments however raise the natural question whether we can improve their efficiency and make better use of the experimenter’s time. In fact, there are a number of scientific problems that require searching for signals, which may be time consuming and inefficient if done manually due to measurements in uninformative regions. Here, we describe a probabilistic active learning approach that not only runs autonomously, i.e., without human interference, but can also directly provide locations for informative measurements in a mathematically sound and methodologically robust way by exploiting log-Gaussian processes. Ultimately, the resulting benefits can be demonstrated on a real TAS experiment and a benchmark including numerous different excitations.
DeMAG predicts the effects of variants in clinically actionable genes by integrating structural and evolutionary epistatic features
Authors: Luppino Federica , Adzhubei Ivan A. , Cassa Christopher A. , Toth-Petroczy Agnes
Published: April 2023

Despite the increasing use of genomic sequencing in clinical practice, the interpretation of rare genetic variants remains challenging even in well-studied disease genes, resulting in many patients with Variants of Uncertain Significance (VUSs). Computational Variant Effect Predictors (VEPs) provide valuable evidence in variant assessment, but they are prone to misclassifying benign variants, contributing to false positives. Here, we develop Deciphering Mutations in Actionable Genes (DeMAG), a supervised classifier for missense variants trained using extensive diagnostic data available in 59 actionable disease genes (American College of Medical Genetics and Genomics Secondary Findings v2.0, ACMG SF v2.0). DeMAG improves performance over existing VEPs by reaching balanced specificity (82%) and sensitivity (94%) on clinical data, and includes a novel epistatic feature, the ‘partners score’, which leverages evolutionary and structural partnerships of residues. The ‘partners score’ provides a general framework for modeling epistatic interactions, integrating both clinical and functional information. We provide our tool and predictions for all missense variants in 316 clinically actionable disease genes (demag.org) to facilitate the interpretation of variants and improve clinical decision-making.
Multi-omic underpinnings of epigenetic aging and human longevity
Authors: Mavromatis Lucas A. , Rosoff Daniel B. , Bell Andrew S. , Jung Jeesun , Wagner Josephin , Lohoff Falk W.
Published: April 2023

Biological aging is accompanied by increasing morbidity, mortality, and healthcare costs; however, its molecular mechanisms are poorly understood. Here, we use multi-omic methods to integrate genomic, transcriptomic, and metabolomic data and identify biological associations with four measures of epigenetic age acceleration and a human longevity phenotype comprising healthspan, lifespan, and exceptional longevity (multivariate longevity). Using transcriptomic imputation, fine-mapping, and conditional analysis, we identify 22 high confidence associations with epigenetic age acceleration and seven with multivariate longevity. FLOT1, KPNA4, and TMX2 are novel, high confidence genes associated with epigenetic age acceleration. In parallel, cis-instrument Mendelian randomization of the druggable genome associates TPMT and NHLRC1 with epigenetic aging, supporting transcriptomic imputation findings. Metabolomics Mendelian randomization identifies a negative effect of non-high-density lipoprotein cholesterol and associated lipoproteins on multivariate longevity, but not epigenetic age acceleration. Finally, cell-type enrichment analysis implicates immune cells and precursors in epigenetic age acceleration and, more modestly, multivariate longevity. Follow-up Mendelian randomization of immune cell traits suggests lymphocyte subpopulations and lymphocytic surface molecules affect multivariate longevity and epigenetic age acceleration. Our results highlight druggable targets and biological pathways involved in aging and facilitate multi-omic comparisons of epigenetic clocks and human longevity.
Atlantic water intrusion triggers rapid retreat and regime change at previously stable Greenland glacier
Authors: Chudley T. R. , Howat I. M. , King M. D. , Negrete A.
Published: April 2023

Ice discharge from Greenland’s marine-terminating glaciers contributes to half of all mass loss from the ice sheet, with numerous mechanisms proposed to explain their retreat. Here, we examine K.I.V Steenstrups Nordre Bræ (‘Steenstrup’) in Southeast Greenland, which, between 2018 and 2021, retreated ~7 km, thinned ~20%, doubled in discharge, and accelerated ~300%. This rate of change is unprecedented amongst Greenland’s glaciers and now places Steenstrup in the top 10% of glaciers by contribution to ice-sheet-wide discharge. In contrast to expected behaviour from a shallow, grounded tidewater glacier, Steenstrup was insensitive to high surface temperatures that destabilised many regional glaciers in 2016, appearing instead to respond to a >2 °C anomaly in deeper Atlantic water (AW) in 2018. By 2021, a rigid proglacial mélange had developed alongside notable seasonal variability. Steenstrup’s behaviour highlights that even long-term stable glaciers with high sills are vulnerable to sudden and rapid retreat from warm AW intrusion.
Calibration of cognitive tests to address the reliability paradox for decision-conflict tasks
Authors: Kucina Talira , Wells Lindsay , Lewis Ian , de Salas Kristy , Kohl Amelia , Palmer Matthew A. , Sauer James D. , Matzke Dora , Aidman Eugene , Heathcote Andrew
Published: April 2023

Standard, well-established cognitive tasks that produce reliable effects in group comparisons also lead to unreliable measurement when assessing individual differences. This reliability paradox has been demonstrated in decision-conflict tasks such as the Simon, Flanker, and Stroop tasks, which measure various aspects of cognitive control. We aim to address this paradox by implementing carefully calibrated versions of the standard tests with an additional manipulation to encourage processing of conflicting information, as well as combinations of standard tasks. Over five experiments, we show that a Flanker task and a combined Simon and Stroop task with the additional manipulation produced reliable estimates of individual differences in under 100 trials per task, which improves on the reliability seen in benchmark Flanker, Simon, and Stroop data. We make these tasks freely available and discuss both theoretical and applied implications regarding how the cognitive testing of individual differences is carried out.
Plasmepsin X activates the PCRCR complex of Plasmodium falciparum by processing PfRh5 for erythrocyte invasion
Authors: Triglia Tony , Scally Stephen W. , Seager Benjamin A. , Pasternak Michał , Dagley Laura F. , Cowman Alan F.
Published: April 2023

Plasmodium falciparum causes the most severe form of malaria in humans. The protozoan parasite develops within erythrocytes to mature schizonts, that contain more than 16 merozoites, which egress and invade fresh erythrocytes. The aspartic protease plasmepsin X (PMX), processes proteins and proteases essential for merozoite egress from the schizont and invasion of the host erythrocyte, including the leading vaccine candidate PfRh5. PfRh5 is anchored to the merozoite surface through a 5-membered complex (PCRCR), consisting of Plasmodium thrombospondin-related apical merozoite protein, cysteine-rich small secreted protein, Rh5-interacting protein and cysteine-rich protective antigen. Here, we show that PCRCR is processed by PMX in micronemes to remove the N-terminal prodomain of PhRh5 and this activates the function of the complex unmasking a form that can bind basigin on the erythrocyte membrane and mediate merozoite invasion. The ability to activate PCRCR at a specific time in merozoite invasion most likely masks potential deleterious effects of its function until they are required. These results provide an important understanding of the essential role of PMX and the fine regulation of PCRCR function in P. falciparum biology.
Causal structure of interacting Weyl fermions in condensed matter systems
Authors: Chiu Wei-Chi , Chang Guoqing , Macam Gennevieve , Belopolski Ilya , Huang Shin-Ming , Markiewicz Robert , Yin Jia-Xin , Cheng Zi-Jia , Lee Chi-Cheng , Chang Tay-Rong , Chuang Feng-Chuan , Xu Su-Yang , Lin Hsin , Hasan M. Zahid , Bansil Arun
Published: April 2023

The spacetime light cone is central to the definition of causality in the theory of relativity. Recently, links between relativistic and condensed matter physics have been uncovered, where relativistic particles can emerge as quasiparticles in the energy-momentum space of matter. Here, we unveil an energy-momentum analogue of the spacetime light cone by mapping time to energy, space to momentum, and the light cone to the Weyl cone. We show that two Weyl quasiparticles can only interact to open a global energy gap if they lie in each other’s energy-momentum dispersion cones–analogous to two events that can only have a causal connection if they lie in each other’s light cones. Moreover, we demonstrate that the causality of surface chiral modes in quantum matter is entangled with the causality of bulk Weyl fermions. Furthermore, we identify a unique quantum horizon region and an associated ‘thick horizon’ in the emergent causal structure.
Turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase
Authors: Maschietto Federica , Morzan Uriel N. , Tofoleanu Florentina , Gheeraert Aria , Chaudhuri Apala , Kyro Gregory W. , Nekrasov Peter , Brooks Bernard , Loria J. Patrick , Rivalta Ivan , Batista Victor S.
Published: April 2023

Allosteric drugs have the potential to revolutionize biomedicine due to their enhanced selectivity and protection against overdosage. However, we need to better understand allosteric mechanisms in order to fully harness their potential in drug discovery. In this study, molecular dynamics simulations and nuclear magnetic resonance spectroscopy are used to investigate how increases in temperature affect allostery in imidazole glycerol phosphate synthase. Results demonstrate that temperature increase triggers a cascade of local amino acid-to-amino acid dynamics that remarkably resembles the allosteric activation that takes place upon effector binding. The differences in the allosteric response elicited by temperature increase as opposed to effector binding are conditional to the alterations of collective motions induced by either mode of activation. This work provides an atomistic picture of temperature-dependent allostery, which could be harnessed to more precisely control enzyme function.
Complex computation from developmental priors
Authors: Barabási Dániel L. , Beynon Taliesin , Katona Ádám , Perez-Nieves Nicolas
Published: April 2023

Machine learning (ML) models have long overlooked innateness: how strong pressures for survival lead to the encoding of complex behaviors in the nascent wiring of a brain. Here, we derive a neurodevelopmental encoding of artificial neural networks that considers the weight matrix of a neural network to be emergent from well-studied rules of neuronal compatibility. Rather than updating the network’s weights directly, we improve task fitness by updating the neurons’ wiring rules, thereby mirroring evolutionary selection on brain development. We find that our model (1) provides sufficient representational power for high accuracy on ML benchmarks while also compressing parameter count, and (2) can act as a regularizer, selecting simple circuits that provide stable and adaptive performance on metalearning tasks. In summary, by introducing neurodevelopmental considerations into ML frameworks, we not only model the emergence of innate behaviors, but also define a discovery process for structures that promote complex computations.
The structural basis of tRNA recognition by arginyl-tRNA-protein transferase
Authors: Abeywansha Thilini , Huang Wei , Ye Xuan , Nawrocki Allison , Lan Xin , Jankowsky Eckhard , Taylor Derek J. , Zhang Yi
Published: April 2023

Arginyl-tRNA-protein transferase 1 (ATE1) is a master regulator of protein homeostasis, stress response, cytoskeleton maintenance, and cell migration. The diverse functions of ATE1 arise from its unique enzymatic activity to covalently attach an arginine onto its protein substrates in a tRNA-dependent manner. However, how ATE1 (and other aminoacyl-tRNA transferases) hijacks tRNA from the highly efficient ribosomal protein synthesis pathways and catalyzes the arginylation reaction remains a mystery. Here, we describe the three-dimensional structures of Saccharomyces cerevisiae ATE1 with and without its tRNA cofactor. Importantly, the putative substrate binding domain of ATE1 adopts a previously uncharacterized fold that contains an atypical zinc-binding site critical for ATE1 stability and function. The unique recognition of tRNAArg by ATE1 is coordinated through interactions with the major groove of the acceptor arm of tRNA. Binding of tRNA induces conformational changes in ATE1 that helps explain the mechanism of substrate arginylation.
CTCF is a DNA-tension-dependent barrier to cohesin-mediated loop extrusion
Authors: Davidson Iain F. , Barth Roman , Zaczek Maciej , van der Torre Jaco , Tang Wen , Nagasaka Kota , Janissen Richard , Kerssemakers Jacob , Wutz Gordana , Dekker Cees , Peters Jan-Michael
Published: April 2023

In eukaryotes, genomic DNA is extruded into loops by cohesin1. By restraining this process, the DNA-binding protein CCCTC-binding factor (CTCF) generates topologically associating domains (TADs)2,3 that have important roles in gene regulation and recombination during development and disease1,4–7. How CTCF establishes TAD boundaries and to what extent these are permeable to cohesin is unclear8. Here, to address these questions, we visualize interactions of single CTCF and cohesin molecules on DNA in vitro. We show that CTCF is sufficient to block diffusing cohesin, possibly reflecting how cohesive cohesin accumulates at TAD boundaries, and is also sufficient to block loop-extruding cohesin, reflecting how CTCF establishes TAD boundaries. CTCF functions asymmetrically, as predicted; however, CTCF is dependent on DNA tension. Moreover, CTCF regulates cohesin’s loop-extrusion activity by changing its direction and by inducing loop shrinkage. Our data indicate that CTCF is not, as previously assumed, simply a barrier to cohesin-mediated loop extrusion but is an active regulator of this process, whereby the permeability of TAD boundaries can be modulated by DNA tension. These results reveal mechanistic principles of how CTCF controls loop extrusion and genome architecture.
Mirusviruses link herpesviruses to giant viruses
Authors: Gaïa Morgan , Meng Lingjie , Pelletier Eric , Forterre Patrick , Vanni Chiara , Fernandez-Guerra Antonio , Jaillon Olivier , Wincker Patrick , Ogata Hiroyuki , Krupovic Mart , Delmont Tom O.
Published: April 2023

DNA viruses have a major influence on the ecology and evolution of cellular organisms1–4, but their overall diversity and evolutionary trajectories remain elusive5. Here we carried out a phylogeny-guided genome-resolved metagenomic survey of the sunlit oceans and discovered plankton-infecting relatives of herpesviruses that form a putative new phylum dubbed Mirusviricota. The virion morphogenesis module of this large monophyletic clade is typical of viruses from the realm Duplodnaviria6, with multiple components strongly indicating a common ancestry with animal-infecting Herpesvirales. Yet, a substantial fraction of mirusvirus genes, including hallmark transcription machinery genes missing in herpesviruses, are closely related homologues of giant eukaryotic DNA viruses from another viral realm, Varidnaviria. These remarkable chimaeric attributes connecting Mirusviricota to herpesviruses and giant eukaryotic viruses are supported by more than 100 environmental mirusvirus genomes, including a near-complete contiguous genome of 432 kilobases. Moreover, mirusviruses are among the most abundant and active eukaryotic viruses characterized in the sunlit oceans, encoding a diverse array of functions used during the infection of microbial eukaryotes from pole to pole. The prevalence, functional activity, diversification and atypical chimaeric attributes of mirusviruses point to a lasting role of Mirusviricota in the ecology of marine ecosystems and in the evolution of eukaryotic DNA viruses.
The Smc5/6 complex is a DNA loop-extruding motor
Authors: Pradhan Biswajit , Kanno Takaharu , Umeda Igarashi Miki , Loke Mun Siong , Baaske Martin Dieter , Wong Jan Siu Kei , Jeppsson Kristian , Björkegren Camilla , Kim Eugene
Published: April 2023

Structural maintenance of chromosomes (SMC) protein complexes are essential for the spatial organization of chromosomes1. Whereas cohesin and condensin organize chromosomes by extrusion of DNA loops, the molecular functions of the third eukaryotic SMC complex, Smc5/6, remain largely unknown2. Using single-molecule imaging, we show that Smc5/6 forms DNA loops by extrusion. Upon ATP hydrolysis, Smc5/6 reels DNA symmetrically into loops at a force-dependent rate of one kilobase pair per second. Smc5/6 extrudes loops in the form of dimers, whereas monomeric Smc5/6 unidirectionally translocates along DNA. We also find that the subunits Nse5 and Nse6 (Nse5/6) act as negative regulators of loop extrusion. Nse5/6 inhibits loop-extrusion initiation by hindering Smc5/6 dimerization but has no influence on ongoing loop extrusion. Our findings reveal functions of Smc5/6 at the molecular level and establish DNA loop extrusion as a conserved mechanism among eukaryotic SMC complexes.