bluuebunny/crossref_metadata_2025 huggingface dataset:
Trajectory of emotion dysregulation in positive and negative affect across childhood predicts adolescent emotion dysregulation and overall functioning
Authors: Vogel Alecia C. , Tillman Rebecca , El-Sayed Nourhan M. , Jackson Joshua J. , Perlman Susan B. , Barch Deanna M. , Luby Joan L.
Published: December 2021

Emotion dysregulation is cross-diagnostic and impairing. Most research has focused on dysregulated expressions of negative affect, often measured as irritability, which is associated with multiple forms of psychopathology and predicts negative outcomes. However, the Research Domain Criteria (RDoC) include both negative and positive valence systems. Emerging evidence suggests that dysregulated expressions of positive affect, or excitability, in early childhood predict later psychopathology and impairment above and beyond irritability. Typically, irritability declines from early through middle childhood; however, the developmental trajectory of excitability is unknown. The impact of excitability across childhood on later emotion dysregulation is also yet unknown. In a well-characterized, longitudinal sample of 129 children studied from ages 3 to 5.11 years through 14 to 19 years, enriched for early depression and disruptive symptoms, we assessed the trajectory of irritability and excitability using multilevel modeling and how components of these trajectories impact later emotion dysregulation. While irritability declines across childhood, excitability remains remarkably stable both within and across the group. Overall levels of excitability (excitability intercept) predict later emotion dysregulation as measured by parent and self-report and predict decreased functional magnetic resonance imaging activity in cognitive emotion regulation regions during an emotion regulation task. Irritability was not related to any dysregulation outcome above and beyond excitability.
Using ecological momentary assessment to enhance irritability phenotyping in a transdiagnostic sample of youth
Authors: Naim Reut , Smith Ashley , Chue Amanda , Grassie Hannah , Linke Julia , Dombek Kelly , Shaughnessy Shannon , McNeil Cheri , Cardinale Elise , Agorsor Courtney , Cardenas Sofia , Brooks Julia , Subar Anni R. , Jones Emily L. , Do Quyen B. , Pine Daniel S. , Leibenluft Ellen , Brotman Melissa A. , Kircanski Katharina
Published: December 2021

Irritability is a transdiagnostic symptom dimension in developmental psychopathology, closely related to the Research Domain Criteria (RDoC) construct of frustrative nonreward. Consistent with the RDoC framework and calls for transdiagnostic, developmentally-sensitive assessment methods, we report data from a smartphone-based, naturalistic ecological momentary assessment (EMA) study of irritability. We assessed 109 children and adolescents (Mage= 12.55 years; 75.20% male) encompassing several diagnostic groups – disruptive mood dysregulation disorder (DMDD), attention-deficit/hyperactivity disorder (ADHD), anxiety disorders (ANX), healthy volunteers (HV). The participants rated symptoms three times per day for 1 week. Compliance with the EMA protocol was high. As tested using multilevel modeling, EMA ratings of irritability were strongly and consistently associated with in-clinic, gold-standard measures of irritability. Further, EMA ratings of irritability were significantly related to subjective frustration during a laboratory task eliciting frustrative nonreward. Irritability levels exhibited an expected graduated pattern across diagnostic groups, and the different EMA items measuring irritability were significantly associated with one another within all groups, supporting the transdiagnostic phenomenology of irritability. Additional analyses utilized EMA ratings of anxiety as a comparison with respect to convergent validity and transdiagnostic phenomenology. The results support new measurement tools that can be used in future studies of irritability and frustrative nonreward.
Applying new RDoC dimensions to the development of emotion regulation: Examining the influence of maternal emotion regulation on within-individual change in child emotion regulation
Authors: Byrd Amy L. , Lee Angela H. , Frigoletto Olivia A. , Zalewski Maureen , Stepp Stephanie D.
Published: December 2021

While the Research Domain Criteria (RDoC) acknowledges that environmental and developmental influences represent important elements of the RDoC framework, there is little specificity regardinghowandwhento systematically examine the impact of these dimensions on domains of function. The primary aims of this paper are to demonstrate the ways in which the RDoC can be expanded to include an explicit emphasis on (a) assessing within-individual change in developmental processes over time and (b) evaluating the extent to which selective and measurable environmental influences drive meaningful change during key developmental periods. We provide data from an ongoing randomized control trial as a proof of concept to highlight how repeated assessments within an experimental intervention design affords the unique opportunity to test the impact of environmental influences on within-individual change. Using preliminary data from 77 mother–child dyads repeatedly assessed across 12 months during the sensitive preschool period, we demonstrate the impact of change in maternal emotion regulation (ER) on within-individual growth in child ER and link that growth to fewer teacher-reported externalizing problems. In line with this Special Issue, findings are discussed within the context of expanding and clarifying the existing RDoC framework to explicitly incorporate environmental and developmental dimensions.
The regulatory governance conditions that lead to food policies achieving improvements in population nutrition outcomes: a qualitative comparative analysis
Authors: Ngqangashe Yandisa , Friel Sharon , Schram Ashley
Published: December 2021

Objective:

To identify the regulatory governance factors that lead to food policies achieving improvements in food environment, consumer behaviour and diet-related health outcomes.

Design:

Qualitative comparative analysis (QCA) was used to investigate the relationship between regulatory governance conditions and population nutrition outcomes. The regulatory governance conditions examined entailed: high industry involvement in the policy process, regulatory design, policy instrument design, policy monitoring and enforcement.

Participants:

n29 policy cases in the policy areas of food reformulation, nutrition labelling, food taxation and food marketing.

Setting:

Policies implemented in thirteen countries.

Results:

Comprehensive monitoring was identified as anecessaryregulatory governance condition for food policies to have an impact and was present in 94 % of policy cases that had a positive impact on nutrition outcomes. We identified twosufficientcombinations of regulatory governance conditions. The firstsufficientcombination of conditions comprised an absence of high industry involvement in the policy process, combined with the presence of strict regulatory design, best-practice instrument design, and comprehensive monitoring and enforcement. Ninety-six percent of policy cases with positive impacts on nutrition outcomes displayed this combination. The secondsufficientcombination of conditions comprised an absensce of high industry involvement in the policy process, best practice instrument design and comprehensive monitoring. Eighty-two percent of policy cases with positive impacts on nutrition outcomes displayed this combination.

Conclusion:

These findings show the importance of regulatory governance on policy outcomes. They suggest a need for more government-led nutrition policy processes and transparent monitoring systems that are independent from industry.
Making ideas actionable in institutionalism: the case of trade liberalization in Kennedy's foreign economic policy
Authors: McAdam Mark
Published: December 2021

This article challenges exclusively rationalist accounts of and offers a complementary explanation for the emergence of liberal trade policy in the Kennedy administration. I draw on recent insights in constructivist institutionalism to emphasize the need to take agency seriously in institutionalist research. Using archival records, I analyze the decisive role Kennedy's advisers played as carriers of ideas in advocating for liberal trade policy by ‘constructing the national interest’, thus convincing a reticent president to support attempts aimed at achieving closer economic integration, culminating in the Trade Expansion Act of 1962. Insights from their role as advisers can help in specifying the role of agency in the ideas and institutional change literature, through strategic action which shaped a political leader's belief and put political issues on the agenda. By grasping agency in terms of making ideas actionable, an important step is taken in advancing endogenous approaches of institutional change.
Fluvial Organic Carbon Composition Regulated by Seasonal Variability in Lowland River Migration and Water Discharge
Authors: Golombek Nina Y. , Scheingross Joel S. , Repasch Marisa N. , Hovius Niels , Menges Johanna , Sachse Dirk , Lupker Maarten , Eglinton Timothy I. , Haghipour Negar , Poulson Simon R. , Gröcke Darren R. , Latosinski Francisco G. , Szupiany Ricardo N.
Published: December 2021

Identifying drivers of seasonal variations in fluvial particulate organic carbon (POC) composition can aid sediment provenance and biogeochemical cycling studies. We evaluate seasonal changes in POC composition in the Río Bermejo, Argentina, a lowland river running ∼1,270 km without tributaries. Weekly POC concentration and isotopic composition from 2016 to 2018 show that during the wet season, increased lateral channel migration generates an influx of 13C‐enriched and 14C‐enriched floodplain‐sourced material, overprinting the 13C‐depleted and 14C‐depleted headwater signature that is observed during the dry season. These findings demonstrate how channel morphodynamics can drive variability of POC composition in lowland rivers, and may modulate the composition of POC preserved in sedimentary archives.
Identifying Data Needed to Reduce Parameter Uncertainty in a Coupled Microbial Soil C and N Decomposition Model
Authors: Saifuddin Mustafa , Abramoff Rose Z. , Davidson Eric A. , Dietze Michael C. , Finzi Adrien C.
Published: December 2021

Advancements in microbially explicit ecosystem models incorporate increasingly accurate representations of microbial physiology and enzyme‐mediated depolymerization of soil organic matter in predicting biogeochemical responses to global change. However, a major challenge with model structural improvements is the requirement for additional parameters, which are often poorly constrained sources of uncertainty. Furthermore, it is often unclear how to best focus data collection efforts toward reducing model uncertainty. Here, we use Dual Arrhenius Michaelis‐Menten Microbial Carbon and Nitrogen Physiology, a microbially mediated, coupled soil C and N cycling model, as a tool to explore the influence of microbial physiological and enzyme kinetic parameters on model estimates. We first quantify the potential for constraining model parameters using empirical measurements of soil respiration. We then use simulated data to identify which additional sources of data collection from the field would provide the greatest impact for constraining model estimates. We find that modeled soil C and N pools and fluxes are disproportionately sensitive to only a few parameters (e.g., activation energies and microbial CUE), while others exert less influence (e.g., Michaelis‐Menten half‐saturation constants). While some parameters can be constrained by the available data on heterotrophic respiration, the collection of additional data on dissolved organic C and N pools in the soil is identified as a high‐priority data need. Improving our ability to model the interactions of soil microbial physiology, soil chemistry, enzyme activities, and environmental factors on C and N cycling will require closely considering model uncertainties and prioritizing future data collection opportunities based on their impact on model performance.
BIX01294 inhibits EGFR signaling in EGFR-mutant lung adenocarcinoma cells through a BCKDHA-mediated reduction in the EGFR level
Authors: Kim Ji Hye , Kim Jongwook , Im Se Seul , Lee Ji Hyeon , Hwang Sein , Chang Eun-Ju , Shin Dong-Myung , Rho Jin Kyung , Son Jaekyoung
Published: December 2021

BIX01294 (BIX), an inhibitor of the G9a histone methyltransferase, has been reported to have antitumor activity against a variety of cancers. However, the molecular mechanisms underlying its anticancer effects, particularly those against lung cancer, remain unclear. Here, we report that BIX induces apoptotic cell death in EGFR-mutant non-small cell lung cancer (NSCLC) cells but not in their wild-type counterparts. Treatment with BIX resulted in a significant reduction in the EGFR level and inhibition of EGFR signaling only in EGFR-mutant NSCLC cells, leading to apoptosis. BIX also inhibited mitochondrial metabolic function and decreased the cellular energy levels that are critical for maintaining the EGFR level. Furthermore, BIX transcriptionally downregulated the transcription of branched-chain α-keto acid dehydrogenase (BCKDHA), which is essential for fueling the tricarboxylic acid (TCA) cycle. Interestingly, this BCKDHA downregulation was due to inhibition of Jumanji-domain histone demethylases but not the G9a histone methyltransferase. We observed that KDM3A, a Jumonji histone demethylase, epigenetically regulates BCKDHA expression by binding to the BCKDHA gene promoter. BIX exposure also led to a significant decrease in the EGFR level, causing apoptosis in EGFR-TKI (tyrosine kinase inhibitor)-resistant cell lines, which are dependent on EGFR signaling for survival. Taken together, our current data suggest that BIX triggers apoptosis only in EGFR-mutant NSCLC cells via inhibition of BCKDHA-mediated mitochondrial metabolic function.
miR-140-3p enhanced the osteo/odontogenic differentiation of DPSCs via inhibiting KMT5B under hypoxia condition
Authors: Zheng Han , Wang Ning , Li Le , Ge Lihua , Jia Haichao , Fan Zhipeng
Published: December 2021

Human dental pulp stem cells (DPSCs) have emerged as an important source of stem cells in the tissue engineering, and hypoxia will change various innate characteristics of DPSCs and then affect dental tissue regeneration. Nevertheless, little is known about the complicated molecular mechanisms. In this study, we aimed to investigate the influence and mechanism of miR-140-3p on DPSCs under hypoxia condition. Hypoxia was induced in DPSCs by Cobalt chloride (CoCl2) treatment. The osteo/dentinogenic differentiation capacity of DPSCs was assessed by alkaline phosphatase (ALP) activity, Alizarin Red S staining and main osteo/dentinogenic markers. A luciferase reporter gene assay was performed to verify the downstream target gene of miR-140-3p. This research exhibited that miR-140-3p promoted osteo/dentinogenic differentiation of DPSCs under normoxia environment. Furthermore, miR-140-3p rescued the CoCl2-induced decreased osteo/odontogenic differentiation potentials in DPSCs. Besides, we investigated that miR-140-3p directly targeted lysine methyltransferase 5B (KMT5B). Surprisingly, we found inhibition of KMT5B obviously enhanced osteo/dentinogenic differentiation of DPSCs both under normoxia and hypoxia conditions. In conclusion, our study revealed the role and mechanism of miR-140-3p for regulating osteo/dentinogenic differentiation of DPSCs under hypoxia, and discovered that miR-140-3p and KMT5B might be important targets for DPSC-mediated tooth or bone tissue regeneration.
Underlying mechanisms of glucocorticoid-induced β-cell death and dysfunction: a new role for glycogen synthase kinase 3
Authors: Delangre Etienne , Liu Junjun , Tolu Stefania , Maouche Kamel , Armanet Mathieu , Cattan Pierre , Pommier Gaëlle , Bailbé Danielle , Movassat Jamileh
Published: December 2021

Glucocorticoids (GCs) are widely prescribed for their anti-inflammatory and immunosuppressive properties as a treatment for a variety of diseases. The use of GCs is associated with important side effects, including diabetogenic effects. However, the underlying mechanisms of GC-mediated diabetogenic effects in β-cells are not well understood. In this study we investigated the role of glycogen synthase kinase 3 (GSK3) in the mediation of β-cell death and dysfunction induced by GCs. Using genetic and pharmacological approaches we showed that GSK3 is involved in GC-induced β-cell death and impaired insulin secretion. Further, we unraveled the underlying mechanisms of GC-GSK3 crosstalk. We showed that GSK3 is marginally implicated in the nuclear localization of GC receptor (GR) upon ligand binding. Furthermore, we showed that GSK3 regulates the expression of GR at mRNA and protein levels. Finally, we dissected the proper contribution of each GSK3 isoform and showed that GSK3β isoform is sufficient to mediate the pro-apoptotic effects of GCs in β-cells. Collectively, in this work we identified GSK3 as a viable target to mitigate GC deleterious effects in pancreatic β-cells.
Metabolism of tissue macrophages in homeostasis and pathology
Authors: Wculek Stefanie K. , Dunphy Gillian , Heras-Murillo Ignacio , Mastrangelo Annalaura , Sancho David
Published: December 2021

Cellular metabolism orchestrates the intricate use of tissue fuels for catabolism and anabolism to generate cellular energy and structural components. The emerging field of immunometabolism highlights the importance of cellular metabolism for the maintenance and activities of immune cells. Macrophages are embryo- or adult bone marrow-derived leukocytes that are key for healthy tissue homeostasis but can also contribute to pathologies such as metabolic syndrome, atherosclerosis, fibrosis or cancer. Macrophage metabolism has largely been studied in vitro. However, different organs contain diverse macrophage populations that specialize in distinct and often tissue-specific functions. This context specificity creates diverging metabolic challenges for tissue macrophage populations to fulfill their homeostatic roles in their particular microenvironment and conditions their response in pathological conditions. Here, we outline current knowledge on the metabolic requirements and adaptations of macrophages located in tissues during homeostasis and selected diseases.
Viral evasion of the integrated stress response through antagonism of eIF2-P binding to eIF2B
Authors: Schoof Michael , Wang Lan , Cogan J. Zachery , Lawrence Rosalie E. , Boone Morgane , Wuerth Jennifer Deborah , Frost Adam , Walter Peter
Published: December 2021

Viral infection triggers activation of the integrated stress response (ISR). In response to viral double-stranded RNA (dsRNA), RNA-activated protein kinase (PKR) phosphorylates the translation initiation factor eIF2, converting it from a translation initiator into a potent translation inhibitor and this restricts the synthesis of viral proteins. Phosphorylated eIF2 (eIF2-P) inhibits translation by binding to eIF2’s dedicated, heterodecameric nucleotide exchange factor eIF2B and conformationally inactivating it. We show that the NSs protein of Sandfly Fever Sicilian virus (SFSV) allows the virus to evade the ISR. Mechanistically, NSs tightly binds to eIF2B (KD = 30 nM), blocks eIF2-P binding, and rescues eIF2B GEF activity. Cryo-EM structures demonstrate that SFSV NSs and eIF2-P directly compete, with the primary NSs contacts to eIF2Bα mediated by five ‘aromatic fingers’. NSs binding preserves eIF2B activity by maintaining eIF2B’s conformation in its active A-State.
Glacier retreat creating new Pacific salmon habitat in western North America
Authors: Pitman Kara J. , Moore Jonathan W. , Huss Matthias , Sloat Matthew R. , Whited Diane C. , Beechie Tim J. , Brenner Rich , Hood Eran W. , Milner Alexander M. , Pess George R. , Reeves Gordan H. , Schindler Daniel E.
Published: December 2021

Glacier retreat poses risks and benefits for species of cultural and economic importance. One example is Pacific salmon (Oncorhynchus spp.), supporting subsistence harvests, and commercial and recreational fisheries worth billions of dollars annually. Although decreases in summer streamflow and warming freshwater is reducing salmon habitat quality in parts of their range, glacier retreat is creating new streams and lakes that salmon can colonize. However, potential gains in future salmon habitat associated with glacier loss have yet to be quantified across the range of Pacific salmon. Here we project future gains in Pacific salmon freshwater habitat by linking a model of glacier mass change for 315 glaciers, forced by five different Global Climate Models, with a simple model of salmon stream habitat potential throughout the Pacific Mountain ranges of western North America. We project that by the year 2100 glacier retreat will create 6,146 (±1,619) km of new streams accessible for colonization by Pacific salmon, of which 1,930 (±569) km have the potential to be used for spawning and juvenile rearing, representing 0 to 27% gains within the 18 sub-regions we studied. These findings can inform proactive management and conservation of Pacific salmon in this era of rapid climate change.
Unveiling charge dynamics of visible light absorbing oxysulfide for efficient overall water splitting
Authors: Nandal Vikas , Shoji Ryota , Matsuzaki Hiroyuki , Furube Akihiro , Lin Lihua , Hisatomi Takashi , Kaneko Masanori , Yamashita Koichi , Domen Kazunari , Seki Kazuhiko
Published: December 2021

Oxysulfide semiconductor, Y2Ti2O5S2, has recently discovered its exciting potential for visible-light-induced overall water splitting, and therefore, imperatively requires the probing of unknown fundamental charge loss pathways to engineer the photoactivity enhancement. Herein, transient diffuse reflectance spectroscopy measurements are coupled with theoretical calculations to unveil the nanosecond to microsecond time range dynamics of the photogenerated charge carriers. In early nanosecond range, the pump-fluence-dependent decay dynamics of the absorption signal is originated from the bimolecular recombination of mobile charge carriers, in contrast, the power-law decay kinetics in late microsecond range is dominated by hole detrapping from exponential tail trap states of valence band. A well-calibrated theoretical model estimates various efficiency limiting material parameters like recombination rate constant, n-type doping density and tail-states parameters. Compared to metal oxides, longer effective carrier lifetime ~6 ns is demonstrated. Different design routes are proposed to realize efficiency beyond 10% for commercial solar-to-hydrogen production from oxysulfide photocatalysts.
Visualizing nanometric structures with sub-millimeter waves
Authors: Ingar Romero Alonso , Mukherjee Amlan kusum , Fernandez Olvera Anuar , Méndez Aller Mario , Preu Sascha
Published: December 2021

The resolution along the propagation direction of far field imagers can be much smaller than the wavelength by exploiting coherent interference phenomena. We demonstrate a height profile precision as low as 31 nm using wavelengths between 0.375 mm and 0.5 mm (corresponding to 0.6 THz–0.8 THz) by evaluating the Fabry-Pérot oscillations within surface-structured samples. We prove the extreme precision by visualizing structures with a height of only 49 nm, corresponding to 1:7500 to 1:10000 vacuum wavelengths, a height difference usually only accessible to near field measurement techniques at this wavelength range. At the same time, the approach can determine thicknesses in the centimeter range, surpassing the dynamic range of any near field measurement system by orders of magnitude. The measurement technique combined with a Hilbert-transform approach yields the (optical) thickness extracted from the relative phase without any extraordinary wavelength stabilization.
Legless soft robots capable of rapid, continuous, and steered jumping
Authors: Chen Rui , Yuan Zean , Guo Jianglong , Bai Long , Zhu Xinyu , Liu Fuqiang , Pu Huayan , Xin Liming , Peng Yan , Luo Jun , Wen Li , Sun Yu
Published: December 2021

Jumping is an important locomotion function to extend navigation range, overcome obstacles, and adapt to unstructured environments. In that sense, continuous jumping and direction adjustability can be essential properties for terrestrial robots with multimodal locomotion. However, only few soft jumping robots can achieve rapid continuous jumping and controlled turning locomotion for obstacle crossing. Here, we present an electrohydrostatically driven tethered legless soft jumping robot capable of rapid, continuous, and steered jumping based on a soft electrohydrostatic bending actuator. This 1.1 g and 6.5 cm tethered soft jumping robot is able to achieve a jumping height of 7.68 body heights and a continuous forward jumping speed of 6.01 body lengths per second. Combining two actuator units, it can achieve rapid turning with a speed of 138.4° per second. The robots are also demonstrated to be capable of skipping across a multitude of obstacles. This work provides a foundation for the application of electrohydrostatic actuation in soft robots for agile and fast multimodal locomotion.
Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood
Authors: Kariotis Sokratis , Jammeh Emmanuel , Swietlik Emilia M. , Pickworth Josephine A. , Rhodes Christopher J. , Otero Pablo , Wharton John , Iremonger James , Dunning Mark J. , Pandya Divya , Mascarenhas Thomas S. , Errington Niamh , Thompson A. A. Roger , Romanoski Casey E. , Rischard Franz , Garcia Joe G. N. , Yuan Jason X.-J. , An Tae-Hwi Schwantes , Desai Ankit A. , Coghlan Gerry , Lordan Jim , Corris Paul A. , Howard Luke S. , Condliffe Robin , Kiely David G. , Church Colin , Pepke-Zaba Joanna , Toshner Mark , Wort Stephen , Gräf Stefan , Morrell Nicholas W. , Wilkins Martin R. , Lawrie Allan , Wang Dennis ,   UK National PAH Cohort Study Consortium, Bleda Marta , Hadinnapola Charaka , Haimel Matthias , Auckland Kate , Tilly Tobias , Martin Jennifer M. , Yates Katherine , Treacy Carmen M. , Day Margaret , Greenhalgh Alan , Shipley Debbie , Peacock Andrew J. , Irvine Val , Kennedy Fiona , Moledina Shahin , MacDonald Lynsay , Tamvaki Eleni , Barnes Anabelle , Cookson Victoria , Chentouf Latifa , Ali Souad , Othman Shokri , Ranganathan Lavanya , Gibbs J. Simon R. , DaCosta Rosa , Pinguel Joy , Dormand Natalie , Parker Alice , Stokes Della , Ghedia Dipa , Tan Yvonne , Ngcozana Tanaka , Wanjiku Ivy , Polwarth Gary , Mackenzie Ross Rob V. , Suntharalingam Jay , Grover Mark , Kirby Ali , Grove Ali , White Katie , Seatter Annette , Creaser-Myers Amanda , Walker Sara , Roney Stephen , Elliot Charles A. , Charalampopoulos Athanasios , Sabroe Ian , Hameed Abdul , Armstrong Iain , Hamilton Neil , Rothman Alex M. K. , Swift Andrew J. , Wild James M. , Soubrier Florent , Eyries Mélanie , Humbert Marc , Montani David , Girerd Barbara , Scelsi Laura , Ghio Stefano , Gall Henning , Ghofrani Ardi , Bogaard Harm J. , Vonk Noordegraaf Anton , Houweling Arjan C. , Veld Anna Huis in’t , Schotte Gwen , Trembath Richard C.
Published: December 2021

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH.
eIF2B-capturing viral protein NSs suppresses the integrated stress response
Authors: Kashiwagi Kazuhiro , Shichino Yuichi , Osaki Tatsuya , Sakamoto Ayako , Nishimoto Madoka , Takahashi Mari , Mito Mari , Weber Friedemann , Ikeuchi Yoshiho , Iwasaki Shintaro , Ito Takuhiro
Published: December 2021

Various stressors such as viral infection lead to the suppression of cap-dependent translation and the activation of the integrated stress response (ISR), since the stress-induced phosphorylated eukaryotic translation initiation factor 2 [eIF2(αP)] tightly binds to eIF2B to prevent it from exchanging guanine nucleotide molecules on its substrate, unphosphorylated eIF2. Sandfly fever Sicilian virus (SFSV) evades this cap-dependent translation suppression through the interaction between its nonstructural protein NSs and host eIF2B. However, its precise mechanism has remained unclear. Here, our cryo-electron microscopy (cryo-EM) analysis reveals that SFSV NSs binds to the α-subunit of eIF2B in a competitive manner with eIF2(αP). Together with SFSV NSs, eIF2B retains nucleotide exchange activity even in the presence of eIF2(αP), in line with the cryo-EM structures of the eIF2B•SFSV NSs•unphosphorylated eIF2 complex. A genome-wide ribosome profiling analysis clarified that SFSV NSs expressed in cultured human cells attenuates the ISR triggered by thapsigargin, an endoplasmic reticulum stress inducer. Furthermore, SFSV NSs introduced in rat hippocampal neurons and human induced-pluripotent stem (iPS) cell-derived motor neurons exhibits neuroprotective effects against the ISR-inducing stress. Since ISR inhibition is beneficial in various neurological disease models, SFSV NSs may be a promising therapeutic ISR inhibitor.
Adiabatic versus non-adiabatic electron transfer at 2D electrode materials
Authors: Liu Dan-Qing , Kang Minkyung , Perry David , Chen Chang-Hui , West Geoff , Xia Xue , Chaudhuri Shayantan , Laker Zachary P. L. , Wilson Neil R. , Meloni Gabriel N. , Melander Marko M. , Maurer Reinhard J. , Unwin Patrick R.
Published: December 2021

2D electrode materials are often deployed on conductive supports for electrochemistry and there is a great need to understand fundamental electrochemical processes in this electrode configuration. Here, an integrated experimental-theoretical approach is used to resolve the key electronic interactions in outer-sphere electron transfer (OS-ET), a cornerstone elementary electrochemical reaction, at graphene as-grown on a copper electrode. Using scanning electrochemical cell microscopy, and co-located structural microscopy, the classical hexaamineruthenium (III/II) couple shows the ET kinetics trend: monolayer > bilayer > multilayer graphene. This trend is rationalized quantitatively through the development of rate theory, using the Schmickler-Newns-Anderson model Hamiltonian for ET, with the explicit incorporation of electrostatic interactions in the double layer, and parameterized using constant potential density functional theory calculations. The ET mechanism is predominantly adiabatic; the addition of subsequent graphene layers increases the contact potential, producing an increase in the effective barrier to ET at the electrode/electrolyte interface.
Vortex clustering, polarisation and circulation intermittency in classical and quantum turbulence
Authors: Polanco Juan Ignacio , Müller Nicolás P. , Krstulovic Giorgio
Published: December 2021

The understanding of turbulent flows is one of the biggest current challenges in physics, as no first-principles theory exists to explain their observed spatio-temporal intermittency. Turbulent flows may be regarded as an intricate collection of mutually-interacting vortices. This picture becomes accurate in quantum turbulence, which is built on tangles of discrete vortex filaments. Here, we study the statistics of velocity circulation in quantum and classical turbulence. We show that, in quantum flows, Kolmogorov turbulence emerges from the correlation of vortex orientations, while deviations—associated with intermittency—originate from their non-trivial spatial arrangement. We then link the spatial distribution of vortices in quantum turbulence to the coarse-grained energy dissipation in classical turbulence, enabling the application of existent models of classical turbulence intermittency to the quantum case. Our results provide a connection between the intermittency of quantum and classical turbulence and initiate a promising path to a better understanding of the latter.
Thawing Yedoma permafrost is a neglected nitrous oxide source
Authors: Marushchak M. E. , Kerttula J. , Diáková K. , Faguet A. , Gil J. , Grosse G. , Knoblauch C. , Lashchinskiy N. , Martikainen P. J. , Morgenstern A. , Nykamb M. , Ronkainen J. G. , Siljanen H. M. P. , van Delden L. , Voigt C. , Zimov N. , Zimov S. , Biasi C.
Published: December 2021

In contrast to the well-recognized permafrost carbon (C) feedback to climate change, the fate of permafrost nitrogen (N) after thaw is poorly understood. According to mounting evidence, part of the N liberated from permafrost may be released to the atmosphere as the strong greenhouse gas (GHG) nitrous oxide (N2O). Here, we report post-thaw N2O release from late Pleistocene permafrost deposits called Yedoma, which store a substantial part of permafrost C and N and are highly vulnerable to thaw. While freshly thawed, unvegetated Yedoma in disturbed areas emit little N2O, emissions increase within few years after stabilization, drying and revegetation with grasses to high rates (548 (133–6286) μg N m−2 day−1; median with (range)), exceeding by 1–2 orders of magnitude the typical rates from permafrost-affected soils. Using targeted metagenomics of key N cycling genes, we link the increase in in situ N2O emissions with structural changes of the microbial community responsible for N cycling. Our results highlight the importance of extra N availability from thawing Yedoma permafrost, causing a positive climate feedback from the Arctic in the form of N2O emissions.
Boosting quantum yields in two-dimensional semiconductors via proximal metal plates
Authors: Lee Yongjun , Forte Johnathas D’arf Severo , Chaves Andrey , Kumar Anshuman , Tran Trang Thu , Kim Youngbum , Roy Shrawan , Taniguchi Takashi , Watanabe Kenji , Chernikov Alexey , Jang Joon I. , Low Tony , Kim Jeongyong
Published: December 2021

Monolayer transition metal dichalcogenides (1L-TMDs) have tremendous potential as atomically thin, direct bandgap semiconductors that can be used as convenient building blocks for quantum photonic devices. However, the short exciton lifetime due to the defect traps and the strong exciton-exciton interaction in TMDs has significantly limited the efficiency of exciton emission from this class of materials. Here, we show that exciton-exciton interaction in 1L-WS2 can be effectively screened using an ultra-flat Au film substrate separated by multilayers of hexagonal boron nitride. Under this geometry, induced dipolar exciton-exciton interaction becomes quadrupole-quadrupole interaction because of effective image dipoles formed within the metal. The suppressed exciton-exciton interaction leads to a significantly improved quantum yield by an order of magnitude, which is also accompanied by a reduction in the exciton-exciton annihilation (EEA) rate, as confirmed by time-resolved optical measurements. A theoretical model accounting for the screening of the dipole-dipole interaction is in a good agreement with the dependence of EEA on exciton densities. Our results suggest that fundamental EEA processes in the TMD can be engineered through proximal metallic screening, which represents a practical approach towards high-efficiency 2D light emitters.
De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities
Authors: Okur Volkan , Chen Zefu , Vossaert Liesbeth , Peacock Sandra , Rosenfeld Jill , Zhao Lina , Du Haowei , Calamaro Emily , Gerard Amanda , Zhao Sen , Kelsay Jill , Lahr Ashley , Mighton Chloe , Porter Hillary M. , Siemon Amy , Silver Josh , Svihovec Shayna , Fong Chin-To , Grant Christina L. , Lerner-Ellis Jordan , Manickam Kandamurugu , Madan-Khetarpal Suneeta , McCandless Shawn E. , Morel Chantal F. , Schaefer G. Bradley , Berry-Kravis Elizabeth M. , Gates Ryan , Gomez-Ospina Natalia , Qiu Guixing , Zhang Terry Jianguo , Wu Zhihong , Meng Linyan , Liu Pengfei , Scott Daryl A. , Lupski James R. , Eng Christine M. , Wu Nan , Yuan Bo
Published: December 2021

The histone H3 variant H3.3, encoded by two genes H3-3A and H3-3B, can replace canonical isoforms H3.1 and H3.2. H3.3 is important in chromatin compaction, early embryonic development, and lineage commitment. The role of H3.3 in somatic cancers has been studied extensively, but its association with a congenital disorder has emerged just recently. Here we report eleven de novo missense variants and one de novo stop-loss variant in H3-3A (n = 6) and H3-3B (n = 6) from Baylor Genetics exome cohort (n = 11) and Matchmaker Exchange (n = 1), of which detailed phenotyping was conducted for 10 individuals (H3-3A = 4 and H3-3B = 6) that showed major phenotypes including global developmental delay, short stature, failure to thrive, dysmorphic facial features, structural brain abnormalities, hypotonia, and visual impairment. Three variant constructs (p.R129H, p.M121I, and p.I52N) showed significant decrease in protein expression, while one variant (p.R41C) accumulated at greater levels than wild-type control. One H3.3 variant construct (p.R129H) was found to have stronger interaction with the chaperone death domain-associated protein 6.
Trophoblast glycoprotein is a new candidate gene for Parkinson’s disease
Authors: Park Sanghyun , Yoo Jeong-Eun , Yeon Gyu-Bum , Kim Jin Hee , Lee Jae Souk , Choi Sung Kyoung , Hwang Young-Gi , Park Chan Wook , Cho Myung Soo , Kim Jongwan , Na Dokyun , Kim Hyung Wook , Kim Dae-Sung , Kim Dong-Wook
Published: December 2021

Parkinson’s disease (PD) is a movement disorder caused by progressive degeneration of the midbrain dopaminergic (mDA) neurons in the substantia nigra pars compacta (SNc). Despite intense research efforts over the past decades, the etiology of PD remains largely unknown. Here, we discovered the involvement of trophoblast glycoprotein (Tpbg) in the development of PD-like phenotypes in mice.Tpbgexpression was detected in the ventral midbrain during embryonic development and in mDA neurons in adulthood. Genetic ablation ofTpbgresulted in mild degeneration of mDA neurons in aged mice (12–14 months) with behavioral deficits reminiscent of PD symptoms. Through in silico analysis, we predicted potential TPBG-interacting partners whose functions were relevant to PD pathogenesis; this result was substantiated by transcriptomic analysis of the SNc of agedTpbgknockout mice. These findings suggest thatTpbgis a new candidate gene associated with PD and provide a new insight into PD pathogenesis.
Personalized modulation of coagulation factors using a thrombin dynamics model to treat trauma-induced coagulopathy
Authors: Ghetmiri Damon E. , Cohen Mitchell J. , Menezes Amor A.
Published: December 2021

Current trauma-induced coagulopathy resuscitation protocols use slow laboratory measurements, rules-of-thumb, and clinician gestalt to administer large volumes of uncharacterized, non-tailored blood products. These one-size-fits-all treatment approaches have high mortality. Here, we provide significant evidence that trauma patient survival 24 h after hospital admission occurs if and only if blood protein coagulation factor concentrations equilibrate at a normal value, either from inadvertent plasma-based modulation or from innate compensation. This result motivates quantitatively guiding trauma patient coagulation factor levels while accounting for protein interactions. Toward such treatment, we develop a Goal-oriented Coagulation Management (GCM) algorithm, a personalized and automated ordered sequence of operations to compute and specify coagulation factor concentrations that rectify clotting. This novel GCM algorithm also integrates new control-oriented advancements that we make in this work: an improvement of a prior thrombin dynamics model that captures the coagulation process to control, a use of rapidly-measurable concentrations to help predict patient state, and an accounting of patient-specific effects and limitations when adding coagulation factors to remedy coagulopathy. Validation of the GCM algorithm’s guidance shows superior performance over clinical practice in attaining normal coagulation factor concentrations and normal clotting profiles simultaneously.
Multi-omic machine learning predictor of breast cancer therapy response
Authors: Sammut Stephen-John , Crispin-Ortuzar Mireia , Chin Suet-Feung , Provenzano Elena , Bardwell Helen A. , Ma Wenxin , Cope Wei , Dariush Ali , Dawson Sarah-Jane , Abraham Jean E. , Dunn Janet , Hiller Louise , Thomas Jeremy , Cameron David A. , Bartlett John M. S. , Hayward Larry , Pharoah Paul D. , Markowetz Florian , Rueda Oscar M. , Earl Helena M. , Caldas Carlos
Published: December 2021

Breast cancers are complex ecosystems of malignant cells and the tumour microenvironment1. The composition of these tumour ecosystems and interactions within them contribute to responses to cytotoxic therapy2. Efforts to build response predictors have not incorporated this knowledge. We collected clinical, digital pathology, genomic and transcriptomic profiles of pre-treatment biopsies of breast tumours from 168 patients treated with chemotherapy with or without HER2 (encoded byERBB2)-targeted therapy before surgery. Pathology end points (complete response or residual disease) at surgery3were then correlated with multi-omic features in these diagnostic biopsies. Here we show that response to treatment is modulated by the pre-treated tumour ecosystem, and its multi-omics landscape can be integrated in predictive models using machine learning. The degree of residual disease following therapy is monotonically associated with pre-therapy features, including tumour mutational and copy number landscapes, tumour proliferation, immune infiltration and T cell dysfunction and exclusion. Combining these features into a multi-omic machine learning model predicted a pathological complete response in an external validation cohort (75 patients) with an area under the curve of 0.87. In conclusion, response to therapy is determined by the baseline characteristics of the totality of the tumour ecosystem captured through data integration and machine learning. This approach could be used to develop predictors for other cancers.
Just noticeable differences for elbow joint torque feedback
Authors: Kim Hubert , Asbeck Alan T.
Published: December 2021

Joint torque feedback is a new and promising means of kinesthetic feedback imposed by a wearable device. The torque feedback provides the wearer temporal and spatial information during a motion task. Nevertheless, little research has been conducted on quantifying the psychophysical parameters of how well humans can perceive external torques under various joint conditions. This study aims to investigate the just noticeable difference (JND) perceptual ability of the elbow joint to joint torques. The paper focuses on the ability of two primary joint proprioceptors, the Golgi-tendon organ (GTO) and muscle spindle (MS), to detect elbow torques, since touch and pressure sensors were masked. We studied 14 subjects while the arm was isometrically contracted (static condition) and was moving at a constant speed (dynamic condition). In total there were 10 joint conditions investigated, which varied the direction of the arm’s movement and the preload direction as well as torque direction. The JND torques under static conditions ranged from 0.097 Nm with no preload to 0.197 Nm with a preload of 1.28 Nm. The maximum dynamic JND torques were 0.799 Nm and 0.428 Nm, when the arm was flexing and extending at 213 degrees per second, respectively.
Distinct characteristics of multisystem inflammatory syndrome in children in Poland
Authors: Ludwikowska Kamila Maria , Okarska-Napierała Magdalena , Dudek Natalia , Tracewski Paweł , Kusa Jacek , Piwoński Krzysztof Piotr , Afelt Aneta , Cysewski Dominik , Biela Mateusz , Werner Bożena , Jackowska Teresa , Suski-Grabowski Catherine , Kursa Miron Bartosz , Kuchar Ernest , Szenborn Leszek ,   MOIS CoR Study Group, Barszcz Marta , Berdej-Szczot Elżbieta , Brzuszkiewicz Sebastian , Buda Piotr , Czajka Alicja , Czech Agnieszka , Czerwińska Ewa , Figlerowicz Magdalena , Firek-Pędras Małgorzata , Gawlik Aneta , Gowin Ewelina , Izdebska Olga , Januszkiewicz-Lewandowska Danuta , Kiepuszka Justyna , Koczwara Agnieszka , Koszałko Danuta , Kośmider-Żurawska Magdalena , Książyk Janusz , Kucińska Beata , Kukawska Martyna , Lackowska Anita , Łapacz Katarzyna , Maliszak Agnieszka , Mania Anna , Mańdziuk Joanna , Mazur Artur , Mazur-Melewska Katarzyna , Niszczota Cezary , Opalińska-Zielonka Paulina , Pałyga-Bysiecka Ilona , Rojewska Katarzyna , Rożnowska-Wójtowicz Anna , Siewert Bartosz , Sobiczewska Paulina , Stopyra Lidia , Stroba-Żelek Agnieszka , Stryczyńska-Kazubska Joanna , Szatkowski Tomasz , Szczepańska Barbara , Szczukocki Maciej , Szylo Robert , Tyc Filip , Wielgos Katarzyna , Wołowska Ewa , Wysocki Jacek , Zacharzewska Anna , Zaniew Marcin , Zielińska Marzena , Zięba-Glonek Katarzyna
Published: December 2021

During the winter months of 2020/2021 a wave of multisystem inflammatory syndrome in children (MIS-C) emerged in Poland. We present the results of a nationwide register aiming to capture and characterise MIS-C with a focus on severity determinants. The first MIS-C wave in Poland was notably high, hence our analysis involved 274 children. The group was 62.8% boys, with a median age of 8.8 years. Besides one Asian, all were White. Overall, the disease course was not as severe as in previous reports, however. Pediatric intensive care treatment was required for merely 23 (8.4%) of children, who were older and exhibited a distinguished clinical picture at hospital admission. We have also identified sex-dependent differences; teenage boys more often had cardiac involvement (decreased ejection fraction in 25.9% vs. 14.7%) and fulfilled macrophage activation syndrome definition (31.0% vs. 15.2%). Among all boys, those hospitalized in pediatric intensive care unit were significantly older (median 11.2 vs. 9.1 years). Henceforth, while ethnicity and sex may affect MIS-C phenotype, management protocols might be not universally applicable, and should rather be adjusted to the specific population.