bluuebunny/crossref_metadata_2025 huggingface dataset:
Congenital tricuspid insufficiency due to rupture of chordae tendinea secondary to intrauterine obliteration of ductus arteriosus
Authors: Sari Gizem , Oteyaka Emre , Kuguoglu Okan Eren , Basunlu Mehmet Turan , Karakurt Yakup , Yozgat Yilmaz , Demirel Gamze , Ugurlucan Murat , Tastekin Ayhan , Turkoglu Halil
Published: May 2022

Congenital rupture of tricuspid chordae tendinea leading to severe tricuspid insufficiency is an extremely rare pathology associated with signs and symptoms of congestive heart failure presenting at birth. If the diagnosis and treatment of this pathology are not made early in life fetal demise may become inevitable.

We herein present a neonate with central cyanosis and congestive heart failure due to rupture of an anterior leaflet chordae resulting in severe insufficiency of the tricuspid valve who was treated with appropriate surgery.
Rare presentation of eosinophilic granulomatosis polyangiitis with left ventricular endomyocardial fibrosis in a child
Authors: Doraiswamy Vinoth , Vengudusamy Sivakumar , Arumugam Jayavardhana
Published: May 2022

Eosinophilic granulomatosis polyangiitis represents less than 2% of vasculitis cases in childhood. Children have worse long-term outcomes and higher mortality. Cardiac involvement portends a worse prognosis. We describe here an adolescent girl who presented with heart failure and stroke. Her blood investigations showed eosinophilia and high IgE levels. Cardiac evaluation revealed myocarditis, intracardiac thrombus, and endomyocardial fibrosis, a rare presentation of this disease in childhood.
Crimean Tatar Infrastructures of Decolonial Care
Authors: Engelhardt Anna , Shestakova Sasha
Published: May 2022

This article employs the framework of critical infrastructure studies to outline the settler–colonial oppression and decolonial resistance in the Crimean Peninsula. It shows how Soviet and Russian colonialism intertwined ongoing landscape destruction with forced displacements and colonial othering. In addition, it outlines the laborious process of decolonial nourishment to define infrastructure beyond settler terms, questioning what counts as such. The text counters Russian colonial understanding of infrastructure that could not comprehend indigenous Crimean Tatar irrigation systems, constructed through intimate relations with soil and water rather than large-scale geoengineering. The Crimean Tatar water infrastructures are considered, in line with other forms of resistance, as ones of decolonial care. They create the possibility of a future which goes against that imposed by the Russian state.
Determinants of egg consumption by infants and young children in Ethiopia
Authors: Kase Bezawit E , Frongillo Edward A , Isanovic Sejla , Gonzalez Wendy , Wodajo Hana Yemane , Djimeu Eric W
Published: May 2022

Objective:

To identify determinants of egg consumption in infants and young children aged 6–23·9 months in Ethiopia.

Design and setting:

Data used were from the cross-sectional baseline survey of an egg campaign in Ethiopia implemented by the Global Alliance for Improved Nutrition.

Participants:

Children aged 6–23·9 months (n 453) were sampled. Data on socio-demographic characteristics, economic resources, caregiver’s behaviour, child health and feeding practices, and egg consumption in the last 7 d were collected using interviewer-administered questionnaires. Multivariable ordinal logistic regression was used to examine the association between explanatory variables and egg consumption in the last 7 d.

Results:

About half of children (53·4 %) did not consume eggs in the last 7 d. The odds of children consuming eggs were 4·33 (P < 0·002) times higher when their caregivers had some college education compared with no education. Wealth was positively (OR, 1·13, P = 0·029) and household food insecurity was negatively (OR, 0·96, P = 0·117) associated with child egg consumption. Purchasing eggs (OR, 9·73, P < 0·001) and caregiver’s positive behavioural determinants (OR, 1·37, P = 0·005) were associated with child egg consumption. The associations of socio-demographic characteristics and economic resources with egg consumption provide evidence of partial mediation through caregiver behaviour and child health.

Conclusions:

About half of children aged 6–23·9 months consumed eggs. Availability of eggs in households, mainly through purchase, was strongly associated with egg consumption. Education of caregivers and household heads and economic resources were associated with egg consumption and may operate through caregiver behaviour.
Group-based nutrition interventions to promote healthy eating and mobility in community-dwelling older adults: a systematic review
Authors: Teggart Kylie , Ganann Rebecca , Sihota Davneet , Moore Caroline , Keller Heather , Senson Christine , Phillips Stuart M , Neil-Sztramko Sarah E
Published: May 2022

Objective:

To identify the efficacy of group-based nutrition interventions to increase healthy eating, reduce nutrition risk, improve nutritional status and improve physical mobility among community-dwelling older adults.

Design:

Systematic review. Electronic databases MEDLINE, CINAHL, EMBASE, PsycINFO and Sociological Abstracts were searched on July 15, 2020 for studies published in English since January 2010. Study selection, critical appraisal (using the Joanna Briggs Institute’s tools) and data extraction were performed in duplicate by two independent reviewers.

Setting:

Nutrition interventions delivered to groups in community-based settings were eligible. Studies delivered in acute or long-term care settings were excluded.

Participants:

Community-dwelling older adults aged 55+ years. Studies targeting specific disease populations or promoting weight loss were excluded.

Results:

Thirty-one experimental and quasi-experimental studies with generally unclear to high risk of bias were included. Interventions included nutrition education with behaviour change techniques (BCT) (e.g. goal setting, interactive cooking demonstrations) (n 21), didactic nutrition education (n 4), interactive nutrition education (n 2), food access (n 2) and nutrition education with BCT and food access (n 2). Group-based nutrition education with BCT demonstrated the most promise in improving food and fluid intake, nutritional status and healthy eating knowledge compared with baseline or control. The impact on mobility outcomes was unclear.

Conclusions:

Group-based nutrition education with BCT demonstrated the most promise for improving healthy eating among community-dwelling older adults. Our findings should be interpreted with caution related to generally low certainty, unclear to high risk of bias and high heterogeneity across interventions and outcomes. Higher quality research in group-based nutrition education for older adults is needed.
Reparations for victims of terrorist acts in Sahel conflicts: The case of Niger
Authors: Koundy Maman Aminou A.
Published: May 2022

After the crisis in Mali erupted in 2012, numerous conflicts have broken out in countries of the Sahel and resulted in many violations of international human rights law and international humanitarian law. While these bodies of law were designed primarily to protect individuals or categories of individuals, they also require that reparations be made for harm suffered by the victims of such violations. Despite the ever-growing number of victims in conflicts in the Sahel in general and in Niger in particular, it is evident that States of the Sahel have not made a priority of meeting the reparation obligation, which falls mainly on them. However, the specific nature of the harm suffered (as a result, in part, of civilians being targeted) in terrorist-related conflicts calls for a prompt reaction by States, as they are the true targets of acts perpetrated by terrorist-designated non-State armed groups, while individuals and communities are only proxy victims. A legal, institutional and operational framework for victim reparations needs to be set up by the States, but that has yet to happen, even though it is one of the conditions of durable conflict resolution. The scattered initiatives that have been launched in Niger would gain from being brought together under a holistic framework with a global strategic vision.
The Relative Impacts of Initialization and Climate Forcing in Coupled Ice Sheet‐Ocean Modeling: Application to Pope, Smith, and Kohler Glaciers
Authors: Goldberg D. N. , Holland P. R.
Published: May 2022

Coupled ice sheet‐ocean models are beginning to be used to study the response of ice sheets to ocean warming. Initializing an ice‐ocean model is challenging and can introduce nonphysical transients, and the extent to which such transients can affect model projections is unclear. We use a synchronously‐coupled ice‐ocean model to investigate evolution of Pope, Smith and Kohler Glaciers, West Antarctica, over the next half‐century. Two methods of initialization are used: In one, the ice‐sheet model is constrained with observed velocities in its initial state; in another, the model is constrained with both velocities and grounded thinning rates over a 4‐year period. Each method is applied to two basal sliding laws. For each resulting initialization, two climate scenarios are considered: one where ocean conditions during the initialization period persist indefinitely, and one where the ocean is in a permanent “warm” state. At first, model runs initialized with thinning data exhibit volume loss rates much closer to observed values than those initialized with velocity only, but after 1–2 decades, the forcing primarily determines rates of volume loss and grounding line retreat. Such behavior is seen for both basal sliding laws, although volume loss rates differ quantitatively. Under the “warm” scenario, a grounding line retreat of ∼30 km is simulated for Smith and Kohler, although variation in total retreat due to initialization is nearly as large as that due to forcing. Furthermore it is questionable whether retreat will continue due to narrowing of submarine troughs and limiting of heat transport by bathymetric obstacles.
Bonded Discrete Element Simulations of Sea Ice With Non‐Local Failure: Applications to Nares Strait
Authors: West Brendan , O’Connor Devin , Parno Matthew , Krackow Max , Polashenski Christopher
Published: May 2022

The discrete element method (DEM) can provide detailed descriptions of sea ice dynamics that explicitly model floes and discontinuities in the ice, which can be challenging to represent accurately with current models. However, floe‐scale stresses that inform lead formation in sea ice are difficult to calculate in current DEM implementations. In this paper, we use the ParticLS software library to develop a DEM that models the sea ice as a collection of discrete rigid particles that are initially bonded together using a cohesive beam model that approximates the response of an Euler‐Bernoulli beam located between particle centroids. Ice fracture and lead formation are determined based on the value of a non‐local Cauchy stress state around each particle and a Mohr‐Coulomb fracture model. Therefore, large ice floes are modeled as continuous objects made up of many bonded particles that can interact with each other, deform, and fracture. We generate particle configurations by discretizing the ice in MODIS satellite imagery into polygonal floes that fill the observed ice shape and extent. The model is tested on ice advecting through an idealized channel and through Nares Strait. The results indicate that the bonded DEM model is capable of qualitatively capturing the dynamic sea ice patterns through constrictions such as ice bridges, arch kinematic features, and lead formation. In addition, we apply spatial and temporal scaling analyses to illustrate the model's ability to capture heterogeneity and intermittency in the simulated ice deformation.
Effect of Macrorough Sidewalls on Flow Resistance in Steep Rough Channels
Authors: Maager F. , Hohermuth B. , Weitbrecht V. , Boes R. M.
Published: May 2022

Previous studies showed that macrorough sidewalls increase the stability of step‐pool sequences in steep narrow channels due to grain‐sidewall interactions (i.e., jamming) and bed shear stress reduction due to sidewall friction. The main goal of this study was to quantify sidewall and bed shear stress for six types of macrorough sidewalls using physical model tests. Experiments were conducted in a tilting flume with initial slopes of 4%–10% with fixed rough beds without step‐pool sequences and mobile rough beds containing step‐pool sequences. A hydraulic geometry relation to predict mean flow velocity was extended with the relative sidewall roughness to account for friction effects of macrorough sidewalls, resulting in mean prediction errors below 8% for the mobile bed experiments. Furthermore, the study presents a method to estimate flow resistance caused by the macrorough sidewalls by applying a modified sidewall correction. For the fixed rough bed, the macrorough sidewalls accounted for 10%–70% of the total shear stress. In the mobile bed experiments, the bed freely adjusted to the flow leading to the formation of step‐pool sequences. Consequently, sidewall friction accounted for 5%–40% of the total shear stress because the step‐pool structures induced larger flow resistance compared to the fixed bed experiments. Overall, the results allow to determine bed and sidewall shear stress in steep channels with macrorough bed and sidewalls, thereby enabling future studies to better quantify the mechanisms responsible for the increase in bed stability in step‐pool channels with macrorough sidewalls.
An Effective Trend Surface Fitting Framework for Spatial Analysis of Extreme Events
Authors: Love Charlotte A. , Skahill Brian E. , Russell Brook T. , Baggett Jeffrey S. , AghaKouchak Amir
Published: May 2022

The estimation of exceedance probabilities for extreme climatic events is critical for infrastructure design and risk assessment. Climatic events occur over a greater space than they are measured with point‐scale in situ gauges. In extreme value theory, the block maxima approach for spatial analysis of extremes depends on properly modeling the spatially varying Generalized Extreme Value marginal parameters (i.e., trend surfaces). Fitting these trend surfaces can be challenging since there are numerous spatial and temporal covariates that are potentially relevant for any given event type and region. Traditionally, covariate selection is based on assumptions regarding the topmost relevant drivers of the event. This work demonstrates the benefit of utilizing elastic‐net regression to support automatic selection from a relatively large set of physically relevant covariates during trend surface estimation. The trend surfaces presented are based on 24‐hr annual maximum precipitation for northeastern Colorado and the Texas‐Louisiana Gulf Coast.
The Mesoscale Gravity Wave Response to the 2022 Tonga Volcanic Eruption: AIRS and MLS Satellite Observations and Source Backtracing
Authors: Ern M. , Hoffmann L. , Rhode S. , Preusse P.
Published: May 2022

On 15 January 2022, the Hunga Tonga–Hunga Ha'apai volcano erupted violently. This exceptional event excited a manifold of atmospheric waves. Here, we focus on the mesoscale part of the wave spectrum. About 8.5 hr after the eruption a strong atmospheric gravity wave (GW) was observed in the stratosphere by the satellite instruments Atmospheric Infrared Sounder (AIRS) and Microwave Limb Sounder (MLS) in the vicinity of Tonga. By ray‐tracing, we confirm the eruption as the source of this GW event. We determine the wave characteristics of the GW in terms of horizontal and vertical wavelengths and GW momentum flux. The strength of the GW is compared to the usual Southern Hemisphere flux values during this week. The event is comparable to the strongest convective events considering MLS, and exceptionally strong considering AIRS, which observes faster waves only.
Responses of East Asian Winter Monsoon‐Australian Summer Monsoon to Local and Remote Orbital Forcing During Holocene
Authors: Wen Qin , Yan Mi , Liu Zhengyu , Liu Jian
Published: May 2022

Here, we perform a set of sensitivity experiments in a climate model to quantify the impacts of local and remote insolation changes on the East Asian winter monsoon (EASM) and Australian summer monsoon (AusSM) at early and middle Holocene relative to the present. We show that the EAWM during Holocene is enhanced, driven overwhelmingly by the local insolation change in the low to mid‐latitude Northern Hemisphere (NH) through its impacts on land‐sea thermal contrast, with the NH high latitude forcing playing a negligible role. In contrast, the AusSM is also enhanced, opposite to the local insolation forcing, because the local forcing impact is overwhelmed by that from the remote forcing of both NH low latitude and Southern Hemisphere high latitude, with the latter dominating in the mid‐Holocene.
Experimental Crystallization of the Lunar Magma Ocean, Initial Selenotherm and Density Stratification, and Implications for Crust Formation, Overturn and the Bulk Silicate Moon Composition
Authors: Schmidt Max W. , Kraettli Giuliano
Published: May 2022

Eleven isobaric experimental series simulate the fractional crystallization of 1,150 km deep lunar magma ocean. Crystallization begins at 1,850°C with olivine (to 32 per cent solidified, pcs), followed at 1,600°C by olivine + opx ± Cr‐spinel (to 62 pcs), at 1,210°C cpx + plagioclase ± olivine ± Ti‐spinel (to 97 pcs) and at 1,060°C quartz + cpx + plagioclase + Ti‐spinel, leaving 1.8 wt% residual magma that crystallizes minor K‐feldspar and apatite in addition. Melt compositions remain near 45 wt% SiO2, while FeO increases from 11 to 26 wt%, TiO2 peaks at 4 wt% at Ti‐spinel saturation. The available experimental liquid lines of descent yield an overall fractional crystallization sequence of olivine→opx→cpx + plagioclase→quartz→FeTi‐oxide. Plagioclase appears concomitantly with cpx, a result of the low magma ocean floor pressures (≤1 GPa) after 66%–76% of olivine + opx‐fractionation. A few wt% of FeTi‐oxides form mostly once the quartz + plagioclase + cpx‐cotectic is reached, cumulate densities remain ≤3,740 kg/m3. Scaled to a full magma ocean, plagioclase appears at 210–120 km depth, mainly as a function of bulk Al2O3. As buoyancy driven plagioclase‐cpx separation is likely limited, these depths may correspond to the primordial lunar crustal thickness. Allowing for complete plagioclase flotation to the quartz + plagioclase + cpx + FeTi‐oxide ± olivine cotectic yields 95–70 km primordial crust of anorthosite and quartz‐gabbro, far in excess of the 35–50 km observed. This supports an overturn of primordial layers, remelting of dense gabbroic cumulates in the harzburgitic cumulate mantle leading to further mixing and differentiation. We posit that such complex density induced convection led to a lunar marble cake mantle with primitive and fairly evolved reprocessed cumulates next to each other.
Investigation on Horizontal and Vertical Traveling Ionospheric Disturbances Propagation in Global‐Scale Using GNSS and Multi‐LEO Satellites
Authors: Ren Xiaodong , Mei Dengkui , Liu Hang , Zhang Xiaohong
Published: May 2022

Global Navigation Satellite System (GNSS) observations from worldwide ground‐based stations have been extensively used in traveling ionospheric disturbance (TID) detections. However, these observations primarily cover land area, thus causing a challenging problem of interpreting the global propagating characteristics of large‐scale TIDs (LSTIDs), especially over the ocean area. Meanwhile, Total Electron Content (TEC) values derived from ground‐based GNSS signals propagating through the whole ionosphere have an integral character, and we were unable to obtain the propagation and dissipation of TIDs in the vertical direction using solely ground‐based GNSS TEC data. In this study, apart from ground‐based GNSS observations, in situ data and GNSS observations from precise orbit determination receivers on board Low‐Earth‐Orbit (LEO) satellites were integrated for the first time for the global large‐scale TID investigation during the St. Patrick's Day geomagnetic storm. Through experiments, we found that LEO satellite observations effectively compensate for areas where the TIDs cannot be detected by sparse ground‐based GNSS data, particularly over the ocean and polar areas. The space‐borne TEC and in situ data provided the new observational evidences of LSTIDs propagating up to the topside ionosphere during the 17 March 2015 storm, serving as great supplements to ground‐based GNSS data. Combining space‐borne GNSS data with in situ data at various orbit altitudes offers opportunities for theoretical studies of TID propagations at different ionospheric heights and for a better understanding of the complex coupled processes of the TIDs with the geospace environment.
Deep learning acceleration of multiscale superresolution localization photoacoustic imaging
Authors: Kim Jongbeom , Kim Gyuwon , Li Lei , Zhang Pengfei , Kim Jin Young , Kim Yeonggeun , Kim Hyung Ham , Wang Lihong V. , Lee Seungchul , Kim Chulhong
Published: May 2022

A superresolution imaging approach that localizes very small targets, such as red blood cells or droplets of injected photoacoustic dye, has significantly improved spatial resolution in various biological and medical imaging modalities. However, this superior spatial resolution is achieved by sacrificing temporal resolution because many raw image frames, each containing the localization target, must be superimposed to form a sufficiently sampled high-density superresolution image. Here, we demonstrate a computational strategy based on deep neural networks (DNNs) to reconstruct high-density superresolution images from far fewer raw image frames. The localization strategy can be applied for both 3D label-free localization optical-resolution photoacoustic microscopy (OR-PAM) and 2D labeled localization photoacoustic computed tomography (PACT). For the former, the required number of raw volumetric frames is reduced from tens to fewer than ten. For the latter, the required number of raw 2D frames is reduced by 12 fold. Therefore, our proposed method has simultaneously improved temporal (via the DNN) and spatial (via the localization method) resolutions in both label-free microscopy and labeled tomography. Deep-learning powered localization PA imaging can potentially provide a practical tool in preclinical and clinical studies requiring fast temporal and fine spatial resolutions.
Long non-coding RNA LINC00926 regulates WNT10B signaling pathway thereby altering inflammatory gene expression in PTSD
Authors: Bam Marpe , Yang Xiaoming , Ginsberg Jay P. , Aiello Allison E. , Uddin Monica , Galea Sandro , Nagarkatti Prakash S. , Nagarkatti Mitzi
Published: May 2022

Post-traumatic stress disorder (PTSD), which frequently occurs in the aftermath of a psychologically traumatic event is characterized by heightened inflammation. People with PTSD also suffer from a number of comorbid clinical and behavioral disorders that are related to chronic inflammation. Thus, understanding the mechanisms of enhanced inflammation in PTSD can provide insights into the relationship between PTSD and associated comorbid disorders. In the current study, we investigated the role of large intervening non-coding RNAs (lincRNAs) in the regulation of inflammation in people diagnosed with PTSD. We observed that WNT ligand, WNT10B, was upregulated in the peripheral blood mononuclear cells (PBMCs) of PTSD patients. This observation was associated with higher H3K4me3 signals around WNT10B promotor in PTSD patients compared to those without PTSD. Increased H3K4me3 resulted from LINC00926, which we found to be upregulated in the PTSD sample, bringing in histone methyltransferase, MLL1, onto WNT10B promotor leading to the introduction of H3K4 trimethylation. The addition of recombinant human WNT10B to pre-activated peripheral blood mononuclear cells (PBMCs) led to increased expression of inflammatory genes such as IFNG and IL17A, suggesting that WNT10B is involved in their upregulation. Together, our data suggested that LINC00926 interacts physically with MLL1 and thereby controls the expression of IFNG and IL17A. This is the first time a long non-coding RNA is shown to regulate the expression of WNT10B and consequently inflammation. This observation has high relevance to our understanding of disease mechanisms of PTSD and comorbidities associated with PTSD.
ADAM10-cleaved ephrin-A5 contributes to prostate cancer metastasis
Authors: Cai Chenchen , Zhang Miaomiao , Liu Lei , Zhang Haoliang , Guo Yi , Lan Ting , Xu Yinhai , Ma Ping , Li Shibao
Published: May 2022

A disintegrin and metalloprotease-10(ADAM10) promotes the metastasis of prostate cancer (PCa), but the specific mechanism is indistinct. Herein, DU145 cell lines with stable overexpression and knockdown of ADAM10 were constructed. We found that ectopic expression of ADAM10 not only significantly facilitated cell proliferation, migration, invasion, and inhibited apoptosis, but also could specifically hydrolyze ephrin-A5 and release the ephrin-A5 soluble ectodomain into extracellular media in vitro. These effects were reversed by ADAM10 depletion or treatment of GI254023X. Meanwhile, the co-location and physical interaction among EphA3, ephrin-A5, and ADAM10 were observed in PCa cells using immunofluorescence and immunoprecipitation techniques. Interestingly, overexpression of EphA3 exerted opposite effects in DU145 (ephrin-A5 + ) cells and PC-3 (ephrin-A5 ± ) cells. In addition, the pro-tumor function of EphA3 was reversed by the treatment with the exogenous ephrin-A5-Fc, which increased the phosphorylation level of EphA3 in PC-3 (ephrin-A5 ± ) cells. In nude mice, ADAM10 accelerated growth of the primary tumor, decreased the level of ephrin-A5 in the tumor tissue, but increased the level of ephrin-A5 in the peripheral blood, accompanied with an increase in the expression of CD31 and VEGF (vascular endothelial growth factor) in the tissue. What is more, the serum ephrin-A5 content of patients with metastatic PCa was significantly higher than that of the non-metastatic group (P < 0.05). The receiver operating characteristic curve(ROC) showed that the area under the curve(AUC) of serum ephrin-A5 as a marker of PCa metastasis was 0.843, with a sensitivity of 93.5% and a specificity of 75%. It is concluded that ADAM10-mediated ephrin-A5 shedding promotes PCa metastasis via transforming the role of EphA3 from ligand-dependent tumor suppressor to ligand-independent promoter, and ephrin-A5 in the blood can be used as a new biomarker for PCa metastasis.
UBR5 targets tumor suppressor CDC73 proteolytically to promote aggressive breast cancer
Authors: Xiang Gang , Wang Shuxuan , Chen Ling , Song Mei , Song Xiaoxu , Wang Huan , Zhou Pengbo , Ma Xiaojing , Yu Jing
Published: May 2022

UBR5, a HECT-domain E3 ubiquitin ligase, is an attractive therapeutic target for aggressive breast cancers. Defining the substrates of UBR5 is crucial for scientific understanding and clinical intervention. Here, we demonstrate that CDC73, a component of the RNA polymerase II-associated factor 1 complex, is a key substrate that impedes UBR5’s profound tumorigenic and metastatic activities in triple-negative breast cancer (TNBC) via mechanisms of regulating the expression of β-catenin and E-cadherin, tumor cell apoptosis and CD8+ T cell infiltration. Expression of CDC73 is also negatively associated with the progression of breast cancer patients. Moreover, we show that UBR5 destabilizes CDC73 by polyubiquitination at Lys243, Lys247, and Lys257 in a non-canonical manner that is dependent on the non-phosphorylation state of CDC73 at Ser465. CDC73 could serve as a molecular switch to modulate UBR5’s pro-tumor activities and may provide a potential approach to developing breast cancer therapeutic interventions.
The kinase p38α functions in dendritic cells to regulate Th2-cell differentiation and allergic inflammation
Authors: Han Miaomiao , Ma Jingyu , Ouyang Suidong , Wang Yanyan , Zheng Tingting , Lu Peishan , Zheng Zihan , Zhao Weiheng , Li Hongjin , Wu Yun , Zhang Baohua , Hu Ran , Otsu Kinya , Liu Xinguang , Wan Ying , Li Huabin , Huang Gonghua
Published: May 2022

Dendritic cells (DCs) play a critical role in controlling T helper 2 (Th2) cell-dependent diseases, but the signaling mechanism that triggers this function is not fully understood. We showed that p38α activity in DCs was decreased upon HDM stimulation and dynamically regulated by both extrinsic signals and Th2-instructive cytokines. p38α-specific deletion in cDC1s but not in cDC2s or macrophages promoted Th2 responses under HDM stimulation. Further study showed that p38α in cDC1s regulated Th2-cell differentiation by modulating the MK2−c-FOS−IL-12 axis. Importantly, crosstalk between p38α-dependent DCs and Th2 cells occurred during the sensitization phase, not the effector phase, and was conserved between mice and humans. Our results identify p38α signaling as a central pathway in DCs that integrates allergic and parasitic instructive signals with Th2-instructive cytokines from the microenvironment to regulate Th2-cell differentiation and function, and this finding may offer a novel strategy for the treatment of allergic diseases and parasitic infection.
Selective plasticity of callosal neurons in the adult contralesional cortex following murine traumatic brain injury
Authors: Empl Laura , Chovsepian Alexandra , Chahin Maryam , Kan Wing Yin Vanessa , Fourneau Julie , Van Steenbergen Valérie , Weidinger Sanofer , Marcantoni Maite , Ghanem Alexander , Bradley Peter , Conzelmann Karl Klaus , Cai Ruiyao , Ghasemigharagoz Alireza , Ertürk Ali , Wagner Ingrid , Kreutzfeldt Mario , Merkler Doron , Liebscher Sabine , Bareyre Florence M.
Published: May 2022

Traumatic brain injury (TBI) results in deficits that are often followed by recovery. The contralesional cortex can contribute to this process but how distinct contralesional neurons and circuits respond to injury remains to be determined. To unravel adaptations in the contralesional cortex, we used chronic in vivo two-photon imaging. We observed a general decrease in spine density with concomitant changes in spine dynamics over time. With retrograde co-labeling techniques, we showed that callosal neurons are uniquely affected by and responsive to TBI. To elucidate circuit connectivity, we used monosynaptic rabies tracing, clearing techniques and histology. We demonstrate that contralesional callosal neurons adapt their input circuitry by strengthening ipsilateral connections from pre-connected areas. Finally, functional in vivo two-photon imaging demonstrates that the restoration of pre-synaptic circuitry parallels the restoration of callosal activity patterns. Taken together our study thus delineates how callosal neurons structurally and functionally adapt following a contralateral murine TBI.
Characterization of RNA content in individual phase-separated coacervate microdroplets
Authors: Wollny Damian , Vernot Benjamin , Wang Jie , Hondele Maria , Safrastyan Aram , Aron Franziska , Micheel Julia , He Zhisong , Hyman Anthony , Weis Karsten , Camp J. Gray , Tang T.‐Y. Dora , Treutlein Barbara
Published: May 2022

Condensates formed by complex coacervation are hypothesized to have played a crucial part during the origin-of-life. In living cells, condensation organizes biomolecules into a wide range of membraneless compartments. Although RNA is a key component of biological condensates and the central component of the RNA world hypothesis, little is known about what determines RNA accumulation in condensates and to which extend single condensates differ in their RNA composition. To address this, we developed an approach to read the RNA content from single synthetic and protein-based condensates using high-throughput sequencing. We find that certain RNAs efficiently accumulate in condensates. These RNAs are strongly enriched in sequence motifs which show high sequence similarity to short interspersed elements (SINEs). We observe similar results for protein-derived condensates, demonstrating applicability across different in vitro reconstituted membraneless organelles. Thus, our results provide a new inroad to explore the RNA content of phase-separated droplets at single condensate resolution.
Plasma-induced surface cooling
Authors: Tomko John A. , Johnson Michael J. , Boris David R. , Petrova Tzvetelina B. , Walton Scott G. , Hopkins Patrick E.
Published: May 2022

Plasmas are an indispensable materials engineering tool due to their unique ability to deliver a flux of species and energy to a surface. This energy flux serves to heat the surface out of thermal equilibrium with bulk material, thus enabling local physicochemical processes that can be harnessed for material manipulation. However, to-date, there have been no reports on the direct measurement of the localized, transient thermal response of a material surface exposed to a plasma. Here, we use time-resolved optical thermometry in-situ to show that the energy flux from a pulsed plasma serves to both heat and transiently cool the material surface. To identify potential mechanisms for this ‘plasma cooling,’ we employ time-resolved plasma diagnostics to correlate the photon and charged particle flux with the thermal response of the material. The results indicate photon-stimulated desorption of adsorbates from the surface is the most likely mechanism responsible for this plasma cooling.
Genome editing in animals with minimal PAM CRISPR-Cas9 enzymes
Authors: Vicencio Jeremy , Sánchez-Bolaños Carlos , Moreno-Sánchez Ismael , Brena David , Vejnar Charles E. , Kukhtar Dmytro , Ruiz-López Miguel , Cots-Ponjoan Mariona , Rubio Alejandro , Melero Natalia Rodrigo , Crespo-Cuadrado Jesús , Carolis Carlo , Pérez-Pulido Antonio J. , Giráldez Antonio J. , Kleinstiver Benjamin P. , Cerón Julián , Moreno-Mateos Miguel A.
Published: May 2022

The requirement for Cas nucleases to recognize a specific PAM is a major restriction for genome editing. SpCas9 variants SpG and SpRY, recognizing NGN and NRN PAMs, respectively, have contributed to increase the number of editable genomic sites in cell cultures and plants. However, their use has not been demonstrated in animals. Here we study the nuclease activity of SpG and SpRY by targeting 40 sites in zebrafish and C. elegans. Delivered as mRNA-gRNA or ribonucleoprotein (RNP) complexes, SpG and SpRY were able to induce mutations in vivo, albeit at a lower rate than SpCas9 in equivalent formulations. This lower activity was overcome by optimizing mRNA-gRNA or RNP concentration, leading to mutagenesis at regions inaccessible to SpCas9. We also found that the CRISPRscan algorithm could help to predict SpG and SpRY targets with high activity in vivo. Finally, we applied SpG and SpRY to generate knock-ins by homology-directed repair. Altogether, our results expand the CRISPR-Cas targeting genomic landscape in animals.
Reconstruct high-resolution 3D genome structures for diverse cell-types using FLAMINGO
Authors: Wang Hao , Yang Jiaxin , Zhang Yu , Qian Jianliang , Wang Jianrong
Published: May 2022

High-resolution reconstruction of spatial chromosome organizations from chromatin contact maps is highly demanded, but is hindered by extensive pairwise constraints, substantial missing data, and limited resolution and cell-type availabilities. Here, we present FLAMINGO, a computational method that addresses these challenges by compressing inter-dependent Hi-C interactions to delineate the underlying low-rank structures in 3D space, based on the low-rank matrix completion technique. FLAMINGO successfully generates 5 kb- and 1 kb-resolution spatial conformations for all chromosomes in the human genome across multiple cell-types, the largest resources to date. Compared to other methods using various experimental metrics, FLAMINGO consistently demonstrates superior accuracy in recapitulating observed structures with raises in scalability by orders of magnitude. The reconstructed 3D structures efficiently facilitate discoveries of higher-order multi-way interactions, imply biological interpretations of long-range QTLs, reveal geometrical properties of chromatin, and provide high-resolution references to understand structural variabilities. Importantly, FLAMINGO achieves robust predictions against high rates of missing data and significantly boosts 3D structure resolutions. Moreover, FLAMINGO shows vigorous cross cell-type structure predictions that capture cell-type specific spatial configurations via integration of 1D epigenomic signals. FLAMINGO can be widely applied to large-scale chromatin contact maps and expand high-resolution spatial genome conformations for diverse cell-types.
Molecular basis for inhibiting human glucose transporters by exofacial inhibitors
Authors: Wang Nan , Zhang Shuo , Yuan Yafei , Xu Hanwen , Defossa Elisabeth , Matter Hans , Besenius Melissa , Derdau Volker , Dreyer Matthias , Halland Nis , He Kaihui Hu , Petry Stefan , Podeschwa Michael , Tennagels Norbert , Jiang Xin , Yan Nieng
Published: May 2022

Human glucose transporters (GLUTs) are responsible for cellular uptake of hexoses. Elevated expression of GLUTs, particularly GLUT1 and GLUT3, is required to fuel the hyperproliferation of cancer cells, making GLUT inhibitors potential anticancer therapeutics. Meanwhile, GLUT inhibitor-conjugated insulin is being explored to mitigate the hypoglycemia side effect of insulin therapy in type 1 diabetes. Reasoning that exofacial inhibitors of GLUT1/3 may be favored for therapeutic applications, we report here the engineering of a GLUT3 variant, designated GLUT3exo, that can be probed for screening and validating exofacial inhibitors. We identify an exofacial GLUT3 inhibitor SA47 and elucidate its mode of action by a 2.3 Å resolution crystal structure of SA47-bound GLUT3. Our studies serve as a framework for the discovery of GLUTs exofacial inhibitors for therapeutic development.
Genomic diversity across the Rickettsia and ‘Candidatus Megaira’ genera and proposal of genus status for the Torix group
Authors: Davison Helen R. , Pilgrim Jack , Wybouw Nicky , Parker Joseph , Pirro Stacy , Hunter-Barnett Simon , Campbell Paul M. , Blow Frances , Darby Alistair C. , Hurst Gregory D. D. , Siozios Stefanos
Published: May 2022

Members of the bacterial genusRickettsiawere originally identified as causative agents of vector-borne diseases in mammals. However, manyRickettsiaspecies are arthropod symbionts and close relatives of ‘CandidatusMegaira’, which are symbiotic associates of microeukaryotes. Here, we clarify the evolutionary relationships between these organisms by assembling 26 genomes ofRickettsiaspecies from understudied groups, including the Torix group, and two genomes of ‘Ca. Megaira’ from various insects and microeukaryotes. Our analyses of the new genomes, in comparison with previously described ones, indicate that the accessory genome diversity and broad host range of TorixRickettsiaare comparable to those of all otherRickettsiacombined. Therefore, the Torix clade may play unrecognized roles in invertebrate biology and physiology. We argue this clade should be given its own genus status, for which we propose the name ‘CandidatusTisiphia’.
Epicardium-derived cells organize through tight junctions to replenish cardiac muscle in salamanders
Authors: Eroglu Elif , Yen Christopher Y. T. , Tsoi Yat-Long , Witman Nevin , Elewa Ahmed , Joven Araus Alberto , Wang Heng , Szattler Tamara , Umeano Chimezie H. , Sohlmér Jesper , Goedel Alexander , Simon András , Chien Kenneth R.
Published: May 2022

The contribution of the epicardium, the outermost layer of the heart, to cardiac regeneration has remained controversial due to a lack of suitable analytical tools. By combining genetic marker-independent lineage-tracing strategies with transcriptional profiling and loss-of-function methods, we report here that the epicardium of the highly regenerative salamander species Pleurodeles waltl has an intrinsic capacity to differentiate into cardiomyocytes. Following cryoinjury, CLDN6+ epicardium-derived cells appear at the lesion site, organize into honeycomb-like structures connected via focal tight junctions and undergo transcriptional reprogramming that results in concomitant differentiation into de novo cardiomyocytes. Ablation of CLDN6+ differentiation intermediates as well as disruption of their tight junctions impairs cardiac regeneration. Salamanders constitute the evolutionarily closest species to mammals with an extensive ability to regenerate heart muscle and our results highlight the epicardium and tight junctions as key targets in efforts to promote cardiac regeneration.
Dorzagliatin add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial
Authors: Yang Wenying , Zhu Dalong , Gan Shenglian , Dong Xiaolin , Su Junping , Li Wenhui , Jiang Hongwei , Zhao Wenjuan , Yao Minxiu , Song Weihong , Lu Yibing , Zhang Xiuzhen , Li Huifang , Wang Guixia , Qiu Wei , Yuan Guoyue , Ma Jianhua , Li Wei , Li Ziling , Wang Xiaoyue , Zeng Jiao’e , Yang Zhou , Liu Jingdong , Liang Yongqian , Lu Song , Zhang Huili , Liu Hui , Liu Ping , Fan Kuanlu , Jiang Xiaozhen , Li Yufeng , Su Qing , Ning Tao , Tan Huiwen , An Zhenmei , Jiang Zhaoshun , Liu Lijun , Zhou Zunhai , Zhang Qiu , Li Xuefeng , Shan Zhongyan , Xue Yaoming , Mao Hong , Shi Lixin , Ye Shandong , Zhang Xiaomei , Sun Jiao , Li Ping , Yang Tao , Li Feng , Lin Jingna , Zhang Zhinong , Zhao Ying , Li Ruonan , Guo Xiaohui , Yao Qi , Lu Weiping , Qu Shen , Li Hongmei , Tan Liling , Wang Wenbo , Yao Yongli , Chen Daoxiong , Li Yulan , Gao Jialin , Hu Wen , Fei Xiaoqiang , Wu Tianfeng , Dong Song , Jin Wenlong , Li Chenzhong , Zhao Dong , Feng Bo , Zhao Yu , Zhang Yi , Li Xiaoying , Chen Li
Published: May 2022

Metformin, the first-line therapy for type 2 diabetes (T2D), decreases hepatic glucose production and reduces fasting plasma glucose levels. Dorzagliatin, a dual-acting orally bioavailable glucokinase activator targeting both the pancreas and liver glucokinase, decreases postprandial glucose in patients with T2D. In this randomized, double-blind, placebo-controlled phase 3 trial, the efficacy and safety of dorzagliatin as an add-on therapy to metformin were assessed in patients with T2D who had inadequate glycemic control using metformin alone. Eligible patients with T2D (n = 767) were randomly assigned to receive dorzagliatin or placebo (1:1 ratio) as an add-on to metformin (1,500 mg per day) for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin (HbA1c) levels from baseline to week 24, and safety was assessed throughout the trial. At week 24, the least-squares mean change from baseline in HbA1c (95% confidence interval (CI)) was −1.02% (−1.11, −0.93) in the dorzagliatin group and −0.36% (−0.45, −0.26) in the placebo group (estimated treatment difference, −0.66%; 95% CI: −0.79, −0.53; P < 0.0001). The incidence of adverse events was similar between groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin and metformin combined therapy group. In patients with T2D who experienced inadequate glycemic control with metformin alone, dorzagliatin resulted in effective glycemic control with good tolerability and safety profile (NCT03141073).
Excitatory deep brain stimulation quenches beta oscillations arising in a computational model of the subthalamo-pallidal loop
Authors: Alavi Seyed Mojtaba , Mirzaei Amin , Valizadeh Alireza , Ebrahimpour Reza
Published: May 2022

Parkinson’s disease (PD) is associated with abnormal $$\beta$$
β
band oscillations (13–30 Hz) in the cortico-basal ganglia circuits. Abnormally increased striato-pallidal inhibition and strengthening the synaptic coupling between subthalamic nucleus (STN) and globus pallidus externa (GPe), due to the loss of dopamine, are considered as the potential sources of $$\beta$$
β
oscillations in the basal ganglia. Deep brain stimulation (DBS) of the basal ganglia subregions is known as a way to reduce the pathological $$\beta$$
β
oscillations and motor deficits related to PD. Despite the success of the DBS, its underlying mechanism is poorly understood and, there is controversy about the inhibitory or excitatory role of the DBS in the literature. Here, we utilized a computational network model of basal ganglia which consists of STN, GPe, globus pallidus interna, and thalamic neuronal population. This model can reproduce healthy and pathological $$\beta$$
β
oscillations similar to what has been observed in experimental studies. Using this model, we investigated the effect of DBS to understand whether its effect is excitatory or inhibitory. Our results show that the excitatory DBS is able to quench the pathological synchrony and $$\beta$$
β
oscillations, while, applying inhibitory DBS failed to quench the PD signs. In light of simulation results, we conclude that the effect of the DBS on its target is excitatory.
The impact of pitolisant, an H3 receptor antagonist/inverse agonist, on perirhinal cortex activity in individual neuron and neuronal population levels
Authors: Hirano Kyosuke , Morishita Yoshikazu , Minami Masabumi , Nomura Hiroshi
Published: May 2022

Histamine is a neurotransmitter that modulates neuronal activity and regulates various brain functions. Histamine H3 receptor (H3R) antagonists/inverse agonists enhance its release in most brain regions, including the cerebral cortex, which improves learning and memory and exerts an antiepileptic effect. However, the mechanism underlying the effect of H3R antagonists/inverse agonists on cortical neuronal activity in vivo remains unclear. Here, we show the mechanism by which pitolisant, an H3R antagonist/inverse agonist, influenced perirhinal cortex (PRh) activity in individual neuron and neuronal population levels. We monitored neuronal activity in the PRh of freely moving mice using in vivo Ca2+ imaging through a miniaturized one-photon microscope. Pitolisant increased the activity of some PRh neurons while decreasing the activity of others without affecting the mean neuronal activity across neurons. Moreover, it increases neuron pairs with synchronous activity in excitatory-responsive neuronal populations. Furthermore, machine learning analysis revealed that pitolisant altered the neuronal population activity. The changes in the population activity were dependent on the neurons that were excited and inhibited by pitolisant treatment. These findings indicate that pitolisant influences the activity of a subset of PRh neurons by increasing the synchronous activity and modifying the population activity.
Electric field induced pure spin-photo current in zigzag stanene and germanene nanoribbons
Authors: Rahimi F. , Phirouznia A.
Published: May 2022

The spin-photo current in single layer stanene and germanene under a linearly polarized light is theoretically investigated based on the tight-binding Hamiltonian combined with the nonequilibrium Green’s function at room temperature. The results show that by considering the simultaneous effect of the linear illumination and a vertical external electric field without any magnetic exchange element, pure spin-photo current without charge current is generated in two-dimensional lattices with a large intrinsic spin–orbit coupling. The necessity of enhanced spin life-time for detection of spin polarization can be explained by spin-valley locking concept. Spin-valley locking arises in buckled two-dimensional materials as a result of the large spin–orbit coupling and electric-field reversible valley spin polarization. Equal absorption of the linearly illumination at both valleys with different spin polarization, leads to pure spin-photo current injection. In addition, an acceptable photoresponsivity has been reported in a broad range of photon energy. The numerical results indicate high quantum efficiency with a maximum of nearly 83% and 50% for stanene and germanene, respectively. This work may pave theoretical reference toward design of new spin-optoelectronic devices based on satanene and germanene junctions with high performance.