bluuebunny/crossref_metadata_2025 huggingface dataset:
The settlement of Yauna, ‘Ionian’ identity and the Greek presence on the Syrian coast in the second half of the eighth century BC: a reassessment of two letters from the Nimrud correspondence
Authors: Radner Karen , Vacek Alexander
Published: March 2023

We offer a reassessment of two letters from the state correspondence of Tiglath-pileser III of Assyria (r. 744–727 BC) with the earliest references to a town called Yauna and a people called the Yauneans, as encountered on the eastern Mediterranean coast by the newly established imperial administration. Past scholarship connected these Assyrian terms with the ethnonym ‘Ionians’ and/or the toponym ‘Ionia’. The study narrows down the location of Yauna, drawing also on a review of the coastal sites that have produced Greek ceramic imports: although identification remains elusive, Yauna was certainly situated in the territory of the kingdom of Hamath, and later the Assyrian province of Ṣimirra. Discussion of the historical and cultural background of Yauna’s foundation highlights its significance for the ‘transfer debate’ and the phenomenon of the ‘Greeks overseas’. We argue that the Assyrians first encountered the Yauneans in this locality and that, to them, they were originally simply the inhabitants of Yauna. Due to the similarities perceived between them and (other?) Greeks appearing in the eastern Mediterranean, the Assyrians came to apply the ethnonym universally to all these people, who eventually adopted it for themselves. Thus, we support the argument that the term ‘Ionian’ originated in external nomenclature.
New Angles on Whiteness and the Making of the Modern World
Authors: Woollacott Angela
Published: March 2023

These four new books on whiteness show its continuing vitality as a scholarly field, while broadening its purview to encompass North America, Africa, India and Australia from the eighteenth to the twentieth centuries. Thematically they draw together the Enlightenment, intellectual and affective history, gender, economics, the field of international relations, labour and immigration. All will help us to combat white supremacy.
The Construction of Consent for High-altitude Resettlement in Tibet
Authors: Nyima Yonten , Yeh Emily T.
Published: March 2023

In 2018, the Tibet Autonomous Region began resettling pastoralists from high-altitude areas to newly built settlements in distant, lower-altitude farming locations under the “extremely high-altitude ecological resettlement” programme, with a stated dual purpose of environmental protection and improving pastoralist well-being. The programme is said to be based on a principle of “government guidance and voluntary participation.” However, despite its stated “voluntary” nature, the government reports a 100 per cent rate of agreement to participate. After examining the ecological rationales for resettlement and pastoralists’ reluctance to move owing to livelihood concerns and attachment to homeland, the article examines how consent is achieved. Based on official documents and reports as well as semi-structured interviews with officials and pastoralists in Nagchu Municipality, the core target area for the programme, the article identifies a three-step “thought-work” oriented process – beginning with an initial survey, followed by group incentives and warnings and then individual incentives and warnings – which is deployed until pastoralists sign a resettlement agreement. The process illustrates the dialectical relationship between coercion and consent.
Investigating European Cities in the Modern Age through the Lens of the Global Urban History Approach
Authors: Camerin Federico
Published: March 2023

This review article focuses on two key developments in urban history. The first is that the new transnational approach to urban history is significantly advancing the field and the second is that within the European context an important new emphasis is being placed on Eastern and Southern Europe. As claimed by Claus Møller Jørgensen in his review of nineteenth-century transnational urban history:

transnational urban history entails a measure of comparative work to find commonalities as hints of connections . . . The enlargement of scale and the search for connections does add new perspectives to urban history and produces new knowledge . . . Focusing on cities as the location of transnational processes of modernity brings urban place more centrally into discussions of national space and national histories.1
MBCT training in IAPT: the experience of the first UK government funded teacher training programme
Authors: Marx Robert , Menzies Pippa , Symon Richard , Turner Sally , Pound Amy
Published: March 2023

This paper reports on the experience of the first cohort of cognitive behaviour therapists completing the first delivery of a UK government-funded mindfulness-based cognitive therapy (MBCT) teacher-training. Trainees completed a new curriculum approved by NHS England and commissioned by Health Education England (HEE) that enabled them to teach MBCT in Improving Access to Psychological Therapies (IAPT) services in England and to meet the criteria for registration for the British Association of Mindfulness-Based Approaches (BAMBA). The components of the training are described. Mixed quantitative and qualitative methods were used to assess the experiences of those trainees who completed that training. High levels of satisfaction were reported and the ‘embodiment’ of the trainers and supervisors was flagged as particularly significant. The retreat was experienced as a core component of the training that helped deepen mindfulness practice. Various challenges were identified, including from the retreat, technical difficulties and challenges with completion for a minority of trainees. Learning from the difficulties and responses to them are reported.

Key learning aims

(1)

To understand the experience of trainees on an MBCT training programme for CBT therapists in Improving Access to Psychological Therapy (IAPT) services in England.

(2)

To identify key features of a training for CBT therapists that were experienced as helping or hindering learning.

(3)

To understand the content and issues involved in delivering a mindfulness-based cognitive therapy training.
What Mediates the Effect of Family Disruption in the COVID-19 Pandemic on Children’s Prosocial Behavior
Authors: Hughes Claire , Ronchi Luca , Heng Jean , Basile Chiara , Del Sette Paola , Lecce Serena ,   the i-FAM COVID-19 Consortium
Published: March 2023

Abstract. At the start of the COVID-19 pandemic, unprecedented social distancing rules (including mass school closures) dramatically constrained children’s social lives, jeopardizing human connections that foster prosocial development. This study of 2,516 families of 3–8-year-olds from six countries (China, Sweden, Australia, Italy, the USA, and the United Kingdom) examined whether children’s understanding or feelings about COVID-19 regulations mediated the expected association between COVID-19-related family disruption and children’s prosocial behavior, as indexed by parental ratings. For all six sites, family disruption indirectly predicted reduced prosocial behavior. Negative feelings about COVID-19 regulations mediated this association in all sites except China. Contrariwise, understanding of COVID-19 regulations was not implicated in the link between family disruption and reduced prosocial behavior.
Dealing With the COVID-19 Pandemic
Authors: Hechler Stefanie , Wendel Clarissa , Schneider Dana
Published: March 2023

Abstract. The COVID-19 pandemic with its substantial changes to social life affects social cognitions, which are important for solidarity during a global crisis. We investigated how distal defense strategies for dealing with threat, perceived threat, and contact experiences relate to people’s empathic reactions during lockdowns in two countries. In three studies ( N = 1,332), we found that more experienced threat is associated with higher personal distress. In Germany, but not in the United Kingdom, people who applied social defenses reported more empathic concern. Additionally, general positive contact experiences related positively to empathic concern and perspective taking. These other-directed empathic reactions correlated highly with solidarity with others across all studies. The findings indicate that people’s empathy changes with their social experiences during this global crisis.
New Insights on Ground Deformation at Campi Flegrei Caldera Inferred From Kinematics and Dynamics Investigation of Borehole Tilt
Authors: Falanga M. , Aquino I. , De Lauro E. , Petrosino S. , Ricco C.
Published: March 2023

The study of the ground deformation in active calderas provides valuable indications of the ongoing dynamical processes. In this framework, we analyze the borehole tiltmeter data recorded at Campi Flegrei (Southern Italy) from their first installation (1 April 2015), in order to retrieve the kinematics of the ground deformation and its main anomalies. Our approach involves the nonlinear dynamics analysis aimed at the identification of the degrees of freedom of the system and thus its complexity. Starting from the second part of the year 2020, the behavior of the dynamical system becomes collective, and a locally significant deviation of the deformative pattern from the background trend is observed. In particular, a series of 15 slow tilt variations (like jumps lasting a few days) appears in the ground deformation. They are associated with a very low‐dimensional system likely generated by a local second‐order source. The latter is related to fluid migration and it is superimposed on the primary one located in Pozzuoli town and driving the current uplift of Campi Flegrei. The effects of such a local, second‐order stress field are, indeed, evident in the area of the volcanic dome of Mt. Olibano, where they are measured as tilt steps. The superposition of primary and second‐order sources of deformation acting contemporaneously can justify the recent variations in geophysical and geochemical parameters. Our approach based on the joint dynamical and kinematical analyses of the tiltmeter data can be applied to other volcanic/tectonic areas or extended to other geophysical and geochemical variables.
Socioecological Predicament on Global Steeply Sloped Cropland
Authors: Wang Ling , Xu Baodong , Zhao Jinsong , Li Cai , Zeng Yi , Niu Yuhua , Yu Shuxia , Wang Zhen , Shi Zhi‐Hua
Published: March 2023

Cropland on steep slopes is crucial for smallholders to maintain food security and their livelihoods, but the social‐ecological predicament on global steeply sloped cropland is largely overlooked and remains unclear. Here we find that global steeply sloped cropland supports ∼168 million people's livelihoods. Large disparities in population pressure on steeply sloped cropland exist across the development spectrum, among which lower‐middle‐income countries have the highest population density (∼222 per km2) and low‐income countries have the largest population growth rate (∼62.1% from 2000 to 2020). Moreover, inhabitants of steeply sloped cropland, especially those belonging to low‐income countries, are marginalized from public services and face more environmental pressure represented by severe soil erosion and low cropland productivity. Our findings imply that residents of steeply sloped cropland deserve more attention to eradicate global poverty and inequality.
Sahel Droughts Induced by Large Volcanic Eruptions Over the Last Millennium in PMIP4/Past1000 Simulations
Authors: Villamayor J. , Khodri M. , Fang S.‐W. , Jungclaus J. H. , Timmreck C. , Zanchettin D.
Published: March 2023

This work provides evidence of the influence of large volcanic eruptions on Sahel rainfall relying on PMIP4/past1000 multi‐model simulations, covering the last millennium. A classification of volcanic eruptions in the last millennium according to the meridional symmetry of the associated radiative forcing reveals different mechanisms of the West African Monsoon response at inter‐annual timescale. In all cases, these simulated changes result in Sahel drying up to 2 years after an eruption. Besides, we add evidence of a role of varying volcanic activity across the past millennium in the Sahel precipitation variability at multi‐decadal to secular timescales.
Intermittent Upwelling Events Trigger Delayed, Major, and Reproducible Pico‐Nanophytoplankton Responses in Coastal Oligotrophic Waters
Authors: Fuchs R. , Rossi V. , Caille C. , Bensoussan N. , Pinazo C. , Grosso O. , Thyssen M.
Published: March 2023

Pico‐nanophytoplankton organisms are dominant in oceanic oligotrophic areas but their adaptive growth rates make their contribution to the carbon cycle difficult to estimate. Here we address their response capacities after sporadic wind gusts causing upwelling events in a coastal Mediterranean station. When the water column is stratified, corresponding to oligotrophic conditions, these events generate intense short‐lived nutrient pulses and seawater temperature drops lasting 6 days on average with decreases up to 10°C. Using an automated flow cytometer and statistical rupture‐detection methods, we characterize the responses of five pico‐nanophytoplankton functional groups at a two‐hour frequency from September 2019 to November 2021. These events trigger delayed increases in both abundances and biomasses following similar patterns for most groups that can overpass spring bloom values, and are immediately followed by an overall decrease, suggesting a clear physical driver. These submesoscale events, due to their short duration, are poorly represented in coastal carbon budgets.
Storm Time Electrified MSTIDs Observed Over Mid‐Latitude North America
Authors: Kelley I. J. , Kunduri B. S. R. , Baker J. B. H. , Ruohoniemi J. M. , Shepherd S. G.
Published: March 2023

Medium‐scale Traveling Ionospheric Disturbances (MSTIDs) are prominent and ubiquitous features of the mid‐latitude ionosphere, and are observed in Super Dual Auroral Radar Network (SuperDARN) and high‐resolution Global Navigational Satellite Service (GNSS) Total Electron Content (TEC) data. The mechanisms driving these MSTIDs are an open area of research, especially during geomagnetic storms. Previous studies have demonstrated that nightside MSTIDs are associated with an electrodynamic instability mechanism like Perkins, especially during geomagnetically quiet conditions. However, dayside MSTIDs are often associated with atmospheric gravity waves. Very few studies have analyzed the mechanisms driving MSTIDs during strong geomagnetic storms at mid‐latitudes. In this study, we present mid‐latitude MSTIDs observed in de‐trended GNSS TEC data and SuperDARN radars over the North American sector, during a geomagnetic storm (peak Kp reaching 9) on 7–8 September 2017. In SuperDARN, MSTIDs were observed in ionospheric backscatter with Line of Sight (LOS) velocities exceeding 800 m/s. Additionally, radar LOS velocities oscillated with amplitudes reaching ±500 m/s as the MSTIDs passed through the fields‐of‐view. In detrended TEC, these MSTIDs produced perturbations reaching ∼50 percent of background TEC magnitude. The MSTIDs were observed to propagate in the westward/south‐westward direction with a time period of ∼15 min. Projecting de‐trended GNSS TEC data along SuperDARN beams showed that enhancements in TEC were correlated with enhancements in SuperDARN SNR and positive LOS velocities. Finally, SuperDARN LOS velocities systematically switched polarities between the crests and the troughs of the MSTIDs, indicating the presence of polarization electric fields and an electrodynamic instability process during these MSTIDs.
Seismotectonics of the Blanco Transform Fault System, Northeast Pacific: Evidence for an Immature Plate Boundary
Authors: Ren Yu , Lange Dietrich , Grevemeyer Ingo
Published: March 2023

At the Blanco transform fault system (BTFS) off Oregon, 138 local earthquakes and 84 double‐couple focal mechanisms from ocean‐bottom‐seismometer recordings jointly discussed with bathymetric features reveal a highly segmented transform system without any prominent fracture zone traces longer than 100 km. In the west, seismicity is focused at deep troughs (i.e., the West and East Blanco, and Surveyor Depressions). In the east, the BTFS lacks a characteristic transform valley and instead developed the Blanco Ridge, which is the most seismically active feature, showing strike‐slip and dip‐slip faulting. Sandwiched between the two main segments of the BTFS is the Cascadia Depression, representing a short intra‐transform spreading segment. Seismic slip vectors reveal that stresses at the eastern BTFS are roughly in line with plate motion. In contrast, stresses to the west are clockwise skewed, indicating ongoing reorganization of the OTF system. As we observed no prominent fracture zones at the BTFS, plate tectonic reconstructions suggest that the BTFS developed from non‐transform offsets rather than pre‐existing transform faults during a series of ridge propagation events. Our observations suggest that the BTFS can be divided into two oceanic transform systems. The eastern BTFS is suggested to be a mature transform plate boundary since ∼0.6 Ma. In contrast, the western BTFS is an immature transform system, which is still evolving to accommodate far‐field stress change. The BTFS acts as a natural laboratory to yield processes governing the development of oceanic transform faults.
Summer Dust Emissions From the Etosha Pan, Namibia: The Role of the Namib Anabatic‐Sea Breeze System
Authors: Clements Matthew , Washington Richard
Published: March 2023

This paper utilizes Aerosol Index (AI) data from the Total Ozone Mapping Spectrometer (TOMS) instrument, along with ERA5 reanalysis data, to identify atmospheric processes contributing to the uplift of dust from the Etosha Pan through the annual cycle. Etosha is one of the most prominent source areas in the Southern Hemisphere, although very little is known about its meteorology outside of the peak dust season (August–October). Emissions in December (AI = 1.6) are shown to be comparable to those in September (AI = 1.7), the dustiest month in the TOMS record. Unlike in September however, when a nocturnal low‐level jet is the primary emission mechanism, uplift in December is associated with an anabatic‐sea breeze that develops along the Namib coast, and propagates inland to reach Etosha during the evening. The system is a response to the thermal contrast between the elevated interior plateau and the adjacent waters of the cool Benguela Upwelling System, and so is at its strongest during austral summer, when the area of maximum diabatic heating shifts south over southern Africa. Topographic channeling of the flow through the east‐west orientated Hoanib River valley is shown to facilitate the inland propagation of the anabatic‐sea breeze, and explains the persistence of the system at Etosha's latitude. Evening surface winds at Etosha, associated with the anabatic‐sea breeze, are significantly stronger in the dustier December months, when diabatic heating over the subcontinent and hence the zonal thermal gradient are enhanced.
Mid‐Tropospheric Layer Temperature Record Derived From Satellite Microwave Sounder Observations With Backward Merging Approach
Authors: Zou Cheng‐Zhi , Xu Hui , Hao Xianjun , Liu Qian
Published: March 2023

We present a new version (v5.0) of the NOAA Center for Satellite Applications and Research (STAR) mid‐tropospheric temperature (TMT) time series. This data set uses a backward‐merging approach to intercalibrate 16 satellite‐based microwave sounding records. The instrument observations included those from the Microwave Sounding Unit (MSU) during 1979–2004, Advanced Microwave Sounding Unit‐A (AMSU‐A) during 1998–2017, and Advanced Technology Microwave Sounder (ATMS) from 2011 to present. A TMT time series during 2002–present based on satellite microwave observations in stable sun‐synchronous orbits was used as a reference in the backward merging process in which earlier satellites were adjusted and merged to the reference. Observations from earlier satellites were recalibrated to remove their calibration drifting errors relative to the reference using sequential overlapping observations. This included removal of spurious warming drifts in the MSU observations onboard NOAA‐11, NOAA‐12, and NOAA‐14 and a spurious cooling drift in the NOAA‐15 AMSU‐A observations. Temperature changes resulting from diurnal sampling drifts were corrected using an observation‐based semi‐physical model developed in this study. Other adjustments included channel frequency differences between MSU and AMSU‐A companion channels and instrument blackbody warm target effect on observed radiances. These adjustments resulted in inter‐consistent TMT records spanning MSU, AMSU‐A, and ATMS. The merged time series produced a global mean TMT trend of 0.092 ± 0.043 K/decade during 1979–2021 and a total tropospheric trend of 0.142 ± 0.045 K/decade after removal of a stratospheric cooling effect in TMT. Remarkably, the total tropospheric trends during the latest half period were nearly doubled the earlier half period over the global ocean.
Quantifying the Impacts of High‐Resolution Urban Information on the Urban Thermal Environment
Authors: Wang Jie , Miao Shiguang , Doan Quang‐Van , Chen Fei , Abolafia‐Rosenzweig Ronnie , Yang Long , Zhang Guwei , Zhang Yizhou , Dou Jingjing , Xu Youpeng
Published: March 2023

Detailed urban information, including land use/land cover (LULC), anthropogenic heat (AH) release, and urban canopy parameters (UCP), play critical roles in meteorological field simulations. It is particularly relevant for the Weather Research and Forecasting (WRF) model coupled with the single‐layer urban canopy model (SLUCM). Thus, we develop high‐resolution LULC, AH, and UCP data sets for Nanjing, a megacity in China, and conduct a series of numerical experiments with WRF/SLUCM to evaluate the impacts of urban parameters on the urban thermal environment. Model simulations with LULC scenarios have good agreement with the observed 2‐m temperature with a correlation coefficient of around 0.85, and present strong spatial homogeneity due to the more realistic representation of urban categories. The LULC change directly decreases the surface wind speed and increases (decreases) the sensible (latent) heat flux ( ()) in urban areas during the daytime; meanwhile increases and releases ground heat storage () during the nighttime, resulting in urban warming by 0.91°C in urban areas, compared with the control simulation (CTL) that does not take into account urban surfaces. In the LULC experiments combined with the UCP or AH, the UCP change enhances and releases more during nighttime, which increases by 0.13°C relative to LULC simulation. Also, the UCP effect reduces surface roughness and increases the width of the urban canopy, resulting in slightly enhanced wind speed, which is favorable for a warming environment in the urban area; the AH change contributes to increasing by 0.19°C through directly enhancing relative to LULC simulation. AH combined with the UCP further strengthens the UCP effect in the urban area. Overall, the influence of urban parameters on the is more pronounced during nighttime than daytime, which presents a decreasing trend with an increase in wind speed and spatial humidity in the urban area.
Interacting Effects of Precipitation and Potential Evapotranspiration Biases on Hydrological Modeling
Authors: Wang Jiao , Zhuo Lu , Rico‐Ramirez Miguel Angel , Abdelhalim Ahmed , Han Dawei
Published: March 2023

The quality of precipitation (P) and potential evapotranspiration (PET) data greatly affects the hydrological modeling performance. Considerable attention has been paid to identifying the influence of biased P or PET inputs independently. However, few studies have explored the joint interaction of biases in P and PET inputs on hydrological simulations. Here, we investigate the mutual compensation of P and PET biases on the performance of two widely used conceptual hydrological models, the Xinanjiang model and the Probability Distributed Model. P and PET from HYREX (HYdrological Radar EXperiment) and CAMELS‐GB (Catchment Attributes and Meteorology for Large‐sample Studies in Great Britain) data sets are collected over five catchments with varying characteristics in Great Britain. Different biases are added to these original time series to generate 6560 biased input scenarios. The results suggest that there is a certain compensational relationship between the biases in P and PET inputs to reproduce desirable streamflow simulations. A new hydrological proxy named Compensational Interaction Angle (CIA) is identified and found to be stationary with various modeling periods, as well as stable with different hydrological models despite model equifinality. Further, the CIA highly relates to the long‐term climate aridity ratio. The catchments with greater aridity have larger CIAs. This study offers a fresh perspective to analyze the input errors in hydrological modeling. The results can help to better understand P and PET interactions in hydrological modeling, and guide the selection/evaluation/bias‐correction of P and PET data sets for hydrological applications.
Whole-genome sequencing reveals an association between small genomic deletions and an increased risk of developing Parkinson’s disease
Authors: Oh Ji-Hye , Jo Sungyang , Park Kye Won , Lee Eun-Jae , Lee Seung Hyun , Hwang Yun Su , Jeon Ha Ra , Ryu Yeonjin , Yoon Hee Jeong , Chun Sung-Min , Kim Chong Jai , Kim Tae Won , Sung Chang Ohk , Chae Sehyun , Chung Sun Ju
Published: March 2023

Single-nucleotide variants (SNVs) associated with Parkinson’s disease (PD) have been investigated mainly through genome-wide association studies. However, other genomic alterations, including copy number variations, remain less explored. In this study, we conducted whole-genome sequencing of primary (310 PD patients and 100 healthy individuals) and independent (100 PD patients and 100 healthy individuals) cohorts from the Korean population to identify high-resolution small genomic deletions, gains, and SNVs. Global small genomic deletions and gains were found to be associated with an increased and decreased risk of PD development, respectively. Thirty significant locus deletions were identified in PD, with most being associated with an increased PD risk in both cohorts. Small genomic deletions in clustered loci located in the GPR27 region had high enhancer signals and showed the closest association with PD. GPR27 was found to be expressed specifically in brain tissue, and GPR27 copy number loss was associated with upregulated SNCA expression and downregulated dopamine neurotransmitter pathways. Clustering of small genomic deletions on chr20 in exon 1 of the GNAS isoform was detected. In addition, we found several PD-associated SNVs, including one in the enhancer region of the TCF7L2 intron, which exhibited a cis-acting regulatory mode and an association with the beta-catenin signaling pathway. These findings provide a global, whole-genome view of PD and suggest that small genomic deletions in regulatory domains contribute to the risk of PD development.
Circulating MiRNA-21-enriched extracellular vesicles promote bone remodeling in traumatic brain injury patients
Authors: Lin Ze , Xiong Yuan , Sun Yun , Zeng Ruiyin , Xue Hang , Hu Yiqiang , Chen Lang , Liu Guodong , Panayi Adriana C. , Zhou Wu , Cao Faqi , Gao Fei , Mi Bobin , Liu Guohui
Published: March 2023

Fracture combined with traumatic brain injury (TBI) is one of the most common and serious types of compound trauma in the clinic and is characterized by dysfunction of cellular communication in injured organs. Our prior studies found that TBI was capable of enhancing fracture healing in a paracrine manner. Exosomes (Exos), as small extracellular vesicles, are important paracrine vehicles for noncell therapy. However, whether circulating Exos derived from TBI patients (TBI-Exos) regulate the prohealing effects of fractures remains unclear. Thus, the present study aimed to explore the biological effects of TBI-Exos on fracture healing and reveal the potential molecular mechanism. TBI-Exos were isolated by ultracentrifugation, and the enriched miR-21-5 p was identified by qRT‒PCR analysis. The beneficial effects of TBI-Exos on osteoblastic differentiation and bone remodeling were determined by a series of in vitro assays. Bioinformatics analyses were conducted to identify the potential downstream mechanisms of the regulatory effect of TBI-Exos on osteoblasts. Furthermore, the role of the potential signaling pathway of TBI-Exos in mediating the osteoblastic activity of osteoblasts was assessed. Subsequently, a murine fracture model was established, and the effect of TBI-Exos on bone modeling was demonstrated in vivo. TBI-Exos can be internalized by osteoblasts, and in vitro, suppression of SMAD7 promoted osteogenic differentiation, whereas knockdown of miR-21-5 p in TBI-Exos strongly inhibited this bone-beneficial effect. Similarly, our results confirmed that preinjection of TBI-Exos led to enhanced bone formation, whereas knockdown of exosomal miR-21-5 p substantially impaired this bone-beneficial effect in vivo.
Short-term tamoxifen administration improves hepatic steatosis and glucose intolerance through JNK/MAPK in mice
Authors: Fang Zhiqiang , Xu Hao , Duan Juanli , Ruan Bai , Liu Jingjing , Song Ping , Ding Jian , Xu Chen , Li Zhiwen , Dou Kefeng , Wang Lin
Published: March 2023

Nonalcoholic fatty liver disease (NAFLD) which is a leading cause of chronic liver diseases lacks effective treatment. Tamoxifen has been proven to be the first-line chemotherapy for several solid tumors in clinics, however, its therapeutic role in NAFLD has never been elucidated before. In vitro experiments, tamoxifen protected hepatocytes against sodium palmitate-induced lipotoxicity. In male and female mice fed with normal diets, continuous tamoxifen administration inhibited lipid accumulation in liver, and improved glucose and insulin intolerance. Short-term tamoxifen administration largely improved hepatic steatosis and insulin resistance, however, the phenotypes manifesting inflammation and fibrosis remained unchanged in abovementioned models. In addition, mRNA expressions of genes related to lipogenesis, inflammation, and fibrosis were downregulated by tamoxifen treatment. Moreover, the therapeutic effect of tamoxifen on NAFLD was not gender or ER dependent, as male and female mice with metabolic disorders shared no difference in response to tamoxifen and ER antagonist (fulvestrant) did not abolish its therapeutic effect as well. Mechanistically, RNA sequence of hepatocytes isolated from fatty liver revealed that JNK/MAPK signaling pathway was inactivated by tamoxifen. Pharmacological JNK activator (anisomycin) partially deprived the therapeutic role of tamoxifen in treating hepatic steatosis, proving tamoxifen improved NAFLD in a JNK/MAPK signaling-dependent manner.
CMV-IgG pre-allogeneic hematopoietic stem cell transplantation and the risk for CMV reactivation and mortality
Authors: Eberhardt Kirsten Alexandra , Jung Verena , Knops Elena , Heger Eva , Wirtz Maike , Steger Gertrud , Kaiser Rolf , Affeldt Patrick , Holtick Udo , Klein Florian , Scheid Christof , Di Cristanziano Veronica
Published: March 2023

Cytomegalovirus (CMV) represents one of the most common infectious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, a common diagnostic test used to stratify the risk for CMV infection in allo-HSCT recipients is the qualitative CMV serology of donor and recipient. A positive serostatus of the recipient is the most important risk factor for CMV reactivation and associated with reduced overall survival post-transplantation (TX). Direct and indirect effects of CMV are involved in the poorer survival outcome. The present study investigated if the quantitative interpretation of anti-CMV IgG before allo-HSCT might serve as a novel parameter for the identification of patients at risk for CMV reactivation and worse outcome post-TX. For this purpose, a cohort of 440 allo-HSCT recipients over a period of 10 years was retrospectively analyzed. Our findings indicated that patients with high CMV IgG pre-allo-HSCT had a higher risk to develop CMV reactivation, including clinically relevant infections, and a worse prognosis 36 months post-allo-HSCT as compared to recipients with low CMV IgG values. In the letermovir (LMV) era, this group of patients might benefit from a closer CMV monitoring, and hence, earlier intervention if needed, especially after discontinuation of prophylaxis.
Mechanotransduction pathways in articular chondrocytes and the emerging role of estrogen receptor-α
Authors: Wang Ning , Lu Yangfan , Rothrauff Benjamin B. , Zheng Aojie , Lamb Alexander , Yan Youzhen , Lipa Katelyn E. , Lei Guanghua , Lin Hang
Published: March 2023

In the synovial joint, mechanical force creates an important signal that influences chondrocyte behavior. The conversion of mechanical signals into biochemical cues relies on different elements in mechanotransduction pathways and culminates in changes in chondrocyte phenotype and extracellular matrix composition/structure. Recently, several mechanosensors, the first responders to mechanical force, have been discovered. However, we still have limited knowledge about the downstream molecules that enact alterations in the gene expression profile during mechanotransduction signaling. Recently, estrogen receptor α (ERα) has been shown to modulate the chondrocyte response to mechanical loading through a ligand-independent mechanism, in line with previous research showing that ERα exerts important mechanotransduction effects on other cell types, such as osteoblasts. In consideration of these recent discoveries, the goal of this review is to position ERα into the mechanotransduction pathways known to date. Specifically, we first summarize our most recent understanding of the mechanotransduction pathways in chondrocytes on the basis of three categories of actors, namely mechanosensors, mechanotransducers, and mechanoimpactors. Then, the specific roles played by ERα in mediating the chondrocyte response to mechanical loading are discussed, and the potential interactions of ERα with other molecules in mechanotransduction pathways are explored. Finally, we propose several future research directions that may advance our understanding of the roles played by ERα in mediating biomechanical cues under physiological and pathological conditions.
Human skin specific long noncoding RNA HOXC13-AS regulates epidermal differentiation by interfering with Golgi-ER retrograde transport
Authors: Zhang Letian , Piipponen Minna , Liu Zhuang , Li Dongqing , Bian Xiaowei , Niu Guanglin , Geara Jennifer , Toma Maria A. , Sommar Pehr , Xu Landén Ning
Published: March 2023

After a skin injury, keratinocytes switch from a state of homeostasis to one of regeneration leading to the reconstruction of the epidermal barrier. The regulatory mechanism of gene expression underpinning this key switch during human skin wound healing is enigmatic. Long noncoding RNAs (lncRNAs) constitute a new horizon in the understanding of the regulatory programs encoded in the mammalian genome. By comparing the transcriptome of an acute human wound and skin from the same donor as well as keratinocytes isolated from these paired tissue samples, we generated a list of lncRNAs showing changed expression in keratinocytes during wound repair. Our study focused onHOXC13-AS, a recently evolved human lncRNA specifically expressed in epidermal keratinocytes, and we found that its expression was temporally downregulated during wound healing. In line with its enrichment in suprabasal keratinocytes,HOXC13-ASwas found to be increasingly expressed during keratinocyte differentiation, but its expression was reduced by EGFR signaling. AfterHOXC13-ASknockdown or overexpression in human primary keratinocytes undergoing differentiation induced by cell suspension or calcium treatment and in organotypic epidermis, we found thatHOXC13-ASpromoted keratinocyte differentiation. Moreover, RNA pull-down assays followed by mass spectrometry and RNA immunoprecipitation analysis revealed that mechanisticallyHOXC13-ASsequestered the coat complex subunit alpha (COPA) protein and interfered with Golgi-to-endoplasmic reticulum (ER) molecular transport, resulting in ER stress and enhanced keratinocyte differentiation. In summary, we identifiedHOXC13-ASas a crucial regulator of human epidermal differentiation.
PVT1/miR-136/Sox2/UPF1 axis regulates the malignant phenotypes of endometrial cancer stem cells
Authors: Li Qing , Kong Fanfei , Cong Rong , Ma Jian , Wang Cuicui , Ma Xiaoxin
Published: March 2023

Tumor stem cells (TSCs) are thought to contribute to the progression and maintenance of cancer. Previous studies have suggested that plasmacytoma variant translocation 1 (PVT1) has a tumor-promoting effect on endometrial cancer; however, its mechanism of action in endometrial cancer stem cells (ECSCs) is unknown. Here, we found that PVT1 was highly expressed in endometrial cancers and ECSCs, correlated with poor patient prognosis, promoted the malignant behavior and the stemness of endometrial cancer cells (ECCs) and ECSCs. In contrast, miR-136, which was lowly expressed in endometrial cancer and ECSCs, had the opposite effect, and knockdown miR-136 inhibited the anticancer effects of down-regulated PVT1. PVT1 affected miR-136 specifically binding the 3’ UTR region of Sox2 by competitively “sponging” miR-136, thus positively saving Sox2. Sox2 promoted the malignant behavior and the stemness of ECCs and ECSCs, and overexpression Sox2 inhibited the anticancer effects of up-regulated miR-136. Sox2 can act as a transcription factor to positively regulate Up-frameshift protein 1 (UPF1) expression, thereby exerting a tumor-promoting effect on endometrial cancer. In nude mice, simultaneously downregulating PVT1 and upregulating miR-136 exerted the strongest antitumor effect. We demonstrate that the PVT1/miR-136/Sox2/UPF1 axis plays an important role in the progression and maintenance of endometrial cancer. The results suggest a novel target for endometrial cancer therapies.
Emergent collective organization of bone cells in complex curvature fields
Authors: Callens Sebastien J. P. , Fan Daniel , van Hengel Ingmar A. J. , Minneboo Michelle , Díaz-Payno Pedro J. , Stevens Molly M. , Fratila-Apachitei Lidy E. , Zadpoor Amir A.
Published: March 2023

Individual cells and multicellular systems respond to cell-scale curvatures in their environments, guiding migration, orientation, and tissue formation. However, it remains largely unclear how cells collectively explore and pattern complex landscapes with curvature gradients across the Euclidean and non-Euclidean spectra. Here, we show that mathematically designed substrates with controlled curvature variations induce multicellular spatiotemporal organization of preosteoblasts. We quantify curvature-induced patterning and find that cells generally prefer regions with at least one negative principal curvature. However, we also show that the developing tissue can eventually cover unfavorably curved territories, can bridge large portions of the substrates, and is often characterized by collectively aligned stress fibers. We demonstrate that this is partly regulated by cellular contractility and extracellular matrix development, underscoring the mechanical nature of curvature guidance. Our findings offer a geometric perspective on cell-environment interactions that could be harnessed in tissue engineering and regenerative medicine applications.
Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis
Authors: Zhu Yujie , Zhang Mingchao , Wang Weiran , Qu Shuang , Liu Minghui , Rong Weiwei , Yang Wenwen , Liang Hongwei , Zeng Caihong , Zhu Xiaodong , Li Limin , Liu Zhihong , Zen Ke
Published: March 2023

Renal tubular atrophy is a hallmark of chronic kidney disease. The cause of tubular atrophy, however, remains elusive. Here we report that reduction of renal tubular cell polynucleotide phosphorylase (PNPT1) causes renal tubular translation arrest and atrophy. Analysis of tubular atrophic tissues from renal dysfunction patients and male mice with ischemia-reperfusion injuries (IRI) or unilateral ureteral obstruction (UUO) treatment shows that renal tubular PNPT1 is markedly downregulated under atrophic conditions. PNPT1 reduction leads to leakage of mitochondrial double-stranded RNA (mt-dsRNA) into the cytoplasm where it activates protein kinase R (PKR), followed by phosphorylation of eukaryotic initiation factor 2α (eIF2α) and protein translational termination. Increasing renal PNPT1 expression or inhibiting PKR activity largely rescues IRI- or UUO-induced mouse renal tubular injury. Moreover, tubular-specific PNPT1-knockout mice display Fanconi syndrome-like phenotypes with impaired reabsorption and significant renal tubular injury. Our results reveal that PNPT1 protects renal tubules by blocking the mt-dsRNA-PKR-eIF2α axis.
The dynamic nature of netrin-1 and the structural basis for glycosaminoglycan fragment-induced filament formation
Authors: Meier Markus , Gupta Monika , Akgül Serife , McDougall Matthew , Imhof Thomas , Nikodemus Denise , Reuten Raphael , Moya-Torres Aniel , To Vu , Ferens Fraser , Heide Fabian , Padilla-Meier Gay Pauline , Kukura Philipp , Huang Wenming , Gerisch Birgit , Mörgelin Matthias , Poole Kate , Antebi Adam , Koch Manuel , Stetefeld Jörg
Published: March 2023

Netrin-1 is a bifunctional chemotropic guidance cue that plays key roles in diverse cellular processes including axon pathfinding, cell migration, adhesion, differentiation, and survival. Here, we present a molecular understanding of netrin-1 mediated interactions with glycosaminoglycan chains of diverse heparan sulfate proteoglycans (HSPGs) and short heparin oligosaccharides. Whereas interactions with HSPGs act as platform to co-localise netrin-1 close to the cell surface, heparin oligosaccharides have a significant impact on the highly dynamic behaviour of netrin-1. Remarkably, the monomer-dimer equilibrium of netrin-1 in solution is abolished in the presence of heparin oligosaccharides and replaced with highly hierarchical and distinct super assemblies leading to unique, yet unknown netrin-1 filament formation. In our integrated approach we provide a molecular mechanism for the filament assembly which opens fresh paths towards a molecular understanding of netrin-1 functions.
Tandem mass tag-based quantitative proteomic profiling identifies candidate serum biomarkers of drug-induced liver injury in humans
Authors: Ravindra Kodihalli C. , Vaidya Vishal S. , Wang Zhenyu , Federspiel Joel D. , Virgen-Slane Richard , Everley Robert A. , Grove Jane I. , Stephens Camilla , Ocana Mireia F. , Robles-Díaz Mercedes , Isabel Lucena M. , Andrade Raul J. , Atallah Edmond , Gerbes Alexander L. , Weber Sabine , Cortez-Pinto Helena , Fowell Andrew J. , Hussaini Hyder , Bjornsson Einar S. , Patel Janisha , Stirnimann Guido , Verma Sumita , Elsharkawy Ahmed M. , Griffiths William J. H. , Hyde Craig , Dear James W. , Aithal Guruprasad P. , Ramaiah Shashi K.
Published: March 2023

Diagnosis of drug-induced liver injury (DILI) and its distinction from other liver diseases are significant challenges in drug development and clinical practice. Here, we identify, confirm, and replicate the biomarker performance characteristics of candidate proteins in patients with DILI at onset (DO; n = 133) and follow-up (n = 120), acute non-DILI at onset (NDO; n = 63) and follow-up (n = 42), and healthy volunteers (HV; n = 104). Area under the receiver operating characteristic curve (AUC) for cytoplasmic aconitate hydratase, argininosuccinate synthase, carbamoylphosphate synthase, fumarylacetoacetase, fructose-1,6-bisphosphatase 1 (FBP1) across cohorts achieved near complete separation (range: 0.94–0.99) of DO and HV. In addition, we show that FBP1, alone or in combination with glutathione S-transferase A1 and leukocyte cell-derived chemotaxin 2, could potentially assist in clinical diagnosis by distinguishing NDO from DO (AUC range: 0.65–0.78), but further technical and clinical validation of these candidate biomarkers is needed.
Cryo-EM structure of human heptameric pannexin 2 channel
Authors: Zhang Hang , Wang Shiyu , Zhang Zhenzhen , Hou Mengzhuo , Du Chunyu , Zhao Zhenye , Vogel Horst , Li Zhifang , Yan Kaige , Zhang Xiaokang , Lu Jianping , Liang Yujie , Yuan Shuguang , Wang Daping , Zhang Huawei
Published: March 2023

Pannexin 2 (Panx2) is a large-pore ATP-permeable channel with critical roles in various physiological processes, such as the inflammatory response, energy production and apoptosis. Its dysfunction is related to numerous pathological conditions including ischemic brain injury, glioma and glioblastoma multiforme. However, the working mechanism of Panx2 remains unclear. Here, we present the cryo-electron microscopy structure of human Panx2 at a resolution of 3.4 Å. Panx2 structure assembles as a heptamer, forming an exceptionally wide channel pore across the transmembrane and intracellular domains, which is compatible with ATP permeation. Comparing Panx2 with Panx1 structures in different states reveals that the Panx2 structure corresponds to an open channel state. A ring of seven arginine residues located at the extracellular entrance forms the narrowest site of the channel, which serves as the critical molecular filter controlling the permeation of substrate molecules. This is further verified by molecular dynamics simulations and ATP release assays. Our studies reveal the architecture of the Panx2 channel and provide insights into the molecular mechanism of its channel gating.
mTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion
Authors: Liu Heng-Jia , Du Heng , Khabibullin Damir , Zarei Mahsa , Wei Kevin , Freeman Gordon J. , Kwiatkowski David J. , Henske Elizabeth P.
Published: March 2023

Identifying the mechanisms underlying the regulation of immune checkpoint molecules and the therapeutic impact of targeting them in cancer is critical. Here we show that high expression of the immune checkpoint B7-H3 (CD276) and high mTORC1 activity correlate with immunosuppressive phenotypes and worse clinical outcomes in 11,060 TCGA human tumors. We find that mTORC1 upregulates B7-H3 expression via direct phosphorylation of the transcription factor YY2 by p70 S6 kinase. Inhibition of B7-H3 suppresses mTORC1-hyperactive tumor growth via an immune-mediated mechanism involving increased T-cell activity and IFN-γ responses coupled with increased tumor cell expression of MHC-II. CITE-seq reveals strikingly increased cytotoxic CD38+CD39+CD4+ T cells in B7-H3-deficient tumors. In pan-human cancers, a high cytotoxic CD38+CD39+CD4+ T-cell gene signature correlates with better clinical prognosis. These results show that mTORC1-hyperactivity, present in many human tumors including tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM), drives B7-H3 expression leading to suppression of cytotoxic CD4+ T cells.
Quantitative analysis of C. elegans transcripts by Nanopore direct-cDNA sequencing reveals terminal hairpins in non trans-spliced mRNAs
Authors: Bernard Florian , Dargère Delphine , Rechavi Oded , Dupuy Denis
Published: March 2023

In nematodes and kinetoplastids, mRNA processing involves a trans-splicing step through which a short sequence from a snRNP replaces the original 5’ end of the primary transcript. It has long been held that 70% of C. elegans mRNAs are submitted to trans-splicing. Our recent work suggested that the mechanism is more pervasive but not fully captured by mainstream transcriptome sequencing methods. Here we use Oxford Nanopore’s long-read amplification-free sequencing technology to perform a comprehensive analysis of trans-splicing in worms. We demonstrate that spliced leader (SL) sequences at the 5’ end of the mRNAs affect library preparation and generate sequencing artefacts due to their self-complementarity. Consistent with our previous observations, we find evidence of trans-splicing for most genes. However, a subset of genes appears to be only marginally trans-spliced. These mRNAs all share the capacity to generate a 5’ terminal hairpin structure mimicking the SL structure and offering a mechanistic explanation for their non conformity. Altogether, our data provide a comprehensive quantitative analysis of SL usage in C. elegans.