bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diversifying models for analysing global change scenarios and sustainability pathways
Authors: Moallemi Enayat A. , Gao Lei , Eker Sibel , Bryan Brett A. 
Published: March 2022

Non-technical summary
Models are increasingly used to inform the transformation of human–Earth systems towards a sustainable future, aligned with the sustainable development goals (SDGs). We argue that a greater diversity of models ought to be used for sustainability analysis to better address complexity and uncertainty. We articulate the steps to model global change socioeconomic and climatic scenarios with new models. Through these steps, we generate new scenario projections using a human–Earth system dynamics model. Our modelling brings new insights about the sensitivity of sustainability trends to future uncertainty and their alignment with or divergence from previous model-based scenario projections.

Technical summary
The future uncertainty and complexity of alternative socioeconomic and climatic scenarios challenge the model-based analysis of sustainable development. Obtaining robust insights requires a systematic processing of uncertainty and complexity not only in input assumptions, but also in the diversity of model structures that simulates the multisectoral dynamics of human and Earth system interactions. Here, we implement the global change scenarios, that is, the shared socioeconomic pathways and the representative concentration pathways, in a feedback-rich, integrated assessment model (IAM) of human–Earth system dynamics, called FeliX, to serve two aims: (1) to provide modellers with well-defined steps for the adoption of established scenarios in new IAMs and (2) to explore the impacts of model uncertainty and its structural complexity on the projection of these scenarios for sustainable development. Our modelling shows internally consistent scenario storylines across sectors, yet with quantitatively different realisations of these scenarios compared to other IAMs due to the new model's structural complexity. The results highlight the importance of enumerating global change scenarios and their uncertainty exploration with a diversity of models of different input assumptions and structures to capture a wider variety of future possibilities and sustainability indicators.

Social media summary
New study highlights the importance of global change scenario analysis with new, SDG-focused IAMs.
Inundation of Stormwater Infrastructure Is Common and Increases Risk of Flooding in Coastal Urban Areas Along the US Atlantic Coast
Authors: Gold Adam C. , Brown Chelsea M. , Thompson Suzanne P. , Piehler Michael F. 
Published: March 2022

AbstractStormwater infrastructure can manage precipitation‐driven flooding when there are no obstructions to draining. Coastal areas increasingly experience recurrent flooding due to elevated water levels from storms or tides, but the inundation of coastal stormwater infrastructure by elevated water levels has not been broadly assessed. We conservatively estimated stormwater infrastructure inundation in municipalities along the Atlantic United States coast by using areas of high‐tide flooding (HTF) on roads as a proxy. We also modeled stormwater infrastructure inundation in four North Carolina municipalities and measured infrastructure inundation in one of the modeled municipalities. Combining methodologies at different scales provides context and allows the scope of stormwater infrastructure inundation to be broadly estimated. We found 137 census‐designated urban areas along the Atlantic coast with road area impacted by HTF, with a median percent of total road area subject to HTF of 0.16% (IQR: 0.02%–0.53%). Based on 2010 census block data, the median number of people per urban area that live in census blocks with HTF on roads was 1,622 (IQR: 366–5,779). In total, we estimate that over 2 million people live in census blocks where HTF occurs on roadways along the US Atlantic coast. Modeling results and water level measurements indicated that extensive inundation of underground stormwater infrastructure likely occurs at water levels within the mean tidal range. These results suggest that stormwater infrastructure inundation along the US Atlantic coast is likely widespread, affects a large number of people, occurs frequently, and increases the occurrence of urban flooding.
Impacts of Global Climate Warming on Meteorological and Hydrological Droughts and Their Propagations
Authors: Wu Guiyang , Chen Jie , Shi Xinyan , Kim Jong‐Suk , Xia Jun , Zhang Liping 
Published: March 2022

AbstractMeteorological to hydrological drought propagation has been widely studied to reflect the relationship between these drought categories and better understand drought mechanisms. However, global warming may alter the drought propagation features, which are not fully understood. This study aims to investigate changes in meteorological and hydrological drought conditions, especially their propagation features in 1.5–3.0°C warmer climates for 8,655 watersheds globally. First, the three‐month scale standardized precipitation index and the standardized runoff index are calculated based on the precipitation simulated by the 15 global climate models and the runoff simulated by the four hydrological models, respectively. Drought events are then identified using the run theory, followed by the calculation of drought propagation features (i.e., pooling, lag, and lengthening) for matched meteorological and hydrological droughts. As a result, both meteorological and hydrological drought conditions (i.e., duration and severity) would relieve in warmer climates due to increased precipitation for regions excluding Western North America, South America, the Mediterranean, Southern Africa, East Asia, and Australia. However, the drought conditions would be more severe during drought propagation from meteorological to hydrological droughts over most regions. During drought propagation, the worsening drought conditions over half of the regions would be more serious first and then relieved with the rising temperature. These results indicate that efforts to slow down global warming can suppress the deterioration of drought conditions in the propagation.
The Role of River Discharge and Geometric Structure on Diurnal Tidal Dynamics, Alabama, USA
Authors: Dykstra Steven L. , Dzwonkowski Brian , Torres Raymond 
Published: March 2022

AbstractAs tides propagate inland, they become distorted by channel geometry and river discharge. Tidal dynamics in fluvial‐marine transitions are commonly observed in high‐energy tidal environments with relatively steady river conditions, leaving the effects of variable river discharge on tides and longitudinal changes poorly understood. To study the effects of variable river discharge on tide‐river interactions, we studied a low‐energy tidal environment where river discharge ranges several orders of magnitude, the diurnal microtidal Tombigbee River‐Mobile Bay fluvial‐marine transition, using water level and velocity observations from 21 stations. Results showed that diurnal tidal attenuation was reduced by the width convergence in seaward reaches and height convergence of the landward backwater reaches, with the channel convergence change location ∼40–50 km inland of the bayhead and seaward of the largest bifurcation. River events amplified tides in seaward regions and attenuated tides in landward regions. This created a region of river‐induced peak amplitude seaward of the flood limit (i.e., bidirectional‐unidirectional current transition), allowing more tidal energy to propagate inland. Tidal currents were attenuated and delayed more by river discharge than water levels, making the phase lag dynamic. The river impacts on the tides were delineated longitudinally and shifted seaward as river discharge increased, ranging up to ∼180 km. Results indicated the longitudinal shifts of river impacts on tides in alluvial systems can be estimated analytically using the ratio of river discharge to tidal discharge and the geometric convergence of the system. Our simple analytical theory provides a pathway for understanding the tide‐river‐geomorphic equilibrium along increasingly dynamic coasts.
MJO Phase Swings Modulate the Recurring Latitudinal Shifts of the 2020 Extreme Summer‐Monsoon Rainfall Around Yangtse
Authors: Wang Yuwen , Ren Hong‐Li , Wei Yuntao , Jin Fei‐Fei , Ren Pengfei , Gao Li , Wu Jie 
Published: March 2022

AbstractConsidering the unprecedented extremity of the Meiyu episodes in early summer of 2020, here the authors perform a comprehensive study of the intraseasonal evolution characteristics of the observed rainfall round Yangtse as well as the potential modulating effect of Madden‐Julian Oscillation (MJO). Results suggest that the Meiyu rainfall manifests as recurring latitudinal shifts around Yangtse during June–July of 2020, corresponding well to the continued swings of MJO circulation and convection between Phase 1 and Phase 2. The MJO affects the meridional migration of the 2020 Meiyu rainfall mainly through regulating the westward extended ridge line and southwesterly of the anomalous anticyclone over the western North Pacific (WNP). Specifically, the northeastward propagation of boreal summer MJO from Phase 1 to 2 shifts the ridge line of the anomalous WNP anticyclone northeastward. Consequently, the associated southwesterly anomaly over the southeastern China penetrates to the north of Yangtse and enhances the lower‐tropospheric moisture flux convergence, supporting heavy precipitation there. However, when the MJO swings back to Phase 1, the anomalous southwesterly and moisture flux convergence retreat southward, so does the Meiyu rain band. The present results advanced our understanding of the interactions between the latitudinal shifts of extreme Meiyu rainfall episodes and MJO Phase swings.
Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects
Authors: Qian Hong-jie , Wang Yu , Zhang Meng-qi , Xie Yuan-chao , Wu Qing-qing , Liang Li-yu , Cao Ye , Duan Hua-qing , Tian Guang-hui , Ma Juan , Zhang Zhuo-bing , Li Ning , Jia Jing-ying , Zhang Jing , Aisa Haji Akber , Shen Jing-shan , Yu Chen , Jiang Hua-liang , Zhang Wen-hong , Wang Zhen , Liu Gang-yi 
Published: March 2022

AbstractVV116 (JT001) is an oral drug candidate of nucleoside analog against SARS-CoV-2. The purpose of the three phase I studies was to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of VV116 in healthy subjects, as well as the effect of food on the pharmacokinetics and safety of VV116. Three studies were launched sequentially: Study 1 (single ascending-dose study, SAD), Study 2 (multiple ascending-dose study, MAD), and Study 3 (food-effect study, FE). A total of 86 healthy subjects were enrolled in the studies. VV116 tablets or placebo were administered per protocol requirements. Blood samples were collected at the scheduled time points for pharmacokinetic analysis. 116-N1, the metabolite of VV116, was detected in plasma and calculated for the PK parameters. In SAD, AUC and Cmax increased in an approximately dose-proportional manner in the dose range of 25–800 mg. T1/2 was within 4.80–6.95 h. In MAD, the accumulation ratio for Cmax and AUC indicated a slight accumulation upon repeated dosing of VV116. In FE, the standard meal had no effect on Cmax and AUC of VV116. No serious adverse event occurred in the studies, and no subject withdrew from the studies due to adverse events. Thus, VV116 exhibited satisfactory safety and tolerability in healthy subjects, which supports the continued investigation of VV116 in patients with COVID-19.
Lon upregulation contributes to cisplatin resistance by triggering NCLX-mediated mitochondrial Ca2+ release in cancer cells
Authors: Tangeda Vidhya , Lo Yu Kang , Babuharisankar Ananth Ponneri , Chou Han-Yu , Kuo Cheng-Liang , Kao Yung-Hsi , Lee Alan Yueh-Luen , Chang Jang-Yang 
Published: March 2022

AbstractMitochondria are the major organelles in sensing cellular stress and inducing the response for cell survival. Mitochondrial Lon has been identified as an important stress protein involved in regulating proliferation, metastasis, and apoptosis in cancer cells. However, the mechanism of retrograde signaling by Lon on mitochondrial DNA (mtDNA) damage remains to be elucidated. Here we report the role of Lon in the response to cisplatin-induced mtDNA damage and oxidative stress, which confers cancer cells on cisplatin resistance via modulating calcium levels in mitochondria and cytosol. First, we found that cisplatin treatment on oral cancer cells caused oxidative damage of mtDNA and induced Lon expression. Lon overexpression in cancer cells decreased while Lon knockdown sensitized the cytotoxicity towards cisplatin treatment. We further identified that cisplatin-induced Lon activates the PYK2-SRC-STAT3 pathway to stimulate Bcl-2 and IL-6 expression, leading to the cytotoxicity resistance to cisplatin. Intriguingly, we found that activation of this pathway is through an increase of intracellular calcium (Ca2+) via NCLX, a mitochondrial Na+/Ca2+ exchanger. We then verified that NCLX expression is dependent on Lon levels; Lon interacts with and activates NCLX activity. NCLX inhibition increased the level of mitochondrial calcium and sensitized the cytotoxicity to cisplatin in vitro and in vivo. In summary, mitochondrial Lon-induced cisplatin resistance is mediated by calcium release into cytosol through NCLX, which activates calcium-dependent PYK2-SRC-STAT3-IL-6 pathway. Thus, our work uncovers the novel retrograde signaling by mitochondrial Lon on resistance to cisplatin-induced mtDNA stress, indicating the potential use of Lon and NCLX inhibitors for better clinical outcomes in chemoresistant cancer patients.
Erythropoietin promotes M2 macrophage phagocytosis of Schwann cells in peripheral nerve injury
Authors: Govindappa Prem Kumar , Elfar John C. 
Published: March 2022

AbstractFollowing acute sciatic nerve crush injury (SNCI), inflammation and the improper phagocytic clearance of dying Schwann cells (SCs) has effects on remodeling that lead to morbidity and incomplete functional recovery. Therapeutic strategies like the use of erythropoietin (EPO) for peripheral nerve trauma may serve to bring immune cell phagocytotic clearance under control to support debris clearance. We evaluated EPO’s effect on SNCI and found EPO treatment increased myelination and sciatic functional index (SFI) and bolstered anti-apoptosis and phagocytosis of myelin debris via CD206+ macrophages when compared to saline treatment. EPO enhanced M2 phenotype activity, both in bone marrow-derived macrophages (BMMØs) and peritoneal-derived macrophages (PMØs) in vitro, as well as in PMØs in vivo. EPO increased efferocytosis of apoptotic sciatic nerve derived Schwann cells (SNSCs) in both settings as demonstrated using immunofluorescence (IF) and flow cytometry. EPO treatment significantly attenuated pro-inflammatory genes (IL1β, iNOS, and CD68) and augmented anti-inflammatory genes (IL10 and CD163) and the cell-surface marker CD206. EPO also increased anti-apoptotic (Annexin V/7AAD) effects after lipopolysaccharide (LPS) induction in macrophages. Our data demonstrate EPO promotes the M2 phenotype macrophages to ameliorate apoptosis and efferocytosis of dying SCs and myelin debris and improves SN functional recovery following SNCI.
Targeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma
Authors: Capparelli Claudia , Purwin Timothy J. , Glasheen McKenna , Caksa Signe , Tiago Manoela , Wilski Nicole , Pomante Danielle , Rosenbaum Sheera , Nguyen Mai Q. , Cai Weijia , Franco-Barraza Janusz , Zheng Richard , Kumar Gaurav , Chervoneva Inna , Shimada Ayako , Rebecca Vito W. , Snook Adam E. , Hookim Kim , Xu Xiaowei , Cukierman Edna , Herlyn Meenhard , Aplin Andrew E. 
Published: March 2022

AbstractCellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, which enable adaptation to metastatic microenvironments and resistance to therapies. Mechanisms underlying tumor cell plasticity remain poorly understood. SOX10, a neural crest lineage transcription factor, is heterogeneously expressed in melanomas. Loss of SOX10 reduces proliferation, leads to invasive properties, including the expression of mesenchymal genes and extracellular matrix, and promotes tolerance to BRAF and/or MEK inhibitors. We identify the class of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) inhibitors as inducing cell death selectively in SOX10-deficient cells. Targeted therapy selects for SOX10 knockout cells underscoring their drug tolerant properties. Combining cIAP1/2 inhibitor with BRAF/MEK inhibitors delays the onset of acquired resistance in melanomas in vivo. These data suggest that SOX10 mediates phenotypic switching in cutaneous melanoma to produce a targeted inhibitor tolerant state that is likely a prelude to the acquisition of resistance. Furthermore, we provide a therapeutic strategy to selectively eliminate SOX10-deficient cells.
Nonlocal pseudopotential energy density functional for orbital-free density functional theory
Authors: Xu Qiang , Ma Cheng , Mi Wenhui , Wang Yanchao , Ma Yanming 
Published: March 2022

AbstractOrbital-free density functional theory (OF-DFT) is an electronic structure method with a low computational cost that scales linearly with the number of simulated atoms, making it suitable for large-scale material simulations. It is generally considered that OF-DFT strictly requires the use of local pseudopotentials, rather than orbital-dependent nonlocal pseudopotentials, for the calculation of electron-ion interaction energies, as no orbitals are available. This is unfortunate situation since the nonlocal pseudopotentials are known to give much better transferability and calculation accuracy than local ones. We report here the development of a theoretical scheme that allows the direct use of nonlocal pseudopotentials in OF-DFT. In this scheme, a nonlocal pseudopotential energy density functional is derived by the projection of nonlocal pseudopotential onto the non-interacting density matrix (instead of “orbitals”) that can be approximated explicitly as a functional of electron density. Our development defies the belief that nonlocal pseudopotentials are not applicable to OF-DFT, leading to the creation for an alternate theoretical framework of OF-DFT that works superior to the traditional approach.
Characterisation and induction of tissue-resident gamma delta T-cells to target hepatocellular carcinoma
Authors: Zakeri Nekisa , Hall Andrew , Swadling Leo , Pallett Laura J. , Schmidt Nathalie M. , Diniz Mariana O. , Kucykowicz Stephanie , Amin Oliver E. , Gander Amir , Pinzani Massimo , Davidson Brian R. , Quaglia Alberto , Maini Mala K. 
Published: March 2022

AbstractImmunotherapy is now the standard of care for advanced hepatocellular carcinoma (HCC), yet many patients fail to respond. A major unmet goal is the boosting of T-cells with both strong HCC reactivity and the protective advantages of tissue-resident memory T-cells (TRM). Here, we show that higher intratumoural frequencies of γδ T-cells, which have potential for HLA-unrestricted tumour reactivity, associate with enhanced HCC patient survival. We demonstrate that γδ T-cells exhibit bona fide tissue-residency in human liver and HCC, with γδTRM showing no egress from hepatic vasculature, persistence for >10 years and superior anti-tumour cytokine production. The Vγ9Vδ2 T-cell subset is selectively depleted in HCC but can efficiently target HCC cell lines sensitised to accumulate isopentenyl-pyrophosphate by the aminobisphosphonate Zoledronic acid. Aminobisphosphonate-based expansion of peripheral Vγ9Vδ2 T-cells recapitulates a TRM phenotype and boosts cytotoxic potential. Thus, our data suggest more universally effective HCC immunotherapy may be achieved by combining aminobisphosphonates to induce Vγ9Vδ2TRM capable of replenishing the depleted pool, with additional intratumoural delivery to sensitise HCC to Vγ9Vδ2TRM-based targeting.
The aberrant upregulation of exon 10-inclusive SREK1 through SRSF10 acts as an oncogenic driver in human hepatocellular carcinoma
Authors: Chang Cunjie , Rajasekaran Muthukumar , Qiao Yiting , Dong Heng , Wang Yu , Xia Hongping , Deivasigamani Amudha , Wu Minjie , Sekar Karthik , Gao Hengjun , Sun Mengqing , Niu Yuqin , Li Qian , Tao Lin , Yan Zhen , Wang Menglan , Chen Shasha , Zhao Shujuan , Chen Dajing , Li Lina , Yang Fan , Gao Haojin , Chen Baodong , Su Ling , Xu Liang , Chen Ye , Seshachalam Veerabrahma Pratap , Chen Gongxing , Gunaratne Jayantha , Hong Wanjin , Shi Junping , Chen Gongying , Grierson David S. , Chabot Benoit , Xie Tian , Hui Kam Man , Chen Jianxiang 
Published: March 2022

AbstractDeregulation of alternative splicing is implicated as a relevant source of molecular heterogeneity in cancer. However, the targets and intrinsic mechanisms of splicing in hepatocarcinogenesis are largely unknown. Here, we report a functional impact of a Splicing Regulatory Glutamine/Lysine-Rich Protein 1 (SREK1) variant and its regulator, Serine/arginine-rich splicing factor 10 (SRSF10). HCC patients with poor prognosis express higher levels of exon 10-inclusive SREK1 (SREK1L). SREK1L can sustain BLOC1S5-TXNDC5 (B-T) expression, a targeted gene of nonsense-mediated mRNA decay through inhibiting exon-exon junction complex binding with B-T to exert its oncogenic role. B-T plays its competing endogenous RNA role by inhibiting miR-30c-5p and miR-30e-5p, and further promoting the expression of downstream oncogenic targets SRSF10 and TXNDC5. Interestingly, SRSF10 can act as a splicing regulator for SREK1L to promote hepatocarcinogenesis via the formation of a SRSF10-associated complex. In summary, we demonstrate a SRSF10/SREK1L/B-T signalling loop to accelerate the hepatocarcinogenesis.
Intralocus conflicts associated with a supergene
Authors: Giraldo-Deck Lina M. , Loveland Jasmine L. , Goymann Wolfgang , Tschirren Barbara , Burke Terry , Kempenaers Bart , Lank David B. , Küpper Clemens 
Published: March 2022

AbstractChromosomal inversions frequently underlie major phenotypic variation maintained by divergent selection within and between sexes. Here we examine whether and how intralocus conflicts contribute to balancing selection stabilizing an autosomal inversion polymorphism in the ruff Calidris pugnax. In this lekking shorebird, three male mating morphs (Independents, Satellites and Faeders) are controlled by an inversion-based supergene. We show that in a captive population, Faeder females, who are smaller and whose inversion haplotype has not undergone recombination, have lower average reproductive success in terms of laying rate, egg size, and offspring survival than Independent females, who lack the inversion. Satellite females, who carry a recombined inversion haplotype and have intermediate body size, more closely resemble Independent than Faeder females in reproductive performance. We inferred that the lower reproductive output of Faeder females is most likely balanced by higher than average reproductive success of individual Faeder males. These findings suggest that intralocus conflicts may play a major role in the evolution and maintenance of supergene variants.