bluuebunny/crossref_metadata_2025_split huggingface dataset:
The application of the principle of distinction in the cyber context: A Chinese perspective
Authors: Huang Zhixiong , Ying Yaohui 
Published: February 2021

AbstractUp to now, the Chinese government has only made very general comments on the application of international humanitarian law to cyberspace. There are indeed Chinese academic papers concerning this issue, but the discussion of the principle of distinction is limited both in length and in academic depth. Compared with the West, research by Chinese scholars on this topic is still in a relatively preliminary stage. At present, there is no specific deconstruction or clarification of the application of the principle of distinction in cyberspace in Chinese academia. As the first paper written by Chinese scholars specifically devoted to this question, this piece provides a different perspective by injecting the positions of Chinese officials and the views of Chinese scholars. The authors aim to clarify whether the existing rules are still completely applicable in the cyber context, and if needed, to find out what kind of improvements and clarifications can be made. Weighing in on these debates, we argue that despite the potential technical challenges and uncertainties, the principle of distinction should be applied to cyberspace. It should also be carefully re-examined and clarified from the standpoint of preventing over-militarization and maximizing the protection of the interests of civilians. For human targets, the elements of combatant status identified in customary international law and relevant treaties are not well suited to the digital battlefield. Nevertheless, cyber combatants are still obligated to distinguish themselves from civilians. In applying the principle of distinction, we argue that it makes more sense to focus on substantive elements over formal elements such as carrying arms openly or having a fixed distinctive sign recognizable at a distance. In interpreting “direct participation in hostilities”, the threshold of harm requires an objective likelihood instead of mere subjective intention; the belligerent nexus should be confirmed, and the causal link should be proximate. Applying the “cyber kill chain” model by analogy helps us to grasp the whole process of direct participation in hostilities during cyber warfare. For non-human targets, all military objectives must cumulatively fulfil both the “effective contribution” and “definite military advantage” criteria, which are equally indispensable. The same requirements apply to dual-use objects. Furthermore, certain data should fall within the ambit of civilian objects.
Constraining 20th‐Century Sea‐Level Rise in the South Atlantic Ocean
Authors: Frederikse Thomas , Adhikari Surendra , Daley Tim J. , Dangendorf Sönke , Gehrels Roland , Landerer Felix , Marcos Marta , Newton Thomas L. , Rush Graham , Slangen Aimée B. A. , Wöppelmann Guy 
Published: February 2021

AbstractSea level in the South Atlantic Ocean has only been measured at a small number of tide‐gauge locations, which causes considerable uncertainty in 20th‐century sea‐level trend estimates in this basin. To obtain a better‐constrained sea‐level trend in the South Atlantic Ocean, this study aims to answer two questions. The first question is: can we combine new observations, vertical land motion estimates, and information on spatial sampling biases to obtain a likely range of 20th‐century sea‐level rise in the South Atlantic? We combine existing observations with recovered observations from Dakar and a high‐resolution sea‐level reconstruction based on salt‐marsh sediments from the Falkland Islands and find that the rate of sea‐level rise in the South Atlantic has likely been between 1.1 and 2.2 mm year−1 (5%–95% confidence intervals), with a central estimate of 1.6 mm year−1. This rate is on the high side, but not statistically different compared to global‐mean trends from recent reconstructions. The second question is: are there any physical processes that could explain a large deviation from the global‐mean sea‐level trend in the South Atlantic? Sterodynamic (changes in ocean dynamics and steric effects) and gravitation, rotation, and deformation effects related to ice mass loss and land water storage have probably led to a 20th‐century sea‐level trend in the South Atlantic above the global mean. Both observations and physical processes thus suggest that 20th‐century sea‐level rise in the South Atlantic has been about 0.3 mm year−1 above the rate of global‐mean sea‐level rise, although even with the additional observations, the uncertainties are still too large to distinguish a statistically significant difference.
Evaluating the Relationship Between Meander‐Bend Curvature, Sediment Supply, and Migration Rates
Authors: Donovan Mitchell , Belmont Patrick , Sylvester Zoltán 
Published: February 2021

AbstractRiver meander migration plays a key role in the unsteady “conveyor belt” of sediment redistribution from source to sink areas. The ubiquity of river meandering is evident from remotely sensed imagery, which has allowed for long‐term, high‐resolution studies of river channel change and form‐process relationships. Empirical, experimental, and theoretical research approaches have described two distinct relationships between channel curvature and river channel migration rates. In this study, we employ a novel application of time‐series algorithms to calculate migration rates and channel curvature at sub‐meander bend length scales using 6 decades of aerial imagery spanning 205 km of the Minnesota River and Root River, Minnesota, USA. Results from the Minnesota River provide the first empirical evidence demonstrating how migration‐curvature relations break down for rivers with low sediment supply, which is supported by the Root River data set. This not only highlights the importance of sediment supply as a driver of river migration, but also supports a simple means to detect river reaches lacking sediment supply. Furthermore, results from both rivers demonstrate that sub‐meander bend measurement scales are most appropriate for studying channel migration rates and further indicate that a quasi‐linear relationship—rather than the more commonly inferred peaked relationship—exists between channel curvature and migration rates. The highest migration rates are associated with the highest measured channel curvatures in our data set, after accounting for a spatial lag of channel widths. These findings are consistent with flume experiments and empirical data across diverse geologic and climatic environments.
Tectonic Controls on Surface Erosion Rates in the Longmen Shan, Eastern Tibet
Authors: Wang Wei , Godard Vincent , Liu‐Zeng Jing , Zhang Jinyu , Li Zhigang , Xu Sheng , Yao Wenqian , Yuan Zhaode , Aumaître Georges , Bourlès Didier L. , Keddadouche Karim 
Published: February 2021

AbstractThe Longmen Shan range, located on the eastern margin of the Tibetan Plateau, is characterized by steep topography and a shortening rate of <3 mm/yr. This peculiar configuration is a source of controversy and questions about the topographic evolution and dynamics of this orogenic plateau margin. Investigating the variations in surface denudation over different spatial and temporal scales is important for a better understanding of topographic evolution, but there is still a lack of erosion‐rate data averaged over millennial timescales along the frontal range of the Longmen Shan, especially in its southern part. We present 25 new catchment‐wide denudation rates derived from 10Be concentrations in river sediments across the southern Longmen Shan. Our results show that average denudation rates increase from <0.15 mm/yr near Ya'an, located in the Sichuan Basin, northwestward to >0.50 mm/yr inside the southern Longmen Shan. The denudation rates correlate with slope gradient, relief, channel steepness, and specific stream power but exhibit a fair degree of scattering at high values. In combination with previous 10Be and low‐temperature thermochronology analyses, we found the denudation rates over kyr‐ to Myr‐timescales to be roughly consistent across the southern Longmen Shan, suggesting this part of the range is close to an exhumational steady state. In terms of spatial distribution, high rates of exhumation and denudation are localized in the hanging walls of major thrust faults, highlighting the role of tectonic structures in regulating the pattern of denudation and topography across the Longmen Shan. Our results favor the “brittle crustal shortening” model in which rock uplift pattern across the Longmen Shan is largely controlled by upper crustal shortening. Along‐strike variations in the distribution of denudation rates and topography can probably be attributed to segmentation of subsurface fault structures.
Effect of prenatal lifestyle intervention on maternal postpartum weight retention and child body mass index z-score at 36 months
Authors: Phelan Suzanne , Hart Chantelle N. , Jelalian Elissa , Muñoz-Christian Karen , Alarcon Noemi , McHugh Angelica , Ventura Alison K. , Wing Rena R. 
Published: February 2021

AbstractBackground/ObjectivesWe previously reported results from a randomized trial showing that a behavioral intervention during pregnancy reduced excess gestational weight gain but did not impact maternal weight at 12 months. We now examine the longer-term effects of this prenatal intervention on maternal postpartum weight retention and toddler body-mass-index z scores (BMIz) over 36 months.Subjects/MethodsPregnant women (N = 264; 13.7 weeks’ gestation; 41.6% Hispanic) with overweight or obesity were randomized into usual care or prenatal intervention. Anthropometric assessments in mothers and toddlers occurred at baseline, 35 weeks’ gestation and after delivery at 6, 12, 18, 24, and 36 months.ResultsAt 36 months, prenatal intervention vs. usual care had no significant effect on the proportion of participants who returned to their early pregnancy weight or below (33.3% vs. 39.5%;p = 0.12) and had no effect on the magnitude of weight retained (2.8 [0.8, 4.8] vs 3.0 kg [1.0, 4.9], respectively; mean difference = 0.14 [−3.0, 2.7]). There was also no statistically significant intervention vs. usual care effect on infant BMIz or skinfold changes over time; toddler BMIz increased by 1.4 [−1.7, 1.0] units in the intervention group and 1.6 [−1.2, 1.8] units in the usual care group from delivery to 36 months (difference = 0.16 [−0.32. 0.63]). The proportion of toddlers at risk for obesity at 36 months was similar in intervention and usual care groups (28/77 [36.4%] vs 30/80 [37.5%];p = 0.77).ConclusionsCompared with usual care, lifestyle intervention during pregnancy resulted in similar maternal and toddler anthropometric outcomes at 36-months postpartum in a diverse US sample of women with overweight and obesity. To sustain improved maternal weight management initiated during pregnancy, continued intervention during the postpartum years may be needed.
Metabolites and diabetes remission after weight loss
Authors: Kwee Lydia Coulter , Ilkayeva Olga , Muehlbauer Michael J. , Bihlmeyer Nathan , Wolfe Bruce , Purnell Jonathan Q. , Xavier Pi-Sunyer F. , Chen Haiying , Bahnson Judy , Newgard Christopher B. , Shah Svati H. , Laferrère Blandine 
Published: February 2021

AbstractThere is marked heterogeneity in the response to weight loss interventions with regards to weight loss amount and metabolic improvement. We sought to identify biomarkers predictive of type 2 diabetes remission and amount of weight loss in individuals with severe obesity enrolled in the Longitudinal Assessment of Bariatric Surgery (LABS) and the Look AHEAD (Action for Health in Diabetes) studies. Targeted mass spectrometry-based profiling of 135 metabolites was performed in pre-intervention blood samples using a nested design for diabetes remission over five years (n = 93 LABS,n = 80 Look AHEAD;n = 87 remitters), and for extremes of weight loss at five years (n = 151 LABS;n = 75 with high weight loss). Principal components analysis (PCA) was used for dimensionality reduction, with PCA-derived metabolite factors tested for association with both diabetes remission and weight loss. Metabolic markers were tested for incremental improvement to clinical models, including the DiaRem score. Two metabolite factors were associated with diabetes remission: one primarily composed of branched chain amino acids (BCAA) and tyrosine (odds ratio (95% confidence interval) [OR (95% CI)] = 1.4 [1.0–1.9],p = 0.045), and one with betaine and choline (OR [95% CI] = 0.7 [0.5–0.9],p = 0.02).These results were not significant after adjustment for multiple tests. Inclusion of these two factors in clinical models yielded modest improvements in model fit and performance: in a constructed clinical model, the C-statistic improved from 0.87 to 0.90 (p = 0.02), while the net reclassification index showed improvement in prediction compared to the DiaRem score (NRI = 0.26,p = 0.0013). No metabolite factors associated with weight loss at five years. Baseline levels of metabolites in the BCAA and trimethylamine-N-oxide (TMAO)-microbiome-related pathways are independently and incrementally associated with sustained diabetes remission after weight loss interventions in individuals with severe obesity. These metabolites could serve as clinically useful biomarkers to identify individuals who will benefit the most from weight loss interventions.
E3 ligase-inactivation rewires CBL interactome to elicit oncogenesis by hijacking RTK–CBL–CIN85 axis
Authors: Ahmed Syed Feroj , Buetow Lori , Gabrielsen Mads , Lilla Sergio , Sibbet Gary J. , Sumpton David , Zanivan Sara , Hedley Ann , Clark William , Huang Danny T. 
Published: February 2021

AbstractCasitas B-lineage lymphoma (CBL) is a ubiquitin ligase (E3) that becomes activated upon Tyr371-phosphorylation and targets receptor protein tyrosine kinases for ubiquitin-mediated degradation. Deregulation of CBL and its E3 activity is observed in myeloproliferative neoplasms and other cancers, including breast, colon, and prostate cancer. Here, we explore the oncogenic mechanism of E3-inactive CBL mutants identified in myeloproliferative neoplasms. We show that these mutants bind strongly to CIN85 under normal growth conditions and alter the CBL interactome. Lack of E3 activity deregulates CIN85 endosomal trafficking, leading to an altered transcriptome that amplifies signaling events to promote oncogenesis. Disruption of CBL mutant interactions with EGFR or CIN85 reduces oncogenic transformation. Given the importance of the CBL–CIN85 interaction in breast cancers, we examined the expression levels of CIN85, CBL, and the status of Tyr371-phosphorylated CBL (pCBL) in human breast cancer tissue microarrays. Interestingly, pCBL shows an inverse correlation with both CIN85 and CBL, suggesting that high expression of inactivated CBL could coordinate with CIN85 for breast cancer progression. Inhibition of the CBL–CIN85 interaction with a proline-rich peptide of CBL that binds CIN85 reduced the proliferation of MDA-MB-231 cells. Together, these results provide a rationale for exploring the potential of targeting the EGFR–CBL–CIN85 axis in CBL-inactivated mutant cancers.
CRL4ADTL degrades DNA-PKcs to modulate NHEJ repair and induce genomic instability and subsequent malignant transformation
Authors: Feng Maoxiao , Wang Yunshan , Bi Lei , Zhang Pengju , Wang Huaizhi , Zhao Zhongxi , Mao Jian-Hua , Wei Guangwei 
Published: February 2021

AbstractGenomic instability induced by DNA damage and improper DNA damage repair is one of the main causes of malignant transformation and tumorigenesis. DNA double strand breaks (DSBs) are the most detrimental form of DNA damage, and nonhomologous end-joining (NHEJ) mechanisms play dominant and priority roles in initiating DSB repair. A well-studied oncogene, the ubiquitin ligase Cullin 4A (CUL4A), is reported to be recruited to DSB sites in genomic DNA, but whether it regulates NHEJ mechanisms of DSB repair is unclear. Here, we discovered that the CUL4A-DTL ligase complex targeted the DNA-PKcs protein in the NHEJ repair pathway for nuclear degradation. Overexpression of either CUL4A or DTL reduced NHEJ repair efficiency and subsequently increased the accumulation of DSBs. Moreover, we demonstrated that overexpression of either CUL4A or DTL in normal cells led to genomic instability and malignant proliferation. Consistent with the in vitro findings, in human precancerous lesions, CUL4A expression gradually increased with increasing malignant tendency and was negatively correlated with DNA-PKcs and positively correlated with γ-H2AX expression. Collectively, this study provided strong evidence that the CUL4A-DTL axis increases genomic instability and enhances the subsequent malignant transformation of normal cells by inhibiting NHEJ repair. These results also suggested that CUL4A may be a prognostic marker of precancerous lesions and a potential therapeutic target in cancer.
Meta-analysis of probability estimates of worldwide variation of CYP2D6 and CYP2C19
Authors: Koopmans Anne B. , Braakman Mario H. , Vinkers David J. , Hoek Hans W. , van Harten Peter N. 
Published: February 2021

AbstractExtensive migration has led to the necessity of knowledge regarding the treatment of migrants with different ethnical backgrounds. This is especially relevant for pharmacological treatment, because of the significant variation between migrant groups in their capacity to metabolize drugs. For psychiatric medications, CYP2D6 and CYP2C19 enzymes are clinically relevant. The aim of this meta-analysis was to analyze studies reporting clinically useful information regarding CYP2D6 and CYP2C19 genotype frequencies, across populations and ethnic groups worldwide. To that end, we conducted a comprehensive meta-analysis using Embase, PubMed, Web of Science, and PsycINFO (>336,000 subjects, 318 reports). A non-normal metabolizer (non-NM) probability estimate was introduced as the equivalent of the sum-prevalence of predicted poor, intermediate, and ultrarapid metabolizer CYP2D6 and CYP2C19 phenotypes. The probability of having a CYP2D6 non-NM predicted phenotype was highest in Algeria (61%) and lowest in Gambia (2.7%) while the probability for CYP2C19 was highest in India (80%) and lowest in countries in the Americas, particularly Mexico (32%). The mean total probability estimates of having a non-NM predicted phenotype worldwide were 36.4% and 61.9% for CYP2D6 and CYP2C19, respectively. We provide detailed tables and world maps summarizing clinically relevant data regarding the prevalence of CYP2D6 and CYP2C19 predicted phenotypes and demonstrating large inter-ethnic differences. Based on the documented probability estimates, pre-emptive pharmacogenetic testing is encouraged for every patient who will undergo therapy with a drug(s) that is metabolized by CYP2D6 and/or CYP2C19 pathways and should be considered in case of treatment resistance or serious side effects.
RNA editing of the 5-HT2C receptor in the central nucleus of the amygdala is involved in resilience behavior
Authors: Warhaftig Gal , Sokolik Chaya Mushka , Khermesh Khen , Lichtenstein Yehuda , Barak Michal , Bareli Tzofnat , Levanon Erez Y. , Yadid Gal 
Published: February 2021

AbstractPost-traumatic-stress-disorder (PTSD) is a stress-related condition that may develop after exposure to a severe trauma-event. One of the core brain areas that is considered to be a key regulatory region of PTSD is the amygdala. Specifically, the central amygdala (CeA) is involved in emotion processing and associative fear learning memory, two main circuits involved in PTSD. Long term dysregulation of trauma-related emotional processing may be caused by neuroadaptations that affect gene expression. The adenosine-(A) to-inosine (I) RNA editing machinery is a post-transcriptional process that converts a genomic encoded A to I and is critical for normal brain function and development. Such editing has the potential to increase the transcriptome diversity, and disruption of this process has been linked to various central nervous system disorders. Here, we employed a unique animal model to examine the possibility that the RNA editing machinery is involved in PTSD. Detection of RNA editing specifically in the CeA revealed changes in the editing pattern of the 5-HT2C serotonin receptor (5-HT2CR) transcript accompanied by dynamic changes in the expression levels of the ADAR family enzymes (ADARandADARb1). Deamination byADARandADARb1enzymes induces conformational changes in the 5-HT2CR that decrease the G-protein-coupling activity, agonist affinity, and thus serotonin signaling. Significantly, a single intra-CeA administration of a 5-HT2CR pharmacological antagonist produced a robust alleviation of PTSD-like behaviors (that was maintained for three weeks) as well as single systemic treatment. This work may suggest the way to a new avenue in the understanding of PTSD regulation.
Chronic mild stress-induced protein dysregulations correlated with susceptibility and resiliency to depression or anxiety revealed by quantitative proteomics of the rat prefrontal cortex
Authors: Liao Wei , Liu Yanchen , Wang Lixiang , Cai Xiao , Xie Hong , Yi Faping , Huang Rongzhong , Fang Chui , Xie Peng , Zhou Jian 
Published: February 2021

AbstractChronic stress is a significant risk factor for depression as well as anxiety disorders. Yet, the stress-induced specific and common molecular dysregulations of these disorders have not been fully understood. Previously, we constructed a chronic mild stress (CMS) rat model to separate and obtain depression-susceptible, anxiety-susceptible, and insusceptible groups. In this study, the prefrontal cortical proteomes of the three stressed groups were comparatively profiled utilizing isobaric tags for relative and absolute quantitation (iTRAQ)-coupled tandem mass spectrometry approach. A total of 212 protein dysregulations were identified, potentially correlating to susceptibility or resilience to CMS-induced depression or anxiety, and thus might serve as potential protein targets for further investigation. In addition, independent analysis by parallel reaction monitoring identified changes in Gfap, Rhog, Gnai2, Ppp1r1b, and Uqcrh; Tubb6, Urod, Cul1, Spred1, and Gpcpd1; Acadl, Ppp1r1a, Grm2, Mtor, Lsm8, Cplx2, and Tsta3 that were distinctly correlated to depression-susceptible, anxiety-susceptible, or insusceptible groups, respectively. This suggested that identical CMS had different effects on the protein regulation system of the rat prefrontal cortex. Collectively, the present proteomics study of the prefrontal cortex established a significant molecular basis and offered new insights into the specificity and commonality of pathophysiologic mechanisms underlying susceptibility and resiliency to stress-induced depression or anxiety.