bluuebunny/crossref_metadata_2025_split huggingface dataset:
The 173‐kyr Obliquity Cycle Pacing the Asian Monsoon in the Eastern Chinese Loess Plateau From Late Miocene to Pliocene
Authors: Zhang Rui , Li Xiaojuan , Xu Yong , Li Jianxing , Sun Lu , Yue Leping , Pan Feng , Xian Feng , Wei Xiaohao , Cao Yuge 
Published: January 2022

AbstractWe conduct magnetostratigraphy and cyclostratigraphy on an eolian red clay sequence spanning 7–3.1 Ma in the eastern Chinese Loess Plateau. We pay more attention to the unconventional 173‐kyr obliquity modulated cycle which is associated with the secular frequency interference of orbital inclinations between Earth and Saturn. Similar to the 405‐kyr eccentricity cycles, the 173‐kyr obliquity band proved to be an important orbital driving component by the latest astronomical findings, and can serve as a chronometer of terrestrial air circulation reconstruction back to 7 Ma. Comparison with magneto‐cyclo‐bio‐stratigraphic timescales of another noted eolian sequence from the adjacent area, the 173‐kyr cycle is exceptionally presented as a robust recognition of the cyclical sedimentary patterns for the East Asia monsoon deposits.
Conjugate Effect of the 2011 Tohoku Reflected Tsunami‐Driven Gravity Waves in the Ionosphere
Authors: Chou Min‐Yang , Yue Jia , Lin Charles C. H. , Rajesh P. K. , Pedatella N. M. 
Published: January 2022

AbstractThis study presents the conjugate ionospheric disturbances triggered by the 2011 Tohoku‐Oki reflected tsunami oceanic waves using the ground‐based Global Navigation Satellite System (GNSS) total electron content (TEC) observations. We found that the equatorward and westward propagating nighttime medium‐scale traveling ionospheric disturbances (MSTIDs) occurred over Japan and Australia simultaneously following the tsunami oceanic waves reflected by the Emperor Seamount Chain in the northern hemisphere. The atmospheric gravity waves driven by reflected tsunami oceanic waves are hypothesized to be the source to trigger the conjugate MSTIDs by transporting the polarization electric fields along the field line to the conjugate hemisphere. Moreover, only the southwestward propagating MSTIDs have this conjugate effect, which could be due to the wavefront orientation. The Perkins instability could also be involved in the interhemispheric coupling process. This study provides the first observational evidence that the reflected tsunami can induce conjugate ionospheric disturbances through electrodynamic forcing.
Cretaceous Rift‐Drift Tectonics Then Paleogene Prearc Subsidence Related to Subduction Initiation: Aotea Basin, Zealandia, Southwest Pacific
Authors: Skinner Callum , Sutherland Rupert 
Published: January 2022

AbstractStratal stacking patterns and termination relationships of Upper Cretaceous and Paleogene strata of Aotea Basin, which is at the southern end of New Caledonia Trough and adjacent to Taranaki Basin, are used to infer vertical movements before, during, and after Tonga‐Kermadec subduction initiation. Regional 2D seismic‐stratigraphic units are tied to petroleum exploration wells, including recently drilled Romney‐1. We identify: (a) an uppermost Cretaceous to Paleocene (70–56 Ma) aggradational shelf sequence, with at least two regressional events linked to eustatic sea‐level falls; (b) a diachronous deepening of the basin from shelfal to bathyal environments, that progressed northwest to southeast during the early to middle Eocene (53–46 Ma); (c) that was contemporaneous with small‐scale volcanism; (d) a brief phase of middle to late Eocene (46–35 Ma) delta development at the western basin margin (Challenger Plateau) that is evidence for local uplift; and (e) an onlapping sequence deposited since the latest Eocene (35–0 Ma) that requires ∼1,300 m of subsidence at the western margin. Paleogeographic maps and a generalized stratigraphic chart summarize our observations. The Eocene phase of tectonic subsidence, uplift, and diffuse volcanism (53–46 Ma) was a precursor to plate motion at the Cenozoic plate boundary through New Zealand and suggests a causal relationship between prearc subsidence, Tonga‐Kermadec subduction initiation, and plate motion change. Delamination of lower crust beneath Aotea Basin during initial subducted slab formation might explain our observations.
CCND3 is indispensable for the maintenance of B-cell acute lymphoblastic leukemia
Authors: Ketzer Franz , Abdelrasoul Hend , Vogel Mona , Marienfeld Ralf , Müschen Markus , Jumaa Hassan , Wirth Thomas , Ushmorov Alexey 
Published: January 2022

AbstractThe D-type cyclins (CCND1, CCND2, and CCND3) in association with CDK4/6 are known drivers of cell cycle progression. We reported previously that inactivation of FOXO1 confers growth arrest and apoptosis in B-ALL, partially mediated by subsequent depletion of CCND3. Given that previously the canonical MYC target CCND2 has been considered to play the major role in B-ALL proliferation, further investigation of the role of FOXO1 in CCND3 transcription and the role of CCND3 in B-ALL is warranted. In this study, we demonstrated that CCND3 is essential for the proliferation and survival of B-ALL, independent of the mutational background. Respectively, its expression at mRNA level exceeds that of CCND1 and CCND2. Furthermore, we identified FOXO1 as a CCND3-activating transcription factor in B-ALL. By comparing the effects of CCND3 depletion and CDK4/6 inhibition by palbociclib on B-ALL cells harboring different driver mutations, we found that the anti-apoptotic effect of CCND3 is independent of the kinase activity of the CCND3-CDK4/6 complex. Moreover, we found that CCND3 contributes to CDK8 transcription, which in part might explain the anti-apoptotic effect of CCND3. Finally, we found that increased CCND3 expression is associated with the development of resistance to palbociclib. We conclude that CCND3 plays an essential role in the maintenance of B-ALL, regardless of the underlying driver mutation. Moreover, downregulation of CCND3 expression might be superior to inhibition of CDK4/6 kinase activity in terms of B-ALL treatment.
Mitochondrial modulators in the treatment of bipolar depression: a systematic review and meta-analysis
Authors: Liang Liang , Chen Junyu , Xiao Ling , Wang Qing , Wang Gaohua 
Published: January 2022

AbstractMitochondrial dysfunction has been implicated in the risk, pathophysiology, and progression of mood disorders, especially bipolar disorder (BD). Thus, the objective of this meta-analysis was to determine the overall antidepressant effect of mitochondrial modulators in the treatment of bipolar depression. Outcomes included improvement in depression scale scores, Young Mania Rating Scale (YMRS) and Clinical Global Impression-Severity Scale (CGI-S) score. Data from randomized controlled trials (RCTs) assessing the antidepressant effect of diverse mitochondrial modulators were pooled to determine standard mean differences (SMDs) compared with placebo.13 RCTs were identified for qualitative review. The overall effect size of mitochondrial modulators on depressive symptoms was −0.48 (95% CI: −0.83 to −0.14, p = 0.007, I2 = 75%), indicative of a statistically significant moderate antidepressant effect. In the subgroup analysis, NAC improved depressive symptoms compared with placebo (−0.88, 95% CI: −1.48 to −0.27, I2 = 81%). In addition, there was no statistical difference between mitochondrial modulators and placebo in YMRS. Although mitochondrial modulators were superior to placebo in CGI-S score (−0.44, 95% CI: −0.83 to −0.06, I2 = 71%), only EPA was superior to placebo in subgroup analysis. Overall, a moderate antidepressant effect was observed for mitochondrial modulators compared with placebo in the treatment of bipolar depression. The small number of studies, diversity of agents, and small sample sizes limited interpretation of the current analysis.
Transdiagnostic phenotypes of compulsive behavior and associations with psychological, cognitive, and neurobiological affective processing
Authors: Den Ouden Lauren , Suo Chao , Albertella Lucy , Greenwood Lisa-Marie , Lee Rico S. C. , Fontenelle Leonardo F. , Parkes Linden , Tiego Jeggan , Chamberlain Samuel R. , Richardson Karyn , Segrave Rebecca , Yücel Murat 
Published: January 2022

AbstractCompulsivity is a poorly understood transdiagnostic construct thought to underlie multiple disorders, including obsessive-compulsive disorder, addictions, and binge eating. Our current understanding of the causes of compulsive behavior remains primarily based on investigations into specific diagnostic categories or findings relying on one or two laboratory measures to explain complex phenotypic variance. This proof-of-concept study drew on a heterogeneous sample of community-based individuals (N = 45; 18–45 years; 25 female) exhibiting compulsive behavioral patterns in alcohol use, eating, cleaning, checking, or symmetry. Data-driven statistical modeling of multidimensional markers was utilized to identify homogeneous subtypes that were independent of traditional clinical phenomenology. Markers were based on well-defined measures of affective processing and included psychological assessment of compulsivity, behavioral avoidance, and stress, neurocognitive assessment of reward vs. punishment learning, and biological assessment of the cortisol awakening response. The neurobiological validity of the subtypes was assessed using functional magnetic resonance imaging. Statistical modeling identified three stable, distinct subtypes of compulsivity and affective processing, which we labeled “Compulsive Non-Avoidant”, “Compulsive Reactive” and “Compulsive Stressed”. They differed meaningfully on validation measures of mood, intolerance of uncertainty, and urgency. Most importantly, subtypes captured neurobiological variance on amygdala-based resting-state functional connectivity, suggesting they were valid representations of underlying neurobiology and highlighting the relevance of emotion-related brain networks in compulsive behavior. Although independent larger samples are needed to confirm the stability of subtypes, these data offer an integrated understanding of how different systems may interact in compulsive behavior and provide new considerations for guiding tailored intervention decisions.
Reward and aversion encoding in the lateral habenula for innate and learned behaviours
Authors: Mondoloni Sarah , Mameli Manuel , Congiu Mauro 
Published: January 2022

AbstractThroughout life, individuals experience a vast array of positive and aversive events that trigger adaptive behavioural responses. These events are often unpredicted and engage actions that are likely anchored on innate behavioural programs expressed by each individual member of virtually all animal species. In a second step, environmental cues, that are initially neutral, acquire value through the association with external sensory stimuli, and become instrumental to predict upcoming positive or negative events. This process ultimately prompts learned goal-directed actions allowing the pursuit of rewarding experience or the avoidance of a danger. Both innate and learned behavioural programs are evolutionarily conserved and fundamental for survival. Among the brain structures participating in the encoding of positive/negative stimuli and contributing to innate and learned behaviours is the epithalamic lateral habenula (LHb). The LHb provides top-down control of monoaminergic systems, responds to unexpected appetitive/aversive stimuli as well as external cues that predict the upcoming rewards or punishments. Accordingly, the LHb controls a number of behaviours that are innate (originating from unpredicted stimuli), and learned (stemming from predictive cues). In this review, we will discuss the progresses that rodent’s experimental work made in identifying how LHb activity governs these vital processes, and we will provide a view on how these findings integrate within a complex circuit connectivity.
Genome-wide DNA methylation profiling in anorexia nervosa discordant identical twins
Authors: Iranzo-Tatay C. , Hervas-Marin D. , Rojo-Bofill L. M. , Garcia D. , Vaz-Leal F. J. , Calabria I. , Beato-Fernandez L. , Oltra S. , Sandoval J. , Rojo-Moreno L. 
Published: January 2022

AbstractUp until now, no study has looked specifically at epigenomic landscapes throughout twin samples, discordant for Anorexia nervosa (AN). Our goal was to find evidence to confirm the hypothesis that epigenetic variations play a key role in the aetiology of AN. In this study, we quantified genome-wide patterns of DNA methylation using the Infinium Human DNA Methylation EPIC BeadChip array (“850 K”) in DNA samples isolated from whole blood collected from a group of 7 monozygotic twin pairs discordant for AN. Results were then validated performing a genome-wide DNA methylation profiling using DNA extracted from whole blood of a group of non-family-related AN patients and a group of healthy controls. Our first analysis using the twin sample revealed 9 CpGs associated to a gene. The validation analysis showed two statistically significant CpGs with the rank regression method related to two genes associated to metabolic traits, PPP2R2C and CHST1. When doing beta regression, 6 of them showed statistically significant differences, including 3 CpGs associated to genes JAM3, UBAP2L and SYNJ2. Finally, the overall pattern of results shows genetic links to phenotypes which the literature has constantly related to AN, including metabolic and psychological traits. The genes PPP2R2C and CHST1 have both been linked to the metabolic traits type 2 diabetes through GWAS studies. The genes UBAP2L and SYNJ2 have been related to other psychiatric comorbidity.
A fragment of cell adhesion molecule L1 reduces amyloid-β plaques in a mouse model of Alzheimer’s disease
Authors: Hu Junkai , Lin Stanley Li , Schachner Melitta 
Published: January 2022

AbstractDeposition of amyloid-β (Aβ) in the brain is one of the important histopathological features of Alzheimer’s disease (AD). Previously, we reported a correlation between cell adhesion molecule L1 (L1) expression and the occurrence of AD, but its relationship was unclear. Here, we report that the expression of L1 and a 70 kDa cleavage product of L1 (L1-70) was reduced in the hippocampus of AD (APPswe) mice. Interestingly, upregulation of L1-70 expression in the hippocampus of 18-month-old APPswe mice, by parabiosis involving the joining of the circulatory system of an 18-month-old APPswe mouse with a 2-month-old wild-type C57BL/6 mouse, reduced amyloid plaque deposition. Furthermore, the reduction was accompanied by the appearance of a high number of activated microglia. Mechanistically, we observed that L1-70 could combine with topoisomerase 1 (Top1) to form a complex, L1-70/Top1, that was able to regulate expression of macrophage migration inhibitory factor (MIF), resulting in the activation of microglia and reduction of Aβ plaques. Also, transforming growth factor β1 (TGFβ-1) transferred from the blood of young wild-type C57BL/6 mice to the aged AD mice, was identified as a circulating factor that induces full-length L1 and L1-70 expression. All together, these findings suggest that L1-70 contributes to the clearance of Aβ in AD, thereby adding a novel perspective in understanding AD pathogenesis.
PGC-1α inhibits the NLRP3 inflammasome via preserving mitochondrial viability to protect kidney fibrosis
Authors: Nam Bo Young , Jhee Jong Hyun , Park Jimin , Kim Seonghun , Kim Gyuri , Park Jung Tak , Yoo Tae-Hyun , Kang Shin-Wook , Yu Je-Wook , Han Seung Hyeok 
Published: January 2022

AbstractThe NLRP3 inflammasome is activated by mitochondrial damage and contributes to kidney fibrosis. However, it is unknown whether PGC-1α, a key mitochondrial biogenesis regulator, modulates NLRP3 inflammasome in kidney injury. Primary renal tubular epithelial cells (RTECs) were isolated from C57BL/6 mice. The NLRP3 inflammasome, mitochondrial dynamics and morphology, oxidative stress, and cell injury markers were examined in RTECs treated by TGF-β1 with or without Ppargc1a plasmid, PGC-1α activator (metformin), and siPGC-1α. In vivo, adenine-fed and unilateral ureteral obstruction (UUO) mice were treated with metformin. In vitro, TGF-β1 treatment to RTECs suppressed the expressions of PGC-1α and mitochondrial dynamic-related genes. The NLRP3 inflammasome was also activated and the expression of fibrotic and cell injury markers was increased. PGC-1α induction with the plasmid and metformin improved mitochondrial dynamics and morphology and attenuated the NLRP3 inflammasome and cell injury. The opposite changes were observed by siPGC-1α. The oxidative stress levels, which are inducers of the NLRP3 inflammasome, were increased and the expression of TNFAIP3, a negative regulator of NLRP3 inflammasome regulated by PGC-1α, was decreased by TGF-β1 and siPGC-1α. However, PGC-1α restoration reversed these alterations. In vivo, adenine-fed and UUO mice models showed suppression of PGC-1α and TNFAIP3 and dysregulated mitochondrial dynamics. Moreover, the activation of oxidative stress and NLRP3 inflammasome, and kidney fibrosis were increased in these mice. However, these changes were significantly reversed by metformin. This study demonstrated that kidney injury was ameliorated by PGC-1α-induced inactivation of the NLRP3 inflammasome via modulation of mitochondrial viability and dynamics.
METTL14 suppresses pyroptosis and diabetic cardiomyopathy by downregulating TINCR lncRNA
Authors: Meng Liping , Lin Hui , Huang Xingxiao , Weng Jingfan , Peng Fang , Wu Shengjie 
Published: January 2022

AbstractN6-methyladenosine (m6A) is one of the most important epigenetic regulation of RNAs, such as lncRNAs. However, the underlying regulatory mechanism of m6A in diabetic cardiomyopathy (DCM) is very limited. In this study, we sought to define the role of METTL14-mediated m6A modification in pyroptosis and DCM progression. DCM rat model was established and qRT-PCR, western blot, and immunohistochemistry (IHC) were used to detect the expression of METTL14 and TINCR. Gain-and-loss functional experiments were performed to define the role of METTL14-TINCR-NLRP3 axis in pyroptosis and DCM. RNA pulldown and RNA immunoprecipitation (RIP) assays were carried out to verify the underlying interaction. Our results showed that pyroptosis was tightly involved in DCM progression. METTL14 was downregulated in cardiomyocytes and hear tissues of DCM rat tissues. Functionally, METTL14 suppressed pyroptosis and DCM via downregulating lncRNA TINCR, which further decreased the expression of key pyroptosis-related protein, NLRP3. Mechanistically, METTL14 increased m6A methylation level of TINCR gene, resulting in its downregulation. Moreover, the m6A reader protein YTHDF2 was essential for m6A methylation and mediated the degradation of TINCR. Finally, TINCR positively regulated NLRP3 by increasing its mRNA stability. To conclude, our work revealed the novel role of METTL14-mediated m6A methylation and lncRNA regulation in pyroptosis and DCM, which could help extend our understanding the epigenetic regulation of pyroptosis in DCM progression.
RNA-binding protein p54nrb/NONO potentiates nuclear EGFR-mediated tumorigenesis of triple-negative breast cancer
Authors: Shen Mengqin , Zhang Ruixue , Jia Wenzhi , Zhu Zongping , Zhao Li , Huang Gang , Liu Jianjun 
Published: January 2022

AbstractNuclear-localized epidermal growth factor receptor (EGFR) highly correlates with the malignant progression and may be a promising therapeutic target for breast cancer. However, molecular mechanisms of nuclear EGFR in triple-negative breast cancer (TNBC) have not been fully elucidated. Here, we performed gene-annotation enrichment analysis for the interactors of nuclear EGFR and found that RNA-binding proteins (RBPs) were closely associated with nuclear EGFR. We further demonstrated p54nrb/NONO, one of the RBPs, significantly interacted with nuclear EGFR. NONO was upregulated in 80 paired TNBC tissues and indicated a poor prognosis. Furthermore, NONO knockout significantly inhibited TNBC proliferation in vitro and in vivo. Mechanistically, NONO increased the stability of nuclear EGFR and recruited CREB binding protein (CBP) and its accompanying E1A binding protein p300, thereby enhancing the transcriptional activity of EGFR. In turn, EGFR positively regulated the affinity of NONO to mRNAs of nuclear EGFR downstream genes. Furthermore, the results indicated that the nuclear EGFR/NONO complex played a critical role in tumorigenesis and chemotherapy resistance. Taken together, our findings indicate that NONO enhances nuclear EGFR-mediated tumorigenesis and may be a potential therapeutic target for TNBC patients with nuclear EGFR expression.
MiRNA-124-3p.1 sensitizes hepatocellular carcinoma cells to sorafenib by regulating FOXO3a by targeting AKT2 and SIRT1
Authors: Dong Zhe-bin , Wu Heng-miao , He Yi-cheng , Huang Zhong-ting , Weng Yi-hui , Li Hong , Liang Chao , Yu Wei-ming , Chen Wei 
Published: January 2022

AbstractAs a multikinase inhibitor, sorafenib is commonly used to treat patients with advanced hepatocellular carcinoma (HCC), however, acquired resistance to sorafenib is a major obstacle to the effectiveness of this treatment. Thus, in this study, we investigated the mechanisms underlying sorafenib resistance as well as approaches devised to increase the sensitivity of HCC to sorafenib. We demonstrated that miR-124-3p.1 downregulation is associated with early recurrence in HCC patients who underwent curative surgery and sorafenib resistance in HCC cell lines. Regarding the mechanism of this phenomenon, we identified FOXO3a, an important cellular stress transcriptional factor, as the key factor in the function of miR-124-3p.1 in HCC. We showed that miR-124-3p.1 binds directly to AKT2 and SIRT1 to reduce the levels of these proteins. Furthermore, we showed that AKT2 and SIRT1 phosphorylate and deacetylate FOXO3a. We also found that miR-124-3p.1 maintains the dephosphorylation and acetylation of FOXO3a, leading to the nuclear location of FOXO3a and enhanced sorafenib-induced apoptosis. Moreover, the combination of miR-124-3p.1 mimics and sorafenib significantly enhanced the curative efficacy of sorafenib in a nude mouse HCC xenograft model. Collectively, our data reveal that miR-124-3p.1 represents a predictive indicator of early recurrence and sorafenib sensitivity in HCC. Furthermore, we demonstrate that miR-124-3p.1 enhances the curative efficacy of sorafenib through dual effects on FOXO3a. Thus, the miR-124-3p.1-FOXO3a axis is implicated as a potential target for the diagnosis and treatment of HCC.
ATF4/CEMIP/PKCα promotes anoikis resistance by enhancing protective autophagy in prostate cancer cells
Authors: Yu Ying , Liu Bing , Li Xuexiang , Lu Dingheng , Yang Likun , Chen Liang , Li Yunxue , Cheng Lulin , Lv Fang , Zhang Pu , Song Yarong , Xing Yifei 
Published: January 2022

AbstractThe survival of cancer cells after detaching from the extracellular matrix (ECM) is essential for the metastatic cascade. The programmed cell death after detachment is known as anoikis, acting as a metastasis barrier. However, the most aggressive cancer cells escape anoikis and other cell death patterns to initiate the metastatic cascade. This study revealed the role of cell migration-inducing protein (CEMIP) in autophagy modulation and anoikis resistance during ECM detachment. CEMIP amplification during ECM detachment resulted in protective autophagy induction via a mechanism dependent on the dissociation of the B-cell lymphoma-2 (Bcl-2)/Beclin1 complex. Additional investigation revealed that acting transcription factor 4 (ATF4) triggered CEMIP transcription and enhanced protein kinase C alpha (PKCα) membrane translocation, which regulated the serine70 phosphorylation of Bcl-2, while the subsequent dissociation of the Bcl-2/Beclin1 complex led to autophagy. Therefore, CEMIP antagonization attenuated metastasis formation in vivo. In conclusion, inhibiting CEMIP-mediated protective autophagy may provide a therapeutic strategy for metastatic prostate cancer (PCa). This study delineates a novel role of CEMIP in anoikis resistance and provides new insight into seeking therapeutic strategies for metastatic PCa.