bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mineral Magnetic Characterization of High‐Latitude Sediments From Lake Levinson‐Lessing, Siberia
Authors: Scheidt Stephanie , Egli Ramon , Lenz Matthias , Rolf Christian , Fabian Karl , Melles Martin 
Published: May 2021

AbstractLevinson‐Lessing Lake in northern Central Siberia is a sedimentary archive characterized by continuous, widely constant sedimentation at high rates (0.7 m ka−1 for >32 ka). This study provides the first evidence of the suitability of the lake′s sediments for paleomagnetic analyses using the 46‐m‐long core Co1401. Although the lowermost 8 m are disturbed, the upper 38 m of Co1401 provide the preconditions for an exceptional, high‐resolution paleomagnetic record located within the tangent cylinder of the inner core. High‐resolution analyses of magnetic susceptibility, anhysteretic remanent magnetization, isothermal remanent magnetization, and hysteresis parameters show largely uniform mineral magnetic properties. First‐order reversal curves indicate magnetite particles in pseudo‐single domain state are the main remanence carrier, supplemented by single‐domain particles, originating likely from magnetotactic bacteria. Above 6.7 m, the bulk magnetic mineralogy is slightly harder than below and initial greigite formation occurs. However, the main remanence carriers are still of detrital origin.
Seismic Diffusivity and the Influence of Heterogeneity on Injection‐Induced Seismicity
Authors: Haagenson Ryan , Rajaram Harihar 
Published: May 2021

AbstractThe spatiotemporal patterns of injection‐induced seismicity (IIS) are commonly interpreted with the concept of a triggering front, which propagates in a diffusion‐like manner with an associated diffusivity parameter. Here, we refer to this diffusivity as the “seismic diffusivity.” Several previous studies implicitly assume that seismic diffusivity is equivalent to the effective hydraulic diffusivity of the subsurface, which describes the behavior of the mean pressure field in heterogeneous porous media. Seismicity‐based approaches for hydraulic characterization or simulations of IIS using domains of homogeneous equivalent porous media are implicitly based on this assumed equivalence. However, seismicity is expected to propagate with the threshold triggering pressure, and thus not be controlled by the evolution of the mean pressure field. We present numerical simulations of fluid injection to compare the seismic and effective hydraulic diffusivities in heterogeneous formations (including fractured rock). The numerical model combines uncoupled, linear pressure diffusion with the Mohr‐Coulomb failure criterion to simulate IIS. We demonstrate that connected pathways of relatively high hydraulic diffusivity in heterogeneous media (particularly in fractured rock domains) allow the threshold triggering pressure to propagate more rapidly than predicted by the effective hydraulic diffusivity. As a result, the seismic diffusivity is greater than the effective hydraulic diffusivity in heterogeneous porous media, possibly by an order of magnitude or more. Additionally, we present a case study of IIS near Soultz‐sous‐Forêts where seismic diffusivity is found to be at least one order of magnitude larger than the effective hydraulic diffusivity.
ST6Gal1 targets the ectodomain of ErbB2 in a site-specific manner and regulates gastric cancer cell sensitivity to trastuzumab
Authors: Duarte Henrique O. , Rodrigues Joana G. , Gomes Catarina , Hensbergen Paul J. , Ederveen Agnes L. Hipgrave , de Ru Arnoud H. , Mereiter Stefan , Polónia António , Fernandes Elisabete , Ferreira José A. , van Veelen Peter A. , Santos Lúcio L. , Wuhrer Manfred , Gomes Joana , Reis Celso A. 
Published: May 2021

AbstractThe clinical performance of the therapeutic monoclonal antibody trastuzumab in the treatment of ErbB2-positive unresectable gastric cancer (GC) is severely hampered by the emergence of molecular resistance. Trastuzumab’s target epitope is localized within the extracellular domain of the oncogenic cell surface receptor tyrosine kinase (RTK) ErbB2, which is known to undergo extensive N-linked glycosylation. However, the site-specific glycan repertoire of ErbB2, as well as the detailed molecular mechanisms through which specific aberrant glycan signatures functionally impact the malignant features of ErbB2-addicted GC cells, including the acquisition of trastuzumab resistance, remain elusive. Here, we demonstrate that ErbB2 is modified with both α2,6- and α2,3-sialylated glycan structures in GC clinical specimens. In-depth mass spectrometry-based glycomic and glycoproteomic analysis of ErbB2’s ectodomain disclosed a site-specific glycosylation profile in GC cells, in which the ST6Gal1 sialyltransferase specifically targets ErbB2 N-glycosylation sites occurring within the receptor’s trastuzumab-binding domain. Abrogation of ST6Gal1 expression reshaped the cellular and ErbB2-specific glycomes, expanded the cellular half-life of the ErbB2 receptor, and sensitized ErbB2-dependent GC cells to trastuzumab-induced cytotoxicity through the stabilization of ErbB dimers at the cell membrane, and the decreased activation of both ErbB2 and EGFR RTKs. Overall, our data demonstrates that ST6Gal1-mediated aberrant α2,6-sialylation actively tunes the resistance of ErbB2-driven GC cells to trastuzumab.
LRIG1 is a conserved EGFR regulator involved in melanoma development, survival and treatment resistance
Authors: Billing Ola , Holmgren Ylva , Nosek Daniel , Hedman Håkan , Hemmingsson Oskar 
Published: May 2021

AbstractLeucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a pan-negative regulator of receptor tyrosine kinase (RTK) signaling and a tumor suppressor in several cancers, but its involvement in melanoma is largely unexplored. Here, we aim to determine the role of LRIG1 in melanoma tumorigenesis, RTK signaling, and BRAF inhibitor resistance. We find that LRIG1 is downregulated during early tumorigenesis and that LRIG1 affects activation of the epidermal growth factor receptor (EGFR) in melanoma cells. LRIG1-dependent regulation of EGFR signaling is evolutionary conserved to the roundworm C. elegans, where negative regulation of the EGFR-Ras-Raf pathway by sma-10/LRIG completely depends on presence of the receptor let-23/EGFR. In a cohort of metastatic melanoma patients, we observe an association between LRIG1 and survival in the triple wild-type subtype and in tumors with high EGFR expression. During in vitro development of BRAF inhibitor resistance, LRIG1 expression decreases; and mimics LRIG1 knockout cells for increased EGFR expression. Treating resistant cells with recombinant LRIG1 suppresses AKT activation and proliferation. Together, our results show that sma-10/LRIG is a conserved regulator of RTK signaling, add to our understanding of LRIG1 in melanoma and identifies recombinant LRIG1 as a potential therapeutic against BRAF inhibitor-resistant melanoma.
YWHAE-NUTM2 oncoprotein regulates proliferation and cyclin D1 via RAF/MAPK and Hippo pathways
Authors: Ou Wen-Bin , Lundberg Meijun Z. , Zhu Shuihao , Bahri Nacef , Kyriazoglou Anastasios , Xu Liangliang , Chen Ting , Mariño-Enriquez Adrian , Fletcher Jonathan A. 
Published: May 2021

AbstractEndometrial stromal sarcoma (ESS) is the second most common subtype of uterine mesenchymal cancer, after leiomyosarcoma, and oncogenic fusion proteins are found in many ESS. Our previous studies demonstrated transforming properties and diagnostic relevance of the fusion oncoprotein YWHAE–NUTM2 in high-grade endometrial stromal sarcoma (HG-ESS) and showed that cyclin D1 is a diagnostic biomarker in these HG-ESS. However, YWHAE–NUTM2 mechanisms of oncogenesis and roles in cyclin D1 expression have not been characterized. In the current studies, we show YWHAE-NUTM2 complexes with both BRAF/RAF1 and YAP/TAZ in HG-ESS. These interactions are functionally relevant because YWHAE-NUTM2 knockdown in HG-ESS and other models inhibits RAF/MEK/MAPK phosphorylation, cyclin D1 expression, and cell proliferation. Further, cyclin D1 knockdown in HG-ESS dephosphorylates RB1 and inhibits proliferation. In keeping with these findings, we show that MEK and CDK4/6 inhibitors have anti-proliferative effects in HG-ESS, and combinations of these inhibitors have synergistic activity. These findings establish that YWHAE-NUTM2 regulates cyclin D1 expression and cell proliferation by dysregulating RAF/MEK/MAPK and Hippo/YAP-TAZ signaling pathways. Recent studies demonstrate Hippo/YAP-TAZ pathway aberrations in many sarcomas, but this is among the first studies to demonstrate a well-defined oncogenic mechanism as the cause of Hippo pathway dysregulation.
Moderation of the transgenerational transference of antenatal stress-induced anxiety
Authors: Burstein Or , Simon Noam , Simchon-Tenenbaum Yaarit , Rehavi Moshe , Franko Motty , Shamir Alon , Doron Ravid 
Published: May 2021

AbstractMaternal stress has debilitating implications for both mother and child, including increased risk for anxiety. The current COVID-19 pandemic escalates these phenomena, thus, urging the need to further explore and validate feasible therapeutic options. Unlike the protracted nature of clinical studies, animal models could offer swift evidence. Prominent candidates for treatment are selective serotonin reuptake inhibitors (SSRIs) to the mother, that putatively accommodate maternal functioning, and, thereby, also protect the child. However, SSRIs might have deleterious effects. It is important to assess whether SSRIs and other pharmacotherapies can moderate the transference of anxiety by soothing maternal anxiety and to examine the extent of offspring’s exposure to the drugs via lactation. To our knowledge, the possibility that antenatal stress exacerbates lactation-driven exposure to SSRIs has not been tested yet. Thirty ICR-outbred female mice were exposed to stress during gestation and subsequently administered with either the SSRI, escitalopram, or the novel herbal candidate, shan-zha, during lactation. Upon weaning, both dams’ and pups’ anxiety-like behavior and serum escitalopram levels were assessed. The major findings of the current study show that both agents moderated the antenatal stress-induced transgenerational transference of anxiety by ameliorating dams’ anxiety. Interestingly though, pups’ exposure to escitalopram via lactation was exacerbated by antenatal stress. The latter finding provides a significant insight into the mechanism of lactation-driven exposure to xenobiotics and calls for a further consideration vis-à-vis the administration of other drugs during breastfeeding.
The role of the orbitofrontal cortex and the nucleus accumbens for craving in alcohol use disorder
Authors: Bracht Tobias , Soravia Leila , Moggi Franz , Stein Maria , Grieder Matthias , Federspiel Andrea , Tschümperlin Raphaela , Batschelet Hallie M. , Wiest Roland , Denier Niklaus 
Published: May 2021

AbstractThis study aimed to investigate structural and functional alterations of the reward system and the neurobiology of craving in alcohol use disorder (AUD). We hypothesized reduced volume of the nucleus accumbens (NAcc), reduced structural connectivity of the segment of the supero-lateral medial forebrain bundle connecting the orbitofrontal cortex (OFC) with the NAcc (OFC-NAcc), and reduced resting-state OFC-NAcc functional connectivity (FC). Furthermore, we hypothesized that craving is related to an increase of OFC-NAcc FC. Thirty-nine recently abstinent patients with AUD and 18 healthy controls (HC) underwent structural (T1w-MP2RAGE, diffusion-weighted imaging (DWI)) and functional (resting-state fMRI) MRI-scans. Gray matter volume of the NAcc, white matter microstructure (fractional anisotropy (FA)) and macrostructure (tract length) of the OFC-NAcc connection and OFC-NAcc FC were compared between AUD and HC using a mixed model MANCOVA controlling for age and gender. Craving was assessed using the thoughts subscale of the obsessive-compulsive drinking scale (OCDS) scale and was correlated with OFC-NAcc FC. There was a significant main effect of group. Results were driven by a volume reduction of bilateral NAcc, reduced FA in the left hemisphere, and reduced tract length of bilateral OFC-NAcc connections in AUD patients. OFC-NAcc FC did not differ between groups. Craving was associated with increased bilateral OFC-NAcc FC. In conclusion, reduced volume of the NAcc and reduced FA and tract length of the OFC-NAcc network suggest structural alterations of the reward network in AUD. Increased OFC-NAcc FC is associated with craving in AUD, and may contribute to situational alcohol-seeking behavior in AUD.
Structure of the full-length human Pannexin1 channel and insights into its role in pyroptosis
Authors: Zhang Sensen , Yuan Baolei , Lam Jordy Homing , Zhou Jun , Zhou Xuan , Ramos-Mandujano Gerardo , Tian Xueyuan , Liu Yang , Han Renmin , Li Yu , Gao Xin , Li Mo , Yang Maojun 
Published: May 2021

AbstractPannexin1 (PANX1) is a large-pore ATP efflux channel with a broad distribution, which allows the exchange of molecules and ions smaller than 1 kDa between the cytoplasm and extracellular space. In this study, we show that in human macrophages PANX1 expression is upregulated by diverse stimuli that promote pyroptosis, which is reminiscent of the previously reported lipopolysaccharide-induced upregulation of PANX1 during inflammasome activation. To further elucidate the function of PANX1, we propose the full-length human Pannexin1 (hPANX1) model through cryo-electron microscopy (cryo-EM) and molecular dynamics (MD) simulation studies, establishing hPANX1 as a homo-heptamer and revealing that both the N-termini and C-termini protrude deeply into the channel pore funnel. MD simulations also elucidate key energetic features governing the channel that lay a foundation to understand the channel gating mechanism. Structural analyses, functional characterizations, and computational studies support the current hPANX1-MD model, suggesting the potential role of hPANX1 in pyroptosis during immune responses.
Unique reactivity of nanoporous cellulosic materials mediated by surface-confined water
Authors: Beaumont Marco , Jusner Paul , Gierlinger Notburga , King Alistair W. T. , Potthast Antje , Rojas Orlando J. , Rosenau Thomas 
Published: May 2021

AbstractThe remarkable efficiency of chemical reactions is the result of biological evolution, often involving confined water. Meanwhile, developments of bio-inspired systems, which exploit the potential of such water, have been so far rather complex and cumbersome. Here we show that surface-confined water, inherently present in widely abundant and renewable cellulosic fibres can be utilised as nanomedium to endow a singular chemical reactivity. Compared to surface acetylation in the dry state, confined water increases the reaction rate and efficiency by 8 times and 30%, respectively. Moreover, confined water enables control over chemical accessibility of selected hydroxyl groups through the extent of hydration, allowing regioselective reactions, a major challenge in cellulose modification. The reactions mediated by surface-confined water are sustainable and largely outperform those occurring in organic solvents in terms of efficiency and environmental compatibility. Our results demonstrate the unexploited potential of water bound to cellulosic nanostructures in surface esterifications, which can be extended to a wide range of other nanoporous polymeric structures and reactions.
Bandwidth-control orbital-selective delocalization of 4f electrons in epitaxial Ce films
Authors: Wu Yi , Fang Yuan , Li Peng , Xiao Zhiguang , Zheng Hao , Yuan Huiqiu , Cao Chao , Yang Yi-feng , Liu Yang 
Published: May 2021

AbstractThe 4f-electron delocalization plays a key role in the low-temperature properties of rare-earth metals and intermetallics, and it is normally realized by the Kondo coupling between 4f and conduction electrons. Due to the large Coulomb repulsion of 4f electrons, the bandwidth-control Mott-type delocalization, commonly observed in d-electron systems, is difficult in 4f-electron systems and remains elusive in spectroscopic experiments. Here we demonstrate that the bandwidth-control orbital-selective delocalization of 4f electrons can be realized in epitaxial Ce films by thermal annealing, which results in a metastable surface phase with reduced layer spacing. The quasiparticle bands exhibit large dispersion with exclusive 4f character near $$\bar{{{\Gamma }}}$$

Γ

¯

and extend reasonably far below the Fermi energy, which can be explained from the Mott physics. The experimental quasiparticle dispersion agrees well with density-functional theory calculation and also exhibits unusual temperature dependence, which could arise from the delicate interplay between the bandwidth-control Mott physics and the coexisting Kondo hybridization. Our work opens up the opportunity to study the interaction between two well-known localization-delocalization mechanisms in correlation physics, i.e., Kondo vs Mott, which can be important for a fundamental understanding of 4f-electron systems.
Intrinsic functional neuron-type selectivity of transcranial focused ultrasound neuromodulation
Authors: Yu Kai , Niu Xiaodan , Krook-Magnuson Esther , He Bin 
Published: May 2021

AbstractTranscranial focused ultrasound (tFUS) is a promising neuromodulation technique, but its mechanisms remain unclear. We hypothesize that if tFUS parameters exhibit distinct modulation effects in different neuron populations, then the mechanism can be understood through identifying unique features in these neuron populations. In this work, we investigate the effect of tFUS stimulation on different functional neuron types in in vivo anesthetized rodent brains. Single neuron recordings were separated into regular-spiking and fast-spiking units based on their extracellular spike shapes acquired through intracranial electrophysiological recordings, and further validated in transgenic optogenetic mice models of light-excitable excitatory and inhibitory neurons. We show that excitatory and inhibitory neurons are intrinsically different in response to ultrasound pulse repetition frequency (PRF). The results suggest that we can preferentially target specific neuron types noninvasively by tuning the tFUS PRF. Chemically deafened rats and genetically deafened mice were further tested for validating the directly local neural effects induced by tFUS without potential auditory confounds.
Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 infection
Authors: Diao Bo , Wang Chenhui , Wang Rongshuai , Feng Zeqing , Zhang Ji , Yang Han , Tan Yingjun , Wang Huiming , Wang Changsong , Liu Liang , Liu Ying , Liu Yueping , Wang Gang , Yuan Zilin , Hou Xiaotao , Ren Liang , Wu Yuzhang , Chen Yongwen 
Published: May 2021

AbstractIt is unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can directly infect human kidney, thus leading to acute kidney injury (AKI). Here, we perform a retrospective analysis of clinical parameters from 85 patients with laboratory-confirmed coronavirus disease 2019 (COVID-19); moreover, kidney histopathology from six additional COVID-19 patients with post-mortem examinations was performed. We find that 27% (23/85) of patients exhibited AKI. The elderly patients and cases with comorbidities (hypertension and heart failure) are more prone to develop AKI. Haematoxylin & eosin staining shows that the kidneys from COVID-19 autopsies have moderate to severe tubular damage. In situ hybridization assays illustrate that viral RNA accumulates in tubules. Immunohistochemistry shows nucleocapsid and spike protein deposits in the tubules, and immunofluorescence double staining shows that both antigens are restricted to the angiotensin converting enzyme-II-positive tubules. SARS-CoV-2 infection triggers the expression of hypoxic damage-associated molecules, including DP2 and prostaglandin D synthase in infected tubules. Moreover, it enhances CD68+ macrophages infiltration into the tubulointerstitium, and complement C5b-9 deposition on tubules is also observed. These results suggest that SARS-CoV-2 directly infects human kidney to mediate tubular pathogenesis and AKI.
Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures
Authors: Franciosa Giulia , Smits Jos G. A. , Minuzzo Sonia , Martinez-Val Ana , Indraccolo Stefano , Olsen Jesper V. 
Published: May 2021

AbstractNotch1 is a crucial oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL), making it an attractive therapeutic target. However, the success of targeted therapy using γ-secretase inhibitors (GSIs), small molecules blocking Notch cleavage and subsequent activation, has been limited due to development of resistance, thus restricting its clinical efficacy. Here, we systematically compare GSI resistant and sensitive cell states by quantitative mass spectrometry-based phosphoproteomics, using complementary models of resistance, including T-ALL patient-derived xenografts (PDX) models. Our datasets reveal common mechanisms of GSI resistance, including a distinct kinase signature that involves protein kinase C delta. We demonstrate that the PKC inhibitor sotrastaurin enhances the anti-leukemic activity of GSI in PDX models and completely abrogates the development of acquired GSI resistance in vitro. Overall, we highlight the potential of proteomics to dissect alterations in cellular signaling and identify druggable pathways in cancer.
Disruption of insect immunity using analogs of the pleiotropic insect peptide hormone Neb-colloostatin: a nanotech approach for pest control II
Authors: Nowicki Patryk , Kuczer Mariola , Schroeder Grzegorz , Czarniewska Elżbieta 
Published: May 2021

AbstractThis work continues our studies on the pleiotropic activity of the insect peptide Neb-colloostatin in insects. In vivo immunological bioassays demonstrated that hemocytotoxic analogs of Neb-colloostatin injected into Tenebrio molitor significantly reduced the number of hemocytes in the hemolymph and impaired phagocytosis, nodulation and phenoloxidase activities in the insects. Among the analogs tested, [Ala1]-,[Val1]-, [Hyp4]- and [Ach4]-colloostatin were particularly potent in disrupting cellular immunity in larvae, pupae and adult insects. This result suggests that the most effective analogs showed increases in the bioactivity period in the hemolymph of insects when compared to Neb-colloostatin. Recently, we demonstrated that it is possible to introduce Neb-colloostatin through the cuticle of an insect into the hemolymph when the peptide is coupled with nanodiamonds. In this study, we showed that [Ala1]-, [Val1]-, [Hyp4]- and [Ach4]-colloostatin, when complexed with nanodiamonds, may also pass through the cuticle into the hemolymph and induce long-term impairments of immunity in T. molitor at all developmental stages. Studies on the tissue selectivity and effectiveness of Neb-colloostatin analogs and efficient methods for their introduction into insects may contribute to the development of eco-friendly pest control methods based on bioactive peptidomimetics.