bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shear‐Wave Velocity Structure of the Southern African Upper Mantle: Implications for Craton Structure and Plateau Uplift
Authors: White‐Gaynor A. L. , Nyblade A. A. , Durrheim R. J. , Raveloson R. , van der Meijde M. , Fadel I. , Paulssen H. , Kwadiba M. , Ntibinyane O. , Titus N. , Sitali M. 
Published: February 2021

AbstractWe present a 3D shear‐wave velocity model of the southern African upper mantle developed using 30–200 s period Rayleigh waves recorded on regional seismic networks spanning the subcontinent. The model shows high velocities (∼4.7–4.8 km/s) at depths of 50–250 km beneath the Archean nucleus and several surrounding Paleoproterozoic and Mesoproterozoic terranes, placing the margin of the greater Kalahari Craton along the southern boundary of the Damara Belt and the eastern boundaries of the Gariep and Namaqua‐Natal belts. At depths ≥250 km, there is little difference in velocities beneath the craton and off‐craton regions, suggesting that the cratonic lithosphere extends to depths of about 200–250 km. Upper mantle velocities beneath uplifted areas of southern Africa are higher than the global average and significantly higher than beneath eastern Africa, indicating there that is little thermal modification of the upper mantle present today beneath the Southern African Plateau.
How Do Extreme Summer Precipitation Events Over Eastern China Subregions Change?
Authors: He Linqiang , Hao Xin , Li Hua , Han Tingting 
Published: February 2021

AbstractIn this study, observations from the CN05.1 daily data set and K‐means clustering were used to capture spatiotemporal characteristics of extreme precipitation events (EPEs) during summer over eastern China subregions from 1961 to 2018. Five subregions including South China (SC), the Yangtze River Basin (YRB), the HeTao Area (HTA), North China (NC), and Northeast China (NEC) are identified, which is distinct from previous studies. There were significant rates of EPEs transfer from the YRB‐type to SC‐type (18%), HTA‐type to YRB‐type (16%), HTA‐type to NC‐type (22%), and NC‐type to NEC‐type (25%), and the associated processes of synoptic evolution are addressed. Within these types of regional EPEs, intrinsic relationships exist that have not been recorded by previous studies. The intraseasonal evolution of summer EPEs shows a northward migration of the rainbelt influenced by the East Asian summer monsoon system. Moreover, temporal variations of regional EPEs from interannual timescales to long‐term trends are examined.
Changes of Event Size Distribution During Episodes of Shallow Tectonic Tremor, Nankai Trough
Authors: Nakano Masaru , Yabe Suguru 
Published: February 2021

AbstractSlow earthquakes follow a power‐law size distribution with an exponential taper for the largest events. We investigated changes in the size distribution of shallow tectonic tremor events during two prolonged tremor episodes (>1 month) along the Nankai trough and found that the slope of the size distributions increased while the cut‐off magnitudes decreased late during each episode, as tremor activity waned. Interpreting these changes with the two‐dimensional probabilistic cell automaton model of slow earthquakes, we found that a decrease in event ignition probability or an increase in energy dissipation during slip can qualitatively explain the observed changes. These changes imply that a decrease in accumulated stress or pore‐fluid pressure on the fault interface occurred during each tremor episode. Because the tremor source migrates during an episode, the changes in the size distribution parameters can be attributed to spatial variations or temporal changes in the source characteristics.
Using the Mid‐Holocene “Greening” of the Sahara to Narrow Acceptable Ranges on Climate Model Parameters
Authors: Hopcroft Peter O. , Valdes Paul J. , Ingram William 
Published: February 2021

AbstractDuring the early to mid‐Holocene vegetation expanded to cover much of the present‐day Sahara. Although driven by a well‐understood difference in the orbital configuration, general circulation models have generally failed to simulate the required rainfall increase. One possible explanation is the presence of systematic biases in the representations of atmospheric convection which might also impact future projections. We employ a Bayesian method to learn from an ensemble of present day and mid‐Holocene simulations that vary parameters in the convection, boundary layer and cloud schemes. The model can reproduce the “Green Sahara” rainfall if mixing between convective plumes and the environment is increased in the upper troposphere relative to lower down. This does not appreciably impact the present day simulation, meaning that the paleoclimate reconstructions are able to narrow constraints on suitable parameter ranges. This suggests that other uncertain components of climate models could be targeted in this way.
Ocean Eddy Signature on SAR‐Derived Sea Ice Drift and Vorticity
Authors: Cassianides Angelina , Lique Camille , Korosov Anton 
Published: February 2021

AbstractIn the Arctic Ocean, the observation of mesoscale eddies is impeded by the presence of sea ice. To address this problem, we develop a new method of ocean eddy detection based on their signature in sea ice vorticity retrieved from synthetic‐aperture radar (SAR) images. We examine the case of one eddy in October 2017 in the marginal ice zone of the Canadian Basin, which was sampled by mooring observations. Although the eddy could not be identified by visual inspection of the SAR images, its signature is revealed as a dipole anomaly in sea ice vorticity, which suggests that the eddy is a dipole composed of a cyclone and an anticyclone, with a horizontal scale of 80–100 km and persisted over a week. The robustness of our method will allow us to detect more eddies as more SAR observations become available in the future.
Dysbindin-1 regulates mitochondrial fission and gamma oscillations
Authors: Zhao Jun , Zhu Huiwen , Duan Kaizheng , Petralia Ronald S. , Wang Ya-Xian , Gu Qinhua , Panja Debabrata , Li Zheng 
Published: February 2021

AbstractMitochondria are cellular ATP generators. They are dynamic structures undergoing fission and fusion. While much is known about the mitochondrial fission machinery, the mechanism of initiating fission and the significance of fission to neurophysiology are largely unclear. Gamma oscillations are synchronized neural activities that impose a great energy challenge to synapses. The cellular mechanism of fueling gamma oscillations has yet to be defined. Here, we show that dysbindin-1, a protein decreased in the brain of individuals with schizophrenia, is required for neural activity-induced fission by promoting Drp1 oligomerization. This process is engaged by gamma-frequency activities and in turn, supports gamma oscillations. Gamma oscillations and novel object recognition are impaired in dysbindin-1 null mice. These defects can be ameliorated by increasing mitochondrial fission. These findings identify a molecular mechanism for activity-induced mitochondrial fission, a role of mitochondrial fission in gamma oscillations, and mitochondrial fission as a potential target for improving cognitive functions.
Injectable hydrogels of newly designed brush biopolymers as sustained drug-delivery vehicle for melanoma treatment
Authors: Shukla Aparna , Singh Akhand Pratap , Maiti Pralay 
Published: February 2021

AbstractNovel biocompatible and brush copolymers have been developed for cancer treatment using its controlled drug-release potential. Polyurethane graft on linear dextrin has been synthesized to control the hydrophilic–hydrophobic balance for regulated drug delivery. The properties of the graft copolymers have been tuned through graft density. The prepared grafts are thermally stable and mechanically strong. An injectable hydrogel has been developed by embedding the drug-loaded brush copolymers in methyl cellulose to better control the release for a prolonged period, importantly by keeping the drug release at a constant rate. Cellular studies indicate the biocompatible nature of the brush copolymers whose controlled and slow release of drug exhibit significant cytotoxic effects on cancer cells. Endocytosis of drug tagged contrast agent indicates greater transport of biologically active material inside cell as observed through cellular uptake studies. In vivo studies on melanoma mice exhibit the real efficacy of the controlled drug release from the injectable hydrogel with significant melanoma suppression without any side effects as opposed to severe toxic effects observed in conventional chemotherapy. Special application method of drug-loaded hydrogel just beneath the tumor makes this system incredibly effective through confinement. Thus, brush copolymer injectable hydrogel is a promising vehicle for control release of drug for cancer treatment in future.
UBE2S interacting with TRIM28 in the nucleus accelerates cell cycle by ubiquitination of p27 to promote hepatocellular carcinoma development
Authors: Zhang Ren-Yu , Liu Ze-Kun , Wei Ding , Yong Yu-Le , Lin Peng , Li Hao , Liu Man , Zheng Nai-Shan , Liu Ke , Hu Cai-Xia , Yang Xiao-Zhen , Chen Zhi-Nan , Bian Huijie 
Published: February 2021

AbstractGenomic sequencing analysis of tumors provides potential molecular therapeutic targets for precision medicine. However, identifying a key driver gene or mutation that can be used for hepatocellular carcinoma (HCC) treatment remains difficult. Here, we performed whole-exome sequencing on genomic DNA obtained from six pairs of HCC and adjacent tissues and identified two novel somatic mutations of UBE2S (p. Gly57Ala and p. Lys63Asn). Predictions of the functional effects of the mutations showed that two amino-acid substitutions were potentially deleterious. Further, we observed that wild-type UBE2S, especially in the nucleus, was significantly higher in HCC tissues than that in adjacent tissues and closely related to the clinicopathological features of patients with HCC. Functional assays revealed that overexpression of UBE2S promoted the proliferation, invasion, metastasis, and G1/S phase transition of HCC cells in vitro, and promoted the tumor growth significantly in vivo. Mechanistically, UBE2S interacted with TRIM28 in the nucleus, both together enhanced the ubiquitination of p27 to facilitate its degradation and cell cycle progression. Most importantly, the small-molecule cephalomannine was found by a luciferase-based sensitive high-throughput screen (HTS) to inhibit UBE2S expression and significantly attenuate HCC progression in vitro and in vivo, which may represent a promising strategy for HCC therapy.
Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis
Authors: Palladini Giovanni , Paiva Bruno , Wechalekar Ashutosh , Massa Margherita , Milani Paolo , Lasa Marta , Ravichandran Sriram , Krsnik Isabel , Basset Marco , Burgos Leire , Nuvolone Mario , Lecumberri Ramón , Foli Andrea , Puig Noemi , Sesta Melania Antonietta , Bozzola Margherita , Cascino Pasquale , Nevone Alice , Ripepi Jessica , Berti Pierpaolo , Casarini Simona , Annibali Ombretta , Orfao Alberto , San-Miguel Jesus , Merlini Giampaolo 
Published: February 2021

AbstractLight chain (AL) amyloidosis is caused by a small B-cell clone producing light chains that form amyloid deposits and cause organ dysfunction. Chemotherapy aims at suppressing the production of the toxic light chain (LC) and restore organ function. However, even complete hematologic response (CR), defined as negative serum and urine immunofixation and normalized free LC ratio, does not always translate into organ response. Next-generation flow (NGF) cytometry is used to detect minimal residual disease (MRD) in multiple myeloma. We evaluated MRD by NGF in 92 AL amyloidosis patients in CR. Fifty-four percent had persistent MRD (median 0.03% abnormal plasma cells). There were no differences in baseline clinical variables in patients with or without detectable MRD. Undetectable MRD was associated with higher rates of renal (90% vs 62%, p = 0.006) and cardiac response (95% vs 75%, p = 0.023). Hematologic progression was more frequent in MRD positive (0 vs 25% at 1 year, p = 0.001). Altogether, NGF can detect MRD in approximately half the AL amyloidosis patients in CR, and persistent MRD can explain persistent organ dysfunction. Thus, this study supports testing MRD in CR patients, especially if not accompanied by organ response. In case MRD persists, further treatment could be considered, carefully balancing residual organ damage, patient frailty, and possible toxicity.
Caspase 3/GSDME-dependent pyroptosis contributes to chemotherapy drug-induced nephrotoxicity
Authors: Shen Xiujin , Wang Haibing , Weng Chunhua , Jiang Hong , Chen Jianghua 
Published: February 2021

AbstractChemotherapy drug-induced nephrotoxicity limits clinical applications for treating cancers. Pyroptosis, a newly discovered programmed cell death, was recently reported to be associated with kidney diseases. However, the role of pyroptosis in chemotherapeutic drug-induced nephrotoxicity has not been fully clarified. Herein, we demonstrate that the chemotherapeutic drug cisplatin or doxorubicin, induces the cleavage of gasdermin E (GSDME) in cultured human renal tubular epithelial cells, in a time- and concentration-dependent manner. Morphologically, cisplatin- or doxorubicin-treated renal tubular epithelial cells exhibit large bubbles emerging from the cell membrane. Furthermore, activation of caspase 3, not caspase 9, is associated with GSDME cleavage in cisplatin- or doxorubicin-treated renal tubular epithelial cells. Meanwhile, silencing GSDME alleviates cisplatin- or doxorubicin-induced HK-2 cell pyroptosis by increasing cell viability and decreasing LDH release. In addition, treatment with Ac-DMLD-CMK, a polypeptide targeting mouse caspase 3-Gsdme signaling, inhibits caspase 3 and Gsdme activation, alleviates the deterioration of kidney function, attenuates renal tubular epithelial cell injury, and reduces inflammatory cytokine secretion in vivo. Specifically, GSDME cleavage depends on ERK and JNK signaling. NAC, a reactive oxygen species (ROS) inhibitor, reduces GSDME cleavage through JNK signaling in human renal tubular epithelial cells. Thus, we speculate that renal tubular epithelial cell pyroptosis induced by chemotherapy drugs is mediated by ROS-JNK-caspase 3-GSDME signaling, implying that therapies targeting GSDME may prove efficacious in overcoming chemotherapeutic drug-induced nephrotoxicity.
Neuroinflammation induces synaptic scaling through IL-1β-mediated activation of the transcriptional repressor REST/NRSF
Authors: Buffolo Federica , Petrosino Valentina , Albini Martina , Moschetta Matteo , Carlini Federico , Floss Thomas , Kerlero de Rosbo Nicole , Cesca Fabrizia , Rocchi Anna , Uccelli Antonio , Benfenati Fabio 
Published: February 2021

AbstractNeuroinflammation is associated with synapse dysfunction and cognitive decline in patients and animal models. One candidate for translating the inflammatory stress into structural and functional changes in neural networks is the transcriptional repressor RE1-silencing transcription factor (REST) that regulates the expression of a wide cluster of neuron-specific genes during neurogenesis and in mature neurons. To study the cellular and molecular pathways activated under inflammatory conditions mimicking the experimental autoimmune encephalomyelitis (EAE) environment, we analyzed REST activity in neuroblastoma cells and mouse cortical neurons treated with activated T cell or microglia supernatant and distinct pro-inflammatory cytokines. We found that REST is activated by a variety of neuroinflammatory stimuli in both neuroblastoma cells and primary neurons, indicating that a vast transcriptional change is triggered during neuroinflammation. While a dual activation of REST and its dominant-negative splicing isoform REST4 was observed in N2a neuroblastoma cells, primary neurons responded with a pure full-length REST upregulation in the absence of changes in REST4 expression. In both cases, REST upregulation was associated with activation of Wnt signaling and increased nuclear translocation of β-catenin, a well-known intracellular transduction pathway in neuroinflammation. Among single cytokines, IL-1β caused a potent and prompt increase in REST transcription and translation in neurons, which promoted a delayed and strong synaptic downscaling specific for excitatory synapses, with decreased frequency and amplitude of spontaneous synaptic currents, decreased density of excitatory synaptic connections, and decreased frequency of action potential-evoked Ca2+ transients. Most important, the IL-1β effects on excitatory transmission were strictly REST dependent, as conditional deletion of REST completely occluded the effects of IL-1β activation on synaptic transmission and network excitability. Our results demonstrate that REST upregulation represents a new pathogenic mechanism for the synaptic dysfunctions observed under neuroinflammatory conditions and identify the REST pathway as therapeutic target for EAE and, potentially, for multiple sclerosis.
Antenna arrangement and energy-transfer pathways of PSI–LHCI from the moss Physcomitrella patens
Authors: Yan Qiujing , Zhao Liang , Wang Wenda , Pi Xiong , Han Guangye , Wang Jie , Cheng Lingpeng , He Yi-Kun , Kuang Tingyun , Qin Xiaochun , Sui Sen-Fang , Shen Jian-Ren 
Published: February 2021

AbstractPlants harvest light energy utilized for photosynthesis by light-harvesting complex I and II (LHCI and LHCII) surrounding photosystem I and II (PSI and PSII), respectively. During the evolution of green plants, moss is at an evolutionarily intermediate position from aquatic photosynthetic organisms to land plants, being the first photosynthetic organisms that landed. Here, we report the structure of the PSI–LHCI supercomplex from the moss Physcomitrella patens (Pp) at 3.23 Å resolution solved by cryo-electron microscopy. Our structure revealed that four Lhca subunits are associated with the PSI core in an order of Lhca1–Lhca5–Lhca2–Lhca3. This number is much decreased from 8 to 10, the number of subunits in most green algal PSI–LHCI, but the same as those of land plants. Although Pp PSI–LHCI has a similar structure as PSI–LHCI of land plants, it has Lhca5, instead of Lhca4, in the second position of Lhca, and several differences were found in the arrangement of chlorophylls among green algal, moss, and land plant PSI–LHCI. One chlorophyll, PsaF–Chl 305, which is found in the moss PSI–LHCI, is located at the gap region between the two middle Lhca subunits and the PSI core, and therefore may make the excitation energy transfer from LHCI to the core more efficient than that of land plants. On the other hand, energy-transfer paths at the two side Lhca subunits are relatively conserved. These results provide a structural basis for unravelling the mechanisms of light-energy harvesting and transfer in the moss PSI–LHCI, as well as important clues on the changes of PSI–LHCI after landing.
Implications of hematopoietic stem cells heterogeneity for gene therapies
Authors: Epah Jeremy , Schäfer Richard 
Published: February 2021

AbstractHematopoietic stem cell transplantation (HSCT) is the therapeutic concept to cure the blood/immune system of patients suffering from malignancies, immunodeficiencies, red blood cell disorders, and inherited bone marrow failure syndromes. Yet, allogeneic HSCT bear considerable risks for the patient such as non-engraftment, or graft-versus host disease. Transplanting gene modified autologous HSCs is a promising approach not only for inherited blood/immune cell diseases, but also for the acquired immunodeficiency syndrome. However, there is emerging evidence for substantial heterogeneity of HSCs in situ as well as ex vivo that is also observed after HSCT. Thus, HSC gene modification concepts are suggested to consider that different blood disorders affect specific hematopoietic cell types. We will discuss the relevance of HSC heterogeneity for the development and manufacture of gene therapies and in exemplary diseases with a specific emphasis on the key target HSC types myeloid-biased, lymphoid-biased, and balanced HSCs.
Real-time prediction of COVID-19 related mortality using electronic health records
Authors: Schwab Patrick , Mehrjou Arash , Parbhoo Sonali , Celi Leo Anthony , Hetzel Jürgen , Hofer Markus , Schölkopf Bernhard , Bauer Stefan 
Published: February 2021

AbstractCoronavirus disease 2019 (COVID-19) is a respiratory disease with rapid human-to-human transmission caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to the exponential growth of infections, identifying patients with the highest mortality risk early is critical to enable effective intervention and prioritisation of care. Here, we present the COVID-19 early warning system (CovEWS), a risk scoring system for assessing COVID-19 related mortality risk that we developed using data amounting to a total of over 2863 years of observation time from a cohort of 66 430 patients seen at over 69 healthcare institutions. On an external cohort of 5005 patients, CovEWS predicts mortality from 78.8% (95% confidence interval [CI]: 76.0, 84.7%) to 69.4% (95% CI: 57.6, 75.2%) specificity at sensitivities greater than 95% between, respectively, 1 and 192 h prior to mortality events. CovEWS could enable earlier intervention, and may therefore help in preventing or mitigating COVID-19 related mortality.
Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis
Authors: Sakaue Saori , Yamaguchi Etsuro , Inoue Yoshikazu , Takahashi Meiko , Hirata Jun , Suzuki Ken , Ito Satoru , Arai Toru , Hirose Masaki , Tanino Yoshinori , Nikaido Takefumi , Ichiwata Toshio , Ohkouchi Shinya , Hirano Taizou , Takada Toshinori , Miyawaki Satoru , Dofuku Shogo , Maeda Yuichi , Nii Takuro , Kishikawa Toshihiro , Ogawa Kotaro , Masuda Tatsuo , Yamamoto Kenichi , Sonehara Kyuto , Tazawa Ryushi , Morimoto Konosuke , Takaki Masahiro , Konno Satoshi , Suzuki Masaru , Tomii Keisuke , Nakagawa Atsushi , Handa Tomohiro , Tanizawa Kiminobu , Ishii Haruyuki , Ishida Manabu , Kato Toshiyuki , Takeda Naoya , Yokomura Koshi , Matsui Takashi , Watanabe Masaki , Inoue Hiromasa , Imaizumi Kazuyoshi , Goto Yasuhiro , Kida Hiroshi , Fujisawa Tomoyuki , Suda Takafumi , Yamada Takashi , Satake Yasuomi , Ibata Hidenori , Hizawa Nobuyuki , Mochizuki Hideki , Kumanogoh Atsushi , Matsuda Fumihiko , Nakata Koh , Hirota Tomomitsu , Tamari Mayumi , Okada Yukinori 
Published: February 2021

AbstractPulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6–7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2;P = 2.4 × 10−12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8;P = 4.8 × 10−12), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28;P = 3.4 × 10−7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (β = 0.32;P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.