bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes of Event Size Distribution During Episodes of Shallow Tectonic Tremor, Nankai Trough
Authors: Nakano Masaru , Yabe Suguru
Published: February 2021

Slow 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

During 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

In 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

Mitochondria 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

Novel 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

Genomic 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

Light 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

Chemotherapy 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

Neuroinflammation 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

Plants 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

Hematopoietic 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

Coronavirus 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

Pulmonary 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.
Insight-HXMT observations of jet-like corona in a black hole X-ray binary MAXI J1820+070
Authors: You Bei , Tuo Yuoli , Li Chengzhe , Wang Wei , Zhang Shuang-Nan , Zhang Shu , Ge Mingyu , Luo Chong , Liu Bifang , Yuan Weimin , Dai Zigao , Liu Jifeng , Qiao Erlin , Jin Chichuan , Liu Zhu , Czerny Bozena , Wu Qingwen , Bu Qingcui , Cai Ce , Cao Xuelei , Chang Zhi , Chen Gang , Chen Li , Chen Tianxiang , Chen Yibao , Chen Yong , Chen Yupeng , Cui Wei , Cui Weiwei , Deng Jingkang , Dong Yongwei , Du Yuanyuan , Fu Minxue , Gao Guanhua , Gao He , Gao Min , Gu Yudong , Guan Ju , Guo Chengcheng , Han Dawei , Huang Yue , Huo Jia , Jia Shumei , Jiang Luhua , Jiang Weichun , Jin Jing , Jin Yongjie , Kong Lingda , Li Bing , Li Chengkui , Li Gang , Li Maoshun , Li Tipei , Li Wei , Li Xian , Li Xiaobo , Li Xufang , Li Yanguo , Li Zhengwei , Liang Xiaohua , Liao Jinyuan , Liu Congzhan , Liu Guoqing , Liu Hongwei , Liu Xiaojing , Liu Yinong , Lu Bo , Lu Fangjun , Lu Xuefeng , Luo Qi , Luo Tao , Ma Xiang , Meng Bin , Nang Yi , Nie Jianyin , Ou Ge , Qu Jinlu , Sai Na , Shang Rencheng , Song Liming , Song Xinying , Sun Liang , Tan Ying , Tao Lian , Wang Chen , Wang Guofeng , Wang Juan , Wang Lingjun , Wang Wenshuai , Wang Yusa , Wen Xiangyang , Wu Baiyang , Wu Bobing , Wu Mei , Xiao Guangcheng , Xiao Shuo , Xiong Shaolin , Xu Yupeng , Yang Jiawei , Yang Sheng , Yang Yanji , Yi Qibin , Yin Qianqing , You Yuan , Zhang Aimei , Zhang Chengmo , Zhang Fan , Zhang Hongmei , Zhang Juan , Zhang Tong , Zhang Wanchang , Zhang Wei , Zhang Wenzhao , Zhang Yi , Zhang Yifei , Zhang Yongjie , Zhang Yue , Zhang Zhao , Zhang Ziliang , Zhao Haisheng , Zhao Xiaofan , Zheng Shijie , Zhou Dengke , Zhou Jianfeng , Zhu Yuxuan , Zhu Yue
Published: February 2021

A black hole X-ray binary produces hard X-ray radiation from its corona and disk when the accreting matter heats up. During an outburst, the disk and corona co-evolves with each other. However, such an evolution is still unclear in both its geometry and dynamics. Here we report the unusual decrease of the reflection fraction in MAXI J1820+070, which is the ratio of the coronal intensity illuminating the disk to the coronal intensity reaching the observer, as the corona is observed to contrast during the decay phase. We postulate a jet-like corona model, in which the corona can be understood as a standing shock where the material flowing through. In this dynamical scenario, the decrease of the reflection fraction is a signature of the corona’s bulk velocity. Our findings suggest that as the corona is observed to get closer to the black hole, the coronal material might be outflowing faster.
Distinct subtypes of proprioceptive dorsal root ganglion neurons regulate adaptive proprioception in mice
Authors: Wu Haohao , Petitpré Charles , Fontanet Paula , Sharma Anil , Bellardita Carmelo , Quadros Rolen M. , Jannig Paulo R. , Wang Yiqiao , Heimel J. Alexander , Cheung Kylie K. Y. , Wanderoy Simone , Xuan Yang , Meletis Konstantinos , Ruas Jorge , Gurumurthy Channabasavaiah B. , Kiehn Ole , Hadjab Saida , Lallemend François
Published: February 2021

Proprioceptive neurons (PNs) are essential for the proper execution of all our movements by providing muscle sensory feedback to the central motor network. Here, using deep single cell RNAseq of adult PNs coupled with virus and genetic tracings, we molecularly identify three main types of PNs (Ia, Ib and II) and find that they segregate into eight distinct subgroups. Our data unveil a highly sophisticated organization of PNs into discrete sensory input channels with distinct spatial distribution, innervation patterns and molecular profiles. Altogether, these features contribute to finely regulate proprioception during complex motor behavior. Moreover, while Ib- and II-PN subtypes are specified around birth, Ia-PN subtypes diversify later in life along with increased motor activity. We also show Ia-PNs plasticity following exercise training, suggesting Ia-PNs are important players in adaptive proprioceptive function in adult mice.
RNF167 activates mTORC1 and promotes tumorigenesis by targeting CASTOR1 for ubiquitination and degradation
Authors: Li Tingting , Wang Xian , Ju Enguo , da Silva Suzane Ramos , Chen Luping , Zhang Xinquan , Wei Shan , Gao Shou-Jiang
Published: February 2021

mTORC1, a central controller of cell proliferation in response to growth factors and nutrients, is dysregulated in cancer. Whereas arginine activates mTORC1, it is overridden by high expression of cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1). Because cancer cells often encounter low levels of nutrients, an alternative mechanism might exist to regulate CASTOR1 expression. Here we show K29-linked polyubiquitination and degradation of CASTOR1 by E3 ubiquitin ligase RNF167. Furthermore, AKT phosphorylates CASTOR1 at S14, significantly increasing its binding to RNF167, and hence its ubiquitination and degradation, while simultaneously decreasing its affinity to MIOS, leading to mTORC1 activation. Therefore, AKT activates mTORC1 through both TSC2- and CASTOR1-dependent pathways. Several cell types with high CASTOR1 expression are insensitive to arginine regulation. Significantly, AKT and RNF167-mediated CASTOR1 degradation activates mTORC1 independent of arginine and promotes breast cancer progression. These results illustrate a mTORC1 regulating mechanism and identify RNF167 as a therapeutic target for mTORC1-dysregulated diseases.
The genetic basis of cytoplasmic male sterility and fertility restoration in wheat
Authors: Melonek Joanna , Duarte Jorge , Martin Jerome , Beuf Laurent , Murigneux Alain , Varenne Pierrick , Comadran Jordi , Specel Sebastien , Levadoux Sylvain , Bernath-Levin Kalia , Torney François , Pichon Jean-Philippe , Perez Pascual , Small Ian
Published: February 2021

Hybrid wheat varieties give higher yields than conventional lines but are difficult to produce due to a lack of effective control of male fertility in breeding lines. One promising system involves the Rf1 and Rf3 genes that restore fertility of wheat plants carrying Triticum timopheevii-type cytoplasmic male sterility (T-CMS). Here, by genetic mapping and comparative sequence analyses, we identify Rf1 and Rf3 candidates that can restore normal pollen production in transgenic wheat plants carrying T-CMS. We show that Rf1 and Rf3 bind to the mitochondrial orf279 transcript and induce cleavage, preventing expression of the CMS trait. The identification of restorer genes in wheat is an important step towards the development of hybrid wheat varieties based on a CMS-Rf system. The characterisation of their mode of action brings insights into the molecular basis of CMS and fertility restoration in plants.
Positioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation
Authors: Dobersch Stephanie , Rubio Karla , Singh Indrabahadur , Günther Stefan , Graumann Johannes , Cordero Julio , Castillo-Negrete Rafael , Huynh Minh Bao , Mehta Aditi , Braubach Peter , Cabrera-Fuentes Hector , Bernhagen Jürgen , Chao Cho-Ming , Bellusci Saverio , Günther Andreas , Preissner Klaus T. , Kugel Sita , Dobreva Gergana , Wygrecka Malgorzata , Braun Thomas , Papy-Garcia Dulce , Barreto Guillermo
Published: February 2021

In addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of high-mobility group proteins during transcription initiation remain unclear. Here we show that high-mobility group AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support the concept that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure genome integrity.
Base-pair resolution analysis of the effect of supercoiling on DNA flexibility and major groove recognition by triplex-forming oligonucleotides
Authors: Pyne Alice L. B. , Noy Agnes , Main Kavit H. S. , Velasco-Berrelleza Victor , Piperakis Michael M. , Mitchenall Lesley A. , Cugliandolo Fiorella M. , Beton Joseph G. , Stevenson Clare E. M. , Hoogenboom Bart W. , Bates Andrew D. , Maxwell Anthony , Harris Sarah A.
Published: February 2021

In the cell, DNA is arranged into highly-organised and topologically-constrained (supercoiled) structures. It remains unclear how this supercoiling affects the detailed double-helical structure of DNA, largely because of limitations in spatial resolution of the available biophysical tools. Here, we overcome these limitations, by a combination of atomic force microscopy (AFM) and atomistic molecular dynamics (MD) simulations, to resolve structures of negatively-supercoiled DNA minicircles at base-pair resolution. We observe that negative superhelical stress induces local variation in the canonical B-form DNA structure by introducing kinks and defects that affect global minicircle structure and flexibility. We probe how these local and global conformational changes affect DNA interactions through the binding of triplex-forming oligonucleotides to DNA minicircles. We show that the energetics of triplex formation is governed by a delicate balance between electrostatics and bonding interactions. Our results provide mechanistic insight into how DNA supercoiling can affect molecular recognition, that may have broader implications for DNA interactions with other molecular species.
Proteome-wide and matrisome-specific alterations during human pancreas development and maturation
Authors: Li Zihui , Tremmel Daniel M. , Ma Fengfei , Yu Qinying , Ma Min , Delafield Daniel G. , Shi Yatao , Wang Bin , Mitchell Samantha A. , Feeney Austin K. , Jain Vansh S. , Sackett Sara Dutton , Odorico Jon S. , Li Lingjun
Published: February 2021

The extracellular matrix (ECM) is unique to each tissue and capable of guiding cell differentiation, migration, morphology, and function. The ECM proteome of different developmental stages has not been systematically studied in the human pancreas. In this study, we apply mass spectrometry-based quantitative proteomics strategies using N,N-dimethyl leucine isobaric tags to delineate proteome-wide and ECM-specific alterations in four age groups: fetal (18-20 weeks gestation), juvenile (5-16 years old), young adults (21-29 years old) and older adults (50-61 years old). We identify 3,523 proteins including 185 ECM proteins and quantify 117 of them. We detect previously unknown proteome and matrisome features during pancreas development and maturation. We also visualize specific ECM proteins of interest using immunofluorescent staining and investigate changes in ECM localization within islet or acinar compartments. This comprehensive proteomics analysis contributes to an improved understanding of the critical roles that ECM plays throughout human pancreas development and maturation.
Seismic control of large prehistoric rockslides in the Eastern Alps
Authors: Oswald Patrick , Strasser Michael , Hammerl Christa , Moernaut Jasper
Published: February 2021

Large prehistoric rockslides tend to occur within spatio-temporal clusters suggesting a common trigger such as earthquake shaking or enhanced wet periods. Yet, trigger assessment remains equivocal due to the lack of conclusive observational evidence. Here, we use high-resolution lacustrine paleoseismology to evaluate the relation between past seismicity and a spatio-temporal cluster of large prehistoric rockslides in the Eastern Alps. Temporal and spatial coincidence of paleoseismic evidence with multiple rockslides at ~4.1 and ~3.0 ka BP reveals that severe earthquakes (local magnitude ML 5.5–6.5; epicentral intensity I0 VIII¼–X¾) have triggered these rockslides. A series of preceding severe earthquakes is likely to have progressively weakened these rock slopes towards critical state. These findings elucidate the role of seismicity in preparing and triggering large prehistoric rockslides in the European Alps, where rockslides and earthquakes typically occur in clusters. Such integration of multiple datasets in other formerly glaciated regions with low to moderate seismicity will improve our understanding of catastrophic rockslide drivers.
Unravelling the intertwined atomic and bulk nature of localised excitons by attosecond spectroscopy
Authors: Lucchini Matteo , Sato Shunsuke A. , Lucarelli Giacinto D. , Moio Bruno , Inzani Giacomo , Borrego-Varillas Rocío , Frassetto Fabio , Poletto Luca , Hübener Hannes , De Giovannini Umberto , Rubio Angel , Nisoli Mauro
Published: February 2021

The electro-optical properties of most semiconductors and insulators of technological interest are dominated by the presence of electron-hole quasi-particles, called excitons. The manipulation of excitons in dielectrics has recently received great attention, with possible applications in different fields including optoelectronics and photonics. Here, we apply attosecond transient reflection spectroscopy in a sequential two-foci geometry and observe sub-femtosecond dynamics of a core-level exciton in bulk MgF2 single crystals. Furthermore, we access absolute phase delays, which allow for an unambiguous comparison with theoretical calculations. Our results show that excitons surprisingly exhibit a dual atomic- and solid-like character, which manifests itself on different time scales. While the former is responsible for a femtosecond optical Stark effect, the latter dominates the attosecond excitonic response. Further theoretical investigation reveals a link with the exciton sub-femtosecond nanometric motion and allows us to envision a new route to control exciton dynamics in the close-to-petahertz regime.
Chromosomal coordination and differential structure of asynchronous replicating regions
Authors: Blumenfeld Britny , Masika Hagit , Farago Marganit , Yehuda Yishai , Halaseh Lamia , Vardi Oriya , Rapoport Rachel , Levin-Klein Rena , Cedar Howard , Bergman Yehudit , Simon Itamar
Published: February 2021

Stochastic asynchronous replication timing (AS-RT) is a phenomenon in which the time of replication of each allele is different, and the identity of the early allele varies between cells. By taking advantage of stable clonal pre-B cell populations derived from C57BL6/Castaneous mice, we have mapped the genome-wide AS-RT loci, independently of genetic differences. These regions are characterized by differential chromatin accessibility, mono-allelic expression and include new gene families involved in specifying cell identity. By combining population level mapping with single cell FISH, our data reveal the existence of a novel regulatory program that coordinates a fixed relationship between AS-RT regions on any given chromosome, with some loci set to replicate in a parallel and others set in the anti-parallel orientation. Our results show that AS-RT is a highly regulated epigenetic mark established during early embryogenesis that may be used for facilitating the programming of mono-allelic choice throughout development.
Six degrees head-down tilt bed rest caused low-grade hemolysis: a prospective randomized clinical trial
Authors: Culliton Kathryn , Louati Hakim , Laneuville Odette , Ramsay Tim , Trudel Guy
Published: February 2021

This study aimed to measure hemolysis before, during and after 60 days of the ground-based spaceflight analog bed rest and the effect of a nutritional intervention through a prospective randomized clinical trial. Twenty male participants were hospitalized for 88 days comprised of 14 days of ambulatory baseline, 60 days of 6° head-down tilt bed rest and 14 days of reambulation. Ten participants each received a control diet or daily polyphenol associated with omega-3, vitamin E, and selenium supplements. The primary outcome was endogenous carbon monoxide (CO) elimination measured by gas chromatography. Hemolysis was also measured with serial bilirubin, iron, transferrin saturation blood levels and serial 3-day stool collections were used to measure urobilinoid excretion using photometry. Total hemoglobin mass (tHb) was measured using CO-rebreathing. CO elimination increased after 5, 11, 30, and 57 days of bed rest: +289 ppb (95% CI 101–477 ppb;p = 0.004), +253 ppb (78–427 ppb;p = 0.007), +193 ppb (89–298 ppb;p = 0.001) and +858 ppb (670–1046 ppb;p < 0.000), respectively, compared to baseline. Bilirubin increased after 20 and 49 days of bed rest +0.8 mg/l (p = 0.013) and +1.1 mg/l (p = 0.012), respectively; and iron increased after 20 days of bed rest +10.5 µg/dl (p = 0.032). The nutritional intervention did not change CO elimination. THb was lower after 60 days of bed rest −0.9 g/kg (p = 0.001). Bed rest enhanced hemolysis as measured through all three by-products of heme oxygenase. Ongoing enhanced hemolysis over 60 days contributed to a 10% decrease in tHb mass. Modulation of red blood cell control towards increased hemolysis may be an important mechanism causing anemia in astronauts.
A review of alterations to the brain during spaceflight and the potential relevance to crew in long-duration space exploration
Authors: Roy-O’Reilly Meaghan , Mulavara Ajitkumar , Williams Thomas
Published: February 2021

During spaceflight, the central nervous system (CNS) is exposed to a complex array of environmental stressors. However, the effects of long-duration spaceflight on the CNS and the resulting impact to crew health and operational performance remain largely unknown. In this review, we summarize the current knowledge regarding spaceflight-associated changes to the brain as measured by magnetic resonance imaging, particularly as they relate to mission duration. Numerous studies have reported macrostructural changes to the brain after spaceflight, including alterations in brain position, tissue volumes and cerebrospinal fluid distribution and dynamics. Changes in brain tissue microstructure and connectivity were also described, involving regions related to vestibular, cerebellar, visual, motor, somatosensory and cognitive function. Several alterations were also associated with exposure to analogs of spaceflight, providing evidence that brain changes likely result from cumulative exposure to multiple independent environmental stressors. Whereas several studies noted that changes to the brain become more pronounced with increasing mission duration, it remains unclear if these changes represent compensatory phenomena or maladaptive dysregulations. Future work is needed to understand how spaceflight-associated changes to the brain affect crew health and performance, with the goal of developing comprehensive monitoring and countermeasure strategies for future long-duration space exploration.
Flexible Hall sensor made of laser-scribed graphene
Authors: Kaidarova By Altynay , Liu Wenhao , Swanepoel Liam , Almansouri Abdullah , Geraldi Nathan R. , Duarte Carlos.M. , Kosel Jurgen
Published: February 2021

Graphene has shown considerable potential for sensing magnetic fields based on the Hall Effect, due to its high carrier mobility, low sheet carrier density, and low-temperature dependence. However, the cost of graphene in comparison to conventional materials has meant that its uptake in electronic manufacturing has been slow. To lower technological barriers and bring more widespread adoption of graphene Hall sensors, we are using a one-step laser scribing process that does not rely on multiple steps, toxic chemicals, and subsequent treatments. Laser-scribed graphene Hall sensors offer a linear response to magnetic fields with a normalized sensitivity of ~1.12 V/AT. They also exhibit a low constant noise voltage floor of ~ 50 nV/$$\sqrt {{\mathrm{Hz}}}$$

Hz

for a bias current of 100 µA at room temperature, which is comparable with state-of-the-art low-noise Hall sensors. The sensors combine a high bendability, come with high robustness and operating temperatures up to 400 °C. They enable device ideas in various areas, for instance, soft robotics. As an example, we combined a laser-scribed graphene sensor with a deformable elastomer and flexible magnet to realize low-cost, compliant, and customizable tactile sensors.
Coherent manipulation and quantum phase interference in a fullerene-based electron triplet molecular qutrit
Authors: Wang Ye-Xin , Liu Zheng , Fang Yu-Hui , Zhou Shen , Jiang Shang-Da , Gao Song
Published: February 2021

High-spin magnetic molecules are promising candidates for quantum information processing because their intrinsic multiplicity facilitates information storage and computational operations. However, due to the absence of suitable sublevel splittings, their susceptibility to environmental disturbances and limitation from the selection rule, the arbitrary control of the quantum state of a molecular electron multiplet has not been realized. Here, we exploit the photoexcited triplet of C70 as a molecular electron spin qutrit with pulsed electron paramagnetic resonance. We prepared the system into 3-level superposition states characteristic of a qutrit and validated them by the tomography of their density matrices. To further elucidate the coherence of the operation and the nature of the system as a qutrit, we demonstrated the quantum phase interference in the superposition. The interference pattern is further interpreted as a map of possible evolution paths in the space of phase factors, representing the quantum nature of the 3-level system.
Consensus terminology for preclinical phases of psoriatic arthritis for use in research studies: results from a Delphi consensus study
Authors: Perez-Chada Lourdes M. , Haberman Rebecca H. , Chandran Vinod , Rosen Cheryl F. , Ritchlin Christopher , Eder Lihi , Mease Philip , Reddy Soumya , Ogdie Alexis , Merola Joseph F. , Scher Jose U.
Published: February 2021

The concept of psoriatic arthritis (PsA) prevention is gaining increased interest owing to the physical limitation, poor quality of life and low remission rates that are achieved with current therapies for PsA. The psoriasis-to-PsA transition offers a unique opportunity to identify individuals at increased risk of developing PsA and to implement preventive strategies. However, identifying individuals at increased risk of developing PsA is challenging as there is no consensus on how this population should be defined. This Consensus Statement puts forward recommended terminology from the Psoriasis and Psoriatic Arthritis Clinics Multicenter Advancement Network (PPACMAN) for defining specific subgroups of individuals during the preclinical and early clinical phases of PsA to be used in research studies. Following a three-round Delphi process, consensus was reached for three terms and definitions: ‘increased risk for PsA’, ‘psoriasis with asymptomatic synovio-entheseal imaging abnormalities’ and ‘psoriasis with musculoskeletal symptoms not explained by other diagnosis’. These terms and their definitions will enable improved identification and standardization of study populations in clinical research. In the future, as increasing evidence emerges regarding the molecular and clinical features of the psoriasis-to-PsA continuum, these terms and definitions will be further refined and updated.
Molecular changes tracking through multiscale fluorescence microscopy differentiate Meningioma grades and non-tumoral brain tissues
Authors: Mehidine Hussein , Refregiers Matthieu , Jamme Frédéric , Varlet Pascale , Juchaux Marjorie , Devaux Bertrand , Abi Haidar Darine
Published: February 2021

Meningioma is the most common primary intracranial extra-axial tumor. Total surgical removal is the standard therapeutic method to treat this type of brain tumors. However, the risk of recurrence depends on the tumor grade and the extent of the resection including the infiltrated dura mater and, if necessary, the infiltrated bone. Therefore, proper resection of all invasive tumor borders without touching eloquent areas is of primordial in order to decrease the risk of recurrence. Nowadays, none of the intraoperative used tools is able to provide a precise real-time histopathological information on the tumor surrounding areas to help the surgeon to achieve a gross total removal. To respond to this problem, our team is developing a multimodal two-photon fluorescence endomicroscope, compatible with the surgeon tool, to better delimitate tumor boundaries, relying on the endogenous fluorescence of brain tissues. In this context, we are building a tissue database in order to specify each brain tissue, whether healthy or tumoral, with its specific optical signature. In this study, we present a multimodal and multiscale optical measurements on non-tumoral control brain tissue obtained in epilepsy surgery patients and several meningioma grades. We investigated tissue auto-fluorescence to track the molecular changes associated with the tumor grade from deep ultra-violet (DUV) to near infrared (NIR) excitation. Micro-spectroscopy, fluorescence lifetime imaging, two-photon fluorescence imaging and Second Harmonic Generation (SHG) imaging were performed. Several optically derived parameters such as collagen crosslinks fluorescence in DUV, SHG emission in NIR and long lifetime intensity fraction of Nicotinamide Adenine Dinucleotide and Flavins were correlated to discriminate cancerous tissue from control one. While collagen response managed to discriminate meningioma grades from control samples with a 100% sensitivity and 90% specificity through a 3D discriminative algorithm.