bluuebunny/crossref_metadata_2025 huggingface dataset:
Seismic Attenuation During Magma Vesiculation: A Combination of Laboratory Constraints and Modeling
Authors: Pistone Mattia , Fife Julie L. , Tisato Nicola , Caricchi Luca , Reusser Eric , Ulmer Peter , Mader Kevin , Marone Federica
Published: April 2021

Assessing the potential and likelihood of explosive eruptions is vital for almost 800 million people living near active volcanoes. Magma reservoirs are not directly accessible, limiting our capability to understand the prerequisites for an explosive eruption and our ability to perform experiments that simulate magmatic processes at depth. Therefore, deciphering volcanic precursors is key to forecasting volcanic eruptions. In this study, we used synchrotron‐based X‐ray tomographic microscopy to observe felsic magma vesiculation at high temperature (1,100°C) to establish the pre‐eruptive conditions that favor explosive activity. Specifically, we studied the increase of seismic attenuation with increasing gas content during magma vesiculation. These results are applied to the natural range of volcanic tremors (0.2–5 Hz) to detect the proximity of gas‐charged magma to the surface prior to volcanic eruption: gas‐rich, crystal‐free felsic magmas are detected at larger depth (40 MPa) than gas‐rich, crystal‐bearing systems (10 MPa).
Development of Coupled Data Assimilation With the BCC Climate System Model: Highlighting the Role of Sea‐Ice Assimilation for Global Analysis
Authors: Liu X. , Yao J. , Wu T. , Zhang S. , Xu F. , Zhang L. , Jie W. , Zhou W. , Li Q. , Liang X. , Chu M. , Yan J. , Nie S. , Cheng Y.
Published: April 2021

The coupled data assimilation (CDA) system consisting of ocean, sea‐ice, and atmosphere data assimilation components with the Beijing Climate Center (BCC) Climate System Model has been developed to provide reliable analyses of the atmosphere, ocean, and sea‐ice states. It incorporates ocean temperature/salinity profiles, sea surface temperature, sea level height, and sea‐ice concentration observations at a daily frequency, and atmosphere reanalysis at a 6‐hourly frequency. Results show that the system is capable of realistically reproducing the climatology and variability of ocean, sea‐ice, and atmosphere. The performances in analyzing ocean component are comparable to those of well‐known ocean reanalyses that were once used to initialize the BCC model for climate predictions. A series of experiments with and without sea‐ice observations in the CDA framework are designed to explore the role of sea‐ice data assimilation (DA). The addition of sea‐ice DA exerts very small influence to the analysis of upper ocean temperature over the Arctic area, but leads to an evident reduction of temperature error in the upper 1000 m of ocean south of 60°S. Particularly, only the inclusion of sea‐ice DA can make the ocean/ocean‐atmosphere DA effective in providing skillful analysis in the high‐latitude Southern Ocean. Furthermore, we find that only on the basis of ocean DA, can the addition of sea‐ice concentration assimilation improve the analysis of tropical tropospheric atmosphere, along with a better analysis of mid‐ and high‐latitude stratospheric atmosphere. These results address the importance of coordination of sea‐ice observations and ocean observations in CDA.
Investigation of VLF Radio Sounding for Studying Semi‐Diurnal Tide and Gravity Waves
Authors: Mahmoudian Alireza , Mohebalhojeh Ali Reza , Safari Mohsen
Published: April 2021

The present paper is the investigation of the semi‐diurnal tide (SDT) and gravity waves (GW) through coupling effects on propagating Very low frequency (VLF) signal. One year of recorded VLF data is used. The first modulation of the VLF signal with SDTs and GWs is presented. The structures associated with SDT and GW are analyzed, and the daily and monthly variations are determined. Wavelet and spectrum analysis is applied to the data to determine the origin of the SDT. The corresponding period of the observed SDT is matched with solar SDT (SSDT). Seasonal variability of the SSDT in the lower ionosphere has been investigated using the VLF radio sounding for the first time. Developmental, evolution, and dissipation phases of GW with daytime and month are resolved. A plan to deploy 8 VLF stations to probe the shoreline and characterize the generation and development of SDT and GWs along the coastline is discussed.
Child marriage, maternal serum metal exposure, and risk of preterm birth in rural Bangladesh: evidence from mediation analysis
Authors: Huang Hui , Wei Yongyue , Xia Yankai , Wei Liangmin , Chen Xin , Zhang Ruyang , Su Li , Rahman Mohammad L. , Rahman Mahmudur , Qamruzzaman Quazi , Guo Wenhui , Shen Hongbing , Hu Zhibin , Christiani David C. , Chen Feng
Published: April 2021

Background

The prevalence of preterm birth in Bangladesh is estimated to be 19.1%, the highest in the world. Although prenatal exposure to several metals has been linked with preterm birth, fewer prospective studies have investigated the socioeconomic factors that affect metal exposure, leading to preterm birth risk.

Objective

We aim to identify novel metal biomarkers and their critical exposure windows, as well as the upstream socioeconomic risk factors for preterm birth in rural Bangladeshi, to shed light for future interventional strategies.

Methods

This study included data from 780 mother–offspring pairs, who were recruited to participate in a prospective birth cohort in Bangladesh (2008–2011). Serum concentrations of 19 metals were measured in the first and second trimesters using inductively coupled plasma mass spectrometry. Mediation analysis was performed to explore the upstream socioeconomic factors that affect the risk of preterm birth mediated via metal exposure concentrations.

Results

Early pregnancy exposure to serum zinc, arsenic, and strontium and mid-pregnancy exposure to barium were significantly associated with risk of preterm birth. Furthermore, younger marriage age was associated with an exponential increase in the risk of preterm birth, and women who married after 18 years old had a considerably lower risk of preterm birth. Mediation analysis indicated that these four elements mediated 30.2% of the effect of marriage age on preterm birth.

Conclusion

This study indicated that maternal serum metal exposure mediates the impact of child marriage on the increased risk of preterm birth via metal exposures. The findings shed light on the mechanisms underlying such association and provide insights into future interventional strategies.
Persistent organic pollutants in pregnant women potentially affect child development and thyroid hormone status
Authors: Krönke Anna A. , Jurkutat Anne , Schlingmann Maike , Poulain Tanja , Nüchter Matthias , Hilbert Anja , Kiviranta Hannu , Körner Antje , Vogel Mandy , Söder Olle , Bornehag Carl G. , Kiess Wieland
Published: April 2021

Background

Potentially harmful effects of persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane (DDT) on prenatal development and the endocrine system have been controversially discussed.

Methods

Working with a German cohort of 324 pregnant women, we assessed POP levels and used robust linear regression models to determine potential associations between maternal POP concentrations and pre- and postnatal development in the children, as well as the thyroid hormone status of the mother and child.

Results

Maternal p,p′-dichlorodiphenyldichloroethylene (p,p′-DDE) and most measured PCBs positively correlated with postnatal weight gain. We detected no correlation between newborn birth weight and head circumference, respectively, and maternal PCB and p,p′-DDE serum levels, while body length at birth was negatively associated with the maternal serum concentration of PCB 183. Maternal p,p′-DDE and nearly all PCB serum levels showed a negative correlation with maternal free triiodothyronine (FT3). p,p′-DDE and PCB 74 and 118 were negatively associated with maternal thyroid-stimulating hormone levels. In addition, we identified significant associations between maternal POP levels and thyroid hormone parameters of the child.

Conclusions

These results indicate that POP exposure likely affects different aspects of pre- and postnatal development and impacts the thyroid hormone status of both mother and child.

Impact

Pregnant women in a German cohort display a substantial accumulation of POPs.

Body mass index and age influence maternal serum POP levels.

Maternal POP levels show correlations with the child’s length at birth and weight gain, and FT3 levels in the mother and child.

Our data provide additional evidence for the potentially harmful influence of POPs.

Our data indicate that POPs influence pre- and postnatal development.
Antibiotics at birth and later antibiotic courses: effects on gut microbiota
Authors: Ainonen Sofia , Tejesvi Mysore V , Mahmud Md. Rayhan , Paalanne Niko , Pokka Tytti , Li Weizhong , Nelson Karen E , Salo Jarmo , Renko Marjo , Vänni Petri , Pirttilä Anna Maria , Tapiainen Terhi
Published: April 2021

Background

Intrapartum antibiotic prophylaxis (IAP) is widely used, but the evidence of the long-term effects on the gut microbiota and subsequent health of children is limited. Here, we compared the impacts of perinatal antibiotic exposure and later courses of antibiotic courses on gut microbiota.

Methods

This was a prospective, controlled cohort study among 100 vaginally delivered infants with different perinatal antibiotic exposures: control (27), IAP (27), postnatal antibiotics (24), and IAP and postnatal antibiotics (22). At 1 year of age, we performed next-generation sequencing of the bacterial 16S ribosomal RNA gene of fecal samples.

Results

Exposure to the perinatal antibiotics had a clear impact on the gut microbiota. The abundance of the Bacteroidetes phylum was significantly higher in the control group, whereas the relative abundance of Escherichia coli was significantly lower in the control group. The impact of the perinatal antibiotics on the gut microbiota composition was greater than exposure to later courses of antibiotics (28% of participants).

Conclusions

Perinatal antibiotic exposure had a marked impact on the gut microbiota at the age of 1 year. The timing of the antibiotic exposure appears to be the critical factor for the changes observed in the gut microbiota.

Impact

Infants are commonly exposed to IAP and postnatal antibiotics, and later to courses of antibiotics during the first year of life.

Perinatal antibiotics have been associated with an altered gut microbiota during the first months of life, whereas the evidence regarding the long-term impact is more limited.

Perinatal antibiotic exposure had a marked impact on the infant’s gut microbiota at 1 year of age.

Impact of the perinatal antibiotics on the gut microbiota composition was greater than that of the later courses of antibiotics at the age of 1 year.
Cesarean delivery and metabolic health and inflammation biomarkers during mid-childhood and early adolescence
Authors: Mínguez-Alarcón Lidia , Rifas-Shiman Sheryl L. , Mitchell Caroline , Sordillo Joanne , Aris Izzuddin M. , Hivert Marie-France , Oken Emily , Chavarro Jorge E.
Published: April 2021

Background

We assessed differences in plasma levels of metabolic health and inflammation biomarkers during mid-childhood and early adolescence between children born by cesarean section vs. vaginal delivery.

Methods

Mother–child pairs (N = 942) enrolled during pregnancy in obstetric practices and child follow-up started at birth. Risk biomarkers were assessed in blood samples collected at the mild-childhood (median = 7 years) and early adolescence (median = 13 years) in-person visits.

Results

Two hundred and six children (22%) were born by cesarean section. There were no significant differences in biomarker levels between children born by cesarean and children born vaginally in mid-childhood. However, adolescents born by cesarean section had significantly lower adiponectin [% difference (95% confidence interval (CI)) = −11.3 (−18.1, −4.0) µg/mL] compared to vaginal delivery. We also found some suggestion of higher insulin resistance [insulin levels % difference (95% CI) = 11.5 (−0.40, 25.0) µU/mL and HOMA-IR (homeostatic model assessment of insulin resistance) % difference (95% CI) = 9.1 (−2.30, 21.8) U] in adolescents born by cesarean section compared to those born vaginally.

Conclusions

We found suggestive evidence that adolescents born by cesarean section show differences in certain metabolic health biomarkers relative to adolescents born by vaginal delivery. Further studies are needed to reevaluate these associations since the clinical significance of these differences is unclear.

Impact

Multiple studies show that children born by cesarean section are at higher risk of obesity compared to those born vaginally.

It is unclear yet to what extent this elevated risk may extend to a more adverse profile of biomarkers of metabolic health and inflammation.

Adolescents born by cesarean section show small differences in adiponectin and insulin relative to adolescents born by vaginal delivery.

Adolescents born by cesarean section may be at higher risk to a more adverse profile of biomarkers of metabolic health and inflammation, but the clinical significance of these differences is uncertain.
Correction: Quorum sensing provides a molecular mechanism for evolution to tune and maintain investment in cooperation
Authors: Bruger Eric L , Snyder Daniel J , Cooper Vaughn S , Waters Christopher M
Published: April 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41396-021-00972-4.
Breast cancer as an example of tumour heterogeneity and tumour cell plasticity during malignant progression
Authors: Lüönd Fabiana , Tiede Stefanie , Christofori Gerhard
Published: April 2021

Heterogeneity within a tumour increases its ability to adapt to constantly changing constraints, but adversely affects a patient’s prognosis, therapy response and clinical outcome. Intratumoural heterogeneity results from a combination of extrinsic factors from the tumour microenvironment and intrinsic parameters from the cancer cells themselves, including their genetic, epigenetic and transcriptomic traits, their ability to proliferate, migrate and invade, and their stemness and plasticity attributes. Cell plasticity constitutes the ability of cancer cells to rapidly reprogramme their gene expression repertoire, to change their behaviour and identities, and to adapt to microenvironmental cues. These features also directly contribute to tumour heterogeneity and are critical for malignant tumour progression. In this article, we use breast cancer as an example of the origins of tumour heterogeneity (in particular, the mutational spectrum and clonal evolution of progressing tumours) and of tumour cell plasticity (in particular, that shown by tumour cells undergoing epithelial-to-mesenchymal transition), as well as considering interclonal cooperativity and cell plasticity as sources of cancer cell heterogeneity. We review current knowledge on the functional contribution of cell plasticity and tumour heterogeneity to malignant tumour progression, metastasis formation and therapy resistance.
Sunglasses to hide behind may also prevent melanoma of the eyes
Authors: Dhomen Nathalie , Mundra Piyushkumar A. , Marais Richard
Published: April 2021

In 1967, Sandy Posey pronounced that sunglasses are essential beachwear (https://www.youtube.com/watch?v=4HVBEb-GA1Y). Now, whole-genome sequencing reveals that ultraviolet radiation (UVR) can contribute to melanomas in the iris and conjunctiva, data that provide a molecular explanation for why it is important to protect our eyes from exposure to UVR.
Tumour neoantigen mimicry by microbial species in cancer immunotherapy
Authors: Boesch Maximilian , Baty Florent , Rothschild Sacha I. , Tamm Michael , Joerger Markus , Früh Martin , Brutsche Martin H.
Published: April 2021

Tumour neoantigens arising from cancer-specific mutations generate a molecular fingerprint that has a definite specificity for cancer. Although this fingerprint perfectly discriminates cancer from healthy somatic and germline cells, and is therefore therapeutically exploitable using immune checkpoint blockade, gut and extra-gut microbial species can independently produce epitopes that resemble tumour neoantigens as part of their natural gene expression programmes. Such tumour molecular mimicry is likely not only to influence the quality and strength of the body’s anti-cancer immune response, but could also explain why certain patients show favourable long-term responses to immune checkpoint blockade while others do not benefit at all from this treatment. This article outlines the requirement for tumour neoantigens in successful cancer immunotherapy and draws attention to the emerging role of microbiome-mediated tumour neoantigen mimicry in determining checkpoint immunotherapy outcome, with far-reaching implications for the future of cancer immunotherapy.
The long-noncoding RNA SOCS2-AS1 suppresses endometrial cancer progression by regulating AURKA degradation
Authors: Jian Fangfang , Che Xiaoxia , Zhang Jingjing , Liu Chang , Liu Gedan , Tang Yujing , Feng Weiwei
Published: April 2021

Aberrant long-noncoding RNA (lncRNA) expression has been shown to be involved in the pathogenesis of endometrial cancer (EC). Herein, we report a novel tumor suppressor lncRNA SOCS2-AS1 in EC. Quantitative real-time PCR was performed to detect RNA expression. In situ hybridization and nuclear/cytoplasmic fractionation assays were used to detect the subcellular location. We found that SOCS2-AS1 was downregulated in EC tissues. Its reduced expression was correlated with advanced clinical stage and poor prognosis. Forced expression of SOCS2-AS1 suppressed EC cell proliferation and induced cell-cycle arrest and apoptosis. SOCS2-AS1-binding proteins were detected using RNA pull-down assay and mass spectrometry. Mechanistically, SOCS2-AS1 bound to Aurora kinase A (AURKA) and increased its degradation through the ubiquitin-proteasome pathway. In conclusion, SOCS2-AS1 may thus serve as a prognostic predictor and a biomarker for AURKA-inhibitor treatment in EC patients.
CREG ameliorates the phenotypic switching of cardiac fibroblasts after myocardial infarction via modulation of CDC42
Authors: Liu Dan , Tian Xiaoxiang , Liu Yanxia , Song Haixu , Cheng Xiaoli , Zhang Xiaolin , Yan Chenghui , Han Yaling
Published: April 2021

Phenotype switching of cardiac fibroblasts into myofibroblasts plays important role in cardiac fibrosis following myocardial infarction (MI). Cellular repressor of E1A-stimulated genes (CREG) protects against vascular and cardiac remodeling induced by angiotensin-II. However, the effects and mechanisms of CREG on phenotype switching of cardiac fibroblasts after MI are unknown. This study aimed to investigate the role of CREG on the phenotype switching of cardiac fibroblasts following MI and its mechanism. Our findings demonstrated that, compared with littermate control mice, cardiac function was deteriorated in CREG+/− mice on day 14 post-MI. Fibrosis size, αSMA, and collagen-1 expressions were increased in the border regions of CREG+/− mice on day 14 post-MI. Conversely, exogenous CREG protein significantly improved cardiac function, inhibited fibrosis, and reduced the expressions of αSMA and collagen-1 in the border regions of C57BL/6J mice on day 14. In vitro, CREG recombinant protein inhibited αSMA and collagen-1 expression and blocked the hypoxia-induced proliferation and migration of cardiac fibroblasts, which was mediated through the inhibition of cell division control protein 42 (CDC42) expression. Our findings could help in establishing new strategies based on the clarification of the role of the key molecule CREG in phenotype switching of cardiac fibroblasts following MI.
ADCK1 activates the β-catenin/TCF signaling pathway to promote the growth and migration of colon cancer cells
Authors: Ji Yong , Liu Yiqian , Sun Changchun , Yu Lijiang , Wang Zhao , Du Xu , Yang Wu , Zhang Chenggong , Tao Chunmu , Wang Jianjiang , Yang Xi , Di Sun , Huang Yufeng
Published: April 2021

As a result of mutations in the upstream components of the Wnt/β-catenin signaling pathway, this cascade is abnormally activated in colon cancer. Hence, identifying the activation mechanism of this pathway is an urgent need for the treatment of colon cancer. Here, we found an increase in ADCK1 (AarF domain-containing kinase 1) expression in clinical specimens of colon cancer and animal models. Upregulation of ADCK1 expression promoted the colony formation and infiltration of cancer cells. Downregulation of ADCK1 expression inhibited the colony formation and infiltration of cancer cells, in vivo tumorigenesis, migration, and organoid formation. Molecular mechanistic studies demonstrated that ADCK1 interacted with TCF4 (T-cell factor 4) to activate the β-catenin/TCF signaling pathway. In conclusion, our research revealed the functions of ADCK1 in the development of colon cancer and provided potential therapeutic targets.
ADGRA1 negatively regulates energy expenditure and thermogenesis through both sympathetic nervous system and hypothalamus–pituitary–thyroid axis in male mice
Authors: Zhang Xiao-Hong , Tang Ling-Yun , Wang Xi-Yi , Shen Chun-Ling , Xiong Wen-Feng , Shen Yan , Wan Ying-Han , Wu You-Bing , Wang Yi-Cheng , Zhang Hong-Xin , Lu Shun-Yuan , Fei Jian , Wang Zhu-Gang
Published: April 2021

Adhesion G protein-coupled receptor A1 (ADGRA1, also known as GPR123) belongs to the G protein-coupled receptors (GPCRs) family and is well conserved in the vertebrate lineage. However, the structure of ADGRA1 is unique and its physiological function remains unknown. Previous studies have shown that Adgra1 is predominantly expressed in the central nervous system (CNS), indicating its important role in the transduction of neural signals. The aim of this study is to investigate the central function of Adgra1 in vivo and clarify its physiological significance by establishing an Adgra1-deficient mouse (Adgra1−/−) model. The results show that Adgra1−/− male mice exhibit decreased body weight with normal food intake and locomotion, shrinkage of body mass, increased lipolysis, and hypermetabolic activity. Meanwhile, mutant male mice present elevated core temperature coupled with resistance to hypothermia upon cold stimulus. Further studies show that tyrosine hydroxylase (TH) and β3-adrenergic receptor (β3-AR), indicators of sympathetic nerve excitability, are activated as well as their downstream molecules including uncoupling protein 1 (UCP1), coactivator 1 alpha (PGC1-α) in brown adipose tissue (BAT), and hormone-sensitive lipase (HSL) in white adipose tissue (WAT). In addition, mutant male mice have higher levels of serum T3, T4, accompanied by increased mRNAs of hypothalamus–pituitary–thyroid axis. Finally, Adgra1−/− male mice present abnormal activation of PI3K/AKT/GSK3β and MEK/ERK pathways in hypothalamus. Overexpression of ADGRA1 in Neuro2A cell line appears to suppress these two signaling pathways. In contrast, Adgra1−/− female mice show comparable body weight along with normal metabolic process to their sex-matched controls. Collectively, ADGRA1 is a negative regulator of sympathetic nervous system (SNS) and hypothalamus–pituitary–thyroid axis by regulating PI3K/AKT/GSK3β and MEK/ERK pathways in hypothalamus of male mice, suggesting an important role of ADGRA1 in maintaining metabolic homeostasis including energy expenditure and thermogenic balance.
The effect of extracellular vesicles on the regulation of mitochondria under hypoxia
Authors: Zhang Yaodan , Tan Jin , Miao Yuyang , Zhang Qiang
Published: April 2021

Mitochondria are indispensable organelles for maintaining cell energy metabolism, and also are necessary to retain cell biological function by transmitting information as signal organelles. Hypoxia, one of the important cellular stresses, can directly regulates mitochondrial metabolites and mitochondrial reactive oxygen species (mROS), which affects the nuclear gene expression through mitochondrial retrograde signal pathways, and also promotes the delivery of signal components into cytoplasm, causing cellular injury. In addition, mitochondria can also trigger adaptive mechanisms to maintain mitochondrial function in response to hypoxia. Extracellular vesicles (EVs), as a medium of information transmission between cells, can change the biological effects of receptor cells by the release of cargo, including nucleic acids, proteins, lipids, mitochondria, and their compositions. The secretion of EVs increases in cells under hypoxia, which indirectly changes the mitochondrial function through the uptake of contents by the receptor cells. In this review, we focus on the mitochondrial regulation indirectly through EVs under hypoxia, and the possible mechanisms that EVs cause the changes in mitochondrial function. Finally, we discuss the significance of this EV-mitochondria axis in hypoxic diseases.
Somatic CG6015 mediates cyst stem cell maintenance and germline stem cell differentiation via EGFR signaling in Drosophila testes
Authors: Zheng Qianwen , Chen Xia , Qiao Chen , Wang Min , Chen Wanyin , Luan Xiaojin , Yan Yidan , Shen Cong , Fang Jie , Hu Xing , Zheng Bo , Wu Yibo , Yu Jun
Published: April 2021

Stem cell niche is regulated by intrinsic and extrinsic factors. In the Drosophila testis, cyst stem cells (CySCs) support the differentiation of germline stem cells (GSCs). However, the underlying mechanisms remain unclear. In this study, we found that somatic CG6015 is required for CySC maintenance and GSC differentiation in a Drosophila model. Knockdown of CG6015 in CySCs caused aberrant activation of dpERK in undifferentiated germ cells in the Drosophila testis, and disruption of key downstream targets of EGFR signaling (Dsor1 and rl) in CySCs results in a phenotype resembling that of CG6015 knockdown. CG6015, Dsor1, and rl are essential for the survival of Drosophila cell line Schneider 2 (S2) cells. Our data showed that somatic CG6015 regulates CySC maintenance and GSC differentiation via EGFR signaling, and inhibits aberrant activation of germline dpERK signals. These findings indicate regulatory mechanisms of stem cell niche homeostasis in the Drosophila testis.
Lysine-specific demethylase 1 inhibition enhances autophagy and attenuates early-stage post-spinal cord injury apoptosis
Authors: Gu Yang , Chen Dehui , Zhou Linquan , Zhao Xin , Lin Jiemin , Lin Bin , Lin Taotao , Chen Zhi , Chen Zhaohong , Wang Zhenyu , Liu Wenge
Published: April 2021

Neuron death in spinal cords is caused primarily by apoptosis after spinal cord injury (SCI). Autophagy can act as a cellular response to maintain neuron homeostasis that can reduce apoptosis. Although more studies have shown that an epigenetic enzyme called Lysine-specific demethylase 1 (LSD1) can negatively regulate autophagy during cancer research, existing research does not focus on impacts related to LSD1 in nerve injury diseases. This study was designed to determine whether inhibiting LSD1 could enhance autophagy against apoptosis and provide effective neuroprotection in vitro and vivo after SCI. The results showed that LSD1 inhibition treatment significantly reduced spinal cord damage in SCI rat models and was characterized by upregulated autophagy and downregulated apoptosis. Further research demonstrated that using both pharmacological inhibition and gene knockdown could enhance autophagy and reduce apoptosis for in vitro simulation of SCI-caused damage models. Additionally, 3-methyladenine (3-MA) could partially eliminate the effect of autophagy enhancement and apoptosis suppression. These findings demonstrated that LSD1 inhibition could protect against SCI by activating autophagy and hindering apoptosis, suggesting a potential candidate for SCI therapy.
Identification of an endogenous glutamatergic transmitter system controlling excitability and conductivity of atrial cardiomyocytes
Authors: Xie Duanyang , Xiong Ke , Su Xuling , Wang Guanghua , Ji Qiang , Zou Qicheng , Wang Lingling , Liu Yi , Liang Dandan , Xue Jinfeng , Wang Luxin , Gao Xueting , Gu Xingdong , Liu Hongyu , He Xiaoyu , Li Li , Yang Jian , Lu Youming , Peng Luying , Chen Yi-Han
Published: April 2021

As an excitatory transmitter system, the glutamatergic transmitter system controls excitability and conductivity of neurons. Since both cardiomyocytes and neurons are excitable cells, we hypothesized that cardiomyocytes may also be regulated by a similar system. Here, we have demonstrated that atrial cardiomyocytes have an intrinsic glutamatergic transmitter system, which regulates the generation and propagation of action potentials. First, there are abundant vesicles containing glutamate beneath the plasma membrane of rat atrial cardiomyocytes. Second, rat atrial cardiomyocytes express key elements of the glutamatergic transmitter system, such as the glutamate metabolic enzyme, ionotropic glutamate receptors (iGluRs), and glutamate transporters. Third, iGluR agonists evoke iGluR-gated currents and decrease the threshold of electrical excitability in rat atrial cardiomyocytes. Fourth, iGluR antagonists strikingly attenuate the conduction velocity of electrical impulses in rat atrial myocardium both in vitro and in vivo. Knockdown of GRIA3 or GRIN1, two highly expressed iGluR subtypes in atria, drastically decreased the excitatory firing rate and slowed down the electrical conduction velocity in cultured human induced pluripotent stem cell (iPSC)-derived atrial cardiomyocyte monolayers. Finally, iGluR antagonists effectively prevent and terminate atrial fibrillation in a rat isolated heart model. In addition, the key elements of the glutamatergic transmitter system are also present and show electrophysiological functions in human atrial cardiomyocytes. In conclusion, our data reveal an intrinsic glutamatergic transmitter system directly modulating excitability and conductivity of atrial cardiomyocytes through controlling iGluR-gated currents. Manipulation of this system may open potential new avenues for therapeutic intervention of cardiac arrhythmias.
A slowly cleaved viral signal peptide acts as a protein-integral immune evasion domain
Authors: Seidel Einat , Dassa Liat , Kahlon Shira , Tirosh Boaz , Halenius Anne , Seidel Malkinson Tal , Mandelboim Ofer
Published: April 2021

Stress can induce cell surface expression of MHC-like ligands, including MICA, that activate NK cells. Human cytomegalovirus (HCMV) glycoprotein US9 downregulates the activating immune ligand MICA*008 to avoid NK cell activation, but the underlying mechanism remains unclear. Here, we show that the N-terminal signal peptide is the major US9 functional domain targeting MICA*008 to proteasomal degradation. The US9 signal peptide is cleaved with unusually slow kinetics and this transiently retained signal peptide arrests MICA*008 maturation in the endoplasmic reticulum (ER), and indirectly induces its degradation via the ER quality control system and the SEL1L-HRD1 complex. We further identify an accessory, signal peptide-independent US9 mechanism that directly binds MICA*008 and SEL1L. Collectively, we describe a dual-targeting immunoevasin, demonstrating that signal peptides can function as protein-integral effector domains.
Neuroimaging evidence for a network sampling theory of individual differences in human intelligence test performance
Authors: Soreq Eyal , Violante Ines R. , Daws Richard E. , Hampshire Adam
Published: April 2021

Despite a century of research, it remains unclear whether human intelligence should be studied as one dominant, several major, or many distinct abilities, and how such abilities relate to the functional organisation of the brain. Here, we combine psychometric and machine learning methods to examine in a data-driven manner how factor structure and individual variability in cognitive-task performance relate to dynamic-network connectomics. We report that 12 sub-tasks from an established intelligence test can be accurately multi-way classified (74%, chance 8.3%) based on the network states that they evoke. The proximities of the tasks in behavioural-psychometric space correlate with the similarities of their network states. Furthermore, the network states were more accurately classified for higher relative to lower performing individuals. These results suggest that the human brain uses a high-dimensional network-sampling mechanism to flexibly code for diverse cognitive tasks. Population variability in intelligence test performance relates to the fidelity of expression of these task-optimised network states.
Thiazoline-related innate fear stimuli orchestrate hypothermia and anti-hypoxia via sensory TRPA1 activation
Authors: Matsuo Tomohiko , Isosaka Tomoko , Hayashi Yuichiro , Tang Lijun , Doi Akihiro , Yasuda Aiko , Hayashi Mikio , Lee Chia-Ying , Cao Liqin , Kutsuna Natsumaro , Matsunaga Sachihiro , Matsuda Takeshi , Yao Ikuko , Setou Mitsuyoshi , Kanagawa Dai , Higasa Koichiro , Ikawa Masahito , Liu Qinghua , Kobayakawa Reiko , Kobayakawa Ko
Published: April 2021

Thiazoline-related innate fear-eliciting compounds (tFOs) orchestrate hypothermia, hypometabolism, and anti-hypoxia, which enable survival in lethal hypoxic conditions. Here, we show that most of these effects are severely attenuated in transient receptor potential ankyrin 1 (Trpa1) knockout mice. TFO-induced hypothermia involves theTrpa1-mediated trigeminal/vagal pathways and non-Trpa1olfactory pathway. TFOs activateTrpa1-positive sensory pathways projecting from trigeminal and vagal ganglia to the spinal trigeminal nucleus (Sp5) and nucleus of the solitary tract (NTS), and their artificial activation induces hypothermia. TFO presentation activates the NTS-Parabrachial nucleus pathway to induce hypothermia and hypometabolism; this activation was suppressed inTrpa1knockout mice. TRPA1 activation is insufficient to trigger tFO-mediated anti-hypoxic effects; Sp5/NTS activation is also necessary. Accordingly, we find a novel molecule that enables mice to survive in a lethal hypoxic condition ten times longer than known tFOs. Combinations of appropriate tFOs and TRPA1 command intrinsic physiological responses relevant to survival fate.
Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12
Authors: Khan Omar M. , Almagro Jorge , Nelson Jessica K. , Horswell Stuart , Encheva Vesela , Keyan Kripa S. , Clurman Bruce E. , Snijders Ambrosius P. , Behrens Axel
Published: April 2021

The tumour suppressor FBW7 is a substrate adaptor for the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF), that targets several oncoproteins for proteasomal degradation. FBW7 is widely mutated and FBW7 protein levels are commonly downregulated in cancer. Here, using an shRNA library screen, we identify the HECT-domain E3 ubiquitin ligase TRIP12 as a negative regulator of FBW7 stability. We find that SCFFBW7-mediated ubiquitylation of FBW7 occurs preferentially on K404 and K412, but is not sufficient for its proteasomal degradation, and in addition requires TRIP12-mediated branched K11-linked ubiquitylation. TRIP12 inactivation causes FBW7 protein accumulation and increased proteasomal degradation of the SCFFBW7 substrate Myeloid Leukemia 1 (MCL1), and sensitizes cancer cells to anti-tubulin chemotherapy. Concomitant FBW7 inactivation rescues the effects of TRIP12 deficiency, confirming FBW7 as an essential mediator of TRIP12 function. This work reveals an unexpected complexity of FBW7 ubiquitylation, and highlights branched ubiquitylation as an important signalling mechanism regulating protein stability.
Dominant role of CDKN2B/p15INK4B of 9p21.3 tumor suppressor hub in inhibition of cell-cycle and glycolysis
Authors: Xia Yong , Liu Yan , Yang Chao , Simeone Diane M. , Sun Tung-Tien , DeGraff David J. , Tang Moon-shong , Zhang Yingkai , Wu Xue-Ru
Published: April 2021

Human chromosome 9p21.3 is susceptible to inactivation in cell immortalization and diseases, such as cancer, coronary artery disease and type-2 diabetes. Although this locus encodes three cyclin-dependent kinase (CDK) inhibitors (p15INK4B, p14ARF and p16INK4A), our understanding of their functions and modes of action is limited to the latter two. Here, we show that in vitro p15INK4B is markedly stronger than p16INK4A in inhibiting pRb1 phosphorylation, E2F activity and cell-cycle progression. In mice, urothelial cells expressing oncogenic HRas and lacking p15INK4B, but not those expressing HRas and lacking p16INK4A, develop early-onset bladder tumors. The potency of CDKN2B/p15INK4B in tumor suppression relies on its strong binding via key N-terminal residues to and inhibition of CDK4/CDK6. p15INK4B also binds and inhibits enolase-1, a glycolytic enzyme upregulated in most cancer types. Our results highlight the dual inhibition of p15INK4B on cell proliferation, and unveil mechanisms whereby p15INK4B aberrations may underpin cancer and non-cancer conditions.
Giant c-axis nonlinear anomalous Hall effect in Td-MoTe2 and WTe2
Authors: Tiwari Archana , Chen Fangchu , Zhong Shazhou , Drueke Elizabeth , Koo Jahyun , Kaczmarek Austin , Xiao Cong , Gao Jingjing , Luo Xuan , Niu Qian , Sun Yuping , Yan Binghai , Zhao Liuyan , Tsen Adam W.
Published: April 2021

While the anomalous Hall effect can manifest even without an external magnetic field, time reversal symmetry is nonetheless still broken by the internal magnetization of the sample. Recently, it has been shown that certain materials without an inversion center allow for a nonlinear type of anomalous Hall effect whilst retaining time reversal symmetry. The effect may arise from either Berry curvature or through various asymmetric scattering mechanisms. Here, we report the observation of an extremely large c-axis nonlinear anomalous Hall effect in the non-centrosymmetric Td phase of MoTe2 and WTe2 without intrinsic magnetic order. We find that the effect is dominated by skew-scattering at higher temperatures combined with another scattering process active at low temperatures. Application of higher bias yields an extremely large Hall ratio of E⊥/E|| = 2.47 and corresponding anomalous Hall conductivity of order 8 × 107 S/m.
A policy roadmap for negative emissions using direct air capture
Authors: Meckling Jonas , Biber Eric
Published: April 2021

Negative emission strategies are central to avoiding catastrophic climate change. Engineered solutions such as direct air capture are far from cost-competitive. As past low-carbon technology transitions suggest, this calls for policy and political strategies beyond carbon pricing. We adopt a policy sequencing perspective that identifies policies that could create niche markets, building political support for later widespread deployment of direct air capture. Climate leaders could pursue an “incentives + mandates” policy strategy targeted at the oil and gas industry. These early moves could create global spillovers for follower countries by reducing technology cost and facilitating knowledge transfer through global firms.
Discovery of $${\hat{\boldsymbol{C}}}_2$$ rotation anomaly in topological crystalline insulator SrPb
Authors: Fan Wenhui , Nie Simin , Wang Cuixiang , Fu Binbin , Yi Changjiang , Gao Shunye , Rao Zhicheng , Yan Dayu , Ma Junzhang , Shi Ming , Huang Yaobo , Shi Youguo , Wang Zhijun , Qian Tian , Ding Hong
Published: April 2021

Topological crystalline insulators (TCIs) are insulating electronic states with nontrivial topology protected by crystalline symmetries. Recently, theory has proposed new classes of TCIs protected by rotation symmetries$$\hat C_n$$Ĉn, which have surface rotation anomaly evading the fermion doubling theorem, i.e.,ninstead of 2nDirac cones on the surface preserving the rotation symmetry. Here, we report the first realization of the$$\hat C_2$$Ĉ2rotation anomaly in a binary compound SrPb. Our first-principles calculations reveal two massless Dirac fermions protected by the combination of time-reversal symmetry$$\hat T$$T̂and$$\hat C_{2y}$$Ĉ2yon the (010) surface. Using angle-resolved photoemission spectroscopy, we identify two Dirac surface states inside the bulk band gap of SrPb, confirming the$$\hat C_2$$Ĉ2rotation anomaly in the new classes of TCIs. The findings enrich the classification of topological phases, which pave the way for exploring exotic behavior of the new classes of TCIs.
Biochemical and structural characterization of the BioZ enzyme engaged in bacterial biotin synthesis pathway
Authors: Zhang Sitao , Xu Yongchang , Guan Hongxin , Cui Tao , Liao Yuling , Wei Wenhui , Li Jun , Hassan Bachar H. , Zhang Huimin , Jia Xu , Ouyang Songying , Feng Youjun
Published: April 2021

Biotin is an essential micro-nutrient across the three domains of life. The paradigm earlier step of biotin synthesis denotes “BioC-BioH” pathway inEscherichia coli. Here we report that BioZ bypasses the canonical route to begin biotin synthesis. In addition to its origin ofRhizobiales, protein phylogeny infers that BioZ is domesticated to gain an atypical role of β-ketoacyl-ACP synthase III. Genetic and biochemical characterization demonstrates that BioZ catalyzes the condensation of glutaryl-CoA (or ACP) with malonyl-ACP to give 5’-keto-pimeloyl ACP. This intermediate proceeds via type II fatty acid synthesis (FAS II) pathway, to initiate the formation of pimeloyl-ACP, a precursor of biotin synthesis. To further explore molecular basis of BioZ activity, we determine the crystal structure ofAgrobacterium tumefaciensBioZ at 1.99 Å, of which the catalytic triad and the substrate-loading tunnel are functionally defined. In particular, we localize that three residues (S84, R147, and S287) at the distant bottom of the tunnel might neutralize the charge of free C-carboxyl group of the primer glutaryl-CoA. Taken together, this study provides molecular insights into the BioZ biotin synthesis pathway.
Coordinated interactions between endothelial cells and macrophages in the islet microenvironment promote β cell regeneration
Authors: Saunders Diane C. , Aamodt Kristie I. , Richardson Tiffany M. , Hopkirk Alexander J. , Aramandla Radhika , Poffenberger Greg , Jenkins Regina , Flaherty David K. , Prasad Nripesh , Levy Shawn E. , Powers Alvin C. , Brissova Marcela
Published: April 2021

Endogenous β cell regeneration could alleviate diabetes, but proliferative stimuli within the islet microenvironment are incompletely understood. We previously found that β cell recovery following hypervascularization-induced β cell loss involves interactions with endothelial cells (ECs) and macrophages (MΦs). Here we show that proliferative ECs modulate MΦ infiltration and phenotype during β cell loss, and recruited MΦs are essential for β cell recovery. Furthermore, VEGFR2 inactivation in quiescent ECs accelerates islet vascular regression during β cell recovery and leads to increased β cell proliferation without changes in MΦ phenotype or number. Transcriptome analysis of β cells, ECs, and MΦs reveals that β cell proliferation coincides with elevated expression of extracellular matrix remodeling molecules and growth factors likely driving activation of proliferative signaling pathways in β cells. Collectively, these findings suggest a new β cell regeneration paradigm whereby coordinated interactions between intra-islet MΦs, ECs, and extracellular matrix mediate β cell self-renewal.
Author Correction: Detection of untreated sewage discharges to watercourses using machine learning
Authors: Hammond Peter , Suttie Michael , Lewis Vaughan T. , Smith Ashley P. , Singer Andrew C.
Published: April 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41545-021-00116-3
Catalyst-loaded micro-encapsulated phase change material for thermal control of exothermic reaction
Authors: Takahashi Tatsuya , Koide Hiroaki , Sakai Hiroki , Ajito Daisuke , Kurniawan Ade , Kunisada Yuji , Nomura Takahiro
Published: April 2021

CO2 methanation is a promising technology to enable the use of CO2 as a resource. Thermal control of CO2 methanation, which is a highly active exothermic reaction, is important to avoid thermal runaway and subsequent degradation of the catalyst. Using the heat storage capacity of a phase change material (PCM) for thermal control of the reaction is a novel passive approach. In this study a novel structure was developed, wherein catalysts were directly loaded onto a micro-encapsulated PCM (MEPCM). The MEPCM was prepared in three steps consisting of a boehmite treatment, precipitation treatment, and heat oxidation treatment, and an impregnation process was adopted to prepare a Ni catalyst. The catalyst-loaded MEPCM did not show any breakage or deformation of the capsule or a decrease in the heat storage capacity after the impregnation treatment. MEPCM demonstrated a higher potential as an alternative catalyst support in CO2 methanation than the commercially available α-Al2O3 particle. In addition, the heat storage capacity of the catalyst-loaded MEPCM suppressed the temperature rise of the catalyst bed at a high heat absorption rate (2.5 MW m−3). In conclusion, the catalyst-loaded MEPCM is a high-speed, high-precision thermal control device because of its high-density energy storage and resolution of a spatial gap between the catalyst and cooling devices. This novel concept has the potential to overcome the technical challenges faced by efficiency enhancement of industrial chemical reactions.
The effect of dietary supplementation with Nigella sativa (black seeds) mediates immunological function in male Wistar rats
Authors: Mahmoud Hany Salah , Almallah Amani A. , Gad EL-Hak Heba Nageh , Aldayel Tahany Saleh , Abdelrazek Heba M. A. , Khaled Howayda E.
Published: April 2021

This experiment aimed to investigate the effect of dietary Nigella sativa on the cell-mediated immune response. Eighteen male Wistar rats were divided equally into a control group and treated groups that received black seeds at rates of 30 and 50 g/kg in the diet (Sa30 and Sa50 groups, respectively, for 30 days. The weight gain, feed intake, feed conversion ratio (FCR), and cell-mediated immune response were monitored after the injection of 0.1 mL of 10% phytohemagglutinin (PHA). The intumesce index, serum total antioxidant capacity (TAC), catalase (CAT), interleukin-12 (IL-12), gamma interferon (γ-IF) and tumor necrosis factor alpha (TNF-α) were determined. Histopathological examination and an immunohistochemistry analysis of splenic caspase-3 and CD8 were performed.Nigella sativa significantly improved the weight gain and FCR. Intumesce index of Sa50 group was significantly increased.Nigella sativasignificantly increased TAC, CAT, IL-12, γ-IF and TNF-α. A histological examination of PHA-stimulated foot pads showed increased leukocyte infiltration and edema in a dose-dependent pattern. Splenic caspase-3 and CD8 showed significant decreases and increases, respectively, in the Sa30 and Sa50 groups. The results indicate thatNigella sativaseeds exhibit immunostimulatory function through their antioxidant potential, induction of cytokine production, promotion of CD8 expression and reduction of splenic apoptosis.
Improves symptoms and urinary biomarkers in refractory interstitial cystitis/bladder pain syndrome patients randomized to extracorporeal shock wave therapy versus placebo
Authors: Shen Yuan-Chi , Tyagi Pradeep , Lee Wei-Chia , Chancellor Michael , Chuang Yao-Chi
Published: April 2021

Extracorporeal shock wave therapy (ESWT) has been shown to improve symptoms in patients with interstitial cystitis/bladder pain syndrome (IC/BPS); however, there is a lack of objective evidence. We measured change of urinary biomarker levels in 25 patients with IC/BPS received ESWT or placebo once a week for 4 weeks. Urines were collected from participants at baseline, 4 and 12 weeks post treatment. A representative 41 inflammatory growth factors, cytokines, and chemokines in urine were measured using a MILLIPLEX immunoassay kit. Symptom bother was assessed by O’Leary-Sant symptom scores (OSS), and visual analog scale (VAS) for pain. The ESWT group exhibited a significant reduction in the OSS and VAS compared to the placebo group 4 weeks post-treatment (P < 0.05), and the effects were persistent at 12 weeks. The difference in urinary markers change in ESWT versus placebo was P = 0.054 for IL4, P = 0.013 for VEGF, and P = 0.039 for IL9 at 4 weeks. The change of urine biomarker was not significant in other biomarkers or all the measured proteins at 12 weeks. The current data suggest that IL4, IL9, and VEGF mediation may be involved in its pathophysiologic mechanisms and response to LESW treatment.