bluuebunny/crossref_metadata_2025 huggingface dataset:
A Two‐Phase, Pore‐Scale Reactive Transport Model for the Kinetic Interface‐Sensitive Tracer
Authors: Gao H. , Tatomir A. B. , Karadimitriou N. K. , Steeb H. , Sauter M.
Published: April 2021

Previous laboratory experiments with the kinetic interface sensitive (KIS) tracers have shown promising results with respect to the quantification of the fluid‐fluid interfacial area (IFA) under dynamic, two‐phase flow conditions. However, pore‐scale effects relevant to two‐phase flow (e.g., the formation of hydrodynamically stagnant/immobile zones) are not yet fully understood, and quantitative information about how far these effects influence the transport of the tracer reaction products is not yet available. Therefore, a pore‐scale numerical model that includes two‐phase, reactive flow, and transport of the KIS tracer at the fluid‐fluid interface is developed. We propose a new method to quantitatively analyze how the mass of the KIS‐tracer reaction product in the flowing water is affected by the presence of the immobile zones. The model employs the phase field method (PFM) and a new continuous mass transfer formulation, consistent with the PFM. We verify the model with the analytical solutions of transport involving advection, reaction and diffusion processes. The model is tested for two‐phase flow conditions in a conceptual 2D slit. The applicability of the model is demonstrated in NAPL/water drainage scenarios in a conceptual porous domain, comparing the results in terms of the spatial distribution of the phases and solute concentration. Furthermore, we distinguish the mobile and immobile zones based on the local Péclet number, and the corresponding IFA, and solute mass in these two zones is quantified. Finally, we show that the solute mass in flowing water can be employed to selectively determine the mobile part of the IFA.
Mitigated PM2.5Changes by the Regional Transport During the COVID‐19 Lockdown in Shanghai, China
Authors: Gu Yixuan , Yan Fengxia , Xu Jianming , Duan Yusen , Fu Qingyan , Qu Yuanhao , Liao Hong
Published: April 2021

Intensive observations and WRF‐Chem simulations are applied in this study to investigate the adverse impacts of regional transport on the PM2.5(fine particulate matter; diameter ≤2.5 μm) changes in Shanghai during the Coronavirus Disease 2019 lockdown. As the local atmospheric oxidation capacity was observed to be generally weakened, strong regional transport carried by the frequent westerly winds is suggested to be the main driver of the unexpected pollution episodes, increasing the input of both primary and secondary aerosols. Contributing 40%–80% to the PM2.5, the transport contributed aerosols are simulated to exhibit less decreases (13.2%–21.8%) than the local particles (37.1%–64.8%) in urban Shanghai due to the lockdown, which largely results from the less decreased industrial and residential emissions in surrounding provinces. To reduce the influence of the transport, synergetic emission control, especially synergetic ammonia control, measures are proved to be effective strategies, which need to be considered in future regulations.
Gravity Wave Weakening During the 2019 Antarctic Stratospheric Sudden Warming
Authors: Kogure Masaru , Yue Jia , Liu Huixin
Published: April 2021

A rare Antarctic stratospheric sudden warming (SSW) occurred on August 30, 2019, and was a minor warming event. We investigated variations in gravity wave (GW) activity before and after this Antarctic SSW event using two satellite measurements (AIRS and CIPS) and reanalysis data (GEOS‐5 FP). GW activity over the Andes decreased after August 30, although the westerly wind was 40–60 ms−1 and cannot filter out GWs with small zonal phase speed. This decline over the Andes was probably caused by wave saturation. Zonal mean GW activity over Antarctica and the Southern Ocean likewise decreased, with a weakening of zonal wind. The zonal mean GW activity further decreased around September 8 which coincided with a reversal of the zonal mean zonal wind at 40 km. The decline in the zonal mean GW activity after August 30 was probably caused by wind filtering and polar night jet breaking.
High‐Latitude Stratospheric Aerosol Geoengineering Can Be More Effective if Injection Is Limited to Spring
Authors: Lee Walker Raymond , MacMartin Douglas G. , Visioni Daniele , Kravitz Ben
Published: April 2021

Stratospheric aerosol geoengineering focused on the Arctic could substantially reduce local and worldwide impacts of anthropogenic global warming. Because the Arctic receives little sunlight during the winter, stratospheric aerosols present in the winter at high latitudes have little impact on the climate, whereas stratospheric aerosols present during the summer achieve larger changes in radiative forcing. Injecting SO2 in the spring leads to peak aerosol optical depth (AOD) in the summer. We demonstrate that spring injection produces approximately twice as much summer AOD as year‐round injection and restores approximately twice as much September sea ice, resulting in less increase in stratospheric sulfur burden, stratospheric heating, and stratospheric ozone depletion per unit of sea ice restored. We also find that differences in AOD between different seasonal injection strategies are small compared to the difference between annual and spring injection.
A Concise Empirical Formula for the Field‐Aligned Distribution of Auroral Kilometeric Radiation Based on Arase Satellite and Van Allen Probes
Authors: Zhang Sai , Liu Si , Li Wentao , He Yihua , Yang Qiwu , Xiao Fuliang , Kumamoto Atsushi , Miyoshi Yoshizumi , Nakamura Yosuke , Tsuchiya Fuminori , Kasahara Yoshiya , Shinohara Iku
Published: April 2021

Auroral kilometric radiations (AKR) are strong radio emission phenomena, and can produce significant acceleration or scattering of radiation belt electrons. The variation of AKR wave amplitude with the latitude (λ) has not been reported so far owing to lack of measurements. Here, using observations of the Arase satellite and Van Allen Probes from March 23, 2017 to July 31, 2019, we present the first statistical study on the AKR electric field amplitude (Et) in the radiation belts for |λ| = 0° − 40° and L‐shell L = 3.0–6.2. Results (totally 14,770 samples) show that Et can be described by a concise formula: Et(λ) = E0  exp(ξ sin |λ|), decreasing with decreasing latitude. Fitting parameters E0 and ξ are limited in the ranges: E0 = 0.054–0.340 mV/m and ξ = 3.0–4.2. Wave amplitudes are greater (smaller) under intense (weak) geomagnetic conditions. This study helps to better quantify the gyroresonance between AKR and radiation belt electrons.
Individualized plasticity autograft mimic with efficient bioactivity inducing osteogenesis
Authors: Wei Yan , Zhu Guixin , Zhao Zifan , Yin Chengcheng , Zhao Qin , Xu Hudi , Wang Jinyang , Zhang Jinglun , Zhang Xiaoxin , Zhang Yufeng , Xia Haibin
Published: April 2021

Mineralized tissue regeneration is an important and challenging part of the field of tissue engineering and regeneration. At present, autograft harvest procedures may cause secondary trauma to patients, while bone scaffold materials lack osteogenic activity, resulting in a limited application. Loaded with osteogenic induction growth factor can improve the osteoinductive performance of bone graft, but the explosive release of growth factor may also cause side effects. In this study, we innovatively used platelet-rich fibrin (PRF)-modified bone scaffolds (Bio-Oss®) to replace autograft, and used cytokine (BMP-2) to enhance osteogenesis. Encouragingly, this mixture, which we named “Autograft Mimic (AGM)”, has multiple functions and advantages. (1) The fiber network provided by PRF binds the entire bone scaffold together, thereby shaping the bone grafts and maintaining the space of the defect area. (2) The sustained release of BMP-2 from bone graft promoted bone regeneration continuously. (3) AGM recruited bone marrow mesenchymal stem cells (BMSCs) and promote their proliferation, migration, and osteogenic differentiation. Thus, AGM developed in this study can improve osteogenesis, and provide new guidance for the development of clinical bone grafts.
Nutrient supplementation experiments with saltern microbial communities implicate utilization of DNA as a source of phosphorus
Authors: Hua Zhengshuang , Ouellette Matthew , Makkay Andrea M , Papke R Thane , Zhaxybayeva Olga
Published: April 2021

All environments including hypersaline ones harbor measurable concentrations of dissolved extracellular DNA (eDNA) that can be utilized by microbes as a nutrient. However, it remains poorly understood which eDNA components are used, and who in a community utilizes it. For this study, we incubated a saltern microbial community with combinations of carbon, nitrogen, phosphorus, and DNA, and tracked the community response in each microcosm treatment via 16S rRNA and rpoB gene sequencing. We show that microbial communities used DNA only as a phosphorus source, and provision of other sources of carbon and nitrogen was needed to exhibit a substantial growth. The taxonomic composition of eDNA in the water column changed with the availability of inorganic phosphorus or supplied DNA, hinting at preferential uptake of eDNA from specific organismal sources. Especially favored for growth was eDNA from the most abundant taxa, suggesting some haloarchaea prefer eDNA from closely related taxa. The preferential eDNA consumption and differential growth under various nutrient availability regimes were associated with substantial shifts in the taxonomic composition and diversity of microcosm communities. Therefore, we conjecture that in salterns the microbial community assembly is driven by the available resources, including eDNA.
HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry
Authors: Konte Bettina , Walters James T. R. , Rujescu Dan , Legge Sophie E. , Pardiñas Antonio F. , Cohen Dan , Pirmohamed Munir , Tiihonen Jari , Hartmann Annette M. , Bogers Jan P. , van der Weide Jan , van der Weide Karen , Putkonen Anu , Repo-Tiihonen Eila , Hallikainen Tero , Silva Ed , Ingimarsson Oddur , Sigurdsson Engilbert , Kennedy James L. , Sullivan Patrick F. , Rietschel Marcella , Breen Gerome , Stefansson Hreinn , Stefansson Kari , Collier David A. , O’Donovan Michael C. , Giegling Ina
Published: April 2021

The atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm3 and 1500/mm3 were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E−06) and agranulocytosis (OR = 10.49, P = 1.83E−06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E−08; agranulocytosis: OR = 16.31, P = 1.39E−06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.
A miRNA signature predicts benefit from addition of hypoxia-modifying therapy to radiation treatment in invasive bladder cancer
Authors: Khan Mairah T. , Irlam-Jones Joely J. , Pereira Ronnie Rodrigues , Lane Brian , Valentine Helen R. , Aragaki Kai , Dyrskjøt Lars , McConkey David J. , Hoskin Peter J. , Choudhury Ananya , West Catharine M. L.
Published: April 2021

Background

miRNAs are promising biomarkers in oncology as their small size makes them less susceptible to degradation than mRNA in FFPE tissue. We aimed to derive a hypoxia-associated miRNA signature for bladder cancer.

Methods

Taqman miRNA array cards identified miRNA seed genes induced under hypoxia in bladder cancer cell lines. A signature was derived using feature selection methods in a TCGA BLCA training data set. miRNA expression data were generated for 190 tumours from the BCON Phase 3 trial and used for independent validation.

Results

A 14-miRNA hypoxia signature was derived, which was prognostic for poorer overall survival in the TCGA BLCA cohort (n = 403,p = 0.001). Univariable analysis showed that the miRNA signature predicted an overall survival benefit from having carbogen–nicotinamide with radiotherapy (HR = 0.30, 95% CI 0.094–0.95,p = 0.030) and performed similarly to a 24-gene mRNA signature (HR = 0.47, 95% CI 0.24–0.92,p = 0.025). Combining the signatures improved performance (HR = 0.26, 95% CI 0.08–0.82,p = 0.014) with borderline significance for an interaction test (p = 0.065). The interaction test was significant for local relapse-free survival LRFS (p = 0.033).

Conclusion

A 14-miRNA hypoxia signature can be used with an mRNA hypoxia signature to identify bladder cancer patients benefitting most from having carbogen and nicotinamide with radiotherapy.
Correction: Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study
Authors: Dave Rajiv V. , Kim Baek , Courtney Alona , O’Connell Rachel , Rattay Tim , Taxiarchi Vicky P. , Kirkham Jamie J. , Camacho Elizabeth M. , Fairbrother Patricia , Sharma Nisha , Cartlidge Christopher W. J. , Horgan Kieran , McIntosh Stuart A. , Leff Daniel R. , Vidya Raghavan , Potter Shelley , Holcombe Chris , Copson Ellen , Coles Charlotte E. , Cutress Ramsey I. , Gandhi Ashu , Kirwan Cliona C. ,   on behalf of the B-MaP-C study collaborative
Published: April 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41416-021-01378-x
The transcription factor Sox7 modulates endocardiac cushion formation contributed to atrioventricular septal defect through Wnt4/Bmp2 signaling
Authors: Hong Nanchao , Zhang Erge , Xie Huilin , Jin Lihui , Zhang Qi , Lu Yanan , Chen Alex F. , Yu Yongguo , Zhou Bin , Chen Sun , Yu Yu , Sun Kun
Published: April 2021

Cardiac septum malformations account for the largest proportion in congenital heart defects. The transcription factor Sox7 has critical functions in the vascular development and angiogenesis. It is unclear whether Sox7 also contributes to cardiac septation development. We identified a de novo 8p23.1 deletion with Sox7 haploinsufficiency in an atrioventricular septal defect (AVSD) patient using whole exome sequencing in 100 AVSD patients. Then, multiple Sox7 conditional loss-of-function mice models were generated to explore the role of Sox7 in atrioventricular cushion development. Sox7 deficiency mice embryos exhibited partial AVSD and impaired endothelial to mesenchymal transition (EndMT). Transcriptome analysis revealed BMP signaling pathway was significantly downregulated in Sox7 deficiency atrioventricular cushions. Mechanistically, Sox7 deficiency reduced the expressions of Bmp2 in atrioventricular canal myocardium and Wnt4 in endocardium, and Sox7 binds to Wnt4 and Bmp2 directly. Furthermore, WNT4 or BMP2 protein could partially rescue the impaired EndMT process caused by Sox7 deficiency, and inhibition of BMP2 by Noggin could attenuate the effect of WNT4 protein. In summary, our findings identify Sox7 as a novel AVSD pathogenic candidate gene, and it can regulate the EndMT involved in atrioventricular cushion morphogenesis through Wnt4–Bmp2 signaling. This study contributes new strategies to the diagnosis and treatment of congenital heart defects.
Simvastatin accelerated motoneurons death in SOD1G93A mice through inhibiting Rab7-mediated maturation of late autophagic vacuoles
Authors: Bai Lin , Wang Yafei , Huo Jia , Li Shuai , Wen Ya , Liu Qi , Yang Jing , Liu Yaling , Li Rui
Published: April 2021

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by motoneuron loss, for which there is currently no effective treatment. Statins, as inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, are used as drugs for treatment for a variety of disease such as ischemic diseases, neurodegenerative diseases, cancer, and inflammation. However, our previous evidence has demonstrated that simvastatin leads to cytotoxicity in NSC34-hSOD1G93A cells by aggravating the impairment of autophagic flux, but the role of simvastatin in ALS model remains elusive. In present study, we reported that after simvastatin treatment, SOD1G93A mice showed early onset of the disease phenotype and shortened life span, with aggravated autophagic flux impairment and increased aggregation of SOD1 protein in spinal cord motoneurons (MNs) of SOD1G93A mice. In addition, simvastatin repressed the ability of Rab7 localization on the membrane by inhibiting isoprenoid synthesis, leading to impaired late stage of autophagic flux rather than initiation. This study suggested that simvastatin significantly worsened impairment of late autophagic flux, resulting in massive MNs death in spinal cord and accelerated disease progression of SOD1G93A mice. Together, these findings might imply a potential risk of clinic application of statins in ALS.
TRIM39 deficiency inhibits tumor progression and autophagic flux in colorectal cancer via suppressing the activity of Rab7
Authors: Hu Jia , Ding Xueliang , Tian Shaobo , Chu Yanan , Liu Zhibo , Li Yuqin , Li Xiaoqiong , Wang Guobin , Wang Lin , Wang Zheng
Published: April 2021

The biological function of TRIM39, a member of TRIM family, remains largely unexplored in cancer, especially in colorectal cancer (CRC). In this study, we show that TRIM39 is upregulated in tumor tissues compared to adjacent normal tissues and associated with poor prognosis in CRC. Functional studies demonstrate that TRIM39 deficiency restrains CRC progression in vitro and in vivo. Our results further find that TRIM39 is a positive regulator of autophagosome–lysosome fusion. Mechanistically, TRIM39 interacts with Rab7 and promotes its activity via inhibiting its ubiquitination at lysine 191 residue. Depletion of TRIM39 inhibits CRC progression and autophagic flux in a Rab7 activity-dependent manner. Moreover, TRIM39 deficiency suppresses CRC progression through inhibiting autophagic degradation of p53. Thus, our findings uncover the roles as well as the relevant mechanisms of TRIM39 in CRC and establish a functional relationship between autophagy and CRC progression, which may provide promising approaches for the treatment of CRC.
Reduced IQGAP2 expression promotes EMT and inhibits apoptosis by modulating the MEK-ERK and p38 signaling in breast cancer irrespective of ER status
Authors: Kumar Dinesh , Patel Saket Awadesbhai , Hassan Md. Khurshidul , Mohapatra Nachiketa , Pattanaik Niharika , Dixit Manjusha
Published: April 2021

IQGAP2, a member of the IQGAP family, functions as a tumor suppressor in most of the cancers. Unlike IQGAP1 and IQGAP3, which function as oncogenes in breast cancer, the role of IQGAP2 is still unexplored. Here we report a reduced expression of IQGAP2, which was associated with lymph node positivity, lymphovascular invasion, and higher age in breast cancer patients. We found an inverse correlation of IQGAP2 expression levels with oncogenic properties of breast cancer cell lines in estrogen receptor (ER) independent manner. IQGAP2 expression enhanced apoptosis via reactive oxygen species (ROS)-P38-p53 pathway and reduced epithelial–mesenchymal transition (EMT) in a MEK-ERK-dependent manner. IQGAP2-IQGAP1 ratio correlated negatively with phospho-ERK levels in breast cancer patients. Pull-down assay showed interaction of IQGAP1 and IQGAP2. IQGAP2 overexpression rescued, IQGAP1-mediated ERK activation, suggesting the possibility of IQGAP1 sequestration by IQGAP2. IQGAP2 depletion, in a tumor xenograft model, increased tumor volume, tumor weight, and phospho-ERK expression. Overall, our findings suggest that IQGAP2 is negatively associated with proliferative and metastatic abilities of breast cancer cells. Suppression of IQGAP1-mediated ERK activation is a possible route via which IQGAP2 restricts oncogenic properties of breast cancer cells. Our study highlights the candidature of IQGAP2 as a potent target for therapeutic intervention.
mTORC1 mediates fiber type-specific regulation of protein synthesis and muscle size during denervation
Authors: You Jae-Sung , Kim Kookjoo , Steinert Nathaniel D. , Chen Jie , Hornberger Troy A.
Published: April 2021

Skeletal muscle denervation occurs in diverse conditions and causes severe muscle atrophy. Signaling by mammalian target of rapamycin complex 1 (mTORC1) plays a central role in the maintenance of skeletal muscle mass by regulating net protein balance; yet, its role in denervation-induced atrophy is unclear. In this study, by using skeletal muscle-specific and inducible raptor knockout mice, we demonstrate that signaling through mTORC1 is activated during denervation and plays an essential role in mitigating the atrophy of non-type IIB muscle fibers. Measurements of protein synthesis rates of individual fibers suggest that denervation increases protein synthesis specifically in non-type IIB muscle fibers and that mTORC1 is required for this event. Furthermore, denervation induced a more pronounced increase in the level of phosphorylated ribosomal S6 protein in non-type IIB muscle fibers than in type IIB muscle fibers. Collectively, our results unveil a novel role for mTORC1 in mediating a fiber type-specific regulation of muscle size and protein synthesis during denervation.
What people really change after genetic testing (GT) performed in private labs: results from an Italian study
Authors: Oliveri Serena , Cincidda Clizia , Ongaro Giulia , Cutica Ilaria , Gorini Alessandra , Spinella Francesca , Fiorentino Francesco , Baldi Marina , Pravettoni Gabriella
Published: April 2021

Despite the widespread diffusion of direct-to-consumer genetic testing (GT), it is still unclear whether people who learn about their genetic susceptibility to a clinical condition change their behaviors, and the psychological factors involved. The aim of the present study is to investigate long-term changes in health-related choices, individual tendencies and risk attitudes in an Italian sample of GT users. In the context of the Mind the Risk study, which investigated a sample of Italian adults who underwent GT in a private laboratory, 99 clients participated in the follow up assessment. They completed a self-administered questionnaire investigating: (a) clinical history and motivation for testing, (b) lifestyle and risk behaviors, (c) individual tendencies toward health, and (d) risk-taking attitude and risk tolerance. Such variables were measured at three different time-points: T0—before GT, T1—at 6 months after genetic results, and T2—at 1 year from results. Results showed that, at baseline, participants who stated they intended to modify their behavior after GT results, effectively did so over time. This result held both for participants who received a positive or negative test result. In general, a healthier diet was the most frequently observed long-term behavioral change. As regards psychological variables, a risk-taking attitude and risk tolerance did not seem to affect the decision to change the lifestyle. Finally, we found an overall reduction in anxiety and worry over health over time, but also a reduction in the motivation for health promotion and prevention, health esteem, and positive expectations for their health in the future.
Biallelic loss-of-function variants in KCNJ16 presenting with hypokalemic metabolic acidosis
Authors: Webb Bryn D. , Hotchkiss Hilary , Prasun Pankaj , Gelb Bruce D. , Satlin Lisa
Published: April 2021

KCNJ16encodes Kir5.1 and acts in combination with Kir4.1, encoded byKCNJ10, to form an inwardly rectifying K+channel expressed at the basolateral membrane of epithelial cells in the distal nephron. This Kir4.1/Kir5.1 channel is critical for controlling basolateral membrane potential and K+recycling, the latter coupled to Na-K-ATPase activity, which determines renal Na+handling. Previous work has shown thatKcnj16−/−mice and SSKcnj16−/−rats demonstrate hypokalemic, hyperchloremic metabolic acidosis. Here, we present the first report of a patient identified to have biallelic loss-of-function variants inKCNJ16by whole exome sequencing who presented with chronic metabolic acidosis with exacerbations triggered by minor infections.
How the west was won: genetic reconstruction of rapid wolf recolonization into Germany’s anthropogenic landscapes
Authors: Jarausch Anne , Harms Verena , Kluth Gesa , Reinhardt Ilka , Nowak Carsten
Published: April 2021

Following massive persecution and eradication, strict legal protection facilitated a successful reestablishment of wolf packs in Germany, which has been ongoing since 2000. Here, we describe this recolonization process by mitochondrial DNA control-region sequencing, microsatellite genotyping and sex identification based on 1341 mostly non-invasively collected samples. We reconstructed the genealogy of German wolf packs between 2005 and 2015 to provide information on trends in genetic diversity, dispersal patterns and pack dynamics during the early expansion process. Our results indicate signs of a founder effect at the start of the recolonization. Genetic diversity in German wolves is moderate compared to other European wolf populations. Although dispersal among packs is male-biased in the sense that females are more philopatric, dispersal distances are similar between males and females once only dispersers are accounted for. Breeding with close relatives is regular and none of the six male wolves originating from the Italian/Alpine population reproduced. However, moderate genetic diversity and inbreeding levels of the recolonizing population are preserved by high sociality, dispersal among packs and several immigration events. Our results demonstrate an ongoing, rapid and natural wolf population expansion in an intensively used cultural landscape in Central Europe.
The white matter is a pro-differentiative niche for glioblastoma
Authors: Brooks Lucy J. , Clements Melanie P. , Burden Jemima J. , Kocher Daniela , Richards Luca , Devesa Sara Castro , Zakka Leila , Woodberry Megan , Ellis Michael , Jaunmuktane Zane , Brandner Sebastian , Morrison Gillian , Pollard Steven M. , Dirks Peter B. , Marguerat Samuel , Parrinello Simona
Published: April 2021

Glioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma stem cells are maintained in specialised microenvironments, but whether, or how, they undergo lineage progression outside of these niches remains unclear. Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte lineage competency. Tumour cells in contact with white matter acquire pre-oligodendrocyte fate, resulting in decreased proliferation and invasion. Differentiation is a response to white matter injury, which is caused by tumour infiltration itself in a tumoursuppressive feedback loop. Mechanistically, tumour cell differentiation is driven by selective white matter upregulation of SOX10, a master regulator of normal oligodendrogenesis. SOX10 overexpression or treatment with myelination-promoting agents that upregulate endogenous SOX10, mimic this response, leading to niche-independent pre-oligodendrocyte differentiation and tumour suppression in vivo. Thus, glioblastoma recapitulates an injury response and exploiting this latent programme may offer treatment opportunities for a subset of patients.
Structural plasticity of KIR2DL2 and KIR2DL3 enables altered docking geometries atop HLA-C
Authors: Moradi Shoeib , Stankovic Sanda , O’Connor Geraldine M. , Pymm Phillip , MacLachlan Bruce J. , Faoro Camilla , Retière Christelle , Sullivan Lucy C. , Saunders Philippa M. , Widjaja Jacqueline , Cox-Livingstone Shea , Rossjohn Jamie , Brooks Andrew G. , Vivian Julian P.
Published: April 2021

The closely related inhibitory killer-cell immunoglobulin-like receptors (KIR), KIR2DL2 and KIR2DL3, regulate the activation of natural killer cells (NK) by interacting with the human leukocyte antigen-C1 (HLA-C1) group of molecules. KIR2DL2, KIR2DL3 and HLA-C1 are highly polymorphic, with this variation being associated with differences in the onset and progression of some human diseases. However, the molecular bases underlying these associations remain unresolved. Here, we determined the crystal structures of KIR2DL2 and KIR2DL3 in complex with HLA-C*07:02 presenting a self-epitope. KIR2DL2 differed from KIR2DL3 in docking modality over HLA-C*07:02 that correlates with variabilty of recognition of HLA-C1 allotypes. Mutagenesis assays indicated differences in the mechanism of HLA-C1 allotype recognition by KIR2DL2 and KIR2DL3. Similarly, HLA-C1 allotypes differed markedly in their capacity to inhibit activation of primary NK cells. These functional differences derive, in part, from KIR2DS2 suggesting KIR2DL2 and KIR2DL3 binding geometries combine with other factors to distinguish HLA-C1 functional recognition.
Human anogenital monocyte-derived dendritic cells and langerin+cDC2 are major HIV target cells
Authors: Rhodes Jake W. , Botting Rachel A. , Bertram Kirstie M. , Vine Erica E. , Rana Hafsa , Baharlou Heeva , Vegh Peter , O’Neil Thomas R. , Ashhurst Anneliese S. , Fletcher James , Parnell Grant P. , Graham J. Dinny , Nasr Najla , Lim Jake J. K. , Barnouti Laith , Haertsch Peter , Gosselink Martijn P. , Di Re Angelina , Reza Faizur , Ctercteko Grahame , Jenkins Gregory J. , Brooks Andrew J. , Patrick Ellis , Byrne Scott N. , Hunter Eric , Haniffa Muzlifah A. , Cunningham Anthony L. , Harman Andrew N.
Published: April 2021

Tissue mononuclear phagocytes (MNP) are specialised in pathogen detection and antigen presentation. As such they deliver HIV to its primary target cells; CD4 T cells. Most MNP HIV transmission studies have focused on epithelial MNPs. However, as mucosal trauma and inflammation are now known to be strongly associated with HIV transmission, here we examine the role of sub-epithelial MNPs which are present in a diverse array of subsets. We show that HIV can penetrate the epithelial surface to interact with sub-epithelial resident MNPs in anogenital explants and define the full array of subsets that are present in the human anogenital and colorectal tissues that HIV may encounter during sexual transmission. In doing so we identify two subsets that preferentially take up HIV, become infected and transmit the virus to CD4 T cells; CD14+CD1c+ monocyte-derived dendritic cells and langerin-expressing conventional dendritic cells 2 (cDC2).
Astigmatic traction force microscopy (aTFM)
Authors: Li Di , Colin-York Huw , Barbieri Liliana , Javanmardi Yousef , Guo Yuting , Korobchevskaya Kseniya , Moeendarbary Emad , Li Dong , Fritzsche Marco
Published: April 2021

Quantifying small, rapidly progressing three-dimensional forces generated by cells remains a major challenge towards a more complete understanding of mechanobiology. Traction force microscopy is one of the most broadly applied force probing technologies but ascertaining three-dimensional information typically necessitates slow, multi-frame z-stack acquisition with limited sensitivity. Here, by performing traction force microscopy using fast single-frame astigmatic imaging coupled with total internal reflection fluorescence microscopy we improve the temporal resolution of three-dimensional mechanical force quantification up to 10-fold compared to its related super-resolution modalities. 2.5D astigmatic traction force microscopy (aTFM) thus enables live-cell force measurements approaching physiological sensitivity.
Reovirus directly engages integrin to recruit clathrin for entry into host cells
Authors: Koehler Melanie , Petitjean Simon J. L. , Yang Jinsung , Aravamudhan Pavithra , Somoulay Xayathed , Lo Giudice Cristina , Poncin Mégane A. , Dumitru Andra C. , Dermody Terence S. , Alsteens David
Published: April 2021

Reovirus infection requires the concerted action of viral and host factors to promote cell entry. After interaction of reovirus attachment protein σ1 with cell-surface carbohydrates and proteinaceous receptors, additional host factors mediate virus internalization. In particular, β1 integrin is required for endocytosis of reovirus virions following junctional adhesion molecule A (JAM-A) binding. While integrin-binding motifs in the surface-exposed region of reovirus capsid protein λ2 are thought to mediate integrin interaction, evidence for direct β1 integrin-reovirus interactions and knowledge of how integrins function to mediate reovirus entry is lacking. Here, we use single-virus force spectroscopy and confocal microscopy to discover a direct interaction between reovirus and β1 integrins. Comparison of interactions between reovirus disassembly intermediates as well as mutants and β1 integrin show that λ2 is the integrin ligand. Finally, using fluidic force microscopy, we demonstrate a functional role for β1 integrin interaction in promoting clathrin recruitment to cell-bound reovirus. Our study demonstrates a direct interaction between reovirus and β1 integrins and offers insights into the mechanism of reovirus cell entry. These results provide new perspectives for the development of efficacious antiviral therapeutics and the engineering of improved viral gene delivery and oncolytic vectors.
Optical spin-state polarization in a binuclear europium complex towards molecule-based coherent light-spin interfaces
Authors: Kumar Kuppusamy Senthil , Serrano Diana , Nonat Aline M. , Heinrich Benoît , Karmazin Lydia , Charbonnière Loïc J. , Goldner Philippe , Ruben Mario
Published: April 2021

The success of the emerging field of solid-state optical quantum information processing (QIP) critically depends on the access to resonant optical materials. Rare-earth ion (REI)-based molecular systems, whose quantum properties could be tuned taking advantage of molecular engineering strategies, are one of the systems actively pursued for the implementation of QIP schemes. Herein, we demonstrate the efficient polarization of ground-state nuclear spins—a fundamental requirement for all-optical spin initialization and addressing—in a binuclear Eu(III) complex, featuring inhomogeneously broadened 5D0 → 7F0 optical transition. At 1.4 K, long-lived spectral holes have been burnt in the transition: homogeneous linewidth (Γh) = 22 ± 1 MHz, which translates as optical coherence lifetime (T2opt) = 14.5 ± 0.7 ns, and ground-state spin population lifetime (T1spin) = 1.6 ± 0.4 s have been obtained. The results presented in this study could be a progressive step towards the realization of molecule-based coherent light-spin QIP interfaces.
Autonomous Purkinje cell activation instructs bidirectional motor learning through evoked dendritic calcium signaling
Authors: Bonnan Audrey , Rowan Matthew M. J. , Baker Christopher A. , Bolton M. McLean , Christie Jason M.
Published: April 2021

The signals in cerebellar Purkinje cells sufficient to instruct motor learning have not been systematically determined. Therefore, we applied optogenetics in mice to autonomously excite Purkinje cells and measured the effect of this activity on plasticity induction and adaptive behavior. Ex vivo, excitation of channelrhodopsin-2-expressing Purkinje cells elicits dendritic Ca2+ transients with high-intensity stimuli initiating dendritic spiking that additionally contributes to the Ca2+ response. Channelrhodopsin-2-evoked Ca2+ transients potentiate co-active parallel fiber synapses; depression occurs when Ca2+ responses were enhanced by dendritic spiking. In vivo, optogenetic Purkinje cell activation drives an adaptive decrease in vestibulo-ocular reflex gain when vestibular stimuli are paired with relatively small-magnitude Purkinje cell Ca2+ responses. In contrast, pairing with large-magnitude Ca2+ responses increases vestibulo-ocular reflex gain. Optogenetically induced plasticity and motor adaptation are dependent on endocannabinoid signaling, indicating engagement of this pathway downstream of Purkinje cell Ca2+ elevation. Our results establish a causal relationship among Purkinje cell Ca2+ signal size, opposite-polarity plasticity induction, and bidirectional motor learning.
Increased respiratory morbidity associated with exposure to a mature volcanic plume from a large Icelandic fissure eruption
Authors: Carlsen Hanne Krage , Ilyinskaya Evgenia , Baxter Peter J. , Schmidt Anja , Thorsteinsson Throstur , Pfeffer Melissa Anne , Barsotti Sara , Dominici Francesca , Finnbjornsdottir Ragnhildur Gudrun , Jóhannsson Thorsteinn , Aspelund Thor , Gislason Thorarinn , Valdimarsdóttir Unnur , Briem Haraldur , Gudnason Thorolfur
Published: April 2021

The 2014–15 Holuhraun eruption in Iceland was the largest fissure eruption in over 200 years, emitting prodigious amounts of gas and particulate matter into the troposphere. Reykjavík, the capital area of Iceland (250 km from eruption site) was exposed to air pollution events from advection of (i) a relatively young and chemically primitive volcanic plume with a high sulphur dioxide gas (SO2) to sulphate PM (SO42−) ratio, and (ii) an older and chemically mature volcanic plume with a low SO2/SO42− ratio. Whereas the advection and air pollution caused by the primitive plume were successfully forecast and forewarned in public advisories, the mature plume was not. Here, we show that exposure to the mature plume is associated with an increase in register-measured health care utilisation for respiratory disease by 23% (95% CI 19.7–27.4%) and for asthma medication dispensing by 19.3% (95% CI 9.6–29.1%). Absence of public advisories is associated with increases in visits to primary care medical doctors and to the hospital emergency department. We recommend that operational response to volcanic air pollution considers both primitive and mature types of plumes.
In-situ plasmonic tracking oxygen evolution reveals multistage oxygen diffusion and accumulating inhibition
Authors: Wang Jun-Gang , Shi Lifang , Su Yingying , Liu Liwei , Yang Zhenzhong , Huang Rong , Xie Jing , Tian Yang , Li Di
Published: April 2021

Understanding mass transfer processes concomitant with electrochemical conversion for gas evolution reactions at the electrode-electrolyte interface plays a key role in advancing renewable energy storage and conversion. However, due to the complicated diffusion behavior of gas at the dynamic catalytic interfaces, it is still a great challenge to accurately portray mass transfer of gas during electrocatalysis process. Here, we track the diffusion of dissolved oxygen on Cu nanostructured plasmonic interface, which reveals multistage oxygen diffusion behaviors, including premature oxygen accumulation, spontaneous diffusion and accelerated oxygen dissipation. This work uncovers an accumulating inhibition effect on oxygen evolution arising from interfacial dissolved oxygen. With these knowledges, we develop a programmable potential scan strategy to eliminate interfacial gas products, which alleviates the concentration polarization, releases accessible actives sites and promotes electrocatalytic performance. Our findings provide a direct observation of the interfacial mass transfer processes that governs the kinetics of gas-involved multiphases catalysis.
The E3 ligase MREL57 modulates microtubule stability and stomatal closure in response to ABA
Authors: Dou Liru , He Kaikai , Peng Jialin , Wang Xiangfeng , Mao Tonglin
Published: April 2021

Regulation of stomatal movement is critical for plant adaptation to environmental stresses. The microtubule cytoskeleton undergoes disassembly, which is critical for stomatal closure in response to abscisic acid (ABA). However, the mechanism underlying this regulation largely remains unclear. Here we show that a ubiquitin-26S proteasome (UPS)-dependent pathway mediates microtubule disassembly and is required for ABA-induced stomatal closure. Moreover, we identify and characterize the ubiquitin E3 ligase MREL57 (MICROTUBULE-RELATED E3 LIGASE57) and the microtubule-stabilizing protein WDL7 (WAVE-DAMPENED2-LIKE7) inArabidopsisand show that the MREL57-WDL7 module regulates microtubule disassembly to mediate stomatal closure in response to drought stress and ABA treatment. MREL57 interacts with, ubiquitinates and degrades WDL7, and this effect is clearly enhanced by ABA. ABA-induced stomatal closure and microtubule disassembly are significantly suppressed inmrel57mutants, and these phenotypes can be restored whenWDL7expression is decreased. Our results unravel UPS-dependent mechanisms and the role of an MREL57-WDL7 module in microtubule disassembly and stomatal closure in response to drought stress and ABA.
Therapeutic B-cell depletion reverses progression of Alzheimer’s disease
Authors: Kim Ki , Wang Xin , Ragonnaud Emeline , Bodogai Monica , Illouz Tomer , DeLuca Marisa , McDevitt Ross A. , Gusev Fedor , Okun Eitan , Rogaev Evgeny , Biragyn Arya
Published: April 2021

The function of B cells in Alzheimer’s disease (AD) is not fully understood. While immunoglobulins that target amyloid beta (Aβ) may interfere with plaque formation and hence progression of the disease, B cells may contribute beyond merely producing immunoglobulins. Here we show that AD is associated with accumulation of activated B cells in circulation, and with infiltration of B cells into the brain parenchyma, resulting in immunoglobulin deposits around Aβ plaques. Using three different murine transgenic models, we provide counterintuitive evidence that the AD progression requires B cells. Despite expression of the AD-fostering transgenes, the loss of B cells alone is sufficient to reduce Aβ plaque burden and disease-associated microglia. It reverses behavioral and memory deficits and restores TGFβ+ microglia, respectively. Moreover, therapeutic depletion of B cells at the onset of the disease retards AD progression in mice, suggesting that targeting B cells may also benefit AD patients.
Learning cis-regulatory principles of ADAR-based RNA editing from CRISPR-mediated mutagenesis
Authors: Liu Xin , Sun Tao , Shcherbina Anna , Li Qin , Jarmoskaite Inga , Kappel Kalli , Ramaswami Gokul , Das Rhiju , Kundaje Anshul , Li Jin Billy
Published: April 2021

Adenosine-to-inosine (A-to-I) RNA editing catalyzed by ADAR enzymes occurs in double-stranded RNAs. Despite a compelling need towards predictive understanding of natural and engineered editing events, how the RNA sequence and structure determine the editing efficiency and specificity (i.e., cis-regulation) is poorly understood. We apply a CRISPR/Cas9-mediated saturation mutagenesis approach to generate libraries of mutations near three natural editing substrates at their endogenous genomic loci. We use machine learning to integrate diverse RNA sequence and structure features to model editing levels measured by deep sequencing. We confirm known features and identify new features important for RNA editing. Training and testing XGBoost algorithm within the same substrate yield models that explain 68 to 86 percent of substrate-specific variation in editing levels. However, the models do not generalize across substrates, suggesting complex and context-dependent regulation patterns. Our integrative approach can be applied to larger scale experiments towards deciphering the RNA editing code.
Extracellular cap domain is an essential component of the TRPV1 gating mechanism
Authors: Nadezhdin Kirill D. , Neuberger Arthur , Nikolaev Yury A. , Murphy Lyle A. , Gracheva Elena O. , Bagriantsev Sviatoslav N. , Sobolevsky Alexander I.
Published: April 2021

Transient receptor potential (TRP) channels are polymodal molecular sensors involved in numerous physiological processes and implicated in a variety of human diseases. Several structures of the founding member of the TRP channel family, TRPV1, are available, all of which were determined for the protein missing the N- and C-termini and the extracellular S5-P-loop. Here, we present structures of the full-length thirteen-lined ground squirrel TRPV1 solved by cryo-EM. Our structures resolve the extracellular cap domain formed by the S5-P-loops and the C-terminus that wraps around the three-stranded β-sheet connecting elements of the TRPV1 intracellular skirt. The cap domain forms a dome above the pore’s extracellular entrance, with four portals leading to the ion conductance pathway. Deletion of the cap increases the TRPV1 average conductance, reduces the open probability and affects ion selectivity. Our data show that both the termini and the cap domain are critical determinants of TRPV1 function.
Discovery of higher-order topological insulators using the spin Hall conductivity as a topology signature
Authors: Costa Marcio , Schleder Gabriel R. , Mera Acosta Carlos , Padilha Antonio C. M. , Cerasoli Frank , Buongiorno Nardelli Marco , Fazzio Adalberto
Published: April 2021

The discovery and realization of topological insulators, a phase of matter which hosts metallic boundary states when the d-dimension insulating bulk is confined to (d − 1)-dimensions, led to several potential applications. Recently, it was shown that protected topological states can manifest in (d − 2)-dimensions, such as hinge and corner states for three- and two-dimensional systems, respectively. These nontrivial materials are named higher-order topological insulators (HOTIs). Here we show a connection between spin Hall effect and HOTIs using a combination of ab initio calculations and tight-binding modeling. The model demonstrates how a non-zero bulk midgap spin Hall conductivity (SHC) emerges within the HOTI phase. Following this, we performed high-throughput density functional theory calculations to find unknown HOTIs, using the SHC as a criterion. We calculated the SHC of 693 insulators resulting in seven stable two-dimensional HOTIs. Our work guides novel experimental and theoretical advances towards higher-order topological insulator realization and applications.
Synucleinopathy-associated pathogenesis in Parkinson’s disease and the potential for brain-derived neurotrophic factor
Authors: Miller Kathryn M. , Mercado Natosha M. , Sortwell Caryl E.
Published: April 2021

The lack of disease-modifying treatments for Parkinson’s disease (PD) is in part due to an incomplete understanding of the disease’s etiology. Alpha-synuclein (α-syn) has become a point of focus in PD due to its connection to both familial and idiopathic cases—specifically its localization to Lewy bodies (LBs), a pathological hallmark of PD. Within this review, we will present a comprehensive overview of the data linking synuclein-associated Lewy pathology with intracellular dysfunction. We first present the alterations in neuronal proteins and transcriptome associated with LBs in postmortem human PD tissue. We next compare these findings to those associated with LB-like inclusions initiated by in vitro exposure to α-syn preformed fibrils (PFFs) and highlight the profound and relatively unique reduction of brain-derived neurotrophic factor (BDNF) in this model. Finally, we discuss the multitude of ways in which BDNF offers the potential to exert disease-modifying effects on the basal ganglia. What remains unknown is the potential for BDNF to mitigate inclusion-associated dysfunction within the context of synucleinopathy. Collectively, this review reiterates the merit of using the PFF model as a tool to understand the physiological changes associated with LBs, while highlighting the neuroprotective potential of harnessing endogenous BDNF.