bluuebunny/crossref_metadata_2025 huggingface dataset:
Force and the city: occupying and controlling Madrid in the aftermath of the Spanish Civil War
Authors: Pérez-Olivares Alejandro
Published: November 2020

For some years, the historiography on Francoist violence has engaged with debates developed by European scholars on the importance of citizen collaboration in authoritarian regimes. In some cases, denunciations made by ‘ordinary men’ have been quantified to establish the extent of violence in everyday life, without taking other qualitative criteria into account. This article explores the importance of urban criteria such as neighbourhood, sociability and mobility in the scope of Francoist violence, taking the military occupation of Madrid at the end of the Spanish Civil War as a case-study.
Interventions on patent ductus arteriosus and its impact on congenital heart disease
Authors: Zaidi Mariam , Sorathia Nilofer , Abbasi Hannah , Khashkhusha Arwa , Harky Amer
Published: November 2020

The ductus arteriosus (DA) connects the pulmonary artery to the aorta to bypass the pulmonary circulation in utero. It normally closes within 24–72 hours after birth due to increased pulmonary resistance from an increase in oxygen partial pressure with the baby’s first breath. Medical treatment can help close the DA in certain situations where closure is delayed. However, in duct-dependent cardiac defects, the presence of the DA is crucial for survival and as such medical and surgical techniques have evolved to prevent closure. This review aims to outline the two main management options for keeping a ductus arteriosus patent. This includes stenting the PDA and shunting via a modified Blalock–Taussig shunt. Whilst both techniques exist, multicentre trials have found equal mortality end points but significantly reduced morbidity with stenting than shunting. This is also reflected by shorter recovery times, reduced requirement for extracorporeal membrane oxygenation (ECMO), and improved quality of life, although stent longevity remains a limiting factor.
How food companies use social media to influence policy debates: a framework of Australian ultra-processed food industry Twitter data
Authors: Hunt Daniel
Published: November 2020

Objective:

To understand if, and how, Australian ultra-processed food industry actors use Twitter to influence food and health policy debates and produce a conceptual framework to describe such influence.

Design:

Twitter data of prominent industry actors were defined through purposive sampling and inductively coded to investigate possible influence on food and health policy debates. These are described using descriptive statistics and coded extracts.

Setting:

Australia.

Participants:

Twitter accounts of nine prominent ultra-processed food industry actors, including major trade associations.

Results:

Ultra-processed food industry actors actively used Twitter to influence food and health policy debates. Seven overarching strategies were identified: co-opting public health narratives; opposing regulation; supporting voluntary, co- or self-regulation; engaging policy processes and decision-makers; linking regulatory environments to the need for ongoing profitability; affecting public perceptions and value judgements; and using ignorance claims to distort policy narratives. Each lobbying strategy is underpinned with tactics described throughout and captured in a framework.

Conclusions:

The current study creates a framework to monitor how food industry actors can use social media to influence food and health policy debates. As such, social media appears to be not only an important commercial determinant of health for brand marketing, but also an extension of lobbying practices to reshape public perceptions of corporate conduct and policy-making.
Predictors of recovery in children aged 6–59 months with uncomplicated severe acute malnutrition: a multicentre study
Authors: David Sam Marconi , Ragasudha Preethi N , Taneja Sunita , Mohan Sanjana Brahmawar , Iyengar Sharad D , Pricilla Ruby Angeline , Martines Jose , Sachdev Harshpal Singh , Suhalka Virendra , Mohan Venkata Raghava , Mazumder Sarmila , Chowdhury Ranadip , Bahl Rajiv , Bose Anuradha
Published: November 2020

Objective:

To identify predictors of recovery in children with uncomplicated severe acute malnutrition (SAM).

Design:

This is a secondary data analysis from an individual randomised controlled trial, where children with uncomplicated SAM were randomised to three feeding regimens, namely ready-to-use therapeutic food (RUTF) sourced from Compact India, locally prepared RUTF or augmented home-prepared foods, under two age strata (6–17 months and 18–59 months) for 16 weeks or until recovery. Three sets of predictors that could influence recovery, namely child, family and nutritional predictors, were analysed.

Setting:

Rural and urban slum areas of three states of India, namely Rajasthan, Delhi and Tamil Nadu.

Participants:

In total, 906 children (age: 6–59 months) were analysed to estimate the adjusted hazard ratio (AHR) using the Cox proportional hazard ratio model to identify various predictors.

Results:

Being a female child (AHR: 1·269 (1·016, 1·584)), better employment status of the child’s father (AHR: 1·53 (1·197, 1·95)) and residence in a rental house (AHR: 1·485 (1·137, 1·94)) increased the chances of recovery. No hospitalisation (AHR: 1·778 (1·055, 2·997)), no fever, (AHR: 2·748 (2·161, 3·494)) and ≤ 2 episodes of diarrhoea (AHR: 1·579 (1·035, 2·412)) during the treatment phase; availability of community-based peer support to mothers for feeding (AHR: 1·61 (1·237, 2·097)) and a better weight-for-height Z-score (WHZ) at enrolment (AHR: 1·811 (1·297, 2·529)) predicted higher chances of recovery from SAM.

Conclusion:

The probability of recovery increases in children with better WHZ and with the initiation of treatment for acute illnesses to avoid hospitalisation, availability of peer support and better employment status of the father.
Early consumption of ultra-processed foods among children under 2 years old in Brazil
Authors: Spaniol Ana Maria , da Costa Teresa Helena Macedo , Souza Amanda de Moura , Gubert Muriel Bauermann
Published: November 2020

Objective:

To evaluate the complementary food consumption according to the extent and purpose of food processing based on NOVA classification among children aged 6–24 months of Federal District, Brazil.

Design:

We performed a cross-sectional study using a 24-h recall to estimate the daily energy intake and nutrients according to NOVA classification. We conducted a linear regression to assess the association between the processed and ultra-processed foods (UPF) energy intake and the daily energy intake from saturated fat, daily energy intake from total sugars and daily intake of sodium.

Setting:

Federal District, Brazil.

Participants:

Five hundred and thirty-eight children aged between 6 and 24 months attended at Primary Health Care Units from March 2017 to March 2018.

Results:

On average, children aged from 6 to 12 and from 12 to 24 months consumed 2393 and 4054 kJ/d, respectively, and processed and UPF represented one-third of dietary energy intake. Group 2 (processed and UPF) was higher carbohydrate contributors, and lower protein, fibre and most micronutrient contributors, when compared with Group 1 (unprocessed, minimally processed foods and processed culinary ingredients). In addition, the higher the energy intake from processed and UPF, the higher was the daily energy intake from saturated fat, daily energy intake from total sugar and daily intake of sodium.

Conclusion:

Children are being exposed early to processed and UPF and their share affect the diet’s nutritional quality.
The environmental and economic efficacy of on-farm beneficial management practices for mitigating soil-related greenhouse gas emissions in Ontario, Canada
Authors: Yanni Sandra F. , De Laporte Aaron , Rajsic Predrag , Wagner-Riddle Claudia , Weersink Alfons
Published: November 2020

Agriculture is a large source of greenhouse gas (GHG) emissions but changing management practices to those more beneficial to the environment could help mitigate climate change as long as they are economically and environmentally viable. This study examines the environmental (public) and economic (private) effects of adopting ten different beneficial management practices on a representative corn farm in Ontario, Canada. The study integrates changes in GHG emissions in carbon equivalents (CO2e) and changes in profit from changes in costs and revenues in two dimensions to reveal the scope and scale of different kinds of practices. 4R nitrogen management practices are smaller in scale compared to cropping practices and, therefore, have smaller potential costs and benefits. Land use changes, from practices including biomass, afforestation, crop rotation and cover cropping, have larger impacts on soil sequestration and carbon-equivalent GHG reduction, but with significantly greater costs. Seven practices were found to, at least partially, be economically and environmentally beneficial. The adoption of no-till and N-rate reduction is firmly positive, whereas the production of biomass has the largest potential economic and environmental gains. Crop rotation and diversification and cover cropping can be mutually beneficial, as can changing N-application practices. The use of inhibitors may be economically beneficial if yield gains outweigh purchase costs.
Relationships Between Health Promoting Activities, Life Satisfaction, and Depressive Symptoms in Unemployed Individuals
Authors: Chatzisarantis Nikos L. D. , Kamarova Sviatlana , Twomey Chris , Hansen Graham , Harris Mark , Windus John , Bateson Alan , Hagger Martin S.
Published: November 2020

Abstract. Background: Previous research has documented that unemployed individuals who engage in recreational activities, either alone or with others, experience higher levels of mental health and psychological well-being relative to those who do not engage in recreational activities. Aims: In this study, we examined whether engagement in health promoting activities, alone or with other family members, is associated with reduced levels of depression and enhanced levels of life satisfaction in unemployed individuals. Method: We employed a cross-sectional design in which we measured life satisfaction, depressive symptoms, consumption of healthy meals and engagement in physical activities in 203 unemployed individuals (male = 90, female = 113, age= 33.79, SD = 11.16). Results: Independent of age, gender, and partner employment status, hierarchical regression analyses revealed statistically significant effects for social forms of healthy eating (consumption of healthy meals with others) and solitary forms of physical activity (exercising alone) on depressive symptoms and life satisfaction. Limitations: The research design was cross-sectional using self-report questionnaires. The present study does not to explain why and how health promoting activities enhance well-being outcomes among the unemployed. Conclusions: These findings highlight the importance of measuring engagement in health promoting activities through separate constructs that capture engagement in social and solitary health promoting activities and suggest that unemployed individuals are likely to experience optimal levels of psychological well-being if they exercise alone and consume healthy meals with other family members.
Automated enumeration and phenotypic characterization of CTCs and tdEVs in patients with metastatic castration resistant prostate cancer
Authors: Oeyen Steffi , Liégeois Vincent , De Laere Bram , Buys Andy , Strijbos Michiel , Dirix Piet , Meijnders Paul , Vermeulen Peter , Van Laere Steven , Dirix Luc
Published: November 2020

Background

Although most patients with metastatic castration-resistant prostate cancer (mCRPC) initially benefit from treatment with androgen receptor signaling inhibitors (ARSi), resistance inevitably occurs. Hence, we investigated the prognostic value of automated circulating tumor cell (CTC) and tumor-derived extracellular vesicle (tdEV) enumeration and their dynamics, in patients with mCRPC in the context of the initiation of treatment with ARSi. Furthermore, we hypothesize that CTC phenotypic heterogeneity might serve as a measurable biomarker under these circumstances.

Methods

Using an image analysis tool, we reanalyzed all CellSearch images previously acquired in the context of a prospective, multicenter clinical study for patients with mCRPC (n = 170) starting a new line of ARSi, for CTC and tdEV detection and enumeration. CTC (n = 19 129) phenotypic diversity was quantified by the Shannon index (SI). Progression-free survival (PFS) and overall survival (OS) were compared between groups of patients stratified according to CTC, tdEV, and SI levels.

Results

Automated CTC enumeration provided similar clinical prognostication compared with operator-based counts. Patients demonstrating high CTC phenotypic heterogeneity before therapy had a shorter median PFS (4.82 vs. 8.49 months, HR 1.79; P = 0.03) and OS (12.6 months vs. not reached, HR 2.32; P = 0.03), compared to patients with low diversity, irrespective of CTC level. Multivariable analysis showed how the prognostic value of the baseline SI was lost by pretreatment chemotherapy status, CTC counts, and PSA levels.

Conclusions

Automated CTC counts are a reliable substitute for reviewer-based enumeration, as they are equally informative for prognosis assessment in patients with mCRPC. Beyond enumeration, we demonstrated the added value of studying CTC phenotypic diversity for patient prognostication, warranting future investigation.
Metabolic versatility of the nitrite-oxidizing bacterium Nitrospira marina and its proteomic response to oxygen-limited conditions
Authors: Bayer Barbara , Saito Mak A , McIlvin Matthew R , Lücker Sebastian , Moran Dawn M , Lankiewicz Thomas S , Dupont Christopher L , Santoro Alyson E
Published: November 2020

The genus Nitrospira is the most widespread group of nitrite-oxidizing bacteria and thrives in diverse natural and engineered ecosystems. Nitrospira marina Nb-295T was isolated from the ocean over 30 years ago; however, its genome has not yet been analyzed. Here, we investigated the metabolic potential of N. marina based on its complete genome sequence and performed physiological experiments to test genome-derived hypotheses. Our data confirm that N. marina benefits from additions of undefined organic carbon substrates, has adaptations to resist oxidative, osmotic, and UV light-induced stress and low dissolved pCO2, and requires exogenous vitamin B12. In addition, N. marina is able to grow chemoorganotrophically on formate, and is thus not an obligate chemolithoautotroph. We further investigated the proteomic response of N. marina to low (∼5.6 µM) O2 concentrations. The abundance of a potentially more efficient CO2-fixing pyruvate:ferredoxin oxidoreductase (POR) complex and a high-affinity cbb3-type terminal oxidase increased under O2 limitation, suggesting a role in sustaining nitrite oxidation-driven autotrophy. This putatively more O2-sensitive POR complex might be protected from oxidative damage by Cu/Zn-binding superoxide dismutase, which also increased in abundance under low O2 conditions. Furthermore, the upregulation of proteins involved in alternative energy metabolisms, including Group 3b [NiFe] hydrogenase and formate dehydrogenase, indicate a high metabolic versatility to survive conditions unfavorable for aerobic nitrite oxidation. In summary, the genome and proteome of the first marine Nitrospira isolate identifies adaptations to life in the oxic ocean and provides insights into the metabolic diversity and niche differentiation of NOB in marine environments.
Ecological drivers switch from bottom–up to top–down during model microbial community successions
Authors: Tobias-Hünefeldt Sven P , Wenley Jess , Baltar Federico , Morales Sergio E
Published: November 2020

Bottom–up selection has an important role in microbial community assembly but is unable to account for all observed variance. Other processes like top–down selection (e.g., predation) may be partially responsible for the unexplained variance. However, top–down processes and their interaction with bottom–up selective pressures often remain unexplored. We utilised an in situ marine biofilm model system to test the effects of bottom–up (i.e., substrate properties) and top–down (i.e., large predator exclusion via 100 µm mesh) selective pressures on community assembly over time (56 days). Prokaryotic and eukaryotic community compositions were monitored using 16 S and 18 S rRNA gene amplicon sequencing. Higher compositional variance was explained by growth substrate in early successional stages, but as biofilms mature, top–down predation becomes progressively more important. Wooden substrates promoted heterotrophic growth, whereas inert substrates’ (i.e., plastic, glass, tile) lack of degradable material selected for autotrophs. Early wood communities contained more mixotrophs and heterotrophs (e.g., the total abundance of Proteobacteria and Euglenozoa was 34% and 41% greater within wood compared to inert substrates). Inert substrates instead showed twice the autotrophic abundance (e.g., cyanobacteria and ochrophyta made up 37% and 10% more of the total abundance within inert substrates than in wood). Late native (non-enclosed) communities were mostly dominated by autotrophs across all substrates, whereas high heterotrophic abundance characterised enclosed communities. Late communities were primarily under top–down control, where large predators successively pruned heterotrophs. Integrating a top–down control increased explainable variance by 7–52%, leading to increased understanding of the underlying ecological processes guiding multitrophic community assembly and successional dynamics.
Venetoclax-based chemotherapy in acute and chronic myeloid neoplasms: literature survey and practice points
Authors: Gangat Naseema , Tefferi Ayalew
Published: November 2020

Venetoclax (VEN), a small-molecule inhibitor of B cell leukemia/lymphoma-2, is now FDA approved (November 2018) for use in acute myeloid leukemia (AML), specific to newly diagnosed elderly or unfit patients, in combination with a hypomethylating agent (HMA; including azacitidine or decitabine) or low-dose cytarabine. A recent phase-3 study compared VEN combined with either azacitidine or placebo, in the aforementioned study population; the complete remission (CR) and CR with incomplete count recovery (CRi) rates were 28.3% and 66.4%, respectively, and an improvement in overall survival was also demonstrated. VEN-based chemotherapy has also shown activity in relapsed/refractory AML (CR/CRi rates of 33–46%), high-risk myelodysplastic syndromes (CR 39% in treatment naïve, 5–14% in HMA failure), and blast-phase myeloproliferative neoplasm (CR 25%); in all instances, an additional fraction of patients met less stringent criteria for overall response. Regardless, venetoclax-induced remissions were often short-lived (less than a year) but long enough to allow some patients transition to allogeneic stem cell transplant. Herein, we review the current literature on the use of VEN-based combination therapy in both acute and chronic myeloid malignancies and also provide an outline of procedures we follow at our institution for drug administration, monitoring of adverse events and dose adjustments.
Aberrant transcriptional and post-transcriptional regulation of SPAG5, a YAP-TAZ-TEAD downstream effector, fuels breast cancer cell proliferation
Authors: Canu Valeria , Donzelli Sara , Sacconi Andrea , Lo Sardo Federica , Pulito Claudio , Bossel Noa , Di Benedetto Anna , Muti Paola , Botti Claudio , Domany Eytan , Bicciato Silvio , Strano Sabrina , Yarden Yosef , Blandino Giovanni
Published: November 2020

Sperm-associated antigen 5 (SPAG5) is an important driver of the cell mitotic spindle required for chromosome segregation and progression into anaphase. SPAG5 has been identified as an important proliferation marker and chemotherapy-sensitivity predictor, especially in estrogen receptor-negative breast cancer subtypes. Here, we report that SPAG5 is a direct target of miR-10b-3p, and its aberrantly high expression associates with poor disease-free survival in two large cohorts of breast cancer patients. SPAG5 depletion strongly impaired cancer cell cycle progression, proliferation, and migration. Interestingly, high expression of SPAG5 pairs with a YAP/TAZ-activated signature in breast cancer patients. Reassuringly, the depletion of YAP, TAZ, and TEAD strongly reduced SPAG5 expression and diminished its oncogenic effects. YAP, TAZ coactivators, and TEAD transcription factors are key components of the Hippo signaling pathway involved in tumor initiation, progression, and metastasis. Furthermore, we report that SPAG5 is a direct transcriptional target of TEAD/YAP/TAZ, and pharmacological targeting of YAP and TAZ severely reduces SPAG5 expression. Collectively, our data uncover an oncogenic feedback loop, comprising miR-10b-3p, SPAG5, and YAP/TAZ/TEAD, which fuels the aberrant proliferation of breast cancer.
Exosomal circ_DLGAP4 promotes diabetic kidney disease progression by sponging miR-143 and targeting ERBB3/NF-κB/MMP-2 axis
Authors: Bai Shoujun , Xiong Xiaoyan , Tang Bo , Ji Tingting , Li Xiaoying , Qu Xiaolei , Li Weiliang
Published: November 2020

Diabetic kidney disease (DKD) is closely associated with the high risk of cardiovascular disease and mortality. Exosomal circRNAs can exert significant roles in the pathology of various diseases. Nevertheless, the role of exosomal circRNAs in DKD progression remains barely known. Circular RNA DLGAP4 has been reported to be in involved in acute ischemic stroke. In our study, we found exosomal circ_DLGAP4 was increased in the exosomes isolated from HG-treated mesangial cells (MCs), DKD patients, and DKD rat models compared with the corresponding normal subjects. Then, we observed that exo-circ_DLGAP4 significantly promoted proliferation and fibrosis of MCs cells. Moreover, to study the underlying mechanism of circ_DLGAP4 in regulating DKD, bioinformatics method was consulted and miR-143 was predicted as its target. The direct correlation between miR-143 and circ_DLGAP4 was validated in MCs. MCs proliferation and fibrosis were increased by circ_DLGAP4, which could be decreased by mimic-miR-143. Next, elevated expression of Erb-b2 receptor tyrosine kinase 3 (ERBB3) is involved in various diseases. However, the function of ERBB3 in DKD development remains poorly known. Next, ERBB3 was predicted as the downstream target for miR-143. It was displayed that circ_DLGAP4 promoted proliferation and fibrosis of MCs by sponging miR-143 and regulating ERBB3/NF-κB/MMP-2 axis. Meanwhile, the loss of exo-circ_DLGAP4 induced miR-143 and repressed ERBB3/NF-κB/MMP-2 expression in MCs. Subsequently, in vivo assays were performed and it was proved that overexpression of circ_DLGAP4 markedly promoted DKD progression in vivo via modulating miR-143/ERBB3/NF-κB/MMP-2. In conclusion, we indicated that exosomal circ_DLGAP4 could prove a novel insight for DKD development.
Calcium and TRPV4 promote metastasis by regulating cytoskeleton through the RhoA/ROCK1 pathway in endometrial cancer
Authors: Li Xingchen , Cheng Yuan , Wang Zhiqi , Zhou Jingyi , Jia Yuanyuan , He Xiangjun , Zhao Lijun , Dong Yangyang , Fan Yuan , Yang Xiao , Shen Boqiang , Wu Xiaotong , Wang Jiaqi , Xiong Chunyang , Wei Lihui , Li Xiaoping , Wang Jianliu
Published: November 2020

Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable cation channel that has been associated with several types of cancer. However, its biological significance, as well as its related mechanism in endometrial cancer (EC) still remains elusive. In this study, we examined the function of calcium in EC, with a specific focus on TRPV4 and its downstream pathway. We reported here on the findings that a high level of serum ionized calcium was significantly correlated with advanced EC progression, and among all the calcium channels, TRPV4 played an essential role, with high levels of TRPV4 expression associated with cancer progression both in vitro and in vivo. Proteomic and bioinformatics analysis revealed that TRPV4 was involved in cytoskeleton regulation and Rho protein pathway, which regulated EC cell migration. Mechanistic investigation demonstrated that TRPV4 and calcium influx acted on the cytoskeleton via the RhoA/ROCK1 pathway, ending with LIMK/cofilin activation, which had an impact on F-actin and paxillin (PXN) levels. Overall, our findings indicated that ionized serum calcium level was significantly associated with poor outcomes and calcium channel TRPV4 should be targeted to improve therapeutic and preventive strategies in EC.
Correction: Targeting tumor cell-derived CCL2 as a strategy to overcome Bevacizumab resistance in ETV5+ colorectal cancer
Authors: Feng Haoran , Liu Kun , Shen Xiaonan , Liang Juyong , Wang Changgang , Qiu Weihua , Cheng Xi , Zhao Ren
Published: November 2020

A Correction to this paper has been published: https://doi.org/10.1038/s41419-020-03208-z
Ionizing radiation results in a mixture of cellular outcomes including mitotic catastrophe, senescence, methuosis, and iron-dependent cell death
Authors: Adjemian Sandy , Oltean Teodora , Martens Sofie , Wiernicki Bartosz , Goossens Vera , Vanden Berghe Tom , Cappe Benjamin , Ladik Maria , Riquet Franck B. , Heyndrickx Liesbeth , Bridelance Jolien , Vuylsteke Marnik , Vandecasteele Katrien , Vandenabeele Peter
Published: November 2020

Radiotherapy is commonly used as a cytotoxic treatment of a wide variety of tumors. Interestingly, few case reports underlined its potential to induce immune-mediated abscopal effects, resulting in regression of metastases, distant from the irradiated site. These observations are rare, and apparently depend on the dose used, suggesting that dose-related cellular responses may be involved in the distant immunogenic responses. Ionizing radiation (IR) has been reported to elicit immunogenic apoptosis, necroptosis, mitotic catastrophe, and senescence. In order to link a cellular outcome with a particular dose of irradiation, we performed a systematic study in a panel of cell lines on the cellular responses at different doses of X-rays. Remarkably, we observed that all cell lines tested responded in a similar fashion to IR with characteristics of mitotic catastrophe, senescence, lipid peroxidation, and caspase activity. Iron chelators (but not Ferrostatin-1 or vitamin E) could prevent the formation of lipid peroxides and cell death induced by IR, suggesting a crucial role of iron-dependent cell death during high-dose irradiation. We also show that in K-Ras-mutated cells, IR can induce morphological features reminiscent of methuosis, a cell death modality that has been recently described following H-Ras or K-Ras mutation overexpression.
Biallelic loss of function NEK3 mutations deacetylate α-tubulin and downregulate NUP205 that predispose individuals to cilia-related abnormal cardiac left–right patterning
Authors: Zhang Yuan , Chen Weicheng , Zeng Weijia , Lu Zhouping , Zhou Xiangyu
Published: November 2020

Defective left–right (LR) organization involving abnormalities in cilia ultrastructure causes laterality disorders including situs inversus (SI) and heterotaxy (Htx) with the prevalence approximately 1/10,000 births. In this study, we describe two unrelated family trios with abnormal cardiac LR patterning. Through whole-exome sequencing (WES), we identified compound heterozygous mutations (c.805-1G >C; p. Ile269GlnfsTer8/c.1117dupA; p.Thr373AsnfsTer19) (c.29T>C; p.Ile10Thr/c.356A>G; p.His119Arg) of NEK3, encoding a NIMA (never in mitosis A)-related kinase, in two affected individuals, respectively. Protein levels of NEK3 were abrogated in Patient-1 with biallelic loss-of function (LoF) NEK3 mutations that causes premature stop codon. Subsequence transcriptome analysis revealed that NNMT (nicotinamide N-methyltransferase) and SIRT2 (sirtuin2) was upregulated by NEK3 knockdown in human retinal pigment epithelial (RPE) cells in vitro, which associates α-tubulin deacetylation by western blot and immunofluorescence. Transmission electron microscopy (TEM) analysis further identified defective ciliary ultrastructure in Patient-1. Furthermore, inner ring components of nuclear pore complex (NPC) including nucleoporin (NUP)205, NUP188, and NUP155 were significantly downregulated in NEK3-silenced cells. In conclusion, we identified biallelic mutations of NEK3 predispose individual to abnormal cardiac left–right patterning via SIRT2-mediated α-tubulin deacetylation and downregulation of inner ring nucleoporins. Our study suggested that NEK3 could be a candidate gene for human ciliopathies.
Strain-induced creation and switching of anion vacancy layers in perovskite oxynitrides
Authors: Yamamoto Takafumi , Chikamatsu Akira , Kitagawa Shunsaku , Izumo Nana , Yamashita Shunsuke , Takatsu Hiroshi , Ochi Masayuki , Maruyama Takahiro , Namba Morito , Sun Wenhao , Nakashima Takahide , Takeiri Fumitaka , Fujii Kotaro , Yashima Masatomo , Sugisawa Yuki , Sano Masahito , Hirose Yasushi , Sekiba Daiichiro , Brown Craig M. , Honda Takashi , Ikeda Kazutaka , Otomo Toshiya , Kuroki Kazuhiko , Ishida Kenji , Mori Takao , Kimoto Koji , Hasegawa Tetsuya , Kageyama Hiroshi
Published: November 2020

Perovskite oxides can host various anion-vacancy orders, which greatly change their properties, but the order pattern is still difficult to manipulate. Separately, lattice strain between thin film oxides and a substrate induces improved functions and novel states of matter, while little attention has been paid to changes in chemical composition. Here we combine these two aspects to achieve strain-induced creation and switching of anion-vacancy patterns in perovskite films. Epitaxial SrVO3 films are topochemically converted to anion-deficient oxynitrides by ammonia treatment, where the direction or periodicity of defect planes is altered depending on the substrate employed, unlike the known change in crystal orientation. First-principles calculations verified its biaxial strain effect. Like oxide heterostructures, the oxynitride has a superlattice of insulating and metallic blocks. Given the abundance of perovskite families, this study provides new opportunities to design superlattices by chemically modifying simple perovskite oxides with tunable anion-vacancy patterns through epitaxial lattice strain.
Non-Abelian Bloch oscillations in higher-order topological insulators
Authors: Di Liberto M. , Goldman N. , Palumbo G.
Published: November 2020

Bloch oscillations (BOs) are a fundamental phenomenon by which a wave packet undergoes a periodic motion in a lattice when subjected to a force. Observed in a wide range of synthetic systems, BOs are intrinsically related to geometric and topological properties of the underlying band structure. This has established BOs as a prominent tool for the detection of Berry-phase effects, including those described by non-Abelian gauge fields. In this work, we unveil a unique topological effect that manifests in the BOs of higher-order topological insulators through the interplay of non-Abelian Berry curvature and quantized Wilson loops. It is characterized by an oscillating Hall drift synchronized with a topologically-protected inter-band beating and a multiplied Bloch period. We elucidate that the origin of this synchronization mechanism relies on the periodic quantum dynamics of Wannier centers. Our work paves the way to the experimental detection of non-Abelian topological properties through the measurement of Berry phases and center-of-mass displacements.
Altered conformational sampling along an evolutionary trajectory changes the catalytic activity of an enzyme
Authors: Kaczmarski Joe A. , Mahawaththa Mithun C. , Feintuch Akiva , Clifton Ben E. , Adams Luke A. , Goldfarb Daniella , Otting Gottfried , Jackson Colin J.
Published: November 2020

Several enzymes are known to have evolved from non-catalytic proteins such as solute-binding proteins (SBPs). Although attention has been focused on how a binding site can evolve to become catalytic, an equally important question is: how do the structural dynamics of a binding protein change as it becomes an efficient enzyme? Here we performed a variety of experiments, including propargyl-DO3A-Gd(III) tagging and double electron–electron resonance (DEER) to study the rigid body protein dynamics of reconstructed evolutionary intermediates to determine how the conformational sampling of a protein changes along an evolutionary trajectory linking an arginine SBP to a cyclohexadienyl dehydratase (CDT). We observed that primitive dehydratases predominantly populate catalytically unproductive conformations that are vestiges of their ancestral SBP function. Non-productive conformational states, including a wide-open state, are frozen out of the conformational landscape via remote mutations, eventually leading to extant CDT that exclusively samples catalytically relevant compact states. These results show that remote mutations can reshape the global conformational landscape of an enzyme as a mechanism for increasing catalytic activity.
ETNK1 mutations induce a mutator phenotype that can be reverted with phosphoethanolamine
Authors: Fontana Diletta , Mauri Mario , Renso Rossella , Docci Mattia , Crespiatico Ilaria , Røst Lisa M. , Jang Mi , Niro Antonio , D’Aliberti Deborah , Massimino Luca , Bertagna Mayla , Zambrotta Giovanni , Bossi Mario , Citterio Stefania , Crescenzi Barbara , Fanelli Francesca , Cassina Valeria , Corti Roberta , Salerno Domenico , Nardo Luca , Chinello Clizia , Mantegazza Francesco , Mecucci Cristina , Magni Fulvio , Cavaletti Guido , Bruheim Per , Rea Delphine , Larsen Steen , Gambacorti-Passerini Carlo , Piazza Rocco
Published: November 2020

Recurrent somatic mutations in ETNK1 (Ethanolamine-Kinase-1) were identified in several myeloid malignancies and are responsible for a reduced enzymatic activity. Here, we demonstrate in primary leukemic cells and in cell lines that mutated ETNK1 causes a significant increase in mitochondrial activity, ROS production, and Histone H2AX phosphorylation, ultimately driving the increased accumulation of new mutations. We also show that phosphoethanolamine, the metabolic product of ETNK1, negatively controls mitochondrial activity through a direct competition with succinate at mitochondrial complex II. Hence, reduced intracellular phosphoethanolamine causes mitochondria hyperactivation, ROS production, and DNA damage. Treatment with phosphoethanolamine is able to counteract complex II hyperactivation and to restore a normal phenotype.
Polycomb group-mediated histone H2A monoubiquitination in epigenome regulation and nuclear processes
Authors: Barbour Haithem , Daou Salima , Hendzel Michael , Affar El Bachir
Published: November 2020

Histone posttranslational modifications are key regulators of chromatin-associated processes including gene expression, DNA replication and DNA repair. Monoubiquitinated histone H2A, H2Aub (K118 in Drosophila or K119 in vertebrates) is catalyzed by the Polycomb group (PcG) repressive complex 1 (PRC1) and reversed by the PcG-repressive deubiquitinase (PR-DUB)/BAP1 complex. Here we critically assess the current knowledge regarding H2Aub deposition and removal, its crosstalk with PcG repressive complex 2 (PRC2)-mediated histone H3K27 methylation, and the recent attempts toward discovering its readers and solving its enigmatic functions. We also discuss mounting evidence of the involvement of H2A ubiquitination in human pathologies including cancer, while highlighting some knowledge gaps that remain to be addressed.
SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease
Authors: Gut Philipp , Matilainen Sanna , Meyer Jesse G. , Pällijeff Pieti , Richard Joy , Carroll Christopher J. , Euro Liliya , Jackson Christopher B. , Isohanni Pirjo , Minassian Berge A. , Alkhater Reem A. , Østergaard Elsebet , Civiletto Gabriele , Parisi Alice , Thevenet Jonathan , Rardin Matthew J. , He Wenjuan , Nishida Yuya , Newman John C. , Liu Xiaojing , Christen Stefan , Moco Sofia , Locasale Jason W. , Schilling Birgit , Suomalainen Anu , Verdin Eric
Published: November 2020

Mitochondrial acyl-coenzyme A species are emerging as important sources of protein modification and damage. Succinyl-CoA ligase (SCL) deficiency causes a mitochondrial encephalomyopathy of unknown pathomechanism. Here, we show that succinyl-CoA accumulates in cells derived from patients with recessive mutations in the tricarboxylic acid cycle (TCA) gene succinyl-CoA ligase subunit-β (SUCLA2), causing global protein hyper-succinylation. Using mass spectrometry, we quantify nearly 1,000 protein succinylation sites on 366 proteins from patient-derived fibroblasts and myotubes. Interestingly, hyper-succinylated proteins are distributed across cellular compartments, and many are known targets of the (NAD+)-dependent desuccinylase SIRT5. To test the contribution of hyper-succinylation to disease progression, we develop a zebrafish model of the SCL deficiency and find that SIRT5 gain-of-function reduces global protein succinylation and improves survival. Thus, increased succinyl-CoA levels contribute to the pathology of SCL deficiency through post-translational modifications.
Unconventional Hall response in the quantum limit of HfTe5
Authors: Galeski S. , Zhao X. , Wawrzyńczak R. , Meng T. , Förster T. , Lozano P. M. , Honnali S. , Lamba N. , Ehmcke T. , Markou A. , Li. Q. , Gu G. , Zhu W. , Wosnitza J. , Felser C. , Chen G. F. , Gooth J.
Published: November 2020

Interacting electrons confined to their lowest Landau level in a high magnetic field can form a variety of correlated states, some of which manifest themselves in a Hall effect. Although such states have been predicted to occur in three-dimensional semimetals, a corresponding Hall response has not yet been experimentally observed. Here, we report the observation of an unconventional Hall response in the quantum limit of the bulk semimetal HfTe5, adjacent to the three-dimensional quantum Hall effect of a single electron band at low magnetic fields. The additional plateau-like feature in the Hall conductivity of the lowest Landau level is accompanied by a Shubnikov-de Haas minimum in the longitudinal electrical resistivity and its magnitude relates as 3/5 to the height of the last plateau of the three-dimensional quantum Hall effect. Our findings are consistent with strong electron-electron interactions, stabilizing an unconventional variant of the Hall effect in a three-dimensional material in the quantum limit.
Prebiotically-relevant low polyion multivalency can improve functionality of membraneless compartments
Authors: Cakmak Fatma Pir , Choi Saehyun , Meyer McCauley O. , Bevilacqua Philip C. , Keating Christine D.
Published: November 2020

Multivalent polyions can undergo complex coacervation, producing membraneless compartments that accumulate ribozymes and enhance catalysis, and offering a mechanism for functional prebiotic compartmentalization in the origins of life. Here, we evaluate the impact of lower, more prebiotically-relevant, polyion multivalency on the functional performance of coacervates as compartments. Positively and negatively charged homopeptides with 1–100 residues and adenosine mono-, di-, and triphosphate nucleotides are used as model polyions. Polycation/polyanion pairs are tested for coacervation, and resulting membraneless compartments are analyzed for salt resistance, ability to provide a distinct internal microenvironment (apparent local pH, RNA partitioning), and effect on RNA structure formation. We find that coacervates formed by phase separation of the shorter polyions more effectively generated distinct pH microenvironments, accumulated RNA, and preserved duplexes than those formed by longer polyions. Hence, coacervates formed by reduced multivalency polyions are not only viable as functional compartments for prebiotic chemistries, they can outperform higher molecular weight analogues.
Nanoparticles suppress fluid instabilities in the thermal drawing of ultralong nanowires
Authors: Hwang Injoo , Guan Zeyi , Cao Chezheng , Tang Wenliang , Chui Chi On , Li Xiaochun
Published: November 2020

Ultra-long metal nanowires and their facile fabrication have been long sought after as they promise to offer substantial improvements of performance in numerous applications. However, ultra-long metal ultrafine/nanowires are beyond the capability of current manufacturing techniques, which impose limitations on their size and aspect ratio. Here we show that the limitations imposed by fluid instabilities with thermally drawn nanowires can be alleviated by adding tungsten carbide nanoparticles to the metal core to arrive at wire lengths more than 30 cm with diameters as low as 170 nm. The nanoparticles support thermal drawing in two ways, by increasing the viscosity of the metal and lowering the interfacial energy between the boron silicate and zinc phase. This mechanism of suppressing fluid instability by nanoparticles not only enables a scalable production of ultralong metal nanowires, but also serves for widespread applications in other fluid-related fields.
Publisher Correction: Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma
Authors: Marchetto Aruna , Ohmura Shunya , Orth Martin F. , Knott Maximilian M. L. , Colombo Maria V. , Arrigoni Chiara , Bardinet Victor , Saucier David , Wehweck Fabienne S. , Li Jing , Stein Stefanie , Gerke Julia S. , Baldauf Michaela C. , Musa Julian , Dallmayer Marlene , Romero-Pérez Laura , Hölting Tilman L. B. , Amatruda James F. , Cossarizza Andrea , Henssen Anton G. , Kirchner Thomas , Moretti Matteo , Cidre-Aranaz Florencia , Sannino Giuseppina , Grünewald Thomas G. P.
Published: November 2020

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20017-2
Mitochondrial dysfunction in neurological disorders: Exploring mitochondrial transplantation
Authors: Norat Pedro , Soldozy Sauson , Sokolowski Jennifer D. , Gorick Catherine M. , Kumar Jeyan S. , Chae Youngrok , Yağmurlu Kaan , Prada Francesco , Walker Melanie , Levitt Michael R. , Price Richard J. , Tvrdik Petr , Kalani M. Yashar S.
Published: November 2020

Mitochondria are fundamental for metabolic homeostasis in all multicellular eukaryotes. In the nervous system, mitochondria-generated adenosine triphosphate (ATP) is required to establish appropriate electrochemical gradients and reliable synaptic transmission. Notably, several mitochondrial defects have been identified in central nervous system disorders. Membrane leakage and electrolyte imbalances, pro-apoptotic pathway activation, and mitophagy are among the mechanisms implicated in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s disease, as well as ischemic stroke. In this review, we summarize mitochondrial pathways that contribute to disease progression. Further, we discuss pathological states that damaged mitochondria impose on normal nervous system processes and explore new therapeutic approaches to mitochondrial diseases.
Polygenic risk scores for late smoking initiation associated with the risk of schizophrenia
Authors: Ohi Kazutaka , Nishizawa Daisuke , Muto Yukimasa , Sugiyama Shunsuke , Hasegawa Junko , Soda Midori , Kitaichi Kiyoyuki , Hashimoto Ryota , Shioiri Toshiki , Ikeda Kazutaka
Published: November 2020

Patients with schizophrenia display characteristic smoking-related behaviors and genetic correlations between smoking behaviors and schizophrenia have been identified in European individuals. However, the genetic etiology of the association remains to be clarified. The present study investigated transethnic genetic overlaps between European-based smoking behaviors and the risk of Japanese schizophrenia by conducting polygenic risk score (PRS) analyses. Large-scale European genome-wide association study (GWAS) datasets (n = 24,114–74,035) related to four smoking-related intermediate phenotypes [(i) smoking initiation, (ii) age at smoking initiation, (iii) smoking quantity, and (iv) smoking cessation] were utilized as discovery samples. PRSs derived from these discovery GWASs were calculated for 332 Japanese subjects [schizophrenia patients, their unaffected first-degree relatives (FRs), and healthy controls (HCs)] as a target sample. Based on GWASs of European smoking phenotypes, we investigated the effects of PRSs on smoking phenotypes and the risk of schizophrenia in the Japanese population. Of the four smoking-related behaviors, the PRSs for age at smoking initiation in Europeans significantly predicted the age at smoking initiation (R2 = 0.049, p = 0.026) and the PRSs for smoking cessation significantly predicted the smoking cessation (R2 = 0.092, p = 0.027) in Japanese ever-smokers. Furthermore, the PRSs related to age at smoking initiation in Europeans were higher in Japanese schizophrenia patients than in the HCs and those of the FRs were intermediate between those of patients with schizophrenia and those of the HCs (R2 = 0.015, p = 0.015). In our target subjects, patients with schizophrenia had a higher mean age at smoking initiation (p = 0.018) and rate of daily smoking initiation after age 20 years (p = 0.023) compared with the HCs. A total of 60.6% of the patients started to smoke before the onset of schizophrenia. These findings suggest that genetic factors affecting late smoking initiation are associated with the risk of schizophrenia.
LILBID laser dissociation curves: a mass spectrometry-based method for the quantitative assessment of dsDNA binding affinities
Authors: Young Phoebe , Hense Genia , Immer Carina , Wöhnert Jens , Morgner Nina
Published: November 2020

One current goal in native mass spectrometry is the assignment of binding affinities to noncovalent complexes. Here we introduce a novel implementation of the existing laser-induced liquid bead ion desorption (LILBID) mass spectrometry method: this new method, LILBID laser dissociation curves, assesses binding strengths quantitatively. In all LILBID applications, aqueous sample droplets are irradiated by 3 µm laser pulses. Variation of the laser energy transferred to the droplet during desorption affects the degree of complex dissociation. In LILBID laser dissociation curves, laser energy transfer is purposely varied, and a binding affinity is calculated from the resulting complex dissociation. A series of dsDNAs with different binding affinities was assessed using LILBID laser dissociation curves. The binding affinity results from the LILBID laser dissociation curves strongly correlated with the melting temperatures from UV melting curves and with dissociation constants from isothermal titration calorimetry, standard solution phase methods. LILBID laser dissociation curve data also showed good reproducibility and successfully predicted the melting temperatures and dissociation constants of three DNA sequences. LILBID laser dissociation curves are a promising native mass spectrometry binding affinity method, with reduced time and sample consumption compared to melting curves or titrations.