bluuebunny/crossref_metadata_2025 huggingface dataset:
On Cloud Studies
Authors: Shayya Fadi , Walker Stephen
Published: April 2022

Suspend your disbelief for a second, and ask yourself: what is architectural about clouds? For many researchers, practitioners and students of the field, a concern with the architectural is a concern with stable forms, organised layouts, inert materials, and recognisable cultural expressions. Yet in recent decades, relational and process-oriented approaches to analysing ‘the social’ have advanced architectural concerns with intensities of human and nonhuman flows, regulating energy exchanges and microclimatic milieux, and territorialising space through built enclosures and envelopes. The notion of flows in architecture is not only a philosophical category but a practical and programmatic one.
‘Irrational Nuances’: Interpreting Stockhausen'sKlavierstück I
Authors: JONES GABRIEL
Published: April 2022

The performance practice of European serial music has long been misunderstood. This article uses Stockhausen'sKlavierstück I(1952–3) as a lens through which to view the realities of this practice, drawing on close contextual analysis of the affordances of the score and the now significant corpus of recordings. These findings are used to extend M. J. Grant's view of serial aesthetics and to provide a practical basis for what she calls ‘serial listening’. Three principal styles of performance are identified and attendant modes of listening suggested, relating to the non-thematic principles and hermeneutic contexts of serial music, which include the embodied response of the performer to defamiliarized musical material and the nascent dialectic of instrumental and electronic composition. This investigation – informing serious judgements of value and taste – has broader implications for the development of Stockhausen's notation and temporal theory in the 1950s and for the performance practice of new music.
Magnesium Isotope Fractionation During Silicate Weathering: Constrains From Riverine Mg Isotopic Composition in the Southeastern Coastal Region of China
Authors: Zhao Tong , Liu Wenjing , Xu Zhifang
Published: April 2022

Mg isotopic composition of river water is dominantly controlled by the dissolution of both silicate and carbonate sources and a series of biogeochemical processes. However, the relative importance of source and isotopic fractionation control at basin/global scale is poorly constrained. This study presents the Mg isotopic composition of river water and suspended load in river draining silicate rocks in the southeastern coastal region of China. The fractionation effect of silicate weathering on Mg isotopes is documented in both dissolved and solid phases. Mg isotopic composition of rivers draining silicate rocks exhibit ∼0.3‰ δ26Mg difference, the release of Mg from Mg‐rich minerals and formation of clays are the dominant processes controlling Mg isotopic composition of river water. The variation of Mg isotopic compositions of suspended load is closely related to the species of secondary clays (illite and chlorite); the fractionation direction during illite and chlorite formation contrasts, isotopically heavy Mg preferentially incorporates into illite while light Mg incorporates into chlorite. Furthermore, the negative correlation between 1/Mg and Mg isotopic compositions of river water indicates the Mg re‐distribution and isotope fractionation between weathering solutions and secondary clays during silicate weathering. Such isotope fractionation‐induced Mg isotope variations could be employed to estimate the contribution of Mg from silicate weathering at basin/continental scale.
Modeling Subsurface Hydrogen Storage With Transport Properties From Entropy Scaling Using the PC‐SAFT Equation of State
Authors: Eller Johannes , Sauerborn Tim , Becker Beatrix , Buntic Ivan , Gross Joachim , Helmig Rainer
Published: April 2022

Hydrogen is a promising alternative to carbon based energy carriers and may be stored in large quantities in subsurface storage deposits. This work assesses the impact of static (density and phase equilibria) and dynamic (viscosity and diffusion coefficients) properties on the pressure field during the injection and extraction of hydrogen in the porous subsurface. In a first step, we derive transport properties for water, hydrogen and their mixture using the Perturbed‐Chain Statistical Associating Fluid Theory equation of state in combination with an entropy scaling approach and compare model predictions to alternative models from the literature. Our model compares excellently to experimental transport coefficients and models from literature with a higher number of adjustable parameters, such as GERG2008, and shows a clear improvement over empirical correlations for transport coefficients of hydrogen. In a second step, we determine the effect of further model reduction by comparing our against a much simpler model applying empirical transport coefficients from the literature. For this purpose, hydrogen is periodically injected into and extracted out of a dome‐shaped porous aquifer under a caprock. Our results show that density and viscosity of hydrogen have the highest impact on the pressure field, and that a thermodynamic model like the new model presented here is essential for modeling the storage aquifer, while keeping the number of coefficients at a minimum. In diffusion‐dominated settings such as the diffusion of hydrogen through the caprock, our developed diffusion coefficients show a much improved dependence on temperature and pressure, leading to a more accurate approximation of the diffusive fluxes.
Realization of quantum secure direct communication over 100 km fiber with time-bin and phase quantum states
Authors: Zhang Haoran , Sun Zhen , Qi Ruoyang , Yin Liuguo , Long Gui-Lu , Lu Jianhua
Published: April 2022

Rapid progress has been made in quantum secure direct communication in recent years. For practical application, it is important to improve the performances, such as the secure information rate and the communication distance. In this paper, we report an elaborate physical system design and protocol with much enhanced performance. This design increased the secrecy capacity greatly by achieving an ultra-low quantum bit error rate of <0.1%, one order of magnitude smaller than that of existing systems. Compared to previous systems, the proposed scheme uses photonic time-bin and phase states, operating at 50 MHz of repetition rate, which can be easily upgraded to over 1 GHz using current on-the-shelf technology. The results of our experimentation demonstrate that the proposed system can tolerate more channel loss, from 5.1 dB, which is about 28.3 km in fiber in the previous scheme, to 18.4 dB, which corresponds to fiber length of 102.2 km. Thus, the experiment shows that intercity quantum secure direct communication through fiber is feasible with present-day technology.
Convergent selective signaling impairment exposes the pathogenicity of latrophilin-3 missense variants linked to inheritable ADHD susceptibility
Authors: Moreno-Salinas Ana L. , Holleran Brian J. , Ojeda-Muñiz Estefania Y. , Correoso-Braña Kerlys G. , Ribalta-Mena Sheila , Ovando-Zambrano José-Carlos , Leduc Richard , Boucard Antony A.
Published: April 2022

Latrophilin-3 (Lphn3; also known as ADGRL3) is a member of the adhesion G Protein Coupled Receptor subfamily, which participates in the stabilization and maintenance of neuronal networks by mediating intercellular adhesion through heterophilic interactions with transmembrane ligands. Polymorphisms modifying the Lphn3 gene are associated with attention-deficit/hyperactivity disorder (ADHD) in children and its persistence into adulthood. How these genetic alterations affect receptor function remains unknown. Here, we conducted the functional validation of distinct ADHD-related Lphn3 variants bearing mutations in the receptor’s adhesion motif-containing extracellular region. We found that all variants tested disrupted the ability of Lphn3 to stabilize intercellular adhesion in a manner that was distinct between ligands classes, but which did not depend on ligand-receptor interaction parameters, thus pointing to altered intrinsic receptor signaling properties. Using G protein signaling biosensors, we determined that Lphn3 couples to Gαi1, Gαi2, Gαs, Gαq, and Gα13. However, all ADHD-related receptor variants consistently lacked intrinsic as well as ligand-dependent Gα13 coupling efficiency while maintaining unaltered coupling to Gαi, Gαs, and Gαq. Consistent with these alterations, actin remodeling functions as well as actin-relevant RhoA signaling normally displayed by the constitutively active Lphn3 receptor were impeded by select receptor variants, thus supporting additional signaling defects. Taken together, our data point to Gα13 selective signaling impairments as representing a disease-relevant pathogenicity pathway that can be inherited through Lphn3 gene polymorphisms. This study highlights the intricate interplay between Lphn3 GPCR functions and the actin cytoskeleton in modulating neurodevelopmental cues related to ADHD etiology.
Neural responses to reward anticipation and feedback in adult and adolescent cannabis users and controls
Authors: Skumlien Martine , Mokrysz Claire , Freeman Tom P. , Wall Matthew B. , Bloomfield Michael , Lees Rachel , Borissova Anna , Petrilli Kat , Carson James , Coughlan Tiernan , Ofori Shelan , Langley Christelle , Sahakian Barbara J. , Curran H. Valerie , Lawn Will
Published: April 2022

Chronic use of drugs may alter the brain’s reward system, though the extant literature concerning long-term cannabis use and neural correlates of reward processing has shown mixed results. Adolescents may be more vulnerable to the adverse effects of cannabis than adults; however, this has not been investigated for reward processing. As part of the ‘CannTeen’ study, in the largest functional magnetic resonance imaging study of reward processing and cannabis use to date, we investigated reward anticipation and feedback in 125 adult (26–29 years) and adolescent (16–17 years) cannabis users (1–7 days/week cannabis use) and gender- and age-matched controls, using the Monetary Incentive Delay task. Blood-oxygen-level-dependent responses were examined using region of interest (ROI) analyses in the bilateral ventral striatum for reward anticipation and right ventral striatum and left ventromedial prefrontal cortex for feedback, and exploratory whole-brain analyses. Results showed no User-Group or User-Group × Age-Group effects during reward anticipation or feedback in pre-defined ROIs. These null findings were supported by post hoc Bayesian analyses. However, in the whole-brain analysis, cannabis users had greater feedback activity in the prefrontal and inferior parietal cortex compared to controls. In conclusion, cannabis users and controls had similar neural responses during reward anticipation and in hypothesised reward-related regions during reward feedback. The whole-brain analysis revealed tentative evidence of greater fronto-parietal activity in cannabis users during feedback. Adolescents showed no increased vulnerability compared with adults. Overall, reward anticipation and feedback processing appear spared in adolescent and adult cannabis users, but future longitudinal studies are needed to corroborate this.
eccDNAdb: a database of extrachromosomal circular DNA profiles in human cancers
Authors: Peng Li , Zhou Nan , Zhang Chao-Yang , Li Guan-Cheng , Yuan Xiao-Qing
Published: April 2022

Extrachromosomal circular DNA (eccDNA) elements are circular DNA molecules that are derived from but are independent of chromosomal DNA. EccDNA is emerging as a rising star because of its ubiquitous existence in cancers and its crucial role in oncogene amplification and tumor progression. In the present study, whole-genome sequencing (WGS) data of cancer samples were downloaded from public repositories. Afterwards, eccDNAs were identified from WGS data via bioinformatic analyses. To leverage database coverage, eccDNAs were also collected by manual curation of literatures. Gene expression and clinical data were downloaded from TCGA and CCLE and then used to investigate the roles of eccDNAs in cancers. Finally, the first integrated database of eccDNAs, eccDNAdb, was developed. eccDNAdb currently includes 1270 eccDNAs, which were identified in 480 samples (of 42 cancers) after analyzing a total number of 3395 tumor samples (of 57 cancers) including patient tissues, patient-derived xenografts, and cancer cell lines. A total number of 54,901 eccDNA genes were annotated and included in the database as well. With the integration of gene expression, clinical information and chromatin accessibility data, eccDNAdb enables users to easily determine the biological function and clinical relevance of eccDNAs in human cancers. In conclusion, eccDNAdb is freely accessible at http://www.eccdnadb.org. To our knowledge, eccDNAdb is the first database in the eccDNA research field. It is expected to provide insight for novel cancer therapies.
Cannabis suppresses antitumor immunity by inhibiting JAK/STAT signaling in T cells through CNR2
Authors: Xiong Xinxin , Chen Siyu , Shen Jianfei , You Hua , Yang Han , Yan Chao , Fang Ziqian , Zhang Jianeng , Cai Xiuyu , Dong Xingjun , Kang Tiebang , Li Wende , Zhou Penghui
Published: April 2022

The combination of immune checkpoint blockade (ICB) with chemotherapy significantly improves clinical benefit of cancer treatment. Since chemotherapy is often associated with adverse events, concomitant treatment with drugs managing side effects of chemotherapy is frequently used in the combination therapy. However, whether these ancillary drugs could impede immunotherapy remains unknown. Here, we showed that ∆9-tetrahydrocannabinol (THC), the key ingredient of drugs approved for the treatment of chemotherapy-caused nausea, reduced the therapeutic effect of PD-1 blockade. The endogenous cannabinoid anandamide (AEA) also impeded antitumor immunity, indicating an immunosuppressive role of the endogenous cannabinoid system (ECS). Consistently, high levels of AEA in the sera were associated with poor overall survival in cancer patients. We further found that cannabinoids impaired the function of tumor-specific T cells through CNR2. Using a knock-in mouse model expressing a FLAG-tagged Cnr2 gene, we discovered that CNR2 binds to JAK1 and inhibits the downstream STAT signaling in T cells. Taken together, our results unveiled a novel mechanism of the ECS-mediated suppression on T-cell immunity against cancer, and suggest that cannabis and cannabinoid drugs should be avoided during immunotherapy.
Maternal levels of acute phase proteins in early pregnancy and risk of autism spectrum disorders in offspring
Authors: Brynge Martin , Gardner Renee , Sjöqvist Hugo , Karlsson Håkan , Dalman Christina
Published: April 2022

Previous research supports a contribution of early-life immune disturbances in the etiology of autism spectrum disorders (ASD). Biomarker studies of the maternal innate (non-adaptive) immune status related to ASD risk have focused on one of the acute phase proteins (APP), C-reactive protein (CRP), with conflicting results. We evaluated levels of eight different APP in first-trimester maternal serum samples, from 318 mothers to ASD cases and 429 mothers to ASD-unaffected controls, nested within the register-based Stockholm Youth Cohort. While no overall associations between high levels of APP and ASD were observed, associations varied across diagnostic sub-groups based on co-occurring conditions. Maternal levels of CRP in the lowest compared to the middle tertile were associated with increased risk of ASD without ID or ADHD in offspring (OR = 1.92, 95% CI 1.08–3.42). Further, levels of maternal ferritin in the lowest (OR = 1.78, 95% CI 1.18–2.69) and highest (OR = 1.64, 95% CI 1.11–2.43) tertiles were associated with increased risk of any ASD diagnosis in offspring, with stronger associations still between the lowest (OR = 3.81, 95% CI 1.91–7.58) and highest (OR = 3.36, 95% CI 1.73–6.53) tertiles of ferritin and risk of ASD with ID. The biological interpretation of lower CRP levels among mothers to ASD cases is not clear but might be related to the function of the maternal innate immune system. The finding of aberrant levels of ferritin conferring risk of ASD-phenotypes indicates a plausibly important role of iron during neurodevelopment.
Exosomal HMGA2 protein from EBV-positive NPC cells destroys vascular endothelial barriers and induces endothelial-to-mesenchymal transition to promote metastasis
Authors: Li Deng-Ke , Chen Xing-Rui , Wang Li-Na , Wang Jia-Hong , Li Ji-Ke , Zhou Zi-Ying , Li Xin , Cai Lin-Bo , Zhong Shui-Sheng , Zhang Jing-Jing , Zeng Yu-Mei , Zhang Qian-Bing , Fu Xiao-Yan , Lyu Xiao-Ming , Li Min-Ying , Huang Zhong-Xi , Yao Kai-Tai
Published: April 2022

Increased vascular permeability facilitates metastasis. Cancer-secreted exosomes are emerging mediators of cancer-host crosstalk. Epstein-Barr virus (EBV), identified as the first human tumor-associated virus, plays a crucial role in metastatic tumors, especially in nasopharyngeal carcinoma (NPC). To date, whether and how exosomes from EBV-infected NPC cells affect vascular permeability remains unclear. Here, we show that exosomes from EBV-positive NPC cells, but not exosomes from EBV-negative NPC cells, destroy endothelial cell tight junction (TJ) proteins, which are natural barriers against metastasis, and promote endothelial-to-mesenchymal transition (EndMT) in endothelial cells. Proteomic analysis revealed that the level of HMGA2 protein was higher in exosomes derived from EBV-positive NPC cells compared with that in exosomes derived from EBV-negative NPC cells. Depletion of HMGA2 in exosomes derived from EBV-positive NPC cells attenuates endothelial cell dysfunction and tumor cell metastasis. In contrast, exosomes from HMGA2 overexpressing EBV-negative NPC cells promoted these processes. Furthermore, we showed that HMGA2 upregulates the expression of Snail, which contributes to TJ proteins reduction and EndMT in endothelial cells. Moreover, the level of HMGA2 in circulating exosomes is significantly higher in NPC patients with metastasis than in those without metastasis and healthy negative controls, and the level of HMGA2 in tumor cells is associated with TJ and EndMT protein expression in endothelial cells. Collectively, our findings suggest exosomal HMGA2 from EBV-positive NPC cells promotes tumor metastasis by targeting multiple endothelial TJ and promoting EndMT, which highlights secreted HMGA2 as a potential therapeutic target and a predictive marker for NPC metastasis.
Harnessing Rift Valley fever virus NSs gene for cancer gene therapy
Authors: Davis Alicia M. , Scott Tristan A. , Morris Kevin V.
Published: April 2022

One of the greatest challenges in the treatment of cancer is tumor heterogeneity which results in differential responses to chemotherapy and drugs that work through a single pathway. A therapeutic agent that targets cancer cells for death through multiple mechanisms could be advantageous as a broad inhibitor for many types of cancers and the heterogeneous alterations they possess. Several viral proteins have been exploited for antiproliferative and apoptotic effect in cancer cells by disrupting critical survival pathways. Here, we report the use of the non-structural protein on the S segment (NSs) gene from the Rift Valley fever virus (RVFV) to induce cancer cell death. NSs has immune evasion functions in the context of RVFV with many of these functions affecting proliferation pathways and DNA damage signaling, which could be leveraged against cancer cells. We find that expression of NSs in multiple cancer cell lines leads to a rapid decline in cell viability and induction of apoptosis. Interestingly, we observed reduced toxicity in normal cells suggesting cancer cells may be more susceptible to NSs-mediated cell death. To enhance specificity of NSs for use in hepatocellular carcinoma, we incorporated four miR-122 binding sites in the 3’ untranslated region (UTR) of the NSs mRNA to achieve cell type specific expression. Observations presented here collectively suggest that delivery of the NSs gene may provide a unique therapeutic approach in a broad range of cancers.
NrCAM secreted by endometrial stromal cells enhances the progestin sensitivity of endometrial cancer cells through epigenetic modulation of PRB
Authors: Cheng Yali , Xie Liying , Xu Zhiying , Hao Mengxin , Yang Bingyi , Shan Weiwei , Wang Yiqin , Lv Qiaoying , Chen Xiaojun
Published: April 2022

Progestin is one of the main hormone treatment regimens for early-stage estrogen receptor- and progesterone receptor (PR)-positive endometrial cancer (EC). However, the response rate of EC to progestins is unsatisfactory. Investigating the mechanisms related to progestin treatment could help improve treatment efficacy. Studies have demonstrated that normal endometrial stromal cells (ESCs) increase the inhibitory effect of progestin on EC cell proliferation via paracrine signaling, but the mechanisms involved remain unclear. In this study, we found that ESCs had different morphological features between progestin-sensitive and -insensitive EC tissues. ESCs presented typical decidualization changes in progestin-sensitive cases, while they remained slim in progestin-insensitive EC lesions, indicating no response. Furthermore, ESCs enhanced the inhibitory effect of medroxyprogesterone acetate (MPA) on EC cell proliferation by secreting neuron cell adhesion molecule (NrCAM). MPA treatment enhanced NrCAM secretion by ESCs. EC xenografts in BALB/C nude mice demonstrated that MPA combined with NrCAM had an increased tumor inhibitory effect compared with MPA or NrCAM alone. Mechanistically, MPA upregulated NrCAM expression in ESCs through PR. Specifically, NrCAM increased PR expression in EC cells through TET1-induced hydroxymethylation of the PRB gene promoter region. These findings indicate that NrCAM or NrCAM combined with progestins could be a new EC treatment.
Spontaneous activity of the mitochondrial apoptosis pathway drives chromosomal defects, the appearance of micronuclei and cancer metastasis through the Caspase-Activated DNAse
Authors: Haimovici Aladin , Höfer Christoph , Badr Mohamed Tarek , Bavafaye Haghighi Elham , Amer Tarek , Boerries Melanie , Bronsert Peter , Glavynskyi Ievgen , Fanfone Deborah , Ichim Gabriel , Thilmany Nico , Weber Arnim , Brummer Tilman , Spohr Corinna , Öllinger Rupert , Janssen Klaus-Peter , Rad Roland , Häcker Georg
Published: April 2022

Micronuclei are DNA-containing structures separate from the nucleus found in cancer cells. Micronuclei are recognized by the immune sensor axis cGAS/STING, driving cancer metastasis. The mitochondrial apoptosis apparatus can be experimentally triggered to a non-apoptotic level, and this can drive the appearance of micronuclei through the Caspase-activated DNAse (CAD). We tested whether spontaneously appearing micronuclei in cancer cells are linked to sub-lethal apoptotic signals. Inhibition of mitochondrial apoptosis or of CAD reduced the number of micronuclei in tumor cell lines as well as the number of chromosomal misalignments in tumor cells and intestinal organoids. Blockade of mitochondrial apoptosis or deletion of CAD reduced, while experimental activation CAD, STING-dependently, enhanced aggressive growth of tumor cells in vitro. Deletion of CAD from human cancer cells reduced metastasis in xenograft models. CAD-deficient cells displayed a substantially altered gene-expression profile, and a CAD-associated gene expression ‘signature’ strongly predicted survival in cancer patients. Thus, low-level activity in the mitochondrial apoptosis apparatus operates through CAD-dependent gene-induction and STING-activation and has substantial impact on metastasis in cancer.
Targeting nicotinamide N-methyltransferase overcomes resistance to EGFR-TKI in non-small cell lung cancer cells
Authors: Wang Jun , Liu Xi , Huang Yuanfeng , Li Pan , Yang Minqiang , Zeng Shanshan , Chen Danyang , Wang Qian , Liu Hao , Luo Kai , Deng Jin
Published: April 2022

Activating mutations of epidermal growth factor receptor (EGFR) contributes to the progression of non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitor (TKI)-targeted therapy has become the standard treatment for NSCLC patients with EGFR-mutations. However, acquired resistance to these agents remains a major obstacle for managing NSCLC. Here, we investigated a novel strategy to overcome EGFR TKI resistance by targeting the nicotinamide N-methyltransferase (NNMT). Using iTRAQ-based quantitative proteomics analysis, we identified that NNMT was significantly increased in EGFR-TKI-resistant NSCLC cells. Moreover, we found that NNMT expression was increased in EGFR-TKI-resistant NSCLC tissue samples, and higher levels were correlated with shorter progression-free survival in EGFR-TKI-treated NSCLC patients. Knockdown of NNMT rendered EGFR-TKI-resistant cells more sensitive to EGFR-TKI, whereas overexpression of NNMT in EGFR-TKI-sensitive cells resulted in EGFR-TKI resistance. Mechanically, upregulation of NNMT increased c-myc expression via SIRT1-mediated c-myc deacetylation, which in turn promoted glycolysis and EGFR-TKI resistance. Furthermore, we demonstrated that the combination of NNMT inhibitor and EGFR-TKI strikingly suppressed the growth of EGFR-TKI-resistant NSCLC cells both in vitro and in vivo. In conclusion, our research indicated that NNMT overexpression is important for acquired resistance to EGFR-TKI and that targeting NNMT might be a potential therapeutic strategy to overcome resistance to EGFR TKI.
Trade-offs in the genetic control of functional and nutritional quality traits in UK winter wheat
Authors: Fradgley Nick S. , Gardner Keith , Kerton Matt , Swarbreck Stéphanie M. , Bentley Alison R.
Published: April 2022

A complex network of trade-offs exists between wheat quality and nutritional traits. We investigated the correlated relationships among several milling and baking traits as well as mineral density in refined white and whole grain flour. Our aim was to determine their pleiotropic genetic control in a multi-parent population over two trial years with direct application to practical breeding. Co-location of major quantitative trait loci (QTL) and principal component based multi-trait QTL mapping increased the power to detect QTL and revealed pleiotropic effects explaining many complementary and antagonistic trait relationships. High molecular weight glutenin subunit genes explained much of the heritable variation in important dough rheology traits, although additional QTL were detected. Several QTL, including one linked to the TaGW2 gene, controlled grain size and increased flour extraction rate. The semi-dwarf Rht-D1b allele had a positive effect on Hagberg falling number, but reduced grain size, specific weight, grain protein content and flour water absorption. Mineral nutrient concentrations were lower in Rht-D1b lines for many elements, in wholemeal and white flour, but potassium concentration was higher in Rht-D1b lines. The presence of awns increased calcium content without decreasing extraction rate, despite the negative correlation between these traits. QTL were also found that affect the relative concentrations of key mineral nutrients compared to phosphorus which may help increase bioavailability without associated anti-nutritional effects of phytic acid. Taken together these results demonstrate the potential for marker-based selection to optimise trait trade-offs and enhance wheat nutritional value by considering pleiotropic genetic effects across multiple traits.
A robust and interpretable machine learning approach using multimodal biological data to predict future pathological tau accumulation
Authors: Giorgio Joseph , Jagust William J. , Baker Suzanne , Landau Susan M. , Tino Peter , Kourtzi Zoe ,   Alzheimer’s Disease Neuroimaging Initiative
Published: April 2022

The early stages of Alzheimer’s disease (AD) involve interactions between multiple pathophysiological processes. Although these processes are well studied, we still lack robust tools to predict individualised trajectories of disease progression. Here, we employ a robust and interpretable machine learning approach to combine multimodal biological data and predict future pathological tau accumulation. In particular, we use machine learning to quantify interactions between key pathological markers (β-amyloid, medial temporal lobe  atrophy, tau and APOE 4) at mildly impaired and asymptomatic stages of AD. Using baseline non-tau markers we derive a prognostic index that: (a) stratifies patients based on future pathological tau accumulation, (b) predicts individualised regional future rate of tau accumulation, and (c) translates predictions from deep phenotyping patient cohorts to cognitively normal individuals. Our results propose a robust approach for fine scale stratification and prognostication with translation impact for clinical trial design targeting the earliest stages of AD.
Modification of BRCA1-associated breast cancer risk by HMMR overexpression
Authors: Mateo Francesca , He Zhengcheng , Mei Lin , de Garibay Gorka Ruiz , Herranz Carmen , García Nadia , Lorentzian Amanda , Baiges Alexandra , Blommaert Eline , Gómez Antonio , Mirallas Oriol , Garrido-Utrilla Anna , Palomero Luis , Espín Roderic , Extremera Ana I. , Soler-Monsó M. Teresa , Petit Anna , Li Rong , Brunet Joan , Chen Ke , Tan Susanna , Eaves Connie J. , McCloskey Curtis , Hakem Razq , Khokha Rama , Lange Philipp F. , Lázaro Conxi , Maxwell Christopher A. , Pujana Miquel Angel
Published: April 2022

Breast cancer risk for carriers of BRCA1 pathological variants is modified by genetic factors. Genetic variation in HMMR may contribute to this effect. However, the impact of risk modifiers on cancer biology remains undetermined and the biological basis of increased risk is poorly understood. Here, we depict an interplay of molecular, cellular, and tissue microenvironment alterations that increase BRCA1-associated breast cancer risk. Analysis of genome-wide association results suggests that diverse biological processes, including links to BRCA1-HMMR profiles, influence risk. HMMR overexpression in mouse mammary epithelium increases Brca1-mutant tumorigenesis by modulating the cancer cell phenotype and tumor microenvironment. Elevated HMMR activates AURKA and reduces ARPC2 localization in the mitotic cell cortex, which is correlated with micronucleation and activation of cGAS-STING and non-canonical NF-κB signaling. The initial tumorigenic events are genomic instability, epithelial-to-mesenchymal transition, and tissue infiltration of tumor-associated macrophages. The findings reveal a biological foundation for increased risk of BRCA1-associated breast cancer.
Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19
Authors: Liu Hengrui , Iketani Sho , Zask Arie , Khanizeman Nisha , Bednarova Eva , Forouhar Farhad , Fowler Brandon , Hong Seo Jung , Mohri Hiroshi , Nair Manoj S. , Huang Yaoxing , Tay Nicholas E. S. , Lee Sumin , Karan Charles , Resnick Samuel J. , Quinn Colette , Li Wenjing , Shion Henry , Xia Xin , Daniels Jacob D. , Bartolo-Cruz Michelle , Farina Marcelo , Rajbhandari Presha , Jurtschenko Christopher , Lauber Matthew A. , McDonald Thomas , Stokes Michael E. , Hurst Brett L. , Rovis Tomislav , Chavez Alejandro , Ho David D. , Stockwell Brent R.
Published: April 2022

The SARS-CoV-2 3CL protease is a critical drug target for small molecule COVID-19 therapy, given its likely druggability and essentiality in the viral maturation and replication cycle. Based on the conservation of 3CL protease substrate binding pockets across coronaviruses and using screening, we identified four structurally distinct lead compounds that inhibit SARS-CoV-2 3CL protease. After evaluation of their binding specificity, cellular antiviral potency, metabolic stability, and water solubility, we prioritized the GC376 scaffold as being optimal for optimization. We identified multiple drug-like compounds with <10 nM potency for inhibiting SARS-CoV-2 3CL and the ability to block SARS-CoV-2 replication in human cells, obtained co-crystal structures of the 3CL protease in complex with these compounds, and determined that they have pan-coronavirus activity. We selected one compound, termed coronastat, as an optimized lead and characterized it in pharmacokinetic and safety studies in vivo. Coronastat represents a new candidate for a small molecule protease inhibitor for the treatment of SARS-CoV-2 infection for eliminating pandemics involving coronaviruses.
MiDAS 4: A global catalogue of full-length 16S rRNA gene sequences and taxonomy for studies of bacterial communities in wastewater treatment plants
Authors: Dueholm Morten Kam Dahl , Nierychlo Marta , Andersen Kasper Skytte , Rudkjøbing Vibeke , Knutsson Simon ,   MiDAS Global Consortium, Arriaga Sonia , Bakke Rune , Boon Nico , Bux Faizal , Christensson Magnus , Chua Adeline Seak May , Curtis Thomas P. , Cytryn Eddie , Erijman Leonardo , Etchebehere Claudia , Fatta-Kassinos Despo , Frigon Dominic , Garcia-Chaves Maria Carolina , Gu April Z. , Horn Harald , Jenkins David , Kreuzinger Norbert , Kumari Sheena , Lanham Ana , Law Yingyu , Leiknes TorOve , Morgenroth Eberhard , Muszyński Adam , Petrovski Steve , Pijuan Maite , Pillai Suraj Babu , Reis Maria A. M. , Rong Qi , Rossetti Simona , Seviour Robert , Tooker Nick , Vainio Pirjo , van Loosdrecht Mark , Vikraman R. , Wanner Jiří , Weissbrodt David , Wen Xianghua , Zhang Tong , Nielsen Per H. , Albertsen Mads , Nielsen Per Halkjær
Published: April 2022

Microbial communities are responsible for biological wastewater treatment, but our knowledge of their diversity and function is still poor. Here, we sequence more than 5 million high-quality, full-length 16S rRNA gene sequences from 740 wastewater treatment plants (WWTPs) across the world and use the sequences to construct the ‘MiDAS 4’ database. MiDAS 4 is an amplicon sequence variant resolved, full-length 16S rRNA gene reference database with a comprehensive taxonomy from domain to species level for all sequences. We use an independent dataset (269 WWTPs) to show that MiDAS 4, compared to commonly used universal reference databases, provides a better coverage for WWTP bacteria and an improved rate of genus and species level classification. Taking advantage of MiDAS 4, we carry out an amplicon-based, global-scale microbial community profiling of activated sludge plants using two common sets of primers targeting regions of the 16S rRNA gene, revealing how environmental conditions and biogeography shape the activated sludge microbiota. We also identify core and conditionally rare or abundant taxa, encompassing 966 genera and 1530 species that represent approximately 80% and 50% of the accumulated read abundance, respectively. Finally, we show that for well-studied functional guilds, such as nitrifiers or polyphosphate-accumulating organisms, the same genera are prevalent worldwide, with only a few abundant species in each genus.
Asymmetric structure of the native Rhodobacter sphaeroides dimeric LH1–RC complex
Authors: Tani Kazutoshi , Kanno Ryo , Kikuchi Riku , Kawamura Saki , Nagashima Kenji V. P. , Hall Malgorzata , Takahashi Ai , Yu Long-Jiang , Kimura Yukihiro , Madigan Michael T. , Mizoguchi Akira , Humbel Bruno M. , Wang-Otomo Zheng-Yu
Published: April 2022

Rhodobacter sphaeroides is a model organism in bacterial photosynthesis, and its light-harvesting-reaction center (LH1–RC) complex contains both dimeric and monomeric forms. Here we present cryo-EM structures of the native LH1–RC dimer and an LH1–RC monomer lacking protein-U (ΔU). The native dimer reveals several asymmetric features including the arrangement of its two monomeric components, the structural integrity of protein-U, the overall organization of LH1, and rigidities of the proteins and pigments. PufX plays a critical role in connecting the two monomers in a dimer, with one PufX interacting at its N-terminus with another PufX and an LH1 β-polypeptide in the other monomer. One protein-U was only partially resolved in the dimeric structure, signaling different degrees of disorder in the two monomers. The ΔU LH1–RC monomer was half-moon-shaped and contained 11 α- and 10 β-polypeptides, indicating a critical role for protein-U in controlling the number of αβ-subunits required for dimer assembly and stabilization. These features are discussed in relation to membrane topology and an assembly model proposed for the native dimeric complex.
Introducing principles of synaptic integration in the optimization of deep neural networks
Authors: Dellaferrera Giorgia , Woźniak Stanisław , Indiveri Giacomo , Pantazi Angeliki , Eleftheriou Evangelos
Published: April 2022

Plasticity circuits in the brain are known to be influenced by the distribution of the synaptic weights through the mechanisms of synaptic integration and local regulation of synaptic strength. However, the complex interplay of stimulation-dependent plasticity with local learning signals is disregarded by most of the artificial neural network training algorithms devised so far. Here, we propose a novel biologically inspired optimizer for artificial and spiking neural networks that incorporates key principles of synaptic plasticity observed in cortical dendrites: GRAPES (Group Responsibility for Adjusting the Propagation of Error Signals). GRAPES implements a weight-distribution-dependent modulation of the error signal at each node of the network. We show that this biologically inspired mechanism leads to a substantial improvement of the performance of artificial and spiking networks with feedforward, convolutional, and recurrent architectures, it mitigates catastrophic forgetting, and it is optimally suited for dedicated hardware implementations. Overall, our work indicates that reconciling neurophysiology insights with machine intelligence is key to boosting the performance of neural networks.
Collateral sensitivity to pleuromutilins in vancomycin-resistant Enterococcus faecium
Authors: Li Qian , Chen Shang , Zhu Kui , Huang Xiaoluo , Huang Yucheng , Shen Zhangqi , Ding Shuangyang , Gu Danxia , Yang Qiwen , Sun Hongli , Hu Fupin , Wang Hui , Cai Jiachang , Ma Bing , Zhang Rong , Shen Jianzhong
Published: April 2022

The acquisition of resistance to one antibiotic sometimes leads to collateral sensitivity to a second antibiotic. Here, we show that vancomycin resistance in Enterococcus faecium is associated with a remarkable increase in susceptibility to pleuromutilin antibiotics (such as lefamulin), which target the bacterial ribosome. The trade-off between vancomycin and pleuromutilins is mediated by epistasis between the van gene cluster and msrC, encoding an ABC-F protein that protects bacterial ribosomes from antibiotic targeting. In mouse models of vancomycin-resistant E. faecium colonization and septicemia, pleuromutilin treatment reduces colonization and improves survival more effectively than standard therapy (linezolid). Our findings suggest that pleuromutilins may be useful for the treatment of vancomycin-resistant E. faecium infections.
Data-driven discovery of high performance layered van der Waals piezoelectric NbOI2
Authors: Wu Yaze , Abdelwahab Ibrahim , Kwon Ki Chang , Verzhbitskiy Ivan , Wang Lin , Liew Weng Heng , Yao Kui , Eda Goki , Loh Kian Ping , Shen Lei , Quek Su Ying
Published: April 2022

Using high-throughput first-principles calculations to search for layered van der Waals materials with the largest piezoelectric stress coefficients, we discover NbOI2 to be the one among 2940 monolayers screened. The piezoelectric performance of NbOI2 is independent of thickness, and its electromechanical coupling factor of near unity is a hallmark of optimal interconversion between electrical and mechanical energy. Laser scanning vibrometer studies on bulk and few-layer NbOI2 crystals verify their huge piezoelectric responses, which exceed internal references such as In2Se3 and CuInP2S6. Furthermore, we provide insights into the atomic origins of anti-correlated piezoelectric and ferroelectric responses in NbOX2 (X = Cl, Br, I), based on bond covalency and structural distortions in these materials. Our discovery that NbOI2 has the largest piezoelectric stress coefficients among 2D materials calls for the development of NbOI2-based flexible nanoscale piezoelectric devices.
FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice
Authors: Hill Cristal M. , Albarado Diana C. , Coco Lucia G. , Spann Redin A. , Khan Md Shahjalal , Qualls-Creekmore Emily , Burk David H. , Burke Susan J. , Collier J. Jason , Yu Sangho , McDougal David H. , Berthoud Hans-Rudolf , Münzberg Heike , Bartke Andrzej , Morrison Christopher D.
Published: April 2022

Dietary protein restriction is increasingly recognized as a unique approach to improve metabolic health, and there is increasing interest in the mechanisms underlying this beneficial effect. Recent work indicates that the hormone FGF21 mediates the metabolic effects of protein restriction in young mice. Here we demonstrate that protein restriction increases lifespan, reduces frailty, lowers body weight and adiposity, improves physical performance, improves glucose tolerance, and alters various metabolic markers within the serum, liver, and adipose tissue of wildtype male mice. Conversely, mice lacking FGF21 fail to exhibit metabolic responses to protein restriction in early life, and in later life exhibit early onset of age-related weight loss, reduced physical performance, increased frailty, and reduced lifespan. These data demonstrate that protein restriction in aging male mice exerts marked beneficial effects on lifespan and metabolic health and that a single metabolic hormone, FGF21, is essential for the anti-aging effect of this dietary intervention.
DNA methylation in newborns conceived by assisted reproductive technology
Authors: Håberg Siri E. , Page Christian M. , Lee Yunsung , Nustad Haakon E. , Magnus Maria C. , Haftorn Kristine L. , Carlsen Ellen Ø. , Denault William R. P. , Bohlin Jon , Jugessur Astanand , Magnus Per , Gjessing Håkon K. , Lyle Robert
Published: April 2022

Assisted reproductive technology (ART) may affect fetal development through epigenetic mechanisms as the timing of ART procedures coincides with the extensive epigenetic remodeling occurring between fertilization and embryo implantation. However, it is unknown to what extent ART procedures alter the fetal epigenome. Underlying parental characteristics and subfertility may also play a role. Here we identify differences in cord blood DNA methylation, measured using the Illumina EPIC platform, between 962 ART conceived and 983 naturally conceived singleton newborns. We show that ART conceived newborns display widespread differences in DNA methylation, and overall less methylation across the genome. There were 607 genome-wide differentially methylated CpGs. We find differences in 176 known genes, including genes related to growth, neurodevelopment, and other health outcomes that have been associated with ART. Both fresh and frozen embryo transfer show DNA methylation differences. Associations persist after controlling for parents’ DNA methylation, and are not explained by parental subfertility.
Reshuffling of the ancestral core-eudicot genome shaped chromatin topology and epigenetic modification in Panax
Authors: Wang Zhen-Hui , Wang Xin-Feng , Lu Tianyuan , Li Ming-Rui , Jiang Peng , Zhao Jing , Liu Si-Tong , Fu Xue-Qi , Wendel Jonathan F. , Van de Peer Yves , Liu Bao , Li Lin-Feng
Published: April 2022

All extant core-eudicot plants share a common ancestral genome that has experienced cyclic polyploidizations and (re)diploidizations. Reshuffling of the ancestral core-eudicot genome generates abundant genomic diversity, but the role of this diversity in shaping the hierarchical genome architecture, such as chromatin topology and gene expression, remains poorly understood. Here, we assemble chromosome-level genomes of one diploid and three tetraploid Panax species and conduct in-depth comparative genomic and epigenomic analyses. We show that chromosomal interactions within each duplicated ancestral chromosome largely maintain in extant Panax species, albeit experiencing ca. 100–150 million years of evolution from a shared ancestor. Biased genetic fractionation and epigenetic regulation divergence during polyploidization/(re)diploidization processes generate remarkable biochemical diversity of secondary metabolites in the Panax genus. Our study provides a paleo-polyploidization perspective of how reshuffling of the ancestral core-eudicot genome leads to a highly dynamic genome and to the metabolic diversification of extant eudicot plants.
Angular and linear speed cells in the parahippocampal circuits
Authors: Spalla Davide , Treves Alessandro , Boccara Charlotte N.
Published: April 2022

An essential role of the hippocampal region is to integrate information to compute and update representations. How this transpires is highly debated. Many theories hinge on the integration of self-motion signals and the existence of continuous attractor networks (CAN). CAN models hypothesise that neurons coding for navigational correlates – such as position and direction – receive inputs from cells conjunctively coding for position, direction, and self-motion. As yet, very little data exist on such conjunctive coding in the hippocampal region. Here, we report neurons coding for angular and linear velocity, uniformly distributed across the medial entorhinal cortex (MEC), the presubiculum and the parasubiculum, except for MEC layer II. Self-motion neurons often conjunctively encoded position and/or direction, yet lacked a structured organisation. These results offer insights as to how linear/angular speed – derivative in time of position/direction – may allow the updating of spatial representations, possibly uncovering a generalised algorithm to update any representation.
Promoting favorable interfacial properties in lithium-based batteries using chlorine-rich sulfide inorganic solid-state electrolytes
Authors: Zeng Dewu , Yao Jingming , Zhang Long , Xu Ruonan , Wang Shaojie , Yan Xinlin , Yu Chuang , Wang Lin
Published: April 2022

The use of inorganic solid-state electrolytes is considered a viable strategy for developing high-energy Li-based metal batteries. However, suppression of parasitic interfacial reactions and growth of unfavorable Li metal depositions upon cycling are challenging aspects and not yet fully addressed. Here, to better understand these phenomena, we investigate various sulfide inorganic solid electrolytes (SEs), i.e., Li7−xPS6−xClx (x = 0.6, 1.0, 1.3, 1.45, and 1.6), via ex situ and in situ physicochemical and electrochemical measurements. We found that the Cl distribution and the cooling process applied during the SE synthesis strongly influence the evolution of the Li|SE interface in terms of microstructure, interphase composition, and morphology. Indeed, for a SE with a moderate chlorine content (i.e., x = 1.3) and obtained via a slow cooling process after sintering, the Cl atoms are located on the surface of the SE grains as interconnected LiCl nanoparticles that form an extended LiCl-based framework. This peculiar microstructure facilitates the migration of the Cl ions to the Li|SE interface during electrochemical cycling, thus, favouring the formation of a LiCl-rich interphase layer capable of improving the battery cycling performances.