bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapping modifiable determinants of medication adherence in bipolar disorder (BD) to the theoretical domains framework (TDF): a systematic review
Authors: Prajapati Asta Ratna , Dima Alexandra , Mosa George , Scott Sion , Song Fujian , Wilson Jonathan , Bhattacharya Debi
Published: May 2021

Background

Around 40% of people with bipolar disorder (BD) are non-adherent to medication leading to relapse, hospitalisation and increased suicide risk. Limited progress in addressing non-adherence may be partly attributable to insufficient understanding of the modifiable determinants of adherence that require targeting in interventions. We synthesised the modifiable determinants of adherence in BD and map them to the theoretical domains framework (TDF).

Method

We searched CINAHL, Cochrane Library, Embase, LILACS, Medline, PsychINFO and PubMed until February 2020. We included studies reporting modifiable determinants of adherence in BD. Two reviewers independently screened studies, assessed quality, extracted modifiable determinants and mapped them to TDF.

Results

We included 57 studies involving 32 894 participants. Determinants reported by patients spanned 11 of the 14 TDF domains compared to six domains represented by clinician/researcher. The TDF domains most commonly represented (% and example) in studies were: ‘Environmental context and resources’ (63%, e.g. experiencing side effects), ‘Beliefs about consequences’ (63%, e.g. beliefs about medication effects), ‘Knowledge’ (40%, e.g. knowledge about disorder), ‘Social influences’ (33%, e.g. support from family/clinicians), ‘Memory, attention and decision processes’ (33%, e.g. forgetfulness), ‘Emotion’ (21%, e.g. fear of addiction) and ‘Intentions’ (21%, e.g. wanting alternative treatment). ‘Intentions’, ‘Memory, attention and decision processes’ and ‘Emotion’ domains were only reported by patients but not clinicians.

Conclusions

Clinicians may be underappreciating the full range of modifiable determinants of adherence and thus not providing adherence support reflective of patients' needs. Reporting of modifiable determinants in behavioural terms facilitates developing theory-based interventions to address non-adherence in BD.
Higher order functions and Brouwer’s thesis
Authors: STERLING JONATHAN
Published: May 2021

Extending Martín Escardó’seffectful forcingtechnique, we give a new proof of a well-known result: Brouwer’s monotone bar theorem holds for any bar that can be realized by a functional of type (ℕ→ℕ)→ℕ in Gödel’sSystem T. Effectful forcing is an elementary alternative to standard sheaf-theoretic forcing arguments, using ideas from programming languages, including computational effects, monads, the algebra interpretation of call-by-name λ-calculus, and logical relations.

Our argument proceeds by interpretingSystem Tprograms as well-founded dialogue trees whose nodes branch on a query to an oracle of type ℕ→ℕ, lifted to higher type along a call-by-name translation. To connect this interpretation to the bar theorem, we then show that Brouwer’s famous “mental constructions” of barhood constitute an invariant form of these dialogue trees in which queries to the oracle are made maximally and in order.
Pronominally headed relative clauses in early English
Authors: ALLEN CYNTHIA L.
Published: May 2021

Present-day English is unlike Old English in not using singular demonstrative pronouns with anaphoric reference to human beings. This article adds to the contributions of Cole (2017) and Los & van Kemenade (2018) in our understanding of the factors determining the choice between personal and demonstrative pronouns in Old English by documenting the hitherto unexamined use of these pronouns as heads of relative clauses. It also traces how the singular demonstrative pronouns referring to humans retreated as heads of relative clauses in Early Middle English. A corpus-based study shows that third-person personal pronouns were unusual as heads of relative clauses in Old English and normally referred to specific individuals, while demonstratives were the pronouns of choice for generic reference but could also refer to specific individuals. The increased use of personal pronouns for generic reference is well underway in Early Middle English. While the retreat of the singular demonstrative pronouns to refer to humans in Early Middle English seems to have some connection with the reduced marking of feature distinctions in that period, a simple explanation in terms of loss of gender is untenable.
Rain fade margin of terrestrial line-of-sight (LOS) links for 5G networks in Peninsular Malaysia
Authors: Seah Shi Jie , Jong Siat Ling , Lam Hong Yin , Din Jafri
Published: May 2021

Advanced telecommunication systems are moving toward a high data transfer rate and wider bandwidth. The 5G communication network has recently been implemented for such aims. However, 5G networks operating with high operating frequency (typically above 20 GHz) could lead to impairments because of the atmospheric phenomena mainly precipitation and especially heavy rain. To address this, an optimum rain fade margin for the 5G network in Peninsular Malaysia is proposed using 77 sites of the rain-gauge network, which convert 1-h rain data to 1-min rain data by means of the international telecommunication union recommendation (ITU-R) P.837-7 model. Long-term rain attenuation statistics are obtained from ITU-R P.530-17 and the synthetic storm technique. The predicted rain attenuation is also presented in monthly statistics and in rain attenuation contour maps. The analysis showed that at 99.99% of link availability, the optimum rain fade margin operating at 26 GHz link should be in the range of 6.50 to 10 dB and 7 to 11 dB at 28 GHz link for a 5G network. Such information is useful for network operators and system engineers for the operation of 5G terrestrial microwave links in heavy rain regions.
Insights on Nitrogen and Phosphorus Co‐Limitation in Global Croplands From Theoretical and Modeling Fertilization Experiments
Authors: Ringeval Bruno , Kvakić Marko , Augusto Laurent , Ciais Philippe , Goll Daniel S. , Mueller Nathaniel D. , Müller Christoph , Nesme Thomas , Vuichard Nicolas , Wang Xuhui , Pellerin Sylvain
Published: May 2021

Single and combined fertilization additions are a common tool to assess the interactions between nutrients in a given ecosystem. While such experiments can allow systems to be defined into categories of nutrient interactions, for example, simultaneous co‐limitation or single resource response, this categorization may itself be sensitive to way nutrient interactions are mathematically formulated. To this end, we developed a theoretical analysis of nitrogen (N) and phosphorus (P) fertilization experiments based on the computation of ratios between plant demand and soil supply for each nutrient to explore two mathematical interaction formalisms: Liebig's law of minimum (LM) and the multiple limitation hypothesis (MH). We defined, for each interaction formalism, what conditions (in terms of supply and demand in N and P) are required to make the ecosystem in each category of nutrient interaction. Notably, we showed that synergistic co‐limitation could occur even using LM formalism under certain conditions. We then applied our framework to global maps of soil nutrient supply and of crop nutrient demand to achieve the potential yield. This was done to examine how the choice of interaction formalism influenced the occurrence of nutrient interaction categories. MH predicts true co‐limitation for ∼40% of the global maize area where LM predicts other categories of nutrient interaction, particularly single resource P limitation (whose the exact occurrence is, however, sensitive to the amount of P applied in the fertilization experiments). Our study identified areas where real fertilization experiments are required to choose between LM or MH to best represent nutrient interaction in croplands.
Monitoring Seismic Vibrations During a Pandemic
Authors: Kish Stacy
Published: May 2021

Researchers in Spain monitored variations in seismic noise across Barcelona as the city locked down during the pandemic, clarifying the seismic band associated with human activity.
Post‐2018 Caldera Collapse Re‐Inflation Uniquely Constrains Kīlauea's Magmatic System
Authors: Wang Taiyi , Zheng Yujie , Pulvirenti Fabio , Segall Paul
Published: May 2021

From August 2018 to May 2019, Kīlauea’s summit exhibited unique, simultaneous, inflation and deflation, apparent in both GPS time series and cumulative InSAR displacement maps. This deformation pattern provides clear evidence that the Halema‘uma‘u (HMM) and South Caldera (SC) reservoirs are distinct. Post‐collapse inflation of the East Rift Zone (ERZ), as captured by InSAR, indicates concurrent magma transfer from the summit reservoirs to the ERZ. We present a physics‐based model that couples pressure‐driven flow between these magma reservoirs to simulate time dependent summit deformation. We take a two‐step approach to quantitatively constrain Kīlauea’s magmatic plumbing system. First, we jointly invert the InSAR displacement maps and GPS offsets for the location and geometry of the summit reservoirs, approximated as spheroidal chambers. We find that HMM reservoir has an aspect ratio of ∼1.8 (prolate) and a depth of ∼2.2 km (below surface). The SC reservoir has an aspect ratio of ∼0.14 (oblate) and a depth of ∼3.6 km. Second, we utilize the flux model to invert GPS time series from 8 summit stations. Results favor a shallow HMM‐ERZ pathway an order of magnitude more hydraulically conductive than the deep SC‐ERZ pathway. Further analysis shows that the HMM‐ERZ pathway is required to explain the deformation time series. Given high‐quality geodetic data, such an approach promises to quantify the connectivity of magmatic pathways between reservoirs in other similar volcanic systems.
Novel prostate cancer susceptibility gene SP6 predisposes patients to aggressive disease
Authors: Sipeky Csilla , Tammela Teuvo L. J. , Auvinen Anssi , Schleutker Johanna
Published: May 2021

Prostate cancer (PrCa) is one of the most common cancers in men, but little is known about factors affecting its clinical outcomes. Genome-wide association studies have identified more than 170 germline susceptibility loci, but most of them are not associated with aggressive disease. We performed a genome-wide analysis of 185,478 SNPs in Finnish samples (2738 cases, 2400 controls) from the international Collaborative Oncological Gene-Environment Study (iCOGS) to find underlying PrCa risk variants. We identified a total of 21 common, low-penetrance susceptibility loci, including 10 novel variants independently associated with PrCa risk. Novel risk loci were located in the 8q24 (CASC8 rs16902147, OR 1.86, padj = 3.53 × 10−8 and rs58809953, OR 1.71, padj = 4.00 × 10−6; intergenic rs79012498, OR 1.81, padj = 4.26 × 10−8), 17q21 (SP6 rs2074187, OR 1.66, padj = 3.75 × 10−5), 11q13 (rs12795301, OR 1.42, padj = 2.89 × 10−5) and 8p21 (rs995432, OR 1.38, padj = 3.00 × 10−11) regions. Here, we describe SP6, a transcription factor gene, as a new, potentially high-risk gene for PrCa. The intronic variant rs2074187 in SP6 was associated not only with overall susceptibility to PrCa (OR 1.66) but also with a higher odds ratio for aggressive PrCa (OR 1.89) and lower odds for non-aggressive PrCa (OR 1.43). Furthermore, the new intergenic variant rs79012498 at 8q24 conferred risk for aggressive PrCa. Our findings highlighted the power of a population-stratified approach to identify novel, clinically actionable germline PrCa risk loci and strongly suggested SP6 as a new PrCa candidate gene that may be involved in the pathogenesis of PrCa.
The prognostic power of 18F-FDG PET/CT extends to estimating systemic treatment response duration in metastatic castration-resistant prostate cancer (mCRPC) patients
Authors: Bauckneht Matteo , Bertagna Francesco , Donegani Maria Isabella , Durmo Rexhep , Miceli Alberto , De Biasi Vincenzo , Laudicella Riccardo , Fornarini Giuseppe , Berruti Alfredo , Baldari Sergio , Versari Annibale , Giubbini Raffaele , Sambuceti Gianmario , Morbelli Silvia , Albano Domenico
Published: May 2021

Background

We aimed to test whether the prognostic value of 18 F‐Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT) in metastatic castration-resistant prostate cancer (mCRPC) extends to the estimation of systemic treatment response duration.

Methods

mCRPC patients submitted to FDG-PET/CT in four Italian centers from 2005 to 2020 were retrospectively enrolled. Clinical and biochemical data at the time of imaging were collected, and SUV max of the hottest lesion, total metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated. The correlation between PET- and biochemical-derived parameters with Overall Survival (OS) was analysed. The prediction of treatment response duration was assessed in the subgroup submitted to FDG-PET/CT in the six months preceding Chemotherapy (namely Docetaxel or Cabazitaxel, 24 patients) or Androgen-Receptor Targeted Agents (ARTA, namely Abiraterone or Enzalutamide, 20 patients) administration.

Results

We enrolled 114 mCRPC patients followed-up for a median interval lasting 15 months. While at univariate analysis, prostate-specific antigen (PSA), Alkaline Phosphatase (ALP), MTV, and TLG were associated with OS, at the multivariate Cox regression analysis, the sole MTV could independently predict OS (p < 0.0001). In the subgroup submitted to FDG-PET/CT before the systemic treatment initiation, PSA and TLG could also predict treatment response duration independently (p < 0.05). Of note, while PSA could not indicate the best treatment choice, lower TLG was associated with higher success rates for ARTA but had no impact on chemotherapy efficacy.

Conclusions

FDG-PET/CT’s prognostic value extends to predicting treatment response duration in mCRPC, thus potentially guiding the systemic treatment selection.
Metaplasmidome-encoded functions of Siberian low-centered polygonal tundra soils
Authors: Gorecki Adrian , Holm Stine , Dziurzynski Mikolaj , Winkel Matthias , Yang Sizhong , Liebner Susanne , Wagner Dirk , Dziewit Lukasz , Horn Fabian
Published: May 2021

Plasmids have the potential to transfer genetic traits within bacterial communities and thereby serve as a crucial tool for the rapid adaptation of bacteria in response to changing environmental conditions. Our knowledge of the environmental pool of plasmids (the metaplasmidome) and encoded functions is still limited due to a lack of sufficient extraction methods and tools for identifying and assembling plasmids from metagenomic datasets. Here, we present the first insights into the functional potential of the metaplasmidome of permafrost-affected active-layer soil—an environment with a relatively low biomass and seasonal freeze–thaw cycles that is strongly affected by global warming. The obtained results were compared with plasmid-derived sequences extracted from polar metagenomes. Metaplasmidomes from the Siberian active layer were enriched via cultivation, which resulted in a longer contig length as compared with plasmids that had been directly retrieved from the metagenomes of polar environments. The predicted hosts of plasmids belonged to Moraxellaceae, Pseudomonadaceae, Enterobacteriaceae, Pectobacteriaceae, Burkholderiaceae, and Firmicutes. Analysis of their genetic content revealed the presence of stress-response genes, including antibiotic and metal resistance determinants, as well as genes encoding protectants against the cold.
Marine signature taxa and core microbial community stability along latitudinal and vertical gradients in sediments of the deepest freshwater lake
Authors: Reboul Guillaume , Moreira David , Annenkova Nataliia V , Bertolino Paola , Vershinin Konstantin E , López-García Purificación
Published: May 2021

Lake Baikal is the deepest (~1.6 km) and most voluminous freshwater reservoir on Earth. Compared to plankton, its benthos remains poorly explored. Here, we ask whether latitude and/or depth determine benthic microbial community structure and how Baikal communities compare to those of other freshwater, brackish and marine sediments. To answer, we collected sediment upper layers (0–1 cm) across a ~600 km North-South transect covering the three basins of the lake and from littoral to bathybenthic depths (0.5–1450  m). Analysis of 16S and 18S rRNA gene amplicon sequences revealed communities with high richness and evenness where rare operational taxonomic units (OTUs) collectively dominated. Archaea represented up to 25% or prokaryotic sequences. Baikal sediments harbored typically marine eukaryotic and prokaryotic OTUs recently identified in some lakes (diplonemids, Bolidophyceae, Mamiellales, SAR202, marine-like Synechococcus, Pelagibacterales) but also SAR324, Syndiniales and Radiolaria. We hypothesize that, beyond the salinity barrier, adaptation to oligotrophy explains the presence of these otherwise typically marine lineages. Baikal core benthic communities were relatively stable across sites and seemed not determined by depth or latitude. Comparative analyses with other freshwater, brackish and marine prokaryotic sediment communities confirmed the distinctness of Baikal benthos, which include elements of similarity to marine and hydrothermally influenced systems.
Alternative polyadenylation trans-factor FIP1 exacerbates UUO/IRI-induced kidney injury and contributes to AKI-CKD transition via ROS-NLRP3 axis
Authors: Zheng Tong , Tan Yuqin , Qiu Jiang , Xie Zhenwei , Hu Xiao , Zhang Jinhua , Na Ning
Published: May 2021

NLRP3, a decisive role in inflammation regulation, is obviously upregulated by oxidative stress in kidney injury. The NLRP3 upregulation leads to unsolved inflammation and other pathological effects, contributing to aggravation of kidney injury and even transition to chronic kidney disease (CKD). However, the mechanism for NLRP3 upregulation and further aggravation of kidney injury remains largely elusive. In this study, we found NLRP3 3′UTR was shortened in response to kidney injury in vivo and oxidative stress in vitro. Functionally, such NLRP3 3′UTR shortening upregulated NLRP3 expression and amplified inflammation, fibrogenesis, ROS production and apoptosis, depending on stabilizing NLRP3 mRNA. Mechanistically, FIP1 was found to bind to pPAS of NLRP3 mRNA via its arginine-rich domain and to induce NLRP3 3′UTR shortening. In addition, FIP1 was upregulated in CKD specimens and negatively associated with renal function of CKD patients. More importantly, we found FIP1 was upregulated by oxidative stress and required for oxidative stress-induced NLRP3 upregulation, inflammation activation, cell damage and apoptosis. Finally, we proved that FIP1 silencing attenuated the inflammation activation, fibrogenesis, ROS production and apoptosis induced by UUO or IRI. Taken together, our results demonstrated that oxidative stress-upregulated FIP1 amplified inflammation, fibrogenesis, ROS production and apoptosis via inducing 3′UTR shortening of NLRP3, highlighting the importance of crosstalk between oxidative stress and alternative polyadenylation in AKI-CKD transition, as well as the therapeutic potential of FIP1 in kidney injury treatment.
MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma
Authors: Lu Yuxiong , Yang Qing , Su Yubin , Ji Yin , Li Guobang , Yang Xianzhi , Xu Liyan , Lu Zhaoliang , Dong Jiajun , Wu Yi , Bei Jin-Xin , Pan Chaoyun , Gu Xiaoqiong , Li Bo
Published: May 2021

MYCN amplification is tightly associated with the poor prognosis of pediatric neuroblastoma (NB). The regulation of NB cell death by MYCN represents an important aspect, as it directly contributes to tumor progression and therapeutic resistance. However, the relationship between MYCN and cell death remains elusive. Ferroptosis is a newly identified cell death mode featured by lipid peroxide accumulation that can be attenuated by GPX4, yet whether and how MYCN regulates ferroptosis are not fully understood. Here, we report that MYCN-amplified NB cells are sensitive to GPX4-targeting ferroptosis inducers. Mechanically, MYCN expression reprograms the cellular iron metabolism by upregulating the expression of TFRC, which encodes transferrin receptor 1 as a key iron transporter on the cell membrane. Further, the increased iron uptake promotes the accumulation of labile iron pool, leading to enhanced lipid peroxide production. Consistently, TFRC overexpression in NB cells also induces selective sensitivity to GPX4 inhibition and ferroptosis. Moreover, we found that MYCN fails to alter the general lipid metabolism and the amount of cystine imported by System Xc(−) for glutathione synthesis, both of which contribute to ferroptosis in alternative contexts. In conclusion, NB cells harboring MYCN amplification are prone to undergo ferroptosis conferred by TFRC upregulation, suggesting that GPX4-targeting ferroptosis inducers or TFRC agonists can be potential strategies in treating MYCN-amplified NB.
SRSF1 promotes the inclusion of exon 3 of SRA1 and the invasion of hepatocellular carcinoma cells by interacting with exon 3 of SRA1pre-mRNA
Authors: Lei Sijia , Zhang Bin , Huang Luyuan , Zheng Ziyou , Xie Shaohan , Shen Lianghua , Breitzig Mason , Czachor Alexander , Liu Hongtao , Luo Huiru , Chen Yanxia , Liu Kangshou , Sun Hanxiao , Zheng Qing , Li Qiang , Wang Feng
Published: May 2021

Steroid receptor RNA activator 1 (SRA1) has been described as a novel transcriptional co-activator that affects the migration of cancer cells. Through RT-PCR, we identified that skipping exon 3 of SRA1 produces two isoforms, including the truncated short isoform, SRA1-S, and the long isoform, SRA1-L. However, the effect of these two isomers on the migration of HCC cells, as well as the specific mechanism of exon 3 skipping remain unclear. In this study, we found up regulated expression of SRSF1 and SRA1-L in highly metastatic HCCLM3, as well as in HCCs with SRSF1 demonstrating the strongest correlation with SRA1-L. In contrast, we observed a constitutively low expression of SRA1-S and SRSF1 in lowly metastatic HepG2 cells. Overexpression of SRSF1 or SRA1-L promoted migration and invasion by increasing the expression of CD44, while SRA1-S reversed the effect of SRSF1 and SRA1-L in vitro. In addition, lung metastasis in mice revealed that, knockdown of SRSF1 or SRA1-L inhibited the migration of HCC cells, while SRA1-L overexpression abolished the effect of SRSF1 knockout and instead promoted HCC cells migration in vivo. More importantly, RNA immunoprecipitation and Cross-link immunoprecipitation analyses showed that SRSF1 interacts with exon 3 of SRA1 to up regulate the expression of SRA1-L in HCC cells. RNA pull-down results indicated that SRSF1 could also bind to exon 3 of SRA1 in vitro. Finally, minigene -MS2 mutation experiments showed that mutation of the SRA1 exon 3 binding site for SRSF1 prevented the binding of SRA1 pre-mRNA. In summary, our results provide experimental evidence that SRA1 exon 3 inclusion is up regulated by SRSF1 to promote tumor invasion and metastasis in hepatocellular carcinoma.
Quantitative trait locus analysis of parasitoid counteradaptation to symbiont-conferred resistance
Authors: Ulrich Gabriel F. , Zemp Niklaus , Vorburger Christoph , Boulain Hélène
Published: May 2021

Insect hosts and parasitoids are engaged in an intense struggle of antagonistic coevolution. Infection with heritable bacterial endosymbionts can substantially increase the resistance of aphids to parasitoid wasps, which exerts selection on parasitoids to overcome this symbiont-conferred protection (counteradaptation). Experimental evolution in the laboratory has produced counteradapted populations of the parasitoid waspLysiphlebus fabarum. These populations can parasitize black bean aphids (Aphis fabae) protected by the bacterial endosymbiontHamiltonella defensa, which confers high resistance againstL. fabarum. We used two experimentally evolved parasitoid populations to study the genetic architecture of the counteradaptation to symbiont-conferred resistance by QTL analysis. With simple crossing experiments, we showed that the counteradaptation is a recessive trait depending on the maternal genotype. Based on these results, we designed a customized crossing scheme to genotype a mapping population phenotyped for the ability to parasitizeHamiltonella-protected aphids. Using 1835 SNP markers obtained by ddRAD sequencing, we constructed a high-density linkage map consisting of six linkage groups (LGs) with an overall length of 828.3 cM and an average marker spacing of 0.45 cM. We identified a single QTL associated with the counteradaptation toHamiltonellainL. fabarumon linkage group 2. Out of 120 genes located in this QTL, several genes encoding putative venoms may represent candidates for counteradaptation, as parasitoid wasps inject venoms into their hosts during oviposition.
Acceleration of lipid reproduction by emergence of microscopic motion
Authors: Babu Dhanya , Scanes Robert J. H. , Plamont Rémi , Ryabchun Alexander , Lancia Federico , Kudernac Tibor , Fletcher Stephen P. , Katsonis Nathalie
Published: May 2021

Self-reproducing molecules abound in nature where they support growth and motion of living systems. In artificial settings, chemical reactions can also show complex kinetics of reproduction, however integrating self-reproducing molecules into larger chemical systems remains a challenge towards achieving higher order functionality. Here, we show that self-reproducing lipids can initiate, sustain and accelerate the movement of octanol droplets in water. Reciprocally, the chemotactic movement of the octanol droplets increases the rate of lipid reproduction substantially. Reciprocal coupling between bond-forming chemistry and droplet motility is thus established as an effect of the interplay between molecular-scale events (the self-reproduction of lipid molecules) and microscopic events (the chemotactic movement of the droplets). This coupling between molecular chemistry and microscopic motility offers alternative means of performing work and catalysis in micro-heterogeneous environments.
MIF is a 3’ flap nuclease that facilitates DNA replication and promotes tumor growth
Authors: Wang Yijie , Chen Yan , Wang Chenliang , Yang Mingming , Wang Yanan , Bao Lei , Wang Jennifer E. , Kim BongWoo , Chan Kara Y. , Xu Weizhi , Capota Emanuela , Ortega Janice , Nijhawan Deepak , Li Guo-Min , Luo Weibo , Wang Yingfei
Published: May 2021

How cancer cells cope with high levels of replication stress during rapid proliferation is currently unclear. Here, we show that macrophage migration inhibitory factor (MIF) is a 3’ flap nuclease that translocates to the nucleus in S phase. Poly(ADP-ribose) polymerase 1 co-localizes with MIF to the DNA replication fork, where MIF nuclease activity is required to resolve replication stress and facilitates tumor growth. MIF loss in cancer cells leads to mutation frequency increases, cell cycle delays and DNA synthesis and cell growth inhibition, which can be rescued by restoring MIF, but not nuclease-deficient MIF mutant. MIF is significantly upregulated in breast tumors and correlates with poor overall survival in patients. We propose that MIF is a unique 3’ nuclease, excises flaps at the immediate 3’ end during DNA synthesis and favors cancer cells evading replication stress-induced threat for their growth.
Ecological and biogeographic drivers of biodiversity cannot be resolved using clade age-richness data
Authors: Rabosky Daniel L. , Benson Roger B. J.
Published: May 2021

Estimates of evolutionary diversification rates – speciation and extinction – have been used extensively to explain global biodiversity patterns. Many studies have analyzed diversification rates derived from just two pieces of information: a clade’s age and its extant species richness. This “age-richness rate” (ARR) estimator provides a convenient shortcut for comparative studies, but makes strong assumptions about the dynamics of species richness through time. Here we demonstrate that use of the ARR estimator in comparative studies is problematic on both theoretical and empirical grounds. We prove mathematically that ARR estimates are non-identifiable: there is no information in the data for a single clade that can distinguish a process with positive net diversification from one where net diversification is zero. Using paleontological time series, we demonstrate that the ARR estimator has no predictive ability for real datasets. These pathologies arise because the ARR inference procedure yields “point estimates” that have been computed under a saturated statistical model with zero degrees of freedom. Although ARR estimates remain useful in some contexts, they should be avoided for comparative studies of diversification and species richness.
INDEEDopt: a deep learning-based ReaxFF parameterization framework
Authors: Sengul Mert Y. , Song Yao , Nayir Nadire , Gao Yawei , Hung Ying , Dasgupta Tirthankar , van Duin Adri C. T.
Published: May 2021

Empirical interatomic potentials require optimization of force field parameters to tune interatomic interactions to mimic ones obtained by quantum chemistry-based methods. The optimization of the parameters is complex and requires the development of new techniques. Here, we propose an INitial-DEsign Enhanced Deep learning-based OPTimization (INDEEDopt) framework to accelerate and improve the quality of the ReaxFF parameterization. The procedure starts with a Latin Hypercube Design (LHD) algorithm that is used to explore the parameter landscape extensively. The LHD passes the information about explored regions to a deep learning model, which finds the minimum discrepancy regions and eliminates unfeasible regions, and constructs a more comprehensive understanding of physically meaningful parameter space. We demonstrate the procedure here for the parameterization of a nickel–chromium binary force field and a tungsten–sulfide–carbon–oxygen–hydrogen quinary force field. We show that INDEEDopt produces improved accuracies in shorter development time compared to the conventional optimization method.
The nutritional quality of cereals varies geospatially in Ethiopia and Malawi
Authors: Gashu D. , Nalivata P. C. , Amede T. , Ander E. L. , Bailey E. H. , Botoman L. , Chagumaira C. , Gameda S. , Haefele S. M. , Hailu K. , Joy E. J. M. , Kalimbira A. A. , Kumssa D. B. , Lark R. M. , Ligowe I. S. , McGrath S. P. , Milne A. E. , Mossa A. W. , Munthali M. , Towett E. K. , Walsh M. G. , Wilson L. , Young S. D. , Broadley M. R.
Published: May 2021

Micronutrient deficiencies (MNDs) remain widespread among people in sub-Saharan Africa1–5, where access to sufficient food from plant and animal sources that is rich in micronutrients (vitamins and minerals) is limited due to socioeconomic and geographical reasons4–6. Here we report the micronutrient composition (calcium, iron, selenium and zinc) of staple cereal grains for most of the cereal production areas in Ethiopia and Malawi. We show that there is geospatial variation in the composition of micronutrients that is nutritionally important at subnational scales. Soil and environmental covariates of grain micronutrient concentrations included soil pH, soil organic matter, temperature, rainfall and topography, which were specific to micronutrient and crop type. For rural households consuming locally sourced food—including many smallholder farming communities—the location of residence can be the largest influencing factor in determining the dietary intake of micronutrients from cereals. Positive relationships between the concentration of selenium in grain and biomarkers of selenium dietary status occur in both countries. Surveillance of MNDs on the basis of biomarkers of status and dietary intakes from national- and regional-scale food-composition data1–7 could be improved using subnational data on the composition of grain micronutrients. Beyond dietary diversification, interventions to alleviate MNDs, such as food fortification8,9 and biofortification to increase the micronutrient concentrations in crops10,11, should account for geographical effects that can be larger in magnitude than intervention outcomes.
Seasonal forecasts offer economic benefit for hydrological decision making in semi-arid regions
Authors: Portele Tanja C. , Lorenz Christof , Dibrani Berhon , Laux Patrick , Bliefernicht Jan , Kunstmann Harald
Published: May 2021

Increasing frequencies of droughts require proactive preparedness, particularly in semi-arid regions. As forecasting of such hydrometeorological extremes several months ahead allows for necessary climate proofing, we assess the potential economic value of the seasonal forecasting system SEAS5 for decision making in water management. For seven drought-prone regions analyzed in America, Africa, and Asia, the relative frequency of drought months significantly increased from 10 to 30% between 1981 and 2018. We demonstrate that seasonal forecast-based action for droughts achieves potential economic savings up to 70% of those from optimal early action. For very warm months and droughts, savings of at least 20% occur even for forecast horizons of several months. Our in-depth analysis for the Upper-Atbara dam in Sudan reveals avoidable losses of 16 Mio US$ in one example year for early-action based drought reservoir operation. These findings stress the advantage and necessity of considering seasonal forecasts in hydrological decision making.
Bat responses to changes in forest composition and prey abundance depend on landscape matrix and stand structure
Authors: Froidevaux Jérémy S. P. , Barbaro Luc , Vinet Olivier , Larrieu Laurent , Bas Yves , Molina Jérôme , Calatayud François , Brin Antoine
Published: May 2021

Despite the key importance of the landscape matrix for bats, we still not fully understand how the effect of forest composition interacts at combined stand and landscape scales to shape bat communities. In addition, we lack detailed knowledge on the effects of local habitat structure on bat-prey relationships in forested landscapes. We tested the assumptions that (i) forest composition has interacting effects on bats between stand and landscape scales; and (ii) stand structure mediates prey abundance effects on bat activity. Our results indicated that in conifer-dominated landscapes (> 80% of coniferous forests) bat activity was higher in stands with a higher proportion of deciduous trees while bats were less active in stands with a higher proportion of deciduous trees in mixed forest landscapes (~ 50% of deciduous forests). Moth abundance was selected in the best models for six among nine bat species. The positive effect of moth abundance onBarbastella barbastelluswas mediated by vegetation clutter, with dense understory cover likely reducing prey accessibility. Altogether, our findings deepen our understanding of the ecological processes affecting bats in forest landscapes and strengthen the need to consider both landscape context and trophic linkage when assessing the effects of stand-scale compositional and structural attributes on bats.
A super-potent tetramerized ACE2 protein displays enhanced neutralization of SARS-CoV-2 virus infection
Authors: Miller Ami , Leach Adam , Thomas Jemima , McAndrew Craig , Bentley Emma , Mattiuzzo Giada , John Lijo , Mirazimi Ali , Harris Gemma , Gamage Nadisha , Carr Stephen , Ali Hanif , Van Montfort Rob , Rabbitts Terence
Published: May 2021

Approaches are needed for therapy of the severe acute respiratory syndrome from SARS-CoV-2 coronavirus (COVID-19). Interfering with the interaction of viral antigens with the angiotensin converting enzyme 2 (ACE-2) receptor is a promising strategy by blocking the infection of the coronaviruses into human cells. We have implemented a novel protein engineering technology to produce a super-potent tetravalent form of ACE2, coupled to the human immunoglobulin γ1 Fc region, using a self-assembling, tetramerization domain from p53 protein. This high molecular weight Quad protein (ACE2-Fc-TD) retains binding to the SARS-CoV-2 receptor binding spike protein and can form a complex with the spike protein plus anti-viral antibodies. The ACE2-Fc-TD acts as a powerful decoy protein that out-performs soluble monomeric and dimeric ACE2 proteins and blocks both SARS-CoV-2 pseudovirus and SARS-CoV-2 virus infection with greatly enhanced efficacy. The ACE2 tetrameric protein complex promise to be important for development as decoy therapeutic proteins against COVID-19. In contrast to monoclonal antibodies, ACE2 decoy is unlikely to be affected by mutations in SARS-CoV-2 that are beginning to appear in variant forms. In addition, ACE2 multimeric proteins will be available as therapeutic proteins should new coronaviruses appear in the future because these are likely to interact with ACE2 receptor.
The antagonistic Metschnikowia andauensis produces extracellular enzymes and pulcherrimin, whose production can be promoted by the culture factors
Authors: Horváth Enikő , Dályai Lívia , Szabó Erna , Barna Teréz , Kalmár László , Posta József , Sipiczki Matthias , Csoma Hajnalka , Miklós Ida
Published: May 2021

Biological control against microbial infections has a great potential as an alternative approach instead of fungicidal chemicals, which can cause environmental pollution. The pigment producerMetschnikowia andauensisbelongs to the antagonistic yeasts, but details of the mechanism by which it inhibits growth of other microbes are less known. Our results confirmed its antagonistic capacity on other yeast species isolated from fruits or flowers and demonstrated that the antagonistic capacity was well correlated with the size of the red pigmented zone. We have isolated and characterized its red pigment, which proved to be the iron chelating pulcherrimin. Its production was possible even in the presence of 0.05 mg/ml copper sulphate, which is widely used in organic vineyards because of its antimicrobial properties. Production and localisation of the pulcherrimin strongly depended on composition of the media and other culture factors. Glucose, galactose, disaccharides and the presence of pectin or certain amino acids clearly promoted pigment production. Higher temperatures and iron concentration decreased the diameter of red pigmented zones. The effect of pH on pigment production varied depending of whether it was tested in liquid or solid media. In addition, our results suggest that other mechanisms besides the iron depletion of the culture media may contribute to the antagonistic capacity ofM. andauensis.
Quantitative evaluation of macromolecular crowding environment based on translational and rotational diffusion using polarization dependent fluorescence correlation spectroscopy
Authors: Yamamoto Johtaro , Matsui Akito , Gan Fusako , Oura Makoto , Ando Riku , Matsuda Takahiro , Gong Jian Ping , Kinjo Masataka
Published: May 2021

Macromolecular crowding (MMC) in cells is a hot topic in biology; therefore, well-characterized measurement standards for the evaluation of the nano-environment in MMC solutions are necessary. We propose to use polarization-dependent fluorescence correlation spectroscopy (Pol-FCS) for evaluation of macromolecular crowding in solutions. Pol-FCS can simultaneously measure the relaxation times of rotational and translational diffusion of fluorescent molecules at the same position, even in living cells with low damage. In this report, the differences in the nano-environment among solutions of small molecules, gels, and MMC solutions were evaluated by comparing their rotational and translational diffusion using Pol-FCS. Moreover, this method could distinguish the phase shift in the polyethylene glycol solution. Finally, we separately evaluated the nano-environment in the cytosol and nucleus of living cells in different cell lines and cell cycles. We expect this evaluation method to be useful in characterizing the nano-environment in MMC studies. In addition, the proposed method may be useful for other nano-environments such as liquid–liquid phase separation.
MMP20-generated amelogenin cleavage products prevent formation of fan-shaped enamel malformations
Authors: Bartlett John D. , Smith Charles E. , Hu Yuanyuan , Ikeda Atsushi , Strauss Mike , Liang Tian , Hsu Ya-Hsiang , Trout Amanda H. , McComb David W. , Freeman Rebecca C. , Simmer James P. , Hu Jan C.-C.
Published: May 2021

Dental enamel forms extracellularly as thin ribbons of amorphous calcium phosphate (ACP) that initiate on dentin mineral in close proximity to the ameloblast distal membrane. Secreted proteins are critical for this process. Enam−/− and Ambn−/− mice fail to form enamel. We characterize enamel ribbon formation in wild-type (WT), Amelx−/− and Mmp20−/− mouse mandibular incisors using focused ion beam scanning electron microscopy (FIB-SEM) in inverted backscatter mode. In Amelx−/− mice, initial enamel mineral ribbons extending from dentin are similar in form to those of WT mice. As early enamel development progresses, the Amelx−/− mineral ribbons develop multiple branches, resembling the staves of a Japanese fan. These striking fan-shaped structures cease growing after attaining ~ 20 µm of enamel thickness (WT is ~ 120 µm). The initial enamel mineral ribbons in Mmp20−/− mice, like those of the Amelx−/− and WT, extend from the dentin surface to the ameloblast membrane, but appear to be fewer in number and coated on their sides with organic material. Remarkably, Mmp20−/− mineral ribbons also form fan-like structures that extend to ~ 20 µm from the dentin surface. However, these fans are subsequently capped with a hard, disorganized outer mineral layer. Amelogenin cleavage products are the only matrix components absent in both Amelx−/− and Mmp20−/− mice. We conclude that MMP20 and amelogenin are not critical for enamel mineral ribbon initiation, orientation, or initial shape. The pathological fan-like plates in these mice may form from the lack of amelogenin cleavage products, which appear necessary to form ordered hydroxyapatite.
Asbestos bodies count and morphometry in bulk lung tissue samples by non-invasive X-ray micro-tomography
Authors: Bardelli Fabrizio , Brun Francesco , Capella Silvana , Bellis Donata , Cippitelli Claudia , Cedola Alessia , Belluso Elena
Published: May 2021

The number of the Asbestos Bodies (AB), i.e. asbestos that developed an iron-protein coating during its permanence in biological tissues, is one of the most accessible markers of asbestos exposure in individuals. The approaches developed to perform AB count in biological tissues are based on the manual examination of tissue digests or histological sections by means of light or electron microscopies. Although these approaches are well established and relatively accessible, manual examination is time-consuming and can be reader-dependent. Besides, approximations are applied because of the limitations of 2D readings and to speed up manual counts. In addition, sample preparation using tissue digests require an amount of tissue that can only be obtained by invasive surgery or post-mortem sampling. In this paper, we propose a new approach to AB counting based on non-destructive 3D imaging, which has the potential to overcome most of the limitations of conventional approaches. This method allows automating the AB count and determining their morphometry distribution in bulk tissue samples (ideally non-invasive needle biopsies), with minimal sample preparation and avoiding approximations. Although the results are promising, additional testing on a larger number of AB-containing biological samples would be required to fully validate the method.
Investigation of the thermal tolerance of silicon-based lateral spin valves
Authors: Yamashita N. , Lee S. , Ohshima R. , Shigematsu E. , Koike H. , Suzuki Y. , Miwa S. , Goto M. , Ando Y. , Shiraishi M.
Published: May 2021

Improvement in the thermal tolerance of Si-based spin devices is realized by employing thermally stable nonmagnetic (NM) electrodes. For Au/Ta/Al electrodes, intermixing between Al atoms and Au atoms occurs at approximately 300 °C, resulting in the formation of a Au/Si interface. The Au–Si liquid phase is formed and diffuses mainly along an in-plane direction between the Si and AlN capping layers, eventually breaking the MgO layer of the ferromagnetic (FM) metal/MgO electrodes, which is located 7 µm away from the NM electrodes. By changing the layer structure of the NM electrode from Au/Ta/Al to Au/Ta, the thermal tolerance is clearly enhanced. Clear spin transport signals are obtained even after annealing at 400 °C. To investigate the effects of Mg insertion in FM electrodes on thermal tolerance, we also compare the thermal tolerance among Fe/Co/MgO, Fe/Co/Mg/MgO and Fe/Co/MgO/Mg contacts. Although a highly efficient spin injection has been reported by insertion of a thin Mg layer below or above the MgO layer, these thermal tolerances decrease obviously.
Behavior and properties of water in silicate melts under deep mantle conditions
Authors: Karki Bijaya B. , Ghosh Dipta B. , Karato Shun-ichiro
Published: May 2021

Water (H2O) as one of the most abundant fluids present in Earth plays crucial role in the generation and transport of magmas in the interior. Though hydrous silicate melts have been studied extensively, the experimental data are confined to relatively low pressures and the computational results are still rare. Moreover, these studies imply large differences in the way water influences the physical properties of silicate magmas, such as density and electrical conductivity. Here, we investigate the equation of state, speciation, and transport properties of water dissolved in Mg1−xFexSiO3and Mg2(1−x)Fe2xSiO4melts (forx = 0 and 0.25) as well as in its bulk (pure) fluid state over the entire mantle pressure regime at 2000–4000 K using first-principles molecular dynamics. The simulation results allow us to constrain the partial molar volume of the water component in melts along with the molar volume of pure water. The predicted volume of silicate melt + water solution is negative at low pressures and becomes almost zero above 15 GPa. Consequently, the hydrous component tends to lower the melt density to similar extent over much of the mantle pressure regime irrespective of composition. Our results also show that hydrogen diffuses fast in silicate melts and enhances the melt electrical conductivity in a way that differs from electrical conduction in the bulk water. The speciation of the water component varies considerably from the bulk water structure as well. Water is dissolved in melts mostly as hydroxyls at low pressure and as –O–H–O–, –O–H–O–H– and other extended species with increasing pressure. On the other hand, the pure water behaves as a molecular fluid below 15 GPa, gradually becoming a dissociated fluid with further compression. On the basis of modeled density and conductivity results, we suggest that partial melts containing a few percent of water may be gravitationally trapped both above and below the upper mantle-transition region. Moreover, such hydrous melts can give rise to detectable electrical conductance by means of electromagnetic sounding observations.