bluuebunny/crossref_metadata_2025 huggingface dataset:
CoCoNet: an efficient deep learning tool for viral metagenome binning
Authors: Arisdakessian Cédric G , Nigro Olivia D , Steward Grieg F , Poisson Guylaine , Belcaid Mahdi
Published: April 2021

Motivation

Metagenomic approaches hold the potential to characterize microbial communities and unravel the intricate link between the microbiome and biological processes. Assembly is one of the most critical steps in metagenomics experiments. It consists of transforming overlapping DNA sequencing reads into sufficiently accurate representations of the community’s genomes. This process is computationally difficult and commonly results in genomes fragmented across many contigs. Computational binning methods are used to mitigate fragmentation by partitioning contigs based on their sequence composition, abundance or chromosome organization into bins representing the community’s genomes. Existing binning methods have been principally tuned for bacterial genomes and do not perform favorably on viral metagenomes.

Results

We propose Composition and Coverage Network (CoCoNet), a new binning method for viral metagenomes that leverages the flexibility and the effectiveness of deep learning to model the co-occurrence of contigs belonging to the same viral genome and provide a rigorous framework for binning viral contigs. Our results show that CoCoNet substantially outperforms existing binning methods on viral datasets.

Availability and implementation

CoCoNet was implemented in Python and is available for download on PyPi (https://pypi.org/). The source code is hosted on GitHub at https://github.com/Puumanamana/CoCoNet and the documentation is available at https://coconet.readthedocs.io/en/latest/index.html. CoCoNet does not require extensive resources to run. For example, binning 100k contigs took about 4 h on 10 Intel CPU Cores (2.4 GHz), with a memory peak at 27 GB (see Supplementary Fig. S9). To process a large dataset, CoCoNet may need to be run on a high RAM capacity server. Such servers are typically available in high-performance or cloud computing settings.

Supplementary information

Supplementary data are available at Bioinformatics online.
Optimal Bayesian supervised domain adaptation for RNA sequencing data
Authors: Boluki Shahin , Qian Xiaoning , Dougherty Edward R
Published: April 2021

Motivation

When learning to subtype complex disease based on next-generation sequencing data, the amount of available data is often limited. Recent works have tried to leverage data from other domains to design better predictors in the target domain of interest with varying degrees of success. But they are either limited to the cases requiring the outcome label correspondence across domains or cannot leverage the label information at all. Moreover, the existing methods cannot usually benefit from other information available a priori such as gene interaction networks.

Results

In this article, we develop a generative optimal Bayesian supervised domain adaptation (OBSDA) model that can integrate RNA sequencing (RNA-Seq) data from different domains along with their labels for improving prediction accuracy in the target domain. Our model can be applied in cases where different domains share the same labels or have different ones. OBSDA is based on a hierarchical Bayesian negative binomial model with parameter factorization, for which the optimal predictor can be derived by marginalization of likelihood over the posterior of the parameters. We first provide an efficient Gibbs sampler for parameter inference in OBSDA. Then, we leverage the gene-gene network prior information and construct an informed and flexible variational family to infer the posterior distributions of model parameters. Comprehensive experiments on real-world RNA-Seq data demonstrate the superior performance of OBSDA, in terms of accuracy in identifying cancer subtypes by utilizing data from different domains. Moreover, we show that by taking advantage of the prior network information we can further improve the performance.

Availability and implementation

The source code for implementations of OBSDA and SI-OBSDA are available at the following link. https://github.com/SHBLK/BSDA.

Supplementary information

Supplementary data are available at Bioinformatics online.
Feasible TLC-Spectro-Densitometry Technique for Simultaneous Determination of Two Hepatitis C Antiviral Drugs, Sofosbuvir and Simeprevir: Application to Combined Pharmaceutical Dosage Forms and Human Plasma
Authors: Mohammed Bassam Shaaban , Derayea Sayed M , Hamad Amal E
Published: April 2021

A high-performance thin-layer chromatographic method was developed and validated for the concurrent determination of simeprevir (SMV) and sofosbuvir (SOF). The chromatographic separation was attained on silica gel 60 F254 as stationary phase and ethyl acetate–hexane–methanol (5.0:4.0:1.0, v/v/v) as developing solvent with UV detection at 273 nm. The RF values were 0.67±0.02 and 0.43±0.02 for SMV and SOF, respectively. The method has been validated in respect to the guidelines of the International Conference on Harmonization. Linearity was maintained between 60–1,000 and 70–1,200 ng/band for SMV and SOF, respectively, with good correlation coefficients (0.9993–0.9997) for both drugs. The suggested method was highly sensitive as the calculated detection limits were 15 and 22 ng/band, while the quantitation limits were 44 and 66 ng/ band for SMV and SOF, respectively. The suggested methodology has been effectively employed for the determination of the mentioned drugs in their pure forms and their pharmaceutical dosage forms as well as human plasma without significant interference of the pharmaceutical excipients or plasma components.
eCK-Secure Authenticated Key Exchange against Auxiliary Input Leakage
Authors: Li Sujuan , Zhang Futai
Published: April 2021

Authenticated key exchange protocols are quite important primitives for practical applications, since they enable two parties to generate a shared high entropy secret key. In this paper we mainly focus on the authenticated key exchange (AKE) against auxiliary input leakage. As the major contribution of this work, we present a generic framework for the construction of AKE protocols that are secure against auxiliary input leakage. An instantiation based on the generalized decisional Diffie-Hellman (GDDH) assumption in the standard model is also given to demonstrate the feasibility of our proposed framework. We also give a comparison among the existing leakage resilient AKE protocols with auxiliary inputs.
Young adults’ coping strategies against loneliness during the COVID-19-related quarantine in Greece
Authors: Golemis Adrianos , Voitsidis Panteleimon , Parlapani Eleni , Nikopoulou Vasiliki A , Tsipropoulou Virginia , Karamouzi Panayiota , Giazkoulidou Aikaterini , Dimitriadou Aikaterini , Kafetzopoulou Christina , Holeva Vasiliki , Diakogiannis Ioannis
Published: April 2021

COVID-19 and the related quarantine disrupted young adults’ academic and professional life, daily routine and socio-emotional well-being. This cross-sectional study focused on the emotional and behavioural responses of a young adult population during the COVID-19-related quarantine in April 2020, in Greece. The study was conducted through an online survey. A total of 1559 young adults, aged 18−30 years, completed Steele’s Social Responsibility Motivation Scale and the De Jong Gierveld Loneliness Scale, and answered questions about compliance with instructions, quarantine-related behaviours and coping strategies. According to the results, participants displayed a relatively high sense of social responsibility (M = 16.09, SD = 2.13) and a trend towards moderate feeling of loneliness (M = 2.65, SD = 1.62); young women reported significantly higher levels of loneliness than men. The majority complied with instructions often (46.4%) or always (44.8%). Significantly more women created a new social media account and used the social media longer than 5 h/day, compared with men. Resorting to religion, practicing sports and sharing thoughts and feelings about COVID-19 with others predicted higher levels of social responsibility; humour, practicing sports and sharing thoughts and feelings about COVID-19 with others predicted lower levels of loneliness. Conclusively, COVID-19 is expected to have a significant psychological impact on young adults. Currently, Greece is going through the second quarantine period. This study raises awareness about loneliness in young adults during the COVID-19-related quarantine and highlights the importance of developing online programmes, attractive to younger people, to nurture adaptive coping strategies against loneliness.
Proteomic analysis of aged and OPTN E50K retina in the development of normal tension glaucoma
Authors: Liu Xinna , Wang Qi , Shao Zhengbo , Zhang Shiqi , Hou Mingying , Jiang Menglu , Du Mengxian , Li Jing , Yuan Huiping
Published: April 2021

Progressive degeneration of retinal ganglion cells (RGCs) is a major characteristic of glaucoma, whose underlying mechanisms are still largely unknown. An E50K mutation in the Optineurin (OPTN) gene is a leading cause of normal tension glaucoma (NTG), directly affecting RGCs without high intraocular pressure and causing severe glaucomatous symptoms in clinical settings. A systematic analysis of the NTG mouse model is crucial for better understanding of the underlying pathological mechanisms for glaucoma. To elucidate proteomic and biochemical pathway alterations during NTG development, we established an OPTN E50K mutant mouse model through CRISPR/Cas9. Retinal proteins from resulting mice exhibiting glaucomatous phenotypes were subject to tandem mass tag-labeled quantitative proteomics and then analyzed through bioinformatics methods to characterize the molecular and functional signatures of NTG. We identified 6364 quantitative proteins in our proteomic analysis. Bioinformatics analysis revealed that OPTN E50K mice experienced protein synthesis dysregulation, age-dependent energy defects and autophagy-lysosome pathway dysfunction. Certain biological features, including amyloid deposition, RNA splicing, microglia activation and reduction of crystallin production, were similar to Alzheimer’s disease. Our study is the first to describe proteomic and biochemical pathway alterations in NTG pathogenesis during disease advancement. Several proteomic signatures overlapped with retinal changes found in the ad mice model, suggesting the presence of common mechanisms between age-related degenerative disorders, as well as prospective new targets for diagnostic and therapeutic strategies.
Perspective on integration of concentrated solar power plants
Authors: Yousef Bashria A A , Hachicha Ahmed A , Rodriguez Ivette , Abdelkareem Mohammad Ali , Inyaat Abrar
Published: April 2021

Integration concept of energy resources can complement between the competing energy technologies. This manuscript presents a comprehensive review on the state-of-the-art of concentrated solar power (CSP) integration technology with various energy sources. Compared to CSP alone, integration of CSP and fossil fuel provides promising solution to solar energy intermittence, emissions and installation cost reduction, with 25% increase in electric power generation. On the other hand, integration of CSP with other sources such as geothermal and biomass can supply dispatchable power with almost zero emissions. The electricity produced via integrated CSP and photovoltaic (PV) has better power quality and less cost compared to that produced by PV alone or CSP alone, respectively. Integration of CSP and wind energy can meet peak demand, reduce power fluctuation and provide electrical power at a high capacity factor. However, the lack of reliable biomass, geothermal and wind data with the solar availability at specific locations is the main obstacle for the acceptance and further deployment of hybridization systems. The advantages and limitations of the hybrid technologies presented in this paper according to the literature are reviewed. Moreover, future directions of CSP such as production of hydrogen, solid particles receivers and the integration of supercritical carbon dioxide cycle are also discussed.
Development of the perceptions of preventable adverse events assessment tool (PPAEAT): measurement properties and patients’ mental health status
Authors: Keller Franziska Maria , Derksen Christina , Kötting Lukas , Schmiedhofer Martina , Lippke Sonia
Published: April 2021

Background

Patient-centered care and patient involvement have been increasingly recognized as crucial elements of patient safety. However, patient safety has rarely been evaluated from the patient perspective with a quantitative approach aiming at making patient safety and preventable adverse events measurable.

Objectives

The objectives of this study were to develop and evaluate the psychometric properties of a questionnaire assessing patient safety by perceived triggers of preventable adverse events among patients in primary health-care settings while considering mental health.

Methods

Two hundred and ten participants were recruited through various digital and print channels and asked to complete an online survey between November 2019 and April 2020. Exploratory factor analysis was performed to identify domains of triggers of preventable adverse events affecting patient safety. Furthermore, a multi-trait scaling analysis was performed to evaluate internal reliability as well as item-scale convergent–discriminant validity. A multivariate analysis of covariance evaluated whether individuals below and above the symptom threshold for depression and generalized anxiety perceive triggers of preventable adverse events differently.

Results

The five factors determined were information and communication with patients, time constraints of health-care professionals, diagnosis and treatment, hygiene and communication among health-care professionals, and knowledge and operational procedures. The questionnaire demonstrated a good total and subscale internal consistency (α = 0.90, range = 0.75–0.88), good item-scale convergent validity with significant correlations between 0.57 and 0.78 (P < 0.05; P < 0.01) for all items with their associated subscales, and satisfactory item-scale discriminant validity between 0.14 and 0.55 (P > 0.05) with no significant correlations between the items and their competing subscales. The questionnaire further revealed to be a generic measure irrespective of patients’ mental health status. Patients older than 50 years of age perceived a significantly greater threat to their own safety compared to patients below that age.

Conclusion

The developed Perceptions of Preventable Adverse Events Assessment Tool (PPAEAT) exhibits good psychometric properties, which supports its use in future research and primary health-care practice. Further validation of the PPAEAT in different settings, languages and larger samples is needed. The results of this study need to be considered when assessing patient safety in the context of health-care research.
The Looping Structure of Buddhist Thought (Or, How Chan Buddhism Resolves the Quantum Measurement Problem)
Authors: Sharf Robert H
Published: April 2021

Is there a world out there when nobody is looking? This is a question that medieval Buddhist scholiasts struggled with over many centuries, giving rise to a variety of competing positions. In this article, I identify a loop that runs through and structures seemingly antithetical positions—some realist, some antirealist—in these debates. My claim is that the loop is a feature of our lifeworld, and thus any serious reflection on the mind/world relationship is bound to get entangled in it. Even modern physics has come up against it, such that rival positions advanced by quantum theorists are structurally analogous to positions proffered in medieval Buddhist writings. I conclude by turning to the Chan Buddhist tradition, which is often mischaracterized as hostile to philosophical analysis. Chan is among the few Buddhist schools that recognize, foreground, and celebrate the manner in which mind and world enfold each other. As such, this paper foregrounds the decidedly philosophical insights of the Chan tradition.
Robot-assisted thoracoscopic surgery using a narrow-profile vascular stapler through an 8-mm robotic port
Authors: Shidei Hiroaki , Mitsuboshi Shota , Akihiro Koen , Aoshima Hiroe , Isaka Tamami , Kanzaki Masato
Published: April 2021

The number of robot-assisted thoracoscopic surgery (RATS) procedures performed for thoracic disease has been increasing. Recently, a narrow-profile vascular stapler (Signia small-diameter reload, Covidien Japan, Tokyo, Japan) has been developed to provide superior access and precise staple placement in video-assisted thoracoscopic surgery (VATS) procedures. A 70-year-old man who was an exsmoker visited our hospital with a complaint of coughing. Chest computed tomography revealed a tumor with a cavity, ~55 mm in diameter, in the right-middle lobe. A 4-arm RATS right-middle lobectomy was performed with a 4-cm utility thoracotomy with da Vinci Xi (Intuitive Surgical, Sunnyvale, CA, USA). The pulmonary vessels were divided using a narrow-profile vascular stapler through an 8-mm port. No complications occurred in the postoperative course. With a narrow-profile vascular stapler, portal RATS can be performed after VATS lung biopsy using 8-mm ports.
Involvement of the R2R3-MYB transcription factor MYB21 and its homologs in regulating flavonol accumulation in Arabidopsis stamen
Authors: Zhang Xueying , He Yuqing , Li Linying , Liu Hongru , Hong Gaojie
Published: April 2021

Commonly found flavonols in plants are synthesized from dihydroflavonols by flavonol synthase (FLS). The genome of Arabidopsis thaliana contains six FLS genes, among which FLS1 encodes a functional enzyme. Previous work has demonstrated that the R2R3-MYB subgroup 7 transcription factors MYB11, MYB12, and MYB111 redundantly regulate flavonol biosynthesis. However, flavonol accumulation in pollen grains was unaffected in the myb11myb12myb111 triple mutant. Here we show that MYB21 and its homologs MYB24 and MYB57, which belong to subgroup 19, promote flavonol biosynthesis through regulation of FLS1 gene expression. We used a combination of genetic and metabolite analysis to identify the role of MYB21 in regulating flavonol biosynthesis through direct binding to the GARE cis-element in the FLS1 promoter. Treatment with kaempferol or overexpression of FLS1 rescued stamen defects in the myb21 mutant. We also observed that excess reactive oxygen species (ROS) accumulated in the myb21 stamen, and that treatment with the ROS inhibitor diphenyleneiodonium chloride partly rescued the reduced fertility of the myb21 mutant. Furthermore, drought increased ROS abundance and impaired fertility in myb21, myb21myb24myb57, and chs, but not in the wild type or myb11myb12myb111, suggesting that pollen-specific flavonol accumulation contributes to drought-induced male fertility by ROS scavenging in Arabidopsis.
PHYTOCHROME INTERACTING FACTORS PIF4 and PIF5 promote heat stress induced leaf senescence in Arabidopsis
Authors: Li Na , Bo Cunpei , Zhang Yuanyuan , Wang Lei
Published: April 2021

Leaf senescence can be triggered by multiple abiotic stresses including darkness, nutrient limitation, salinity, and drought. Recently, heatwaves have been occurring more frequently, and they dramatically affect plant growth and development. However, the underlying molecular networks of heat stress-induced leaf senescence remain largely uncharacterized. Here we showed that PHYTOCHROME INTERACTING FACTOR 4 (PIF4) and PIF5 proteins could efficiently promote heat stress-induced leaf senescence in Arabidopsis. Transcriptomic profiling analysis revealed that PIF4 and PIF5 are likely to function through multiple biological processes including hormone signaling pathways. Further, we characterized NAC019, SAG113, and IAA29 as direct transcriptional targets of PIF4 and PIF5. The transcription of NAC019, SAG113, and IAA29 changes significantly in daytime after heat treatment. In addition, we demonstrated that PIF4 and PIF5 proteins were accumulated during the recovery after heat treatment. Moreover, we showed that heat stress-induced leaf senescence is gated by the circadian clock, and plants might be more actively responsive to heat stress-induced senescence during the day. Taken together, our findings proposed important roles for PIF4 and PIF5 in mediating heat stress-induced leaf senescence, which may help to fully illustrate the molecular network of heat stress-induced leaf senescence in higher plants and facilitate the generation of heat stress-tolerant crops.
Low-temperature acclimation and legacy effects of summer water deficits in olive freezing resistance
Authors: Arias Nadia S , Scholz Fabián G , Goldstein Guillermo , Bucci Sandra J
Published: April 2021

Low temperatures and drought are the main environmental factors affecting plant growth and productivity across most of the terrestrial biomes. The objective of this study was to analyze the effects of water deficits before the onset of low temperatures in winter to enhance freezing resistance in olive trees. The study was carried out near the coast of Chubut, Argentina. Plants of five olive cultivars were grown outdoor in pots and exposed to different water deficit treatments. We assessed leaf water relations, ice nucleation temperature (INT), cell damage (LT50), plant growth and leaf nitrogen content during summer and winter in all cultivars and across water deficit treatments. Leaf INT and LT50 decreased significantly from summer to winter within each cultivar and between treatments. We observed a trade-off between resources allocation to freezing resistance and vegetative growth, such that an improvement in resistance to sub-zero temperatures was associated with lower growth in tree height. Water deficit applied during summer increased the amount of osmotically active solutes and decreased the leaf water potentials. This type of legacy effect persists during the winter after the water deficit even when treatment was removed by natural rainfalls.
Weevil borers affect the spatio-temporal dynamics of banana Fusarium wilt
Authors: Heck Daniel , Alves Gabriel , Mizubuti Eduardo S. G.
Published: April 2021

Dispersal of propagules of a pathogen has remarkable effects on the development of epidemics. Previous studies suggested that insect pests play a role in the development of Fusarium wilt (FW) epidemics in banana fields. We provided complementary evidence for the involvement of two insect pests of banana, the weevil borer (Cosmopolites sordidusL. - WB) and the false weevil borer (Metamasius hemipterusL. - FWB), in the dispersal ofFusarium oxysporumf. sp.cubense(Foc) using a comparative epidemiology approach under field conditions. Two banana plots located in a field with historical records of FW epidemics were used, one was managed withBeauveria bassianato reduce the population of weevils, and the other was left withoutB. bassianaapplications. The number of WB and FWB was monitored biweekly and the FW incidence was quantified bimonthly during two years. The population of WB and the incidence (6.7%) of FW in the plot managed withB. bassianawere lower than in the plot left unmanaged (13%). The monomolecular model best fitted the FW disease progress data and, as expected, the average estimated disease progress rate was lower in the plot managed with the entomopathogenic fungus (r= 0.0024) compared to the unmanaged plot (r= 0.0056). Aggregation of FW was higher in the field with WB management. WB affected the spatial and temporal dynamics of FW epidemics under field conditions and brought evidence that managing the insects may reduce FW of bananas intensity.
Accelerating Strain Engineering using Desorption Electrospray Ionization-Imaging Mass Spectrometry and Untargeted Molecular Analysis of Intact Microbial Colonies
Authors: Ellis Berkley M. , Babele Piyoosh , May Jody C. , Johnson Carl H. , Pfleger Brian F. , Young Jamey D. , McLean John A.
Published: April 2021

Progress in the fields of genomic and biologic sciences has yielded microbial bioprocesses for the advanced production of chemicals. While biomanufacturing has the potential to address global demands for renewable fuels and chemicals, engineering microbial cell factories that can compete with synthetic chemical processes remains a challenge. Optimizing strains for enhanced chemical production is no longer limited by reading and writing DNA, rather it is impeded by the lack of high-throughput platforms for characterizing the metabolic phenotypes resulting from specific gene editing events. To address this issue, we have developed a desorption electrospray ionization- imaging mass spectrometry (DESI-IMS) screening assay that is conducive to both multiplexed sampling and untargeted analyses. This technology bridges the gap between genomic and metabolomic timescales by simultaneously characterizing the chemical output of various engineeredEscherichia colistrains rapidly and directly under ambient conditions. The developed method was used to phenotype fourE. colistrains on the basis of measured metabolomes, which were validated via PCR genotyping. Untargeted DESI-IMS phenotyping suggests multiple strategies for future engineering which include: (i) relative amounts of specific biosynthetic products, (ii) identification of secondary products, and (iii) the metabolome of engineered organisms. In sum, we present a workflow to accelerate strain engineering by providing rapid, untargeted, and multiplexed analyses of microbial metabolic phenotypes.
Nutrient cycling is an important mechanism for homeostasis in plant cells
Authors: Dreyer Ingo
Published: April 2021

Homeostasis in living cells refers to the steady state of internal, physical, and chemical conditions. It is maintained by self-regulation of the dynamic cellular system. In order to gain insight into homeostatic mechanisms that keep cytosolic nutrient concentrations in plant cells within a homeostatic range, I performed computational cell biology experiments. Systems of membrane transporters were modelled mathematically followed by the simulation of their dynamics. The detailed analyses of ‘what-if’ scenarios demonstrate that a single transporter type for a nutrient, irrespective whether it is a channel or a co-transporter, is not sufficient to set a desired cytosolic concentration. A cell cannot flexibly react on different external conditions. At least two different transporter types for the same nutrient are required, which are energized differently. The gain of flexibility in adjusting the nutrient concentration was accompanied by the establishment of energy-consuming nutrient cycles at the membrane suggesting that these sometimes called ‘futile’ cycles are not as futile as they appear. This understanding may help in future to design new strategies for increasing nutrient use efficiency of crop plants taking into account the complex interplay of transporter networks at the cellular level.

One sentence summary

First principles of membrane transport explain why the maintenance of a constant cytosolic nutrient concentration is often accompanied by the ‘futile’ cycling of the nutrient across the membrane.
Activation of GPR116/ADGRF5 by its tethered agonist requires key amino acids in extracellular loop 2 of the transmembrane region
Authors: Bridges James P. , Safina Caterina , Pirard Bernard , Brown Kari , Filuta Alyssa , Bouhelal Rochdi , Patel Sejal , Seuwen Klaus , Miller William E. , Ludwig Marie-Gabrielle
Published: April 2021

The mechanistic details of the tethered agonist mode of activation for adhesion GPCRs has not been completely deciphered. We set out to investigate the physiologic importance of autocatalytic cleavage upstream of the agonistic peptide sequence, an event necessary for NTF displacement and subsequent receptor activation. To examine this hypothesis, we characterized tethered agonist-mediated activation of GPR116in vitroandin vivo. A knock-in mouse expressing a non-cleavable GPR116 mutant phenocopies the pulmonary phenotype of GPR116 knock-out mice, demonstrating that tethered agonist-mediated receptor activation is indispensable for functionin vivo. Using site-directed mutagenesis and species swapping approaches we identified key conserved amino acids for GPR116 activation in the tethered agonist sequence and in extracellular loops 2/3 (ECL2/3). We further highlight residues in transmembrane7 (TM7) that mediate stronger signaling in mouse versus human GPR116 and recapitulate these findings in a model supporting tethered agonist:ECL2 interactions for GPR116 activation.

Grant support

This work was supported in part by HL131634 (JPB) from the National Heart, Lung and Blood Institute of the National Institutes of Health.
Downregulation of NCL attenuates tumor formation and growth in cervical cancer by targeting the PI3K/AKT pathway
Authors: Ying Jun , Pan Ruowang , Tang Zhouhao , Zhu Jiayin , Ren Ping , Lou Yang , Zhang Enyong , Huang Dadao , Hu Penghong , Li Dong , Bao Qiyu , Li Peizhen
Published: April 2021

Nucleolin (NCL, C23) is a multifunctional phosphoprotein that plays a vital role in modulating the survival, proliferation and apoptosis of cancer cells. However, the effects of NCL on cervical cancer and the underlying mechanisms behind this are poorly understood. In the study presented here, Hela cells were transfected with shRNAs targeting the endogenous NCL gene (sh-NCL-Hela). NCL knockdown inhibited cell proliferation and promoted apoptosis bothin vivoandin vitro. Mechanistic studies revealed that NCL knockdown inhibited the PI3K/AKT pathway by upregulating FGF, ITGA, TNXB, VEGF, Caspase 3, and Bax, as well as by downregulating AKT, GNB4, CDK6, IL6R, LAMA, PDGFD, PPP2RSA and BCL-2. In addition, the expression levels of apoptosis-related genes after using a PI3K inhibitor LY294002 were consistent with shRNA studies, while treatment with a 740Y-P agonist showed the opposite effect. Altogether, this study uncovered that downregulation of NCL may be a novel treatment strategy for cervical cancer.
Changes in body shape implicate cuticle stretch inC. elegansgrowth control
Authors: Nyaanga Joy , Goss Christina , Zhang Gaotian , Ahmed Hannah N. , Andersen Elliot J. , Miller Isabella R. , Rozenich Justine K. , Swarthout Iris L. , Vaughn Jordan A. , Mangan Niall M. , Shirman Sasha , Andersen Erik C.
Published: April 2021

Growth control establishes organism size, requiring mechanisms to sense and adjust growth during development. Studies of single cells revealed that size homeostasis uses distinct control methods. In multicellular organisms, mechanisms that regulate single cell growth must integrate control across organs and tissues during development to generate adult size and shape. We leveraged the roundwormCaenorhabditis elegansas a scalable and tractable model to collect precise growth measurements of thousands of individuals, measure feeding behavior, and quantify changes in animal size and shape during a densely sampled developmental time course. As animals transitioned from one developmental stage to the next, we observed changes in body aspect ratio while body volume remained constant. Then, we modeled a physical mechanism by which constraints on cuticle stretch could cause changes inC. elegansbody shape. The model-predicted shape changes are consistent with those observed in the data. Theoretically, cuticle stretch could be sensed by the animal to initiate larval-stage transitions, providing a means for physical constraints to influence developmental timing and growth rate inC. elegans.

Highlights

Body size measurements of thousands of animals in a dense developmental time course

Growth rate exhibits nonlinear dynamics in both length and width

Changes in body shape but not volume occur during periods of increased quiescence

Dynamics of animal shape consistent with a length-based threshold in cuticle stretch

Modeling of cuticle stretch dynamics suggests a novel mode for growth control
Host defense mechanisms induce genome instability in an opportunistic fungal pathogen
Authors: Smith Amanda , Hickman Meleah A.
Published: April 2021

The ability to generate genetic variation facilitates rapid adaptation in stressful environments. The opportunistic fungal pathogenCandida albicansfrequently undergoes large-scale genomic changes, including aneuploidy and loss-of heterozygosity (LOH), following exposure to physiological stressors and host environments. However, the specific host factors that induceC. albicansgenome instability remains largely unknown. Here, we leveraged genetically-tractable nematode hosts to specifically investigate the innate immune components driving host-associatedC. albicansgenome instability, which include host production of antimicrobial peptides (AMPs) and reactive oxygen species (ROS).C. albicansassociated with wildtype, immunocompetent hosts carried multiple large-scale genomic changes including LOH, whole chromosome, and segmental aneuploidies. In contrast,C. albicansassociated with immunocompromised hosts deficient in AMPs or ROS production had reduced LOH frequencies and fewer, if any, additional genomic changes. We also found thatC. albicans cap1Δ/Δ strains deficient in ROS detoxification, were more susceptible to host-produced ROS genome instability compared to wildtypeC. albicans. Further, genomic perturbations resulting from host-produced ROS are mitigated by the addition of antioxidants. Taken together, this work suggests that host-produced ROS and AMPs induces genotypic plasticity inC. albicanswhich may facilitate rapid adaptation and lead to phenotypic changes.
Polymer additives to personal protective equipment can inactivate pathogens
Authors: Dogan Alan B. , Dabkowski Katherine , von Recum Horst A.
Published: April 2021

Face masks have been proven to be medicine’s best public health tool for preventing transmission of airborne pathogens. However, in situations with continuous exposure, lower quality and “do-it-yourself” face masks cannot provide adequate protection against pathogens, especially when mishandled. In addition, the use of multiple face masks each day places a strain on personal protective equipment (PPE) supply and is not environmentally sustainable. Therefore, there is a significant clinical and commercial need for a reusable, pathogen-inactivating face mask. Herein, we propose adding quaternary poly(dimethylaminohexadecyl methacrylate), q(PDMAHDM), abbreviated to q(PDM), to existing fabric networks to generate “contact-killing” face masks – effectively turning cotton, polypropylene, and polyester into pathogen resistant materials. It was found that q(PDM)-integrated face masks were able to inactivate both Gram-positive and Gram-negative bacteria in liquid culture and aerosolized droplets. Furthermore, q(PDM) was electrospun into homogeneous polymer fibers, which makes the polymer practical for low-cost, scaled-up production.

Graphical Abstract
Phagocytic Uptake of Polymeric Particles by Immune cells Under Flow Conditions
Authors: Srinivas Megha , Sharma Preeti , Jhunjhunwala Siddharth
Published: April 2021

Particles injected intravenously are thought to be cleared by macrophages residing in the liver and spleen, but they also encounter circulating immune cells. It remains to be established if the circulating cells can take up particles while flowing, and if the uptake capacity is similar under static and flow conditions. Here, we use an in vitro peristaltic pump setup that mimics pulsatile blood flow to determine if immune cells take up particles under constant fluidic flow. We use polystyrene particles of varying sizes as the model of a polymeric particle for these studies. Our results show that the immune cells do phagocytose under flow conditions. We demonstrate that cell lines representing myeloid cells, primary human neutrophils and monocytes take up sub-micrometer-sized particles at similar or better rates under flow compared to static conditions. Experiments with whole human blood show that even under the crowding effects of red blood cells, neutrophils and monocytes take up particles while flowing. Together, these data suggest that circulating immune cells are likely to phagocytose intravenously injected particulates, which has implications for design of particles to evade or target these cells.
The Exon Junction Complex Core Represses Caner-specific Mature mRNA Re-splicing: A Potential Key Role in Terminating Splicing
Authors: Otani Yuta , Fujita Ken-ichi , Kameyama Toshiki , Mayeda Akila
Published: April 2021

Using the TSG101 pre-mRNA, we previously discovered cancer-specific resplicing of mature mRNA that generates aberrant transcripts/proteins. The fact that mRNA is aberrantly re-spliced in various cancer cells implies there must be an important mechanism to prevent deleterious re-splicing on the spliced mRNA in normal cells. We thus postulated that the mRNA re-splicing is controlled by specific repressors, and we searched for repressor candidates by siRNA-based screening for mRNA re-splicing activity. We found that knockdown of EIF4A3, which is a core component of the exon junction complex (EJC), significantly promoted mRNA re-splicing. Remarkably, we could recapitulate cancer-specific mRNA resplicing in normal cells by knock-down of any of the core EJC proteins, EIF4A3, MAGOH or RBM8A (Y14), implicating the EJC core as the repressor of mRNA re-splicing often observed in cancer cells. We propose that the EJC core is a critical mRNA quality control factor to prevent over-splicing of mature mRNA.
Anatomy and Development of the Pectoral Fin Vascular Network in the Zebrafish
Authors: Paulissen Scott , Castranova Daniel , Krispin Shlomo , Burns Margaret , Weinstein Brant M.
Published: April 2021

The pectoral fins of teleost fish are analogous structures to human forelimbs, and the developmental mechanisms directing their initial growth and patterning are conserved between fish and tetrapods. The forelimb vasculature is critical for limb function, and it appears to play important roles during development by promoting development of other limb structures, but the steps leading to its formation are poorly understood. In this study, we use high-resolution imaging to document the stepwise assembly of the zebrafish pectoral fin vasculature. We show that fin vascular network formation is a stereotyped, choreographed process that begins with the growth of an initial vascular loop around the pectoral fin. This loop connects to the dorsal aorta to initiate pectoral vascular circulation. Pectoral fin vascular development continues with concurrent formation of three elaborate vascular plexuses, one in the distal fin that develops into the fin ray vasculature and two near the base of the fin in association with the developing fin musculature. Our findings detail a complex yet highly choreographed series of steps involved in the development of a complete, functional organ-specific vascular network.

SUMMARY STATEMENT

The stereotyped assembly of the pectoral fin vasculature is documented from first migratory sprout into the limb bud, to the adult-like form of the four week old larva.
An immunoinformatics approach to study the epitopes contributed by Nsp13 of SARS-CoV-2
Authors: Kumar Sushant , Azad Gajendra Kumar
Published: April 2021

The on-going coronavirus disease-19 (COVID-19) pandemic caused by SARS-CoV-2 has infected hundreds of millions of people and killed more than two million people worldwide. Currently, there are no effective drugs available for treating SARS-CoV-2 infections; however, vaccines are now being administered worldwide to control this virus. In this study, we have studied SARS-CoV-2 helicase, Nsp13, which is critical for viral replication. We compared the Nsp13 sequences reported from India with the first reported sequence from Wuhan province, China to identify and characterize the mutations occurring in this protein. To correlate the functional impact of these mutations, we characterised the most prominent B cell and T cell epitopes contributed by Nsp13. Our data revealed twenty-one epitopes, which exhibited high antigenicity, stability and interactions with MHC class-I and class-II molecules. Subsequently, the physiochemical properties of these epitopes were also analysed. Furthermore, several of these Nsp13 epitopes harbour mutations, which were further characterised by secondary structure and per-residue disorderness, stability and dynamicity predictions. Altogether, we report the candidate epitopes of Nsp13 that may help the scientific community to understand the evolution of SARS-CoV-2 variants and their probable implications.
SARS-CoV-2 B.1.1.7 infection of Syrian hamster does not cause more severe disease and is protected by naturally acquired immunity
Authors: Nuñez Ivette A. , Lien Christopher Z. , Selvaraj Prabhuanand , Stauft Charles B. , Liu Shufeng , Starost Matthew F. , Wang Tony T.
Published: April 2021

Epidemiological studies have revealed the emergence of multiple SARS-CoV-2 variants of concern (VOC), including the lineage B.1.1.7 that is rapidly replacing old variants. The B.1.1.7 variant has been linked to increased morbidity rates, transmissibility, and potentially mortality (1). To assess viral fitness in vivo and to address whether the B.1.1.7 variant is capable of immune escape, we conducted infection and re-infection studies in naïve and convalescent Syrian hamsters (>10 months old). Hamsters infected by either a B.1.1.7 variant or a B.1 (G614) variant exhibited comparable viral loads and pathology. Convalescent hamsters that were previously infected by the original D614 variant were protected from disease following B.1.1.7 challenge with no observable clinical signs or lung pathology. Altogether, our study did not find that the B.1.1.7 variant significantly differs from the B.1 variant in pathogenicity in hamsters and that natural infection-induced immunity confers protection against a secondary challenge by the B1.1.7 variant.
Discovery and in-vitro evaluation of potent SARS-CoV-2 entry inhibitors
Authors: Acharya Arpan , Pandey Kabita , Thurman Michellie , Klug Elizabeth , Trivedi Jay , Lorson Christian L. , Singh Kamal , Byrareddy Siddappa N.
Published: April 2021

SARS-CoV-2 infection initiates with the attachment of spike protein to the ACE2 receptor. While vaccines have been developed, no SARS-CoV-2 specific small molecule inhibitors have been approved. Herein, utilizing the crystal structure of the ACE2/Spike receptor binding domain (S-RBD) complex in computer-aided drug design (CADD) approach, we docked ∼8 million compounds within the pockets residing at S-RBD/ACE2 interface. Five best hits depending on the docking score, were selected and tested for their in vitro efficacy to block SARS-CoV-2 replication. Of these, two compounds (MU-UNMC-1 and MU-UNMC-2) blocked SARS-CoV-2 replication at sub-micromolar IC50 in human bronchial epithelial cells (UNCN1T) and Vero cells. Furthermore, MU-UNMC-2 was highly potent in blocking the virus entry by using pseudoviral particles expressing SARS-CoV-2 spike. Finally, we found that MU-UNMC-2 is highly synergistic with remdesivir (RDV), suggesting that minimal amounts are needed when used in combination with RDV, and has the potential to develop as a potential entry inhibitor for COVID-19.
HAP40 orchestrates huntingtin structure for differential interaction with polyglutamine expanded exon 1
Authors: Harding Rachel J. , Deme Justin C. , Hevler Johannes F. , Tamara Sem , Lemak Alexander , Cantle Jeffrey P. , Szewczyk Magdalena M. , Zuo Xiaobing , Loppnau Peter , Seitova Alma , Hutchinson Ashley , Fan Lixin , Schapira Matthieu , Carroll Jeffrey B. , Heck Albert J. R. , Lea Susan M. , Arrowsmith Cheryl H.
Published: April 2021

Huntington’s disease results from expansion of a glutamine-coding CAG tract in the huntingtin (HTT) gene, producing an aberrantly functioning form of HTT. Both wildtype and disease-state HTT form a hetero-dimer with HAP40 of unknown functional relevance. We demonstratein vivothat HTT and HAP40 cellular abundance are coupled. Integrating data from a 2.6 Å cryo-electron microscopy structure, cross-linking mass spectrometry, small-angle X-ray scattering, and modeling, we provide a near-atomic-level view of HTT, its molecular interaction surfaces and compacted domain architecture, orchestrated by HAP40. Native mass-spectrometry reveals a remarkably stable hetero-dimer, potentially explaining the cellular inter-dependence of HTT and HAP40. The polyglutamine tract containing N-terminal exon 1 region of HTT is dynamic, but shows greater conformational variety in the mutant than wildtype exon 1. By providing novel insight into the structural consequences of HTT polyglutamine expansion, our data provide a foundation for future functional and drug discovery studies targeting Huntington’s disease.
Impact of an Urban Sanitation Intervention on Enteric Pathogen Detection in Soils
Authors: Capone Drew , Berendes David , Cumming Oliver , Holcomb David , Knee Jackie , Konstantinidis Konstantinos T. , Levy Karen , Nalá Rassul , Risk Benjamin B. , Stewart Jill , Brown Joe
Published: April 2021

Environmental fecal contamination is common in many low-income cities, contributing to a high burden of enteric infections and associated negative sequelae. To evaluate the impact of a shared onsite sanitation intervention in Maputo, Mozambique on enteric pathogens in the domestic environment, we collected 179 soil samples at shared latrine entrances from intervention (n= 49) and control (n= 51) compounds during baseline (pre-intervention) and after 24 months (post-intervention) as part of the Maputo Sanitation Trial. We tested soils for the presence of nucleic acids associated with 20 enteric pathogens using a multiplex reverse transcription qPCR platform. We detected at least one pathogen-associated target in 91% (163/179) of soils and a median of 3 (IQR=1.5, 5) pathogens. Using a difference-in-difference analysis and adjusting for compound population, visibly wet soil, sun exposure, wealth, temperature, animal presence, and visible feces, we estimate the intervention reduced the probability of ≥1 pathogen detected by 15% (adjusted prevalence ratio, aPR=0.85; 95% CI: 0.70, 1.0) and the total number of pathogens detected by 35% (aPR =0.65; 0.44, 0.95) in soil 24 months following the intervention. These results suggest that the intervention reduced the presence of some fecal contamination in the domestic environment, but pathogen detection remained prevalent 24-months following the introduction of new latrines.
Sex- and context-dependent effects of acute isolation on vocal and non-vocal social behaviors in mice
Authors: Zhao Xin , Ziobro Patryk , Pranic Nicole M. , Chu Samantha , Rabinovich Samantha , Chan William , Zhao Jennifer , Kornbrek Caroline , He Zichen , Tschida Katherine A.
Published: April 2021

Humans are extraordinarily social, and social isolation has profound effects on our behavior, ranging from increased social motivation following short periods of social isolation to increased anti-social behaviors following long-term social isolation. Mice are frequently used as a model to understand how social isolation impacts the brain and behavior. While the effects of chronic social isolation on mouse social behavior have been well studied, much less is known about how acute isolation impacts mouse social behavior and whether these effects vary according to the sex of the mouse and the behavioral context of the social encounter. To address these questions, we characterized the effects of acute (3-day) social isolation on the vocal and non-vocal social behaviors of male and female mice during same-sex and opposite-sex social interactions. Our experiments uncovered pronounced effects of acute isolation on social interactions between female mice, while revealing more subtle effects on the social behaviors of male mice during same-sex and opposite-sex interactions. Our findings advance the study of same-sex interactions between female mice as an attractive paradigm to investigate neural mechanisms through which acute isolation enhances social motivation and promotes social behavior.