bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of an Age-Structured Deterministic Endemic Model for Disease Control in Nigeria
Authors: Victor A. O. , Oduwole H. K.
Published: March 2020

This paper focuses on the development and analysis of the endemic model for disease control in an aged-structured population in Nigeria. Upon the model framework development, the model equations were transformed into proportions with rate of change of the different compartments forming the model, thereby reducing the model equations from twelve to ten homogenous ordinary differential equations. The model exhibits two equilibria, the endemic state and the disease-free equilibrium state while successfully achieving a Reproductive Number R0 = 0.

The deterministic endemic susceptible-exposed-infected-removed-undetectable=untransmissible-susceptible (SEIRUS) model is analyzed for the existence and stability of the disease-free equilibrium state. We established that a disease-free equilibrium state exists and is locally asymptotically stable when the basic reproduction number 0 ≤ R0 < 1. Furthermore, numerical simulations were carried to complement the analytical results in investigating the effect treatment rate and the net transmission rate on recovery for both juvenile and adult sub-population in an age-structured population.
Orthogonal genome-wide screenings in bat cells identify MTHFD1 as a target of broad antiviral therapy
Authors: Anderson Danielle E , Cui Jin , Ye Qian , Huang Baoying , Zu Wenhong , Gong Jing , Liu Weiqiang , Kim So Young , Yan Biao Guo , Sigmundsson Kristmundur , Lim Xiao Fang , Ye Fei , Niu Peihua , Zhou Xuming , Tan Wenjie , Wang Lin-Fa , Tan Xu
Published: March 2020

Bats are responsible for the zoonotic transmission of several major viral diseases including the 2003 SARS outbreak and the ongoing COVID-19 pandemic. While bat genomic sequencing studies have revealed characteristic adaptations of the innate immune system, functional genomic studies are urgently needed to provide a foundation for the molecular dissection of the tolerance of viral infections in bats. Here we report the establishment and screening of genome-wide RNAi library and CRISPR library for the model megabat,Pteropus Alecto. We used the complementary RNAi and CRISPR libraries to interrogatePteropus Alectocells for infection with two different viruses, mumps virus and Influenza A virus, respectively. Screening results converged on the endocytosis pathway and the protein secretory pathway as required for both viral infections. Additionally, we revealed a general dependence of the C-1-tetrahydrofolate synthase gene, MTHFD1, for viral replication in bat cells as well as in human cells. MTHFD1 inhibitor carolacton potently blocked replication of several RNA viruses including SARS-CoV-2. Our studies provide a resource for systematic inquiry into the genetic underpinnings of bat biology and a potential target for developing broad spectrum antiviral therapy.
Antioxidant, Anti-inflammatory and Anticancer activities of Methanolic Extract ofThottea siliquosa:An In Vitro study
Authors: Koottasseri Amrutha , Babu Amal , Augustin Anna , Job Joice Tom , Narayanankutty Arunaksharan
Published: March 2020

Background and Aim

Oxidative stress and inflammation are the predominant cause of chronic diseases including cancers, thereby making it as an essential target for preventing these disorders. Various natural products and plants have been shown to prevent the process of free radical induced damages. The present study evaluated the biological properties ofThottea siliquosa,belonging to the family Aristolochiaceae, which is a traditionally used Ayurvedic plant.

Experimental Procedure

Antioxidant assays carried out were DPPH, FRAP, hydrogen peroxide scavenging and hemolysis inhibition assay; nitric oxide and lipoxygenase inhibition assays were used for anti-inflammatory studies. Anticancer activity was done using human endometrial and breast cancer cells by MTT assay.

Results and Conclusion

The results of the present study showed antioxidant properties for the methanolic crude extract ofT. siliquosaas DPPH radical scavenging (110.40± 4.5μg/mL), FRAP capacity (41.1± 6.2), peroxide scavenging (233.4± 14.2 μg/mL) etc. In addition, anti-inflammatory properties are also evident in terms of nitric oxide radical scavenging (28.76± 3.9 μg/mL) and lipoxygenase inhibition (39.2± 3.2 μg/mL) assays. Further, the anticancer activity of these extract has been identified against human endometrial and breast cancer cells. Further studies together with a bioassay guided fractionation may identify possible bioactive compounds.

Highlights

Thottea siliquosa is a traditional Ayurvedic medicine

T. siliquosa exhibits significant anti-inflammatory and anticancer properties

Polyphenolic compounds may be responsible for the bioactivities of T. siliquosa

T. siliquosa may be a source for novel bioactive components
CIS checkpoint deletion enhances the fitness of cord blood derived natural killer cells transduced with a chimeric antigen receptor
Authors: Daher May , Basar Rafet , Gokdemir Elif , Baran Natalia , Uprety Nadima , Nunez Cortes Ana Karen , Mendt Mayela , Kerbauy Lucila Nassif , Banerjee Pinaki P. , Sanabria Mayra Hernandez , Imahashi Nobuhiko , Li Li , Wei Inng Lim Francesca Lorraine , Fathi Mohsen , Rezvan Ali , Mohanty Vakul , Shen Yifei , Shaim Hila , Lu Junjun , Ozcan Gonca , Ensley Emily , Kaplan Mecit , Nandivada Vandana , Bdaiwi Mustafa , Acharya Sunil , Xi Yuanxin , Wan Xinhai , Mak Duncan , Liu Enli , Ang Sonny , Muniz-Feliciano Luis , Li Ye , Wang Jing , Kordasti Shahram , Petrov Nedyalko , Varadarajan Navin , Marin David , Brunetti Lorenzo , Skinner Richard J. , Lyu Shangrong , Silva Leiser , Turk Rolf , Schubert Mollie S. , Rettig Garrett R. , McNeill Matthew S. , Kurgan Gavin , Behlke Mark A. , Li Heng , Fowlkes Natalie W. , Chen Ken , Konopleva Marina , Champlin Richard , Shpall Elizabeth J. , Rezvani Katayoun
Published: March 2020

Immune checkpoint therapy has produced remarkable improvements in the outcome for certain cancers. To broaden the clinical impact of checkpoint targeting, we devised a strategy that couples targeting of the cytokine-inducible SH2-containing (CIS) protein, a key negative regulator of interleukin (IL)-15 signaling, with chimeric antigen receptor (CAR) engineering of natural killer (NK) cells. This combined strategy boosted NK cell effector function through enhancing the Akt/mTORC1 axis and c-MYC signaling, resulting in increased aerobic glycolysis. When tested in a lymphoma mouse model, this combined approach improved NK cell anti-tumor activity more than either alteration alone, eradicating lymphoma xenografts without signs of any measurable toxicity. We conclude that combining CIS checkpoint deletion with CAR engineering promotes the metabolic fitness of NK cells in an otherwise suppressive tumor microenvironment. This approach, together with the prolonged survival afforded by CAR modification, represents a promising milestone in the development of the next generation of NK cells for cancer immunotherapy.
Cardio-centric hemodynamic management improves spinal cord oxygenation and mitigates hemorrhage in acute spinal cord injury
Authors: Williams Alexandra M. , Manouchehri Neda , Erskine Erin , Tauh Keerit , So Kitty , Streijger Femke , Shortt Katelyn , Kim Kyoung-Tae , Kwon Brian K. , West Christopher R.
Published: March 2020

Chronic high-thoracic and cervical spinal cord injury (SCI) results in a complex phenotype of cardiovascular consequences, including impaired left-ventricular contractility. Here, we sought to determine whether such dysfunction manifests immediately post-injury, and if so, whether correcting impaired contractility can improve spinal cord oxygenation (SCO2), blood flow (SCBF) and metabolism. Using a porcine model of SCI, we demonstrate that high-thoracic SCI acutely impairs cardiac contractility and causes substantial reductions in intraparenchymal SCO2and SCBF within the first hours post-injury. Utilizing the same model, we next show that treating the reduced contractile function with the β-agonist dobutamine is more efficacious at increasing SCO2and SCBF than the current clinical standard of vasopressor therapy, whilst also mitigating increased anaerobic metabolism and hemorrhage in the injured cord. Our data provide compelling evidence that cardio-centric hemodynamic management represents a novel and advantageous alternative to the current clinical standard of vasopressor therapy for acute traumatic SCI.
Alzheimer’s disease risk geneBIN1induces Tau-dependent network hyperexcitability
Authors: Voskobiynyk Yuliya , Roth Jonathan R. , Cochran J. Nicholas , Rush Travis , Carullo Nancy V. N. , Mesina Jacob S. , Waqas Mohammad , Vollmer Rachael M. , Day Jeremy J. , McMahon Lori L. , Roberson Erik D.
Published: March 2020

Genome-wide association studies identified theBIN1locus as a leading modulator of genetic risk in Alzheimer’s disease (AD). One limitation in understandingBIN1’s contribution to AD is its unknown function in the brain. AD-associatedBIN1variants are generally noncoding and likely change expression. Here, we determined the effects of increasing expression of the major neuronal isoform of human BIN1 in cultured hippocampal neurons. Higher BIN1 induced network hyperexcitability on multielectrode arrays, increased frequency of synaptic transmission, and elevated calcium transients, indicating that increasing BIN1 drives greater neuronal activity. In exploring the mechanism of these effects on neuronal physiology, we found that BIN1 interacted with L-type voltage-gated calcium channels (LVGCCs) and that BIN1–LVGCCs interactions were modulated by Tauin vitroandin vivo. Finally, Tau reduction prevented BIN1-induced network hyperexcitability. These data shed light on BIN1’s neuronal function and suggest that it may contribute to Tau-dependent hyperexcitability in AD.
Highly Versatile, Non-Invasive Method for Collecting Buccal DNA from Free-Ranging Non-Human Primates
Authors: Toyoda Aru , Matsudaira Kazunari , Maruhashi Tamaki , Malaivijitnond Suchinda , Kawamoto Yoshi
Published: March 2020

Non-invasive techniques for collection of DNA samples of suitable quality and quantity are important for improving the efficiency of genetic wildlife research. The development of a non-invasive method for collection of DNA samples from wild stump-tailed macaques (Macaca arctoides) is described herein. Sterilized polyester rope was cut into 10 cm pieces, which were then soaked in a 20% sugar solution to bait individuals. Rope swabs were immediately collected and transferred to a lysis buffer solution after subjects had picked up, chewed, and discarded them. DNA was later extracted from the buffer. Quantitative real-time PCR and both allelic dropout and genotype failure rates were used to compare the quantity and quality of the buccal DNA samples to those of intestinal slough cell DNA samples collected from freshly dropped feces. The buccal samples yielded significantly more DNA (27.1 ± 33.8 ng/µL) than did the fecal samples (11.4 ± 15.4 ng/µL) and exhibited lower allelic dropout and genotyping failure rates for the 10 autosomal microsatellites investigated. Buccal cell collection was also simple, inexpensive, reliable, and less time-consuming compared to fecal sampling. Thus, this method should facilitate genome-wide studies of non-human primates and other wildlife species.
Mutual regulation between GDF11 and TET2 prevents senescence of mesenchymal stem cells
Authors: Gao Jiaming , Wang Hao , Shen Junyan , Liu Xiaojing , Zhu Xiaoqi , Zhao Enfeng , Li Gongchen , Sun Yao , Yin Feng , Liu Zhongmin , Sun Yi Eve , Liu Hailiang
Published: March 2020

The authors have withdrawn their manuscript since they no longer stand by some of the conclusions presented. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Dopamine promotes instrumental motivation, but reduces reward-related vigour
Authors: Grogan J.P. , Sandhu T.R. , Hu M.T. , Manohar S.G.
Published: March 2020

We can be motivated when reward depends on performance, or merely by the prospect of a guaranteed reward. Performance-dependent (contingent) reward is instrumental, relying on an internal action-outcome model, whereas motivation by guaranteed reward may serve to minimise opportunity cost in reward-rich environments. Competing theories propose that each type of motivation should be dependent on dopaminergic activity. We contrasted these two types of motivation with a rewarded saccade task, in patients with Parkinson’s disease (PD). When PD patients were ON dopamine, they had greater response vigour (peak saccadic velocity) forcontingentrewards, whereas when PD patients were OFF medication, they had greater vigour forguaranteedrewards. These results support the view that reward expectation and contingency drive distinct motivational processes, and can be dissociated by manipulating dopaminergic activity. We posit that dopamine is necessary for goal-directed motivation, but dampens reward-driven vigour, challenging the theory that tonic dopamine encodes reward expectation.
HIV-1 promoter is gradually silenced when integrated intoBACH2
Authors: Inderbitzin Anne , Kok Yik Lim , Jörimann Lisa , Kelley Audrey , Neumann Kathrin , Heinzer Daniel , Cathomen Toni , Metzner Karin J.
Published: March 2020

The persistence of the latent HIV-1 reservoir is a major obstacle to cure HIV-1 infection. HIV-1 integrates into the cellular genome and some targeted genomic loci are frequently detected in clonally expanded latently HIV-1 infected cells, for instance, the geneBTB domain and CNC homology 2 (BACH2). We investigated HIV-1 promoter activity after integration into specific sites inBACH2. The HIV-1-based vector LTatCL[M] contains two fluorophores: 1.) Cerulean, which reports the activity of the HIV-1 promoter, and 2.) mCherry driven by a constitutive promotor and flanked by genetic insulators. This vector was inserted into introns 2 and 5 ofBACH2of Jurkat T-cells via CRISPR/Cas9 technology in the same and convergent transcriptional orientation ofBACH2, and into the genomic safe harbour AAVS1. Single cell clones representing active (Cerulean+/mCherry+) and inactive (Cerulean−/mCherry+) HIV-1 promoters were characterized. Upon targeted integration of the 5.3 kb vector LTatCL[M] intoBACH2, active HIV-1 promoters were gradually silenced as reflected by decrease in Cerulean expression over a period of 162 days in culture. Silenced HIV-1 promoters could be reactivated by TNF-α and Romidepsin. This observation was independent of the targeted intron and the transcriptional orientation. BACH2 mRNA and protein expression was not impaired by mono-allelic integration of LTatCL[M]. Our results show that the HIV-1 promoter is silenced when integrated intoBACH2without impairing BACH2 mRNA and protein expression. This might contribute to HIV-1 persistence, enabling infected T-cells to complete differentiation into a memory phenotype, persist, and clonally expand over time.
The drought-responsiveZmFDL1gene regulates cuticle biosynthesis and cuticle-dependent leaf permeability
Authors: Castorina Giulia , Domergue Frédéric , Chiara Matteo , Zilio Massimo , Persico Martina , Ricciardi Valentina , Horner David Stephen , Consonni Gabriella
Published: March 2020

In higher plants, the outer surface of the aerial parts is covered by the cuticle, a complex lipid layer that constitutes a barrier against damages caused by environmental factors and provides protection against non-stomatal water loss. We show in this study that cuticle deposition, during the juvenile phase of in maize (Zea mays) plant development, and cuticle-dependent leaf permeability are controlled by the MYB transcription factorZmMYB94/FUSED LEAVES1(ZmFDL1).

Biochemical analysis showed that infdl1-1mutant seedlings at the coleoptile stage both cutin and wax biosynthesis and deposition were altered. Among cutin compounds, ω-hydroxy fatty acids and polyhydroxy-fatty acids were specifically affected, while the reduction of epicuticular waxes, was mainly observed in primary long chain alcohols, and to a minor extent, long-chain wax esters.

Transcriptome analysis allowed the identification of novel candidate genes involved in lipid metabolism and the assembly of a proposed pathway for cuticle biosynthesis in maize. Lack of ZmFDL1 affects the expression of genes located in different modules of the pathway and correspondence between gene transcriptional variations and biochemical defects have been highlighted.

A decrease in cuticle-dependent leaf permeability was observed in maize seedlings exposed to drought as well as ABA treatment, which implies coordinated changes in the transcript levels ofZmFDL1and associated genes. Overall, our results suggest that the response to water stress implies the activation of wax biosynthesis and the involvement of by both ZmFDL1 and ABA regulatory pathways.

One-Sentence Summary

Cuticle biosynthesis and cuticle-mediated drought-response during the juvenile phase of maize plant growth, are regulated by the MYB transcription factor fused leaves1 (ZmFDL1) and influenced by ABA.
Overexpression of Mdm36 reveals Num1 foci that mediate dynein-dependent microtubule sliding in budding yeast
Authors: Omer Safia , Brock Katia , Beckford John , Lee Wei-Lih
Published: March 2020

Current model for spindle positioning requires attachment of the microtubule (MT) motor cytoplasmic dynein to the cell cortex, where it generates pulling force on astral MTs to effect spindle displacement. How dynein is anchored by cortical attachment machinery to generate large spindle-pulling forces remains unclear. Here, we show that cortical clustering of Num1, the yeast dynein attachment molecule, is limited by Mdm36. Overexpression of Mdm36 results in an overall enhancement of Num1 clustering but reveals a population of dim Num1 clusters that mediate dynein-anchoring at the cell cortex. Direct imaging shows that bud-localized, dim Num1 clusters containing only ∼6 copies of Num1 molecules mediate dynein-dependent spindle pulling via lateral MT sliding mechanism. Mutations affecting Num1 clustering interfere with mitochondrial tethering but not dynein-based spindle-pulling function of Num1. We propose that formation of small ensembles of attachment molecules is sufficient for dynein anchorage and cortical generation of large spindle-pulling force.
Loss of mutant TP53 does not impair the sustained proliferation, survival or metastasis of diverse cancer cells
Authors: Wang Zilu , Vaillant François , Chang Catherine , Riffkin Chris , Lieschke Elizabeth , Diepstraten Sarah , Huang David CS , Visvader Jane E , Herold Marco J , Kelly Gemma L , Strasser Andreas
Published: March 2020

The tumour suppressorTP53is the most frequently mutated gene in human cancer and these aberrations confer poor chemotherapeutic responses1-3. Point mutations typically cluster in the DNA binding domain, with certain ‘hot-spot’ residues disproportionally represented1-4These mutations abrogate binding of the TP53 transcription factor to DNA and thereby prevent upregulation of genes critical for tumour suppression (loss-of-function)1-3. Mutant TP53 is reported to additionally contribute to tumour development, sustained growth and metastasis not only through dominant-negative effects on wild-type TP535but also through neomorphic gain-of-function (GOF) activities6. Understanding the contributions of these postulated attributes of mutant TP53 to the development and expansion of tumours will facilitate the design of rational therapeutic strategies. Here we used CRISPR/CAS9 to delete mutantTP53in a panel of diverse human cancer cell lines. The loss of mutantTP53expression had no impact on the survival, proliferative capacity or metabolic state of the tumour cells, nor did it sensitise them to cellular stresses and chemotherapeutic agents. These data suggest that putative GOF effects of mutant TP53 are not universally required for the sustained survival and proliferation of fully malignant cells. Therefore, therapeutic approaches that abrogate expression or function of mutant TP53 would not be expected to have substantial impact.
Improving a probabilistic cytoarchitectonic atlas of auditory cortex using a novel method for inter-individual alignment
Authors: Gulban Omer Faruk , Goebel Rainer , Moerel Michelle , Zachlod Daniel , Mohlberg Hartmut , Amunts Katrin , De Martino Federico
Published: March 2020

The human superior temporal plane, the site of the auditory cortex, displays a high inter-individual macro-anatomical variation. This questions the validity of curvature based alignment (CBA) methods for in vivo imaging data. Here, we have addressed this issue by developing CBA+, which is a cortical surface registration method that uses prior macro-anatomical knowledge. We validate this method by using cyto-architectonic areas on ten individual brains (which we make publicly available). Compared to volumetric and standard surface registration, CBA+ results in a more accurate cyto-architectonic auditory atlas. The improved correspondence of micro-anatomy following the improved alignment of macro-anatomy validates the superiority of CBA+ compared to CBA. In addition, we use CBA+ to align in vivo and post mortem data. This allows projection of functional and anatomical information collected in vivo onto the cyto-architectonic areas, which has potential to contribute to ongoing debate on the parcellation of the human auditory cortex.
Distinct ensembles in the noradrenergic locus coeruleus evoke diverse cortical states
Authors: Noei Shahryar , Zouridis Ioannis S. , Logothetis Nikos K. , Panzeri Stefano , Totah Nelson K.
Published: March 2020

The noradrenergic locus coeruleus (LC) is a crucial controller of brain and behavioral states. Activating LC neurons synchronouslyen masseby electrical or optogenetic stimulation promotes a stereotypical “activated” high-frequency cortical state. However, it has been recently reported that spontaneous LC cell-pairs have sparse yet structured time-averaged cross-correlations, which is unlike the high synchrony ofen masseneuronal stimulation. This suggests the untested possibility that LC population activity may be made of distinct multi-cell ensembles each with unique temporal evolution of activity. We used non-negative matrix factorization (NMF) to analyze large populations of LC single units simultaneously recorded in the rat LC. Synthetic spike train simulations showed that NMF, unlike the traditional time-averaged pairwise correlations, detects both the precise neuronal composition and the activation time courses of each ensemble. NMF identified the existence of robust ensembles of spontaneously co-active LC neurons. Since LC neurons selectively project to specific forebrain regions, we hypothesized that individual LC ensembles produce different cortical states. To test this hypothesis, we triggered local field potentials (LFP) in cortical area 24a on the activation of distinct LC ensembles. We found four cortical states, each with different spectro-temporal LFP characteristics, that were robust across sessions and animals. While some LC ensembles triggered the activated state, others were associated with a beta oscillation-specific state or a reduced high frequency oscillation state. Thus – in contrast to the stereotypical “activated” brain state evoked byen masseLC stimulation – spontaneous activation of distinct LC ensembles can control a multitude of cortical states.
On the accuracy of molecular simulation-based predictions of koffvalues: a Metadynamics study
Authors: Capelli Riccardo , Lyu Wenping , Bolnykh Viacheslav , Meloni Simone , Haugaard Olsen Jógvan Magnus , Rothlisberger Ursula , Parrinello Michele , Carloni Paolo
Published: March 2020

Molecular simulations have made great progresses in predictingkoffvalues—the kinetic constant of drug unbinding, a key parameter for modern pharmacology—yet computed values under- or over-estimate experimental data in a system- and/or technique-dependent way. In an effort at gaining insights on this issue, here we used an established method to calculatekoffvalues—frequency-adaptive metadynamics with force field— and a subsequent QM/MM descriptions of the interactions. First, using force field-based metadynamics, we calculatekoffof the Positron Emission Tomography (PET) ligand iperoxo targeting the human muscarinic acetylcholine receptor M2. In line with previously performedin silicostudies, the prediction (3.7 ± 0.7 ⋅ 10−4s−1) turned out to differ significantly from the experimentally measured value (1.0 ± 0.2 ⋅ 10−2s−1). Next, we use DFT-based QM/MM simulations to show that this discrepancy arises from erroneous force field energetics at the transition state. It turns out that this discrepancy is partly caused by lack of electronic polarization and/or charge transfer in commonly employed force field. We expect these issues to arise also in other systems where charged portions of the system play a pivotal role, such as protein- or DNA-protein complexes.

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Illuminating host-mycobacterial interactions with functional genomic screening to inhibit mycobacterial pathogenesis
Authors: Lai Yong , Babunovic Gregory H. , Cui Liang , Dedon Peter C. , Doench John G. , Fortune Sarah M. , Lu Timothy K.
Published: March 2020

Existing antibiotics are inadequate to defeat tuberculosis (TB), a leading cause of death worldwide. We sought potential targets for host-directed therapies (HDTs) by investigating the host immune response to mycobacterial infection. We used CRISPR/Cas9-mediated high-throughput genetic screens to identify perturbations that improve the survival of human phagocytic cells infected withMycobacterium bovisBCG (Bacillus Calmette-Guérin), as a proxy forMycobacterium tuberculosis(Mtb). Many of these perturbations constrained the growth of intracellular mycobacteria. We identified over 100 genes associated with diverse biological pathways as potential HDT targets. We validated key components of the type I interferon and aryl hydrocarbon receptor signaling pathways that respond to the small-molecule inhibitors cerdulatinib and CH223191, respectively; these inhibitors enhanced human macrophage survival and limited the intracellular growth of Mtb. Thus, high-throughput functional genomic screens can elucidate highly complex host-pathogen interactions and serve to identify HDTs with the potential to improve TB treatment.
Prediction and discrimination of skeletal muscle function by bioelectrical impedance vector analysis using a standing impedance analyzer in healthy Taiwanese adults
Authors: Lee Li-Wen , Lu Hsueh-Kuan , Chen Yu-Yawn , Lai Chung-Liang , Chu Lee-Ping , Hsieh Meng-Che , Hsieh Kuen-Chang
Published: March 2020

Background

Bioelectrical impedance vector analysis (BIVA) has been used for prediction of muscle performance. However, little is known about BIVA in Asian adults, and even less is known about using standing BIVA devices. Standing impedance analyzer allows quicker and more convenient way to gather data than conventional supine analyzer and is more suitable for clinical practice. This study aimed to investigate the relations between muscle function and BIVA parameters measured with a standing impedance analyzer in healthy Taiwanese adults.

Methods

A total of 406 healthy subjects (age 34.5 ± 17.3 years, body mass index 24.1 ± 4.1 kg/m2) were recruited for BIVA and handgrip strength (HGS) measurements. Impedance parameters, including resistance (R) and reactance (Xc), were measured and normalized to body size by dividing by height (H). The resulting phase angle (PhA) was calculated. HGS in the dominant, left, and right hands were referred to as HGSDH, HGSLH, and HGSRH, respectively. All subjects were divided into 5 grades according to HGS.

Results

Muscle strength in the dominant, right, and left arms was correlated with variables in the order of sex, weight, age, height, Xc/H, and R/H (all, p < 0.001). Using all 6 variables, the determination coefficients were 0.792, 0.782, and 0.745, respectively, whereas the standard errors of estimates were 56.89, 58.01, and 56.67 N for HGSDH, HGSLH, and HGSRH, respectively. HGS was positively correlated with PhA, and negatively correlated with Xc/H and R/H.

Conclusions

BIVA parameters measured with a standing impedance analyzer and anthropometric variables can predict and discriminate muscle function with good performance in healthy Asian adults.
A network model of the barrel cortex combined with a differentiator detector reproduces features of the behavioral response to single-neuron stimulation
Authors: Bernardi Davide , Doron Guy , Brecht Michael , Lindner Benjamin
Published: March 2020

The stimulation of a single neuron in the rat somatosensory cortex can elicit a behavioral response. The probability of a behavioral response does not depend appreciably on the duration or intensity of a constant stimulation, whereas the response probability increases significantly upon injection of an irregular current. Biological mechanisms that can potentially suppress a constant input signal are present in the dynamics of both neurons and synapses and seem ideal candidates to explain these experimental findings. Here, we study a large network of integrate-and-fire neurons with several salient features of neuronal populations in the rat barrel cortex. The model includes cellular spike-frequency adaptation, experimentally constrained numbers and types of chemical synapses endowed with short-term plasticity, and gap junctions. Numerical simulations of this model indicate that cellular and synaptic adaptation mechanisms alone may not be sufficient to account for the experimental results if the local network activity is read out by an integrator. However, a differentiator circuit can detect the single-cell stimulation with a reliability that barely depends on the length or intensity of the stimulus, but that increases when an irregular signal is used. This finding is in accordance with the experimental results obtained for the stimulation of a regularly-spiking excitatory cell.

Author summary

It is widely assumed that only a large group of neurons can encode a stimulus or control behavior. This tenet of neuroscience has been challenged by experiments in which stimulating a single cortical neuron has had a measurable effect on an animal’s behavior. Recently, theoretical studies have explored how a single-neuron stimulation could be detected in a large recurrent network. However, these studies missed essential biological mechanisms of cortical networks and are unable to explain more recent experiments in the barrel cortex. Here, to describe the stimulated brain area, we propose and study a network model endowed with many important biological features of the barrel cortex. Importantly, we also investigate different readout mechanisms, i.e. ways in which the stimulation effects can propagate to other brain areas. We show that a readout network which tracks rapid variations in the local network activity is in agreement with the experiments. Our model demonstrates a possible mechanism for how the stimulation of a single neuron translates into a signal at the population level, which is taken as a proxy of the animal’s response. Our results illustrate the power of spiking neural networks to properly describe the effects of a single neuron’s activity.
UV radiation increases flavonoid protection but decreased reproduction inSilene littorea
Authors: Del Valle J. C. , Buide M. L. , Whittall J. B. , Valladares F. , Narbona E.
Published: March 2020

Plants respond to changes in ultraviolet (UV) radiation via morphological and physiological changes. Among the variety of plant UV-responses, the synthesis of UV-absorbing flavonoids constitutes an effective non-enzymatic mechanism to mitigate photoinhibitory and photooxidative damage caused by UV stress, either reducing the penetration of incident UV radiation or acting as quenchers of reactive oxygen species (ROS). In this study, we designed a UV-exclusion experiment to investigate the effects of UV radiation inSilene littorea. We spectrophotometrically quantified concentrations of both anthocyanins and non-anthocyanin flavonoids (flavones) in petals, calyces, leaves and stems. Furthermore, we analyzed the UV effect on the photosynthetic activity in hours of maximum solar radiation and we tested the impact of UV radiation on male and female reproductive performance. We found that anthocyanin concentrations showed a significant decrease of about 20% with UV-exclusion in petals and stems, and 30% in calyces. Flavone concentrations showed a significant reduction of approximately 25% in calyces and stems, and 12% in leaves. Photochemical efficiency of plants grown under UV stress decreased sharply at maximum light stress, but their ability for recovery after light-stress was not affected. In addition, exposure to UV radiation does not seem to affect ovule production or seed set, but decreases the total seed production per plant and pollen production by 69% and 31%, respectively. Our results demonstrate that UV radiation produced opposite effects on flavonoid accumulation and reproduction inS. littorea. UV stress increased flavonoid concentrations, suggesting a photoprotective role of flavonoids against UV radiation, but had negative consequences for reproduction. We propose that this trade-off helps this species to occupy exposed habitats with high UV radiation.
The Regulation of Developmental Diapause is Coordinated with Molting and Olfaction
Authors: Carstensen Heather R. , Villalon Reinard M. , Vertiz Johnny , Banerjee Navonil , Hallem Elissa A. , Hong Ray L.
Published: March 2020

Developmental and behavioral plasticity allow animals to prioritize alternative genetic programs during fluctuating environments. Behavioral remodeling may be acute in animals that interact with host organisms, since reproductive adults and the developmentally arrested larvae often have different ethological needs for chemical stimuli. To understand the genes that coordinate development and behavior, we used the nematode modelPristionchus pacificusto characterize mutants that inappropriately enter developmental diapause to become dauer larvae (Daf-c). We found several key olfactory differences betweenP. pacificusandC. elegansDaf-c dauers. In addition, the twoP. pacificusDaf-c alleles disrupt steroid synthesis required for proper regulation of the conserved canonical steroid hormone receptor DAF-12, whose dauer-constitutive and cuticle exsheathment phenotypes can be rescued by the feeding of Δ7-dafachronic acid. One allele,csu60, has a deletion in the sole HydroxySteroid Dehydrogenase (HSD) inP. pacificus.Bothhsd-2(csu60)adults and dauers show enhanced attraction to a beetle pheromone, possibly due to the heterochronic activation of dauer-specific neuronal development in the adults. Surprisingly, this enhanced odor attraction acts independently ofdaf-12, revealing unexpected targets of steroid hormones regulating ecdysis and olfaction inP. pacificus.

Author Summary

The remarkable evolutionary success of nematodes can be attributed to their dispersal ability as stress-resistant dauer larvae and the equivalent parasitic infective larvae. The decision to enter dauer development is regulated by a conserved steroid hormone receptor that receives multiple external and internal cues, though the extent in which these cues also coordinate other physiological and behavioral processes is not well understood in divergent species. We used the insect-associated nematodePristionchus pacificusto genetically dissect two mutants that form dauers inappropriately, and found that one mutation in a steroidogenic enzyme,Ppa-hsd-2, is predicted to abolish the biosynthesis of the hormones needed to negatively regulate dauer entry when food is available. Unexpectedly,Ppa-HSD-2 is also required to properly complete the dauer larval molt, known as exsheathment, as well as to confer differences in adult versus dauer larvae chemotaxis behavior towards a host pheromone. Given that dauers are the host-seeking stage of parasitic nematodes, hormonal disruption represents a tenable target for biological control.
Criticality in the conformational phase transition among self-similar groups in intrinsically disordered proteins: probed by salt-bridge dynamics
Authors: Bandyopadhyay Abhirup , Basu Sankar
Published: March 2020

Intrinsically disordered proteins (IDP) serve as one of the key components in the global proteome. In contrast to the dominant class of cytosolic globular proteins, they harbor an enormous amount of physical flexibility and structural plasticity enforcing them to be retained in conformational ensembles rather than well defined stable folds. Previous studies in an aligned direction have revealed the importance of transient dynamical phenomena like that of saltbridge formation in IDPs to support their physical flexibility and have further highlighted their functional relevance. For this characteristic flexibility, IDPs remain amenable and accessible to different ordered binding partners, supporting their potential multi-functionality. The current study further addresses this complex structure-functional interplay in IDPs using phase transition dynamics to conceptualize the underlying (avalanche type) mechanism of their being distributed across and hopping around degenerate structural states (conformational ensembles). For this purpose, extensive molecular dynamics simulations have been done and the data analyzed from a statistical physics perspective. Investigation of the plausible scope ‘selforganized criticality’ (SOC) to fit into the complex dynamics of IDPs was found to be assertive, relating the conformational degeneracy of these proteins to their multi-functionality. In accordance with the transient nature of ‘salt-bridge dynamics’, the study further uses it as a probe to explain the structural basis of the proposed criticality in the conformational phase transition among self-similar groups in IDPs. The analysis reveal scale-invariant self-similar fractal geometries in structural conformations of different IDPs. Also, as discussed in the conclusion, the study has the potential to benefit structural tinkering of bio-medically relevant IDPs in the design of biotherapeutics against them.
Genome-wide transposon mutagenesis of paramyxoviruses reveals constraints on genomic plasticity
Authors: Ikegame S. , Beaty S. M. , Stevens C. , Won S. T. , Park A. , Sachs D. , Hong P. , Thibault P. A. , Lee B.
Published: March 2020

The antigenic and genomic stability of paramyxoviruses remains a mystery. Here, we evaluate the genetic plasticity of Sendai virus (SeV) and mumps virus (MuV), sialic acid-using paramyxoviruses that infect mammals from twoParamyxoviridaesubfamilies (OrthoparamyxovirinaeandRubulavirinae). We performed saturating whole-genome transposon insertional mutagenesis, and identified important commonalities: disordered regions in the N and P genes near the 3’ genomic end were more tolerant to insertional disruptions; but the envelope glycoproteins were not, highlighting structural constraints that contribute to the restricted antigenic drift in paramyxoviruses. Nonetheless, when we applied our strategy to a fusion-defective Newcastle disease virus (Avulavirinaesubfamily), we could select for F-revertants and other insertants in the 5’ end of the genome. Our genome-wide interrogation of representative paramyxovirus genomes from all threeParamyxoviridaesubfamilies provides a family-wide context in which to explore specific variations within and among paramyxovirus genera and species.
Small molecule inhibition of human cGAS reduces total cGAMP output and cytokine expression in cells
Authors: Wiser Caroline , Kim Byungil , Vincent Jessica , Ascano Manuel
Published: March 2020

The cGAS-STING pathway is a major mechanism that mammalian cells utilize to detect cytoplasmic dsDNA from incoming viruses, bacteria, or self. CYCLIC GMP-AMP SYNTHASE (cGAS) is the sensor protein that directly binds dsDNAs. cGAS synthesizes cyclic GMP-AMP (cGAMP), which binds to the adaptor STIMULATOR OF INTERFERON GENES (STING), activating an INTERFERON REGULATORY FACTOR 3 (IRF3)-mediated immune response. Constitutive activation can result in interferonopathies such as Aicardi-Goutieres Syndrome (AGS) or other lupus-like autoimmune disorders. While inhibitors targeting mouse or human cGAS have been reported, the identification of a small molecule that targets both homologs of cGAS has been challenging. Here, we show that RU.521 is capable of potently and selectively inhibiting mouse and human cGAS in cell lines and human primary cells. This inhibitory activity requires the presence of cGAS, but it cannot suppress an immune response in cells activated by RNA, Toll-like receptor ligands, cGAMP, or recombinant interferon. Importantly, when RU.521 is applied to cells, the production of dsDNA-induced intracellular cGAMP is suppressed in a dose-dependent manner. Our work validates the use of RU.521 for probing DNA-induced innate immune responses and underscores its potential as an ideal scaffold towards pre-clinical development, given its potency against human and mouse cGAS.
A territory-wide study of early COVID-19 outbreak in Hong Kong community: A clinical, epidemiological and phylogenomic investigation
Authors: Leung Kenneth Siu-Sing , Ng Timothy Ting-Leung , Wu Alan Ka-Lun , Yau Miranda Chong-Yee , Lao Hiu-Yin , Choi Ming-Pan , Tam Kingsley King-Gee , Lee Lam-Kwong , Wong Barry Kin-Chung , Ho Alex Yat-Man , Yip Kam-Tong , Lung Kwok-Cheung , Liu Raymond Wai-To , Tso Eugene Yuk-Keung , Leung Wai-Shing , Chan Man-Chun , Ng Yuk-Yung , Sin Kit-Man , Fung Kitty Sau-Chun , Chau Sandy Ka-Yee , To Wing-Kin , Que Tak-Lun , Shum David Ho-Keung , Yip Shea Ping , Yam Wing Cheong , Siu Gilman Kit-Hang
Published: March 2020

Initial cases of COVID-19 reported in Hong Kong were mostly imported from China. However, most cases reported in February 2020 were locally-acquired infections, indicating local community transmissions. We extracted the demographic, clinical and epidemiological data from 50 COVID-19 patients, who accounted for 53.8% of the cases in Hong Kong by February 2020. Whole-genome sequencing of the SARS-CoV-2 were conducted to determine the phylogenetic relatedness and transmission dynamics. Only three (6.0%) patients required ICU admission. Phylogenetic analysis identified six transmission clusters. All locally-acquired cases harboured a common mutationOrf3aG251V and were clustered in two subclades in global phylogeny of SARS-CoV-2. The estimated time to the most recent common ancestor of local COVID-2019 outbreak was December 24, 2019 with an evolutionary rate of 3.04×10−3substitutions per site per year. The reproduction number value was 1.84. Social distancing and vigilant epidemiological control are crucial to the containment of COVID-19 transmission.

Article summary lines

A combined epidemiological and phylogenetic analysis of early COVID-19 outbreak in Hong Kong revealed that a SARS-CoV-2 variant withORF3aG251V mutation accounted for all locally acquired cases, and that asymptomatic carriers could be a huge public health risk for COVID-19 control.
A 4.2-to-5.4 GHz stacked GaAs HBT power amplifier for C-band applications
Authors: Liu Min , Xu Panpan , Zhang Jincan , Liu Bo , Zhang Liwen
Published: March 2020

Purpose

Power amplifiers (PAs) play an important role in wireless communications because they dominate system performance. High-linearity broadband PAs are of great value for potential use in multi-band system implementation. The purpose of this paper is to present a cascode power amplifier architecture to achieve high power and high efficiency requirements for 4.2∼5.4 GHz applications.

Design/methodology/approach

A common emitter (CE) configuration with a stacked common base configuration of heterojunction bipolar transistor (HBT) is used to achieve high power. T-type matching network is used as input matching network. To increase the bandwidth, the output matching networks are implemented using the two L-networks.

Findings

By using the proposed method, the stacked PA demonstrates a maximum saturated output power of 26.2 dBm, a compact chip size of 1.17 × 0.59 mm2 and a maximum power-added efficiency of 46.3 per cent. The PA shows a wideband small signal gain with less than 3 dB variation over working frequency. The saturated output power of the proposed PA is higher than 25 dBm between 4.2 and 5.4 GHz.

Originality/value

The technology adopted for the design of the 4.2-to-5.4 GHz stacked PA is the 2-µm gallium arsenide HBT process. Based on the proposed method, a better power performance of 3 dB improvement can be achieved as compared with the conventional CE or common-source amplifier because of high output stacking impedance.
Estimation of optimal cutting conditions during machining of CP-Ti grade 2 in fuzzy–VIKOR context
Authors: Khan Akhtar , Maity Kalipada
Published: March 2020

Purpose

To explore a hybrid approach in order to attain optimal cutting conditions proficient of generating adequate dimensional accuracy in combination with virtuous surface finish during turning of commercially pure titanium (CP-Ti) grade 2.

Design/methodology/approach

In the present paper, an application of the hybrid fuzzy–VIKOR method has been proposed to estimate an optimal combination of process variables during turning of commercially pure titanium (CP-Ti) grade 2. Three distinct input factors, namely, cutting speed, feed rate and depth of cut, were selected, each varied at three levels. Thus, a series of experiments were performed based on Taguchi's 3-factor-3-level (L27) orthogonal array. The major attention was given to acquire minimum cutting force and flank wear along with good surface finish. The adequacy of the proposed methodology was verified with the help of ANOVA test.

Findings

The results of the investigation revealed that the suggested hybrid technique is quite effective, easily understandable and time-saving approach, which can be successfully implemented to solve various problems either of similar or of different kinds.

Originality/value

Increasing demand of qualitative as well as low cost products is identified as the main challenging task in the current competitive market. Therefore, estimation and selection of the most suitable machining environment are of paramount importance in a real-time manufacturing system. Machining process involves both qualitative and quantitative factors, may be conflicting in nature, all to be considered together. Consequently, an appropriate combination of the machining variables is evidently desirable to meet the aforesaid challenges effectively.