bluuebunny/crossref_metadata_2025 huggingface dataset:
Long‐term Use of Bisacodyl in Pediatric Functional Constipation Refractory to Conventional Therapy
Authors: Bonilla Silvana , Nurko Samuel , Rodriguez Leonel
Published: May 2020

Objectives:

Standard therapy for pediatric constipation includes osmotic laxatives with stimulant laxatives use only as rescue therapy. Limited information is available on regular and long‐term use of bisacodyl in pediatric population despite its common use in adult and pediatric constipation.

Methods:

Retrospective review of patients with functional constipation refractory to conventional therapy (regular use of osmotic laxatives and intermittent use of stimulant laxatives only as a rescue therapy) referred to tertiary care children's hospital (January 2007–December 2014). Patients had a bowel movement (BM) frequency of ≤2 per week and were treated with bisacodyl regularly for longer than 4 weeks. Demographic variables, bisacodyl dose and treatment duration, number of BM/week before and after treatment, side effects, and length of follow‐up were recorded. Response to therapy was successful when frequency of BM increased from baseline to ≥3 BM/wk.

Results:

A total of 164 patients were included, 52% girls, median age 9.45 years (0.9–21 years). Bisacodyl median dose was 5 mg/day, median duration of treatment was 14 months (1–77 months) with 90% of patients taking the medication for <36 months. Median number of BM/wk doubled after initiation of bisacodyl from 2 to 4 bm/w (P < 0.001). Approximately 57% of patients had successful response. At long‐term follow‐up 55% of patients were successfully weaned off bisacodyl (median time of 18 months). Side effects reported in 9% of patients.

Conclusions:

Bisacodyl is effective and well tolerated in the long‐term treatment of pediatric functional constipation refractory to conventional therapy. Most of patients with a favorable response were successfully weaned off the medication.
Current cannabis-related situation in the Asia-Pacific region
Authors: Areesantichai Chitlada , Perngparn Usaneya , Pilley Catherine
Published: May 2020

Purpose of review

We present information on cannabis policy, demand, and supply in the Asia-Pacific region.

Method

A systematic review of peer-reviewed articles using PubMed, MEDLINE, and reliable sources was conducted. We classified the policy implemented in each country into conducting research, legalization of medical and recreational use, decriminalization, cultivation, and others.

Recent findings

In Australia, New Zealand, and Thailand, medical use has been approved, whereas it is limited in South Korea and Singapore and illegal in other countries. Except Australia, none of the Asia-Pacific region countries allows recreational use. China and Japan are expected to approve medical use, whereas Australia and New Zealand work on decriminalization. Most cultivation is allowed and regulated for medical use. Cannabis seizures have changed in accordance with these policies. Although the national surveys of four countries, that is, Australia, New Zealand, Japan, and Thailand were conducted in different years, the use of cannabis among the general population has increased.

Any change in the legal status of cannabis must be undertaken with caution and fully evaluated at each stage to determine the extent to which these changes are leading to increased numbers of users, oversupply, and health risks including cannabis-related harm.
Duganella albus sp. nov., Duganella aquatilis sp. nov., Duganella pernnla sp. nov. and Duganella levis sp. nov., isolated from subtropical streams in China
Authors: Lu Huibin , Deng Tongchu , Liu Feifei , Wang Yonghong , Yang Xunan , Xu Meiying
Published: May 2020

Six Gram-stain-negative, catalase- and oxidase-positive, rod-shaped and motile strains (FT9WT, FT25W, FT26WT, FT109WT, FT134W and CY42WT) were isolated from subtropical streams in China. Comparisons based on 16S rRNA gene sequences showed that the six strains shared similarities of less than 98.1 % with other species within the family

Oxalobacteraceae

and formed two separately distinct clades in phylogenetic trees. The 16S rRNA gene sequence similarities between strains FT9WT and FT25W, and between strains FT109WT and FT134W were both 99.7 %. The genome sizes of strains FT9WT, FT25W, FT26WT, FT109WT, FT134W and CY42WT were 6.45, 6.45, 6.54, 6.43, 6.52 and 6.74 Mbp with G+C contents of 64.0, 64.0, 63.8, 63.2, 63.2 and 62.5 %, respectively. The calculated pairwise average nucleotide (ANI) values among the six strains and other related species were less than 93.9 %, except that the values were 99.9 % between strains FT9WT and FT25W, 98.2 % between strains FT109WT and FT134W, and 95.0 and 95.1 % between strain FT26WT and strains FT9WT and FT25W, respectively. However, strain FT26WT shared 16S rRNA gene sequence similarities of only 98.3 and 98.2 % with FT9WT and FT25W, respectively. The respiratory quinone of the six strains was determined to be Q-8. The major fatty acids were C16 : 1
ω7c, C16 : 0 and C12 : 0. The predominant polar lipids included phosphatidylethanolamine and phosphatidylglycerol. Considering the phenotypic, biochemical, genotypic and ANI data, strains FT9WT and FT25W, and FT109WT and FT134W may belong to the same species, respectively. Although the pairwise ANI values between strain FT26WT and each of strains FT9WT and FT25W were located in the transition region of species demarcation, the dissimilarities among them indicated that strain FT26WT could represent an independent novel species. The reconstructed phylogenomic tree based on a concatenation of 92 core genes showed that the six strains clustered closely with

Duganella sacchari

Sac-22T and

Duganella radicis

KCTC 22382T, and supported that these six strains belong to the genus

Duganella

. The names Duganella albus sp. nov. (type strain FT9WT=GDMCC 1.1637T=KACC 21313T), Duganella aquatilis sp. nov. (type strain FT26WT=GDMCC 1.1641T=KACC 21315T), Duganella pernnla sp. nov. (type strain FT109WT=GDMCC 1.1688T=KACC 21480T) and Duganella levis sp. nov. (type strain CY42WT=GDMCC 1.1673T=KACC 21465T) are proposed.
Busting biofilms: free-living amoebae disrupt preformed methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium bovis biofilms
Authors: Martin Kevin H. , Borlee Grace I. , Wheat William H. , Jackson Mary , Borlee Bradley R.
Published: May 2020

Biofilm-associated infections are difficult to eradicate because of their ability to tolerate antibiotics and evade host immune responses. Amoebae and/or their secreted products may provide alternative strategies to inhibit and disperse biofilms on biotic and abiotic surfaces. We evaluated the potential of five predatory amoebae – Acanthamoeba castellanii, Acanthamoeba lenticulata, Acanthamoeba polyphaga, Vermamoeba vermiformis and Dictyostelium discoideum – and their cell-free secretions to disrupt biofilms formed by methicillin-resistant

Staphylococcus aureus

(MRSA) and

Mycobacterium bovis

. The biofilm biomass produced by MRSA and

M. bovis

was significantly reduced when co-incubated with A. castellanii, A. lenticulata and A. polyphaga, and their corresponding cell-free supernatants (CFS). Acanthamoeba spp. generally produced CFS that mediated biofilm dispersal rather than directly killing the bacteria; however, A. polyphaga CFS demonstrated active killing of MRSA planktonic cells when the bacteria were present at low concentrations. The active component(s) of the A. polyphaga CFS is resistant to freezing, but can be inactivated to differing degrees by mechanical disruption and exposure to heat. D. discoideum and its CFS also reduced preformed

M. bovis

biofilms, whereas V. vermiformis only decreased

M. bovis

biofilm biomass when amoebae were added. These results highlight the potential of using select amoebae species or their CFS to disrupt preformed bacterial biofilms.
Cdk1-dependent destabilization of long astral microtubules is required for spindle orientation
Authors: Singh Divya , Schmidt Nadine , Müller Franziska , Bange Tanja , Bird Alexander W.
Published: May 2020

The precise execution of mitotic spindle orientation in response to cell shape cues is important for tissue organization and development. The presence of astral microtubules extending from the centrosome towards the cell cortex is essential for this process, but little is understood about the contribution of astral microtubule dynamics to spindle positioning, or how astral microtubule dynamics are regulated spatiotemporally. The mitotic regulator Cdk1-CyclinB promotes destabilization of centrosomal microtubules and increased microtubule dynamics as cells transition from interphase to mitosis, but how Cdk1 activity specifically modulates astral microtubule stability, and whether it impacts spindle positioning, is unknown. Here we uncover a mechanism revealing that Cdk1 destabilizes astral microtubules to ensure spindle reorientation in response to cell shape. Phosphorylation of the EB1-dependent microtubule plus-end tracking protein GTSE1 by Cdk1 in early mitosis abolishes its interaction with EB1 and recruitment to microtubule plus-ends. Loss of Cdk1 activity, or mutation of phosphorylation sites in GTSE1, induces recruitment of GTSE1 to growing microtubule plus-ends in mitosis. This decreases the catastrophe frequency of astral microtubules, and causes an increase in the number of long astral microtubules reaching the cell cortex, which restrains the ability of cells to reorient spindles along the long cellular axis in early mitosis. Astral microtubules must thus not only be present, but also dynamic to allow the spindle to reorient in response to cell shape, a state achieved by selective destabilization of long astral microtubules via Cdk1.
Single cell resolution regulatory landscape of the mouse kidney highlights cellular differentiation programs and renal disease targets
Authors: Miao Zhen , Balzer Michael S. , Ma Ziyuan , Liu Hongbo , Wu Junnan , Shrestha Rojesh , Aranyi Tamas , Kwan Amy , Kondo Ayano , Pontoglio Marco , Kim Junhyong , Li Mingyao , Kaestner Klaus H. , Susztak Katalin
Published: May 2020

Determining the epigenetic program that generates unique cell types in the kidney is critical for understanding cell-type heterogeneity during tissue homeostasis and injury response.

Here, we profiled open chromatin and gene expression in developing and adult mouse kidneys at single cell resolution. We show critical reliance of gene expression on distal regulatory elements (enhancers). We define key cell type-specific transcription factors and major gene-regulatory circuits for kidney cells. Dynamic chromatin and expression changes during nephron progenitor differentiation demonstrated that podocyte commitment occurs early and is associated with sustainedFoxl1expression. Renal tubule cells followed a more complex differentiation, whereHfn4awas associated with proximal andTfap2bwith distal fate. Mapping single nucleotide variants associated with human kidney disease identified critical cell types, developmental stages, genes, and regulatory mechanisms.

We provide a global single cell resolution view of chromatin accessibility of kidney development. The dataset is available via interactive public websites.
Selective Labeling and Identification of the Tumor Cell Proteome of Pancreatic CancerIn Vivo
Authors: Azizian Nancy G. , Sullivan Delaney K. , Nie Litong , Pardo Sammy , Molleur Dana , Chen Junjie , Weintraub Susan T. , Li Yulin
Published: May 2020

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers. Dissecting the tumor cell proteome from that of the non-tumor cells in the PDAC tumor bulk is critical for tumorigenesis studies, biomarker discovery, and development of therapeutics. However, investigating the tumor cell proteome has proven evasive due to the tumor’s extremely complex cellular composition. To circumvent this technical barrier, we have combined bioorthogonal non-canonical amino acid tagging (BONCAT) and data-independent acquisition mass spectrometry (DIA-MS) in an orthotopic PDAC model to specifically identify the tumor cell proteomein vivo. Utilizing the tumor cell-specific expression of a mutant tRNA synthetase transgene, this approach provides tumor cells with the exclusive ability to incorporate an azide-bearing methionine analog into newly synthesized proteins. The azide-tagged tumor cell proteome is subsequently enriched and purified via a bioorthogonal reaction and then identified and quantified using DIA-MS. Applying this workflow to the orthotopic PDAC model, we have identified thousands of proteins expressed by the tumor cells. Furthermore, by comparing the tumor cell and tumor bulk proteomes, we showed that the approach can distinctly differentiate proteins produced by tumor-cells from non-tumor cells within the tumor microenvironment. Our study, for the first time, reveals the tumor cell proteome of PDAC under physiological conditions, providing broad applications for tumorigenesis, therapeutics, and biomarker studies in various human cancers.
Improvements in task performance after practice are associated with scale-free dynamics of brain activity
Authors: Kardan Omid , Stier Andrew J. , Layden Elliot A. , Choe Kyoung Whan , Lyu Muxuan , Zhang Xihan , Beilock Sian L. , Rosenberg Monica D. , Berman Marc G.
Published: May 2020

Although practicing a task generally benefits later performance on that same task, there are individual differences in practice effects. One avenue to model such differences comes from research showing that brain networks extract functional advantages from operating in the vicinity of criticality, a state in which brain network activity is more scale-free. We hypothesized that higher scale-free signal from fMRI data, measured with the Hurst exponent (H), indicates closer proximity to critical states. We tested whether individuals with higherHduring repeated task performance would show greater practice effects. In Study 1, participants performed a dual-n-back task (DNB) twice during MRI (n = 56). In Study 2, we used two runs of n-back task (NBK) data from the Human Connectome Project sample (n = 599). In Study 3, participants performed a word completion task (CAST) across 6 runs (n = 44). In all three studies, multivariate analysis was used to test whether higherHwas related to greater practice-related performance improvement. Supporting our hypothesis, we found patterns of higherHthat reliably correlated with greater performance improvement across participants in all three studies. However, the predictive brain regions were distinct, suggesting that the specific spatialH↑ patterns are not task-general.
Generation of human bronchial organoids for SARS-CoV-2 research
Authors: Suzuki Tatsuya , Itoh Yumi , Sakai Yusuke , Saito Akatsuki , Okuzaki Daisuke , Motooka Daisuke , Minami Shohei , Kobayashi Takeshi , Yamamoto Takuya , Okamoto Toru , Takayama Kazuo
Published: May 2020

Coronavirus disease 2019 (COVID-19) is a disease that causes fatal disorders including severe pneumonia. To develop a therapeutic drug for COVID-19, a model that can reproduce the viral life cycle and evaluate the drug efficacy of anti-viral drugs is essential. In this study, we established a method to generate human bronchial organoids (hBO) from commercially available cryopreserved human bronchial epithelial cells and examined whether they could be used as a model for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research. Our hBO contain basal, club, ciliated, and goblet cells. Angiotensin-converting enzyme 2 (ACE2), which is a receptor for SARS-CoV-2, and transmembrane serine proteinase 2 (TMPRSS2), which is an essential serine protease for priming spike (S) protein of SARS-CoV-2, were highly expressed. After SARS-CoV-2 infection, not only the intracellular viral genome, but also progeny virus, cytotoxicity, pyknotic cells, and moderate increases of the type I interferon signal could be observed. Treatment with camostat, an inhibitor of TMPRSS2, reduced the viral copy number to 2% of the control group. Furthermore, the gene expression profile in SARS-CoV-2-infected hBO was obtained by performing RNA-seq analysis. In conclusion, we succeeded in generating hBO that can be used for SARS-CoV-2 research and COVID-19 drug discovery.

Graphical abstract
Reprocessing N95 Respirators During the COVID-19 Pandemic: Moist Heat Inactivates SARS-CoV-2 and Maintains N95 Filtration
Authors: Daeschler Simeon C. , Manson Niclas , Joachim Kariym , Chin Alex W. H. , Chan Katelyn , Chen Paul Z. , Tajdaran Kiana , Mirmoeini Kaveh , Zhang Jennifer J. , Maynes Jason T. , Science Michelle , Darbandi Ali , Stephens Derek , Poon Leo L. M. , Gu Frank , Borschel Gregory H.
Published: May 2020

Background

The unprecedented demand and consequent global shortage of N95 respirators during the COVID-19 pandemic have left frontline workers vulnerable to infection. To potentially expand the supply, we validated a rapidly applicable low-cost decontamination protocol in compliance with regulatory standards to enable the safe reuse of personalized, disposable N95-respirators.

Methods

Four common models of N95-respirators were disinfected for 60 minutes at 70°C either at 0% or 50% relative humidity (RH). Effective inactivation of SARS-CoV-2 and E. coli was evaluated in inoculated masks. The N95 filter integrity was examined with scanning electron microscopy. The protective function of disinfected N95 respirators was tested against US NIOSH standards for particle filtration efficiency, breathing resistance and respirator fit.

Results

A single heat treatment inactivated both SARS-CoV-2 (undetectable, detection limit: 100 TCID50/ml) and E. coli (0 colonies at 50%RH) in all four respirator models. Even N95-respirators that underwent ten decontamination cycles maintained their integrity and met US-governmental criteria for approval regarding fit, filtration efficiency and breathing resistance. Scanning electron microscopy demonstrated maintained N95 fiber diameter compared to baseline.

Interpretation

Thermal disinfection enables large-scale, low cost decontamination of existing N95 respirators using commonly sourced equipment during the COVID-19 pandemic. This process could be used in hospitals and long term care facilities and also provides a feasible approach to expand the N95 supply in low- and middle-income regions.
Elastin levels are higher in healing tendons than in intact tendons and influence tissue compliance
Authors: Svärd Anna , Hammerman Malin , Eliasson Pernilla
Published: May 2020

Elastic fibers containing elastin play an important role in tendon functionality, but the knowledge on presence and function of elastin during tendon healing is limited. The aim of this study was to investigate elastin content and distribution in intact and healing Achilles tendons and to understand how elastin influence the viscoelastic properties of tendons. The right Achilles tendon was completely transected in 81 Sprague-Dawley rats. Elastin content was quantified in intact and healing tendons (7, 14, and 28 days post-surgery) and elastin distribution was visualized by immunohistochemistry. Degradation of elastin by elastase incubation was used to study the role of elastin on viscoelastic properties. Mechanical testing was either performed as a cyclic test (20x 10 N) or as a creep test. We found significantly higher levels of elastin in healing tendons at all time-points compared to intact tendons (4% in healing tendons 28 days post-surgery vs 2% in intact tendons). The elastin was more widely distributed throughout the extracellular matrix in the healing tendons in contrast to the intact tendon where the distribution was not so pronounced. Elastase incubation reduced the elastin levels by approximately 30% and led to a 40-50% reduction in creep. This reduction was seen in both intact and healing tendons. Our results show that healing tendons contain more elastin and is more compliable than intact tendons. The role of elastin in tendon healing and tissue compliance indicate a protective role of elastic fibers to prevent re-injuries during early tendon healing.

PLAIN LANGUAGE SUMMARY

Tendons transfer high loads from muscles to bones during locomotion. They are primarily made by the protein collagen, a protein that provide strength to the tissues. Besides collagen, tendons also contain other building blocks such as e.g. elastic fibers. Elastic fibers contain elastin and elastin is important for the extensibility of the tendon. When a tendon is injured and ruptured the tissue heals through scar formation. This scar tissue is different from a normal intact tendon and it is important to understand how the tendons heal. Little is known about the presence and function of elastin during healing of tendon injuries. We have shown, in animal experiments, that healing tendons have higher amounts of elastin compared to intact tendons. The elastin is also spread throughout the tissue. When we reduced the levels of this protein, we discovered altered mechanical properties of the tendon. The healing tendon can normally extend quite a lot, but after elastin removal this extensibility was less obvious. The ability of the healing tissue to extend is probably important to protect the tendon from re-injuries during the first months after rupture. We therefore propose that the tendons heal with a large amount of elastin to prevent re-ruptures during early locomotion.
Autoregulatory circuit regulating basolateral cargo export from the TGN: role of the orphan receptor GPRC5A in PKD signaling and cell polarity
Authors: Di Martino Rosaria , Capalbo Anita , Sticco Lucia , Varavallo Alessandra , Kunnathully Vidya , De Luca Valentina , Iyengar Namrata Ravi , Monte Matteo Lo , Henklein Petra , Cancino Jorge , Luini Alberto
Published: May 2020

The membrane transport apparatus comprises a series of separate membrane bound compartments, or transport stations, that are responsible for the synthesis, processing, transport, sorting and delivery to their final cellular destinations of most transmembrane and soluble lumenal proteins. Over the last decades the membrane transport system has been shown to be extensively regulated both by environmental inputs and by internal homeostatic signalling systems, or control systems, that operate to maintain the homeostasis and optimal functionality of the main transport stations, such as the endoplasmic reticulum and the Golgi, in the face of internal and external perturbations. The trans-Golgi network (TGN) is a major transport and processing station and the main sorting compartment of the transport apparatus. However, the mechanisms that control cargo export and sorting at the TGN have so far remained elusive. Here we focus on the sorting of basolateral cargo proteins and show that these proteins bind to the TGN localized orphan receptor GPRC5A. The cargo-GPRC5A complex triggers the activation of a signaling pathway that involves the Gβγ subunits dependent activation of the phospholipase C beta 3 (PLCβ3), which inturn induces diacyl glycerol (DAG) production. DAG recruits and activates protein kinase D (PKD) and the phosphorylation of its substrates. This step results in the formation of basolateral carriers for delivery of these cargoes to the basolateral plasma membrane domain. We term this mechanism “ARTG” (AutoRegulation ofTGN export). Remarkably, the impairment of ARTG pathway components, and in particular of GPRC5A, causes defects in the polarized organization of epithelial cells.
Sources of variation and establishment of Russian reference intervals for major hormones and tumor markers
Authors: Ruzhanskaya Anna , Ichihara Kiyoshi , Evgina Svetlana , Skibo Irina , Vybornova Nina , Vasiliev Anton , Agarkova Galina , Emanuel Vladimir
Published: May 2020

Objectives

A multicenter study was organized to explore sources of variation (SVs) of reference values (RVs) for 24 major immunochemistry analytes and to determine reference intervals (RIs) for the Russian population.

Methods

According to IFCC Committee on Reference Intervals and Decision Limits (C-RIDL) protocol, 793 healthy volunteers were recruited in St. Petersburg, Moscow, and Yekaterinburg. Serum samples were tested for five tumor markers, 19 hormones and related tests by Beckman Coulter’s UniCel DxI 800 immunochemistry analyzer. SVs were explored using multiple regression analysis and ANOVA. Standard deviation ratio (SDR) of 0.4 was used as primary guide for partitioning RIs by gender and age.

Results

SDR for between-city difference was <0.4 for all analytes. Secondary exclusion of individuals was done under the following conditions: for female sex-hormones, those with contraceptives (8%); for CA19-9, those supposed to have negative Lewis blood-group (10.5%); for insulin, those with BMI≥28 kg/m2(29.9%); for the thyroid panel, those with anti-thyroid antibodies (10.3% in males; 24.5% in females). Gender-specific RIs were required for all analytes except CA19-9, CA15-3, thyroid-related tests, parathyroid hormone, and insulin. Age-specific RIs were required for α-fetoprotein and all sex-hormones except testosterone. RIs were generally derived by parametric method after Gaussian transformation using modified Box-Cox formula. Exceptions were growth hormone, estradiol, and progesterone, for which nonparametric method was required due to bimodal distribution and/or insufficient detection limit.

Conclusion

RIs for major hormones and tumor markers specific for the Russian population were derived based on the up-to-date internationally harmonized protocol by careful consideration of analyte-specific SVs.
Assessment of the relationships between agroecosystem condition and soil erosion regulating ecosystem service in Northern Germany
Authors: Rendon Paula , Steinhoff-Knopp Bastian , Saggau Philipp , Burkhard Benjamin
Published: May 2020

Ecosystems provide multiple services that are necessary to maintain human life and activities. Agroecosystems are very productive suppliers of biomass-related provisioning ecosystem services, e.g. food, fibre and energy. At the same time, they are highly dependent on respective ecosystem condition and regulating ecosystem services such as soil fertility, water supply or soil erosion regulation. Assessments of this interplay of ecosystem conditions and services are very important to understand the relationships in highly managed systems. Therefore, the aim of this study is twofold: First, to test the concept and indicators proposed by the European Union Working Group on Mapping and Assessment of Ecosystems and their Services (MAES) for the assessment of agroecosystem condition at a regional level. Second, to identify the relationships between ecosystem condition and the delivery of ecosystem services. For this purpose, we applied an operational framework for integrated mapping and assessment of ecosystems and their services. We used the proposed indicators to assess the condition of agroecosystems in Northern Germany and the provision of the regulating ecosystem service control of erosion rates. We used existing data that are available from official databases for the calculation of the different indicators. We show maps of environmental pressures, ecosystem condition and ecosystem service indicators for the Federal State of Lower Saxony. Furthermore, we identified areas within the state where pressures are high, conditions are limited, and more sustainable management practices are needed.

Despite the limitations of the indicators and data availability, our results show positive, negative and no significant correlations between the different pressures and condition indicators, and the control of erosion rates. Although the idea behind the MAES framework is to show the general condition of an ecosystem, when looking at the relationships between condition and ecosystem services, we identified that not all the indicators - as they are proposed- are suitable to explain to what extent ecosystems are able to provide certain ecosystem services. Further research on other ecosystem services provided by agroecosystems would facilitate the identification of synergies and trade-offs. Moreover, the definition of a reference condition, although complicated for anthropogenically highly modified agroecosystems, would provide a benchmark to compare information on the condition of the ecosystems, leading to better land use policy and management decisions
Mammalian copper homeostasis requires retromer-dependent recycling of the high-affinity copper transporter 1 (CTR1/SLC31A1)
Authors: Curnock Rachel , Cullen Peter J.
Published: May 2020

The mammalian cell surface is decorated with a plethora of integral membrane proteins including those required for the transport of micronutrients, such as copper, which are essential to cellular health. The concentration of micronutrients within the cell is tightly regulated to avoid their adverse deficiency and toxicity effects. The sorting and recycling of nutrients transporters within the endo-lysosomal network is recognised as an essential process in regulating nutrient balance. The evolutionarily conserved endosomal sorting complex, retromer, coordinates integral membrane protein recognition and retrieval. Cellular copper homeostasis is regulated primarily by two transporters: the major copper influx transporter copper transporter 1 (CTR1/SLC31A1), which controls the uptake of copper from the extracellular environment and is essential for early embryonic development, and the established retromer cargo, the copper-transporting ATPase, ATP7A. Here, we show that in response to fluctuating extracellular copper the retromer complex controls the delivery of CTR1 to the cell surface. Following copper exposure, CTR1 is endocytosed to prevent excessive copper uptake. We reveal that internalised CTR1 localises on retromer-positive endosomes and in response to decreased extracellular copper retromer controls the recycling of CTR1 back to the cell surface to maintain copper homeostasis. In addition to copper, CTR1 plays a central role in platinum uptake. Significantly, the efficacy of platinum-based cancer drugs has been correlated with CTR1 expression. Consistent with this, we demonstrate that retromer-deficient cells show reduced sensitivity to the platinum-based drug, cisplatin.
A Hyperactive Kunjin Virus NS3 Helicase Mutant Demonstrates Increased Dissemination and Mortality in Mosquitoes
Authors: Du Pont Kelly E. , Sexton Nicole R. , McCullagh Martin , Ebel Gregory D. , Geiss Brian J.
Published: May 2020

The unwinding of double-stranded RNA intermediates is critical for replication and packaging of flavivirus RNA genomes. This unwinding activity is achieved by the ATP-dependent nonstructural protein 3 (NS3) helicase. In previous studies, we investigated the mechanism of energy transduction between the ATP and RNA binding pockets using molecular dynamics simulations and enzymatic characterization. Our data corroborated the hypothesis that Motif V is a communication hub for this energy transduction. More specifically, mutations T407A and S411A in Motif V exhibit a hyperactive helicase phenotype leading to the regulation of translocation and unwinding during replication. However, the effect of these mutations on viral infection in cell culture andin vivois not well understood. Here, we investigated the role of Motif V in viral replication using T407A and S411A West Nile virus (Kunjin subtype) mutants in cell culture andin vivo.We were able to recover S411A Kunjin but unable to recover T407A Kunjin. Our results indicated that S411A Kunjin decreased viral infection, and increased cytopathogenicity in cell culture as compared to WT Kunjin. Similarly, decreased infection rates in surviving S411A-infectedCulex quinquefasciatusmosquitoes were observed, but S411A Kunjin infection resulted in increased mortality compared to WT Kunjin. Additionally, S411A Kunjin increased viral dissemination and saliva positivity rates in surviving mosquitoes compared to WT Kunjin. These data suggest that S411A Kunjin increases pathogenesis in mosquitoes. Overall, these data indicate that NS3 Motif V may play a role in the pathogenesis, dissemination, and transmission efficiency of Kunjin virus.

IMPORTANCE

Kunjin and West Nile viruses belong to the arthropod-borne flaviviruses, which can result in severe symptoms including encephalitis, meningitis, and death. Flaviviruses have expanded into new populations and emerged as novel pathogens repeatedly in recent years demonstrating they remain a global threat. Currently, there are no approved anti-viral therapeutics against either Kunjin or West Nile viruses. Thus, there is a pressing need for understanding the pathogenesis of these viruses in humans. In this study, we investigate the role of the Kunjin virus helicase on infection in cell culture andin vivo. This work provides new insight into how flaviviruses control pathogenesis and mosquito transmission through the nonstructural protein 3 helicase.
Cystic fibrosis transmembrane conductance regulator (CFTR) inhibition results in mucus accumulation in human airway epithelia Calu-3 cells: Experimental and Machine Learning Studies
Authors: Laethem Brandon S. , Lewis Kenneth T. , Ramos Rafael , Hou Xia , Sun Fei , Taatjes Douglas J. , Jena Bhanu P. , Arslanturk Suzan
Published: May 2020

Porosomes are cup-shaped lipoprotein structures at the cell plasma membrane involved in fractional release of intra-vesicular contents during secretion. At the base of the porosome facing the cell cytoplasm, secretory vesicles dock, fuse and swell, to release intra-vesicular content during secretion. Earlier studies demonstrate the cystic fibrosis trans-membrane conductance regulator (CFTR) associated with the porosome in human airways epithelial Calu-3 mucous-secreting cells, suggesting its possible involvement in porosome-mediated mucus secretion. The current study was undertaken to test this hypothesis. Electron microscopy followed by morphometric analysis using manual and computational machine learning approaches were used to assess changes in secretory vesicle size and content, following stimulation of secretion in the absence and presence of CFTR inhibitors. Results from the study demonstrate that stimulated Calu-3 cells pre-exposed to CFTR inhibitors, demonstrate attenuation of secretory vesicle swelling and the release of mucin. Consequently, accumulation of intracellular mucin is observed in cells exposed to CFTR inhibitors. These results further suggest that mucin secretion from Calu-3 cells involve CFTR both at the secretory vesicle membrane to regulate vesicle volume and hydration, and at the porosome to facilitate mucin hydration and secretion. These new findings progress our understanding of the involvement of CFTR on mucus hydration and secretion, providing critical insights into the etiology of CF disease.
Globally altered epigenetic landscape and lagging osteogenic differentiation in H3.3-G34W-mutant giant cell tumor of bone
Authors: Lutsik Pavlo , Baude Annika , Mancarella Daniela , Oez Simin , Kuehn Alexander , Toth Reka , Hey Joschka , Toprak Umut H. , Lim Jinyeong , Nguyen Viet Ha , Jiang Chao , Mayakonda Anand , Hartmann Mark , Rosemann Felix , Breuer Kersten , Vonficht Dominik , Gruenschlaeger Florian , Lee Suman , Schuhmacher Maren Kirstin , Kusevic Denis , Jauch Anna , Weichenhan Dieter , Zustin Jozef , Schlesner Matthias , Haas Simon , Park Joo Hyun , Park Yoon Jung , Oppermann Udo , Jeltsch Albert , Haller Florian , Fellenberg Joerg , Lindroth Anders , Plass Christoph
Published: May 2020

The neoplastic stromal cells of giant cell tumor of bone (GCTB) carry a mutation in H3F3A, leading to a mutant histone variant, H3.3-G34W, as a sole recurrent genetic alteration. We show that in patient-derived stromal cells H3.3-G34W is incorporated into the chromatin and associates with massive epigenetic alterations on the DNA methylation, chromatin accessibility and histone modification level that can be partially recapitulated in an orthogonal cell line system by the introduction of H3.3-G34W. These epigenetic alterations affect mainly heterochromatic and bivalent regions and provide possible explanations for the genomic instability as well as the osteolytic phenotype of GCTB. The mutation occurs in differentiating mesenchymal stem cells and associates with an impaired osteogenic differentiation. We propose that the observed epigenetic alterations reflect distinct differentiation stages of H3.3 WT and H3.3 MUT stromal cells and add to H3.3-G34W associated changes.
Combining fine-scale social contact data with epidemic modelling reveals interactions between contact tracing, quarantine, testing and physical distancing for controlling COVID-19
Authors: Firth Josh A. , Hellewell Joel , Klepac Petra , Kissler Stephen ,   CMMID COVID-19 working group, Kucharski Adam J. , Spurgin Lewis G.
Published: May 2020

Case isolation and contact tracing can contribute to the control of COVID-19 outbreaks1,2. However, it remains unclear how real-world networks could influence the effectiveness and efficiency of such approaches. To address this issue, we simulated control strategies for SARS-CoV-2 in a real-world social network generated from high resolution GPS data3,4. We found that tracing contacts-of-contacts reduced the size of simulated outbreaks more than tracing of only contacts, but resulted in almost half of the local population being quarantined at a single point in time. Testing and releasing non-infectious individuals led to increases in outbreak size, suggesting that contact tracing and quarantine may be most effective when it acts as a ‘local lockdown’ when contact rates are high. Finally, we estimated that combining physical distancing with contact tracing could enable epidemic control while reducing the number of quarantined individuals. Our approach highlights the importance of network structure and social dynamics in evaluating the potential impact of SARS-CoV-2 control.
Number of term-time working hours among undergraduate students
Authors: Tan Tong Sheng , Lim Eivon , Loke Yiing Jia
Published: May 2020

Purpose

The purpose of this study is to investigate the prevalence of term-time employment among undergraduate students and to identify the factors that affect the number of working hours in term-time employment. The study also aims to explore if students work during term time due to self-development or financial needs.

Design/methodology/approach

A self-administered questionnaire was used to collect data from 400 undergraduates in a public university in Malaysia. A Tobit regression model was used to identify the factors that can significantly explain the varying working hours per week in the student sample.

Findings

Only 20.8% of the students in the sample undertook term-time employment, with an average of 16 working hours a week. The financial motivations to work were driven more by the need to sustain a desired lifestyle compared to financing basic living expenses. Students’ perceptions towards term-time employment significantly affected their working hours and likelihood of undertaking term-time employment.

Practical implications

As students want to excel academically and at the same time gain working experience and skills, universities may want to revisit the higher education curriculum and reconsider the course credit weightage for academic and practical experience.

Originality/value

Instead of just documenting the number of working hours among students, the study empirically explores the factors that affect the number of working hours and sheds light on the allocation of time and priorities by students among academics, self-development and social life.
Difference equation vs differential equation on different scales
Authors: He Ji-Huan , Ji Fei-Yu , Mohammad-Sedighi Hamid
Published: May 2020

Purpose

The purpose of this paper is to demonstrate that the numerical method is not everything for nonlinear equations. Some properties cannot be revealed numerically; an example is used to elucidate the fact.

Design/methodology/approach

A variational principle is established for the generalized KdV – Burgers equation by the semi-inverse method, and the equation is solved analytically by the exp-function method, and some exact solutions are obtained, including blowup solutions and discontinuous solutions. The solution morphologies are studied by illustrations using different scales.

Findings

Solitary solution is the basic property of nonlinear wave equations. This paper finds some new properties of the KdV–Burgers equation, which have not been reported in open literature and cannot be effectively elucidated by numerical methods. When the solitary solution or the blowup solution is observed on a much small scale, their discontinuous property is first found.

Originality/value

The variational principle can explain the blowup and discontinuous properties of a nonlinear wave equation, and the exp-function method is a good candidate to reveal the solution properties.
Legal implications governing medical negligence in India: creating awareness through six-dimensional framework of effective communication
Authors: Sethi Deepa , Arya Vikas
Published: May 2020

Purpose

The purpose of this study is to determine the existing legal implications for medical negligence in India and recommending how open communication and empathy by the doctors can help prevent these implications.

Design/methodology/approach

This research is based on a qualitative method. Indian laws, Indian constitution, journal articles, books and other writings have been reviewed to develop this study.

Findings

There are many legal implications for medical negligence in India, and justice can be demanded under a number of Indian laws. This study also found that it is important to create awareness regarding the laws governing medical negligence through effective communication and empathy.

Originality/value

Extant literature discusses in detail the various laws related to medical negligence and few talk about creating awareness about these laws amongst people, and while some researchers understand the importance of sensitizing health professionals of the nitty-gritty of the legal implication governing medical negligence, none provides a framework of medical negligence with the help of sensitizing health professionals through communication. This study fills the gap by focusing on prevention than cure.
Decent work and healthy employment: a qualitative case study about Colombian millennials
Authors: Gallo Óscar , Gonzales–Miranda Diego René , Roman-Calderon Juan Pablo , García Gustavo A.
Published: May 2020

Purpose

The purpose of this article is to show how a group of Colombian millennials perceive different aspects of working life and how their ideas about job satisfaction, professional expectations and levels of autonomy are related to contemporary demands about inclusion, diversity, equity, autonomy and control.

Design/methodology/approach

With this objective, 167 semi-structured interviews were conducted with millennials who work at 10 Colombian companies from the manufacturing and service sectors, located in the five main cities of the country. With a qualitative approach, in the interviews, the research team used a strategy inspired by the technique of generating visual structures associated with grounded theory.

Findings

It is concluded that new generations of Colombian workers know of the importance of rewards and autonomy in work and are more critical and less passive in the face of unhealthy working conditions. At the same time, their conduct and speeches are the consequence of the characteristics of the Colombian labour market. The document responds to the need to deepen the debates on welfare and happiness in organizations and to include the demands of millennials in the reflective and political horizon of the ideas of healthy employment and decent work. In practice, this article seeks to demystify ideas about millennials in Colombia and critically contribute to reflection on intergenerational relations in organizations and salary and welfare models. As a Latin American case, it is an original contribution that avoids the common places and the frivolity with which the insertion of the new generations into the working world has been analysed.

Practical implications

In practice, this paper seeks to demystify ideas about millennials in Colombia and critically contribute to reflection on intergenerational relations in organizations and salary and welfare models.

Originality/value

As a Latin American case, it is an original contribution that avoids the common places and the frivolity with which the insertion of the new generations into the working world has been analysed.
Price discovery and volatility spillover: an empirical evidence from spot and futures agricultural commodity markets in India
Authors: R L Manogna , Mishra Aswini Kumar
Published: May 2020

Purpose

Price discovery and spillover effect are prominent indicators in the commodity futures market to protect the interest of consumers, farmers and to hedge sharp price fluctuations. The purpose of this paper is to investigate empirically the price discovery and volatility spillover in Indian agriculture spot and futures commodity markets.

Design/methodology/approach

This study uses Granger causality, vector error correction model (VECM) and exponential generalized autoregressive conditional heteroskedasticity (EGARCH) to examines the price discovery and spillover effects for nine most liquid agricultural commodities in spot and futures markets traded on National Commodity and Derivatives Exchange (NCDEX).

Findings

The VECM results show that price discovery exists in all the nine commodities with futures market leading the spot in case of six commodities, namely soybean seed, coriander, turmeric, castor seed, guar seed and chana. Whereas in case of three commodities (cotton seed, rape mustard seed and jeera), price discovery takes place in the spot market. The Granger causality tests indicate that futures markets have stronger ability to predict spot prices. Supporting these, the results from EGARCH volatility test reveal that there exist mutual spillover effects on futures and spot markets. Thus, it could be inferred that futures market is more efficient in price discovery of agricultural commodities in India.

Research limitations/implications

These results can help the market participants to benefit by hedging out the uncertainty and the policymakers to design futures contracts to improve the efficiency of the agricultural commodity derivatives market.

Practical implications

The findings provide fresh view on lead–lag relationship between future and spot prices using the latest data confirming that futures market indeed is dominant in price discovery.

Originality/value

There are very few studies that have explored the efficiency of the agricultural commodity spot and futures markets in India using both price discovery and volatility spillover in a detailed manner, especially at the individual agriculture commodity level.