bluuebunny/crossref_metadata_2025 huggingface dataset:
Do Health-Care Students Know About Chemical Biological Radioactive Nuclear Weapons?
Authors: Yigitbas Cagla
Published: November 2021

Objective:

The aim of this study was to determine the level of knowledge of students receiving different levels of health-care education (doctors, nurses, paramedics) on chemical, biological, radioactive, and nuclear weapons (CBRNW).

Methods:

This study was designed as a qualitative, descriptive, and cross-sectional research. The study reached 87.68% of the population. A survey form was created by the researcher in line with the literature. Ethical permission and verbal consents were obtained. The data were collected by face-to-face interviews.

Results:

It was observed that there was no difference between the enrolled departments, that the participants had very low levels of knowledge on the subject despite considering it a likely threat for Turkey, and that they thought the public and the health-care professionals in this field had insufficient knowledge. Sex, age, and field education were the variables that created a difference.

Conclusion:

Training regarding CBRNW should be further questioned and individuals should receive ongoing training to increase and update their knowledge and skills.
The enduring problem of ‘grey’ drone violence
Authors: Enemark Christian
Published: November 2021

This article addresses the problem of drone violence that is ‘grey’ in the sense of being hard to categorise. It focuses on circumstances, such as arose in Pakistan, in which a foreign government's armed drones are a constant presence. A lesson from US experience there is that the persistent threat of drone strikes is intended to suppress activities that endanger the drone-using state's security. However, this threat inevitably affects innocent people living within potential strike zones. To judge such drone use by reference to military ethics principles is to assume that ‘war’ is going on, but indefinite drone deployments are difficult to conceptualise as war, so traditional Just War thinking does not suffice as a basis for moral judgement. In assessing the US government's commitment to drone-based containment of risks emerging along its ‘terror frontier’, the article considers three alternative conceptualisations of drone violence arising in non-war contexts: vim (‘force short of war’), terrorism, and imperialism. It then rejects all three and proposes that such violence is better conceptualised as being merely ‘quasi-imperialistic’. On this basis, however, the sustaining of a drone strike campaign against a series of suspected terrorists can still be condemned as violating the right to life.
Vortex-induced vibration of a sphere close to or piercing a free surface
Authors: Rajamuni Methma M. , Hourigan Kerry , Thompson Mark C.
Published: November 2021

Vortex-induced vibration (VIV) of an elastically mounted sphere placed close to or piercing a free surface (FS) was investigated numerically. The submergence depth (

$h$

) was systematically varied between

$1$

and

$-$

0.75 sphere diameters (

$D$

) and the response simulated over the reduced velocity range

$U^*\in [3.5,14]$

. The incompressible flow was coupled with the sphere motion modelled by a spring–mass–damper system, treating the free-surface boundary as a slip wall. In line with the previous experimental findings, as the submergence depth was decreased from

$h^* = h/D =1$

, the maximum response amplitude of the fully submerged sphere decreased; however, as the sphere pierced the FS, the amplitude increased until

$h^* = -0.375$

, and then decreased beyond that point. The fluctuating components of the lift and drag coefficients also followed the same pattern. The variation of the near-wake vortex dynamics over this submergence range was examined in detail to understand the effects of

$h^*$

on the VIV response. It was found that

$h^* = 1$

is a critical submergence depth, beyond which, as

$h^*$

is decreased, the vortical structures in the wake vary significantly. For a fully submerged sphere, the influence of the stress-free condition on the VIV response was dominant over the kinematic constraint preventing flow through the surface. For piercing sphere cases, two previously unseen vortical recirculations were formed behind the sphere near times of maximal displacement, enhancing the VIV response. These were strongest at

$h^* = -0.375$

, and much weaker for small submergence depths, explaining the observed response-amplitude variation.
Perceptions of co-worker exclusion and performance outcomes: are different forms of support helpful or hurtful?
Authors: Cruz Kevin S. , Zagenczyk Thomas J. , Scott Kristin L. , Purvis Russell L.
Published: November 2021

We argue that social support can be helpfulorhurtful in the context of performance outcomes for employees experiencing co-worker exclusion. We contend that employees' perceptions of co-worker exclusion are negatively associated with task performance and citizenship, and positively associated with interpersonal deviance. We further contend that whether social support strengthens or weakens the negative performance outcomes of co-worker exclusion depends on whether the source of social support is from co-workers or family and friends. Using data obtained from 135 supervisor–subordinate dyads across various occupational positions, we find that co-worker support is hurtful, whereas family and friends support is helpful. We also find a three-way interaction: task performance suffers most when employees who feel highly excluded also perceive higher co-worker support and lower family and friends support. These results suggest a need for a more nuanced view of social exchange/support, and build our knowledge about ambivalent relationships.
A NOTE ON GIRSTMAIR’S IRREDUCIBILITY CRITERION
Authors: SINGH JITENDER , KUMAR SANJEEV
Published: November 2021

Girstmair [‘On an irreducibility criterion of M. Ram Murty’, Amer. Math. Monthly112(3) (2005), 269–270] gave a generalisation of Ram Murty’s irreducibility criterion. We further generalise these criteria.
What effect might border screening have on preventing the importation of COVID-19 compared with other infections? A modelling study
Authors: Bays Declan , Bennett Emma , Finnie Thomas
Published: November 2021

The effectiveness of screening travellers during times of international disease outbreak is contentious, especially as the reduction in the risk of disease importation can be very small. Border screening typically consists of travellers being thermally scanned for signs of fever and/or completing a survey declaring any possible symptoms prior to admission to their destination country; while more thorough testing typically exists, these would generally prove more disruptive to deploy. In this paper, we describe a simple Monte Carlo based model that incorporates the epidemiology of coronavirus disease-2019 (COVID-19) to investigate the potential decrease in risk of disease importation that might be achieved by requiring travellers to undergo screening upon arrival during the current pandemic. This is a purely theoretical study to investigate the maximum impact that might be attained by deploying a test or testing programme simply at the point of entry, through which we may assess such action in the real world as a method of decreasing the risk of importation. We, therefore, assume ideal conditions such as 100% compliance among travellers and the use of a ‘perfect’ test. In addition to COVID-19, we also apply the presented model to simulated outbreaks of influenza, severe acute respiratory syndrome (SARS) and Ebola for comparison. Our model only considers screening implemented at airports, being the predominant method of international travel. Primary results showed that in the best-case scenario, screening at the point of entry may detect a maximum of 8.8% of travellers infected with COVID-19, compared to 34.8.%, 9.7% and 3.0% for travellers infected with influenza, SARS and Ebola respectively. While results appear to indicate that screening is more effective at preventing disease ingress when the disease in question has a shorter average incubation period, our results suggest that screening at the point of entry alone does not represent a sufficient method to adequately protect a nation from the importation of COVID-19 cases.
Modulation of Whistler Mode Waves by Ultra‐Low Frequency Wave in a Macroscale Magnetic Hole: MMS Observations
Authors: Zhang He , Zhong Zhihong , Tang Rongxin , Deng Xiaohua , Li Haimeng , Wang Dedong
Published: November 2021

We report the quasi‐periodic whistler‐mode waves corresponding to electron temperature anisotropy T⊥/T// < 1 at the center of a macroscale magnetic hole (MH) near the Earth's magnetopause observed by the Magnetospheric Multiscale mission. A significant ultra‐low frequency (ULF) wave of background magnetic field was observed in this MH. The ULF wave dramatically exacerbates the evolution of MH and the formation of the donut‐shaped electron pitch angle distribution (PAD) in the macroscale MH. When the whistler‐mode waves were generated, they are consistent with troughs of the ULF wave and density increases, which is also related to the butterfly type PAD at those moments. The analysis of dispersion relation and cyclotron resonance condition indicate that whistler‐mode waves were mainly generated by the butterfly type PAD of electrons. Our results provides new insights into one possible excitation mechanism of whistler‐mode wave.
Vitamin D and the risk of treatment-resistant and atypical depression: A Mendelian randomization study
Authors: Arathimos Ryan , Ronaldson Amy , Howe Laurence J. , Fabbri Chiara , Hagenaars Saskia , Hotopf Matthew , Gaughran Fiona , Lewis Cathryn M. , Dregan Alexandru
Published: November 2021

Observational evidence has implicated vitamin D levels as a risk factor in major depressive disorder (MDD). Confounding or reverse causation may be driving these observed associations, with studies using genetics indicating little evidence of an effect. However, genetic studies have relied on broad definitions of depression. The genetic architecture of different depression subtypes may vary since MDD is a highly heterogenous condition, implying potentially diverging requirements in therapeutic approaches. We explored the associations between vitamin D and two subtypes of MDD, for which evidence of a causal link could have the greatest clinical benefits: treatment-resistant depression (TRD) and atypical depression (AD). We used a dual approach, combining observational data with genetic evidence from polygenic risk scores (PRS) and two-sample Mendelian randomization (MR), in the UK Biobank. There was some evidence of a weak association between vitamin D and both incident TRD (Ncases = 830) and AD (Ncases = 2366) in observational analyses, which largely attenuated when adjusting for confounders. Genetic evidence from PRS and two-sample MR, did not support a causal link between vitamin D and either TRD (Ncases = 1891, OR = 1.01 [95%CI 0.78, 1.31]) or AD (Ncases = 2101, OR = 1.04 [95%CI 0.80, 1.36]). Our comprehensive investigations indicated some evidence of an association between vitamin D and TRD/AD observationally, but little evidence of association when using PRS and MR, mirroring findings of genetic studies of vitamin D on broad depression phenotypes. Results do not support further clinical trials of vitamin D in these MDD subtypes but do not rule out that small effects may exist that require larger samples to detect.
Intrinsic S phase checkpoint enforced by an antiproliferative oncosuppressor cytokine
Authors: Mallucci Livio , Wells Valerie
Published: November 2021

The cell cycle is strictly programmed with control mechanisms that dictate order in cell cycle progression to ensure faithful DNA replication, whose deviance may lead to cancer. Checkpoint control at the G1/S, S/G2 and G2/M portals have been defined but no statutory time-programmed control for securing orderly transition through S phase has so far been identified. Here we report that in normal cells DNA synthesis is controlled by a checkpoint sited within the early part of S phase, enforced by the βGBP cytokine an antiproliferative molecule otherwise known for its oncosuppressor properties that normal cells constitutively produce for self-regulation. Suppression of active Ras and active MAPK, block of cyclin A gene expression and suppression of CDK2-cyclin A activity are events which while specific to the control of a cell cycle phase in normal cells are part of the apoptotic network in cancer cells.
Higher intake of whole grains and dietary fiber are associated with lower risk of liver cancer and chronic liver disease mortality
Authors: Liu Xing , Yang Wanshui , Petrick Jessica L. , Liao Linda M. , Wang Weibing , He Na , Campbell Peter T. , Zhang Zuo-Feng , Giovannucci Edward , McGlynn Katherine A. , Zhang Xuehong
Published: November 2021

The relationship between dietary factors and liver disease remains poorly understood. This study evaluated the associations of whole grain and dietary fiber intake with liver cancer risk and chronic liver disease mortality. The National Institutes of Health–American Association of Retired Persons Diet and Health Study cohort recruited 485, 717 retired U.S. participants in 1995–1996. Follow-up through 2011 identified 940 incident liver cancer cases and 993 deaths from chronic liver disease. Compared with the lowest, the highest quintile of whole grain intake was associated with lower liver cancer risk (Hazard ratio [HR]Q5 vs. Q1 = 0.78, 95% confidence interval [CI]: 0.63–0.96) and chronic liver disease mortality (HRQ5 vs. Q1 = 0.44, 95% CI: 0.35–0.55) in multivariable Cox models. Dietary fiber was also associated with lower liver cancer risk (HRQ5 vs. Q1 = 0.69, 95% CI: 0.53–0.90) and chronic liver disease mortality (HRQ5 vs. Q1 = 0.37, 95% CI: 0.29–0.48). Fiber from vegetables, beans and grains showed potential protective effect. Here, we show that higher intake of whole grain and dietary fiber are associated with lower risk of liver cancer and liver disease mortality.
Drosophila ßHeavy-Spectrin is required in polarized ensheathing glia that form a diffusion-barrier around the neuropil
Authors: Pogodalla Nicole , Kranenburg Holger , Rey Simone , Rodrigues Silke , Cardona Albert , Klämbt Christian
Published: November 2021

In the central nervous system (CNS), functional tasks are often allocated to distinct compartments. This is also evident in the Drosophila CNS where synapses and dendrites are clustered in distinct neuropil regions. The neuropil is separated from neuronal cell bodies by ensheathing glia, which as we show using dye injection experiments, contribute to the formation of an internal diffusion barrier. We find that ensheathing glia are polarized with a basolateral plasma membrane rich in phosphatidylinositol-(3,4,5)-triphosphate (PIP3) and the Na+/K+-ATPase Nervana2 (Nrv2) that abuts an extracellular matrix formed at neuropil-cortex interface. The apical plasma membrane is facing the neuropil and is rich in phosphatidylinositol-(4,5)-bisphosphate (PIP2) that is supported by a sub-membranous ßHeavy-Spectrin cytoskeleton. ßHeavy-spectrin mutant larvae affect ensheathing glial cell polarity with delocalized PIP2 and Nrv2 and exhibit an abnormal locomotion which is similarly shown by ensheathing glia ablated larvae. Thus, polarized glia compartmentalizes the brain and is essential for proper nervous system function.
Smad4 controls signaling robustness and morphogenesis by differentially contributing to the Nodal and BMP pathways
Authors: Guglielmi Luca , Heliot Claire , Kumar Sunil , Alexandrov Yuriy , Gori Ilaria , Papaleonidopoulou Foteini , Barrington Christopher , East Philip , Economou Andrew D. , French Paul M. W. , McGinty James , Hill Caroline S.
Published: November 2021

The transcriptional effector SMAD4 is a core component of the TGF-β family signaling pathways. However, its role in vertebrate embryo development remains unresolved. To address this, we deleted Smad4 in zebrafish and investigated the consequences of this on signaling by the TGF-β family morphogens, BMPs and Nodal. We demonstrate that in the absence of Smad4, dorsal/ventral embryo patterning is disrupted due to the loss of BMP signaling. However, unexpectedly, Nodal signaling is maintained, but lacks robustness. This Smad4-independent Nodal signaling is sufficient for mesoderm specification, but not for optimal endoderm specification. Furthermore, using Optical Projection Tomography in combination with 3D embryo morphometry, we have generated a BMP morphospace and demonstrate that Smad4 mutants are morphologically indistinguishable from embryos in which BMP signaling has been genetically/pharmacologically perturbed. Smad4 is thus differentially required for signaling by different TGF-β family ligands, which has implications for diseases where Smad4 is mutated or deleted.
A compendium of chromatin contact maps reflecting regulation by chromatin remodelers in budding yeast
Authors: Jo Hyelim , Kim Taemook , Chun Yujin , Jung Inkyung , Lee Daeyoup
Published: November 2021

We herein employ in situ Hi-C with an auxin-inducible degron (AID) system to examine the effect of chromatin remodeling on 3D genome organization in yeast. Eight selected ATP-dependent chromatin remodelers representing various subfamilies contribute to 3D genome organization differently. Among the studied remodelers, the temporary depletions of Chd1p, Swr1p, and Sth1p (a catalytic subunit of the Remodeling the Structure of Chromatin [RSC] complex) cause the most significant defects in intra-chromosomal contacts, and the regulatory roles of these three remodelers in 3D genome organization differ depending on the chromosomal context and cell cycle stage. Furthermore, even though Chd1p and Isw1p are known to share functional similarities/redundancies, their depletions lead to distinct effects on 3D structures. The RSC and cohesin complexes also differentially modulate 3D genome organization within chromosome arm regions, whereas RSC appears to support the function of cohesin in centromeric clustering at G2 phase. Our work suggests that the ATP-dependent chromatin remodelers control the 3D genome organization of yeast through their chromatin-remodeling activities.
The origin and impeded dissemination of the DNA phosphorothioation system in prokaryotes
Authors: Jian Huahua , Xu Guanpeng , Yi Yi , Hao Yali , Wang Yinzhao , Xiong Lei , Wang Siyuan , Liu Shunzhang , Meng Canxing , Wang Jiahua , Zhang Yue , Chen Chao , Feng Xiaoyuan , Luo Haiwei , Zhang Hao , Zhang Xingguo , Wang Lianrong , Wang Zhijun , Deng Zixin , Xiao Xiang
Published: November 2021

Phosphorothioate (PT) modification by thedndgene cluster is the first identified DNA backbone modification and constitute an epigenetic system with multiple functions, including antioxidant ability, restriction modification, and virus resistance. Despite these advantages for hostingdndsystems, they are surprisingly distributed sporadically among contemporary prokaryotic genomes. To address this ecological paradox, we systematically investigate the occurrence and phylogeny ofdndsystems, and they are suggested to have originated in ancient Cyanobacteria after the Great Oxygenation Event. Interestingly, the occurrence ofdndsystems and prophages is significantly negatively correlated. Further, we experimentally confirm that PT modification activates the filamentous phage SW1 by altering the binding affinity of repressor and the transcription level of its encoding gene. Competition assays, concurrent epigenomic and transcriptomic sequencing subsequently show that PT modification affects the expression of a variety of metabolic genes, which reduces the competitive fitness of the marine bacteriumShewanella piezotoleransWP3. Our findings strongly suggest that a series of negative effects on microorganisms caused bydndsystems limit horizontal gene transfer, thus leading to their sporadic distribution. Overall, our study reveals putative evolutionary scenario of thedndsystem and provides novel insights into the physiological and ecological influences of PT modification.
Graphene’s non-equilibrium fermions reveal Doppler-shifted magnetophonon resonances accompanied by Mach supersonic and Landau velocity effects
Authors: Greenaway M. T. , Kumaravadivel P. , Wengraf J. , Ponomarenko L. A. , Berdyugin A. I. , Li J. , Edgar J. H. , Kumar R. Krishna , Geim A. K. , Eaves L.
Published: November 2021

Oscillatory magnetoresistance measurements on graphene have revealed a wealth of novel physics. These phenomena are typically studied at low currents. At high currents, electrons are driven far from equilibrium with the atomic lattice vibrations so that their kinetic energy can exceed the thermal energy of the phonons. Here, we report three non-equilibrium phenomena in monolayer graphene at high currents: (i) a “Doppler-like” shift and splitting of the frequencies of the transverse acoustic (TA) phonons emitted when the electrons undergo inter-Landau level (LL) transitions; (ii) an intra-LL Mach effect with the emission of TA phonons when the electrons approach supersonic speed, and (iii) the onset of elastic inter-LL transitions at a critical carrier drift velocity, analogous to the superfluid Landau velocity. All three quantum phenomena can be unified in a single resonance equation. They offer avenues for research on out-of-equilibrium phenomena in other two-dimensional fermion systems.
Benchmarking pipelines for subclonal deconvolution of bulk tumour sequencing data
Authors: Tanner Georgette , Westhead David R. , Droop Alastair , Stead Lucy F.
Published: November 2021

Intratumour heterogeneity provides tumours with the ability to adapt and acquire treatment resistance. The development of more effective and personalised treatments for cancers, therefore, requires accurate characterisation of the clonal architecture of tumours, enabling evolutionary dynamics to be tracked. Many methods exist for achieving this from bulk tumour sequencing data, involving identifying mutations and performing subclonal deconvolution, but there is a lack of systematic benchmarking to inform researchers on which are most accurate, and how dataset characteristics impact performance. To address this, we use the most comprehensive tumour genome simulation tool available for such purposes to create 80 bulk tumour whole exome sequencing datasets of differing depths, tumour complexities, and purities, and use these to benchmark subclonal deconvolution pipelines. We conclude that i) tumour complexity does not impact accuracy, ii) increasing either purity or purity-corrected sequencing depth improves accuracy, and iii) the optimal pipeline consists of Mutect2, FACETS and PyClone-VI. We have made our benchmarking datasets publicly available for future use.
The efficacy of chlorine-based disinfectants against planktonic and biofilm bacteria for decentralised point-of-use drinking water
Authors: Clayton Gillian E. , Thorn Robin M. S. , Reynolds Darren M.
Published: November 2021

Chlorine solutions are used extensively for the production of biologically safe drinking water. The capability of point-of-use [POU] drinking water treatment systems has gained interest in locations where centralised treatment systems and distribution networks are not practical. This study investigated the antimicrobial and anti-biofilm activity of three chlorine-based disinfectants (hypochlorite ions [OCl-], hypochlorous acid [HOCl] and electrochemically activated solutions [ECAS]) for use in POU drinking water applications. The relative antimicrobial activity was compared within bactericidal suspension assays (BS EN 1040 and BS EN 1276) using Escherichia coli. The anti-biofilm activity was compared utilising established sessile Pseudomonas aeruginosa within a Centre for Disease Control [CDC] biofilm reactor. HOCl exhibited the greatest antimicrobial activity against planktonic E. coli at >50 mg L−1 free chlorine, in the presence of organic loading (bovine serum albumen). However, ECAS exhibited significantly greater anti-biofilm activity compared to OCl- and HOCl against P. aeruginosa biofilms at ≥50 mg L−1 free chlorine. Based on this evidence disinfectants where HOCl is the dominant chlorine species (HOCl and ECAS) would be appropriate alternative chlorine-based disinfectants for POU drinking water applications.
H3K9me selectively blocks transcription factor activity and ensures differentiated tissue integrity
Authors: Methot Stephen P. , Padeken Jan , Brancati Giovanna , Zeller Peter , Delaney Colin E. , Gaidatzis Dimos , Kohler Hubertus , van Oudenaarden Alexander , Großhans Helge , Gasser Susan M.
Published: November 2021

The developmental role of histone H3K9 methylation (H3K9me), which typifies heterochromatin, remains unclear. In Caenorhabditis elegans, loss of H3K9me leads to a highly divergent upregulation of genes with tissue and developmental-stage specificity. During development H3K9me is lost from differentiated cell type-specific genes and gained at genes expressed in earlier developmental stages or other tissues. The continuous deposition of H3K9me2 by the SETDB1 homolog MET-2 after terminal differentiation is necessary to maintain repression. In differentiated tissues, H3K9me ensures silencing by restricting the activity of a defined set of transcription factors at promoters and enhancers. Increased chromatin accessibility following the loss of H3K9me is neither sufficient nor necessary to drive transcription. Increased ATAC-seq signal and gene expression correlate at a subset of loci positioned away from the nuclear envelope, while derepressed genes at the nuclear periphery remain poorly accessible despite being transcribed. In conclusion, H3K9me deposition can confer tissue-specific gene expression and maintain the integrity of terminally differentiated muscle by restricting transcription factor activity.
Premature differentiation of nephron progenitor cell and dysregulation of gene pathways critical to kidney development in a model of preterm birth
Authors: Cwiek Aleksandra , Suzuki Masako , deRonde Kimberly , Conaway Mark , Bennett Kevin M. , El Dahr Samir , Reidy Kimberly J. , Charlton Jennifer R.
Published: November 2021

Preterm birth is a leading cause of neonatal morbidity. Survivors have a greater risk for kidney dysfunction and hypertension. Little is known about the molecular changes that occur in the kidney of individuals born preterm. Here, we demonstrate that mice delivered two days prior to full term gestation undergo premature cessation of nephrogenesis, resulting in a lower glomerular density. Kidneys from preterm and term groups exhibited differences in gene expression profiles at 20- and 27-days post-conception, including significant differences in the expression of fat-soluble vitamin-related genes. Kidneys of the preterm mice exhibited decreased proportions of endothelial cells and a lower expression of genes promoting angiogenesis compared to the term group. Kidneys from the preterm mice also had altered nephron progenitor subpopulations, early Six2 depletion, and altered Jag1 expression in the nephrogenic zone, consistent with premature differentiation of nephron progenitor cells. In conclusion, preterm birth alone was sufficient to shorten the duration of nephrogenesis and cause premature differentiation of nephron progenitor cells. These candidate genes and pathways may provide targets to improve kidney health in preterm infants.
Biogeochemical impacts of flooding discharge with high suspended sediment on coastal seas: a modeling study for a microtidal open bay
Authors: Hoshiba Yasuhiro , Hasumi Hiroyasu , Itoh Sachihiko , Matsumura Yoshimasa , Nakada Satoshi
Published: November 2021

Freshwater, suspended sediment matter (SSM), and nutrients discharged from rivers into the ocean have large impacts on biological production. In particular, during floods, coastal areas are greatly stirred up and large amounts of nutrients are supplied to the sea surface. We investigate the biogeochemical impact of flooding river discharges containing a large amount of SSM by conducting numerical simulations for a specific flooding event of the Yura River, Japan. Parameters are varied over wide ranges of SSM properties and nutrient content in riverine water. Two qualitatively different regimes of the riverine plume, hypopycnal and hyperpycnal, appear within realistic parameter ranges. Compared with the reference case without SSM, the surface salinity (nutrients) within the riverine plume becomes lower (higher) in hypopycnal cases and higher (lower) in hyperpycnal cases within a few days after the flooding discharge. These results suggest the necessity of properly taking into account the effect of SSM in assessing the influence of high river discharges on coastal biogeochemistry. It is the case not only for the specific river and event we are dealing with but also for other flooding events and other rivers and connecting coastal seas.
High-throughput sequencing for species authentication and contamination detection of 63 cell lines
Authors: Lung Oliver , Candlish Rebecca , Nebroski Michelle , Kruckiewicz Peter , Buchanan Cody , Moniwa Mariko
Published: November 2021

Cell lines are widely used in research and for diagnostic tests and are often shared between laboratories. Lack of cell line authentication can result in the use of contaminated or misidentified cell lines, potentially affecting the results from research and diagnostic activities. Cell line authentication and contamination detection based on metagenomic high-throughput sequencing (HTS) was tested on DNA and RNA from 63 cell lines available at the Canadian Food Inspection Agency’s National Centre for Foreign Animal Disease. Through sequence comparison of the cytochrome c oxidase subunit 1 (COX1) gene, the species identity of 53 cell lines was confirmed, and eight cell lines were found to show a greater pairwise nucleotide identity in the COX1 sequence of a different species within the same expected genus. Two cell lines, LFBK-αvβ6 and SCP-HS, were determined to be composed of cells from a different species and genus. Mycoplasma contamination was not detected in any cell lines. However, several expected and unexpected viral sequences were detected, including part of the classical swine fever virus genome in the IB-RS-2 Clone D10 cell line. Metagenomics-based HTS is a useful laboratory QA tool for cell line authentication and contamination detection that should be conducted regularly.
Carbon range verification with 718 keV Compton imaging
Authors: Parajuli Raj Kumar , Sakai Makoto , Arakawa Kazuo , Kubota Yoshiki , Kubo Nobuteru , Tashiro Mutsumi
Published: November 2021

Carbon ion radiotherapy is a sophisticated radiation treatment modality because of its superiority in achieving precise dosage distribution and high biological effectiveness. However, there exist beam range uncertainties that affect treatment efficiency. This problem can be resolved if the clinical beam could be monitored precisely in real-time, such as by imaging the prompt gamma emission from the target. In this study, we performed real-time detection and imaging of 718 keV prompt gamma emissions using a Si/CdTe Compton camera. We conducted experiments on graphite phantoms using clinical carbon ion beams of 290 MeV/u energy. Compton images were reconstructed using simple back-projection methods from the energy events of 718 keV prompt gamma emissions. The peak intensity position in reconstructed 718 keV prompt gamma images was few millimeters below the Bragg peak position. Moreover, the dual- and triple-energy window images for all positions of phantoms were not affected by scattered gammas, and their peak intensity positions were approximately similar to those observed in the reconstructed 718 keV prompt gamma images. In conclusion, the findings of the current study demonstrate the feasibility of using our Compton camera for real-time beam monitoring of carbon ion beams under clinical beam intensity.
Desmoglein 2 regulates cardiogenesis by restricting hematopoiesis in the developing murine heart
Authors: Moazzen Hoda , Venger Kateryna , Kant Sebastian , Leube Rudolf E. , Krusche Claudia A.
Published: November 2021

Cardiac morphogenesis relies on intricate intercellular signaling. Altered signaling impacts cardiac function and is detrimental to embryonic survival. Here we report an unexpected regulatory role of the desmosomal cell adhesion molecule desmoglein 2 (Dsg2) on murine heart development. A large percentage of Dsg2-mutant embryos develop pericardial hemorrhage. Lethal myocardial rupture is occasionally observed, which is not associated with loss of cardiomyocyte contact but with expansion of abnormal, non-myocyte cell clusters within the myocardial wall. Two types of abnormal cell clusters can be distinguished: Type A clusters involve endocard-associated, round-shaped CD31+ cells, which proliferate and invade the myocardium. They acquire Runx1- and CD44-positivity indicating a shift towards a hematopoietic phenotype. Type B clusters expand subepicardially and next to type A clusters. They consist primarily of Ter119+ erythroid cells with interspersed Runx1+/CD44+ cells suggesting that they originate from type A cell clusters. The observed pericardial hemorrhage is caused by migration of erythrocytes from type B clusters through the epicardium and rupture of the altered cardiac wall. Finally, evidence is presented that structural defects of Dsg2-depleted cardiomyocytes are primary to the observed pathogenesis. We propose that cardiomyocyte-driven paracrine signaling, which likely involves Notch1, directs subsequent trans-differentiation of endo- and epicardial cells. Together, our observations uncover a hitherto unknown regulatory role of Dsg2 in cardiogenesis.
Estimating the impact of virus testing strategies on the COVID-19 case fatality rate using fixed-effects models
Authors: Terriau Anthony , Albertini Julien , Montassier Emmanuel , Poirier Arthur , Le Bastard Quentin
Published: November 2021

The SARS-CoV2 has now spread worldwide causing over four million deaths. Testing strategies are highly variable between countries and their impact on mortality is a major issue. Retrospective multicenter study with a prospective database on all inpatients throughout mainland France. Using fixed effects models, we exploit policy discontinuities at region borders in France to estimate the effect of testing on the case fatality rate. In France, testing policies are determined at a regional level, generating exogenous variation in testing rates between departments on each side of a region border. We compared all contiguous department pairs located on the opposite sides of a region border. The increase of one percentage point in the test rate is associated with a decrease of 0.0015 percentage point in the death rate, that is, for each additional 2000 tests, we could observe three fewer deaths. Our study suggests that COVID-19 population testing could have a significant impact on the mortality rate which should be considered in decision-making. As concern grows over the current second wave of COVID-19, our findings support the implementation of large-scale screening strategies in such epidemic contexts.
Basal and IL-1β enhanced chondrocyte chemotactic activity on monocytes are co-dependent on both IKKα and IKKβ NF-κB activating kinases
Authors: Olivotto Eleonora , Minguzzi Manuela , D’Adamo Stefania , Astolfi Annalisa , Santi Spartaco , Uguccioni Mariagrazia , Marcu Kenneth B. , Borzì Rosa Maria
Published: November 2021

IKKα and IKKβ are essential kinases for activating NF-κB transcription factors that regulate cellular differentiation and inflammation. By virtue of their small size, chemokines support the crosstalk between cartilage and other joint compartments and contribute to immune cell chemotaxis in osteoarthritis (OA). Here we employed shRNA retroviruses to stably and efficiently ablate the expression of each IKK in primary OA chondrocytes to determine their individual contributions for monocyte chemotaxis in response to chondrocyte conditioned media. Both IKKα and IKKβ KDs blunted both the monocyte chemotactic potential and the protein levels of CCL2/MCP-1, the chemokine with the highest concentration and the strongest association with monocyte chemotaxis. These findings were mirrored by gene expression analysis indicating that the lowest levels of CCL2/MCP-1 and other monocyte-active chemokines were in IKKαKD cells under both basal and IL-1β stimulated conditions. We find that in their response to IL-1β stimulation IKKαKD primary OA chondrocytes have reduced levels of phosphorylated NFkappaB p65pSer536 and H3pSer10. Confocal microscopy analysis revealed co-localized p65 and H3pSer10 nuclear signals in agreement with our findings that IKKαKD effectively blunts their basal level and IL-1β dependent increases. Our results suggest that IKKα could be a novel OA disease target.
Novel LysM motifs for antigen display on lactobacilli for mucosal immunization
Authors: Raya-Tonetti Fernanda , Müller Melisa , Sacur Jacinto , Kitazawa Haruki , Villena Julio , Vizoso-Pinto Maria Guadalupe
Published: November 2021

We characterized two LysM domains of Limosilactobacillus fermentum, belonging to proteins Acglu (GenBank: KPH22907.1) and Pgb (GenBank: KPH22047.1) and bacterium like particles (BLP) derived from the immunomodulatory strain Lacticaseibacillus rhamnosus IBL027 (BLPs027) as an antigen display platform. The fluorescence protein Venus fused to the novel LysM domains could bind to the peptidoglycan shell of lactobacilli and resisted harsh conditions such as high NaCl and urea concentrations. Acglu with five LysM domains was a better anchor than Pgb baring only one domain. Six-week-old BALB/c mice were nasally immunized with the complex Venus-Acglu-BLPs027 at days 0, 14 and 28. The levels of specific serum IgG, IgG1 and IgG2a and the levels of total immunoglobulins (IgT) and IgA in broncho-alveolar lavage (BAL) were evaluated ten days after the last boosting. Venus-Acglu-BLPs027, nasally administered, significantly increased specific BAL IgT and IgA, and serum IgG levels. In addition, spleen cells of mice immunized with Venus-Acglu-BLPs027 secreted TNF-α, IFN-γ and IL-4 when stimulated ex vivo in a dose-dependent manner. We constructed a Gateway compatible destination vector to easily fuse the selected LysM domain to proteins of interest for antigen display to develop mucosal subunit vaccines.
Association between antibiotics use and diabetes incidence in a nationally representative retrospective cohort among Koreans
Authors: Park Sun Jae , Park Young Jun , Chang Jooyoung , Choi Seulggie , Lee Gyeongsil , Son Joung Sik , Kim Kyae Hyung , Oh Yun Hwan , Park Sang Min
Published: November 2021

Numerous studies have reported that antibiotics could lead to diabetes, even after adjusting for confounding variables. This study aimed to determine the causal relationship between antibiotics use and diabetes in a nationally representative cohort. This retrospective cohort study included adults aged 40 years or older who were enrolled in the Korean National Health Insurance Service-Health Screening Cohort. Antibiotic exposure was assessed from 2002 to 2005 and newly diagnosed diabetes mellitus was determined based on diagnostic codes and history of antidiabetic medication use from 2006 to 2015. Multivariate Cox proportional hazards model was used to assess the association between antibiotic use and diabetes incidence. The mean age of the 201,459 study subjects was 53.2 years. People who used antibiotics for 90 or more days had a higher risk of diabetes (adjusted hazard ratio [aHR] 1.16, 95% confidence interval [CI] 1.07–1.26) compared to non-users. Those who used five or more classes of antibiotics had a higher risk of diabetes than those who used one antibiotic class (aHR 1.14; 95% CI 1.06–1.23). The clear dose-dependent association between antibiotics and diabetes incidence supports the judicious use of antibiotics in the future.
TGF-β1 is involved in senescence-related pathways in glomerular endothelial cells via p16 translocation and p21 induction
Authors: Ueda Sayo , Tominaga Tatsuya , Ochi Arisa , Sakurai Akiko , Nishimura Kenji , Shibata Eriko , Wakino Shu , Tamaki Masanori , Nagai Kojiro
Published: November 2021

p16 inhibits cyclin-dependent kinases and regulates senescence-mediated arrest as well as p21. Nuclear p16 promotes G1 cell cycle arrest and cellular senescence. In various glomerular diseases, nuclear p16 expression is associated with disease progression. Therefore, the location of p16 is important. However, the mechanism of p16 trafficking between the nucleus and cytoplasm is yet to be fully investigated. TGF-β1, a major cytokine involved in the development of kidney diseases, can upregulate p21 expression. However, the relationship between TGF-β1 and p16 is poorly understood. Here, we report the role of podocyte TGF-β1 in regulating the p16 behavior in glomerular endothelial cells. We analyzed podocyte-specific TGF-β1 overexpression mice. Although p16 was found in the nuclei of glomerular endothelial cells and led to endothelial cellular senescence, the expression of p16 did not increase in glomeruli. In cultured endothelial cells, TGF-β1 induced nuclear translocation of p16 without increasing its expression. Among human glomerular diseases, p16 was detected in the nuclei of glomerular endothelial cells. In summary, we demonstrated the novel role of podocyte TGF-β1 in managing p16 behavior and cellular senescence in glomeruli, which has clinical relevance for the progression of human glomerular diseases.
Silencing of vitellogenin gene contributes to the promise of controlling red palm weevil, Rhynchophorus ferrugineus (Olivier)
Authors: Rasool Khawaja G. , Mehmood Khalid , Tufail Muhammad , Husain Mureed , Alwaneen Waleed S. , Aldawood Abdulrahman S.
Published: November 2021

Red palm weevil [Rhynchophorus ferrugineus (Olivier)], is native to South Asia and expanding its distribution range globally. Recent invasions of red palm weevil around the world, including Saudi Arabia, has become a global constraint for the production of palm species. Although, several control measures have been tested, none of them seemed successful against this invasive species. Therefore, we focused on silencing the reproduction control gene vitellogenin (Vg) based on RNA interference (RNAi) strategy for its possible application in the management of R. ferrugineus. The Vg is a major yolk protein precursor critical for oogenesis. To do this, fat body transcriptome of R. ferrugineus female adults was sequenced, which provided partial Vg gene transcript (FPKM 5731.60). A complete RfVg gene transcript of 5504 bp encoding 1787 amino acids was then sequenced using RCAE-PCR strategy and characterized. Phylogenetic analysis suggested that RfVg has closer ancestry to the coleopteran insects. The RfVg-based RNAi significantly suppressed the expressions of Vg gene. The 15, 20 and 25 days post-injection periods suppressed Vg expressions by 95, 96.6 and 99%, respectively. The suppressed Vg expressions resulted in the dramatic failure of Vg protein expression, which caused atrophied ovaries or no oogenesis and ultimately eggs were not hatched. These results suggest that knockdown of Vg gene involved in R. ferrugineus reproduction is a promising target for RNAi-based management of R. ferrugineus.
Annual assessment of the wastewater treatment capacity of the microalga Scenedesmus almeriensis and optimisation of operational conditions
Authors: Sánchez-Zurano Ana , Morillas-España Ainoa , Gómez-Serrano Cintia , Ciardi Martina , Acién Gabriel , Lafarga Tomás
Published: November 2021

The depth of the culture and the dilution rate have a striking effect on the biomass productivity and the nutrient recovery capacity of microalgal cultures. The combination of culture depth and dilution rate that allows to maximise the performance of the system depends on environmental conditions. In the current study, a response surface methodology was used to explore the relationship between the two most relevant operational conditions and the biomass productivity achieved in 8.3 m2 pilot-scale raceways operated using urban wastewater. Four polynomial models were developed, one for each season of the year. The software predicted biomass productivities of 12.3, 25.6, 32.7, and 18.9 g·m−2·day−1 in winter, spring, summer, and autumn, respectively. The models were further validated at pilot-scale with R2 values ranging within 0.81 and 0.91, depending on the season. Lower culture depths had the advantage of minimising nitrification and stripping but allow to process a lower volume of wastewater per surface area. Biomass productivity was higher at culture depths of 0.05 m, when compared to 0.12 and 0.20 m, while the optimal dilution rate was season-dependent. Results reported herein are useful for optimising the biomass productivity of raceway reactors located outdoors throughout the year.
The transcriptome of Balamuthia mandrillaris trophozoites for structure-guided drug design
Authors: Phan Isabelle Q. , Rice Christopher A. , Craig Justin , Noorai Rooksana E. , McDonald Jacquelyn R. , Subramanian Sandhya , Tillery Logan , Barrett Lynn K. , Shankar Vijay , Morris James C. , Van Voorhis Wesley C. , Kyle Dennis E. , Myler Peter J.
Published: November 2021

Balamuthia mandrillaris, a pathogenic free-living amoeba, causes cutaneous skin lesions as well as granulomatous amoebic encephalitis, a ‘brain-eating’ disease. As with the other known pathogenic free-living amoebas (Naegleria fowleri and Acanthamoeba species), drug discovery efforts to combat Balamuthia infections of the central nervous system are sparse; few targets have been validated or characterized at the molecular level, and little is known about the biochemical pathways necessary for parasite survival. Current treatments of encephalitis due to B. mandrillaris lack efficacy, leading to case fatality rates above 90%. Using our recently published methodology to discover potential drugs against pathogenic amoebas, we screened a collection of 85 compounds with known antiparasitic activity and identified 59 compounds that impacted the growth of Balamuthia trophozoites at concentrations below 220 µM. Since there is no fully annotated genome or proteome of B. mandrillaris, we sequenced and assembled its transcriptome from a high-throughput RNA-sequencing (RNA-Seq) experiment and located the coding sequences of the genes potentially targeted by the growth inhibitors from our compound screens. We determined the sequence of 17 of these target genes and obtained expression clones for 15 that we validated by direct sequencing. These will be used in the future in combination with the identified hits in structure guided drug discovery campaigns to develop new approaches for the treatment of Balamuthia infections.
A large Canadian cohort provides insights into the genetic architecture of human hair colour
Authors: Lona-Durazo Frida , Mendes Marla , Thakur Rohit , Funderburk Karen , Zhang Tongwu , Kovacs Michael A. , Choi Jiyeon , Brown Kevin M. , Parra Esteban J.
Published: November 2021

Hair colour is a polygenic phenotype that results from differences in the amount and ratio of melanins located in the hair bulb. Genome-wide association studies (GWAS) have identified many loci involved in the pigmentation pathway affecting hair colour. However, most of the associated loci overlap non-protein coding regions and many of the molecular mechanisms underlying pigmentation variation are still not understood. Here, we conduct GWAS meta-analyses of hair colour in a Canadian cohort of 12,741 individuals of European ancestry. By performing fine-mapping analyses we identify candidate causal variants in pigmentation loci associated with blonde, red and brown hair colour. Additionally, we observe colocalization of several GWAS hits with expression and methylation quantitative trait loci (QTLs) of cultured melanocytes. Finally, transcriptome-wide association studies (TWAS) further nominate the expression of EDNRB and CDK10 as significantly associated with hair colour. Our results provide insights on the mechanisms regulating pigmentation biology in humans.