bluuebunny/crossref_metadata_2025 huggingface dataset:
First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland
Authors: Simpson C. R. , Shi T. , Vasileiou E. , Katikireddi S. V. , Kerr S. , Moore E. , McCowan C. , Agrawal U. , Shah S. A. , Ritchie L. D. , Murray J. , Pan J. , Bradley D. T. , Stock S. J. , Wood R. , Chuter A. , Beggs J. , Stagg H. R. , Joy M. , Tsang R. S. M. , de Lusignan S. , Hobbs R. , Lyons R. A. , Torabi F. , Bedston S. , O’Leary M. , Akbari A. , McMenamin J. , Robertson C. , Sheikh A.
Published: June 2021

Reports of ChAdOx1 vaccine–associated thrombocytopenia and vascular adverse events have led to some countries restricting its use. Using a national prospective cohort, we estimated associations between exposure to first-dose ChAdOx1 or BNT162b2 vaccination and hematological and vascular adverse events using a nested incident-matched case-control study and a confirmatory self-controlled case series (SCCS) analysis. An association was found between ChAdOx1 vaccination and idiopathic thrombocytopenic purpura (ITP) (0–27 d after vaccination; adjusted rate ratio (aRR) = 5.77, 95% confidence interval (CI), 2.41–13.83), with an estimated incidence of 1.13 (0.62–1.63) cases per 100,000 doses. An SCCS analysis confirmed that this was unlikely due to bias (RR = 1.98 (1.29–3.02)). There was also an increased risk for arterial thromboembolic events (aRR = 1.22, 1.12–1.34) 0–27 d after vaccination, with an SCCS RR of 0.97 (0.93–1.02). For hemorrhagic events 0–27 d after vaccination, the aRR was 1.48 (1.12–1.96), with an SCCS RR of 0.95 (0.82–1.11). A first dose of ChAdOx1 was found to be associated with small increased risks of ITP, with suggestive evidence of an increased risk of arterial thromboembolic and hemorrhagic events. The attenuation of effect found in the SCCS analysis means that there is the potential for overestimation of the reported results, which might indicate the presence of some residual confounding or confounding by indication. Public health authorities should inform their jurisdictions of these relatively small increased risks associated with ChAdOx1. No positive associations were seen between BNT162b2 and thrombocytopenic, thromboembolic and hemorrhagic events.
Central nervous system (CNS) transcriptomic correlates of human immunodeficiency virus (HIV) brain RNA load in HIV-infected individuals
Authors: Sanna Pietro Paolo , Fu Yu , Masliah Eliezer , Lefebvre Celine , Repunte-Canonigo Vez
Published: June 2021

To generate new mechanistic hypotheses on the pathogenesis and disease progression of neuroHIV and identify novel therapeutic targets to improve neuropsychological function in people with HIV, we investigated host genes and pathway dysregulations associated with brain HIV RNA load in gene expression profiles of the frontal cortex, basal ganglia, and white matter of HIV+ patients. Pathway analyses showed that host genes correlated with HIV expression in all three brain regions were predominantly related to inflammation, neurodegeneration, and bioenergetics. HIV RNA load directly correlated particularly with inflammation genesets representative of cytokine signaling, and this was more prominent in white matter and the basal ganglia. Increases in interferon signaling were correlated with high brain HIV RNA load in the basal ganglia and the white matter although not in the frontal cortex. Brain HIV RNA load was inversely correlated with genesets that are indicative of neuronal and synaptic genes, particularly in the cortex, indicative of synaptic injury and neurodegeneration. Brain HIV RNA load was inversely correlated with genesets that are representative of oxidative phosphorylation, electron transfer, and the tricarboxylic acid cycle in all three brain regions. Mitochondrial dysfunction has been implicated in the toxicity of some antiretrovirals, and these results indicate that mitochondrial dysfunction is also associated with productive HIV infection. Genes and pathways correlated with brain HIV RNA load suggest potential therapeutic targets to ameliorate neuropsychological functioning in people living with HIV.
DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia
Authors: Haines Eric , Nishida Yuki , Carr Michael I. , Montoya Rafael Heinz , Ostermann Lauren B. , Zhang Weiguo , Zenke Frank T. , Blaukat Andree , Andreeff Michael , Vassilev Lyubomir T.
Published: June 2021

Peposertib (M3814) is a potent and selective DNA-PK inhibitor in early clinical development. It effectively blocks non-homologous end-joining repair of DNA double-strand breaks (DSB) and strongly potentiates the antitumor effect of ionizing radiation (IR) and topoisomerase II inhibitors. By suppressing DNA-PK catalytic activity in the presence of DNA DSB, M3814 potentiates ATM/p53 signaling leading to enhanced p53-dependent antitumor activity in tumor cells. Here, we investigated the therapeutic potential of M3814 in combination with DSB-inducing agents in leukemia cells and a patient-derived tumor. We show that in the presence of IR or topoisomerase II inhibitors, M3814 boosts the ATM/p53 response in acute leukemia cells leading to the elevation of p53 protein levels as well as its transcriptional activity. M3814 synergistically sensitized p53 wild-type, but not p53-deficient, AML cells to killing by DSB-inducing agents via p53-dependent apoptosis involving both intrinsic and extrinsic effector pathways. The antileukemic effect was further potentiated by enhancing daunorubicin-induced myeloid cell differentiation. Further, combined with the fixed-ratio liposomal formulation of daunorubicin and cytarabine, CPX-351, M3814 enhanced the efficacy against leukemia cells in vitro and in vivo without increasing hematopoietic toxicity, suggesting that DNA-PK inhibition could offer a novel clinical strategy for harnessing the anticancer potential of p53 in AML therapy.
Tailoring of arteriovenous graft-to-vein anastomosis angle to attenuate pathological flow fields
Authors: Williams Dillon , Leuthardt Eric C. , Genin Guy M. , Zayed Mohamed
Published: June 2021

Arteriovenous grafts are routinely placed to facilitate hemodialysis in patients with end stage renal disease. These grafts are conduits between higher pressure arteries and lower pressure veins. The connection on the vein end of the graft, known as the graft-to-vein anastomosis, fails frequently and chronically due to high rates of stenosis and thrombosis. These failures are widely believed to be associated with pathologically high and low flow shear strain rates at the graft-to-vein anastomosis. We hypothesized that consistent with pipe flow dynamics and prior work exploring vein-to-artery anastomosis angles in arteriovenous fistulas, altering the graft-to-vein anastomosis angle can reduce the incidence of pathological shear rate fields. We tested this via computational fluid dynamic simulations of idealized arteriovenous grafts, using the Bird-Carreau constitutive law for blood. We observed that low graft-to-vein anastomosis angles ($$<20^{\circ }$$

<

20
∘

) led to increased incidence of pathologically low shear rates, and that high graft-to-vein anastomosis angles ($$>40^{\circ }$$

>

40
∘

) led to increased incidence of pathologically high shear rates. Optimizations predicted that an intermediate  ($$\sim 30^\circ$$

∼

30
∘

) graft-to-anastomosis angle was optimal. Our study demonstrates that graft-to-vein anastomosis angles can significantly impact pathological flow fields, and can be optimized to substantially improve arteriovenous graft patency rates.
A high-throughput microfluidic bilayer co-culture platform to study endothelial-pericyte interactions
Authors: Rogers Miles T. , Gard Ashley L. , Gaibler Robert , Mulhern Thomas J. , Strelnikov Rivka , Azizgolshani Hesham , Cain Brian P. , Isenberg Brett C. , Haroutunian Nerses J. , Raustad Nicole E. , Keegan Philip M. , Lech Matthew P. , Tomlinson Lindsay , Borenstein Jeffrey T. , Charest Joseph L. , Williams Corin
Published: June 2021

Microphysiological organ-on-chip models offer the potential to improve the prediction of drug safety and efficacy through recapitulation of human physiological responses. The importance of including multiple cell types within tissue models has been well documented. However, the study of cell interactions in vitro can be limited by complexity of the tissue model and throughput of current culture systems. Here, we describe the development of a co-culture microvascular model and relevant assays in a high-throughput thermoplastic organ-on-chip platform, PREDICT96. The system consists of 96 arrayed bilayer microfluidic devices containing retinal microvascular endothelial cells and pericytes cultured on opposing sides of a microporous membrane. Compatibility of the PREDICT96 platform with a variety of quantifiable and scalable assays, including macromolecular permeability, image-based screening, Luminex, and qPCR, is demonstrated. In addition, the bilayer design of the devices allows for channel- or cell type-specific readouts, such as cytokine profiles and gene expression. The microvascular model was responsive to perturbations including barrier disruption, inflammatory stimulation, and fluid shear stress, and our results corroborated the improved robustness of co-culture over endothelial mono-cultures. We anticipate the PREDICT96 platform and adapted assays will be suitable for other complex tissues, including applications to disease models and drug discovery.
Real-Time insight into in vivo redox status utilizing hyperpolarized [1-13C] N-acetyl cysteine
Authors: Yamamoto Kazutoshi , Opina Ana , Sail Deepak , Blackman Burchelle , Saito Keita , Brender Jeffrey R. , Malinowski Ronja M. , Seki Tomohiro , Oshima Nobu , Crooks Daniel R. , Kishimoto Shun , Saida Yu , Otowa Yasunori , Choyke Peter L. , Ardenkjær-Larsen Jan H. , Mitchell James B. , Linehan W. Marston , Swenson Rolf E. , Krishna Murali C.
Published: June 2021

Drastic sensitivity enhancement of dynamic nuclear polarization is becoming an increasingly critical methodology to monitor real-time metabolic and physiological information in chemistry, biochemistry, and biomedicine. However, the limited number of available hyperpolarized 13C probes, which can effectively interrogate crucial metabolic activities, remains one of the major bottlenecks in this growing field. Here, we demonstrate [1-13C] N-acetyl cysteine (NAC) as a novel probe for hyperpolarized 13C MRI to monitor glutathione redox chemistry, which plays a central part of metabolic chemistry and strongly influences various therapies. NAC forms a disulfide bond in the presence of reduced glutathione, which generates a spectroscopically detectable product that is separated from the main peak by a 1.5 ppm shift. In vivo hyperpolarized MRI in mice revealed that NAC was broadly distributed throughout the body including the brain. Its biochemical transformation in two human pancreatic tumor cells in vitro and as xenografts differed depending on the individual cellular biochemical profile and microenvironment in vivo. Hyperpolarized NAC can be a promising non-invasive biomarker to monitor in vivo redox status and can be potentially translatable to clinical diagnosis.
Analysis of the role of Purα in the pathogenesis of Alzheimer's disease based on RNA-seq and ChIP-seq
Authors: Shi Xiaoguang , Ren Shuanglai , Zhang Bingying , Guo Shanshan , He Wenxin , Yuan Chengmin , Yang Xiaofan , Ig-lzevbekhai Kevin , Sun Tao , Wang Qinwen , Cui Jianqi
Published: June 2021

Purine rich element binding protein A (Purα), encoded by the Purα gene, is an important transcriptional regulator that binds to DNA and RNA and is involved in processes such as DNA replication and RNA translation. Purα also plays an important role in the nervous system. To identify the function of Pura, we performed RNA sequence (RNA-seq) analysis of Purɑ-KO mouse hippocampal neuron cell line (HT22) to analyze the effect of Purα deletion on neuronal expression profiles. And combined with ChIP-seq analysis to explore the mechanism of Purα on gene regulation. In the end, totaly 656 differentially expressed genes between HT22 and Purα-KO HT22 cells have been found, which include 7 Alzheimer’s disease (AD)-related genes and 5 Aβ clearance related genes. 47 genes were regulated by Purα directly, the evidence based on CHIP-seq, which include Insr, Mapt, Vldlr, Jag1, etc. Our study provides the important informations of Purα in neuro-development. The possible regulative effects of Purα on AD-related genes consist inthe direct and indirect pathways of Purα in the pathogenesis of AD.
Reproductive plasticity of Hawaiian Montipora corals following thermal stress
Authors: Henley E. Michael , Quinn Mariko , Bouwmeester Jessica , Daly Jonathan , Zuchowicz Nikolas , Lager Claire , Bailey Daniel W. , Hagedorn Mary
Published: June 2021

Ocean warming, fueled by climate change, is the primary cause of coral bleaching events which are predicted to increase in frequency. Bleaching is generally damaging to coral reproduction, can be exacerbated by concomitant stressors like ultraviolet radiation (UVR), and can have lasting impacts to successful reproduction and potential adaptation. We compared morphological and physiological reproductive metrics (e.g., sperm motility, mitochondrial membrane integrity, egg volume, gametes per bundle, and fertilization and settlement success) of two Hawaiian Montipora corals after consecutive bleaching events in 2014 and 2015. Between the species, sperm motility and mitochondrial membrane potential had the most disparate results. Percent sperm motility in M. capitata, which declined to ~ 40% during bleaching from a normal range of 70–90%, was still less than 50% motile in 2017 and 2018 and had not fully recovered in 2019 (63% motile). By contrast, percent sperm motility in Montipora spp. was 86% and 74% in 2018 and 2019, respectively. This reduction in motility was correlated with damage to mitochondria in M. capitata but not Montipora spp. A major difference between these species is the physiological foundation of their UVR protection, and we hypothesize that UVR protective mechanisms inherent in Montipora spp. mitigate this reproductive damage.
Summertime sea-ice prediction in the Weddell Sea improved by sea-ice thickness initialization
Authors: Morioka Yushi , Iovino Doroteaciro , Cipollone Andrea , Masina Simona , Behera Swadhin K.
Published: June 2021

Skillful sea-ice prediction in the Antarctic Ocean remains a big challenge due to paucity of sea-ice observations and insufficient representation of sea-ice processes in climate models. Using a coupled general circulation model, this study demonstrates skillful prediction of the summertime sea-ice concentration (SIC) in the Weddell Sea with wintertime SIC and sea-ice thickness (SIT) initializations. During low sea-ice years of the Weddell Sea, negative SIT anomalies initialized in June retain the memory throughout austral winter owing to horizontal advection of the SIT anomalies. The SIT anomalies continue to develop in austral spring owing to more incoming solar radiation and the associated warming of mixed layer, contributing to further sea-ice decrease during late austral summer-early autumn. Concomitantly, the model reasonably reproduces atmospheric circulation anomalies during austral spring in the Amundsen-Bellingshausen Seas besides the Weddell Sea. These results provide evidence that the wintertime SIT initialization benefits skillful summertime sea-ice prediction in the Antarctic Seas.
Endothelial glycocalyx shields the interaction of SARS-CoV-2 spike protein with ACE2 receptors
Authors: Targosz-Korecka Marta , Kubisiak Agata , Kloska Damian , Kopacz Aleksandra , Grochot-Przeczek Anna , Szymonski Marek
Published: June 2021

Endothelial cells (ECs) play a crucial role in the development and propagation of the severe COVID-19 stage as well as multiorgan dysfunction. It remains, however, controversial whether COVID-19-induced endothelial injury is caused directly by the infection of ECs with SARS-CoV-2 or via indirect mechanisms. One of the major concerns is raised by the contradictory data supporting or denying the presence of ACE2, the SARS-CoV-2 binding receptor, on the EC surface. Here, we show that primary human pulmonary artery ECs possess ACE2 capable of interaction with the viral Spike protein (S-protein) and demonstrate the crucial role of the endothelial glycocalyx in the regulation of the S-protein binding to ACE2 on ECs. Using force spectroscopy method, we directly measured ACE2- and glycocalyx-dependent adhesive forces between S-protein and ECs and characterized the nanomechanical parameters of the cells exposed to S-protein. We revealed that the intact glycocalyx strongly binds S-protein but screens its interaction with ACE2. Reduction of glycocalyx layer exposes ACE2 receptors and promotes their interaction with S-protein. These results indicate that the susceptibility of ECs to COVID-19 infection may depend on the glycocalyx condition.
Impact of reduction of susceptibility to SARS-CoV-2 on epidemic dynamics in four early-seeded metropolitan regions
Authors: Barrett Thomas J. , Patterson Karen C. , James Timothy M. , Krüger Peter
Published: June 2021

As we enter a chronic phase of the SARS-CoV-2 pandemic, with uncontrolled infection rates in many places, relative regional susceptibilities are a critical unknown for policy planning. Tests for SARS-CoV-2 infection or antibodies are indicative but unreliable measures of exposure. Here instead, for four highly-affected countries, we determine population susceptibilities by directly comparing country-wide observed epidemic dynamics data with that of their main metropolitan regions. We find significant susceptibility reductions in the metropolitan regions as a result of earlier seeding, with a relatively longer phase of exponential growth before the introduction of public health interventions. During the post-growth phase, the lower susceptibility of these regions contributed to the decline in cases, independent of intervention effects. Forward projections indicate that non-metropolitan regions will be more affected during recurrent epidemic waves compared with the initially heavier-hit metropolitan regions. Our findings have consequences for disease forecasts and resource utilisation.
Colonisation dynamics of Listeria monocytogenes strains isolated from food production environments
Authors: Gray Jessica , Chandry P. Scott , Kaur Mandeep , Kocharunchitt Chawalit , Fanning Séamus , Bowman John P. , Fox Edward M.
Published: June 2021

Listeria monocytogenes is a ubiquitous bacterium capable of colonising and persisting within food production environments (FPEs) for many years, even decades. This ability to colonise, survive and persist within the FPEs can result in food product cross-contamination, including vulnerable products such as ready to eat food items. Various environmental and genetic elements are purported to be involved, with the ability to form biofilms being an important factor. In this study we examined various mechanisms which can influence colonisation in FPEs. The ability of isolates (n = 52) to attach and grow in biofilm was assessed, distinguishing slower biofilm formers from isolates forming biofilm more rapidly. These isolates were further assessed to determine if growth rate, exopolymeric substance production and/or the agr signalling propeptide influenced these dynamics and could promote persistence in conditions reflective of FPE. Despite no strong association with the above factors to a rapid colonisation phenotype, the global transcriptome suggested transport, energy production and metabolism genes were widely upregulated during the initial colonisation stages under nutrient limited conditions. However, the upregulation of the metabolism systems varied between isolates supporting the idea that L. monocytogenes ability to colonise the FPEs is strain-specific.
DNA degradation in human teeth exposed to thermal stress
Authors: Lozano-Peral Diego , Rubio Leticia , Santos Ignacio , Gaitán María Jesús , Viguera Enrique , Martín-de-las-Heras Stella
Published: June 2021

Human identification from burned remains poses a challenge to forensic laboratories, and DNA profiling is widely used for this purpose. Our aim was to evaluate the effect of temperature on DNA degradation in human teeth. Thirty teeth were exposed to temperatures of 100, 200, or 400 °C for 60 min. DNA was quantified by Real-Time qPCR (Quantifiler Human DNA Quantification Kit) and fluorescence spectroscopy (Qubit 3.0 Fluorometer). DNA degradation was evaluated by using STR markers (AmpFLSTR Identifiler Plus PCR Amplification Kit) to determine the allele and locus dropout, inter-locus balance, and degradation slope (observed (Oa) to expected (Ea) locus peak height ratio against the molecular weight). Most of the genomic DNA was degraded between 100 °C and 200 °C. At 100 °C, locus dropout ratios showed significant differences between the largest loci (FGA, D7S820, D18S51, D16S539, D2S1338 and CSF1PO) and amelogenin. Inter-locus balance values significantly differed between all dye channels except between NED and PET. The dropout ratio between D18S51 (NED) and amelogenin (PET) can be recommended for the evaluation of DNA degradation. The Oa/Ea regression model can predict locus peak heights in DNA degradation (R2 = 0.7881). These findings may be useful to assess the reliability of DNA typing for human identification in teeth subjected to prolonged incineration.
Development of loop-mediated isothermal amplification (LAMP) assay using SYBR safe and gold-nanoparticle probe for detection of Leishmania in HIV patients
Authors: Ruang-areerate Toon , Sukphattanaudomchoke Charanyarut , Thita Thanyapit , Leelayoova Saovanee , Piyaraj Phunlerd , Mungthin Mathirut , Suwannin Patcharapan , Polpanich Duangporn , Tangchaikeeree Tienrat , Jangpatarapongsa Kulachart , Choowongkomon Kiattawee , Siripattanapipong Suradej
Published: June 2021

Asymptomatic leishmaniasis cases have continuously increased, especially among patients with HIV who are at risk to develop further symptoms of cutaneous and visceral leishmaniasis. Thus, early diagnosis using a simple, sensitive and reliable diagnostic assay is important because populations at risk mostly reside in rural communities where laboratory equipment is limited. In this study, the highly sensitive and selective determination of Leishmania infection in asymptomatic HIV patients was achieved using dual indicators (SYBR safe and gold-nanoparticle probe; AuNP-probe) in one-step LAMP method based on basic instruments. The assay can be simply evaluated under the naked eye due to clear interpretation of fluorescent emission of LAMP-SYBR safe dye-complex and colorimetric precipitate of specific AuNP-probes. The sensitivities and specificities of fluorescent SYBR safe dye and AuNP-probe indicators were equal, which were as high as 94.1 and 97.1%, respectively. Additionally, detection limits were 102 parasites/mL (0.0147 ng/µL), ten times more sensitivity than other related studies. To empower leishmaniasis surveillance, this inexpensive one-step SYBR safe and AuNP-LAMP assay is reliably fast and simple for field diagnostics to point-of-care settings, which can be set up in all levels of health care facilities including resource limited areas, especially in low to middle income countries.
Comparative transcriptome analysis of inner blood-retinal barrier and blood–brain barrier in rats
Authors: Li Y. , Faiz A. , Moshage H. , Schubert R. , Schilling L. , Kamps J. A.
Published: June 2021

Although retinal microvessels (RMVs) and brain microvessels (BMVs) are closely related in their developmental and share similar blood-neural barriers, studies have reported markedly different responses to stressors such as diabetes. Therefore, we hypothesized that RMVs and BMVs will display substantial differences in gene expression levels even though they are of the same embryological origin. In this study, both RMVs and BMVs were mechanically isolated from rats. Full retinal and brain tissue samples (RT, BT) were collected for comparisons. Total RNA extracted from these four groups were processed on Affymetrix rat 2.0 microarray Chips. The transcriptional profiles of these tissues were then analyzed. In the present paper we looked at differentially expressed genes (DEGs) in RMVs (against RT) and BMVs (against BT) using a rather conservative threshold value of ≥  ± twofold change and a false discovery rate corrected for multiple comparisons (p < 0.05). In RMVs a total of 1559 DEGs were found, of which 1004 genes were higher expressed in RMVs than in RT. Moreover, 4244 DEGs between BMVs and BT were identified, of which 1956 genes were ≥ twofold enriched in BMVs. Using these DEGs, we comprehensively analyzed the actual expression levels and highlighted their involvement in critical functional structures in RMVs and BMVs, such as junctional complex, transporters and signaling pathways. Our work provides for the first time the transcriptional profiles of rat RMVs and BMVs. These results may help to understand why retina and brain microvasculature show different susceptibilities to stressors, and they might even provide new insight for pharmacological interventions.
American martens use vigilance and short-term avoidance to navigate a landscape of fear from fishers at artificial scavenging sites
Authors: Kautz Todd M. , Beyer Dean E. , Farley Zachary , Fowler Nicholas L. , Kellner Kenneth F. , Lutto Ashley L. , Petroelje Tyler R. , Belant Jerrold L.
Published: June 2021

Where two sympatric species compete for the same resource and one species is dominant, there is potential for the subordinate species to be affected through interference competition or energetic costs of avoiding predation. Fishers (Pekania pennanti) and American martens (Martes americana) often have high niche overlap, but fishers are considered dominant and potentially limiting to martens. We observed presence and vigilance of fishers and martens at winter carcass sites using remote cameras in Michigan, USA, to test the hypothesis that interference competition from fishers creates a landscape of fear for martens. Within winters, fishers co-occupied 78–88% of sites occupied by martens, and martens co-occupied 79–88% of sites occupied by fishers. Fishers displaced martens from carcasses during 21 of 6117 marten visits, while martens displaced fishers during 0 of 1359 fisher visits. Martens did not alter diel activity in response to fisher use of sites. Martens allocated 37% of time to vigilance compared to 23% for fishers, and martens increased vigilance up to 8% at sites previously visited by fishers. Fishers increased vigilance by up to 8% at sites previously visited by martens. Our results indicate that fishers were dominant over martens, and martens had greater baseline perception of risk than fishers. However, fishers appeared to be also affected as the dominant competitor by putting effort into scanning for martens. Both species appeared widespread and common in our study area, but there was no evidence that fishers spatially or temporally excluded martens from scavenging at carcasses other than occasional short-term displacement when a fisher was present. Instead, martens appeared to mitigate risk from fishers by using vigilance and short-term avoidance. Multiple short-term anti-predator behaviors within a landscape of fear may facilitate coexistence among carnivore species.
Novel neutralizing human monoclonal antibodies against tetanus neurotoxin
Authors: Minamitani Takeharu , Kiyose Karin , Otsubo Ryota , Ito Toshihiro , Akiba Hiroki , Furuta Rika A. , Inoue Tsuyoshi , Tsumoto Kouhei , Satake Masahiro , Yasui Teruhito
Published: June 2021

Tetanus is a fatal disease caused by tetanus neurotoxin (TeNT). TeNT is composed of a light chain (Lc) and a heavy chain, the latter of which is classified into two domains, N-terminus Hn and C-terminus Hc. Several TeNT-neutralizing antibodies have been reported, but it remains unclear which TeNT domains are involved in neutralization. To further understand the mechanism of these antibodies, we isolated TeNT-reactive human antibody clones from peripheral blood mononuclear cells. We then analyzed the reactivity of the isolated antibody clones to each protein domain and their inhibition of Hc-ganglioside GT1b binding, which is critical for TeNT toxicity. We also investigated the TeNT-neutralizing ability of isolated antibody clones and showed that an Hn-reactive clone protected strongly against TeNT toxicity in mice. Furthermore, combination treatment of Hn-reactive antibody clones with both Hc-reactive and TeNT mix (the mixture of Hc, Hn, and Lc proteins)–reactive antibody clones enhanced the neutralizing effect. These results indicated that antibody clones targeting Hn effectively neutralized TeNT. In addition, the use of a cocktail composed of Hc-, Hn-, and TeNT mix–reactive antibodies provided enhanced protection compared to the use of each antibody alone.
Body weight variability and cancer incidence in men aged 40 years and older-Korean National Insurance Service Cohort
Authors: Cho Yu Jin , Kawk Jin Seul , Yoon Hyung-Jin , Park Minseon
Published: June 2021

Repeated weight fluctuation has been proposed as a potential risk factor for increasing morbidity and mortality including cancer. We aimed to investigate the association between body weight variability (BWV) and all cancer and site-specific cancer incidence and the impact of smoking on these associations. A total of 1,759,848 cancer-free male subjects who had their weight measured at least 5 times from the National Health Insurance Service-Health Screening Cohort from 2002 to 2011 were included and followed up until 2015. BWV was defined as the average absolute difference between successive values (ASV). The risk of cancer and site-specific cancer from BWV was identified using Cox proportional hazards regression analysis using hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for potential confounders including weight, and stratified analysis was also conducted according to smoking status. During the 7,015,413 person-years of follow-up, 11,494 patients (0.65%) developed new-onset cancers. BWV was associated with a higher risk of all cancers after adjustment for confounders. The highest BWV quintile group compared to the lowest had greater risks of all cancers and site-specific cancers including lung, liver, and prostate cancer (HR 1.22, 95% CI 1.15–1.30; HR 1.22, 95% CI 1.07–1.39; HR 1.46, 95% CI 1.19–1.81; HR 1.36, 95% CI 1.15–1.62, in all cancers, lung, liver and prostate cancer, respectively). Due to small number of cancer occurrence, the risk of kidney cancer was increased, but statistically insignificant (HR 1.38, 95% CI 0.91–2.10). Similar results were observed in noncurrent smokers. However, in current smokers, the risks of all cancers and only prostate cancer were significantly increased in the highest BWV quintile group (HR 1.19, 95% CI 1.09–1.31; HR 1.51, 95% CI 1.08–2.11). The risk of kidney cancer also increased in this group, although the finding was not statistically significant (HR 1.77, 95% CI 0.87–3.63) This study suggested BWV is an independent risk factor for cancer in men, especially in lung, liver, and prostate cancer, but evidence was weaker in kidney cancer. This association remained significant only in prostate cancer in current smokers.
Computational and experimental studies of a cell-imprinted-based integrated microfluidic device for biomedical applications
Authors: Yazdian Kashani Sepideh , Keshavarz Moraveji Mostafa , Bonakdar Shahin
Published: June 2021

It has been proved that cell-imprinted substrates molded from template cells can be used for the re-culture of that cell while preserving its normal behavior or to differentiate the cultured stem cells into the template cell. In this study, a microfluidic device was presented to modify the previous irregular cell-imprinted substrate and increase imprinting efficiency by regular and objective cell culture. First, a cell-imprinted substrate from template cells was prepared using a microfluidic chip in a regular pattern. Another microfluidic chip with the same pattern was then aligned on the cell-imprinted substrate to create a chondrocyte-imprinted-based integrated microfluidic device. Computational fluid dynamics (CFD) simulations were used to obtain suitable conditions for injecting cells into the microfluidic chip before performing experimental evaluations. In this simulation, the effect of input flow rate, number per unit volume, and size of injected cells in two different chip sizes were examined on exerted shear stress and cell trajectories. This numerical simulation was first validated with experiments with cell lines. Finally, chondrocyte was used as template cell to evaluate the chondrogenic differentiation of adipose-derived mesenchymal stem cells (ADSCs) in the chondrocyte-imprinted-based integrated microfluidic device. ADSCs were positioned precisely on the chondrocyte patterns, and without using any chemical growth factor, their fibroblast-like morphology was modified to the spherical morphology of chondrocytes after 14 days of culture. Both immunostaining and gene expression analysis showed improvement in chondrogenic differentiation compared to traditional imprinting methods. This study demonstrated the effectiveness of cell-imprinted-based integrated microfluidic devices for biomedical applications.
Intermittency study of global solar radiation under a tropical climate: case study on Reunion Island
Authors: Li Qi , Bessafi Miloud , Li Peng
Published: June 2021

The arbitrary order Hilbert spectral analyses are applied to study the intermittency and multifractality of Global Horizonal Irradiation (GHI) based on one available high sampling rate of 1-year GHI records located at Saint-Denis (Moufia) over Reunion Island. The scaling exponents$$\xi \left( q \right)$$ξqis estimated through the arbitrary order Hilbert spectral analyses, and three parameters: Hurst exponent (H), the fractal co-dimension (C1), and Lévy parameter ($$\alpha$$α) are taken to study the multifractal process of the GHI in the sub-daily, daily fluctuations and also in seasonal variations. A power law behaviour with a spectral exponentβ = 1.68 close to the Kolmogorov spectrum is detected through Fourier spectrum analysis, which indicates that the sub-daily fluctuations of GHI are nonstationary. The scaling exponentζ(q) is then estimated by the arbitrary order Hilbert spectral analysis and the multifractal properties is detected. The log-stable model parameters$$H,{ }C_{1}$$H,C1and$$\alpha$$αcharacterize the concavity of the scaling exponentζ(q) for analysing the intermittency of GHI. The classification method is applied to the daily GHI for analysing the distribution of the daily intermittency process and five classes with GHI andKbare obtained.
Application of fluorescein combined with methylene blue in sentinel lymph node biopsy of breast cancer
Authors: Li Liang , Gao Ning , Yang Ai Qing , Xu Wen Hao , Ding Yu , Chu Jun , Lin Xiao Na , Liu Jia Qi
Published: June 2021

Sentinel lymph node biopsy (SLNB) for axillary lymph node staging in early breast cancer has been widely recognized. The combination of radio-colloids and dye method is the best method recognized. The reagents and equipment required in the process of the combined method are complex and expensive, so there are certain restrictions in the use of primary medical institutions. As a new tracer, fluorescent tracer technology has attracted much attention. We aimed to evaluate the feasibility and safety of fluorescein for SLNB in breast cancer. In this study, a total of 123 patients with breast cancer were divided into group A (n = 67) and group B (n = 56). The efficacy of Indocyanine green (ICG) combined with methylene blue (group A) and fluorescein combined with methylene blue (group B) in SLNB of breast cancer was compared, complications were observed at the same time. No local or systemic reactions were observed in the two groups. In group A, Sentinel lymph nodes of breast cancer were detected in 63 patients, with a detection rate of 94.0% (63/67), a false-negative rate of 7.5% (4/53). In group B, Sentinel lymph nodes of breast cancer were detected in 52 patients, with a detection rate of 92.9% (52/56), a false-negative rate of 7.5% (3/40). There was no significant difference in biopsy results between the two groups. This prospective clinical study suggests that SLNB using fluorescein and ultraviolet LED light is feasible in breast cancer patients. No adverse reactions were observed in this study, but larger studies are needed to properly assess the adverse reaction rate.
The acute effects of high-intensity jack-knife stretching on the flexibility of the hamstrings
Authors: Takeuchi Kosuke , Akizuki Kazunori , Nakamura Masatoshi
Published: June 2021

The purpose of the present study was to examine the acute effects of high-intensity jack-knife stretching for 60 s on flexibility of the hamstrings. Twelve healthy participants underwent jack-knife stretching for 60 s (3 repetitions of 20 s stretching with 30 s intervals) at two different intensities based on the point of discomfort (POD and PODmax). To examine any change in flexibility, knee extension range of motion (ROM), passive torque at end ROM, and muscle–tendon unit stiffness were measured before and after stretching. To evaluate hamstrings pain, a numerical rating scale (NRS) was described. The knee extension ROM (p < 0.01) and passive torque at end ROM (p < 0.05) were significantly increased at both intensities. The muscle–tendon unit stiffness was significantly decreased in PODmax intensity (p < 0.01), but there was no change in POD intensity (p = 0.18). The median values of NRS during the stretching were 0 and 6–7 in POD and PODmax intensity, respectively, although it was 0 immediately after the stretching protocol in both intensities. These data suggested that high-intensity jack-knife stretching is an effective and safe method to decrease muscle–tendon unit stiffness of the hamstrings.
Pregnancy-induced effects on memory B-cell development in multiple sclerosis
Authors: Janssen Malou , Rijvers Liza , Koetzier Steven C. , Wierenga-Wolf Annet F. , Melief Marie-José , van Langelaar Jamie , Runia Tessel F. , de Groot Christianne J. M. , Neuteboom Rinze , Smolders Joost , van Luijn Marvin M.
Published: June 2021

In MS, pathogenic memory B cells infiltrate the brain and develop into antibody-secreting cells. Chemokine receptors not only define their brain-infiltrating capacity, but also assist in their maturation in germinal centers. How this corresponds to pregnancy, as a naturally occurring modifier of MS, is underexplored. Here, we aimed to study the impact of pregnancy on both ex vivo and in vitro B-cell differentiation in MS. The composition and outgrowth of peripheral B cells were compared between 19 MS pregnant patients and 12 healthy controls during the third trimester of pregnancy (low relapse risk) and postpartum (high relapse risk). Transitional, and not naive mature, B-cell frequencies were found to drop in the third trimester, which was most prominent in patients who experienced a pre-pregnancy relapse. Early after delivery, these frequencies raised again, while memory B -cell frequencies modestly declined. CXCR4 was downregulated and CXCR5, CXCR3 and CCR6 were upregulated on postpartum memory B cells, implying enhanced recruitment into germinal center light zones for interaction with T follicular helper (TFH) cells. Postpartum memory B cells of MS patients expressed higher levels of CCR6 and preferentially developed into plasma cells under TFH-like in vitro conditions. These findings imply that memory B- cell differentiation contributes to postpartum relapse risk in MS.
Effect of foot–floor friction on the external moment about the body center of mass during shuffling gait: a pilot study
Authors: Yamaguchi Takeshi , Shibata Kei , Wada Hiromi , Kakehi Hiroshi , Hokkirigawa Kazuo
Published: June 2021

Herein, we investigated the effect of friction between foot sole and floor on the external forward moment about the body center of mass (COM) in normal and shuffling gaits. Five young male adults walked with normal and shuffling gaits, under low- and high-friction surface conditions. The maximum external forward moment about the COM (MEFM-COM) in a normal gait appeared approximately at initial foot contact and was unaffected by floor condition. However, MEFM-COM in a shuffling gait under high-friction conditions exceeded that under low-friction conditions (p < 0.001). Therein, MEFM-COM increased with an increasing utilized coefficient of friction at initial foot contact; this effect was weaker during a normal gait. These findings indicate that increased friction between foot sole and floor might increase tripping risk during a shuffling gait, even in the absence of discrete physical obstacles.
Cystine–glutamate antiporter deletion accelerates motor recovery and improves histological outcomes following spinal cord injury in mice
Authors: Sprimont Lindsay , Janssen Pauline , De Swert Kathleen , Van Bulck Mathias , Rooman Ilse , Gilloteaux Jacques , Massie Ann , Nicaise Charles
Published: June 2021

xCT is the specific subunit of System xc-, an antiporter importing cystine while releasing glutamate. Although xCT expression has been found in the spinal cord, its expression and role after spinal cord injury (SCI) remain unknown. The aim of this study was to characterize the role of xCT on functional and histological outcomes following SCI induced in wild-type (xCT+/+) and in xCT-deficient mice (xCT−/−). In the normal mouse spinal cord,slc7a11/xCT mRNA was detected in meningeal fibroblasts, vascular mural cells, astrocytes, motor neurons and to a lesser extent in microglia.slc7a11/xCT gene and protein were upregulated within two weeks post-SCI. xCT−/− mice recovered muscular grip strength as well as pre-SCI weight faster than xCT+/+ mice. Histology of xCT−/− spinal cords revealed significantly more spared motor neurons and a higher number of quiescent microglia. In xCT−/− mice, inflammatory polarization shifted towards higher mRNA expression ofym1andigf1(anti-inflammatory) while lower levels ofnox2andtnf-a(pro-inflammatory). Although astrocyte polarization did not differ, we quantified an increased expression oflcn2mRNA. Our results show thatslc7a11/xCT is overexpressed early following SCI and is detrimental to motor neuron survival. xCT deletion modulates intraspinal glial activation by shifting towards an anti-inflammatory profile.
Tanshinones induce tumor cell apoptosis via directly targeting FHIT
Authors: Zhou Xianglian , Pan Yuting , Wang Yue , Wang Bojun , Yan Yu , Qu Yi , Ke Xisong
Published: June 2021

The liposoluble tanshinones are bioactive components inSalvia miltiorrhizaand are widely investigated as anti-cancer agents, while the molecular mechanism is to be clarified. In the present study, we identified that the human fragile histidine triad (FHIT) protein is a direct binding protein of sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of Tanshinone IIA (TSA), with a Kd value of 268.4 ± 42.59 nM. We also found that STS inhibited the diadenosine triphosphate (Ap3A) hydrolase activity of FHIT through competing for the substrate-binding site with an IC50value of 2.2 ± 0.05 µM. Notably, near 100 times lower binding affinities were determined between STS and other HIT proteins, including GALT, DCPS, and phosphodiesterase ENPP1, while no direct binding was detected with HINT1. Moreover, TSA, Tanshinone I (TanI), and Cryptotanshinone (CST) exhibited similar inhibitory activity as STS. Finally, we demonstrated that depletion of FHIT significantly blocked TSA’s pro-apoptotic function in colorectal cancer HCT116 cells. Taken together, our study sheds new light on the molecular basis of the anti-cancer effects of the tanshinone compounds.
RANKL immunisation inhibits prostate cancer metastasis by modulating EMT through a RANKL-dependent pathway
Authors: Park Mineon , Cho Yong Jin , Kim Bora , Ko Young Jong , Jang Yuria , Moon Yeon Hee , Hyun Hoon , Lim Wonbong
Published: June 2021

Prostate cancer (PCa) morbidity in the majority of patients is due to metastatic events, which are a clinical obstacle. Therefore, a better understanding of the mechanism underlying metastasis is imperative if we are to develop novel therapeutic strategies. Receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL) regulates bone remodelling. Thus, agents that suppress RANKL signalling may be useful pharmacological treatments. Here, we used preclinical experimental models to investigate whether an inactive form of RANKL affects bone metastasis in RANKL-induced PCa. RANKL was associated with epithelial–mesenchymal transition (EMT) and expression of metastasis-related genes in PC3 cells. Therefore, we proposed a strategy to induce anti-cytokine antibodies using mutant RANKL as an immunogen. RANKL promoted migration and invasion of PC3 cells through EMT, and induced a significant increase in binding of β-catenin to TCF-4, an EMT-induced transcription factor in PCa cells, via mitogen-activated protein kinase and β-catenin/TCF-4 signalling. Thus, RANKL increased EMT and the metastatic properties of PC3 cells, suggesting a role as a therapeutic target to prevent PCa metastasis. Treatment with mutant RANKL reduced EMT and metastasis of PC3 PCa cells in an experimental metastasis model. Thus, mutant RANKL could serve as a potential vaccine to prevent and treat metastatic PCa.
Catheter-related bloodstream infection associated with multiple insertions of the peripherally inserted central catheter in patients with hematological disorders
Authors: Hashimoto Yoshinori , Hosoda Rina , Omura Hiromi , Tanaka Takayuki
Published: June 2021

Patients with hematological disorders are treated with multiple cycles of chemotherapy. As a result, they often require multiple insertions of the peripherally inserted central catheter (PICC) for prolonged periods of time. Although PICCs have been widely used worldwide in various patients, the safety and feasibility of the multiple insertions of the PICC in this population have not been fully verified. We performed a retrospective analysis to clarify the relationship between complications and multiple PICC insertions in patients with hematological disorders who were treated with either chemotherapy or immunotherapy. A total of 651 PICCs were inserted in 261 patients with a median age of 66 years. Acute myeloid leukemia (AML) and non-Hodgkin's lymphoma were the most common diseases in our patient cohort. The total catheter days (CDs) was 29,485 days, with a median catheter duration of 30 days. The rate of catheter-related bloodstream infection (CRBSI) in our patient cohort at high rate of re-insertion was 2.0/1000 CDs. Although multiple PICC insertions were not a risk factor of CRBSI, our findings suggest that a prolonged catheter dwell time may be associated with CRBSI. AML was an important risk factor of CRBSI. While the PICC dwell time depends on the treatment cycle, our findings indicate that it should be limited to approximately 30 days and catheters may be removed and re-inserted as needed.