bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic abnormalities of TP53 define distinct risk groups of paediatric B-cell non-Hodgkin lymphoma
Authors: Newman Alexander M. , Zaka Masood , Zhou Peixun , Blain Alex E. , Erhorn Amy , Barnard Amy , Crossland Rachel E. , Wilkinson Sarah , Enshaei Amir , De Zordi Julian , Harding Fiona , Taj Mary , Wood Katrina M. , Televantou Despina , Turner Suzanne D. , Burke G. A. Amos , Harrison Christine J. , Bomken Simon , Bacon Chris M. , Rand Vikki
Published: October 2021

Children with B-cell non-Hodgkin lymphoma (B-NHL) have an excellent chance of survival, however, current clinical risk stratification places as many as half of patients in a high-risk group receiving very intensive chemo-immunotherapy. TP53 alterations are associated with adverse outcome in many malignancies; however, whilst common in paediatric B-NHL, their utility as a risk classifier is unknown. We evaluated the clinical significance of TP53 abnormalities (mutations, deletion and/or copy number neutral loss of heterozygosity) in a large UK paediatric B-NHL cohort and determined their impact on survival. TP53 abnormalities were present in 54.7% of cases and were independently associated with a significantly inferior survival compared to those without a TP53 abnormality (PFS 70.0% vs 100%, p < 0.001, OS 78.0% vs 100%, p = 0.002). Moreover, amongst patients clinically defined as high-risk (stage III with high LDH or stage IV), those without a TP53 abnormality have superior survival compared to those with TP53 abnormalities (PFS 100% vs 55.6%, p = 0.005, OS 100% vs 66.7%, p = 0.019). Biallelic TP53 abnormalities were either maintained from the presentation or acquired at progression in all paired diagnosis/progression Burkitt lymphoma cases. TP53 abnormalities thus define clinical risk groups within paediatric B-NHL and offer a novel molecular risk stratifier, allowing more personalised treatment protocols.
Endogenous dopamine release in the human brain as a pharmacodynamic biomarker: evaluation of the new GPR139 agonist TAK-041 with [11C]PHNO PET
Authors: Rabiner Eugenii A. , Uz Tolga , Mansur Ayla , Brown Terry , Chen Grace , Wu Jingtao , Atienza Joy , Schwarz Adam J. , Yin Wei , Lewis Yvonne , Searle Graham E. , Dennison Jeremy M. T. J. , Passchier Jan , Gunn Roger N. , Tauscher Johannes
Published: October 2021

The use of positron emission tomography (PET) in early-phase development of novel drugs targeting the central nervous system, is well established for the evaluation of brain penetration and target engagement. However, when novel targets are involved a suitable PET ligand is not always available. We demonstrate an alternative approach that evaluates the attenuation of amphetamine-induced synaptic dopamine release by a novel agonist of the orphan G-protein-coupled receptor GPR139 (TAK-041). GPR139 agonism is a novel candidate mechanism for the treatment of schizophrenia and other disorders associated with social and cognitive dysfunction. Ten healthy volunteers underwent [11C]PHNO PET at baseline, and twice after receiving an oral dose of d-amphetamine (0.5 mg/kg). One of the post-d-amphetamine scans for each subject was preceded by a single oral dose of TAK-041 (20 mg in five; 40 mg in the other five participants). D-amphetamine induced a significant decrease in [11C]PHNO binding potential relative to the non-displaceable component (BPND) in all regions examined (16–28%), consistent with increased synaptic dopamine release. Pre-treatment with TAK-041 significantly attenuated the d-amphetamine-induced reduction in BPND in the a priori defined regions (putamen and ventral striatum: 26% and 18%, respectively). The reduction in BPND was generally higher after the 40 mg than the 20 mg TAK-041 dose, with the difference between doses reaching statistical significance in the putamen. Our findings suggest that TAK-041 enters the human brain and interacts with GPR139 to affect endogenous dopamine release. [11C]PHNO PET is a practical method to detect the effects of novel drugs on the brain dopaminergic system in healthy volunteers, in the early stages of drug development.
Advances in the curative management of oesophageal cancer
Authors: Bolger Jarlath C. , Donohoe Claire L. , Lowery Maeve , Reynolds John V.
Published: October 2021

The incidence of oesophageal cancer, in particular adenocarcinoma, has markedly increased over the last four decades with adenocarcinoma becoming the dominant subtype in the West, and mortality rates are high. Nevertheless, overall survival of patients with oesophageal cancer has doubled in the past 20 years, with earlier diagnosis and improved treatments benefiting those patients who can be treated with curative intent. Advances in endotherapy, surgical approaches, and multimodal and other combination therapies have been reported. New vistas have emerged in targeted therapies and immunotherapy, informed by new knowledge in genomics and molecular biology, which present opportunities for personalised cancer therapy and novel clinical trials. This review focuses exclusively on the curative intent treatment pathway, and highlights emerging advances.
Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells
Authors: Schroeder Barbara , Vander Steen Travis , Espinoza Ingrid , Venkatapoorna Chandra M. Kurapaty , Hu Zeng , Silva Fernando Martín , Regan Kevin , Cuyàs Elisabet , Meng X. Wei , Verdura Sara , Arbusà Aina , Schneider Paula A. , Flatten Karen S. , Kemble George , Montero Joan , Kaufmann Scott H. , Menendez Javier A. , Lupu Ruth
Published: October 2021

Inhibitors of the lipogenic enzyme fatty acid synthase (FASN) have attracted much attention in the last decade as potential targeted cancer therapies. However, little is known about the molecular determinants of cancer cell sensitivity to FASN inhibitors (FASNis), which is a major roadblock to their therapeutic application. Here, we find that pharmacological starvation of endogenously produced FAs is a previously unrecognized metabolic stress that heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors. Evaluation of the death decision circuits controlled by the BCL-2 family of proteins revealed that FASN inhibition is accompanied by the upregulation of the pro-death BH3-only proteins BIM, PUMA, and NOXA. Cell death triggered by FASN inhibition, which causally involves a palmitate/NADPH-related redox imbalance, is markedly diminished by concurrent loss of BIM or PUMA, suggesting that FASN activity controls cancer cell survival by fine-tuning the BH3 only proteins-dependent mitochondrial threshold for apoptosis. FASN inhibition results in a heightened mitochondrial apoptosis priming, shifting cells toward a primed-for-death state “addicted” to the anti-apoptotic protein BCL-2. Accordingly, co-administration of a FASNi synergistically augments the apoptosis-inducing activity of the dual BCL-XL/BCL-2 inhibitor ABT-263 (navitoclax) and the BCL-2 specific BH3-mimetic ABT-199 (venetoclax). FASN inhibition, however, fails to sensitize breast cancer cells to MCL-1- and BCL-XL-selective inhibitors such as S63845 and A1331852. A human breast cancer xenograft model evidenced that oral administration of the only clinically available FASNi drastically sensitizes FASN-addicted breast tumors to ineffective single-agents navitoclax and venetoclax in vivo. In summary, a novel FASN-driven facet of the mitochondrial priming mechanistically links the redox-buffering mechanism of FASN activity to the intrinsic apoptotic threshold in breast cancer cells. Combining next-generation FASNis with BCL-2-specific BH3 mimetics that directly activate the apoptotic machinery might generate more potent and longer-lasting antitumor responses in a clinical setting.
What makes a plant-based diet? a review of current concepts and proposal for a standardized plant-based dietary intervention checklist
Authors: Storz Maximilian Andreas
Published: October 2021

Within the last decades, plant-based diets have received increasing interest for their potential benefits to human and environmental health. The concept of plant-based diet, however, varies widely in its definition. Current definitions range from the exclusion of all animal products to diets that include meat, fish, and dairy in varying quantities. Therefore, the main objectives of this review were twofold: (a) to investigate how researchers use the term plant-based diet in nutrition intervention studies and (b) what types of food a plant-based diet may include. Searching two databases, we found that the term “plant-based diet” evokes varying ideas to researchers and clinicians. Fifty percent of the retrieved studies that included a plant-based dietary intervention completely proscribed animal products and used the term plant-based diet interchangeably with a vegan diet. In contrast, an ~33% of trials included dairy products and 20% of dietary interventions emphasized a semi-vegetarian dietary pattern. Based on specific examples, we point out how the usage of the umbrella term “plant-based diet” may cause significant ambiguity. We often encountered incomplete descriptions of plant-based dietary interventions, which makes comparison and reproducibility of studies difficult. As a consequence, we urge others to use the term “plant-based diet” only in conjunction with a detailed dietary description. To facilitate this process, we provide a template of a standardized plant-based intervention reporting checklist. Finally, the present review also highlights the urgent need for a consensus definition of the term plant-based diet and its content.
StemBond hydrogels control the mechanical microenvironment for pluripotent stem cells
Authors: Labouesse Céline , Tan Bao Xiu , Agley Chibeza C. , Hofer Moritz , Winkel Alexander K. , Stirparo Giuliano G. , Stuart Hannah T. , Verstreken Christophe M. , Mulas Carla , Mansfield William , Bertone Paul , Franze Kristian , Silva José C. R. , Chalut Kevin J.
Published: October 2021

Studies of mechanical signalling are typically performed by comparing cells cultured on soft and stiff hydrogel-based substrates. However, it is challenging to independently and robustly control both substrate stiffness and extracellular matrix tethering to substrates, making matrix tethering a potentially confounding variable in mechanical signalling investigations. Moreover, unstable matrix tethering can lead to poor cell attachment and weak engagement of cell adhesions. To address this, we developed StemBond hydrogels, a hydrogel in which matrix tethering is robust and can be varied independently of stiffness. We validate StemBond hydrogels by showing that they provide an optimal system for culturing mouse and human pluripotent stem cells. We further show how soft StemBond hydrogels modulate stem cell function, partly through stiffness-sensitive ERK signalling. Our findings underline how substrate mechanics impact mechanosensitive signalling pathways regulating self-renewal and differentiation, indicating that optimising the complete mechanical microenvironment will offer greater control over stem cell fate specification.
Regulation of plant phototropic growth by NPH3/RPT2-like substrate phosphorylation and 14-3-3 binding
Authors: Sullivan Stuart , Waksman Thomas , Paliogianni Dimitra , Henderson Louise , Lütkemeyer Melanie , Suetsugu Noriyuki , Christie John M.
Published: October 2021

Polarity underlies all directional growth responses in plants including growth towards the light (phototropism). The plasma-membrane associated protein, NON-PHOTOTROPIC HYPOCOTYL 3 (NPH3) is a key determinant of phototropic growth which is regulated by phototropin (phot) AGC kinases. Here we demonstrate that NPH3 is directly phosphorylated by phot1 within a conserved C-terminal consensus sequence (RxS) that is necessary to promote phototropism and petiole positioning in Arabidopsis. RxS phosphorylation also triggers 14-3-3 binding combined with changes in NPH3 phosphorylation and localisation status. Mutants of NPH3 that are unable to bind or constitutively bind 14-3-3 s show compromised functionality consistent with a model where phototropic curvature is established by signalling outputs arising from a gradient of NPH3 RxS phosphorylation across the stem. Our findings therefore establish that NPH3/RPT2-Like (NRL) proteins are phosphorylation targets for plant AGC kinases. Moreover, RxS phosphorylation is conserved in other members of the NRL family, suggesting a common mechanism of regulating plant growth to the prevailing light environment.
Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region
Authors: Aneas Ivy , Decker Donna C. , Howard Chanie L. , Sobreira Débora R. , Sakabe Noboru J. , Blaine Kelly M. , Stein Michelle M. , Hrusch Cara L. , Montefiori Lindsey E. , Tena Juan , Magnaye Kevin M. , Clay Selene M. , Gern James E. , Jackson Daniel J. , Altman Matthew C. , Naureckas Edward T. , Hogarth Douglas K. , White Steven R. , Gomez-Skarmeta Jose Luis , Schoetler Nathan , Ober Carole , Sperling Anne I. , Nóbrega Marcelo A.
Published: October 2021

Genome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5 kb region within the GWAS-defined segment that acts as an enhancer-blocking element in vivo and in vitro. Chromatin conformation capture showed that this 5 kb region loops to the IL33 promoter, potentially regulating its expression. We show that the asthma-associated single nucleotide polymorphism (SNP) rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein expression in human plasma, potentially through differential binding of OCT-1 (POU2F1) to the asthma-risk allele. Our data demonstrate that asthma-associated variants at the IL33 locus mediate allele-specific regulatory activity and IL33 expression, providing a mechanism through which a regulatory SNP contributes to genetic risk of asthma.
Integrated cooling (i-Cool) textile of heat conduction and sweat transportation for personal perspiration management
Authors: Peng Yucan , Li Wei , Liu Bofei , Jin Weiliang , Schaadt Joseph , Tang Jing , Zhou Guangmin , Wang Guanyang , Zhou Jiawei , Zhang Chi , Zhu Yangying , Huang Wenxiao , Wu Tong , Goodson Kenneth E. , Dames Chris , Prasher Ravi , Fan Shanhui , Cui Yi
Published: October 2021

Perspiration evaporation plays an indispensable role in human body heat dissipation. However, conventional textiles tend to focus on sweat removal and pay little attention to the basic thermoregulation function of sweat, showing limited evaporation ability and cooling efficiency in moderate/profuse perspiration scenarios. Here, we propose an integrated cooling (i-Cool) textile with unique functional structure design for personal perspiration management. By integrating heat conductive pathways and water transport channels decently, i-Cool exhibits enhanced evaporation ability and high sweat evaporative cooling efficiency, not merely liquid sweat wicking function. In the steady-state evaporation test, compared to cotton, up to over 100% reduction in water mass gain ratio, and 3 times higher skin power density increment for every unit of sweat evaporation are demonstrated. Besides, i-Cool shows about 3 °C cooling effect with greatly reduced sweat consumption than cotton in the artificial sweating skin test. The practical application feasibility of i-Cool design principles is well validated based on commercial fabrics. Owing to its exceptional personal perspiration management performance, we expect the i-Cool concept can provide promising design guidelines for next-generation perspiration management textiles.
Orexin-A and endocannabinoids are involved in obesity-associated alteration of hippocampal neurogenesis, plasticity, and episodic memory in mice
Authors: Forte Nicola , Boccella Serena , Tunisi Lea , Fernández-Rilo Alba Clara , Imperatore Roberta , Iannotti Fabio Arturo , De Risi Maria , Iannotta Monica , Piscitelli Fabiana , Capasso Raffaele , De Girolamo Paolo , De Leonibus Elvira , Maione Sabatino , Di Marzo Vincenzo , Cristino Luigia
Published: October 2021

The mammalian brain stores and distinguishes among episodic memories, i.e. memories formed during the personal experience, through a mechanism of pattern separation computed in the hippocampal dentate gyrus. Decision-making for food-related behaviors, such as the choice and intake of food, might be affected in obese subjects by alterations in the retrieval of episodic memories. Adult neurogenesis in the dentate gyrus regulates the pattern separation. Several molecular factors affect adult neurogenesis and exert a critical role in the development and plasticity of newborn neurons. Orexin-A/hypocretin-1 and downstream endocannabinoid 2-arachidonoylglycerol signaling are altered in obese mice. Here, we show that excessive orexin-A/2-arachidonoylglycerol/cannabinoid receptor type-1 signaling leads to the dysfunction of adult hippocampal neurogenesis and the subsequent inhibition of plasticity and impairment of pattern separation. By inhibiting orexin-A action at orexin-1 receptors we rescued both plasticity and pattern separation impairment in obese mice, thus providing a molecular and functional mechanism to explain alterations in episodic memory in obesity.
IL-1-driven stromal–neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies
Authors: Friedrich Matthias , Pohin Mathilde , Jackson Matthew A. , Korsunsky Ilya , Bullers Samuel J. , Rue-Albrecht Kevin , Christoforidou Zoe , Sathananthan Dharshan , Thomas Tom , Ravindran Rahul , Tandon Ruchi , Peres Raphael Sanches , Sharpe Hannah , Wei Kevin , Watts Gerald F. M. , Mann Elizabeth H. , Geremia Alessandra , Attar Moustafa ,   Oxford IBD Cohort Investigators,   Roche Fibroblast Network Consortium, Barone Francesca , Brenner Michael , Buckley Christopher D. , Coles Mark , Frei Andreas P. , Lassen Kara G. , Powrie Fiona M. , McCuaig Sarah , Thomas Lloyd , Collantes Elena , Uhlig Holm H. , Sansom Stephen N. , Easton Alistair , Raychaudhuri Soumya , Travis Simon P. , Powrie Fiona M.
Published: October 2021

Current inflammatory bowel disease (IBD) therapies are ineffective in a high proportion of patients. Combining bulk and single-cell transcriptomics, quantitative histopathology and in situ localization across three cohorts of patients with IBD (total n = 376), we identify coexpressed gene modules within the heterogeneous tissular inflammatory response in IBD that map to distinct histopathological and cellular features (pathotypes). One of these pathotypes is defined by high neutrophil infiltration, activation of fibroblasts and vascular remodeling at sites of deep ulceration. Activated fibroblasts in the ulcer bed display neutrophil-chemoattractant properties that are IL-1R, but not TNF, dependent. Pathotype-associated neutrophil and fibroblast signatures are increased in nonresponders to several therapies across four independent cohorts (total n = 343). The identification of distinct, localized, tissular pathotypes will aid precision targeting of current therapeutics and provides a biological rationale for IL-1 signaling blockade in ulcerating disease.
An Emiliania huxleyi pan-transcriptome reveals basal strain specificity in gene expression patterns
Authors: Feldmesser Ester , Ben-Dor Shifra , Vardi Assaf
Published: October 2021

Emiliania huxleyi is a cosmopolitan coccolithophore widespread in temperate oceans. This unicellular photoautotroph forms massive recurring blooms that play an important role in large biogeochemical cycles of carbon and sulfur, which play a role in climate change. The mechanism of bloom formation and demise, controlled by giant viruses that routinely infect these blooms, is poorly understood. We generated a pan-transcriptome of E. huxleyi, derived from three strains with different susceptibility to viral infection. Expression profiling of E. huxleyi sensitive and resistant strains showed major basal differences, including many genes that are induced upon viral infection. This suggests that basal gene expression can affect the host metabolic state and the susceptibility of E. huxleyi to viruses. Due to its ecological importance, the pan-transcriptome and its protein translation, applicable to many E. huxleyi strains, is a powerful resource for investigation of eukaryotic microbial communities.
Analysis of potential regulatory LncRNAs and CircRNAs in the oxidative myofiber and glycolytic myofiber of chickens
Authors: Ju Xiaojun , Liu Yifan , Shan Yanju , Ji Gaige , Zhang Ming , Tu Yunjie , Zou Jianmin , Chen Xingyong , Geng Zhaoyu , Shu Jingting
Published: October 2021

SART and PMM are mainly composed of oxidative myofibers and glycolytic myofibers, respectively, and myofiber types profoundly influence postnatal muscle growth and meat quality. SART and PMM are composed of lncRNAs and circRNAs that participate in myofiber type regulation. To elucidate the regulatory mechanism of myofiber type, lncRNA and circRNA sequencing was used to systematically compare the transcriptomes of the SART and PMM of Chinese female Qingyuan partridge chickens at their marketing age. The luminance value (L*), redness value (a*), average diameter, cross-sectional area, and density difference between the PMM and SART were significant (p < 0.05). ATPase staining results showed that PMMs were all darkly stained and belonged to the glycolytic type, and the proportion of oxidative myofibers in SART was 81.7%. A total of 5 420 lncRNAs were identified, of which 365 were differentially expressed in the SART compared with the PMM (p < 0.05). The cis-regulatory analysis identified target genes that were enriched for specific GO terms and KEGG pathways (p < 0.05), including striated muscle cell differentiation, regulation of cell proliferation, regulation of muscle cell differentiation, myoblast differentiation, regulation of myoblast differentiation, and MAPK signaling pathway. Pathways and coexpression network analyses suggested that XR_003077811.1, XR_003072304.1, XR_001465942.2, XR_001465741.2, XR_001470487.1, XR_003077673.1 and XR_003074785.1 played important roles in regulating oxidative myofibers by TBX3, QKI, MYBPC1, CALM2, and PPARGC1A expression. A total of 10 487 circRNAs were identified, of which 305 circRNAs were differentially expressed in the SART compared with the PMM (p < 0.05). Functional enrichment analysis showed that differentially expressed circRNAs were involved in host gene expression and were enriched in the AMPK, calcium signaling pathway, FoxO signaling pathway, p53 signaling pathway, and cellular senescence. Novel_circ_004282 and novel_circ_002121 played important roles in regulating oxidative myofibers by PPP3CA and NFATC1 expression. Using lncRNA-miRNA/circRNA-miRNA integrated analysis, we identified many candidate interaction networks that might affect muscle fiber performance. Important lncRNA-miRNA-mRNA networks, such as lncRNA-XR_003074785.1/miR-193-3p/PPARGC1A, regulate oxidative myofibers. This study reveals that lncXR_003077811.1, lncXR_003072304.1, lncXR_001465942.2, lncXR_001465741.2, lncXR_001470487.1, lncXR_003077673.1, XR_003074785.1, novel_circ_004282 and novel_circ_002121 might regulate oxidative myofibers. The lncRNA-XR_003074785.1/miR-193-3p/PPARGC1A pathway might regulate oxidative myofibers. All these findings provide rich resources for further in-depth research on the regulatory mechanism of lncRNAs and circRNAs in myofibers.
Interindividual heterogeneity affects the outcome of human cardiac tissue decellularization
Authors: Tenreiro Miguel F. , Almeida Henrique V. , Calmeiro Tomás , Fortunato Elvira , Ferreira Lino , Alves Paula M. , Serra Margarida
Published: October 2021

The extracellular matrix (ECM) of engineered human cardiac tissues corresponds to simplistic biomaterials that allow tissue assembly, or animal derived off-the-shelf non-cardiac specific matrices. Decellularized ECM from human cardiac tissue could provide a means to improve the mimicry of engineered human cardiac tissues. Decellularization of cardiac tissue samples using immersion-based methods can produce acceptable cardiac ECM scaffolds; however, these protocols are mostly described for animal tissue preparations. We have tested four methods to decellularize human cardiac tissue and evaluated their efficiency in terms of cell removal and preservation of key ECM components, such as collagens and sulfated glycosaminoglycans. Extended exposure to decellularization agents, namely sodium dodecyl sulfate and Triton-X-100, was needed to significantly remove DNA content by approximately 93% in all human donors. However, the biochemical composition of decellularized tissue is affected, and the preservation of ECM architecture is donor dependent. Our results indicate that standardization of decellularization protocols for human tissue is likely unfeasible, and a compromise between cell removal and ECM preservation must be established in accordance with the scaffold’s intended application. Notwithstanding, decellularized human cardiac ECM supported human induced pluripotent-derived cardiomyocyte (hiPSC-CM) attachment and retention for up to 2 weeks of culture, and promoted cell alignment and contraction, providing evidence it could be a valuable tool for cardiac tissue engineering.
Dual recombinase action in the normal and neoplastic mammary gland epithelium
Authors: Rädler Patrick D. , Vistisen Kerry , Triplett Aleata A. , Dennaoui Rayane , Li Yong , Shrestha Hridaya , Ferraiuolo Rosa-Maria , Thangasamy Amalraj , Saur Dieter , Wagner Kay-Uwe
Published: October 2021

We developed a transgenic mouse line that expresses the codon-optimized Flp recombinase under the control of the MMTV promoter in luminal epithelial cells of the mammary gland. In this report, we demonstrate the versatile applicability of the new MMTV-Flp strain to manipulate genes in a temporally and spatially controlled manner in the normal mammary gland, in luminal-type mammary tumors that overexpress ERBB2, and in a new KRAS-associated mammary cancer model. Although the MMTV-Flp is expressed in a mosaic pattern in the luminal epithelium, the Flp-mediated activation of a mutant KrasG12D allele resulted in basal-like mammary tumors that progressively acquired mesenchymal features. Besides its applicability as a tool for gene activation and cell lineage tracing to validate the cellular origin of primary and metastatic tumor cells, we employed the MMTV-Flp transgene together with the tamoxifen-inducible Cre recombinase to demonstrate that the combinatorial action of both recombinases can be used to delete or to activate genes in established tumors. In a proof-of-principle experiment, we conditionally deleted the JAK1 tyrosine kinase in KRAS-transformed mammary cancer cells using the dual recombinase approach and found that lack of JAK1 was sufficient to block the constitutive activation of STAT3. The collective results from the various lines of investigation showed that it is, in principle, feasible to manipulate genes in a ligand-controlled manner in neoplastic mammary epithelial cells, even when cancer cells acquire a state of cellular plasticity that may no longer support the expression of the MMTV-Flp transgene.
Antimicrobial activity and mode of action of 1,8-cineol against carbapenemase-producing Klebsiella pneumoniae
Authors: Moo Chew-Li , Osman Mohd Azuraidi , Yang Shun-Kai , Yap Wai-Sum , Ismail Saila , Lim Swee-Hua-Erin , Chong Chou-Min , Lai Kok-Song
Published: October 2021

Antimicrobial resistance remains one of the most challenging issues that threatens the health of people around the world. Plant-derived natural compounds have received considerable attention for their potential role to mitigate antibiotic resistance. This study was carried out to assess the antimicrobial activity and mode of action of a monoterpene, 1,8-cineol (CN) against carbapenemase-producing Klebsiella pneumoniae (KPC-KP). Results showed that resazurin microplate assay and time-kill analysis revealed bactericidal effects of CN at 28.83 mg/mL. Zeta potential showed that CN increased the surface charge of bacteria and an increase of outer membrane permeability was also detected. CN was able to cause leakage of proteins and nucleic acids in KPC-KP cells upon exposure to CN and ethidium bromide influx/efflux experiment showed the uptake of ethidium bromide into the cell; this was attributed to membrane damage. CN was also found to induce oxidative stress in CN-treated KPC-KP cells through generation of reactive oxygen species which initiated lipid peroxidation and thus damaging the bacterial cell membrane. Scanning and transmission electron microscopies further confirmed the disruption of bacterial cell membrane and loss of intracellular materials. In this study, we demonstrated that CN induced oxidative stress and membrane damage resulting in KPC-KP cell death.
Sake yeast induces the sleep-promoting effects under the stress-induced acute insomnia in mice
Authors: Nishimon Shohei , Sakai Noriaki , Nishino Seiji
Published: October 2021

Sleep deprivation induces adverse effects on the health, productivity, and performance. The individuals who could not get enough sleep temporarily experience the symptoms of an induced acute insomnia. This study investigated the efficacy of sake yeast in treatment of acute insomnia in mice. The results of this study showed that sake yeast induced a significant dose-dependent wake reduction, a rapid eye movement (REM) and a non-REM (NREM) sleep enhancement during the first 6 h after the oral administration of sake yeast with locomotor activity and core body temperature decreases under the stressful environment in a new cage. In fact, the wake amounts at 3 h and 6 h were significantly reduced after the oral administration of sake yeast compared with the vehicle. The NREM sleep amounts at 3 h and 6 h significantly increased after the administration of sake yeast compared with the vehicle. The REM amount at 6 h significantly increased after the administration of sake yeast compared with the vehicle, but not at 3 h. The previous study suggested that the sleep-promoting effects of sake yeast could be referred from the activating effect of adenosine A2A receptor (A2AR). In summary, the sake yeast is an A2AR agonist and may induce sleep due to its stress-reducing and anti-anxiety properties. Further verification of the involvement of adenosine in the pathophysiology of insomnia is needed.
Asymmetric optical cryptosystem for multiple images based on devil’s spiral Fresnel lens phase and random spiral transform in gyrator domain
Authors: Chen Hang , Liu Zhengjun , Tanougast Camel , Blondel Walter
Published: October 2021

An asymmetric cryptosystem is presented for encrypting multiple images in gyrator transform domains. In the encryption approach, the devil’s spiral Fresnel lens variable pure phase mask is first designed for each image band to be encrypted by using devil’ mask, random spiral phase and Fresnel mask, respectively. Subsequently, a novel random devil’ spiral Fresnel transform in optical gyrator transform is implemented to achieved the intermediate output. Then, the intermediate data is divided into two masks by employing random modulus decomposition in the asymmetric process. Finally, a random permutation matrix is utilized to obtain the ciphertext of the intact algorithm. For the decryption approach, two divided masks (private key and ciphertext) need to be imported into the optical gyrator input plane simultaneously. Some numerical experiments are given to verify the effectiveness and capability of this asymmetric cryptosystem.
Inferring a causal relationship between ceramide levels and COVID-19 respiratory distress
Authors: Khodadoust Mehran M.
Published: October 2021

A causal relationship between plasma ceramide concentration and respiratory distress symptoms in COVID-19 patients is inferred. In this study, plasma samples of 52 individuals infected with COVID-19 were utilized in a lipidomic analysis. Lipids belonging to the ceramide class exhibited a 400-fold increase in total plasma concentration in infected patients. Further analysis led to the demonstration of concentration dependency for severe COVID-19 respiratory symptoms in a subclass of ceramides. The subclasses Cer(d18:0/24:1), Cer(d18:1/24:1), and Cer(d18:1/22:0) were shown to be increased by 48-, 40-, and 33-fold, respectively, in infected plasma samples and to 116-, 91- and 50-fold, respectively, in plasma samples with respiratory distress. Hence, monitoring plasma ceramide concentration, can be a valuable tool for measuring effects of therapies on COVID-19 respiratory distress patients.
Potential efficacy of existing drug molecules against severe fever with thrombocytopenia syndrome virus: an in silico study
Authors: Chatterjee Shilpa , Kim Choon-Mee , Kim Dong-Min
Published: October 2021

Severe fever with thrombocytopenia syndrome (SFTS) is a zoonotic disease caused by the SFTS virus (SFTSV). SFTS can be considered a life-threatening notifiable infectious disease. The unavailability of specific therapeutics encourages the investigation of potential efficacy of existing drugs against this infection. Drug repurposing was done by performing  virtual screening of already established drug molecules followed by 100 ns molecular dynamics simulations and molecular mechanics Poisson–Boltzmann surface area–based binding-energy calculation by targeting the SFTS L protein. On the basis of binding energy and protein–ligand interactions, top 10 promising hits were identified, showing stable binding with SFTS L protein. Further 100 ns atomistic MD simulation refined the hits from top 10 to top 4 with docking-based binding energy lesser than −8.0 kcal/mol toward the SFTS L protein and engaged in π–π interactions with pivotal amino acid residues. Various parameters and binding affinity of top 4 ligands towards L protein was computed. Ligand zaltoprofen exhibited best binding energy −220.095 kJ/mol. The present work is the first in silico study to assess bromfenac, cinchophen, elliptinium, and zaltoprofen; four promising hits against SFTS. Nonetheless, further proper biological evaluation is necessary to determine their efficacy against SFTS.
Role of human glutathione transferases in biotransformation of the nitric oxide prodrug JS-K
Authors: Sjödin Birgitta , Mannervik Bengt
Published: October 2021

Nitric oxide (NO) plays a prominent physiological role as a low-molecular-mass signal molecule involved in diverse biological functions. Great attention has been directed to pharmacologically modulating the release of NO for various therapeutic applications. We have focused on O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) as an example of diazeniumdiolate prodrugs with potential for cancer chemotherapy. JS-K is reportedly activated by glutathione conjugation by glutathione transferase (GST), but the scope of activities among the numerous members of the GSTome is unknown. We demonstrate that all human GSTs tested except GST T1-1 are active with JS-K as a substrate, but their specific activities are notably spanning a > 100-fold range. The most effective enzyme was the mu class member GST M2-2 with a specific activity of 273 ± 5 µmol min−1 mg−1 and the kinetic parameters Km 63 µM, kcat 353 s−1, kcat/Km 6 × 106 M−1 s−1. The abundance of the GSTs as an ensemble and their high catalytic efficiency indicate that release of NO occurs rapidly in normal tissues such that this influence must be considered in clarification of the tumor-killing effect of JS-K.
A systematic study on the synergistic effects of MWCNTs and core–shell particles on the physicomechanical properties of epoxy resin
Authors: Gharieh Ali , Seyed Dorraji Mir Saeed
Published: October 2021

Here, core–shell impact modifier particles (CSIMPs) and multiwalled carbon nanotubes (MWCNs) were used as reinforcing agents for improving the toughness and tensile properties of epoxy resin. For this purpose, emulsion polymerization technique was exploited to fabricate poly(butyl acrylate-allyl methacrylate) core-poly(methyl methacrylate-glycidyl methacrylate) shell impact modifier particles with an average particle size of 407 nm. It was revealed that using a combination of the prepared CSIMPs and MWCNTs could significantly enhance the toughness and tensile properties of the epoxy resin. Also, it was observed that the dominant factors for improving the fracture toughness of the ternary composites are crack deflection/arresting as well as enlarged plastic deformation around the growing crack tip induced by the combination of rigid and soft particles. The Response Surface Methodology (RSM) with central composite design (CCD) was utilized to study the effects of the amounts of CSIMPs and MWCNTs on the physicomechanical properties of the epoxy resin. The proposed quadratic models were in accordance with the experimental results with correlation coefficient more than 98%. The optimum condition for maximum toughness, elastic modulus, and tensile strength was 3 wt% MWCNT and 1.03 wt% CSIMPs. The sample fabricated in the optimal condition indicated toughness, elastic modulus, and tensile strength equal to 2.2 MPa m1/2, 3014.5 MPa, and 40.6 MPa, respectively.
A novel multi-biomarker combination predicting relapse from long-term remission after discontinuation of biological drugs in rheumatoid arthritis
Authors: Nagatani Katsuya , Sakashita Eiji , Endo Hitoshi , Minota Seiji
Published: October 2021

Biological disease modifying anti-rheumatic drugs (bDMARDs) show dramatic treatment efficacy in rheumatoid arthritis (RA). Long-term use of bDMARDs, however, has disadvantages such as high costs and infection risk. Therefore, a methodology is needed to predict any future RA relapse. Herein, we report a novel multi-biomarker combination which predicts relapse after bDMARDs-withdrawal in patients in remission. Forty patients with RA in remission for more than 12 months were enrolled. bDMARDs were withdrawn and they were followed monthly for the next 24 months. Fourteen patients (35%) of 40 in the cohort remained in remission at 24 months, whereas 26 (65%) relapsed at various time-points. Serum samples obtained longitudinally from patients in remission were assessed for the relapse-prediction biomarkers and index from 73 cytokines by the exploratory multivariate ROC analysis. The relapse-prediction index calculated from the 5 cytokines, IL-34, CCL1, IL-1β, IL-2 and IL-19, strongly discriminated between patients who relapsed and those who stayed in remission. These findings could contribute to clinical decision-making as to the timing of when to discontinue bDMARDs in RA treatment.
Universal patterns of long-distance commuting and social assortativity in cities
Authors: Bokányi Eszter , Juhász Sándor , Karsai Márton , Lengyel Balázs
Published: October 2021

Millions commute to work every day in cities and interact with colleagues, partners, friends, and strangers. Commuting facilitates the mixing of people from distant and diverse neighborhoods, but whether this has an imprint on social inclusion or instead, connections remain assortative is less explored. In this paper, we aim to better understand income sorting in social networks inside cities and investigate how commuting distance conditions the online social ties of Twitter users in the 50 largest metropolitan areas of the United States. An above-median commuting distance in cities is linked to more diverse individual networks, moreover, we find that longer commutes are associated with a nearly uniform, moderate reduction of overall social tie assortativity across all cities. This suggests a universal relation between long-distance commutes and the integration of social networks. Our results inform policy that facilitating access across distant neighborhoods can advance the social inclusion of low-income groups.
Influence of red blood cell indices on HbA1c performance in detecting dysglycaemia in a Singapore preconception cohort study
Authors: Loy See Ling , Lin Jinjie , Cheung Yin Bun , Sreedharan Aravind Venkatesh , Chin Xinyi , Godfrey Keith M. , Tan Kok Hian , Shek Lynette Pei-Chi , Chong Yap Seng , Leow Melvin Khee-Shing , Khoo Chin Meng , Lee Yung Seng , Chan Shiao-Yng , Lek Ngee , Chan Jerry Kok Yen , Yap Fabian
Published: October 2021

Abnormalities of red blood cell (RBC) indices may affect glycated haemoglobin (HbA1c) levels. We assessed the influence of haemoglobin (Hb) and mean corpuscular volume (MCV) on the performance of HbA1c in detecting dysglycaemia among reproductive aged women planning to conceive. Women aged 18–45 years (n = 985) were classified as normal (12 ≤ Hb ≤ 16 g/dL and 80 ≤ MCV ≤ 100 fL) and abnormal (Hb < 12 g/dL and/or MCV < 80 fL). The Area Under the Receiver Operating Characteristic (AUROC) curve was used to determine the performance of HbA1c in detecting dysglycaemic status (prediabetes and diabetes). There were 771 (78.3%) women with normal RBC indices. The AUROCs for the normal and abnormal groups were 0.75 (95% confidence interval 0.69, 0.81) and 0.80 (0.70, 0.90), respectively, and were not statistically different from one another [difference 0.04 (− 0.16, 0.08)]. Further stratification by ethnicity showed no difference between the two groups among Chinese and Indian women. However, Malay women with normal RBC indices displayed lower AUROC compared to those with abnormal RBC indices (0.71 (0.55, 0.87) vs. 0.98 (0.93, 1.00), p = 0.002). The results suggest that the performance of HbA1c in detecting dysglycaemia was not influenced by abnormal RBC indices based on low Hb and/or low MCV. However, there may be ethnic variations among them.
Nash equilibria in human sensorimotor interactions explained by Q-learning with intrinsic costs
Authors: Lindig-León Cecilia , Schmid Gerrit , Braun Daniel A.
Published: October 2021

The Nash equilibrium concept has previously been shown to be an important tool to understand human sensorimotor interactions, where different actors vie for minimizing their respective effort while engaging in a multi-agent motor task. However, it is not clear how such equilibria are reached. Here, we compare different reinforcement learning models to human behavior engaged in sensorimotor interactions with haptic feedback based on three classic games, including the prisoner’s dilemma, and the symmetric and asymmetric matching pennies games. We find that a discrete analysis that reduces the continuous sensorimotor interaction to binary choices as in classical matrix games does not allow to distinguish between the different learning algorithms, but that a more detailed continuous analysis with continuous formulations of the learning algorithms and the game-theoretic solutions affords different predictions. In particular, we find that Q-learning with intrinsic costs that disfavor deviations from average behavior explains the observed data best, even though all learning algorithms equally converge to admissible Nash equilibrium solutions. We therefore conclude that it is important to study different learning algorithms for understanding sensorimotor interactions, as such behavior cannot be inferred from a game-theoretic analysis alone, that simply focuses on the Nash equilibrium concept, as different learning algorithms impose preferences on the set of possible equilibrium solutions due to the inherent learning dynamics.
A Matlab toolbox for scaled-generic modeling of shoulder and elbow
Authors: Sarshari Ehsan , Boulanaache Yasmine , Terrier Alexandre , Farron Alain , Mullhaupt Philippe , Pioletti Dominique
Published: October 2021

There still remains a barrier ahead of widespread clinical applications of upper extremity musculoskeletal models. This study is a step toward lifting this barrier for a shoulder musculoskeletal model by enhancing its realism and facilitating its applications. To this end, two main improvements are considered. First, the elbow and the muscle groups spanning the elbow are included in the model. Second, scaling routines are developed that scale model’s bone segment inertial properties, skeletal morphologies, and muscles architectures according to a specific subject. The model is also presented as a Matlab toolbox with a graphical user interface to exempt its users from further programming. We evaluated effects of anthropometric parameters, including subject’s gender, height, weight, glenoid inclination, and degenerations of rotator cuff muscles on the glenohumeral joint reaction force (JRF) predictions. An arm abduction motion in the scapula plane is simulated while each of the parameters is independently varied. The results indeed illustrate the effect of anthropometric parameters and provide JRF predictions with less than 13% difference compared to in vivo studies. The developed Matlab toolbox could be populated with pre/post operative patients of total shoulder arthroplasty to answer clinical questions regarding treatments of glenohumeral joint osteoarthritis.
Different patterns of human activities in nature during Covid-19 pandemic and African swine fever outbreak confirm direct impact on wildlife disruption
Authors: Cukor Jan , Linda Rostislav , Mahlerová Karolina , Vacek Zdeněk , Faltusová Monika , Marada Petr , Havránek František , Hart Vlastimil
Published: October 2021

Implementation of various restrictions to eradicate viral diseases has globally affected human activity and subsequently nature. But how can the altered routines of human activity (restrictions, lockdowns) affect wildlife behaviour? This study compared the differences between human and wildlife occurrences in the study forest area with acreage of 5430.6 ha in 2018 (African swine fever outbreak, complete entrance ban), 2019 (standard pattern) and 2020 (COVID-19 restrictions) during the breeding season. The number of visitors was lower by 64% in 2018 (non-respecting of the entry ban by forest visitors) compared to standard 2019, while in 2020, the number of visitors increased to 151%. In the COVID-19 period, distinct peaks in the number of visitors were observed between 8–11 AM and 4–7 PM. The peaks of wildlife activity were recorded between 4–7 AM and 9–12 PM. Animals avoided the localities that were visited by humans during the people-influenced time (24 h after people visit), which confirmed the direct negative impact of human activities on wildlife.
Corrosion behavior of X80 pipeline steel local defect pits under static liquid film
Authors: Tan Zhuowei , Wang Zhenbo , Zhang Shengzhu , Bai Shuyu , Zhang Dalei , Jin Youhai , Xing Shaohua
Published: October 2021

In this work, the corrosion electrochemical information under different thicknesses of liquid film was tested. The local corrosion development process of X80 steel under different thicknesses of liquid film was studied by combining the detection and analysis of scale and the matrix corrosion morphology. The corrosion was studied by EIS. The composition and microstructures of corrosion scale at different locations were detected by EDS and SEM, and the metal matrix was detected by 3D topography technology to analyze the local corrosion. The results show that a liquid film with a thickness greater than or equal to 1 mm has no effect on the mechanism of the corrosion process, but has a control effect on the corrosion rate and the time of each stage in corrosion. The corrosion process can be divided into two stages: in the early stage, the concentration of ions inside and outside ADP is the same, so the corrosion is uniform; in the later stage, due to the influence of CO2 dissolution and mass transfer distance, the cathodic reaction is mainly outside ADP and the anodic reaction is mainly inside ADP. In addition, corrosion acidification occurs in ADP, which enhances the corrosion process in ADP.
De novo structural determination of oligosaccharide isomers in glycosphingolipids using logically derived sequence tandem mass spectrometry
Authors: Liew Chia Yen , Chan Chieh-Kai , Huang Shih-Pei , Cheng Yu-Ting , Tsai Shang-Ting , Hsu Hsu Chen , Wang Cheng-Chung , Ni Chi-Kung
Published: October 2021

Despite the importance of carbohydrates in biological systems, structural determination of carbohydrates remains difficult because of the large number of isomers.