bluuebunny/crossref_metadata_2025 huggingface dataset:
Climatic Effects of Spring Mesoscale Oceanic Eddies in the North Pacific: A Regional Modeling Study
Authors: Cai Zhiying , Xu Haiming , Ma Jing , Deng Jiechun
Published: April 2021

A high-resolution atmospheric model of the Weather Research and Forecast (WRF) is used to investigate the climatic effects of mesoscale oceanic eddies (OEs) in the North Pacific (NPac) in spring and the respective effects of OEs in the northern NPac associated with the Kuroshio Extension (KE) and of OEs in the southern NPac related to the subtropical countercurrent. Results show that mesoscale OEs in the NPac can strengthen the upper-level ridge (trough) in the central (eastern) subtropical NPac, together with markedly weakened (strengthened) westerly winds to its south. The mesoscale OEs in the whole NPac act to weaken the upper-level storm track and strengthen lower-level storm activities in the NPac. However, atmospheric responses to the northern and southern NPac OEs are more prominent. The northern NPac OEs can induce tropospheric barotropic responses with a tripole geopotential height (GPH) anomaly pattern to the north of 30° N, while the OEs in both the northern and southern NPac can enhance the upper-level ridge (trough) in the central (eastern) subtropical NPac. Additionally, the northern NPac OEs can shrink the lower-level subtropical high and weaken the easterly trade winds at the low latitudes, while the southern NPac OEs result in a southward shift of the lower-level subtropical high and an eastward shift of the upper-level westerly jet stream. The southern and northern NPac OEs have similar effects on the storm track, leading to an enhanced lower-level storm track over the KE via moistening the atmospheric boundary layer; and they can also exert significant remote influences on lower- and upper-level storm activities over the Northeast Pacific off the west coast of North America. When the intensities of OEs are doubled in the model, the spatial distribution of atmospheric responses is robust, with a larger and more significant magnitude. Additionally, although OEs are part of the mesoscale oceanic processes, the springtime OEs play an opposite role in mesoscale sea-surface temperature anomalies. These findings point to the potential of improving the forecasts of extratropical springtime storm systems and the projections of their responses to future climate change, by improving the representation of ocean eddy-atmosphere interaction in forecast and climate models.
An Analytic and Numerical Investigation of a Differential Game
Authors: Gibali Aviv , Kelis Oleg
Published: April 2021

In this paper we present an appropriate singular, zero-sum, linear-quadratic differential game. One of the main features of this game is that the weight matrix of the minimizer’s control cost in the cost functional is singular. Due to this singularity, the game cannot be solved either by applying the Isaacs MinMax principle, or the Bellman–Isaacs equation approach. As an application, we introduced an interception differential game with an appropriate regularized cost functional and developed an appropriate dual representation. By developing the variational derivatives of this regularized cost functional, we apply Popov’s approximation method and show how the numerical results coincide with the dual representation.
The χ-Hessian Quotient for Riemannian Metrics
Authors: Laurian-Ioan Pişcoran , Ali Akram , Cătălin Barbu , Alkhaldi Ali H.
Published: April 2021

Pseudo-Riemannian geometry and Hilbert–Schmidt norms are two important fields of research in applied mathematics. One of the main goals of this paper will be to find a link between these two research fields. In this respect, in the present paper, we will introduce and analyze two important quantities in pseudo-Riemannian geometry, namely the H-distorsion and, respectively, the Hessian χ-quotient. This second quantity will be investigated using the Frobenius (Hilbert–Schmidt) norm. Some important examples will be also given, which will prove the validity of the developed theory along the paper.
q-Binomial Convolution and Transformations of q-Appell Polynomials
Authors: Obad Alaa Mohammed , Khan Asif , Nisar Kottakkaran Sooppy , Morsy Ahmed
Published: April 2021

In this paper, binomial convolution in the frame of quantum calculus is studied for the set Aq of q-Appell sequences. It has been shown that the set Aq of q-Appell sequences forms an Abelian group under the operation of binomial convolution. Several properties for this Abelian group structure Aq have been studied. A new definition of the q-Appell polynomials associated with a random variable is proposed. Scale transformation as well as transformation based on expectation with respect to a random variable is used to present the determinantal form of q-Appell sequences.
High-Performance Lithium Sulfur Batteries Based on Multidimensional Graphene-CNT-Nanosulfur Hybrid Cathodes
Authors: Doñoro Álvaro , Muñoz-Mauricio Álvaro , Etacheri Vinodkumar
Published: April 2021

Although lithium-sulfur (Li-S) batteries are one of the promising candidates for next-generation energy storage, their practical implementation is limited by rapid capacity fading due to lithium polysulfide (LiPSs) formation and the low electronic conductivity of sulfur. Herein, we report a high-performance lithium-sulfur battery based on multidimensional cathode architecture consisting of nanosulfur, graphene nanoplatelets (2D) and multiwalled carbon nanotubes (1D). The ultrasonic synthesis method results in the generation of sulfur nanoparticles and their intercalation into the multilayered graphene nanoplatelets. The optimized multidimensional graphene-sulfur-CNT hybrid cathode (GNS58-CNT10) demonstrated a high specific capacity (1067 mAh g−1 @ 50 mA g−1), rate performance (539 @ 1 A g−1), coulombic efficiency (~95%) and cycling stability (726 mAh g−1 after 100 cycles @ 200 mA g−1) compared to the reference cathode. Superior electrochemical performances are credited to the encapsulation of nanosulfur between the individual layers of graphene nanoplatelets with high electronic conductivity, and effective polysulfide trapping by MWCNT bundles.
COVID-19 Diagnostic Strategies. Part I: Nucleic Acid-Based Technologies
Authors: Shaffaf Tina , Ghafar-Zadeh Ebrahim
Published: April 2021

The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused respiratory infection, resulting in more than two million deaths globally and hospitalizing thousands of people by March 2021. A considerable percentage of the SARS-CoV-2 positive patients are asymptomatic or pre-symptomatic carriers, facilitating the viral spread in the community by their social activities. Hence, it is critical to have access to commercialized diagnostic tests to detect the infection in the earliest stages, monitor the disease, and follow up the patients. Various technologies have been proposed to develop more promising assays and move toward the mass production of fast, reliable, cost-effective, and portable PoC diagnostic tests for COVID-19 detection. Not only COVID-19 but also many other pathogens will be able to spread and attach to human bodies in the future. These technologies enable the fast identification of high-risk individuals during future hazards to support the public in such outbreaks. This paper provides a comprehensive review of current technologies, the progress in the development of molecular diagnostic tests, and the potential strategies to facilitate innovative developments in unprecedented pandemics.
Integration of Multiple Resolution Data in 3D Chromatin Reconstruction Using ChromStruct
Authors: Caudai Claudia , Zoppè Monica , Tonazzini Anna , Merelli Ivan , Salerno Emanuele
Published: April 2021

The three-dimensional structure of chromatin in the cellular nucleus carries important information that is connected to physiological and pathological correlates and dysfunctional cell behaviour. As direct observation is not feasible at present, on one side, several experimental techniques have been developed to provide information on the spatial organization of the DNA in the cell; on the other side, several computational methods have been developed to elaborate experimental data and infer 3D chromatin conformations. The most relevant experimental methods are Chromosome Conformation Capture and its derivatives, chromatin immunoprecipitation and sequencing techniques (CHIP-seq), RNA-seq, fluorescence in situ hybridization (FISH) and other genetic and biochemical techniques. All of them provide important and complementary information that relate to the three-dimensional organization of chromatin. However, these techniques employ very different experimental protocols and provide information that is not easily integrated, due to different contexts and different resolutions. Here, we present an open-source tool, which is an expansion of the previously reported code ChromStruct, for inferring the 3D structure of chromatin that, by exploiting a multilevel approach, allows an easy integration of information derived from different experimental protocols and referred to different resolution levels of the structure, from a few kilobases up to Megabases. Our results show that the introduction of chromatin modelling features related to CTCF CHIA-PET data, histone modification CHIP-seq, and RNA-seq data produce appreciable improvements in ChromStruct’s 3D reconstructions, compared to the use of HI-C data alone, at a local level and at a very high resolution.
A Multi-Enzyme Cascade Reaction for the Production of 2′3′-cGAMP
Authors: Becker Martin , Nikel Patrick , Andexer Jennifer N. , Lütz Stephan , Rosenthal Katrin
Published: April 2021

Multi-enzyme cascade reactions for the synthesis of complex products have gained importance in recent decades. Their advantages compared to single biotransformations include the possibility to synthesize complex molecules without purification of reaction intermediates, easier handling of unstable intermediates, and dealing with unfavorable thermodynamics by coupled equilibria. In this study, a four-enzyme cascade consisting of ScADK, AjPPK2, and SmPPK2 for ATP synthesis from adenosine coupled to the cyclic GMP-AMP synthase (cGAS) catalyzing cyclic GMP-AMP (2′3′-cGAMP) formation was successfully developed. The 2′3′-cGAMP synthesis rates were comparable to the maximal reaction rate achieved in single-step reactions. An iterative optimization of substrate, cofactor, and enzyme concentrations led to an overall yield of 0.08 mole 2′3′-cGAMP per mole adenosine, which is comparable to chemical synthesis. The established enzyme cascade enabled the synthesis of 2′3′-cGAMP from GTP and inexpensive adenosine as well as polyphosphate in a biocatalytic one-pot reaction, demonstrating the performance capabilities of multi-enzyme cascades for the synthesis of pharmaceutically relevant products.
Involvement of Opioid System and TRPM8/TRPA1 Channels in the Antinociceptive Effect of Spirulina platensis
Authors: Freitas Mariana A. , Vasconcelos Amanda , Gonçalves Elaine C. D. , Ferrarini Eduarda G. , Vieira Gabriela B. , Cicia Donatella , Cola Maíra , Capasso Raffaele , Dutra Rafael C.
Published: April 2021

Spirulina platensis is a “super-food” and has attracted researchers’ attention due to its anti-inflammatory, antioxidant, and analgesic properties. Herein, we investigated the antinociceptive effects of Spirulina in different rodent behavior models of inflammatory pain. Male Swiss mice were treated with Spirulina (3–300 mg/kg, p.o.), indomethacin (10 mg/kg, p.o.), or vehicle (0.9% NaCl 10 mL/kg). Behavioral tests were performed with administration of acetic acid (0.6%, i.p.), formalin 2.7% (formaldehyde 1%, i.pl.), menthol (1.2 µmol/paw, i.pl.), cinnamaldehyde (10 nmol/paw, i.pl.), capsaicin (1.6 µg/paw, i.pl.), glutamate (20 µmol/paw, i.pl.), or naloxone (1 mg/kg, i.p.). The animals were also exposed to the rotarod and open field test to determine possible effects of Spirulina on locomotion and motor coordination. The quantitative phytochemical assays exhibited that Spirulina contains significant concentrations of total phenols and flavonoid contents, as well as it showed a powerful antioxidant effect with the highest scavenging activity. Oral administration of Spirulina completely inhibited the abdominal contortions induced by acetic acid (ED50 = 20.51 mg/kg). Spirulina treatment showed significant inhibition of formalin-induced nociceptive behavior during the inflammatory phase, and the opioid-selective antagonist markedly blocked this effect. Furthermore, our data indicate that the mechanisms underlying Spirulina analgesia appear to be related to its ability to modulate TRMP8 and TRPA1, but not by TRPV1 or glutamatergic system. Spirulina represents an orally active and safe natural analgesic that exhibits great therapeutic potential for managing inflammatory pain disorders.
Alternative Targets to Fight Alzheimer’s Disease: Focus on Astrocytes
Authors: Valenza Marta , Facchinetti Roberta , Menegoni Giorgia , Steardo Luca , Scuderi Caterina
Published: April 2021

The available treatments for patients affected by Alzheimer’s disease (AD) are not curative. Numerous clinical trials have failed during the past decades. Therefore, scientists need to explore new avenues to tackle this disease. In the present review, we briefly summarize the pathological mechanisms of AD known so far, based on which different therapeutic tools have been designed. Then, we focus on a specific approach that is targeting astrocytes. Indeed, these non-neuronal brain cells respond to any insult, injury, or disease of the brain, including AD. The study of astrocytes is complicated by the fact that they exert a plethora of homeostatic functions, and their disease-induced changes could be context-, time-, and disease specific. However, this complex but fervent area of research has produced a large amount of data targeting different astrocytic functions using pharmacological approaches. Here, we review the most recent literature findings that have been published in the last five years to stimulate new hypotheses and ideas to work on, highlighting the peculiar ability of palmitoylethanolamide to modulate astrocytes according to their morpho-functional state, which ultimately suggests a possible potential disease-modifying therapeutic approach for AD.
Central Alteration in Peripheral Neuropathy of Trembler-J Mice: Hippocampal pmp22 Expression and Behavioral Profile in Anxiety Tests
Authors: Damián Juan Pablo , Vázquez Alberdi Lucia , Canclini Lucía , Rosso Gonzalo , Bravo Silvia Olivera , Martínez Mariana , Uriarte Natalia , Ruiz Paul , Calero Miguel , Di Tomaso María Vittoria , Kun Alejandra
Published: April 2021

Charcot–Marie–Tooth (CMT) type 1 disease is the most common human hereditary demyelinating neuropathy. Mutations in pmp22 cause about 70% of all CMT1. Trembler-J (TrJ/+) mice are an animal model of CMT1E, having the same spontaneous pmp22 mutation that is found in humans. We compared the behavior profile of TrJ/+ and +/+ (wild-type) in open-field and elevated-plus-maze anxiety tests. In these tests, TrJ/+ showed an exclusive head shake movement, a lower frequency of rearing, but a greater frequency of grooming. In elevated-plus-maze, TrJ/+ defecate more frequently, performed fewer total entries, and have fewer entries to closed arms. These hippocampus-associated behaviors in TrJ/+ are consistent with increased anxiety levels. The expression of pmp22 and soluble PMP22 were evaluated in E17-hippocampal neurons and adult hippocampus by in situ hybridization and successive immunohistochemistry. Likewise, the expression of pmp22 was confirmed by RT-qPCR in the entire isolated hippocampi of both genotypes. Moreover, the presence of aggregated PMP22 was evidenced in unmasked granular hippocampal adult neurons and shows genotypic differences. We showed for the first time a behavior profile trait associated with anxiety and a differential expression of pmp22/PMP22 in hippocampal neurons of TrJ/+ and +/+ mice, demonstrating the involvement at the central level in an animal model of peripheral neuropathy (CMT1E).
Podophyllotoxin: History, Recent Advances and Future Prospects
Authors: Shah Zinnia , Gohar Umar Farooq , Jamshed Iffat , Mushtaq Aamir , Mukhtar Hamid , Zia-UI-Haq Muhammad , Toma Sebastian Ionut , Manea Rosana , Moga Marius , Popovici Bianca
Published: April 2021

Podophyllotoxin, along with its various derivatives and congeners are widely recognized as broad-spectrum pharmacologically active compounds. Etoposide, for instance, is the frontline chemotherapeutic drug used against various cancers due to its superior anticancer activity. It has recently been redeveloped for the purpose of treating cytokine storm in COVID-19 patients. Podophyllotoxin and its naturally occurring congeners have low bioavailability and almost all these initially discovered compounds cause systemic toxicity and development of drug resistance. Moreover, the production of synthetic derivatives that could suffice for the clinical limitations of these naturally occurring compounds is not economically feasible. These challenges demanded continuous devotions towards improving the druggability of these drugs and continue to seek structure-optimization strategies. The discovery of renewable sources including microbial origin for podophyllotoxin is another possible approach. This review focuses on the exigency of innovation and research required in the global R&D and pharmaceutical industry for podophyllotoxin and related compounds based on recent scientific findings and market predictions.
Dual Role for Astroglial Copper-Assisted Polyamine Metabolism during Intense Network Activity
Authors: Szabó Zsolt , Péter Márton , Héja László , Kardos Julianna
Published: April 2021

Astrocytes serve essential roles in human brain function and diseases. Growing evidence indicates that astrocytes are central players of the feedback modulation of excitatory Glu signalling during epileptiform activity via Glu-GABA exchange. The underlying mechanism results in the increase of tonic inhibition by reverse operation of the astroglial GABA transporter, induced by Glu-Na+ symport. GABA, released from astrocytes, is synthesized from the polyamine (PA) putrescine and this process involves copper amino oxidase. Through this pathway, putrescine can be considered as an important source of inhibitory signaling that counterbalances epileptic discharges. Putrescine, however, is also a precursor for spermine that is known to enhance gap junction channel communication and, consequently, supports long-range Ca2+ signaling and contributes to spreading of excitatory activity through the astrocytic syncytium. Recently, we presented the possibility of neuron-glia redox coupling through copper (Cu+/Cu2+) signaling and oxidative putrescine catabolism. In the current work, we explore whether the Cu+/Cu2+ homeostasis is involved in astrocytic control on neuronal excitability by regulating PA catabolism. We provide supporting experimental data underlying this hypothesis. We show that the blockade of copper transporter (CTR1) by AgNO3 (3.6 µM) prevents GABA transporter-mediated tonic inhibitory currents, indicating causal relationship between copper (Cu+/Cu2+) uptake and the catabolism of putrescine to GABA in astrocytes. In addition, we show that MnCl2 (20 μM), an inhibitor of the divalent metal transporter DMT1, also prevents the astrocytic Glu-GABA exchange. Furthermore, we observed that facilitation of copper uptake by added CuCl2 (2 µM) boosts tonic inhibitory currents. These findings corroborate the hypothesis that modulation of neuron-glia coupling by copper uptake drives putrescine → GABA transformation, which leads to subsequent Glu-GABA exchange and tonic inhibition. Findings may in turn highlight the potential role of copper signaling in fine-tuning the activity of the tripartite synapse.
Upper-Limb Isometric Force Feasible Set: Evaluation of Joint Torque-Based Models
Authors: Rezzoug Nasser , Hernandez Vincent , Gorce Philippe
Published: April 2021

A force capacity evaluation for a given posture may provide better understanding of human motor abilities for applications in sport sciences, rehabilitation and ergonomics. From data on posture and maximum isometric joint torques, the upper-limb force feasible set of the hand was predicted by four models called force ellipsoid, scaled force ellipsoid, force polytope and scaled force polytope, which were compared with a measured force polytope. The volume, shape and force prediction errors were assessed. The scaled ellipsoid underestimated the maximal mean force, and the scaled polytope overestimated it. The scaled force ellipsoid underestimated the volume of the measured force distribution, whereas that of the scaled polytope was not significantly different from the measured distribution but exhibited larger variability. All the models characterized well the elongated shape of the measured force distribution. The angles between the main axes of the modelled ellipsoids and polytopes and that of the measured polytope were compared. The values ranged from 7.3° to 14.3°. Over the entire surface of the force ellipsoid, 39.7% of the points had prediction errors less than 50 N; 33.6% had errors between 50 and 100 N; and 26.8% had errors greater than 100 N. For the force polytope, the percentages were 56.2%, 28.3% and 15.4%, respectively.
Unaffected Memory and Inhibitory Functioning Several Weeks Postpartum in Women with Pregnancy Complicated by Preeclampsia
Authors: Papousek Ilona , Weiss Elisabeth M. , Moertl Manfred G. , Schmid-Zalaudek Karin , Krenn Edina , Lessiak Verena , Lackner Helmut K.
Published: April 2021

Several studies reported impaired cognitive functioning after pregnancy complicated by preeclampsia. The present study examined cognitive and executive functioning in women with preeclampsia at a time at which immediate effects of gestation have resolved, brain damage due to other risk factors have not yet manifested, and impairments may thus primarily occur as a result of the huge stress induced by the potentially life threatening condition. Verbal learning/memory (California Verbal Learning Test) and inhibitory functioning (Mittenecker Pointing Test) of 35 women with preeclampsia and 38 women with uncomplicated pregnancy were followed over five measurement time points during the period from 16 to 48 weeks postpartum. A further control group comprised 40 women with no history of recent pregnancy. The groups did not differ in their verbal learning/memory performance. Higher levels of currently experienced everyday-life stress were associated with poorer inhibitory control/greater stereotypy in responding, but this effect was not directly connected with pregnancy complications. Taken together, the findings do not indicate rapid-onset cognitive impairment after preeclampsia, brought about by its extremely stressful nature or other factors that take effect during gestation. Deficits observed in later life may develop on a long-term basis through late-diagnosed hypertension and unfavorable lifestyle factors. The large time window in which exaggerated cognitive decline can be prevented or mitigated should be utilized for the control of risk factors and interventions to improve lifestyle where appropriate.
Prospective Comparison of 18-FDG PET/CT and Whole-Body MRI with Diffusion-Weighted Imaging in the Evaluation of Treatment Response of Multiple Myeloma Patients Eligible for Autologous Stem Cell Transplant
Authors: Mesguich Charles , Latrabe Valérie , Hulin Cyrille , Lascaux Axelle , Bordenave Laurence , Hindié Elif , Marit Gerald
Published: April 2021

To compare the prognostic values of 18-FDG PET/CT (FDG-PET) and Whole-Body MRI with Diffusion-Weighted Imaging (WB-DW-MRI) in the evaluation of treatment response of Multiple Myeloma (MM) patients eligible for ASCT. Thirty patients with newly diagnosed MM prospectively underwent FDG-PET and WB-DW-MRI at baseline, after induction chemotherapy and after ASCT. Response on WB-DW-MRI was evaluated with the MY-RADS criteria. FDG-PET was considered positive if residual uptake was superior to liver uptake. Imaging results were not used for treatment modification. The impact of imaging results on PFS was analyzed. After a median follow-up of 32 months, 10 patients relapsed. With WB-DW-MRI, post-induction examination was positive in 3/25 and post-ASCT examination was positive in 3/27 patients. However, neither study showed prognostic impact on PFS. FDG-PET was positive in 5/22 post-induction and 3/26 patients post-ASCT, respectively. Positivity of FDG-PET, post-induction or post-ASCT, was associated with a shorter PFS (post-induction: median PFS 19 months vs. not reached, log-rank p = 0.0089; post-ASCT: median PFS 18 months vs. not reached, log-rank p = 0.0005). Preliminary results from this small, single-center, prospective study show that, whether performed post-induction or post-ASCT, FDG-PET has a higher prognostic value than WB-DW-MRI for treatment response evaluation of newly diagnosed MM.
At What Age Could Screening for Familial Retinoblastoma Be Discontinued? A Systematic Review
Authors: van Hoefen Wijsard Milo , Serné Saskia H. , Otten René H. , Bosscha Machteld I. , Dommering Charlotte J. , Fabius Armida W. , Moll Annette C.
Published: April 2021

The aim of this systematic review is to assess the latest age at diagnosis for detection of familial retinoblastoma in order to evaluate at what age screening of at-risk children could be discontinued. Extended screening beyond this age would result in unnecessary patient burden and costs. However, discontinuing screening prematurely would have the adverse effect of missing tumors. We performed a literature search (PubMed, Embase, CINAHL and the Cochrane Library) up until February of 2021 and systematically included studies where patients had a family history of retinoblastoma, a known age at diagnosis, and who were ophthalmologically screened for retinoblastoma from birth. A total of 176 familial retinoblastoma patients from 17 studies were included in this review. Based on 48 months of age being the latest age of diagnosis, ophthalmological screening for familial retinoblastoma could safely be discontinued at age four years.
The Role of Macrophages in Cancer Development and Therapy
Authors: Cendrowicz Ewa , Sas Zuzanna , Bremer Edwin , Rygiel Tomasz P.
Published: April 2021

Macrophages are critical mediators of tissue homeostasis and influence various aspects of immunity. Tumor-associated macrophages are one of the main cellular components of the tumor microenvironment. Depending on their activation status, macrophages can exert a dual influence on tumorigenesis by either antagonizing the cytotoxic activity of immune cells or, less frequently, by enhancing antitumor responses. In most situations, TAMs suppress T cell recruitment and function or regulate other aspects of tumor immunity. The importance of TAMs targeting in cancer therapy is derived from the strong association between the high infiltration of TAMs in the tumor tissue with poor patient prognosis. Several macrophage-targeting approaches in anticancer therapy are developed, including TAM depletion, inhibition of new TAM differentiation, or re-education of TAM activation for cancer cell phagocytosis. In this review, we will describe the role of TAMs in tumor development, including such aspects as protumorigenic inflammation, immune suppression, neoangiogenesis, and enhancement of tissue invasion and distant metastasis. Furthermore, we will discuss therapeutic approaches that aim to deplete TAMs or, on the contrary, re-educate TAMs for cancer cell phagocytosis and antitumor immunity.
An Alternative Pipeline for Glioblastoma Therapeutics: A Systematic Review of Drug Repurposing in Glioblastoma
Authors: Lyne Seán B. , Yamini Bakhtiar
Published: April 2021

The treatment of glioblastoma (GBM) remains a significant challenge, with outcome for most pa-tients remaining poor. Although novel therapies have been developed, several obstacles restrict the incentive of drug developers to continue these efforts including the exorbitant cost, high failure rate and relatively small patient population. Repositioning drugs that have well-characterized mechanistic and safety profiles is an attractive alternative for drug development in GBM. In ad-dition, the relative ease with which repurposed agents can be transitioned to the clinic further supports their potential for examination in patients. Here, a systematic analysis of the literature and clinical trials provides a comprehensive review of primary articles and unpublished trials that use repurposed drugs for the treatment of GBM. The findings demonstrate that numerous drug classes that have a range of initial indications have efficacy against preclinical GBM models and that certain agents have shown significant potential for clinical benefit. With examination in randomized, placebo-controlled trials and the targeting of particular GBM subgroups, it is pos-sible that repurposing can be a cost-effective approach to identify agents for use in multimodal anti-GBM strategies.
The Targeting of MRE11 or RAD51 Sensitizes Colorectal Cancer Stem Cells to CHK1 Inhibition
Authors: Mattiello Luca , Soliman Abdel Rehim Sara , Musella Martina , Sistigu Antonella , Guarracino Andrea , Vitale Sara , Corradi Francesca , Galassi Claudia , Sperati Francesca , Manic Gwenola , De Maria Ruggero , Vitale Ilio
Published: April 2021

Cancer stem cells (CSCs) drive not only tumor initiation and expansion, but also therapeutic resistance and tumor relapse. Therefore, CSC eradication is required for effective cancer therapy. In preclinical models, CSCs demonstrated high capability to tolerate even extensive genotoxic stress, including replication stress, because they are endowed with a very robust DNA damage response (DDR). This favors the survival of DNA-damaged CSCs instead of their inhibition via apoptosis or senescence. The DDR represents a unique CSC vulnerability, but the abrogation of the DDR through the inhibition of the ATR-CHK1 axis is effective only against some subtypes of CSCs, and resistance often emerges. Here, we analyzed the impact of druggable DDR players in the response of patient-derived colorectal CSCs (CRC-SCs) to CHK1/2 inhibitor prexasertib, identifying RAD51 and MRE11 as sensitizing targets enhancing prexasertib efficacy. We showed that combined inhibition of RAD51 and CHK1 (via B02+prexasertib) or MRE11 and CHK1 (via mirin+prexasertib) kills CSCs by affecting multiple genoprotective processes. In more detail, these two prexasertib-based regimens promote CSC eradication through a sequential mechanism involving the induction of elevated replication stress in a context in which cell cycle checkpoints usually activated during the replication stress response are abrogated. This leads to uncontrolled proliferation and premature entry into mitosis of replication-stressed cells, followed by the induction of mitotic catastrophe. CRC-SCs subjected to RAD51+CHK1 inhibitors or MRE11+CHK1 inhibitors are eventually eliminated, and CRC-SC tumorspheres inhibited or disaggregated, via a caspase-dependent apoptosis. These results support further clinical development of these prexasertib-based regimens in colorectal cancer patients.
Radiation-Induced Pneumonitis in the Era of the COVID-19 Pandemic: Artificial Intelligence for Differential Diagnosis
Authors: Giordano Francesco Maria , Ippolito Edy , Quattrocchi Carlo Cosimo , Greco Carlo , Mallio Carlo Augusto , Santo Bianca , D’Alessio Pasquale , Crucitti Pierfilippo , Fiore Michele , Zobel Bruno Beomonte , D’Angelillo Rolando Maria , Ramella Sara
Published: April 2021

(1) Aim: To test the performance of a deep learning algorithm in discriminating radiation therapy-related pneumonitis (RP) from COVID-19 pneumonia. (2) Methods: In this retrospective study, we enrolled three groups of subjects: pneumonia-free (control group), COVID-19 pneumonia and RP patients. CT images were analyzed by mean of an artificial intelligence (AI) algorithm based on a novel deep convolutional neural network structure. The cut-off value of risk probability of COVID-19 was 30%; values higher than 30% were classified as COVID-19 High Risk, and values below 30% as COVID-19 Low Risk. The statistical analysis included the Mann–Whitney U test (significance threshold at p < 0.05) and receiver operating characteristic (ROC) curve, with fitting performed using the maximum likelihood fit of a binormal model. (3) Results: Most patients presenting RP (66.7%) were classified by the algorithm as COVID-19 Low Risk. The algorithm showed high sensitivity but low specificity in the detection of RP against COVID-19 pneumonia (sensitivity = 97.0%, specificity = 2%, area under the curve (AUC = 0.72). The specificity increased when an estimated COVID-19 risk probability cut-off of 30% was applied (sensitivity 76%, specificity 63%, AUC = 0.84). (4) Conclusions: The deep learning algorithm was able to discriminate RP from COVID-19 pneumonia, classifying most RP cases as COVID-19 Low Risk.
Magnetite-Based Catalyst in the Catalytic Wet Peroxide Oxidation for Different Aqueous Matrices Spiked with Naproxen–Diclofenac Mixture
Authors: Huaccallo-Aguilar Ysabel , Álvarez-Torrellas Silvia , Martínez-Nieves Johanny , Delgado-Adámez Jonathan , Gil María Victoria , Ovejero Gabriel , García Juan
Published: April 2021

Magnetite supported on multiwalled carbon nanotubes catalysts were synthesized by co-precipitation and hydrothermal treatment. The magnetic catalysts were characterized by X-ray diffraction, Fourier-transform infrared spectrometry, thermogravimetric analysis and N2 physisorption. The catalysts were then tested for their ability to remove diclofenac (DCF) and naproxen (NAP) from an aqueous solution at different conditions (pH, temperature, and hydrogen peroxide) to determine the optimum conditions for chemical oxidation. The optimization of the process parameters was conducted using response surface methodology (RSM) coupled with Box–Behnken design (BBD). By RSM–BBD methodology, the optimal parameters (1.75 mM H2O2 dosage, 70 °C and pH 6.5) were determined, and the removal percentages of NAP and DCF were 19 and 54%, respectively. The NAP–DCF degradation by catalytic wet peroxide oxidation (CWPO) was caused by •OH radicals. In CWPO of mixed drug solutions, DCF and NAP showed competitive oxidation. Hydrophobic interactions played an important role during the CWPO process. On the other hand, the magnetic catalyst reduced its activity after the second cycle of reuse. In addition, proof of concept and disinfection tests performed at the operating conditions showed results following the complexity of the water matrices. In this sense, the magnetic catalyst in CWPO has adequate potential to treat water contaminated with NAP–DCF mixtures.
The p23 of Citrus Tristeza Virus Interacts with Host FKBP-Type Peptidyl-Prolylcis-Trans Isomerase 17-2 and Is Involved in the Intracellular Movement of the Viral Coat Protein
Authors: Yang Zuokun , Zhang Yongle , Wang Guoping , Wen Shaohua , Wang Yanxiang , Li Liu , Xiao Feng , Hong Ni
Published: April 2021

Citrus tristeza virus is a member of the genus Closterovirus in the family Closteroviridae. The p23 of citrus tristeza virus (CTV) is a multifunctional protein and RNA silencing suppressor. In this study, we identified a p23 interacting partner, FK506-binding protein (FKBP) 17-2, from Citrus aurantifolia (CaFKBP17-2), a susceptible host, and Nicotiana benthamiana (NbFKBP17-2), an experimental host for CTV. The interaction of p23 with CaFKBP17-2 and NbFKBP17-2 were individually confirmed by yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays. Subcellular localization tests showed that the viral p23 translocated FKBP17-2 from chloroplasts to the plasmodesmata of epidermal cells of N. benthamiana leaves. The knocked-down expression level of NbFKBP17-2 mRNA resulted in a decreased CTV titer in N. benthamiana plants. Further, BiFC and Y2H assays showed that NbFKBP17-2 also interacted with the coat protein (CP) of CTV, and the complexes of CP/NbFKBP17-2 rapidly moved in the cytoplasm. Moreover, p23 guided the CP/NbFKBP17-2 complexes to move along the cell wall. To the best of our knowledge, this is the first report of viral proteins interacting with FKBP17-2 encoded by plants. Our results provide insights for further revealing the mechanism of the CTV CP protein movement.
Polyunsaturated Phospholipids Increase Cell Resilience to Mechanical Constraints
Authors: Kadri Linette , Bacle Amélie , Khoury Spiro , Vandebrouck Clarisse , Bescond Jocelyn , Faivre Jean-François , Ferreira Thierry , Sebille Stéphane
Published: April 2021

If polyunsaturated fatty acids (PUFAs) are generally accepted to be good for health, the mechanisms of their bona fide benefits still remain elusive. Membrane phospholipids (PLs) of the cardiovascular system and skeletal muscles are particularly enriched in PUFAs. The fatty acid composition of PLs is known to regulate crucial membrane properties, including elasticity and plasticity. Since muscle cells undergo repeated cycles of elongation and relaxation, we postulated in the present study that PUFA-containing PLs could be central players for muscle cell adaptation to mechanical constraints. By a combination of in cellulo and in silico approaches, we show that PUFAs, and particularly the ω-3 docosahexaenoic acid (DHA), regulate important properties of the plasma membrane that improve muscle cell resilience to mechanical constraints. Thanks to their unique property to contortionate within the bilayer plane, they facilitate the formation of vacuole-like dilation (VLD), which, in turn, avoid cell breakage under mechanical constraints.
The Influence of the Roll-Laminating Process on the Bonding Quality of Polymer-Coated Steel Interface
Authors: Liu Jiyang , Zhang Qingdong , Zhang Boyang , Yu Mingyang
Published: April 2021

Polymer-coated steel (PCS) is a new type of metal packaging material under development, which has better performance in saving resources, energy, and environmental protection. The lamination process has an important influence on the bonding quality of the PCS interface. PCS samples under different lamination temperatures and lamination speeds were prepared through experiments. A binding rate is defined to represent the real bonding area of the PCS interface. The micro-scratch tester and scanner are used to study the influence of the lamination process on the bonding rate and bonding strength of the PCS interface. It is proposed that the bonding rate and bonding strength of the PCS interface increases with the increase of lamination temperature and increases with the decrease of lamination speed. The PCS interface bonding rate and bonding strength are positively correlated. SEM and DSC experiments revealed the cause of bubbles on the PCS surface. It is proposed that controlling the uniformity of the TFS surface temperature can reduce the quality defects of PCS surface bubbles. Relevant research results bring guiding significance for the formation of enterprises.
Boride-Carbon Hybrid Technology for Ultra-Wear and Corrosive Conditions
Authors: Baule Nina , Kim Young S. , Zeuner André T. , Haubold Lars , Kühne Robert , Eryilmaz Osman L. , Erdemir Ali , Hu Zhong , Zimmermann Martina , Schuelke Thomas , Fan Qi-Hua
Published: April 2021

This work discusses a study on a surface treatment for creating extremely durable low-friction, wear and corrosion-resistant surfaces for tribological components in harsh conditions. A duplex surface treatment was developed that combines the advantages of ultra-fast electrochemical boriding with those of hard tetrahedral amorphous carbon coatings. The friction and wear properties of the duplex treatment are compared to the boride-only treatment of AISI 1045 steel, while corrosion and contact fatigue behaviors of the duplex layer are compared to that of the single-layer carbon coating on low carbon steel. The duplex treatment yields wear rates as low as 6 × 10−8 mm3·N−1·m−1 and a coefficient of friction of 0.14 when tested against a steel counter face. The contact fatigue impact tests reveal that the high hardness of 1200 HV0.05 of the borided layer in the duplex treatment leads to higher resistance against indentation but is accompanied by a higher incidence of crack initiation, being in good agreement with the finite-element modeling of nanoindentation results. The duplex coatings exhibit resistance to pinhole corrosion as evidenced by a 3 h exposure to 15% HCl at room temperature.
Sol–Gel Ceramics for SEIRAS and SERS Substrates
Authors: Garibay’Alvarado Jesús Alberto , Reyes-López Simón Yobanny
Published: April 2021

Surface Enhanced Infrared Absorption Spectroscopy and Surface Enhanced Raman Spectroscopy are analytic techniques that have not been massively adopted since there are issues that still need to be solved with regard to the nature of the signal enhancement substrates used. The sol–gel method for the obtention of ceramics provides an alternative for the production of said substrates. Ceramics are very wear- and heat-resistant, properties that can be used for their regeneration, and through the sol–gel method, ceramics can be produced with high purity as well as can be fashioned in many ways through different techniques, which can be helpful in the pursuit of reproducibility. This paper discusses the different advantages of sol–gel ceramics, their use in the electrospinning technique, and their application in infrared and Raman surface-enhanced spectroscopy.
Application of General Full Factorial Statistical Experimental Design’s Approach for the Development of Sustainable Clay-Based Ceramics Incorporated with Malaysia’s Electric Arc Furnace Steel Slag Waste
Authors: Teo Pao Ter , Zakaria Siti Koriah , Mohd Sharif Nurulakmal , Abu Seman Anasyida , Taib Mustaffa Ali Azhar , Mohamed Julie Juliewatty , Yusoff Mahani , Yusoff Abdul Hafidz , Mohamad Mardawani , Ali Arlina , Masri Mohamad Najmi
Published: April 2021

This study aims to optimize the composition (body formulation) and firing temperature of sustainable ceramic clay-based ceramics incorporated with electric arc furnace (EAF) steel slag waste using general full factorial design (GFFD). The optimization is necessary to minimize drawbacks of high iron oxide’s fluxing agent (originated from electric arc furnace, EAF steel slag waste), which led to severe surface defects and high closed porosity issue of the ceramics. Statistical analysis of GFFD including model adequacy checking, analysis of variance (ANOVA), interaction plots, regression model, contour plot and response optimizer were conducted in the study. The responses (final properties of ceramics) investigated were firing shrinkage, water absorption, apparent porosity, bulk density and modulus of rupture (MOR). Meanwhile, the factors employed in experimental parameters were weight percentage (wt.%) of EAF slag added and firing temperature. Upon statistical analysis, GFFD has deduced that wt.% amount of EAF slag added and firing temperatures are proven to significantly influence the final properties of the clay-based ceramic incorporated with EAF slag. The results of conducted statistical analysis were also highly significant and proven valid for the ceramics. Optimized properties (maximum MOR, minimum water absorption and apparent porosity) of the ceramic were attained at 50 wt.% of EAF slag added and firing temperature of 1180 °C.
The Epidemiology of Myeloproliferative Neoplasms in New Zealand between 2010 and 2017: Insights from the New Zealand Cancer Registry
Authors: Varghese Chris , Immanuel Tracey , Ruskova Anna , Theakston Edward , Kalev-Zylinska Maggie L.
Published: April 2021

Background: There is a paucity of data on ethnic disparities in patients with the classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs): polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF). Methods: This study analysed the demographic data for PV, ET and PMF collected by the New Zealand Cancer Registry (NZCR) between 2010 and 2017. Results: We found that the NZCR capture rates were lower than average international incidence rates for PV and ET, but higher for PMF (0.76, 0.99 and 0.82 per 100,000, respectively). PV patients were older and had worse outcomes than expected, which suggests these patients were reported to the registry at an advanced stage of their disease. Polynesian patients with all MPN subtypes, PV, ET and PMF, were younger than their European counterparts both at the time of diagnosis and death (p < 0.001). Male gender was an independent risk factor for mortality from PV and PMF (hazard ratios (HR) of 1.43 and 1.81, respectively; p < 0.05), and Māori ethnicity was an independent risk factor for mortality from PMF (HR: 2.94; p = 0.006). Conclusions: New Zealand Polynesian patients may have increased genetic predisposition to MPN, thus we advocate for modern genetic testing in this ethnic group to identify the cause. Further work is also required to identify modifiable risk factors for mortality in MPN, in particular those associated with male gender and Māori ethnicity; the results may benefit all patients with MPN.
Do Roads Alter the Trophic Behavior of the Mesocarnivore Community Living Close to Them?
Authors: Ruiz-Capillas Pablo , Mata Cristina , Fernández Beatriz , Fernandes Carlos , Malo Juan E.
Published: April 2021

Roads have impacts on the fauna arising from habitat fragmentation, roadkill and the barrier effect. Furthermore, roads lead species to change their activity with repercussions on predator–prey interactions and trigger indirect effects that are currently unknown. This study analyzes the effect of a motorway on the trophic behavior of the terrestrial carnivore community of its surroundings. Monthly scat sampling was conducted over a year at three distances from a motorway (0–50 m, 500–550 m and 1000–1050 m). We collected 498 scats, these originating from red fox (39.16%), cat (24.50%), stone marten (24.09%) and badger (12.25%). The relative abundance of the trophic resources in them was estimated together with the trophic diversity and niche overlap of the carnivore species. The results showed a distinct effect of distance from the road on trophic behavior of carnivores, as well as differences between species and seasons. The scats nearest the road had 10–20% more biomass of small mammals, equivalent in relative terms to a 21–48% increase in small mammals’ biomass when compared with scats collected further from the road. This finding indicates changes in predator–prey interactions near the road and shows that the human-generated structural and functional changes to ecosystems spread throughout trophic networks.