Diffusion Equations of the Electric Charges and Magnetic Flux

Innovative definitions of the electric and magnetic diffusivities through conducting mediums and innovative diffusion equations of the electric charges and magnetic flux are verified in this article. Such innovations depend on the analogy of the governing laws of diffusion of the thermal, electrical, and magnetic energies and newly defined natures of the electric charges and magnetic flux as energy, or as electromagnetic waves, that have electric and magnetic potentials. The introduced diffusion equations of the electric charges and magnetic flux involve Laplacian operator and the introduced diffusivities. Both equations are applied to determine the electric and magnetic fields in conductors as the heat diffusion equation which is applied to determine the thermal field in steady and unsteady heat diffusion conditions. The use of electric networks for experimental modeling of thermal networks represents sufficient proof of similarity of the diffusion equations of both fields. By analysis of the diffusion phenomena of the three considered modes of energy transfer;the rates of flow of these energies are found to be directly proportional to the gradient of their volumetric concentration, or density, and the proportionality constants in such relations are the diffusivity of each energy. Such analysis leads also to find proportionality relations between the potentials of such energies and their volumetric concentrations. Validity of the introduced diffusion equations is verified by correspondence their solutions to the measurement results of the electric and magnetic fields in microwave ovens.

Behind the curtain of non-coding RNAs; long non-coding RNAs regulating hepatocarcinogenesis

Hepatocellular carcinoma(HCC) is one of the most common and aggressive cancers worldwide. HCC is the fifth common malignancy in the world and the second leading cause of cancer death in Asia. Long non-coding RNAs(lncRNAs) are RNAs with a length greater than 200 nucleotides that do not encode proteins. lncRNAs can regulate gene expression and protein synthesis in several ways by interacting with DNA, RNA and proteins in a sequence specific manner. They could regulate cellular and developmental processes through either gene inhibition or gene activation. Many studies have shown that dysregulation of lncRNAs is related to many human diseases such as cardiovascular diseases, genetic disorders, neurological diseases, immune mediated disorders and cancers. However, the study of lncRNAs is challenging as they are poorly conserved between species, their expression levels aren't as high as that of m RNAs and have great interpatient variations. The study of lncRNAs expression in cancers have been a breakthrough as it unveils potential biomarkers and drug targets for cancer therapy and helps understand the mechanism of pathogenesis. This review discusses many long non-coding RNAs and their contribution in HCC, their role in development, metastasis, and prognosis of HCC and how to regulate and target these lncRNAs as a therapeutic tool in HCC treatment in the future.

Pivotal role of long non-coding ribonucleic acid-X-inactive specific transcript in regulating immune checkpoint programmed death ligand 1 through a shared pathway between miR-194-5p and miR-155-5p in hepatocellular carcinoma

BACKGROUND Anti-programmed death therapy has thrust immunotherapy into the spotlight.However,such therapy has a modest response in hepatocellular carcinoma(HCC).Epigenetic immunomodulation is a suggestive combinatorial therapy with immune checkpoint blockade.Non-coding ribonucleic acid(ncRNA)driven regulation is a major mechanism of epigenetic modulation.Given the wide range of ncRNAs that co-opt in programmed cell-death protein 1(PD-1)/programmed death ligand 1(PD-L1)regulation,and based on the literature,we hypothesized that miR-155-5p,miR-194-5p and long non-coding RNAs(lncRNAs)X-inactive specific transcript(XIST)and MALAT-1 are involved in a regulatory upstream pathway for PD-1/PD-L1.Recently,nutraceutical therapeutics in cancers have received increasing attention.Thus,it is interesting to study the impact of oleuropein on the respective study key players.AIM To explore potential upstream regulatory ncRNAs for the immune checkpoint PD-1/PD-L1.METHODS Bioinformatics tools including microrna.org and lnCeDB software were adopted to detect targeting of miR-155-5p,miR-194-5p and lncRNAs XIST and MALAT-1 to PD-L1 mRNA,respectively.In addition,Diana tool was used to predict targeting of both aforementioned miRNAs to lncRNAs XIST and MALAT-1.HCC and normal tissue samples were collected for scanning of PD-L1,XIST and MALAT-1 expression.To study the interaction among miR-155-5p,miR-194-5p,lncRNAs XIST and MALAT-1,as well as PD-L1 mRNA,a series of transfections of the Huh-7 cell line was carried out.RESULTS Bioinformatics software predicted that miR-155-5p and miR-194-5p can target PDL1,MALAT-1 and XIST.MALAT-1 and XIST were predicted to target PD-L1 mRNA.PD-L1 and XIST were significantly upregulated in 23 HCC biopsies compared to healthy controls;however,MALAT-1 was barely detected.MiR-194 induced expression elevated the expression of PD-L1,XIST and MALAT-1.However,overexpression of miR-155-5p induced the upregulation of PD-L1 and XIST,while it had a negative impact on MALAT-1 expression.Knockdown of XIST did have an impact on PD-L1 expression;however,following knockdown of the negative regulator of X-inactive specific transcript(TSIX),PD-L1 expression was elevated,and abolished MALAT-1 activity.Upon co-transfection of miR-194-5p with siMALAT-1,PD-L1 expression was elevated.Co-transfection of miR-194-5p with siXIST did not have an impact on PD-L1 expression.Upon co-transfection of miR-194 with siTSIX,PD-L1 expression was upregulated.Interestingly,the same PD-L1 expression pattern was observed following miR-155-5p cotransfections.Oleuropein treatment of Huh-7 cells reduced the expression profile of PD-L1,XIST,and miR-155-5p,upregulated the expression of miR-194-5p and had no significant impact on the MALAT-1 expression profile.CONCLUSION This study reported a novel finding revealing that opposing acting miRNAs in HCC,have the same impact on PD-1/PD-L1 immune checkpoint by sharing a common signaling pathway.

Epigenetic regulation of insulin-like growth factor axis in hepatocellular carcinoma

The insulin-like growth factor(IGF) signaling path-way is an important pathway in the process of hepa-tocarcinogenesis,and the IGF network is clearly dysregulated in many cancers and developmental abnormalities.In hepatocellular carcinoma(HCC),only a minority of patients are eligible for curative treatments,such as tumor resection or liver transplant.Unfortunately,there is a high recurrence of HCC after surgical tumor removal.Recent research efforts have focused on targeting IGF axis members in an attempt to find therapeutic options for many health problems.In this review,we shed lights on the regulation of members of the IGF axis,mainly by micro RNAs in HCC.Micro RNAs in HCC attempt to halt the aberrant expression of the IGF network,and a single micro RNA can have multiple downstream targets in one or more signaling pathways.Targeting micro RNAs is a relatively new approach for identifying an efficient radical cure for HCC.

Interplay between micro RNA-17-5p, insulin-like growth factor-Ⅱ through binding protein-3 in hepatocellular carcinoma

AIM: To investigate the effect of microR NA on insulinlike growth factor binding protein-3(IGFBP-3) and hence on insulin-like growth factor-Ⅱ(IGF-Ⅱ) bioavailability in hepatocellular carcinoma(HCC).METHODS: Bioinformatic analysis was performed using microrna.org, DIANA lab and Segal lab softwares. Total RNA was extracted from 23 HCC and 10 healthy liver tissues using mir Vana mi RNA Isolation Kit. microR NA-17-5p(miR-17-5p) expression was mimicked and antagonized in Hu H-7 cell lines using Hi Per Fect Transfection Reagent, then total RNA was extracted using Biozol reagent then reverse transcribed into cD NA followed by quantification of mi R-17-5p and IGFBP-3 expression using Taq Man real-time quantitative PCR. Luciferase reporter assay was performed to validate the binding of miR-17-5p to the 3'UTR of IGFBP-3. Free IGF-Ⅱ protein was measured in transfected Hu H-7 cells using IGF-Ⅱ ELISA kit. RESULTS: Bioinformatic analysis revealed IGFBP-3 as a potential target for miR-17-5p. Screening of miR-17-5p and IGFBP-3 revealed a moderate negative correlation in HCC patients, where mi R-17-5p was extensively underexpressed in HCC tissues(P = 0.0012), while IGFBP-3 showed significant upregulation in the same set of patients(P = 0.0041) compared to healthy donors. Forcing mi R-17-5p expression in Hu H-7 cell lines showed a significant downregulation of IGFBP-3 mR NA expression(P = 0.0267) and a significant increase in free IGF-Ⅱ protein(P = 0.0339) compared to mock untransfected cells using unpaired t-test. Luciferase assay validated IGFBP-3 as a direct target of mi R-17-5p; luciferase activity was inhibited by 27.5% in cells co-transfected with miR-17-5p mimics and the construct harboring the wild-type binding region 2 of IGFBP-3 compared to cells transfected with this construct alone(P = 0.0474).CONCLUSION: These data suggest that regulating IGF-Ⅱ bioavailability and hence HCC progression can be achieved through targeting IGFBP-3 via manipulating the expression of miR NAs.

Why natural killer cells in triple negative breast cancer?

The triple-negative subtype of breast cancer(TNBC)has the bleakest prognosis,owing to its lack of either hormone receptor as well as human epidermal growth factor receptor 2.Henceforth,immunotherapy has emerged as the front-runner for TNBC treatment,which avoids potentially damaging chemotherapeutics.However,despite its documented association with aggressive side effects and developed resistance,immune checkpoint blockade continues to dominate the TNBC immunotherapy scene.These immune checkpoint blockade drawbacks necessitate the exploration of other immunotherapeutic methods that would expand options for TNBC patients.One such method is the exploitation and recruitment of natural killer cells,which by harnessing the innate rather than adaptive immune system could potentially circumvent the downsides of immune checkpoint blockade.In this review,the authors will elucidate the advantageousness of natural killer cell-based immuno-oncology in TNBC as well as demonstrate the need to more extensively research such therapies in the future.

Anti-inflammatory and analgesic properties of Moroccan medicinal plants:Phytochemistry,in vitro and in vivo investigations,mechanism insights,clinical evidences and perspectives

Moroccan medicinal plants exhibit several pharmacological properties such as antimicrobial,anticancer,antidiabetic,analgesic,and anti-inflammatory effects,which are related to the presence of numerous bioactive compounds,including phenolic acids,flavonoids,and terpenoids.In the present review,we systematically evaluate previously published reports on the anti-inflammatory and analgesic effects of Moroccan medicinal plants.The in vitro investigations revealed that Moroccan medicinal plants inhibit several enzymes related to inflammatory processes,whereas in vivo studies noted significant anti-inflammatory and analgesic effects as demonstrated using different experimental models.Various bioactive compounds exhibiting in vitro and in vivo anti-inflammatory and analgesic effects,with diverse mechanisms of action,have been identified.Some plants and their bioactive compounds reveal specific secondary metabolites that possess important anti-inflammatory effects in clinical investigations.Our review proposes the potential applications of Moroccan medicinal plants as sources of anti-inflammatory and analgesic agents.

Design of multi-antenna relaying for OFDM in impulsive noise environment

A low-complexity multi-antenna relaying scheme is proposed for Orthogonal Frequency Division Multiplexing (OFDM) in the presence of Class-A Impulsive Noise (IN). One way and two way relaying are considered. The signal is transmitted and received by two terminal nodes, each with a single antenna in two time phases. In the proposed design, the processing at the relay consists of Maximal-Ratio Combining (MRC) or Power-based Selection Combining (PSC) for receive combining, Amplify and Forward (AF) for power scaling, and Space Time Block Coding (STBC) for transmit diversity. Channel State Information (CSI), Discrete Fourier Transform (DFT), and Inverse Discrete Fourier Transform (IDFT) are not needed. The Selective Mapping (SLM) technique is used at the transmitter to reduce the Peak-to-Average Power Ratio (PAPR) of the OFDM signal. Then, at the receiver, the clipping technique is used to reduce the impulses that result from the impulsive noise. The proposed system reduces the complexity of the conventional system, which uses multi-relay with a single antenna. Simulation results show that the Bit Error Rate (BER) of the proposed scheme outperforms that of the conventional scheme due to the diversity inherent in the proposed scheme.

Uncoupling tumor necrosis factor-αand interleukin-10 at tumor immune microenvironment of breast cancer through miR-17-5p/MALAT-1/H19 circuit

Triple Negative Breast Cancer(TNBC)immunotherapy has recently shown promising approach.However,some TNBC patients presented with resistance.One of the reasons was attributed to the excessive release of cytokines at the tumor microenvironment(TME)such as Tumor necrosis factor alpha(TNF-α)and Interleukin-10(IL-10).Fine regulation of these cytokines’levels via non-coding RNAs(ncRNAs)might alleviate the immune quiescent nature of TME at TNBC tumors.However,the extrapolation of ncRNAs as therapeutic tools is highly challenging.Therefore,disentanglement the nature for the isolation of natural compounds that could modulate the ncRNAs and their respective targets is an applicable translational therapeutic approach.Hence,this study aimed to targeting the chief immune suppressive cytokines at the TME(TNF-αand IL-10)via ncRNAs and to examine the effects of Rosemary aerial parts extract on the expression levels of these ncRNAs in TNBC.Results revealed miR-17-5p as a dual regulator of TNF-αand IL-10.Moreover,an intricate interaction has been shown between miR-17-5p and the oncogenic lncRNAs:MALAT1 and H19.Knocking down of MALAT1 and/or H19 caused an induction in miR-17-5p and reduction in TNF-αand IL-10 expression levels.miR-17-5p was found to be down-regulated,while TNF-α,IL-10,MALAT1 and H19 were up-regulated in BC patients.Forced expression of miR-17-5p in MDA-MB-231 cells reduced TNF-α,IL-10,MALAT1 and H19 expression levels,as well as several BC hallmarks.In a translational approach,ursolic acid(UA)isolated from rosemary induced the expression of miR-17-5p,MALAT1 and decreased H19 expression levels.In conclusion,this study suggests miR-17-5p as a tumor suppressor and an immune-activator miRNA in BC through tuning up the immunological targets TNF-α,IL-10 at the TME and the oncological mediators MALAT1 and H19 lncRNAs.

Incremental Diversity: A Framework for Rate-Adaptation/Energy-Conservation Enhancement in MIMO Systems

In recent years, MIMO technology has emerged as one of the technical breakthroughs in the field of wireless communications. Two famous MIMO techniques have become investigated thoroughly throughout the literature;Spatial Multiplexing, and Space Time Block Coding. On one hand, Spatial Multiplexing offers high data rates. On the other hand, Space Time Block Coding presents transmission fidelity. This imposes a fundamental tradeoff between capacity and reliability. Adaptive MIMO Switching schemes have been proposed to select the MIMO scheme that best fits the channel conditions. However, the switching schemes presented in the literature directly switch between the MIMO endpoints. In this paper, an adaptive MIMO system that incrementally switches from multiplexing towards diversity is proposed. The proposed scheme is referred to as incremental diversity and can be set to operate in two different modes;Rate-Adaptive, and Energy-Conservative Incremental Diversity. Results indicate that the proposed incremental diversity framework achieves transmission reliability offered by MIMO diversity, while maintaining a gradual increase in spectral efficiency (in the Rate-Adaptive mode) or a reduction in required number of received symbols (in the Energy-Conservative mode) with increase in the SNR.

Corporate Internet Disclosure in the Arabian Gulf： An Empirical Examination of Determinants and Attributes

This paper investigates and reports on the extent and nature of corporate internet disclosure and the determinants of internet financial disclosure （IFD） by companies listed in three Gulf Corporation Council （GCC） countries. This paper uses data from 207 listed companies in Muscat Securities Market （MSM）, Dubai Financial Market （DFM）, and Qatar Exchange （QE）. Binary logistic regression analysis is used to examine the determinants of IFD. Kruskal-Wallis test is used to examine the differences in disclosure characteristics among the three countries. The results of this study reveal that firm size is the major factor influencing intemet financial reporting in the GCC. The results reveal that the three countries differ significantly in all the disclosure attributes with the exception of the existence of email link. This paper extends the stream of research that confirms the widespread use of internet in disclosing financial information. The results are consistent with previous literature that corporate size is a major determinant of internet financial reporting. This paper provides insights into corporate internet disclosure in the GCC that will benefit all stakeholders with an interest in corporate reporting in this important region of the world.

Study of the degradation behavior and the biocompatibility of Mg-0.8Ca alloy for orthopedic implant applications

Mg-Ca alloys have recently attracted great attention towards the research in the field of orthopedic biodegradable implants.This study presents an in vitro degradation assessment of Mg-0.8Ca(0.8 wt.%of Ca)alloy in Hank’s balanced salt solution(HBSS).Immersion,hydrogen evolution and electrochemical behavior was studied as well as the cytotoxicity of the degradation products.Morphology and phase composition of the corrosion products were studied using SEM,EDX and XRD techniques.Degradation in HBSS resulted in the formation of the needle-shaped carbonated hydroxyapatite which was similar to the biological apatite in the human bone.Degradation kinetics showed that Mg-0.8Ca alloy had approximately 3-fold faster degradation rate than the pure Mg(1.08±0.38 mm/year for Mg-0.8Ca and 0.35±0.17 mm/year for pure Mg),as observed in two independent experiments.Both,pure Mg and Mg-0.8Ca alloy were biocompatible,generating no cytotoxic degradation products against human-derived HEK 293 cells.Thus,the Mg-0.8Ca alloy was found to be a promising biodegradable implant in terms of bioactivity and compatibility with human cell lines.Depending on the application of the implant and the estimated healing time of the bone,the desired degradation rate of an implant can be controlled by the Mg-Ca composition of such alloys.

Effect of Microalloying Additions on the Microstructure and Mechanical Properties of Low Carbon Steel

Low carbon steels are characterized by good weldability,formability and fracture toughness properties.However,the low strength levels of these steel grades limit their wide applications.On the other hand,increasing the strength by increasing the carbon content and alloying elements deteriorates the other properties.In this study,the microalloying technique was used to examine the possibility of attaining low carbon steels with good combination of strength,ductility and impact properties.A low carbon steel microalloyed with single addition of vanadium and another one microalloyed with combined addition of vanadium and titanium were used in this investigation and their properties were compared with non-microalloyed low carbon steel having the same base composition.Furthermore,other two nonmicroalloyed and V-microalloyed steels with higher carbon,silicon and manganese contents were also investigated to reveal the effect of base composition.Tensile,hardness,room and zero temperature Charpy V-notch impact tests were conducted to evaluate the variations in the mechanical properties of low carbon hot forged steel containing vanadium and combinations of vanadium and titanium.In addition,the microstructures of the different investigated steels were observed using both optical microscope and scanning electron microscope.Furthermore,the hardness of the ferrite phase was also determined using micro-hardness technique.The results showed improvement of the mechanical properties of the investigated steels by both single V-and combined V + Ti-microadditions.Tensile,hardness and impact tests results indicated that good combinations of strength,ductility and impact properties can be achieved by V-microalloying addition.Steel with combination of V and Ti microaddition has much higher hardness,yield strength,ultimate tensile strength and impact energy at both room and zero temperatures compared with non-microalloyed and single Vmicroalloyed steels.Higher C,Si and Mn contents result in increasing the strength accompanied with decreasing the impact energy.Scanning electron microscopy and optical microscopy studies revealed grain refinement effect of both Vand V+Ti-microadditions.The micro-hardness measurements of the ferrite phase confirmed the precipitation strengthening effect of microalloying elements.

miR-29a Promotes Lipid Droplet and Triglyceride Formation in HCV Infection by Inducing Expression of SREBP-1c and CAV1

Aims:To examine the regulation of SREBP-1c and CAV1 by microRNA-29a (miR-29a) in cells infected with hepatitis C virus (HCV) in an attempt to control HCV-induced nonalcoholic fatty liver disease.Methods:In order to examine the manipulation of SREBP-1c and CAV1 by miR-29a,oleic acid (OA)-treated JFH-I-infected Huh-7 cells were used.OA was added 24 h post-transfection and gene expression was investigated by qRT-PCR at 48 h post treatment.The functional impact of the observed alteration in SREBP-1c and CAV1 expression was analyzed by examining lipid droplet (LD) and triglyceride (TG) content at 72 h post-OA treatment using light microscopy and spectrophotometry,respectively.Viral load was quantified by qRT-PCR at 72 h post-transfection.Results:OA treatment induced the expression of miR-29a and SREBP-1c,as compared to untreated cells.Forced miR-29a expression led to a significant up-regulation of SREBP-1c as well as CAV1 compared to mock untransfected cells.Ectopic expression of miR-29a resulted in a marked increase in LDs and their respective TGs,while miR-29a antagomirs decreased both the LD and TG content compared to mock untransfected cells.Moreover,forcing the expression of miR-29a in JFH-1 HCV-infected Huh-7 cells resulted in 53% reduction in viral titers compared to mock untransfected Huh-7 cells.Conclusion:Inducing miR-29a expression significantly induces SREBP-1c and CAV1 expression,thereby increasing LDs as well as their respective TGs.Nonetheless,forcing the expression of miR-29a resulted in reduction of HCV RNA levels in Huh-7 cells.

Mu-based trajectory tracking control for a quad-rotor UAV

In this paper,the design and application of a robust mu-synthesis-based controller for quad-rotor trajectory tracking are presented.The proposed design approach guarantees robust performance over a weakly nonlinear range of operation of the quad-rotor,which is a practical range that suits various applications.The controller considers different structured and unstructured uncertainties,such as unmodeled dynamics and perturbation in the parameters.The controller also provides robustness against external disturbances such as wind gusts and wind turbulence.The proposed controller is fixed and linear;therefore,it has a very low computational cost.Moreover,the controller meets all design specifications without tuning.To validate this control strategy,the proposed approach is compared to a linear quadratic regulator(LQR)controller using a high-fidelity quad-rotor simulation environment.In addition,the experimental results presented show the validity of the proposed control strategy.

An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and airway inflammation

Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases.A natural fragment of serum albumin,named EPI-X4,has previously been identified as endogenous peptide antagonist and inverse agonist of CXCR4 and is a promising compound for the development of improved analogues for the therapy of CXCR4-associated diseases.To generate optimized EPI-X4 derivatives we here performed molecular docking analysis to identify key interaction motifs of EPI-X4/CXCR4.Subsequent rational drug design allowed to increase the anti-CXCR4 activity of EPI-X4.The EPI-X4 derivative JM#21 bound CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved small molecule CXCR4 antagonist AMD3100.EPI-X4 JM#21 did not exert toxic effects in zebrafish embryos and suppressed allergen-induced infiltration of eosinophils and other immune cells into the airways of animals in an asthma mouse model.Moreover,topical administration of the optimized EPI-X4 derivative efficiently prevented inflammation of the skin in a mouse model of atopic dermatitis.Thus,rationally designed EPIX4 JM#21 is a novel potent antagonist of CXCR4 and the first CXCR4 inhibitor with therapeutic efficacy in atopic dermatitis.Further clinical development of this new class of CXCR4 antagonists for the therapy of atopic dermatitis,asthma and other CXCR4-associated diseases is highly warranted.

miR-34a: Multiple Opposing Targets and One Destiny in Hepatocellular Carcinoma

Background and Aims:The role of miR-34a in hepatocellular carcinoma (HCC) is controversial and several unresolved issues remain,including its expression pattern and relevance to tumor etiology,tumor stage and prognosis,and finally,its impact on apoptosis.Methods:miR-34a expression was assessed in hepatitis C virus (HCV)-induced non-metastatic HCC tissues by RT-Q-PCR.Huh-7 cells were transfected with miR-34a mimics and the impact of miR-34a was examined on 84 pro-apoptotic/anti-apoptotic genes using PCR array;its net effect was tested on cell viability via MTTassay.Results:miR-34a expression was up-regulated in HCC tissues.Moreover,miR-34a induced a large set of pro-apoptotic/anti-apoptotic genes,with a net result of triggering apoptosis and repressing cell viability.Conclusions:HCC-related differential expression of miR-34a could be etiology-based or stage-specific,and low expression of miR-34a may predict poor prognosis.This study's findings also emphasize the role of miR-34a in apoptosis.

Islands of stability and quasi-magic numbers for super- and ultra-heavy nuclei

In the framework of Strutinsky＇s approach, we calculated the shell and the residual pairing correction energies for 5569 even-even nuclei in the range 72 ≤ Z ≤ 282 and 96≤N ≤ 540. Quasi-magic numbers and deformed islands of stability that reside in a range defined by Green＇s formula and the two-neutrons drip line are introduced. We present 36 quasi-magic proton and 53 quasi-magic neutron magic numbers that contribute to the formation of 133 deformed islands of stability along the N-Z space. The quasi-magic proton and neutron magic numbers volatile as the mass number increases and other magic numbers take over. Consequently, the deformed islands of stability fail to exhibit a pattern along the search space covered.