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Reference genome assemblies have been created from multiple lineages within the Canidae family; however, despite its phylogenetic relevance as a basal genus within the clade, there is currently no reference genome for the gray fox (Urocyon cinereoargenteus). Here, we present a chromosome-level assembly for the gray fox (U. cinereoargenteus), which represents the most contiguous, non-domestic canid reference genome available to date, with 90% of the genome contained in just 34 scaffolds and a contig N50 and scaffold N50 of 59.4 and 72.9 Megabases, respectively. Repeat analyses identified an increased number of simple repeats relative to other canids. Based on mitochondrial DNA, our Vermont sample clusters with other gray fox samples from the northeastern United States and contains slightly lower levels of heterozygosity than gray foxes on the west coast of California. This new assembly lays the groundwork for future studies to describe past and present population dynamics, including the delineation of evolutionarily significant units of management relevance. Importantly, the phylogenetic position of Urocyon allows us to verify the loss of PRDM9 functionality in the basal canid lineage, confirming that pseudogenization occurred at least 10 million years ago.

Abstract Measurement of cellular resting membrane potential (RMP) is important in understanding ion channels and their role in regulation of cell function across a wide range of cell types. However, methods available for the measurement of RMP (including patch clamp, microelectrodes, and potential-sensitive fluorophores) are expensive, slow, open to operator bias, and often result in cell destruction. We present non-contact, label-free membrane potential estimation which uses dielectrophoresis to determine the cytoplasm conductivity slope as a function of medium conductivity. By comparing this to patch clamp data available in the literature, we have demonstratet the accuracy of this approach using seven different cell types, including primary suspension cells (red blood cells, platelets), cultured suspension cells (THP-1), primary adherent cells (chondrocytes, human umbilical mesenchymal stem cells), and adherent (HeLa) and suspension (Jurkat) cancer cell lines. Analysis of the effect of ion channel inhibitors suggests the effects of pharmaceutical agents (TEA on HeLa; DMSO and neuraminidase on red blood cells) can also be measured. Comparison with published values of membrane potential suggest that the differences between our estimates and values recorded by patch clamp are accurate to within published margins of error. The method is low-cost, non-destructive, operator-independent and label-free, and has previously been shown to allow cells to be recovered after measurement.

In mathematics teaching and learning, mathematics tasks embedded in realistic contexts are crucial for developing mathematical concepts, procedures, and the application of mathematical knowledge. Despite this, mathematics teachers often encounter challenges in designing and implementing such realistic mathematics tasks. Therefore, this study aims to construct a learning trajectory to enhance preservice mathematics teachers' abilities to create and implement Realistic Mathematics Tasks (RMTs). Employing a design research methodology, the study comprises three phases: preliminary design, teaching experiment, and retrospective analysis. The data presented in this article are from the first cycle, encompassing all three phases. The research involved four fourth-year preservice mathematics teachers from Sanata Dharma University in Yogyakarta, Indonesia, participating in a preliminary experiment conducted over three months outside their regular coursework. Data were collected through pre-course written tests, observations, interviews, journal reflections, and analyses of the preservice teachers' work. The findings indicate that the learning trajectory effectively raised awareness among preservice teachers about key characteristics of realistic mathematics tasks. This heightened awareness was evident in their reflections and work. Additionally, observations of their teaching practices revealed that preservice teachers valued student reasoning in solving RMTs. However, they faced difficulties in classroom management and guiding students to construct new knowledge actively through their experiences in solving RMTs.

Background: Following the World Health Organization statement ‘Health for all’, family medicine is a specialty that provides continuing, comprehensive healthcare to individuals and their families. Despite that, it is still not yet utilized to its full potential by the developing Middle-Eastern community. The aim of our study is to assess the perception and utilization of family medicine services among Abu Dhabi Island’s community. Methods: A cross-sectional study was conducted targeting Abu Dhabi Island’s community. A representative sample with 95% confidence level and 5% margin of error was calculated taking into consideration the latest report by the Abu Dhabi Statistics Center. A total of 395 adult participants were included in the study, who were asked to fill in an electronic-based validated questionnaire. SPSS software was then used for data analysis. Results: Majority of participants were UAE nationals (81%) and married (71.1%), with almost equal male (50.4%) to female ratio (49.6%). Participants had positive experiences in primary healthcare (PHC) overall, regardless of their gender, nationality and marital status. Positive experience percentages dropped with higher age and educational level (P-value

Background Obstructive sleep apnea (OSA) is a common comorbidity in patients with heart failure, although current evidence is equivocal regarding the potential benefits of treating OSA with positive airway pressure (PAP) therapy in patients with heart failure. This study assessed the impact of adherence to PAP therapy on health care resource utilization in patients with OSA and heart failure with reduced ejection fraction. Methods and Results Administrative insurance claims data linked with objective PAP therapy use data from patients with OSA and heart failure with reduced ejection fraction were used to determine associations between PAP adherence and a composite outcome of hospitalizations and emergency room visits. One-year PAP adherence was based on an adapted US Medicare definition. Propensity score methods were used to create groups with similar characteristics across PAP adherence levels. The study cohort included 3182 patients (69.9% male, mean age 59.7 years); 39% were considered adherent to PAP therapy (29% intermediate adherent, 31% nonadherent). One year after PAP initiation, adherent patients had fewer composite visits than matched nonadherent patients, driven by a 24% reduction in emergency room visits for adherent patients. Composite visit costs were lower in adherent versus nonadherent patients ($3500 versus $5879, P=0.031), although total health care costs were not statistically different ($13 028 versus $14 729, P=0.889). Conclusions PAP therapy adherence in patients with OSA with heart failure with reduced ejection fraction was associated with a reduction in health care resource utilization. This suggests that greater emphasis should be placed on diagnosing and effectively treating OSA with PAP in patients with heart failure with reduced ejection fraction.

This paper provides a comprehensive overview of microfluidic device (MFD) manufacturing processes. The review starts with an introduction elucidating the significance and advantageous of MFDs. Subsequently, a brief description about the materials that employed in MFD fabrication is presented. The manufacturing process used to create MFDs is then thoroughly examined, with a focus on the application of laser technology.

The stress-strength S-S method employs a variety of estimation techniques, including maximum likelihood, shrinkage and least square, to determine and estimate the reliability of a particular system R = P (Y1 < X < Y2) while the system contains a single component with strength X subject to two stresses, Y1 and Y2. With the consumption of Monte Carlo simulation and the statistical measurement Mean Squared Error (MSE), the various estimation methods have been evaluated according to the Restricted Generalized Weibull Distribution (RGWD), the stresses Y1 and Y2 and the strength X constitute independent, non-identical random variables in our S-S model.

Hareer Fatima,1 Hussain Sohail Rangwala,1 Muhammad Saqlain Mustafa,1 Muhammad Ashir Shafique,1 Syed Raza Abbas,2 Azra Rizwan,3 Tagwa Kalool Fadlalla Ahmed,4 Ainan Arshad3 1Department of Medicine, Jinnah Sindh Medical University, Karachi, Pakistan; 2Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan; 3Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan; 4Department of Medicine, Ahfad University for Women, Omdurman, Al-Khartum, SudanCorrespondence: Tagwa Kalool Fadlalla Ahmed, Department of Medicine, Ahfad University for Women, PO Box 167, Omdurman, Al-Khartum, Sudan, Tel +923412127759, Email tagwa.kalool@gmail.comIntroduction: Diabetes Mellitus (DM) is a significant global health concern, with Type 2 DM (T2DM) being highly prevalent. Glucagon-Like Peptide 1 receptor agonists (GLP-1RA), such as Danuglipron, offer potential benefits in T2DM management. This meta-analysis examines the safety and efficacy of Danuglipron, focusing on adverse outcomes and glycemic parameters.Methods: A systematic search was conducted in PubMed, Scopus, and Cochrane Library for RCTs involving Danuglipron till August 2023, following PRISMA guidelines. The Cochrane risk-of-bias tool was used for quality assessment. Adverse outcomes (diarrhea, nausea, vomiting, headache, decreased appetite, dyspepsia, dizziness) and glycemic parameters like changes in HbA1C, fasting plasma glucose (FPG), and body weight were analyzed.Results: Four RCTs published from 2021 to 2023 were included. Both doses of Danuglipron were associated with diarrhea (RR=2.66, 90% CI: 1.32 to 5.35, p=0.02), nausea (RR=5.5, 90% CI: 3.4 to 8.88, p< 0.00001), and vomiting (RR=5.98, 90% CI: 2.93 to 12.23, p=0.0001). The 120mg dose showed decreased appetite (RR=3.46, 90% CI: 1.57 to 7.62, p=0.01), dyspepsia (RR=4.04, 90% CI: 1.93 to 8.43, p=0.002), and dizziness (RR=5.08, 90% CI: 1.45 to 17.82, p=0.03). Reductions in HbA1C (SMD − 1.09, 90% CI − 1.39 to − 0.8, p < 0.00001), FPG (SMD − 1.10, 90% CI − 1.46 to − 0.75, p < 0.00001), and body weight (SMD − 1.08, 90% CI − 1.42 to − 0.74, p < 0.00001) were observed for both doses.Conclusion: Danuglipron demonstrates potential for glycemic control and weight reduction in T2DM. Adverse outcomes include diarrhea, nausea, vomiting, and decreased appetite, with dose-related effects. Clinicians must weigh benefits against side effects when considering Danuglipron for T2DM management.Keywords: diabetes mellitus, glucagon-like peptide 1 receptor agonists, Danuglipron, adverse outcomes, glycemic parameters

Abstract Introduction Hepatitis E virus (HEV) is the most common cause of acute hepatitis. While symptoms are generally mild and resolve within weeks, some populations (e.g., pregnant women, immunocompromised adults) are at high-risk of severe HEV-related morbidity and mortality. There has not been a recent comprehensive review of contemporary HEV outbreaks, which limits the validity of current disease burden estimates. Therefore, we aimed to characterize global HEV outbreaks and describe data gaps to inform HEV outbreak prevention and response initiatives. Methods We performed a systematic review of peer-reviewed (PubMed, Embase) and gray literature (ProMED) to identify reports of outbreaks published between 2011 and 2022. We included (1) reports with ≥ 5 cases of HEV, and/or (2) reports with 1.5 times the baseline incidence of HEV in a specific population, and (3) all reports with suspected (e.g., clinical case definition) or confirmed (e.g., ELISA or PCR test) cases if they met criterium 1 and/or 2. We describe key outbreak epidemiological, prevention and response characteristics and major data gaps. Results We identified 907 records from PubMed, 468 from Embase, and 247 from ProMED. We screened 1,362 potentially relevant records after deduplication. Seventy-one reports were synthesized, representing 44 HEV outbreaks in 19 countries. The populations at risk, case fatalities, and outbreak durations were not reported in 66% of outbreak reports. No reports described using HEV vaccines. Reported intervention efforts included improving sanitation and hygiene, contact tracing/case surveillance, chlorinating boreholes, and advising residents to boil water. Commonly missing data elements included specific case definitions used, testing strategy and methods, seroprevalence, impacts of interventions, and outbreak response costs. Approximately 20% of HEV outbreaks we found were not published in the peer-reviewed literature. Conclusion HEV represents a significant public health problem. Unfortunately, extensive data shortages and a lack of standardized reporting make it difficult to estimate the HEV disease burden accurately and to implement effective prevention and response activities. Our study has identified major gaps to guide future studies and outbreak reporting systems. Our results support the development of standardized reporting procedures/platforms for HEV outbreaks to ensure accurate and timely data distribution, including active and passive coordinated surveillance systems, particularly among high-risk populations.

Periodontal diseases (PD) are worldwide diseases of humans either in childhood or adults. The present study aimed to find the correlation between some demographic and saliva immunological factors including the determination of saliva TLR-2, IL6, CRP, and α- amylase in patients with periodontal diseases. For this purpose, 60 patients out of which 33were males and 27 were females participated in this study from different Dental treatment Centers (Amirya Specialized Dental Center and Almaamon Specialized Dental Center ) in Baghdad/ Iraq, for the period starting from November / 2021 to February / 2022. Both age ranges for patients and control are (13-70) years, and patients’ mean ages are 34.29±15.01. Additionally, the control specimens were collected randomly from 40 apparently healthy people. The results of some demographic parameters revealed that there were no significant differences between males 55.0% and females 45.0% in PD. As well as, periodontal disease is not directly associated with rising smoking among patients or non-smoking individuals with PD. Acidic oral pH is not significantly found in most PD patients 47.1% and control subjects 66.7%, simultaneously, smoking may not be associated with acidic oral saliva directly. Other tests in concern with PD patients are considered to be very important in many aspects, firstly interleukin (IL6) recorded high non-significant mean occurrence results in both patients’ 50161± 63869 ng/l and control 52087 ± 62756 ng/l groups. Secondly, C-reactive protein (CRP) as IL6, recorded a non-significant increase in the saliva of PD patients at 0.537 ± 0.607 mg/l and control at 0.607 ± 0.266 mg/l. Toll-like receptor-2 (TLR-2) is the third immune parameter measured in saliva which recorded significant differences between PD patients 7.384 ± 4.031 ng/ml and control 5.313 ± 3.106 ng/ml, simultaneously. Then the fourth saliva parameter is α-amylase the results recorded a significant difference between PD patients 2.444 ± 1.870 ng/ml and control 1.041 ± 1.044 ng/ml. Also, the results showed that there was no correlation between measured demographic and immunological parameters.

Abstract Electrical aspects of cell function manifest in many ways. The most widely studied is the cell membrane potential, V m , but others include the conductance and capacitance of the membrane, the conductance of the enclosed cytoplasm, as well as the charge at the cell surface (an electrical double layer) producing an extracellular electrical potential, the ζ-potential. Empirical relationships have been identified between many of these, but not the mechanisms that link them all. Here we examine relationships between V m and the electrical conductivities of both the cytoplasm and extracellular media, using data from a suspensions of red blood cells. We have identified linear relationships between extracellular medium conductivity, cytoplasm conductivity and V m . This is in contrast to the standard model of a resting membrane potential which describes a logarithmic relationship between V m and the concentration of permeable ions in the extracellular medium. The model here suggests that V m is partially electrostatic in origin, arising from a charge imbalance at an inner electrical double-layer, acting across the membrane and double-layer capacitances to produce a voltage. This model describes an origin for coupling between V m and ζ, by which cells can alter their electrostatic relationship with their environment, with implications for modulation of membrane ion transport, adhesion of proteins such as antibodies and wider cell–cell interactions.

Background Obstructive sleep apnea (OSA) is common in heart failure with preserved ejection fraction (HFpEF). However, current evidence is equivocal regarding the potential benefits of treating OSA with positive airway pressure (PAP) therapy in HFpEF. This study assessed the association between adherence to PAP therapy and health care resource use in patients with OSA and HFpEF. Methods and Results Administrative insurance claims data linked with objective PAP therapy usage data from patients with OSA and HFpEF were used to determine associations between PAP adherence and a composite outcome including hospitalizations and emergency room visits. One‐year PAP adherence was based on an adapted US Medicare definition. Propensity score methods were used to create groups with similar characteristics across PAP adherence levels. The study cohort included 4237 patients (54.0% female, mean age 64.1 years); 40% were considered adherent to PAP therapy (30% intermediate adherent, 30% nonadherent). In the matched cohort, PAP‐adherent patients had fewer health care resource use visits than nonadherent patients, a 57% decrease in hospitalizations, and a 36% decrease in emergency room visits versus the year before PAP initiation. Total health care costs were lower in adherent patients than nonadherent patients ($12 732 versus $15 610, P

An ultrasonic treatment was applied to the vacuum gas oil at intervals of 5 to 30 minutes, at 70°C. In this work, the improvement of the important properties of Iraqi vacuum gas oil, such as carbon residue, was studied with several parameter conditions that affect vacuum efficiency, such as sonication time (5, 10, 15, 20, 25, and 30) min, power amplitude (10–50%). After ultrasonic treatment, the carbon residue of vacuum gas oil was evaluated using a Conradson carbon residue meter (ASTM D189). The experiment revealed that the oil's carbon residue had decreased by 16%. As a consequence of the experiment It was discovered that ultrasonic treatment might reduce the carbon residual and density of oil samples being studied. It also noticed that the carbon residue reduced with increased ultrasonic treatment duration and power. The mechanical mixing and cavitation brought about by ultrasonic processing led to a number of modifications in the gas oil molecules. The properties of a typical molecular structure were altered on a microscale.

Background Obstructive sleep apnea (OSA) is a common comorbidity in patients with heart failure, although current evidence is equivocal regarding the potential benefits of treating OSA with positive airway pressure (PAP) therapy in patients with heart failure. This study assessed the impact of adherence to PAP therapy on health care resource utilization in patients with OSA and heart failure with reduced ejection fraction. Methods and Results Administrative insurance claims data linked with objective PAP therapy use data from patients with OSA and heart failure with reduced ejection fraction were used to determine associations between PAP adherence and a composite outcome of hospitalizations and emergency room visits. One‐year PAP adherence was based on an adapted US Medicare definition. Propensity score methods were used to create groups with similar characteristics across PAP adherence levels. The study cohort included 3182 patients (69.9% male, mean age 59.7 years); 39% were considered adherent to PAP therapy (29% intermediate adherent, 31% nonadherent). One year after PAP initiation, adherent patients had fewer composite visits than matched nonadherent patients, driven by a 24% reduction in emergency room visits for adherent patients. Composite visit costs were lower in adherent versus nonadherent patients ($3500 versus $5879, P=0.031), although total health care costs were not statistically different ($13 028 versus $14 729, P=0.889). Conclusions PAP therapy adherence in patients with OSA with heart failure with reduced ejection fraction was associated with a reduction in health care resource utilization. This suggests that greater emphasis should be placed on diagnosing and effectively treating OSA with PAP in patients with heart failure with reduced ejection fraction.

BACKGROUND: Since the occurrence of coronavirus disease in 2019 (COVID-19), the global community has witnessed its exponential spread with devastating outcomes within the general population and specifically within hemodialysis patients. OBJECTIVES: Compare the state of immunity to SARS-CoV-2 among hemodialysis patients and staff. DESIGN: Cross-sectional study with a prospective follow-up period. SETTING: Hemodialysis centers in Madinah region. PATIENTS AND METHODS: We prospectively tested for SARS-CoV-2 antibodies in dialysis patients using dialysis centers staff as controls. The participants were tested on four occasions when feasible for the presence of anti-SARS-CoV-2 antibodies. We also analyzed factors that might be associated with seropositivity. MAIN OUTCOME MEASURES: SARS-CoV-2 positivity using immunoglobulin G (IgG) levels SAMPLE SIZE: 830 participants, 677 patients and 153 dialysis centers staff as controls. RESULTS: Of the total participants, 325 (257 patients and 68 staff) were positive for SARS-CoV-2 IgG antibodies, for a prevalence of 38.0% and 44.4% among patients and staff, respectively (P=.1379). Participants with a history of COVID-19 or related symptoms were more likely to have positive IgG (P

Background: During the Novel Coronavirus disease (COVID-19) pandemic, medical residents were deployed to help with managing patients in a wide range of settings. Unlike other COVID-19-related topics, the psychological impact of the pandemic on medical residents has received little attention. Objective: This study aims to assess the impact of the COVID-19 pandemic on medical residents' well-being, depression, and stress levels. Methods: A cross-sectional study was conducted in the Emirate of Abu Dhabi. A total of 597 medical residents were identified and with the aim of a sample size of 300 participants; 242 responses were collected during the period between November 2020 to February 2021. Data were collected through an online survey utilizing Patient Health Questionnaire and Perceived Stress Scale. SPSS software was used for data analysis. Results: Most of the residents in our study were females (73.6%) and single (60.7%). Around 66.5% were depressed, 87.2% were under low-moderate stress, and 12.8% were under high stress. Majority (73.5%) of the single residents were depressed (P = 0.016). Being male has been found to lower the risk of developing depression (P = 0.042). The need to relocate for family protection increased the risk of developing depression (P = 0.022).Residents who were living with their friends/roommates were found to be under a high level of stress (P = 0.001). Surgical specialties' residents were found to be the most under high stress (P = 0.044). Conclusion: Female gender, single status, and changing housing were risk factors for depression. Conversely, living with friends/roommates and working in surgical specialties were contributing to high-stress levels.

Circadian rhythms are biological adaptations to the day-night cycle, whereby cells adapt to changes in the external environment or internal physiology according to the time of day. Whilst many cellular clock mechanisms involve gene expression feedback mechanisms, clocks operate even where gene expression is absent. For example, red blood cells (RBCs) do not have capacity for gene expression, and instead possess an electrophysiological oscillator where cytosolic potassium plays a key role in timekeeping. We examined murine blood under normal conditions as well as in two perturbed states, malaria infection and induced anemia, to assess changes in baseline cellular electrophysiology and its implications for the electrophysiological oscillator. Blood samples were analyzed at 4-h intervals over 2 days by dielectrophoresis, and microscopic determination of parasitemia. We found that cytoplasmic conductivity (indicating the concentration of free ions in the cytoplasm and related to the membrane potential) exhibited circadian rhythmic behavior in all three cases (control, malaria and anemia). Compared to control samples, cytoplasm conductivity was decreased in the anemia group, whilst malaria-infected samples were in antiphase to control. Furthermore, we identified rhythmic behavior in membrane capacitance of malaria infected cells that was not replicated in the other samples. Finally, we reveal the historically famous rhythmicity of malaria parasite replication is in phase with cytoplasm conductivity. Our findings suggest the electrophysiological oscillator can impact on malaria parasite replication and/or is vulnerable to perturbation by rhythmic parasite activities.

Abstract Even in nonexcitable cells, the membrane potential V m is fundamental to cell function, with roles from ion channel regulation, development, to cancer metastasis. V m arises from transmembrane ion concentration gradients; standard models assume homogeneous extracellular and intracellular ion concentrations, and that V m only exists across the cell membrane and has no significance beyond it. Using red blood cells, we show that this is incorrect, or at least incomplete; V m is detectable beyond the cell surface, and modulating V m produces quantifiable and consistent changes in extracellular potential. Evidence strongly suggests this is due to capacitive coupling between V m and the electrical double layer, rather than molecular transporters. We show that modulating V m changes the extracellular ion composition, mimicking the behaviour if voltage-gated ion channels in non-excitable channels. We also observed V m -synchronised circadian rhythms in extracellular potential, with significant implications for cell–cell interactions and cardiovascular disease.

Preparing young people to be active citizens has to be a core value of schools and higher education institutions. Thus, education for citizenship is important because every society needs people who can contribute effectively to the future health of their communities locally, nationally and globally. The field of citizenship education is one that encompasses an abundance of topics and issues (Cohen, 2010). In an attempt to bring some much needed clarity to this field, this paper presents the theoretical and conceptual background for a field study that intends to examine whether young people graduating from high school in Bahrain are equipped with the civic knowledge and understanding necessary to participate effectively as citizens. It also provides young people's conception of citizenship, their perception of their identity, and their concern about their community issues. Drawing on quantitative and qualitative data, this paper analyses the ways in which young Bahrainis perceive their identity and citizenship status. In this mixed methods approach, a questionnaire was administered to 460 final year secondary school students, followed by in-depth interviews with a stratified sample of 22 young people who had participated in the questionnaire survey. The findings provide valuable insights into the problems encountered by young Bahrainis as they engage in the process of learning about citizenship. This helps the educators, curriculum designers and policy makers to build upon what Bahraini young people already know and understand, and revise the content and types of activities that should be introduced if effective learning is to take place. [A bibliography is included.]

Biosurfactants are amphipathic molecules generated by a variety of microorganisms with different biological functions. In this study, lactic acid bacteria were screened for their emulsification properties. However, the Lactiplantibacillus plantarum strain LBpWAM was molecularly identified using 16S rRNA, and its ability to produce surface-active peptides was investigated. The biosurfactant derived from L. plantarum LBp_WAM was shown to have the potential to reduce water surface tension from 72 mN.m-1 to 32 mN/m within a critical micelle concentration (CMC) of 2.4 mg.ml-1. The emulsification index (E24) values were evaluated for sunflower oil (60 ± 3.0%), glycerol (53.9 ± 0.11 %), olive oil (49.0 ± 2.0 %), mineral oil (50.7 ± 0.60 %), hexane (36.03±0.05 %), and kerosene (31 ±0.05 %). The biosurfactant was purified using gel filtration chromatography (GFC), and the molecular weight was determined using the SDS-PAGE method, indicating an approximate molecular weight of 19 kDa. Thin-layer chromatography (TLC) and Fourier transform infrared spectroscopy (FT-IR) were used to determine the molecular structure of the obtained molecule, which was found to be composed of protein, lipid, and polysaccharides. The biosurfactant's antibacterial activity was also examined, as it showed inhibitory effects against different species of Gram-positive and Gram-negative bacteria.