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Herein, a link has been established between cold acclimation and Cd uptake in Spirogyra aequinoctialis. The water samples supplemented with cadmium (0.1, 0.5, and 1.0 mg/L) were used for plant growth at two different temperatures. Cold-acclimated plants accumulated high concentrations (0.40 ± 0.02 µg/dry biomass) of Cd as compared to non-acclimated plants (0.30 ± 0.08 µg/dry biomass). The negative effects of Cd on the biomass, carotenoids, and chlorophyll contents in non-acclimated plants were more pronounced in non-acclimated plants as compared to the cold-acclimated plants. High concentrations of free proline and total phenolics in cold-acclimated plants were observed as compared to the non-acclimated plants. About 13 different phenolic compounds were identified using high-pressure liquid chromatography. Cold acclimation as well as the presence of Cd in water highly increased the concentrations of polyphenolics, while synergistic increase was recorded with the combination of cold acclimation and Cd treatments. The highest increase in the concentration of polyphenolics was recorded for syringic acid. Significant positive correlations of total phenolics were noted with dry biomass (R 2 = 0.51) and Cd accumulation (R 2 = 0.59) in plant tissues. Free proline concentration also showed positive correlations with dry biomass, Cd accumulation, and chlorophyll contents (R 2 = 0.80).

This article is directed to analyze the transfer of mass and heat in a generalized Maxwell fluid flow unsteadily on a vertical flat plate oscillating in its respective plane and heated exponentially. It explains the transfer of mass and heat using a non-integer order derivative usually called a fractional derivative. It is a generalization of the classical derivatives of the famous Maxwell’s equation to fractional non-integer order derivatives used for one-dimensional flow of fluids. The definition given by Caputo–Fabrizio for the fractional derivative is used for solving the problem mathematically. The Laplace transform method is used for finding the exact analytical solution to a problem by applying it to a set of non-integer order differential equations that are dimensionless in nature. These equations contain concentration, temperature, and velocity equations with specific initial and boundary conditions. Solutions of the three equations are graphically represented to visualize the effects of various parameters, such as the radiation parameter (Nr), the thermal Grashof number, the fractional parameter (α), the mass Grashof number, Prandtl effective number, Schmidt number, Prandtl number, the chemical reaction (η2)({\eta }_{2}), mass, and the temperature during fluid flow.

Vaping electronic cigarettes (e-cigarettes) has become a popular alternative to smoking tobacco. When an e-cigarette is activated, a liquid is vaporized by heating, producing an aerosol that users inhale. While e-cigarettes are marketed as less harmful than traditional cigarettes, there are ongoing concerns about their long-term health effects, including potential lung damage. Therefore, it is essential to closely monitor and study the composition of e-liquids. E-liquids typically consist of propylene glycol, glycerin, flavorings and nicotine, though there have been reports of non-compliant nicotine concentrations and the presence of illegal additives. This study explored spectroscopic techniques to examine the conformity of nicotine labeling and detect the presence of the not-allowed additives: the caffeine, taurine, vitamin E and cannabidiol (CBD) in e-liquids. A total of 236 e-liquid samples were carefully selected for analysis. Chemometric analysis was applied to the collected data, which included mid-infrared (MIR) and near-infrared (NIR) spectra. Supervised modeling approaches such as partial least squares-discriminant analysis (PLS-DA) and soft independent modeling of class analogy (SIMCA) were employed to classify the samples, based on the presence of nicotine and the targeted additives. This study demonstrates the efficacy of MIR and NIR spectroscopic techniques in conjunction with chemometric methods (SIMCA and PLS-DA) for detecting specific molecules in e-liquids. MIR with autoscaling data preprocessing and PLS-DA achieved 100% classification rates for CBD and vitamin E, while NIR with the same approach achieved 100% for CBD and taurine. Overall, MIR combined with PLS-DA yielded the best classification across all targeted molecules, suggesting its preference as a singular technique.

Al Kury LT, Zeb A, Abidin ZU, et al. Drug Des Devel Ther. 2019;13:2715–2727. In the published article, there was an error in Figure 4B on page 2723. The image for Ethanol+celecoxib+mela (Piriform-PIR) was used mistakenly leading to a duplication with the Control (Piriform-PIR) images. A new image for Ethanol+celecoxib+mela (Piriform-PIR) was found from the original data and used as a replacement. The authors apologize for this error and state that this does not change the quality and scientific conclusions of the article. The correct Figure 4 is as follows. Figure 4 Effect of melatonin and celecoxib on neuronal cell death.Notes: (A) Regions of interest analyzed; (B) H&E staining showing the extent of surviving neurons in the cortex and hippocampus. Bar 50 μm, magnification 20×, n=5/group. Surviving neurons were marked by cytoplasmic swelling, scalloped neurons with intense cytoplasmic eosinophilia, and nuclear basophilia. These changes resulted from neuronal necrosis. Some cells had a shrunken appearance, along with pyknotic nuclei. Intensive neuropil vacuolation can be seen in the ethanol-only group. *Significant difference relative to control; #Significant difference relative to ethanol group; θSignificant difference relative to ethanol + melatonin. Data presented as means ± SEM. Data analyzed by one-way ANOVA followed by post hoc Bonferroni multiple comparison using GraphPad Prism 5 software. ***P

Canadian provinces routinely collect patient-level data for administrative purposes. These real-world data (RWD) can be used to generate real-world evidence (RWE) to inform clinical care and healthcare policy. The CanREValue Collaboration is developing a framework for the use of RWE in cancer drug funding decisions. A Data Working Group (WG) was established to identify data assets across Canada for generating RWE of oncology drugs. The mapping exercise was conducted using an iterative scan with informant surveys and teleconference. Data experts from ten provinces convened for a total of three teleconferences and two in-person meetings from March 2018 to September 2019. Following each meeting, surveys were developed and shared with the data experts which focused on identifying databases and data elements, as well as a feasibility assessment of conducting RWE studies using existing data elements and resources. Survey responses were compiled into an interim data report, which was used for public stakeholder consultation. The feedback from the public consultation was used to update the interim data report. We found that databases required to conduct real-world studies are often held by multiple different data custodians. Ninety-seven databases were identified across Canada. Provinces held on average 9 distinct databases (range: 8–11). An Essential RWD Table was compiled that contains data elements that are necessary, at a minimal, to conduct an RWE study. An Expanded RWD Table that contains a more comprehensive list of potentially relevant data elements was also compiled and the availabilities of these data elements were mapped. While most provinces have data on patient demographics (e.g., age, sex) and cancer-related variables (e.g., morphology, topography), the availability and linkability of data on cancer treatment, clinical characteristics (e.g., morphology and topography), and drug costs vary among provinces. Based on current resources, data availability, and access processes, data experts in most provinces noted that more than 12 months would be required to complete an RWE study. The CanREValue Collaboration’s Data WG identified key data holdings, access considerations, as well as gaps in oncology treatment-specific data. This data catalogue can be used to facilitate future oncology-specific RWE analyses across Canada.

Yu G, Ali Z, Sajjad Khan A, et al. Int J Nanomedicine. 2021;16:3255-3273. At the authors request, the Editor and Publisher of International Journal of Nanomedicine wish to retract the published article. Concerns were raised regarding the alleged duplication of images in Figures 9A, 9B and 9C with the same images from a previous article (ud Din et al, 2017 https://doi.org/10.1080/10717544.2016.1272651) by the same authors. Specifically, Figure 9A, Untreated Control, Pure Drug, HePC-NLCs, Normal Saline and all corresponding Tumor mass images appear to have been duplicated with the same images for Figure 6A, Control, Solution, DRTN, and Hydrogel images, respectively, from ud Din et al, 2017. Figure 9B, Pure Drug, Caspas-3; HePC-NLCs, Caspas-3 and Normal Saline, Caspas-3 appear to have been duplicated with the same images from Figure 6C, Solution, Ki-67 and Figure 6B, DRTN, Caspase-3 and Control, Caspase-3, respectively, from ud Din et al, 2017. Figure 9C, Untreated Control, PARP; Pure Drug, PARP; HePC-NLCs, PARP and Normal Saline, PARP appear to have been duplicated with the same images from Figure 6C, Hydrogel, CD31; Figure 6B, Solution, PARP; Figure 6C, Control, CD31 and Figure 6B, Control, PARP, respectively, from ud Din et al, 2017. The authors responded to our queries and agreed with the concerns that had been raised and requested for the retraction of the article. The Editor agreed with this decision and approved the authors retraction request. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Guo Yu, 1 Zakir Ali, 2 Anam Sajjad Khan, 2 Kalim Ullah, 3 Humzah Jamshaid, 2 Alam Zeb, 4 Muhammad Imran, 4 Sadia Sarwar, 4 Han-Gon Choi, 5 Fakhar ud Din 2 1Department of Head and Neck Breast, Xinxiang Central Hospital, Xinxiang City, Henan Province, 453000, People’s Republic of China; 2Nanomedicine Research Group, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan; 3Department of Zoology, Kohat University of Science & Technology, Kohat, Khyber Pakhtunkhwa, Pakistan; 4Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan; 5College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, South KoreaCorrespondence: Fakhar ud Din Tel +92 512-90644314Fax +92 512-90644144Email fudin@qau.edu.pkHan-Gon Choi Email hangon@hanyang.ac.krBackground: The purpose of this study was to investigate the suitability of nanostructured lipid carriers (NLCs) loaded with miltefosine (HePC) as an anticancer drug for the treatment of breast cancer.Methods: HePC-NLCs were prepared using a microemulsion technique and then evaluated for particle size, polydispersity index (PDI), incorporation efficiency, in vitro release of entrapped drug, and hemolytic potential. Furthermore, pharmacokinetic, biodistribution, and liver toxicity analyses were performed in Sprague–Dawley rats, and antitumor efficacy was evaluated in Michigan Cancer Foundation-7 (MCF-7) and squamous cell carcinoma-7 (SCC-7) cells in vitro and in tumour-bearing BALB/c mice in vivo. Advanced analyses including survival rate, immunohistopathology, and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assays were performed to evaluate apoptosis in vivo.Results: The average particle size of the HePC-NLCs was 143 ± 16 nm, with a narrow PDI (0.104 ± 0.002), and the incorporation efficiency was found to be 91 ± 7%. The NLCs released HePC in a sustained manner, and this release was significantly lower than that of free drug. The in vitro hemolytic assay demonstrated a significantly reduced hemolytic potential (∼ 9%) of the NLCs compared to that of the test formulations. The HePC-NLCs demonstrated enhanced pharmacokinetic behaviour over free drug, including extended blood circulation and an abridged clearance rate in rats. Furthermore, the HePC-NLCs exhibited higher cytotoxicity than the free drug in MCF-7 and SCC-7 cells. Moreover, the HePC-NLCs showed significantly enhanced (P < 0.005) antitumor activity compared to that of the control and free drug-treated mouse groups. Tumour cell apoptosis was also confirmed, indicating the antitumor potential of the HePC-NLCs.Conclusion: These findings demonstrate the ability of NLCs as a drug delivery system for enhanced pharmacokinetic, antitumor, and apoptotic effects, most importantly when loaded with HePC.Keywords: breast cancer, miltefosine, nano lipid carriers, bioavailability, pharmacokinetics, antitumor efficacy

This paper is related to the stochastic smoking model for the purpose of creating the effects of smoking that are not observed in deterministic form. First, formulation of the stochastic model is presented. Then the sufficient conditions for extinction and persistence are determined. Furthermore, the threshold of the proposed stochastic model is discussed, when noises are small or large. Finally, the numerical simulations are shown graphically with the software MATLAB.

Wasim Ul Bari,1 Mohammad Zahoor,1 Alam Zeb,2 Muhammad Umar Khayam Sahibzada,3 Riaz Ullah,4 Abdelaat A Shahat,4,5 Hafiz Majid Mahmood,6 Irfan Khan11Department of Chemistry, University of Malakand, Dir Lower, Chakdara, KPK 18800, Pakistan; 2Department of Biotechnology, University of Malakand, Dir Lower, Chakdara, KPK 18800, Pakistan; 3Department of Pharmacy, Sarhad University of Science and Information Technology, Peshawar, KPK 25000, Pakistan; 4Medicinal, Aromatic and Poisonous Plants Research Center (MAPRC), College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; 5Phytochemistry Department, National Research Centre, Giza, Egypt; 6Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaCorrespondence: Mohammad ZahoorDepartment of Chemistry, University of Malakand Chakdara, Dir Lower, KPK 18800, PakistanEmail mohammadzahoorus@yahoo.comMuhammad Umar Khayam SahibzadaDepartment of Pharmacy, Sarhad University of Science and Information Technology, Peshawar, KPK 25000, PakistanEmail umar.sahibzada@gmail.comBackground: Traditionally, Grewia optiva is widely used for the treatment of many diseases like dysentery, fever, typhoid, diarrhea, eczema, smallpox, malaria and cough.Methods: Shade-dried roots of G. optiva were extracted with methanol. Based on HPLC results, chloroform and ethyl acetate fractions were subjected to silica column isolation and four compounds: glutaric acid (V), 3,5 dihydroxy phenyl acrylic acid (VI), (2,5 dihydroxy phenyl) 3’,6’,8’-trihydroxyl-4H chromen-4’-one (VII) and hexanedioic acid (VIII) were isolated in pure form. Ellman’s assay was used to determine the anticholinesterase potential of isolated compounds while their antioxidant potential was estimated by DPPH and ABTS scavenging assays.Results: Amongst the isolated compounds, VI and VII exhibited excellent percent inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) (83.23±1.11, 82.72±2.20 and 82.11±2.11, 82.23±1.21, respectively, at 1000 μg/mL) with IC50 of 76, 90, 78 and 92 μg/mL, respectively. Highest percent radicals scavenging against DPPH and ABTS (87.41±1.20 and 86.13±2.31) with IC50 of 64 and 65 μg/mL, respectively, were observed for compound VII. Molecular docking studies also supported the binding of compound VI and VII with the target enzyme. The para-hydroxyl group of the phenolic moiety is formed hydrogen bonds with the active site water molecule and the side chain carbonyl and hydroxyl residues of enzyme.Conclusion: The isolated compounds inhibited the DPPH and ABTS-free radicals, and AChE and BChE enzymes. It was concluded that these compounds could be used in relieving the oxidative stress and pathological symptoms associated with excessive hydrolysis of acetyl and butyryl choline. The results of the study were supported by docking studies for compounds VI and VII.Keywords: G. optiva, antioxidant, acetylcholinesterase, butyrylcholinesterase, molecular docking

Lina T Al Kury,1 Alam Zeb,2 Zain Ul Abidin,2 Nadeem Irshad,3 Imran Malik,2 Arooj Mohsin Alvi,2 Atif Ali Khan Khalil,4 Sareer Ahmad,4 Muhammad Faheem,2 Arif-Ullah Khan,2 Fawad Ali Shah,2 Shupeng Li51College of Natural and Health Sciences, Zayed University, Abu Dhabi, United Arab Emirates; 2Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan; 3Department of Pharmacy, Quaid-I-Azam University, Islamabad, Pakistan; 4Rehman Medical Institute, Peshawar, Pakistan; 5State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, People’s Republic of ChinaPurpose: Melatonin and celecoxib are antioxidants and anti-inflammatory agents that exert protective effects in different experimental models. In this study, the neuroprotective effects of melatonin and celecoxib were demonstrated against ethanol-induced neuronal injury by in silico, morphological, and biochemical approaches.Methods: For the in silico study, 3-D structures were constructed and docking analysis performed. For in vivo studies, rats were treated with ethanol, melatonin, and celecoxib. Brain samples were collected for biochemical and morphological analysis.Results: Homology modeling was performed to build 3-D structures for IL1β), TNFα, TLR4, and inducible nitric oxide synthase. Structural refinement was achieved via molecular dynamic simulation and processed for docking and postdocking analysis. Further in vivo experiments showed that ethanol induced marked neuronal injury characterized by downregulated glutathione, glutathione S-transferase, and upregulated inducible nitric oxide synthase. Additionally, ethanol increased the expression of TNFα and IL1β. Finally, neuronal apoptosis was demonstrated in ethanol-intoxicated animals using caspase 3 and activated JNK staining. On the other hand, melatonin and celecoxib treatment ameliorated the biochemical and immunohistochemical alterations induced by ethanol.Conclusion: These results demonstrated that ethanol induced neurodegeneration by activating inflammatory and apoptotic proteins in rat brain, while melatonin and celecoxib may protect rat brain by downregulating inflammatory and apoptotic markers.Keywords: simulation, docking, cortex, hippocampus, ethanol, neurodegeneration

Fakhar ud Din,1,* Waqar Aman,2,* Izhar Ullah,3 Omer Salman Qureshi,4 Omer Mustapha,5 Shumaila Shafique,6 Alam Zeb7 1Department of Pharmacy, Quaid-i-Azam University, Islamabad, 2Department of Pharmacy, Kohat University of Science and Technology, Kohat, 3Department of Health and Medical Sciences, University of Poonch, Rawalakot, Azad Kashmir, 4Faculty of Pharmacy, University of Lahore, Lahore, 5Faculty of Pharmacy, Ziauddin University, Karachi, 6Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Dow University of Health Sciences, Karachi, 7Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan *These authors contributed equally to this work Abstract: Nanotechnology has recently gained increased attention for its capability to effectively diagnose and treat various tumors. Nanocarriers have been used to circumvent the problems associated with conventional antitumor drug delivery systems, including their nonspecificity, severe side effects, burst release and damaging the normal cells. Nanocarriers improve the bioavailability and therapeutic efficiency of antitumor drugs, while providing preferential accumulation at the target site. A number of nanocarriers have been developed; however, only a few of them are clinically approved for the delivery of antitumor drugs for their intended actions at the targeted sites. The present review is divided into three main parts: first part presents introduction of various nanocarriers and their relevance in the delivery of anticancer drugs, second part encompasses targeting mechanisms and surface functionalization on nanocarriers and third part covers the description of selected tumors, including breast, lungs, colorectal and pancreatic tumors, and applications of relative nanocarriers in these tumors. This review increases the understanding of tumor treatment with the promising use of nanotechnology. Keywords: nanocarriers, drug delivery, solid lipid nanoparticles, liposomes, polymeric nanoparticles, dendrimers, breast tumor, lungs tumor, colorectal tumor, prostate tumor

Background: Routine collection and analysis of data allows a critical care department to highlight the outcomes of the interventions done and to identify the grounds for improvement. Data on characteristic and outcomes of patients admitted in intensive care units (ICUs) are lacking. Methods: A software (ICU e-monitoring®) was designed to enter for each patient demographic data, SAPS3 on admission, Nine Equivalent Manpower Use Score, presence of medical devices and episodes of hospital acquired infections. We report data collected during 2014 with comparison to data collected with the same methodology in 2008 [1]. Objective: To determine the standardized mortality ratio, the mean length of ICU stay, mean length of mechanical ventilation and ICU acquired infection incidence rate. Study design: Descriptive Place of study: Medical ICU, Pakistan Institute of Medical Sciences Islamabad Results: A total of 196 admissions were recorded during the year 2014 vs 354 in 2008. 47.2% were males and 52.8% were females. Mean age was 32.1 years ± 15.3 SD (37.7 ± 18.9 SD in 2008). A total of 65 (33%) deaths were recorded during the year and standardized mortality ratio was found to be 0.71 vs 1.09 in 2008. Mean Length of stay was 15.9 Days ± 12.9 SD (9.3 days ± 8.9 in 2008) and mean duration of mechanical ventilation was found to be 12.04 Days (8.7 in 2008). Overall ventilator associated pneumonia (VAP) rate was 42.3 cases per 1000 ventilator days. Rate of Catheter Related Blood Stream Infections (CRBSI) was found to be 17.2 cases per 1000 CVC days. Conclusion: Major changes in our patient population characteristics were seen between 2008 and 2013: number of patients and standardized mortality was decreased while incidence of VAP and CRBSI was increased. It is possible to collect meaningful data on ICU performance and activity in resource limited settings.

BACKGROUND: Obesity is a significant health problem worldwide and an alarming problem in the developed world including the United States of America and European populations. Subsequently, obesity can lead to different health problems, such as non-communicable diseases. However, it can be prevented through a healthy diet, exercise, and lifestyle modification. The studys purpose was to analyze the published literature on community-based obesity interventions and to present a comprehensive summary of how to reduce the body weight, Body Mass Index (BMI), and Waist Circumference (WC) among overweight and obese individuals in the community through health education and behavior interventions. MATERIAL AND METHODS: The meta-analysis was conducted in February-July 2021, searching CINAHL, Cochrane Library, Google Scholar, PubMed, and Science Direct databases. Studies published during the prior 12 years on community-based obesity intervention for weight, BMI, and WC were included in this review. Cochrane Revman software was used for meta-analysis. RESULTS: Seventeen studies met the selection criteria for the review. A meta-analysis of the studies on health education and behavioral intervention studies resulted in a statistically significant reduction at 95% confidence intervals in the mean differences of BMI -1.19 (-1.77, -0.62) and WC -1.11 (-1.54, -0.68). CONCLUSIONS: Community-based obesity interventions through health education and behavior interventions effectively reduce the body weight, BMI, and WC. Implementing community-based health education and behavioral interventions effectively prevents and treats obesity in communities.

Alam Zeb, Omer Salman Qureshi, Hyung-Seo Kim, Ji-Hye Cha, Hoo-Seong Kim, Jin-Ki Kim College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi, Republic of Korea Abstract: The aim of this study is to investigate methotrexate-entrapped ultradeformable liposomes (MTX-UDLs) for potential transdermal application. MTX-UDLs were prepared by extrusion method with phosphatidylcholine as a bilayer matrix and sodium cholate or Tween 80 as an edge activator. The physicochemical properties of MTX-UDLs were determined in terms of particle size, polydispersity index, zeta potential, and entrapment efficiency. The deformability of MTX-UDLs was compared with that of methotrexate-entrapped conventional liposomes (MTX-CLs) using a steel pressure filter device. The skin permeation of MTX-UDLs was investigated using Franz diffusion cell, and the skin penetration depth of rhodamine 6G-entrapped UDLs was determined by confocal laser scanning microscopy. MTX-UDLs showed a narrow size distribution, with the particle size of ~100 nm. The deformability of MTX-UDLs was two to five times greater than that of MTX-CLs. The skin permeation of MTX-UDLs was significantly improved compared with MTX-CLs and free MTX solution. The optimized UDLs (phosphatidylcholine: Tween 80 =7:3, w/w) showed a higher fluorescence intensity than conventional liposomes at every increment of skin depth. Thus, the optimized UDLs could be promising nanocarriers for systemic delivery of MTX across skin. Keywords: ultradeformable liposomes, deformability, methotrexate, skin permeation, transdermal delivery

Purpose: This paper aims to examine the opportunities and challenges of using ChatGPT in higher education. Furthermore, it is also discuss the potential risks and plunders of these tools. Design/methodology/approach: The paper discuss the use of artificial intelligence (AI) in academia and explores the opportunities and challenges of using ChatGPT in higher education. It also highlights the difficulties of detecting and preventing academic dishonesty and suggests strategies that universities can adopt to ensure ethical and useful use of these tools. Findings: The paper concludes that while the use of AI tools, ChatGPT in higher education presents both opportunities and challenges. The universities can effectively address these concerns by taking a proactive and ethical approach to the use of these tools. This paper further suggests that universities should develop policies and procedures, provide training and support, to detect and prevent cheating intentions. Originality/value: The paper provides insights into the opportunities and challenges of using ChatGPT in higher education, as well as strategies for addressing concerns related to academic dishonesty. The paper further adds importance to the discussion on the ethical and responsible use of AI tools in higher education.