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Binding Pocket Identification and Determination of Overlapping with Different Software Tools for V8 Protease (1QY6) from Staphylococcus aureus
Get PDFBackground:
Protein-ligand interactions are critical for biochemical functionality in living organisms, and determining the binding pocket characteristics of a protein is essential for designing drugs that interact with specific protein pockets. Several software tools, such as Deepsite, FTSite, CASTp, and F pocket, are available for identifying these binding pockets.
Objective:
This study aimed to determine the percentage overlap and identify the best binding pocket of V8 Protease (1QY6) from Staphylococcus aureus using different software tools.
Method:
The study retrieved the protease protein\u27s PDB file from the Protein Data Bank and used software programs such as Deepsite, CASTp, and FTsite to identify its binding pockets. The amino acid residues that fit into each of the identified pockets were downloaded, and their unique sequence identifiers were noted. The overlap of the binding pockets identified by the software tools was determined by entering the amino acid values into Excel.
Result:
The study found that binding pocket 3 showed the most overlap between Deepsite and CASTp, indicating that Deepsite may have superior specificity and efficiency for determining binding pockets compared to other tools. The total overlap between the software tools was 19%, demonstrating the importance of using multiple tools to identify potential binding pockets.
Conclusion:
The comparison of three different software tools for identifying the binding pocket of the protease protein (1QY6) resulted in different results with no agreement among the binding pockets established by each tool. However, the study\u27s findings suggest that binding pocket 3 of the protease protein (1QY6) may function as the best binding pocket for drug design studies targeting this protein. These findings could aid in the development of new drugs to treat infections caused by Staphylococcus aureus
The combination of Cucurbitacin B and Evodiamine induces apoptosis and inhibits cell propagation in glioma cells
Get PDFBackground
Glioblastoma Multiform (GBM) is a lethal brain tumor. Despite aggressive treatment, the median survival time is 6 to 18 months. These malignant astrocytic tumors exhibit a high proliferation rate and acquire resistance against many existing therapeutic regimens. Temozolomide is a first line chemotherapeutic treatment prescribed along with surgery and radiation but due to the high resistance to the drug and a low patient survival rate, new drugs and drug combinations must continue to be investigated and developed. GBM cells like any cancer cells avoid differentiation and apoptosis. Thus, the induction of differentiation and apoptosis in glioblastoma cells may be considered as a potential treatment strategy. Evodiamine (Evo), a marketed supplement, and Cucurbitacin B (CuB), a compound obtained from natural plants, have been identified as promising candidates to treat various neoplasms but has not been well studied in GBM, and especially as a combination treatment. Their underlying anti-cancer mechanisms are still under investigation. Targeting the intrinsic PI3K/Akt and extrinsic MAPKs apoptotic pathways can prevent cell proliferation, migration and progression. Finally, the cell cycle is responsible for cancer cell division, and targeting the G2M checkpoint can prevent cancer cells from moving to mitosis. Indeed, recent studies have shown that CuB has an effect on the cell cycle by resting the G2M phase.
Objective
This study investigated the anti-neoplastic effects of Evo and CuB individually and in combination in U-87MG cells. Especially, their effect on the PI3k/Akt intrinsic and the MAPKs extrinsic apoptotic pathways, and the cell cycle targeting the G2M checkpoint.
Methods
The U-87MG cells were grown in a tissue culture plate and cell viability was determined using the MTT assay. The expression and activity of PI3K, Akt, JNK, c-Jun, Erk and MAPK 38, and Bax, Bcl2, and Caspase-3 proteins were measured by western blot analysis. A wound healing assay was performed to study the inhibition of cellular migration by Evo and CuB. G2M cell cycle phase arrest was investigated using the flow cytometry analysis. Evo and CuB, individually and in combinations, were also tested in PC-12 cells (Neuronal cell model) using MTT assay to validate the selectivity of combination towards cancer cells over the normal brain cells.
Results
The results show that Evo and CuB significantly decreased the U-87 cell viability. The effect doubled with the combination treatment. CuB and Evo imparted their effect via the PI3K/Akt intrinsic apoptotic pathway by reduced the expression of p-PI3K, p-Akt, Bcl2 and increasing the expression of cleaved Caspase-3, and via the extrinsic apoptotic pathway by increasing the expression of p-JNK, p-c-Jun, and p-MAPK 38. The combination of Evo and CuB showed significantly higher effect on cell the migration as compared to individual treatments. In the presence of the Evo-CuB combination the percentage of cell population in the G2M phase arrest was significantly higher compared to individual treatments. The cytotoxic effect of the combination was also significantly three times lower in neuronal PC-12 cells compared to U-87MG cells.
Conclusion
This in-vitro study demonstrates that the combination treatment of Evo and CuB reduced cellular proliferation and migration, most likely via the intrinsic and extrinsic apoptotic pathways. Thus, mediating an anti-neoplastic effect that is significantly higher than individual treatment against the Glioblastoma Multiform. Overall, Cucurbitacin and evodiamine in combination proved to be an effective potential anti-neoplastic treatment and may be considered as a potential adjuvant therapy in GBM
Make the Soil Rich
No full textThe idea for this quilt came out of the idea of “making the soil rich.” This personal mantra grew out of a desire to find ways that I could effect positive change. With so many massive problems–environmental, economic, social–facing current and future generations, I often wonder what I can possibly do to help. I believe I can make the soil rich, put what I’ve learned from my elders, experiences, community, values, back into the soil for the next generation to grow strong. I can’t control the outcomes, but I can be dedicated to helping those I influence in my life and work, to grow strong, well, and wise by sharing what I know and have learned, and encouraging others to do the same.
As I started on this project, “making the soil rich” took on new meaning. I wondered, what would our societies look like if we poured our resources into our resources, into maintaining and developing them with purpose? What if in building our cities and space we prioritized building in balance with our environment and the essential resources we all depend on, rather than profit? How would those cities grow? How might they be more equitable, sustainable, and healthy? How might they make the soil rich for future generations? Rather than perpetuating a system where we aspire to make ourselves rich, what if we shifted to a world where we invest in making the soil rich to create abundance for all?
My quilted block explores this question.
I used primarily cotton material that I dyed naturally and eco printed with plants and homemade iron water made with rusted nails and horseshoes found in farmed soil and forests to tangibly bring the idea of the richness of the soil into the work.https://digitalcommons.liu.edu/community_usquilt_2023/1008/thumbnail.jp
Between Kedusha and the Sitra Achra: Factors That Contribute to Individuals Leaving ultra-Orthodoxy
Get PDFThe purpose of this study is to understand the most frequently cited factors contributing to individuals leaving ultra-Orthodoxy, as well as the psycho-social implications of doing so. Indeed, there is a dearth of quantitative research on the factors and implications of leaving. Previous research has shown that contributing factors include intellectual contradictions, gender inequality, lack of acceptance of differences, and experiencing physical, emotional, or sexual abuse. The psychosocial implications of leaving include social and educational barriers to integration into secular life and increased depression and loneliness. The current study employed a quantitative, descriptive design to examine the hypothesis that emotional reasons are more frequently cited than intellectual reasons for leaving ultra-orthodoxy. We also examined the hypothesis that leaving ultra-orthodoxy leads to increases in depression and anxiety scores, decreases in well-being, and a loss of social support. Participants completed a questionnaire that assessed the different factors contributing to leaving ultra-orthodoxy using a Likert scale. They were then administered four psychosocial measures to assess anxiety, depression, wellness, and social support. The results showed no significant difference between individuals\u27 levels of agreement with intellectual and emotional reasons to leave. The results indicated elevations in measures of depression and anxiety, but not in measures of social support, after leaving ultra-orthodoxy suggesting that individuals have a hard time with emotional adjustment despite the presence of social support. Finally, there were no significant differences in gender or ultra-Orthodox sect regarding levels of agreement and psychosocial measures. Future studies should build on these findings to further investigate why individuals leave their ultra-Orthodox communities and the psychosocial implications of leaving
Calcium involvement in the mechanism of action of Limonene as a penetration enhancer for topical/transdermal drug products
Get PDFThe addition of chemical permeation enhancers (CPE) to a topical dermatological formulation is the prevalent approach to improve permeability of active pharmaceutical ingredients (API) across the stratum corneum. Terpenes have been used as CPEs for a long time since they are safe and non-irritating. Limonene is one such terpene majorly found in essential oils extracted from citrus fruits and many varieties of cannabis. Studies performed using Limonene as PE show that Limonene was able to increase the flux of the drug by many folds. Limonene acts as an agonist to transient receptor potential ankyrin 1 (TRPA1) receptor – the activity of which is highly Ca2+ dependent. Since, calcium is found in the entire epidermis, the purpose of this study was to evaluate whether the above-mentioned properties of Limonene are related to its penetration enhancing effects. The aim of this study was to investigate whether the permeation enhancers R-Limonene (R-L) & S-Limonene (S-L) might act by decreasing the extracellular Ca2+ concentration that it is responsible for the tight cell-cell adhesion in the stratum corneum. This was followed by testing the suitability of microdialysis technique for DPH and DTZ through recovery and retrodialysis (loss) experiments. Finally, in vivo experiments were performed on a rabbit model. A randomized, crossover, single-dose, four treatment study design was chosen so that each rabbit would receive the test and reference formulation. The four gel combinations – control (5% DPH); test (5% DPH + 1%R-L or 1% S-L); control + DTZ (5% DPH + DTZ); test + DTZ (5% DPH + 1% R-L or 5% DTZ) were applied to the rabbit’s dorsal surface on the same day and dermal concentration profiles of DPH were assessed using microdialysis. The pharmacokinetic parameters such as Cmax and AUCinf were estimated using Phoenix WinNonlin Non Compartmental Analysis and studied for comparison between different formulations. The gels containing R-L or S-L showed slightly higher dermal exposure of DPH compared to the control gel. Whereas the dermal exposure from the gel containing DTZ was not different from the control gel. The results support the hypothesis that Limonene inhibition of Ca+2 activity in the skin might contribute to its penetration enhancing effect, although more in-vivo experiments are necessary to further prove this hypothesis. The first step was to find the optimal concentration of limonene that enhances the penetration of a model drug, diphenhydramine (DPH) from topical dermatological gels. Seven gels containing 5% DPH were prepared with 0 (control) and three increasing concentrations of R-L or S-L (1.00, 1.75, and 2.50 %) using simple dispersion method. An in-vitro release study across regenerated cellulose membrane using Franz cell apparatus was conducted to evaluate any possible physical interaction by assessing release parameters like flux and cumulative amount permeated. Then, an ex vivo study using porcine ear skin was performed to select the optimal percentage of R-L and S-L. The 1.00% R-L and 1.00% S-L increased permeability of DPH by 82.37% and 111.51%, respectively compared to control formulation, whereas higher percentages were not significantly different from control gel. Then, the calcium channel blocker diltiazem (DTZ) was added to the selected formulations to evaluate whether it counteracts the penetration enhancing effects of R-L or S-L. These formulations were tested again in-vitro on regenerated cellulose membrane to evaluate physical interaction before proceeding to the in vivo studies. All gels were tested for consistency, transparency, and uniformity of content. Samples were analyzed with a bioanalytical method specifically developed and validated for DPH/DTZ combination
Utilization of physiological based pharmacokinetic modeling to predict systemic exposure and guide dosing decisions for therapeutic Drug monitoring of Beta-Lactams in critically Ill patients
Get PDFSepsis leads to a continuous pathophysiologic process that dysregulates host response which potentially causes significant organ damage and even death, especially respiratory, renal and cardiac failure. Changes in the clearance and volume of distribution are typically result in pharmacokinetic variabilities and often make it challenging for clinicians to appropriately dose beta-lactam antibiotics. Therapeutic drug monitoring (TDM) is necessary to further optimize beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) parameters to improve clinical outcomes and reduce therapeutic failure.
Cefepime (CEF) and meropenem (MEM) primarily excreted by the kidney, and altered the kidney function of the ICU patients would affect the clearance of the medications. On the other hand, the volume of distribution is usually affected by differences in plasma protein binding and body composition in the septic population. For body composition, the following parameters are considered to contribute the changes in volume of distribution: total body water, extracellular water, intracellular water, total body fat and total body protein. In this research, a mechanistic approach to characterize CEF and MEM absorption, distribution, metabolism and excretion based on the anatomy and physiology of the human body in conjunction with physicochemical properties of the medication and information is needed. PBPK modeling is a good tool to use for this purpose. This dissertation research demonstrated how PBPK modeling and simulation using Simcyp® is a useful tool to predict the pharmacokinetics of cefepime and meropenem. The PBPK model developed in this investigation was designed to predict systemic exposure in the targeted population. Moreover, the PBPK modeling approach in this study was tested in a real-world setting by predicting drug exposure in individual patients when limited plasma sampling was performed.
The new and validated serum assay method with ultra-performance liquid chromatography- photodiode array detector (UPLC-PDA) was developed and used to analyze patients’ blood samples at low concentration levels as an alternative to more resource and time intensive LCMS methods, which can also be used to test the other antibiotics.
A critical care septic population was developed based on the altered subcutaneous/intramuscular fractions and use to capture the changes in the drug distribution induced by the tissue composition changes under the sepsis situation. The model was further modified by adding different physiologic perturbations in ICU sepsis patients. Among these, impaired renal function and a decreased fraction of cardiac output are the most common seen situations happened to the ICU sepsis patients. On the other hand, some ICU sepsis patients have been obese, which causes an increased GFR.
Verification of the developed critical care renally impaired sepsis population was conducted as part of this research. The developed population included altered body composition fractions, modified kidney size for a renal insufficiency function, and decreased cardiac output to create the final renally impaired sepsis population. PBPK model simulated systemic profiles were compared with published clinical data obtained from sepsis patients with impaired kidney function for the probe medication, vancomycin. The calculated fold errors associated with the AUC for both single and multiple doses indicate a good predictability of the model in the developed critical care septic population.
Likewise, the cefepime and meropenem PBPK models developed for healthy volunteers captured observed plasma concentrations from multiple publications evaluating different dose regimens of the medications. The observed PK profiles fitted well with model simulation. Especially, the model simulated elimination phase and Cmin very well, which are helpful to predict the Ctrough if requires. Cmax and area under curve (AUC) are also comparable with publication reported values. Prediction errors calculated for PK parameters suggest good predictability of two models in this population. The developed models can be used for the predictions of the target populations.
The developed and verified PBPK models were then used to predict the plasma exposure of cefepime and meropenem when empiric-dosing regimens were administrated to critically ill sepsis patients in a clinical setting conducted at The Brooklyn Hospital Center (TBHC). The simulations preformed for individual ICU septic patients based on their demographic data were compared with clinical data collected from TBHC. This study enrolled 15 patients including 8 patients treated with CEF, 7 patients treated with MEM. The developed PBPK model captured observed plasma concentrations well from 7 renally impaired sepsis patients. The remaining subjects were obese patients, who all had an increased GFR but the different performance in volume distribution. The simulations for the majority of the subjects were acceptable. For the subjects for which the developed model was not predictive, an extremely small volume distribution in these patients could be a contributing factor.
Overall, this dissertation research highlights the potential of a PBPK modeling approach to evaluate the PK and PK/PD targets in critically ill septic patients treated with beta-lactam antibiotics. Once verified, the model can be used to further optimize empiric dosing of medications in a critical care population with the goal of delivering safe and effective drug therapy in these patients
Racial identity, appraisal, and coping: A moderated mediation of racism-related trauma in Black Americans
Get PDFResearch indicates that Black Americans are at higher risk for trauma symptoms due to exposure to racial discrimination. However, the degree to which Black Americans appraise discriminatory events as threatening and how their coping with discrimination affects traumatization, remains unclear. Additionally, the use of undergraduate student convenience samples limits the generalizability of prior research. In the current study, an online sample of Black American adults (N = 415, age 18 to 75, M = 36.10, SD = 11.18), threat appraisal was tested as a mechanism through which discrimination predicts trauma symptoms, and both coping strategies and racial identity were explored as potentially influencing the impact of discrimination on trauma. Finally, this study investigated the discrimination – trauma relationship within the context of vicarious discrimination. Perceived racial discrimination had a large effect (r = .67) on trauma symptoms, supporting external validation of the traumatic impact of racial discrimination to a broader sample of Black adults. Moreover, both direct and vicarious racial discrimination were positively related to trauma symptoms through threat appraisal. Racial ideology (i.e., Afrocentricity, Multicultural Inclusive, Antiwhite, Assimilation, Miseducation, and Self-hatred) did not protect participants from the effect of discrimination. However, salient negative (i.e., Self-hatred and Miseducation) and conflicted (i.e., Antiwhite) racial identities worsened the effect of vicarious discrimination, while Self-hatred was the only racial identity to exacerbate the impact of direct discrimination. Avoidant coping also strengthened the effect of direct discrimination on trauma symptoms, but problem-focused and social support coping did not influence this relationship. The implications of the findings, possible future directions, and limitations of the study are discussed
Investigation of dosing interval differences for nepafenac ophthalmic suspensions: A suspension-specific PBPK model with improved in vitro dissolution data
Get PDFNepafenac is a nonsteroidal anti-inflammatory drug (NSAID) for the treatment of inflammation associated with cataract surgery. It is marketed as two ophthalmic suspensions—NEVANAC® (0.1% administered three times a day) and ILEVRO® (0.3% administered once a day). The primary mediator of pain relief is amfenac, which is a metabolite of nepafenac. The primary goal of this project was to explain how was the dosing interval affected by changes in formulation properties. The approach incorporated three novel elements. 1) A physiologically based pharmacokinetic (PBPK) model that is specific to this application for nepafenac and amfenac was constructed, which allowed tracking the specific pharmacokinetics while minimizing the use of unnecessary compartments and variables. 2) A precorneal model was constructed to allow the modeling of interactions between formulations and the tear layer and other components on the ocular surface, which allowed assessing differences in formulation properties on the resulting pharmacokinetics. 3) A novel dissolution test (IVDT) was performed on NEVANAC® and ILEVRO® separately to determine the specific drug dissolution and distribution in each formulation and allow improved modeling of the in vivo nepafenac drug delivery. The model was written in the programming language “R” and was used for in silico simulations to assess the reasons for the dosing interval change in terms of formulation properties. This approach aligned with current FDA initiatives in quantitative modeling methods (QMM). This work facilitated explaining the dosing interval question, created increased knowledge of how to construct and evaluate ocular PBPK models, and contributed to advancing the art of ocular PBPK modeling
The effects of music on emotion regulation and stress in test performance
Get PDFThe aim of the present study was to investigate the impact of music on stress and emotion regulation and whether the emotional valence of the music attended to would result in differences in the resulting stress and emotion dysregulation experienced by individuals. A sample of 181 college students, ages 18-50 were recruited via posted flyers and a digital portal for students to volunteer in studies in exchange for class credit and were then randomly assigned to one of two music conditions (music with positive or negative emotional valence). The sample completed a number of self-report measures related to positive and negative affect, emotion regulation, and symptoms related to depression and wore a heart rate monitor to record their heart rate variability (HRV). Participants then listened to music with different emotional valences and engaged in a stressful task, the PASAT-C. Results showed no significant between or within-group changes in self-reported affect or emotion regulation, and no significant change in HRV between groups. There were significant correlations between measures which reflect findings of past studies regarding affect, depressive symptoms, and emotion regulation. There was also a significant difference within the positive music test group indicating a possible impact from the music attended, though further investigation is required to determine the implications of the difference. The limitations of this study and possible directions for future research are discussed in order to further explore the impact of music on stress and emotion regulation
Anxious attachment style and its link to anxiety in young adults
Get PDFNumerous studies have shown that attachment styles develop from primary caregivers and influence our self esteem and ability to trust and maintain healthy relationships. Correlations with different attachment styles and negative outcomes, such as anxiety have been made. This study investigated the relationship between Anxious attachment style and Anxiety in 37 college students 18-30 at an undergraduate college in New York. The Collins Adult Attachment Scale Attachment was used to assess attachment styles and the Hamilton Anxiety Scale for anxiety. In this study, anxious attachment style positively correlated with Anxiety. A secondary finding revealed that religious affiliation negatively correlated with anxiety