Investigating the Effect of GLU283 Protonation State on the Conformational Heterogeneity of CCR5 by Molecular Dynamics Simulations.

CCR5 is a class A GPCR and serves as one of the coreceptors facilitating HIV-1 entry into host cells. This receptor has vital roles in the immune system and is involved in the pathogenesis of different diseases. Various studies were conducted to understand its activation mechanism, including structural studies in which inactive and active states of the receptor were determined in complex with various binding partners. These determined structures provided opportunities to perform molecular dynamics (MD) simulations and to analyze conformational changes observed in the protein structures. The atomic-level dynamic studies allow us to explore the effects of ionizable residues on the receptor. Here, our aim was to investigate the conformational changes in CCR5 when it forms a complex with either the inhibitor maraviroc (MRV), an approved anti-HIV drug, or HIV-1 envelope protein GP120, and compare these changes to the receptor's apo form. In our simulations, we considered both ionized and protonated states of ionizable binding site residue GLU2837.39 in CCR5 as the protonation state of this residue was considered ambiguously in previous studies. Our molecular simulations results suggested that in fact, the change in the protonation state of GLU2837.39 caused interaction profiles to be different between CCR5 and its binding partners, GP120 or MRV. We observed that when the protonated state of GLU2837.39 was considered in complex with the envelope protein GP120, there were substantial structural changes in CCR5, indicating that it adopts a more active-like conformation. On the other hand, CCR5 in complex with MRV always adopted an inactive conformation regardless of the protonation state. Hence, the CCR5 coreceptor displays conformational heterogeneity not only depending on its binding partner but also influenced by the protonation state of the binding site binding site residue GLU2837.39. This outcome is also in accordance with some studies showing that GP120 binding could activate signaling pathways. This outcome could also have significant implications for discovering novel CCR5 inhibitors as anti-HIV drugs using in silico methods such as molecular docking, as it may be necessary to consider the protonated state of GLU2837.39.

Investigation of triticeal cartilage anatomy in forensic autopsy cases.

PURPOSE: This study aims to determine the presence and morphology of triticeal cartilage (TrC) through autopsy cases and to examine its relationship with age, gender, and height, thus contributing to clinical practices and forensic perspective. MATERIALS AND METHODS:  Our study was conducted on a total of 84 autopsy cases between the ages of 20-90 years who came to Tokat Forensic Medicine Institute. The laryngeal region was palpated to determine whether TrC was present. The dimensions of the TrC and the length of the upper horn of thyroid cartilage (UHThC) were measured with precise digital calipers, and its weight was measured with an accurate digital scale. RESULTS: The presence of TrC was identified in 56% of the autopsy cases examined. The prevalence of TrC was higher in males (61.9%) than in females (23.1%). It was determined to be bilateral in 45% of the cases and unilateral in 11%. TrCs had a cylindrical shape in 68.2%, an oval shape in 25.8%, and a pyramidal shape in 5.8%. The average weight of TrC was 67.93 ± 33.91 mg on the right side and 72.67 ± 32.23 mg on the left. As the individual's height increased, the weight of TrC increased (p < 0.001). Additionally, there was a strong positive correlation between the lengths of TrC and UHThC and the individual's height (p < 0.001). CONCLUSION: TrC may be confused with UHThC fractures. Therefore, we believe that knowledge of the presence and morphology of TrC will contribute to clinical approaches and forensic cases, especially in relation to the neck region.

Efficient, rapid, and high-yield synthesis of aryl Schiff base derivatives and their in vitro and in silico inhibition studies of hCA I, hCA II, AChE, and BuChE.

This study reports a rapid and efficient synthesis of four novel aryl Schiff base derivatives. Biological activity and molecular modeling studies were conducted to evaluate the inhibitory effects of these compounds on human carbonic anhydrases (hCA) and cholinesterases. The results indicate that the triazole-ring-containing compounds have strong inhibitory effects on hCA I, hCA II, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) targets. Besides comparing the Schiff bases synthesized in our study to reference molecules, we conducted in silico investigations to examine how these compounds interact with their targets. Our studies revealed that these compounds can occupy binding sites and establish interactions with crucial residues, thus inhibiting the functions of the targets. These findings have significant implications as they can be utilized to develop more potent compounds for treating the diseases that these target proteins play crucial roles in or to obtain drug precursors with enhanced efficacy.

Do intravitreal anti-VEGF injections have an effect on corneal endothelial remodeling in children with premature retinopathy?

PURPOSE: This study was carried out to investigate the effects of retinopathy of prematurity (ROP) and intravitreal antivascular endothelial growth factor (VEGF) injections on the corneal endothelium in the childhood period of patients who have had ROP. METHODS: The material of comparative case-control clinical study consisted of patients followed up with ROP between February 2013 and February 2023. The eyes in the study group were divided into two subgroups consisting of those who received intravitreal anti-VEGF injections (subgroup 1) and those who were followed up only (subgroup 2). Central corneal endothelial cell density (ECD), coefficient of variation (CV), central corneal thickness (CCT), and pleomorphism parameters in the childhood period were evaluated by corneal specular microscopy and compared with age-matched healthy control subjects. RESULTS: There were 84 eyes of 42 patients with ROP in the study group and 80 eyes of 40 healthy children in the control group. Mean CCT was significantly higher in subgroup 1 and the control group than in subgroup 2 (p = 0.037), and mean ECD was significantly higher in subgroup 2 than in subgroup 1 and the control group (p < 0.001). There was no significant difference between subgroup 1 and the control group in mean ECD and CCT values (p = 1.000 for both cases). CONCLUSIONS: Considering that ROP patients who received intravitreal anti-VEGF injections had more advanced-stage ROP than ROP patients who were followed up only, these findings suggest that intravitreal anti-VEGF applications in ROP cases may lead to corneal endothelial parameters similar to those of healthy eyes.

Proximal nailfold videocapillaroscopy findings of patients with idiopathic macular telangiectasia type 2.

PURPOSE: Idiopathic macular telangiectasia type 2 (IMT) is a neurodegenerative disease characterized by bilateral, idiopathic, and perifoveal retinal telangiectatic vessel formations. We aimed to compare proximal nailfold videocapillaroscopy (NV) findings between patients with IMT and healthy individuals and evaluate the optical coherence tomography angiography (OCTA) parameters of the patients with IMT according to their NV findings. METHODS: The study included 43 patients with IMT and 92 healthy controls of similar age and gender without any additional diseases. The OCTA and NV findings of the patients and controls were examined. RESULTS: The mean age was 59.76 ± 5.73 years in the IMT group and 58.23 ± 4.96 years in the control group. Of the 43 patients with IMT, 19 were found to have increased capillary tortuosity, six had microhemorrhage, and 18 had bizarre capillaries (P < 0.001). In the IMT group, the total vascular density value of the superficial capillary plexus was higher among the patients with capillary microhemorrhage (P = 0.001), and the subfoveal choroidal thickness was lower among those with increased capillary tortuosity and bizarre capillaries (P = 0.04 and P = 0.07, respectively). CONCLUSION: This is the first study in which the NV findings of patients with IMT were compared with those of a control group. We found higher rates of increased capillary tortuosity, microhemorrhage, and bizarre capillaries in the IMT group compared to the controls. We consider that this situation is caused by microvascular damage. We also think that IMT is a systemic disease that affects both proximal nailfold capillaries and eye vessels.

Evaluation of Optic Disc, Retinal Vascular Structures, and Acircularity Index in Patients with Idiopathic Macular Telangiectasia Type 2.

BACKGROUND: We aimed to compare the retinal, optic disc vascular density (ODVD) values, and acircularity index (AI) of patients with idiopathic macular telangiectasia type 2 (IMT) and healthy individuals using the optical coherence tomography angiography (OCTA) device. METHODS: The study included 39 patients with IMT and 37 healthy controls. The OCTA findings of the patients and controls were examined. RESULTS: The total, parafoveal and perifoveal vascular density of the superficial capillary plexus, choriocapillaris blood flow, inside-disc ODVD, retinal nerve fiber layer (RNFL), and retinal thicknesses were found to be statistically significantly lower, and the foveal avascular zone value was statistically significantly higher in the IMT group compared to the control group (p = 0.001, p = 0.01, p = 0.02, p = 0.01, p = 0.009, p = 0.002, p = 0.02, respectively). There was a statistically significant negative correlation between best-corrected visual acuity (BCVA) and AI (p = 0.02), and a statistically significant positive correlation between peripapillary vascular density and BCVA (p = 0.04). CONCLUSIONS: We consider that the lower retinal, choriocapillaris, ODVD values, and retinal and RNFL thicknesses in the patients with IMT compared to the controls were due to vascular damage, remodeling, fibrosis, proliferation, and Müller cell damage. Ellipsoid zone defect, AI, and peripapillary vascular density are important indicators in the evaluation of visual acuity in these patients.

Optical coherence tomography angiography evaluation of optic disc and retinal vascular densities in obese patients.

BACKGROUND: To evaluate optic disc and retinal vascular densities in obese patients using optical coherence tomography angiography (OCTA). METHODS: This study included 27 eyes from 27 obese patients with a body mass index (BMI) of ≥35 who were scheduled for bariatric surgery at the general surgery clinic and 26 eyes from 26 healthy individuals with a BMI of 18.5-24.9 kg/m2 who were of similar age and gender to the obese group. The macular vascular densities of the superficial and deep capillary plexuses (SCP and DCP, respectively), choriocapillaris flow area, optic disc peripapillary vascular density, and retinal thicknesses were evaluated using the OCTA device in obese patients and controls. RESULTS: The mean age of the obese patients was 35.89 ± 10.93 years, and that of the controls was 32.31 ± 7.88 years (p = 0.199). The mean BMI values of the obese and control groups were 45.04 ± 6.89 kg/m2 and 23.19 ± 1.66 kg/m2, respectively (p < 0.0001). The whole, parafoveal, and perifoveal vascular density values of the SCP and those of the DCP were statistically significantly lower in the obese group than in the control group (p = 0.004, p = 0.011, p = 0.006, p = 0.036, p = 0.029, and p = 0.024, respectively). There was no significant difference between the two groups in terms of optic disc vascular density. Full retinal perifoveal thickness, full retinal perifoveal volume, inner retinal perifoveal thickness, and inner retinal perifoveal volume were statistically significantly lower in obese patients compared to the controls (p = 0.043, p = 0.042, p = 0.027, and p = 0.024, respectively). In addition, statistically significant negative correlations were found between BMI and the whole, parafoveal, and perifoveal vascular densities of the SCP and DCP and the whole vascular density values of the optic disc for all vessels and small vessels ​​(p = 0.017, r = -0.327; p = 0.043, r = -0.280; p = 0.033, r = -0.293; p = 0.034, r = -0.291; p = 0.017, r = -0.327; p = 0.023, r = -0.311; p = 0.031, r = -0.296; and p = 0.047, r = -0.274, respectively). CONCLUSION: We consider that the decrease in retinal vascular density and retinal thickness in obese patients is responsible for obesity-induced oxidative stress, increased inflammatory cytokines, and microvascular damage.

Investigation of the color discrimination ability using the Farnsworth-Munsell 100-hue test and structural changes by SS-OCT in patients with transfusion-dependent beta-thalassemia.

AIM: This study aimed to examine the color discrimination ability of patients with transfusion-dependent beta-thalassemia (TDß-T) in detail using the Farnsworth Munsell (FM) 100-hue test and to evaluate structural changes by swept source-optical coherence tomography (SS-OCT). MATERIAL AND METHODS: This prospective, sectional study included 40 patients (79 eyes) with TDß-T and 21 controls (42 eyes). The volunteers underwent a detailed ophthalmological examination and SS-OCT (DRI-OCT, Triton) imaging. Excluded were those with congenital color vision defects detected with the Ishihara pseudoisochromatic test. The patients' color vision was examined using the FM 100-hue test. The total error score (TES), the blue-yellow local error score (b-y LES), and the red-green local error score (r-g LES) were calculated. p <0.05 was considered significant. RESULTS: The mean age was 30.34±6.94 years in the patient group and 32.26±6.43 years in the control group (p = 0.078). The patient group had a significantly lower hemoglobin level (9.25±0.87 g/dL vs. 14±1.79 g/dL, p <0.001) and a significantly higher ferritin level (2665.56±2658.05 µg/L vs. 52.87±69.59 µg/L, p<0.001) compared to the control group. The mean TES, b-y LES, and r-g LES were higher in the patients than in the controls (64.84±30.18 vs. 28.45±16.55, p<0.001, 34.21±17.54 vs. 15.67±10.07, p <0.001, and 29.32±15.72 vs. 12.12±7.94, p<0.001, respectively). The patients had a higher b-y LES than r-g LES (34.21±17.54 vs. 29.32±15.72, p = 0.015). Choroidal thickness was lower in the patients than in the controls (284.34±63.55 µm vs. 324.98±88.05 µm, p = 0.043). CONCLUSION: We found that the color discrimination ability of the patients with TDß-T was reduced in both the r-g and b-y color axes compared to the controls, and their color discrimination ability in the b-y color axis was more affected than in the r-g axis.

Prediction of HIV-1 protease resistance using genotypic, phenotypic, and molecular information with artificial neural networks.

Drug resistance is a primary barrier to effective treatments of HIV/AIDS. Calculating quantitative relations between genotype and phenotype observations for each inhibitor with cell-based assays requires time and money-consuming experiments. Machine learning models are good options for tackling these problems by generalizing the available data with suitable linear or nonlinear mappings. The main aim of this study is to construct drug isolate fold (DIF) change-based artificial neural network (ANN) models for estimating the resistance potential of molecules inhibiting the HIV-1 protease (PR) enzyme. Throughout the study, seven of eight protease inhibitors (PIs) have been included in the training set and the remaining ones in the test set. We have obtained 11,803 genotype-phenotype data points for eight PIs from Stanford HIV drug resistance database. Using the leave-one-out (LVO) procedure, eight ANN models have been produced to measure the learning capacity of models from the descriptors of the inhibitors. Mean R2 value of eight ANN models for unseen inhibitors is 0.716, and the 95% confidence interval (CI) is [0.592-0.840]. Predicting the fold change resistance for hundreds of isolates allowed a robust comparison of drug pairs. These eight models have predicted the drug resistance tendencies of each inhibitor pair with the mean 2D correlation coefficient of 0.933 and 95% CI [0.930-0.938]. A classification problem has been created to predict the ordered relationship of the PIs, and the mean accuracy, sensitivity, specificity, and Matthews correlation coefficient (MCC) values are calculated as 0.954, 0.791, 0.791, and 0.688, respectively. Furthermore, we have created an external test dataset consisting of 51 unique known HIV-1 PR inhibitors and 87 genotype-phenotype relations. Our developed ANN model has accuracy and area under the curve (AUC) values of 0.749 and 0.818 to predict the ordered relationships of molecules on the same strain for the external dataset. The currently derived ANN models can accurately predict the drug resistance tendencies of PI pairs. This observation could help test new inhibitors with various isolates.

Optical coherence tomography angiography findings in transfusion-dependent beta-thalassemia patients with and without splenectomy.

BACKGROUND: Ocular involvement is common in transfusion-dependent beta-thalassemia (TDß-T) patients. We aimed to investigate the effect of splenectomy on optical coherence tomography angiography (OCTA) findings in TDß-T patients. METHODS: The study is a prospective cross-sectional study. A total of 45 eyes of 23 patients with splenectomy (34.04±8.83 years), 18 eyes of 9 patients without splenectomy (27.44±5.43 years), and 54 eyes of 27 controls (33.22±6.44 years) were included. Vessel density in superficial capillary plexus, deep capillary plexus and radial peripapillary capillary, foveal avascular zone, choriocapillaris flow area, choroidal and retinal thickness detected by OCTA were evaluated. p < 0.05 was considered significant. RESULTS: Vessel density of superficial capillary plexus and deep capillary plexus were similar in patients with and without splenectomy, and controls. Choriocapillaris flow area was significantly decreased in patients with splenectomy than that in those without splenectomy and controls (2.02±0.12 vs. 2.17±0.1 and 2.14±0.12; p < 0.001). Choroidal thickness was significantly lower in patients without splenectomy than in patients with splenectomy and controls (260.05±61.02 vs. 305.11±42.13 and 298.89±29.14, p = 0.008). Parafoveal and perifoveal thickness of the full retina and outer retina were significantly lower in patients without splenectomy than in patients with splenectomy and controls (301.06±10.0, 279.78±10.28 vs. 311.04±14.89, 290.87±13.67 and 316.63±13.57, 289.56±9.31, p < 0.001 and p = 0.002; 174.72±7.81, 167.17±6.21 vs. 182.87±8.81, 173.60±7.09 and 185.11±9.26, 173.96±6.79, p = 0.001 and p < 0.001, respectively). CONCLUSIONS: OCTA findings can provide information about the microvascular effects of splenectomy on the retina of patients with TDß-T.

Optic disc and retinal vessel densities assessment by optical coherence tomography angiography in patients with keratoconus.

BACKGROUND: This study aimed to evaluate retinal and optic disc vascular changes in patients with keratoconus (KC) using optical coherence tomography angiography (OCTA). METHODS: Thirty-two eyes of 22 patients with KC and 24 eyes of 24 age- and sex-matched healthy controls were included in this study. Corneal topography and OCTA were performed. Quantitative vessel density of the macular superficial capillary plexus (SCP), macular deep capillary plexus (DCP), and radial peripapillary capillaries (RPC); choriocapillaris flow area; and choroidal thickness were compared between the KC and control groups. RESULTS: SCP and DCP vessel densities showed a significant reduction in the KC group compared to that in the control group (p < 0.001 and p < 0.001 in the whole image and parafovea, respectively). Choriocapillaris flow area was significantly higher in patients with KC than in the control group (p = 0.003). The foveal avascular zone area did not significantly differ between the two groups (p = 0.949). RPC inside disc vessel density was significantly decreased in the KC group compared to that in the control group (p < 0.001). CONCLUSION: This study revealed important macular, choroidal, and optic disc vessel densities changes in patients with KC. Macular whole vessel density and parafoveal vessel density of the SCP and DCP decreased, while choriocapillaris flow area increased in patients with KC.

Ocular surface assessment and morphological alterations in meibomian glands with non-contact meibography in electronic cigarette smokers.

PURPOSE: The study aimed to evaluate the ocular surface and meibomian gland morphology in electronic cigarette (e-cigarette) smokers. METHODS: The upper and lower eyelids of 25 male e-cigarette smokers and 25 healthy male non-smoker patients were evaluated using Sirius meibography. Meibomian glands loss was automatically calculated using Phoenix meibography imaging software module, with the result obtained as percentage loss. Ocular Surface Disease Index (OSDI) questionnaire, tear breakup time test, and Schirmer II test were administered and performed in all cases. RESULTS: The mean e-cigarette smoking duration was 4.9 ± 0.9 (range, 3.4-7) years. While the mean Schirmer II test value was 9.16 ± 2.09 mm in e-cigarette group, it was 11.20 ± 2.14 mm in control group (p=0.003). Mean tear breakup time was 6.96 ± 2.31 seconds in e-cigarette group and 9.84 ± 2.13 seconds in control group (p=0.002). The mean OSDI value was 28.60 ± 6.54 and 15.16 ± 7.23 in e-cigarette and control groups, respectively (p<0.001). In Sirius meibography, the average loss for the upper eyelid was 23.08% ± 6.55% in e-cigarette group and 17.60% ± 4.94% in control group (p=0.002), and the average loss for the lower eyelid was 27.84% ± 5.98% and 18.44% ± 5.91%, respectively (p<0.001). Additionally, a significant positive correlation was identified between the loss rates for both upper and lower eyelid meibography with e-cigarette smoking duration (r=0.348, p<0.013 and r=0.550, p<0.001, respectively). CONCLUSION: Long-term e-cigarette smoking causes damage to the meibomian glands; therefore, meibomian gland damage should be considered in ocular surface disorders due to e-ci-garette smoking.

Ocular surface assessment and morphological alterations in meibomian glands with non-contact meibography in electronic cigarette smokers / Avaliação da superfície ocular e das alterações morfológicas nas glândulas meibomianas através de meibografia sem contato em usuários de cigarros eletrônicos

ABSTRACT Purpose: The study aimed to evaluate the ocular surface and meibomian gland morphology in electronic cigarette (e-cigarette) smokers. Methods: The upper and lower eyelids of 25 male e-cigarette smokers and 25 healthy male non-smoker patients were evaluated using Sirius meibography. Meibomian glands loss was automatically calculated using Phoenix meibography imaging software module, with the result obtained as percentage loss. Ocular Surface Disease Index (OSDI) questionnaire, tear breakup time test, and Schirmer II test were administered and performed in all cases. Results: The mean e-cigarette smoking duration was 4.9 ± 0.9 (range, 3.4-7) years. While the mean Schirmer II test value was 9.16 ± 2.09 mm in e-cigarette group, it was 11.20 ± 2.14 mm in control group (p=0.003). Mean tear breakup time was 6.96 ± 2.31 seconds in e-cigarette group and 9.84 ± 2.13 seconds in control group (p=0.002). The mean OSDI value was 28.60 ± 6.54 and 15.16 ± 7.23 in e-cigarette and control groups, respectively (p<0.001). In Sirius meibography, the average loss for the upper eyelid was 23.08% ± 6.55% in e-cigarette group and 17.60% ± 4.94% in control group (p=0.002), and the average loss for the lower eyelid was 27.84% ± 5.98% and 18.44% ± 5.91%, respectively (p<0.001). Additionally, a significant positive correlation was identified between the loss rates for both upper and lower eyelid meibography with e-cigarette smoking duration (r=0.348, p<0.013 and r=0.550, p<0.001, respectively). Conclusion: Long-term e-cigarette smoking causes damage to the meibomian glands; therefore, meibomian gland damage should be considered in ocular surface disorders due to e-ci­garette smoking.

RESUMO Objetivo: Avaliar a superfície ocular e a morfologia da glândula meibomiana em usuários de cigarros eletrônicos. Métodos: Foram avaliadas através de meibografia Sirius as pálpebras superiores e inferiores de 25 usuários de cigarros eletrônicos do sexo masculino e 25 pacientes não usuários saudáveis, também do sexo masculino. A perda nas glândulas meibomianas foi calculada automaticamente com o módulo de software de imagem de meibografia Phoenix. O resultado foi obtido como perda percentual. O questionário Ocular Surface Disease Index (OSDI), o teste do tempo de ruptura lacrimal e o teste de Schirmer II foram administrados em todos os casos. Resultados: A duração média do uso de cigarros eletrônicos foi de 4,9 ± 0,9 anos (intervalo de 3,4-7 anos). O valor médio do teste de Schirmer II foi de 9,16 ± 2,09 mm no grupo de usuários de cigarros eletrônicos e de 11,20 ± 2,14 mm no grupo controle (p=0,003). O valor médio do teste do tempo de ruptura lacrimal foi de 6,96 ± 2,31 segundos no grupo de usuários de cigarros eletrônicos e 9,84 ± 2,13 segundos no grupo controle (p=0,002). O valor médio do Ocular Surface Disease Index foi de 28,60 ± 6,54 e 15,16 ± 7,23 para os grupos de usuários de cigarros eletrônicos e controle, respectivamente (p<0,001). Na meibografia de Sirius, a perda média para a pálpebra superior foi de 23,08 ± 6,55% para o grupo de usuários de cigarros eletrônicos e 17,60 ± 4,94% para o grupo controle (p=0,002), e a perda média para a pálpebra inferior foi de 27,84 ± 5,98% e 18,44 ± 5,91%, respectivamente (p<0,001). Além disso, foi observada uma correlação positiva significativa entre a taxa de perda na meibografia palpebral superior e inferior com a duração do tabagismo eletrônico, respectivamente de (r=0,348, p<0,013) e (r=0,550, p<0,001). Conclusão: O uso prolongado de cigarros eletrônicos causa danos às glândulas meibomianas. Portanto, esses danos devem ser considerados em distúrbios da superfície ocular devidos ao uso desses dispositivos.

A novel BH3 mimetic Bcl-2 inhibitor promotes autophagic cell death and reduces in vivo Glioblastoma tumor growth.

Anti-apoptotic members of the Bcl-2 family proteins play central roles in the regulation of cell death in glioblastoma (GBM), the most malignant type of brain tumor. Despite the advances in GBM treatment, there is still an urgent need for new therapeutic approaches. Here, we report a novel 4-thiazolidinone derivative BH3 mimetic, BAU-243 that binds to Bcl-2 with a high affinity. BAU-243 effectively reduced overall GBM cell proliferation including a subpopulation of cancer-initiating cells in contrast to the selective Bcl-2 inhibitor ABT-199. While ABT-199 successfully induces apoptosis in high BCL2-expressing neuroblastoma SHSY-5Y cells, BAU-243 triggered autophagic cell death rather than apoptosis in GBM A172 cells, indicated by the upregulation of BECN1, ATG5, and MAP1LC3B expression. Lc3b-II, a potent autophagy marker, was significantly upregulated following BAU-243 treatment. Moreover, BAU-243 significantly reduced tumor growth in vivo in orthotopic brain tumor models when compared to the vehicle group, and ABT-199 treated animals. To elucidate the molecular mechanisms of action of BAU-243, we performed computational modeling simulations that were consistent with in vitro results. Our results indicate that BAU-243 activates autophagic cell death by disrupting the Beclin 1:Bcl-2 complex and may serve as a potential small molecule for treating GBM.

Analysis of optical coherence tomography angiographic findings of prematurely born children and its relationship with macular edema of prematurity.

PURPOSE: To compare foveal avascular zone (FAZ) area, foveal vascular density (VD), and foveal thickness in pre- and full-term children and to evaluate their relationship with cystoid macular edema (CME) in the prematurity period using spectral domain optical coherence tomography angiography (SD-OCTA). METHODS: OCTA imaging was performed at 4-6 years of age in 90 eyes of 45 prematurely born children and 50 eyes of 25 term children. Subjects were divided into three groups: prematurely born with CME (group 1); prematurely born without CME (group 2); healthy, term children (group 3). Imaging results in the three groups were compared. RESULTS: FAZ area was significantly larger in group 3 than in groups 1 and 2 (P < 0.001 [ANOVA]). FAZ area was found to be correlated with birth weight (r = 0.511; P < 0.001) and gestational age (r = 0.532; P < 0.001). No significant relationship was found between history of CME and FAZ area. CONCLUSIONS: In our study cohort, FAZ area was smaller in prematurely born children and was correlated with older gestational age and higher birth weight. CME in the neonatal period did not seem to affect retinal microvascular development in premature infants.

Design and synthesis of novel caffeic acid phenethyl ester (CAPE) derivatives and their biological activity studies in glioblastoma multiforme (GBM) cancer cell lines.

Glioblastoma Multiforme (GBM) is the most aggressive brain tumor and classified as one of the deadliest cancers. The current treatment plans for GBM remains to be ineffective because of its rapid progress and inability of the drugs used to cross the blood-brain barrier (BBB). Thus, developing more effective and potent medicines for GBM are needed. There have been several reports demonstrating that CAPE presents reasonably good anti-cancer activity in certain cancer cell lines and can penetrate the blood-brain barrier. Accordingly, in this study we synthesized several novel CAPE analogs with the addition of more druggable handles and solubilizing entities and subsequently evaluated their in vitro therapeutic efficacies in GBM cell lines (T98G and LN229). The most potent compound was then examined extensively and results showed that the 50 µM novel CAPE analog (compound 10) significantly decreases the viability of both T98G and LN229 GBM cells as compared to CAPE itself. Moreover, the compound 10 was not cytotoxic to healthy human cells (fibroblast-like mesenchymal stem cells) at the same concentration. Apoptotic (32.8%, and 44.6%) cell populations were detected in the compound 10 treated groups for LN229 and T98G, respectively. As an indication of apotosis, significantly increased PARP cleavage was detected in compound 10 versus CAPE treated LN229. In addition, we conducted molecular docking and molecular dynamics (MD) simulations studies on certain targets playing roles on GBM disease pathway such as NF-κB, EGFR, TNF-α, ERK2, PAPR1, hCA IX and hCA XII. Our findings demonstrated that designed CAPE analogs have anti-cancer activity on GBM cells and in silico studies also demonstrate the inhibitory ability of suggested compounds via interactions with critical residues in binding pockets of studied targets. Here, we suggest the novel CAPE analog to study further against GBM. Therefore, identification of the compound related molecular signature may provide more to understand the mechanism of action.

Screening of Clinically Approved and Investigation Drugs as Potential Inhibitors of SARS-CoV-2: A Combined in silico and in†vitro Study.

In the current study, we used 7922 FDA approved small molecule drugs as well as compounds in clinical investigation from NIH's NPC database in our drug repurposing study. SARS-CoV-2 main protease as well as Spike protein/ACE2 targets were used in virtual screening and top-100 compounds from each docking simulations were considered initially in short molecular dynamics (MD) simulations and their average binding energies were calculated by MM/GBSA method. Promising hit compounds selected based on average MM/GBSA scores were then used in long MD simulations. Based on these numerical calculations following compounds were found as hit inhibitors for the SARS-CoV-2 main protease: Pinokalant, terlakiren, ritonavir, cefotiam, telinavir, rotigaptide, and cefpiramide. In addition, following 3 compounds were identified as inhibitors for Spike/ACE2: Denopamine, bometolol, and rotigaptide. In order to verify the predictions of in silico analyses, 4 compounds (ritonavir, rotigaptide, cefotiam, and cefpiramide) for the main protease and 2 compounds (rotigaptide and denopamine) for the Spike/ACE2 interactions were tested by in vitro experiments. While the concentration-dependent inhibition of the ritonavir, rotigaptide, and cefotiam was observed for the main protease; denopamine was effective at the inhibition of Spike/ACE2 binding.

Synthesis, molecular docking and molecular dynamics studies of novel tacrine-carbamate derivatives as potent cholinesterase inhibitors.

In the present study, new tacrine derivatives containing carbamate group were synthesized and their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition activities were evaluated. All synthesized compounds inhibited both cholinesterases at nanomolar level. Among them, ((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl(3-nitrophenyl) carbamate (6k) showed the best inhibitor activity against AChE and BuChE with IC50 value of 22.15 nM and 16.96 nM, respectively. The calculated selectivity index revealed that the synthesized compounds (exclude 6l) have stronger inhibitory activity against BuChE than AChE. The most selective compound was 2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl(4-methoxyphenyl)-carbamate (6b) with the selectivity index of 0.12. Molecular modeling approaches were employed to understand the interaction between the synthesized compounds and proteins. As carbamate derivatives can act as pseudo-irreversible inhibitors of AChE and BuChE, covalent docking approaches was applied to determine the binding modes of novel compounds at binding sites of cholinesterase enzymes.

Near-physiological-temperature serial crystallography reveals conformations of SARS-CoV-2 main protease active site for improved drug repurposing.

The COVID-19 pandemic has resulted in 198 million reported infections and more than 4 million deaths as of July 2021 (covid19.who.int). Research to identify effective therapies for COVID-19 includes: (1) designing a vaccine as future protection; (2) de novo drug discovery; and (3) identifying existing drugs to repurpose them as effective and immediate treatments. To assist in drug repurposing and design, we determine two apo structures of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease at ambient temperature by serial femtosecond X-ray crystallography. We employ detailed molecular simulations of selected known main protease inhibitors with the structures and compare binding modes and energies. The combined structural and molecular modeling studies not only reveal the dynamics of small molecules targeting the main protease but also provide invaluable opportunities for drug repurposing and structure-based drug design strategies against SARS-CoV-2.

Structural and Functional Characterization of Allatostatin Receptor Type-C of Thaumetopoea pityocampa, a Potential Target for Next-Generation Pest Control Agents.

Insect neuropeptide receptors, including allatostatin receptor type C (AstR-C), a G protein-coupled receptor, are among the potential targets for designing next-generation pesticides that despite their importance in offering a new mode-of-action have been overlooked. Focusing on AstR-C of Thaumetopoea pityocampa, a common pest in Mediterranean countries, by employing resonance energy transfer-based methods, we showed Gαi/o coupling and ß-arrestin recruitment of the receptor at sub-nanomolar and nanomolar ranges of the endogenous ligand, AST-C, respectively. Molecular docking and molecular dynamics simulation studies revealed the importance of extracellular loop 2 in AstRC/AST-C interaction, and a combination of in silico and in vitro approaches showed the substantial role of Q2716.55 in G protein-dependent activation of AstR-C possibly via contributing to the flexibility of the receptor's structure. The functional and structural insights obtained on T. pit AstR-C positively assist future efforts in developing environmentally friendly pest control agents that are needed urgently.