Bilateral optic neuropathy associated with lorlatinib monotherapy for ALK-positive metastatic lung adenocarcinoma.

Purpose: This report details the characteristics of a case of bilateral optic neuropathy during treatment with oral lorlatinib for ALK-positive metastatic adenocarcinoma of the lung. Observations: A 57-year-old woman with metastatic adenocarcinoma of the lung receiving treatment with lorlatinib presented to the ophthalmology urgent care with bilateral loss of vision that had progressed to no light perception over the previous 2 weeks. She was hospitalized for an extensive autoimmune, infectious, neoplastic, and paraneoplastic workup, which revealed enhancement of both optic nerves extending up to the optic chiasm and an area of restricted diffusion in the splenium of the corpus callosum on MRI. Lorlatinib was discontinued by her oncologist and she received treatment with five days of pulse-dose intravenous solumedrol as well as five days of plasmapheresis with gradual improvement in her vision. In follow-up, her vision had improved to 20/40 and 20/30. Conclusion and importance: There have been few reports describing vision loss associated with lorlatinib, an ALK/ROS1 targeted tyrosine kinase inhibitor used to treat metastatic lung adenocarcinoma. This report details the characteristics of a case of bilateral retrobulbar optic neuropathy as well as the treatment and recovery of such a case. Further exploration is needed in order to improve our understanding of the pathogenesis of this rare but potentially devastating adverse effect.

Changes in the hippocampal level of tau but not beta-amyloid may mediate anxiety-like behavior improvement ensuing from exercise in diabetic female rats.

BACKGROUND: In the present study, we investigated the effect of high-intensity interval training (HIIT) on cognitive behaviors in female rats with a high-fat diet + streptozotocin (STZ)-induced type 2 diabetes. METHODS: Twenty-four female rats were divided into four groups randomly (n = 6): control (C), control + exercise (Co + EX), diabetes mellitus (type 2) (T2D), and diabetes mellitus + exercise (T2D + EX). Diabetes was induced by a two-month high-fat diet and a single dose of STZ (35 mg/kg) in the T2D and T2D + EX groups. The Co + EX and T2D + EX groups performed HIIT for eight weeks (five sessions per week, running on a treadmill at 80-100% of VMax, 4-10 intervals). Elevated plus maze (EPM) and open field test (OFT) were used for assessing anxiety-like behaviors, and passive avoidance test (PAT) and Morris water maze (MWM) were applied for evaluating learning and memory. The hippocampal levels of beta-amyloid (Aß) and Tau were also assessed using Western blot. RESULTS: An increase in fasting blood glucose (FBG), hippocampal level of Tau, and a decrease in the percentage of open arm time (%OAT) as an index of anxiety-like behavior were seen in the female diabetic rats which could be reversed by HIIT. In addition, T2D led to a significant decrease in rearing and grooming in the OFT. No significant difference among groups was seen for the latency time in the PAT and learning and memory in the MWM. CONCLUSIONS: HIIT could improve anxiety-like behavior at least in part through changes in hippocampal levels of Tau.

Pharmacotherapeutic potential of Vitis vinifera(grape) in age-related neurological diseases / Potencial farmacoterapéutico de Vitis vinifera(uva) en enfermedades neurológicas asociadas a la edad

Age-related neurological disorders (ANDs), including neurodegenerative diseases, are complex illnesses with an increasing risk with advancing years. The central nervous system's neuropathological conditions, including oxidative stress, neuroinflammation, and protein misfolding, are what define ANDs. Due to the rise in age-dependent prevalence, efforts have been made to combat ANDs. Vitis viniferahas a long history of usageto treat a variety of illness symptoms. Because multiple ligand sites may be targeted, Vitis viniferacomponents can be employed to treat ANDs. This is demonstrated by the link between the structure and action of these compounds. This review demonstrates that Vitis viniferaand its constituents, including flavonoids, phenolic compounds, stilbenoidsandaromatic acids, are effective at reducing the neurological symptoms and pathological conditions of ANDs. This is done by acting as an antioxidant and anti-inflammatory. The active Vitis vinifera ingredients have therapeutic effects on ANDs, as this review explains.

Las enfermedades neurológicas asociadas a la edad (AND, por su sigla en inglés) incluyendo las enfermedades neurodegenerativas, son enfermedades complejas con un riesgo creciente con la edad. Las condiciones neuropatológicas del sistema nervioso central, que incluyen el estrés oxidativo, la neuro inflamación, y el plegado erróneo de proteínas, son lo que define las AND. Debido al aumento en la prevalencia dependiente de la edad, se han hecho esfuerzos para combatir las AND. Vitis vinifera tiene una larga historia de uso para el tratamiento de síntomas. Puesto que puede hacer objetivo a muchos sitios ligando, los componentes de Vitis viniferase pueden utilizar para tratar AND. Esto se demuestra por el vínculo entre la estructura y la acción de estos compuestos. Esta revisión demuestra que la Vitis viniferay sus constituyentes, incluídos los flavonoides, componentes fenólicos, estilbenoides, y ácidos aromáticos, son efectivos para reducir los síntomas neurológicos y las condiciones patológicas de AND. Esto se produce por su acción como antioxidante y antiinflamatorio. Los ingredientes activos de Vitis vinifera tienen efectos terapéuticos en AND, y esta revisión lo explica.

High Intensity Interval Training can Ameliorate Hypothalamic Appetite Regulation in Male Rats with Type 2 Diabetes: The Role of Leptin.

Disruption of leptin (LEP) signaling in the hypothalamus caused by type 2 diabetes (T2D) can impair appetite regulation. The aim of this study was to investigate whether the improvement in appetite regulation induced by high-intensity interval training (HIIT) in rats with T2D can be mediated by LEP signaling. In this study, 20 male Wister rats were randomly assigned to one of four groups: CO (non-type 2 diabetes control), T2D (type 2 diabetes), EX (non-type 2 diabetes exercise), and T2D + EX (type 2 diabetes + exercise).To induce T2D, a combination of a high-fat diet for 2 months and a single dose of streptozotocin (35 mg/kg) was administered. Rats in the EX and T2D + EX groups performed 4-10 intervals of treadmill running at 80-100% of their maximum velocity (Vmax). Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), serum levels of insulin (INS) and LEP (LEPS) as well as hypothalamic expression of LEP receptors (LEP-R), Janus kinase 2 (JAK-2), signal transducer and activator of transcription 3 (STAT-3), neuropeptide Y (NPY), agouti-related protein (AGRP), pro-opiomelanocortin cocaine (POMC), amphetamine-related transcript (CART), suppressor of cytokine signaling (SOCS3), forkhead box protein O1 (FOXO1) were assessed. ANOVA and Tukey post hoc tests were used to compare the results between the groups. The levels of LEPS and INS, as well as the levels of LEP-R, JAK-2, STAT-3, POMC, and CART in the hypothalamus were found to be higher in the T2D + EX group compared to the T2D group. On the other hand, the levels of HOMA-IR, NPY, AGRP, SOCS3, and FOXO1 were lower in the T2D + EX group compared to the T2D group (P < 0.0001). The findings of this study suggest that HIIT may improve appetite regulation in rats with T2D, and LEP signaling may play a crucial role in this improvement. Graphical abstract (leptin signaling in the hypothalamus), Leptin (LEP), Leptin receptor (LEP-R), Janus kinase 2 (JAK2), Signal transducer and activator of transcription 3 (STAT3), expressing Neuropeptide Y (NPY), Agouti-related protein (AGRP), anorexigenic neurons (expressing pro-opiomelanocortin cocaine (POMC), Amphetamine-related transcript (CART), suppressor of cytokine signaling (SOCS3), forkhead box protein O1 (FOXO1).

Adiponectin receptor 1 could explain the sex differences in molecular basis of cognitive improvements induced by exercise training in type 2 diabetic rats.

Adipokines dysregulation, the main reason for cognitive impairments (CI) induced by diabetes, shows a sex-dependent pattern inherently and in response to exercise. This study aimed to compare the attenuating effect of 8-week high intensity-interval training (HIIT) on type 2 diabetes (T2D)-induced CI between male and female rats with a special focus on adiponectin and leptin. 28 male & 28 female Wistar rats with an average age of 8 weeks were randomly assigned into four groups: control (Con), exercise (EX), Diabetes (T2D), and Type 2 diabetes + exercise (T2D + Ex). Rats in EX and T2D + EX groups performed HIIT for eight weeks (80-100% Vmax, 4-10 intervals). T2D was induced by 2 months of a high-fat diet and a single dose of STZ (35 mg/kg) administration. Leptin and adiponectin levels in serum were measured along with hippocampal expression of leptin and adiponectin receptors, AMP-activated protein kinase (AMPK), dephosphorylated glycogen synthase kinase-3 beta (Dep-GSK3ß), Tau, and beta-amyloid (Aß). Homeostasis model assessments (HOMAs) and quantitative insulin-sensitivity check index (QUICKI) indices were calculated. Our results showed that following T2D, serum levels of APN, and hippocampal levels of adiponectin receptor 1 (APNR1) were higher and HOMA-IR was lower in female than male rats (P < 0.05). However, after 8 weeks of HIIT, hippocampal levels of APNR1 and AMPK as well as QUICKI were lower and hippocampal levels of GSK, Tau, and Aß were higher in females compared to male rats (P < 0.05). While the risk of CI following T2D was more in male than female rats HIIT showed a more ameliorating effect in male animals with APN1 as the main player.

Molecular characterization of rotavirus infections in children less than 5 years of age with acute gastroenteritis in Tehran, Iran, 2021-2022: Emergence of uncommon G9P[4] and G9P[8] rotavirus strains.

The present study was conducted to monitor the genotypes of circulating species A rotavirus (RVA) in Iran and investigate genetic linkages between specific RVA VP7, VP4, VP6, and NSP4 segments. For this purpose, 48 RVA strains were detected during the 2021-2022 seasons. The two combinations of G9P[4] and G9P[8] RVA strains were predominant. However, several other combinations of RVA also were detected. Based on the distribution of I and E genotypes (46 strains) with respect to G and P, the most common strains were G9P[4]-I2-E2 (19.5%), G9P[4]-I2-E1 (6.5%), G9P[4]-I1-E1 (4.3%), G9P[8]-I1-E1 (19.5%), and G9P[8]-I2-E2 (10.9%), which were followed by several other combinations of G and P RVA strains with different pattern of I-E genotypes and also emerging, rare and uncommon strains. The present study described the continued circulation of G9 strains with the emergence of uncommon G9P[4] and G9P[8] reassortants with three and two different I-E genotypes, respectively, which have not been reported previously in Iran. Our findings indicated that these uncommon strains exhibited a unique genotype pattern comprising a mixture of genogroup 1 and 2 genes and suggest the need for further analysis of rare, uncommon, and emerging strains of RVA at all 11 gene segments to determine intergenogroup and intragenotype reassortments.

Evaluation of the Psychometric Properties of the Lebanon Waterpipe Dependence Scale in a Sample of Iranian Waterpipe Smokers.

BACKGROUND: Waterpipe tobacco smoking (WTS) has recently increased in Iran. There is no valid instrument to measure the level of nicotine dependence among its consumers. This study was aimed to investigate the validity and reliability of the Lebanon Waterpipe Dependence Scale-11 (LWDS-11). METHODS: A cross-sectional study was conducted in the year 2017 whereby 367 waterpipe smokers were recruited from Golestan Province of Iran. LWDS-11 scale is composed of 4 subscales: 1) nicotine dependence, 2) negative reinforcement, 3) psychological craving, and 4) positive reinforcement. The validity of the questionnaire was examined using construct validity. Reliability of this scale was examined using test-retest reliability and internal consistency. FINDINGS: The four-factor model for LWDS [comparative fit index (CFI) = 0.985, Tucker-Lewis index (TLI) = 0.979, standardised root mean residual (SRMR) = 0.059, root mean square error of approximation (RMSEA) = 0.049 (0.031, 0.061)] demonstrated good fit to this data. Cronbach's α was 0.825 for total scale and it was 0.818, 0.746, 0.624, and 0.670 for each individual subscale. The test-retest reliability of the scale was 0.925. CONCLUSION: All goodness of fit indices (GFIs) represented a good fit of model. The LWDS-11 scale had an appropriate remarkable validity and reliability for waterpipe consumers to measure the level of nicotine dependence and it appeared to be likely useful for utilizing in the clinical and epidemiological studies.

A new Ru(ii) polypyridyl complex as an efficient photosensitizer for enhancing the visible-light-driven photocatalytic activity of a TiO2/reduced graphene oxide nanocomposite for the degradation of atrazine: DFT and mechanism insights.

TiO2 is one of the most widely used semiconductors for photocatalytic reactions. However, its wide bandgap energy and fast charge recombination limit its catalytic activity. Thus, herein, a new Ru(ii) polypyridyl complex, [Ruii(tptz)(CH3CN)Cl2] (tptz = 2,4,6-tris(2-pyridyl)-1,3,5-triazine), was synthesized and used as a visible-light photosensitizer dye for improving the light harvesting and quantum efficiency of TiO2. Accordingly, a well-designed nanostructured photocatalyst was proposed using mesoporous TiO2 nanocrystals coupled with reduced graphene oxide (rGO) and the polypyridyl Ru(ii) complex, which was tested for the photocatalytic degradation of atrazine (ATZ) as a model of emerging water contaminants. Specifically, the Ru complex (Ru-CMP) served as an electron donor, while rGO acted as an electron acceptor, and the synergistic effect between them promoted the separation of electron-hole pairs and suppressed the charge recombination in the hybridized species. Structural analysis indicated that the TiO2 nanoparticles with an anatase crystal structure had a mesoporous texture and were homogeneously coated on the rGO sheets. The detailed FT-IR, Raman, XPS and UV-vis absorption spectroscopic analyses combined with EDS mapping clearly confirmed the successful loading of the Ru complex onto the catalyst. The PL and EIS results revealed that the addition of the Ru-CMP photosensitizer enhanced the charge separation and transport. The gas-phase geometry and energies of the molecular orbitals of the Ru complex were evaluated via DFT calculations. The results from the DFT calculations were consistent with the experimental results. Compared to pure TiO2, the as-synthesized Ru-CMP-TiO2/rGO hybrid exhibited significantly enhanced photocatalytic activity for the degradation of ATZ. The rate of ATZ degradation in the developed photocatalytic process with the Ru-CMP-TiO2/rGO hybrid was 9 times that with commercial TiO2. The enhanced photocatalytic activity of the prepared catalyst can be attributed to its better light harvesting and efficient electron transportation due to its more suitable LUMO position than the conduction band of TiO2. Moreover, the excellent conductivity and adsorption capacity of graphene contributed to the increase in photocatalytic activity. Thus, these features make the Ru-CMP-TiO2/rGO hybrid nanomaterial an excellent candidate for the photocatalytic purification of contaminated water.

Relations between Structural and Luminescence Properties of Novel Lanthanide Nitrate Complexes with Bis-phosphoramidate Ligands.

Five new bisphosphoramide-based LnIII nitrate complexes [La2(NO3)6L3I] n (1), [Ce2(NO3)6L3I] n (2), [Sm2(NO3)6L3II] n (3), Sm2(NO3)6L3III (4), and Er(NO3)3L2III (5) [LI = piperazine-1,4-diylbis(diphenyl phosphine oxide), LII = N, N'-(ethane-1,2-diyl)bis( N-methyl- P, P-diphenylphosphinic amide, and LIII = N, N'-(ethane-1,2-diyl)bis( P, P-diphenylphosphinic amide)] have been synthesized and characterized by elemental analysis, IR spectroscopy, thermogravimetric analysis (TGA), and single crystal X-ray and powder diffractions. The results of the X-ray diffraction analysis revealed the new polymorph of LIII, and the structural diversity of the synthesized complexes in the solid state. Complexes 1-3 display two-dimensional coordination polymers (2D-CP), containing layers with honeycomb (6, 3) topology. In these 2D-CPs, each Ln center (La, Ce, and Sm in 1, 2, and 3, respectively) could be considered as a triconnected node, linked by three bridging bisphosphoramide ligands as two-connecting linkers. In contrast, 4 is a discrete binuclear complex, in which bidentate LIII ligand has two entirely different conformations: the syn chelating and the anti bridging. Cationic complex 5 shows the monomeric structure, where bidentate LIII adopts the syn-chelating conformation. A comprehensive luminescence investigation has been performed on free ligands and their corresponding complexes as well. The synthesized compounds display a variety of luminescence behavior, including the ligand-centered fluorescence in 1, 2, and 5, two distinct emission peaks in 1 and 2, characteristic Sm-centered f-f emission in 3 and 4, and excitation-dependent emission in LIII, 1, and 2. Furthermore, the time-dependent density functional theory (TD-DFT) study was carried out on the reported compounds to understand the nature of the emission peaks and the observed luminescence properties. The solid-state emission quantum yields of lanthanide complexes were also determined at different excitation wavelengths.

Toward the comprehensive calculations on the relationship between 1 H, 13 C, 31 P chemical shifts, 2 JPH , and the bonding structure of different phosphoryl benzamides.

A comprehensive investigation was performed on 1 H, 13 C, and 31 P nuclear magnetic resonance (NMR) chemical shifts (CSs) of phosphoryl benzamide derivatives (C6 H5 C(O)NHP(O)R1 R2 ), (R1 , R2  = aziridine [L1 ], azetidine [L2 ], pyrrolidine [L3 ], piperidine [L4 ], azepane [L5 ], 4-methylpiperidine [L6 ], propane-2-amine [L7 ], and 2-methylpropane-2-amine [L8 ]) by the gauge-independent atomic orbital method (GIAO) to find the most accordant level of theory with the experimental values. To achieve this goal, all the structures were optimized using the B3LYP, BP86, PBE1PBE, M06-2X, MPWB1K, and MP2 methods with 6-31+G* basis set. Computed structural parameters demonstrate that BP86 has the best agreement to the experimental values between the other methods. The def2-TZVP and aug-cc-pVDZ basis sets were also employed to inspect the effect of different types of basis sets with higher polarization and diffuse functions. The correlation between the empirical and computational values attests that 6-31+G* basis set is the optimum case regarding minimization of the costs and results. The comparison between calculated and experimental CSs at all mentioned combinations illustrated that in accordance with structural results, the best level of theory in CSs is also BP86/6-31+G*. Besides, 2 JPH values were computed with an acceptable agreement to experimental data at the optimum level of theory. The dependency between 2 JPH and the bonding structure of studied ligands was also scrutinized by the Natural Bond Orbital (NBO) analysis that interprets the relationship between the electronic properties and 2 JPH values.

A theoretical study on the coordination behavior of some phosphoryl, carbonyl and sulfoxide derivatives in lanthanide complexation.

The selectivity of phosphoryl P(O)R3, sulfoxide S(O)R2, and carbonyl C(O)R2 (R = NH2, CH3, OH, and F) derivatives with lanthanide cations (La3+, Eu3+, Lu3+) was studied by density functional theory calculations. Theoretical approaches were also used to investigate energy and the nature of metal-ligand interaction in the model complexes. Atoms in molecules and natural bond orbital (NBO) analyses were accomplished to understand the electronic structure of ligands, L, and the related complexes, L-Ln3+. NBO analysis demonstrated that the negative charge on phosphoryl, carbonyl, and sulfoxide oxygen (OP, OC, and OS) has maximum and minimum values when the connected -R groups are -NH2 and -F. The metal-ligand distance declines as, -F > -OH > -CH3 > -NH2. Charge density at the bond critical point and on the lanthanide cation in the L-Ln3+ complexes varies in the order -F < -OH < -CH3 < -NH2, due to greater ligand to metal charge transfer, which is well explained by energy decomposition analysis. It was also illustrated that E(2) values of Lp(N) → σ*(Y-N) vary in the order P=O ˃ S=O ˃ C=O and the related values of Lp(N) → σ*(Y=O) change as C=O ˃ S=O ˃ P=O in (NH2)nYO ligands (Y = P, C, and S). Trends in the L-Ln3+ CP-corrected bond energies are in good accordance with the optimized OY⋯Ln distances. It seems that, comparing the three types of ligands studied, NH2-substituted are the better coordination ligands. Graphical Abstract Density functional theory (B3LYP) calculations were used to compare structural, electronic and energy aspects of lanthanide (La, Eu, Lu) complexes of phosphine derivatives with those of carbonyls and sulfoxides in which the R- groups connected to the P=O, C=O and S=O are -NH2, -CH3, -OH and -F.

Pore formation and the key factors in antibacterial activity of aurein 1.2 and LLAA inside lipid bilayers, a molecular dynamics study.

Aurein 1.2 and LLAA are two antimicrobial peptides with different antibacterial activities (LLAA>Aurein 1.2), though their amino acid sequences are similar. In this manuscript, we study the key features for the different antibacterial activities of these peptides using molecular dynamics simulation. We find that in water, both peptides become disordered and LLAA is observed to have higher water-solubility, a feature which may contribute to enhancing its propensity to disrupt the bilayer and thus higher activity. Both peptides are also investigated while they are initially located inside lipid bilayer as a pre-formed vertical channel composed of five parallel copies of each peptide. LLAA demonstrates larger structural deviation from the initial helical structure and also more structural flexibility which is concluded to be a key feature in its stronger activity. In the presence of LLAA, the bilayer order is perturbed more pronouncedly and the number of water molecules penetrating into bilayer is higher. It is shown that stronger electrostatic interactions, more hydrophobic contacts and more hydrogen bonds between lipid and LLAA also lead to stronger activity of LLAA. The simulation results show instability of the barrel-stave pores for our peptides inside lipid bilayers.

Phosphoramides bearing isoxazole derivative: spectroscopic and structural characterization, study of hydrogen-bonding interactions and two lanthanide complexes (LnIII = Ce and Eu).

In this study, the synthesis and spectroscopic characterization of new phosphoramides based on 3-amino-5-methylisoxazole with the formula R2P(O)[NH-C4H4NO], R = C6H5O (1), C6H5 (2), RP(O)[NH-C4H4NO]2, R = C6H5O (3), CH3-C6H4O (4), C6H5NH (5), (C6H5)ClP(O)[NH-C4H4NO] (6) and two lanthanide complexes [Ln(2)2(NO3)3(EtOH)]·EtOH, Ln(III) = Ce (7) and Eu (8), have been reported. The structural study of (3) shows the presence of two conformers (crystallographically independent molecules) in the crystalline lattice, caused by different orientations of the phenyl and isoxazole rings. For (3), the intermolecular interactions have been studied by Hirshfeld surface analysis and fingerprint plots. Furthermore, the electronic and energy aspects of hydrogen bonds between molecules of (3) have been explored by density functional theory (DFT) calculations. X-ray crystallography of complexes (7) and (8) reveals that two phosphoramide ligands take part in coordination to the metal, one as monodentate from O(phosphoryl), and the other one as chelate through O(phosphoryl) and N(ring). The complexes are also composed of two conformers in the solid-state structure. Quantum theory of atoms in molecules (QTAIM) analysis discloses the electrostatic nature of the Ln-ligand interaction.