Suppression of frontal eye field neuronal responses with maintained fixation.

The decision of where to make an eye movement is thought to be driven primarily by responses to stimuli in neurons' receptive fields (RFs) in oculomotor areas, including the frontal eye field (FEF) of prefrontal cortex. It is also thought that a saccade may be generated when the accumulation of this activity in favor of one location or another reaches a threshold. However, in the reading and scene perception fields, it is well known that the properties of the stimulus at the fovea often affect when the eyes leave that stimulus. We propose that if FEF plays a role in generating eye movements, then the identity of the stimulus at fixation should affect the FEF responses so as to reduce the probability of making a saccade when fixating an item of interest. Using a visual foraging task in which animals could make multiple eye movements within a single trial, we found that responses were strongly modulated by the identity of the stimulus at the fovea. Specifically, responses to the stimulus in the RF were suppressed when the animal maintained fixation for longer durations on a stimulus that could be associated with a reward. We suggest that this suppression, which was predicted by models of eye movement behavior, could be a mechanism by which FEF can modulate the temporal flow of saccades based on the importance of the stimulus at the fovea.

Neurons in FEF Keep Track of Items That Have Been Previously Fixated in Free Viewing Visual Search.

When searching a visual scene for a target, we tend not to look at items or locations we have already searched. It is thought that this behavior is driven by an inhibitory tagging mechanism that inhibits responses on priority maps to the relevant items. We hypothesized that this inhibitory tagging signal should be represented as an elevated response in neurons that keep track of stimuli that have been fixated. We recorded from 231 neurons in the frontal eye field (FEF) of 2 male animals performing a visual foraging task, in which they had to find a reward linked to one of five identical targets (Ts) among five distractors. We identified 38 neurons with activity that was significantly greater when the stimulus in the receptive field had been fixated previously in the trial than when it had not been fixated. The response to a fixated object began before the saccade ended, suggesting that this information is remapped. Unlike most FEF neurons, the activity in these cells was not suppressed during active fixation, had minimal motor responses, and did not change through the trial. Yet using traditional classifications from a memory-guided saccade, they were indistinguishable from the rest of the FEF population. We propose that these neurons keep track of any items that have been fixated within the trial and this signal is propagated by remapping. These neurons could be the source of the inhibitory tagging signal to parietal cortex, where a neuronal instantiation of inhibitory tagging is seen.SIGNIFICANCE STATEMENT When we search a scene for an item, we rarely examine the same location twice. It is thought that this is due to a neural mechanism that keeps track of the items at which we have looked. Here we identified a subset of neurons in the frontal eye field that preferentially responded to items that had been fixated earlier in the trial. These responses were remapped, appearing before the saccade even ended, and were not suppressed during maintained fixation. We propose that these neurons keep track of which items have been examined in search and could be the source of feedback that creates the inhibitory tagging seen in parietal cortex.

Metal-based biologically active azoles and ß-lactams derived from sulfa drugs.

Metal complexes of Schiff bases derived from sulfamethoxazole (SMZ) and sulfathiazole (STZ), converted to their ß-lactam derivatives have been synthesized and experimentally characterized by elemental analysis, spectral (IR, (1)H NMR, (13)C NMR, and EI-mass), molar conductance measurements and thermal analysis techniques. The structural and electronic properties of the studied molecules were investigated theoretically by performing density functional theory (DFT) to access reliable results to the experimental values. The spectral and thermal analysis reveals that the Schiff bases act as bidentate ligands via the coordination of azomethine nitrogen to metal ions as well as the proton displacement from the phenolic group through the metal ions; therefore, Cu complexes can attain the square planner arrangement and Zn complexes have a distorted tetrahedral structure. The thermogravimetric (TG/DTG) analyses confirm high stability for all complexes followed by thermal decomposition in different steps. In addition, the antibacterial activities of synthesized compounds have been screened in vitro against various pathogenic bacterial species. Inspection of the results revealed that all newly synthesized complexes individually exhibit varying degrees of inhibitory effects on the growth of the tested bacterial species, therefore, they may be considered as drug candidates for bacterial pathogens. The free Schiff base ligands (1-2) exhibited a broad spectrum antibacterial activity against Gram negative Escherichia coli, Pseudomonas aeruginosa, and Proteus spp., and Gram positive Staphylococcus aureus bacterial strains. The results also indicated that the ß-lactam derivatives (3-4) have high antibacterial activities on Gram positive bacteria as well as the metal complexes (5-8), particularly Zn complexes, have a significant activity against all Gram negative bacterial strains. It has been shown that the metal complexes have significantly higher activity than corresponding ligands due to chelation process which reduces the polarity of metal ion by coordinating with ligands.

NMR Metabolomics Show Evidence for Mitochondrial Oxidative Stress in a Mouse Model of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is associated with metabolic and endocrine disorders in women of reproductive age. The etiology of PCOS is still unknown. Mice prenatally treated with glucocorticoids exhibit metabolic disturbances that are similar to those seen in women with PCOS. We used an untargeted nuclear magnetic resonance (NMR)-based metabolomics approach to understand the metabolic changes occurring in the plasma and kidney over time in female glucocorticoid-treated (GC-treated) mice. There are significant changes in plasma amino acid levels (valine, tyrosine, and proline) and their intermediates (2-hydroxybutyrate, 4-aminobutyrate, and taurine), whereas in kidneys, the TCA cycle metabolism (citrate, fumarate, and succinate) and the pentose phosphate (PP) pathway products (inosine and uracil) are significantly altered (p < 0.05) from 8 to 16 weeks of age. Levels of NADH, NAD(+), NAD(+)/NADH, and NADH redox in kidneys indicate increased mitochondrial oxidative stress from 8 to 16 weeks in GC-treated mice. These results indicate that altered metabolic substrates in the plasma and kidneys of treated mice are associated with altered amino acid metabolism, increased cytoplasmic PP, and increased mitochondrial activity, leading to a more oxidized state. This study identifies biomarkers associated with metabolic dysfunction in kidney mitochondria of a prenatal gluococorticoid-treated mouse model of PCOS that may be used as early predictive biomarkers of oxidative stress in the PCOS metabolic disorder in women.

Metabolic profiling reveals reprogramming of lipid metabolic pathways in treatment of polycystic ovary syndrome with 3-iodothyronamine.

Complex diseases such as polycystic ovary syndrome (PCOS) are associated with intricate pathophysiological, hormonal, and metabolic feedbacks that make their early diagnosis challenging, thus increasing the prevalence risks for obesity, cardiovascular, and fatty liver diseases. To explore the crosstalk between endocrine and lipid metabolic pathways, we administered 3-iodothyronamine (T1AM), a natural analog of thyroid hormone, in a mouse model of PCOS and analyzed plasma and tissue extracts using multidisciplinary omics and biochemical approaches. T1AM administration induces a profound tissue-specific antilipogenic effect in liver and muscle by lowering gene expression of key regulators of lipid metabolism, PTP1B and PLIN2, significantly increasing metabolites (glucogenic, amino acids, carnitine, and citrate) levels, while enhancing protection against oxidative stress. In contrast, T1AM has an opposing effect on the regulation of estrogenic pathways in the ovary by upregulating STAR, CYP11A1, and CYP17A1. Biochemical measurements provide further evidence of significant reduction in liver cholesterol and triglycerides in post-T1AM treatment. Our results shed light onto tissue-specific metabolic vs. hormonal pathway interactions, thus illuminating the intricacies within the pathophysiology of PCOS This study opens up new avenues to design drugs for targeted therapeutics to improve quality of life in complex metabolic diseases.

A novel series of thiosemicarbazone drugs: from synthesis to structure.

A new series of thiosemicarbazones (TSCs) and their 1,3,4-thiadiazolines (TDZs) containing acetamide group have been synthesized from thiosemicarbazide compounds by the reaction of TSCs with cyclic ketones as well as aromatic aldehydes. The structures of newly synthesized 1,3,4-thiadiazole derivatives obtained by heterocyclization of the TSCs with acetic anhydride were experimentally characterized by spectral methods using IR, (1)H NMR, (13)C NMR and mass spectroscopic methods. Furthermore, the structural, thermodynamic, and electronic properties of the studied compounds were also studied theoretically by performing Density Functional Theory (DFT) to access reliable results to the experimental values. The molecular geometry, the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO) and Mulliken atomic charges of the studied compounds have been calculated at the B3LYP method and standard 6-31+G(d,p) basis set starting from optimized geometry. The theoretical (13)C chemical shift results were also calculated using the gauge independent atomic orbital (GIAO) approach and their respective linear correlations were obtained.

Spectroscopic, thermal analysis and DFT computational studies of salen-type Schiff base complexes.

A new series of metal(II) complexes of Co(II), Ni(II), Cu(II), Zn(II), and Pb(II) have been synthesized from a salen-type Schiff base ligand derived from o-vanillin and 4-methyl-1,2-phenylenediamine and characterized by elemental analysis, spectral (IR, UV-Vis, (1)H NMR, (13)C NMR and EI-mass), molar conductance measurements and thermal analysis techniques. Coats-Redfern method has been utilized to calculate the kinetic and thermodynamic parameters of the metal complexes. The molecular geometry, Mulliken atomic charges of the studied compounds were investigated theoretically by performing density functional theory (DFT) to access reliable results to the experimental values. The theoretical (13)C chemical shift results of the studied compounds have been calculated at the B3LYP, PBEPBE and PW91PW91 methods and standard 6-311+G(d,p) basis set starting from optimized geometry. The comparison of the results indicates that B3LYP/6-311+G(d,p) yields good agreement with the observed chemical shifts. The measured low molar conductance values in DMF indicate that the metal complexes are non-electrolytes. The spectral and thermal analysis reveals that all complexes have octahedral geometry except Cu(II) complex which can attain the square planner arrangement. The presence of lattice and coordinated water molecules are indicated by thermograms of the complexes. The thermogravimetric (TG/DTG) analyses confirm high stability for all complexes followed by thermal decomposition in different steps.