Regioselective Brønsted acid catalyzed ring opening of aziridines by phenols and thiophenols; a gateway to access functionalized indolines, indoles, benzothiazines, dihydrobenzo-thiazines, benzo-oxazines and benzochromenes.

Brønsted acid catalyzed regioselective ring opening of aziridines by phenols and thiophenols have been reported. Involvement of a series of aziridines with a range of phenols and thiophenols offer the generality of the reported protocol. Completion of the reaction at room temperature within very short time brings the uniqueness of the developed technique. To emphasis on the application of the developed methodology, the products have been used for the further synthesis of a range of useful and novel heterocyclic molecules such as indolines, indoles, benzothiazines, dihydrobenzothiazines, benzo-oxazines and benzochromenes.

Homothorax controls a binary Rhodopsin switch in Drosophila ocelli.

Visual perception of the environment is mediated by specialized photoreceptor (PR) neurons of the eye. Each PR expresses photosensitive opsins, which are activated by a particular wavelength of light. In most insects, the visual system comprises a pair of compound eyes that are mainly associated with motion, color or polarized light detection, and a triplet of ocelli that are thought to be critical during flight to detect horizon and movements. It is widely believed that the evolutionary diversification of compound eye and ocelli in insects occurred from an ancestral visual organ around 500 million years ago. Concurrently, opsin genes were also duplicated to provide distinct spectral sensitivities to different PRs of compound eye and ocelli. In the fruit fly Drosophila melanogaster, Rhodopsin1 (Rh1) and Rh2 are closely related opsins that originated from the duplication of a single ancestral gene. However, in the visual organs, Rh2 is uniquely expressed in ocelli whereas Rh1 is uniquely expressed in outer PRs of the compound eye. It is currently unknown how this differential expression of Rh1 and Rh2 in the two visual organs is controlled to provide unique spectral sensitivities to ocelli and compound eyes. Here, we show that Homothorax (Hth) is expressed in ocelli and confers proper rhodopsin expression. We find that Hth controls a binary Rhodopsin switch in ocelli to promote Rh2 expression and repress Rh1 expression. Genetic and molecular analysis of rh1 and rh2 supports that Hth acts through their promoters to regulate Rhodopsin expression in the ocelli. Finally, we also show that when ectopically expressed in the retina, hth is sufficient to induce Rh2 expression only at the outer PRs in a cell autonomous manner. We therefore propose that the diversification of rhodpsins in the ocelli and retinal outer PRs occurred by duplication of an ancestral gene, which is under the control of Homothorax.

Regioselective Transition Metal-Free Catalytic Ring Opening of 2H-Azirines by Phenols and Naphthols; One-Pot Access to Benzo- and Naphthofurans.

Benzofuran and naphthofuran derivatives are synthesized from readily available phenols and naphthols. Regioselective ring openings of 2H-azirine followed by in situ aromatization using a catalytic amount of Brønsted acid have established the novelty of the methodology. The involvement of a series of 2H-azirines with a variety of phenols, 1-naphthols, and 2-naphthols showed the generality of the protocol. In-depth density functional theory calculations revealed the reaction mechanism with the energies of the intermediates and transition states of a model reaction. An alternate pathway of the mechanism has also been proposed with computer modeling.

One-pot C-C, C-N, and C-S bond construction for synthesis of 3-sulfenylindoles directly from unactivated anilines involving dual palladium catalysis and mechanistic insights from DFT.

An efficient dual Pd-catalytic system was developed for one-pot synthesis of 3-sulfenylindoles via C-C, C-N and C-S bond construction directly from unactivated 2-iodo(NH)anilines under mild reaction conditions. Furthermore, 3-selenyl/halo/carbon-functionalized indoles were synthesized in good yields and a short reaction time. The synthetic utility of 3-sulfenylindole was also demonstrated. The key role of solvent in palladium catalysis was unravelled by DFT.

Dopaminergic Axons: Key Recitalists in Parkinson's Disease.

Parkinson's disease (PD) is associated with dopamine depletion in the striatum owing to the selective and progressive loss of the nigrostriatal dopaminergic neurons, which results in motor dysfunction and secondary clinical manifestations. The dopamine level in the striatum is preserved because of the innervation of the substantia nigra (SN) dopaminergic neurons into it. Therefore, protection of the SN neurons is crucial for maintaining the dopamine level in the striatum and for ensuring the desired motor coordination. Several strategies have been devised to protect the degenerating dopaminergic neurons or to restore the dopamine levels for treating PD. Most of the methods focus exclusively on preventing cell body death in the neurons. Although advances have been made in understanding the disease, the search for disease-modifying drugs is an ongoing process. The present review describes the evidence from studies involving patients with PD as well as PD models that axon terminals are highly vulnerable to exogenous and endogenous insults and degenerate at the early stage of the disease. Impairment of mitochondrial dynamics, Ca2+ homeostasis, axonal transport, and loss of plasticity of axon terminals appear before the neuronal degeneration in PD. Furthermore, distortion of synaptic morphology and reduction of postsynaptic dendritic spines are the neuropathological hallmarks of early-stage disease. Thus, the review proposes a shift in focus from discerning the mechanism of neuronal cell body loss and targeting it to an entirely different approach of preventing axonal degeneration. The review also suggests appropriate strategies to prevent the loss of synaptic terminals, which could induce regrowth of the axon and its auxiliary fibers and might offer relief from the symptomatic features of PD.

Multilevel regulation of the glass locus during Drosophila eye development.

Development of eye tissue is initiated by a conserved set of transcription factors termed retinal determination network (RDN). In the fruit fly Drosophila melanogaster, the zinc-finger transcription factor Glass acts directly downstream of the RDN to control identity of photoreceptor as well as non-photoreceptor cells. Tight control of spatial and temporal gene expression is a critical feature during development, cell-fate determination as well as maintenance of differentiated tissues. The molecular mechanisms that control expression of glass, however, remain largely unknown. We here identify complex regulatory mechanisms controlling expression of the glass locus. All information to recapitulate glass expression are contained in a compact 5.2 kb cis-acting genomic element by combining different cell-type specific and general enhancers with repressor elements. Moreover, the immature RNA of the locus contains an alternative small open reading frame (smORF) upstream of the actual glass translation start, resulting in a small peptide instead of the three possible Glass protein isoforms. CRISPR/Cas9-based mutagenesis shows that the smORF is not required for the formation of functioning photoreceptors, but is able to attenuate effects of glass misexpression. Furthermore, editing the genome to generate glass loci eliminating either one or two isoforms shows that only one of the three proteins is critical for formation of functioning photoreceptors, while removing the two other isoforms did not cause defects in developmental or photoreceptor function. Our results show that eye development and function is largely unaffected by targeted manipulations of critical features of the glass transcript, suggesting a strong selection pressure to allow the formation of a functioning eye.

Patterning mechanisms diversify neuroepithelial domains in the Drosophila optic placode.

The central nervous system develops from monolayered neuroepithelial sheets. In a first step patterning mechanisms subdivide the seemingly uniform epithelia into domains allowing an increase of neuronal diversity in a tightly controlled spatial and temporal manner. In Drosophila, neuroepithelial patterning of the embryonic optic placode gives rise to the larval eye primordium, consisting of two photoreceptor (PR) precursor types (primary and secondary), as well as the optic lobe primordium, which during larval and pupal stages develops into the prominent optic ganglia. Here, we characterize a genetic network that regulates the balance between larval eye and optic lobe precursors, as well as between primary and secondary PR precursors. In a first step the proneural factor Atonal (Ato) specifies larval eye precursors, while the orphan nuclear receptor Tailless (Tll) is crucial for the specification of optic lobe precursors. The Hedgehog and Notch signaling pathways act upstream of Ato and Tll to coordinate neural precursor specification in a timely manner. The correct spatial placement of the boundary between Ato and Tll in turn is required to control the precise number of primary and secondary PR precursors. In a second step, Notch signaling also controls a binary cell fate decision, thus, acts at the top of a cascade of transcription factor interactions to define PR subtype identity. Our model serves as an example of how combinatorial action of cell extrinsic and cell intrinsic factors control neural tissue patterning.

Rheological properties of super critical CO2 with CuO: Multi-scale computational modeling.

A multi-scale computational methodology based on the density functional theory and molecular dynamics has been used to investigate the rheological properties of super critical CO2 with CuO nano-particle (NP). Density functional theory which treats the electron density as the central variable has been used to explore the adsorption of CO2 molecules on the two most stable CuO surfaces [i.e., (111) and (011)] at absolute zero. The results of this theory would provide valuable information to make CuO NPs with the surface where the CO2 adsorption is maximum in order to have a stronger mono-layer of adsorbed CO2 molecules on the surface of the NP which is the most crucial factor in formation of a stable nanofluid. The results show that the CO2 molecule is adsorbed more strongly on the (011) surface with an adsorption energy of -99.06 kJ/mol compared to the (111) surface. A computational methodology based on molecular dynamics has been used to evaluate the enhancement of the rheological properties of the super-critical CO2 liquid based nanofluid at different temperatures and pressures. In this scale, first, the CO2 liquid has been modeled by employing the condensed-phase optimized molecular potentials for atomistic simulation studies (COMPASS) force field potential and the fluid properties computed are in excellent agreement with the literature and experiment values. Second, the nanofluid has been modeled in order to study the enhancement of the fluid properties with the CuO NPs. The charged optimized many-body force field potential has been employed to consider the effect of the charge transferring between the NPs and liquid molecules and breaking of existing bonds and the formation of new bonds. The COMPASS force field potential is also employed for the interactions between CO2 molecules. The combination of these potentials is quite a new approach for the study of the super-critical (SC)-CO2 based nanofluid. The results show that the viscosity of the SC-CO2 is enhanced between 1.3 and 2.5 times under the temperature and pressure conditions studied.

Functional genomics identifies regulators of the phototransduction machinery in the Drosophila larval eye and adult ocelli.

Sensory perception of light is mediated by specialized Photoreceptor neurons (PRs) in the eye. During development all PRs are genetically determined to express a specific Rhodopsin (Rh) gene and genes mediating a functional phototransduction pathway. While the genetic and molecular mechanisms of PR development is well described in the adult compound eye, it remains unclear how the expression of Rhodopsins and the phototransduction cascade is regulated in other visual organs in Drosophila, such as the larval eye and adult ocelli. Using transcriptome analysis of larval PR-subtypes and ocellar PRs we identify and study new regulators required during PR differentiation or necessary for the expression of specific signaling molecules of the functional phototransduction pathway. We found that the transcription factor Krüppel (Kr) is enriched in the larval eye and controls PR differentiation by promoting Rh5 and Rh6 expression. We also identified Camta, Lola, Dve and Hazy as key genes acting during ocellar PR differentiation. Further we show that these transcriptional regulators control gene expression of the phototransduction cascade in both larval eye and adult ocelli. Our results show that PR cell type-specific transcriptome profiling is a powerful tool to identify key transcriptional regulators involved during several aspects of PR development and differentiation. Our findings greatly contribute to the understanding of how combinatorial action of key transcriptional regulators control PR development and the regulation of a functional phototransduction pathway in both larval eye and adult ocelli.

Cytochrome P450 2D6 and Parkinson's Disease: Polymorphism, Metabolic Role, Risk and Protection.

Cytochrome P450 (CYP) 2D6 is one of the most highly active, oxidative and polymorphic enzymes known to metabolize Parkinsonian toxins and clinically established anti-Parkinson's disease (PD) drugs. Albeit CYP2D6 gene is not present in rodents, its orthologs perform almost the similar function with imprecise substrate and inhibitor specificity. CYP2D6 expression and catalytic activity are found to be regulated at every stage of the central dogma except replication as well as at the epigenetic level. CYP2D6 gene codes for a set of alternate splice variants that give rise to a range of enzymes possessing variable catalytic activity. Case-control studies, meta-analysis and systemic reviews covering CYP2D6 polymorphism and PD risk have demonstrated that poor metabolizer phenotype possesses a considerable genetic susceptibility. Besides, ultra-rapid metabolizer offers protection against the risk in some populations while lack of positive or inverse association is also reported in other inhabitants. CYP2D6 polymorphisms resulting into deviant protein products with differing catalytic activity could lead to inter-individual variations, which could be explained to certain extent on the basis of sample size, life style factors, food habits, ethnicity and tools used for statistical analysis across various studies. Current article describes the role played by polymorphic CYP2D6 in the metabolism of anti-PD drugs/Parkinsonian toxins and how polymorphisms determine PD risk or protection. Moreover, CYP2D6 orthologs and their roles in rodent models of Parkinsonism have also been mentioned. Finally, a perspective on inconsistency in the findings and futuristic relevance of CYP2D6 polymorphisms in disease diagnosis and treatment has also been highlighted.

Nucleophilic ipso-Substitution of Aryl Methyl Ethers through Aryl C-OMe Bond Cleavage; Access to Functionalized Bisthiophenes.

A metal and solvent free strategy to functionalize aryl methyl ethers through direct nucleophilic substitution of aryl C-OMe bond has been described. A wide range of O, S, N, and C-centered uncharged nucleophiles has been successfully employed. Using this protocol, functional derivatives of bisthiophene have been synthesized in a straightforward way. The reactions are highly atom-efficient and generate methanol as the only byproduct.

Brønsted Acid Catalyzed Functionalization of Aromatic Alcohols through Nucleophilic Substitution of Hydroxyl Group.

The hydroxyl groups of naphthol and tautomerizable phenol derivatives have been substituted by O-, S-, N-, and C-centered nucleophiles under solvent-free reaction conditions. The products are generated in good to excellent yields. para-Toluenesulfonic acid exhibits the best catalytic activity compared to other Brønsted acids. Experimental observations suggest that the reaction proceeds through the intermediacy of the keto tautomer of naphthol. Nucleophilic addition to the carbonyl group followed by elimination of water generates the desired product. The present methodology provides access to substituted naphtho[2,1-b]furan derivatives. The products generated using N-centered nucleophiles can be further transformed to important classes of organic molecules such as benzocarbazole and imidazole derivatives.

A density functional theory study of the adsorption behaviour of CO2 on Cu2O surfaces.

Copper has many applications, particularly in electro-catalysis, where the oxidation state of the copper electrode plays a significant role in the selectivity towards products. Although copper-based materials have clear potential as catalysts in the reduction of CO2 and conversion to products, fundamental understanding of CO2 adsorption and activation on different copper oxide surfaces is still limited. We have used DFT+U methodology to study the surface reconstruction of the three most exposed (111), (110), and (001) surfaces of Cu2O with different possible terminations. Considering several adsorbate geometries, we have investigated CO2 adsorption on five different possible terminations and proposed eight different configurations in which CO2 binds with the surface. Similar to earlier findings, CO2 binds weakly with the most stable Cu2O(111):O surface showing no molecular activation, whereas a number of other surfaces, which can appear in the Cu2O particles morphology, show stronger binding as well as activation of the CO2 molecule. Different CO2 coverages were studied and a detailed structural and electronic charge analysis is presented. The activation of the CO2 molecule is characterized by structural transformations and charge transfer between the surface and the CO2 molecule, which is further confirmed by considerable red shifts in the vibrational frequencies.

Binary cell fate decisions and fate transformation in the Drosophila larval eye.

The functionality of sensory neurons is defined by the expression of specific sensory receptor genes. During the development of the Drosophila larval eye, photoreceptor neurons (PRs) make a binary choice to express either the blue-sensitive Rhodopsin 5 (Rh5) or the green-sensitive Rhodopsin 6 (Rh6). Later during metamorphosis, ecdysone signaling induces a cell fate and sensory receptor switch: Rh5-PRs are re-programmed to express Rh6 and become the eyelet, a small group of extraretinal PRs involved in circadian entrainment. However, the genetic and molecular mechanisms of how the binary cell fate decisions are made and switched remain poorly understood. We show that interplay of two transcription factors Senseless (Sens) and Hazy control cell fate decisions, terminal differentiation of the larval eye and its transformation into eyelet. During initial differentiation, a pulse of Sens expression in primary precursors regulates their differentiation into Rh5-PRs and repression of an alternative Rh6-cell fate. Later, during the transformation of the larval eye into the adult eyelet, Sens serves as an anti-apoptotic factor in Rh5-PRs, which helps in promoting survival of Rh5-PRs during metamorphosis and is subsequently required for Rh6 expression. Comparably, during PR differentiation Hazy functions in initiation and maintenance of rhodopsin expression. Hazy represses Sens specifically in the Rh6-PRs, allowing them to die during metamorphosis. Our findings show that the same transcription factors regulate diverse aspects of larval and adult PR development at different stages and in a context-dependent manner.

Causal Relationships Between Physical Activity and Arthrokinematic Integrity of the Ankle Joint-Foot Complex Across Normal and Pathological Phenomena: A Case-Control Analysis.

Introduction Muscles, ligaments, tendons, bones, and cartilage undergo age-related changes, affecting the foot-ankle joint complex biomechanics in both genders. While international studies have extensively researched these dynamics, Indian studies are limited. Our study aims to fill this gap by analyzing the anthropometric and biomechanical function of the foot-ankle joint complex in normal individuals and those with painful pathologies at All India Institute of Medical Sciences (AIIMS) Rajkot's OPD. Methods In a two-year case-control study of the cross-sectional type conducted at AIIMS Rajkot's OPD, 158 patients with similar pain intensity on the Numeric Pain Rating Scale were examined. Anthropometric and biomechanical measurements were taken for both affected and non-affected foot and ankle joints. Cases comprised patients with foot and ankle joint pain, while controls were selected based on predefined criteria and were without such pain. Ethical approval was acquired from the Institutional Ethical Committee of AIIMS Rajkot. Results The sprain of the ankle joint and foot was the most common musculoskeletal pathology (65 out of 158 cases, i.e., 41.13%) affecting the ankle joint-foot complex. Patients involved in occupations requiring higher physical inactivity suffer more commonly from ankle joint-foot pathologies. The mean difference in the range of motion, i.e., dorsiflexion, plantar flexion, inversion, and eversion, between affected and non-affected feet was found to be lower in the patients who belonged to occupations involving low physical activity compared to those patients having occupations with high physical activity. Conclusion Reduced physical activity increases the stiffness and reduces the flexibility of the tendons, muscles, and ligaments of any joint (the ankle joint-foot complex in this study) and is associated with a higher incidence of musculoskeletal pathologies.

Ab initio investigations of the structure-stability, mechanical, electronic, thermodynamic and optical properties of Ti2FeAs Heusler alloy.

In this study, we employed density functional theory coupled with the full-potential linearized augmented plane-wave method (FP-LAPW) to investigate the structural, electronic, and magnetic properties of the Ti2FeAs alloy adopting the Hg2CuTi-type structure. Our findings demonstrate that all the examined structures exhibit ferromagnetic (FM) behaviour. By conducting electronic band structure calculations, we observed an energy gap of 0.739 eV for Ti2FeAs in the spin-down state and metallic intersections at the Fermi level in the spin-up state. These results suggest the half-metallic (HM) nature of Ti2FeAs, where the Ti-d and Fe-d electronic states play a significant role near the Fermi level. Additionally, the obtained total magnetic moments are consistent with the Slater-Pauling rule (Mtot = Ztot - 18), indicating 100% spin polarization for these compounds. To explore their optical properties, we employed the dielectric function to compute various optical parameters, including absorption spectra, energy-loss spectra, refractive index, reflectivity, and conductivity. Furthermore, various thermodynamic parameters were evaluated at different temperatures and pressures. The results obtained from the elastic parameters reveal the anisotropic and ductile nature of the Ti2FeAs compound. These findings suggest that Ti2FeAs has potential applications in temperature-tolerant devices and optoelectronic devices as a UV absorber.

Graphene: a reusable substrate for unprecedented adsorption of pesticides.

Unprecedented adsorption of chlorpyrifos (CP), endosulfan (ES), and malathion (ML) onto graphene oxide (GO) and reduced graphene oxide (RGO) from water is reported. The observed adsorption capacities of CP, ES, and ML are as high as ~1200, 1100, and 800 mg g(-1) , respectively. Adsorption is found to be insensitive to pH or background ions. The adsorbent is reusable and can be applied in the field with suitable modifications. A first-principles pseudopotential-based density functional analysis of graphene-water-pesticide interactions showed that the adsorption is mediated through water, while direct interactions between graphene and the pesticides is rather weak or unlikely.

Role of graphene in scavenging methyl cations: a DFT study.

CONTEXT: It is known that methylating agents methylate DNA by transferring a methyl cation (CH3+) to the nucleophilic sites in DNA bases and DNA methylation is implicated in cancer and other pathological conditions. Therefore, it is important to scavenge CH3+ ion in order to protect DNA from methylation. Graphene is considered to be a versatile material for use in a wide variety of fields including sensors, antioxidants, drug delivery and DNA sequencing. In this work, we have theoretically investigated the interaction of CH3+ ions with graphene surface with an aim to understand if pristine graphene can be used as a substrate to adsorb CH3+ cations generated from harmful methylating agents. The computed adsorption energies show that adsorption of one, two and three CH3+ ions on graphene is favourable as the adducts thus formed are found to be substantially stable in both gas phase and aqueous media. The Bader charge transfer analysis and density of states (DOS) calculation also indicate a strong interaction between graphene and CH3+ ions. Thus, our results show that pristine graphene can be used as a substrate to scavenge CH3+ ions. METHODS: The spin polarised density functional theory (DFT) calculations employing PBE functional, ultrasoft pseudopotentials and plane wave basis set having kinetic energy cut-offs of 40 Ry and 400 Ry, respectively, for wave functions and charge densities were carried out to study the adsorption of CH3+ ion(s) on the pristine graphene surface. The Grimme's DFT-D2 method was used for the estimation of van der Waals interactions. The 'dipole correction' along z-direction was also applied for adsorption study. The Marzari-Vanderbilt smearing and Monkhorst-Pack k-point grid were employed for the Brillouin zone sampling. A 6 × 6 graphene supercell with a vertical cell dimension of 18 Å was considered for the adsorption study. The charge transfer between the CH3+ ion(s) and graphene was estimated using Bader charge analysis. The implicit solvation model (SCCS) was used to estimate the solvent effect of aqueous media. All the calculations were performed using QUANTUM ESPRESSO package.

Structural dynamics of chlorpromazine (CPZ) drug with dipalmitoylphosphatidylcholine (DPPC) lipid: a potential drug for SARS-CoV-2.

There is an urgent requirement for drug discovery and more importantly drug repositioning due to infectious new Severe Acute Respiratory Syndrome coronavirus 2. As per the recent report published in the journal L'Encéphale in May 2020, there is a planned ReCoVery Study examining the repurposing the chlorpromazine for the treatment of COVID-19. Here, we apply a combined Raman microspectroscopy and DFT-MD approach to investigate the structural dynamics of the Chlorpromazine (CPZ) drug with dipalmitoylphosphatidylcholine (DPPC) lipid bilayer, identifying the specific position of the drug in the DPPC lipid bilayer. The intensity ratios of the Raman peaks I2935/I2880, I1097/I1064 and I1097/I1129 are representative of the interaction of drugs with lipid alkyl chains and furnish conformation of lipid alkyl chains. Raman imaging microscopy for the study of the distribution of CPZ inside the lipid vesicles is reported. We also investigated the influence of order and disorder ratio in the CPZ on the DPPC liposomes prepared on phase transition temperature. HIGHLIGHTSDrug-membrane interactions using micromolar concentrations of both lipid and drugs.Neuroleptic drug and DPPC vesicles composed of DPPC/drug mixtures reveal qualitative differences between the Raman spectraThe temperature-controlled Raman microspectroscopic study has demonstrated that below phase-transition temperature, the fatty acid chains of the phospholipids are stiff and packed in a highly ordered array.DFT and MD simulations to understand molecular interactions, structural dynamics, and Raman spectra.Above phase-transition temperature, the chains are disordered and possess more motional freedom. Communicated by Ramaswamy H. Sarma.