On the instability of iodides of heavy main group atoms in their higher oxidation state.

The inert pair effect-the tendency of the s orbital of heavy atoms to stay unreactive, is a consequence of the relativistic contraction of the s orbitals. While the manifestations of this on the reactivity depend on the nature of the substituents, this aspect is often overlooked. Divalent Pb prefers inorganic substituents, whereas tetravalent Pb prefers organic substituents. Among the inorganic substituents, again there are specific preferences-tetravalent Pb prefers F and Cl more than Br and I. It is as though the relativistic contraction of the s orbital of Pb is more significant with Br and I substituents than with Cl, F, and alkyl substituents. Herein, we address this problem using the molecular orbital approach and support it with quasi-relativistic density functional computations. We explain why typical hypervalent systems, like 12-X-6, and 10-X-5 (X is a heavy atom, the number preceding X is the number of valence electrons surrounding X, and the number after X is the coordination number) with less electronegative substituents carrying a lone pair (such as iodine), and Lewis octet molecules like PbI4 are unstable, but their dianions (14-X-6, 12-X-5, PbI42-) are not. For heavy atoms, the relativistic contraction of the s orbital renders the antibonding combination of s with ligand orbitals (σ1*) very low-lying, making it a good acceptor of electrons. Thus, compounds where σ1* is empty are kinetically unstable when an electron donor with appropriate energy (such as the lone pair on iodine or bromine) is present in the vicinity. Donor-acceptor interaction between σ1* and the lone pair on I or Br (F and Cl lone pairs are energetically far away from σ1*) is responsible for the instability of such compounds. The kinetic stability of tetraalkyl lead compounds is due to the absence of lone pairs on the alkyl substituents. This work illustrates the key factor responsible for the instability of heavy element iodides by taking into consideration the covalent nature of the bonds, while the existing explanations assume a purely ionic bonding, which is an oversimplification.

COVID-19 disease and immune dysregulation.

The SARS-CoV-2 virus has complex and divergent immune alterations in differing hosts and over disease evolution. Much of the nuanced COVID-19 disease immune dysregulation was originally dominated by innate cytokine changes, which has since been replaced with a more complex picture of innate and adaptive changes characterized by simultaneous hyperinflammatory and immunosuppressive phenomena in effector cells. These intricacies are summarized in this review as well as potential relevance from acute infection to a multisystem inflammatory syndrome commonly seen in children. Additional consideration is made for the influence of variant to variant host cellular changes and the impact of potential vaccination upon these phenotypes. Finally, therapeutic benefit for immune alterations are discussed.

Multi-objective Genetic Algorithm for De Novo Drug Design (MoGADdrug).

BACKGROUND: A multi-objective genetic algorithm for De novo drug design (MoGADdrug) has been proposed in this paper for the design of novel drug-like molecules similar to some reference molecules. The algorithm developed accepts a set of fragments extracted from approved drugs and available in fragment libraries and combines them according to specified rules to discover new drugs through the in-silico method. METHODS: For this process, a genetic algorithm has been used, which encodes the fragments as genes of variable length chromosomes and applies various genetic operators throughout the generations. A weighted sum approach is used to simultaneously optimize the structural similarity of the new drug to a reference molecule as well as its drug-likeness property. RESULTS: Five reference molecules namely Lidocaine, Furano-pyrimidine derivative, Imatinib, Atorvastatin and Glipizide have been chosen for the performance evaluation of the algorithm. CONCLUSION: Also, the newly designed molecules were analyzed using ZINC, PubChem databases and docking investigations.

Metamaterial Analogues of Molecular Aggregates.

Molecular aggregates are a fascinating and important class of materials, particularly in the context of optical (pigmented) materials. In nature, molecular aggregates are employed in photosynthetic light harvesting structures, while synthetic aggregates are employed in new generation molecular sensors and magnets. The roles of disorder and symmetry are vital in determining the photophysical properties of molecular aggregates, but have been hard to investigate experimentally, owing to a lack of sufficient structural control at the molecular level and the challenge of probing their optical response with molecular spatial resolution. We present a new approach using microwave analogues of molecular aggregates to study the properties of both individual meta-molecules and 1D molecular chains. We successfully replicate J- and H-aggregate behavior and demonstrate the power of our approach through the controlled introduction of structural symmetry breaking. Our results open a new area of study, combining concepts from molecular science and metamaterials.

Antibacterial and cytotoxic assessment of poly (methyl methacrylate) based hybrid nanocomposites.

Poly (methyl methacrylate) (PMMA) is an extensively used implant material in biomedical devices. Biofilm formation creates issues in PMMA-based biomedical implants, while emergence of drug resistant pathogens poses an additional complication. Hence development of surfaces that resist bacterial colonisation is extremely desirable. In this context, nanomaterials are among the potential choices. In the present work, nanocomposites (NCs) were developed by incorporation of chemically synthesized nanoparticles of CuO, cetyl trimethyl ammonium bromide (CTAB) capped CuO and ZnO (singly and in combination) in PMMA. The efficacy of these NCs was assessed against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) bacteria which are prevalent in many implant-associated infections. Results revealed species-specific response of the bacteria towards nanomaterials. CuO NC (0.1% (w/v)) was more effective against E. coli, while CTAB capped CuO NC and ZnO NC were very effective against S. aureus. Furthermore, combination of nanoparticles improved efficacy of nanocomposites against both the bacterial species. In vitro cytotoxicity assay using L6 myoblast cell line showed that all NCs at 0.1% (w/v) were biocompatible, showing >85% cell viability. The present study suggests that combination of NPs is a promising option to combat implant infection by multiple organisms.

Association Between Residential Greenness and Cardiovascular Disease Risk.

Background Exposure to green vegetation has been linked to positive health, but the pathophysiological processes affected by exposure to vegetation remain unclear. To study the relationship between greenness and cardiovascular disease, we examined the association between residential greenness and biomarkers of cardiovascular injury and disease risk in susceptible individuals. Methods and Results In this cross-sectional study of 408 individuals recruited from a preventive cardiology clinic, we measured biomarkers of cardiovascular injury and risk in participant blood and urine. We estimated greenness from satellite-derived normalized difference vegetation index ( NDVI ) in zones with radii of 250 m and 1 km surrounding the participants' residences. We used generalized estimating equations to examine associations between greenness and cardiovascular disease biomarkers. We adjusted for residential clustering, demographic, clinical, and environmental variables. In fully adjusted models, contemporaneous NDVI within 250 m of participant residence was inversely associated with urinary levels of epinephrine (-6.9%; 95% confidence interval, -11.5, -2.0/0.1 NDVI ) and F2-isoprostane (-9.0%; 95% confidence interval, -15.1, -2.5/0.1 NDVI ). We found stronger associations between NDVI and urinary epinephrine in women, those not on ß-blockers, and those who had not previously experienced a myocardial infarction. Of the 15 subtypes of circulating angiogenic cells examined, 11 were inversely associated (8.0-15.6% decrease/0.1 NDVI ), whereas 2 were positively associated (37.6-45.8% increase/0.1 NDVI ) with contemporaneous NDVI . Conclusions Independent of age, sex, race, smoking status, neighborhood deprivation, statin use, and roadway exposure, residential greenness is associated with lower levels of sympathetic activation, reduced oxidative stress, and higher angiogenic capacity.

Circulating angiogenic stem cells in type 2 diabetes are associated with glycemic control and endothelial dysfunction.

Circulating angiogenic cells (CACs) of various described phenotypes participate in the regeneration of the damaged endothelium, but the abundance of these cells is highly influenced by external cues including diabetes. It is not entirely clear which CAC populations are most reflective of endothelial function nor which are impacted by diabetes. To answer these questions, we enrolled a human cohort with variable CVD risk and determined relationships between stratified levels of CACs and indices of diabetes and vascular function. We also determined associations between CAC functional markers and diabetes and identified pro-angiogenic molecules which are impacted by diabetes. We found that subjects with low levels of CD34+/AC133+/CD31+/CD45dim cells (CAC-3) had a significantly higher incidence of diabetes (p = 0.004), higher HbA1c levels (p = 0.049) and higher CVD risk scores. Furthermore, there was an association between low CAC-3 levels and impaired vascular function (p = 0.023). These cells from diabetics had reduced levels of CXCR4 and VEGFR2, while diabetics had higher levels of certain cytokines and pro-angiogenic molecules. These results suggest that quantitative and functional defects of CD34+/AC133+/CD31+/CD45dim cells are associated with diabetes and vascular impairment and that this cell type may be a prognostic indicator of CVD and vascular dysfunction.

[Objective tinnitus].

Objective tinnitus is a known but rare otologic symptom. This is a case report about a six-year-old boy, who was referred to a hearing clinic for further investigation of an audible clicking sound. He experienced clicking sounds, and his parents were able to hear the sounds when listening nearby. This objective tinnitus is caused by myoclonus of either the m. tensor tympani or the m. stapedius. We discuss methods to evaluate objective tinnitus including the clinical use of a stethoscope and also the possibility of using impedance measuring in patients with objective tinnitus.

Inhibition of epidermal growth factor receptor by ferulic acid and 4-vinylguaiacol in human breast cancer cells.

OBJECTIVES: To examine the potential of ferulic acid and 4-vinylguaiacol for inhibiting epidermal growth factor receptor (EGFR) in human breast cancer cells in vitro. RESULTS: Ferulic acid and 4-vinylguaiacol limit the EGF (epidermal growth factor)-induced breast cancer proliferation and new DNA synthesis. Western blot analysis revealed both ferulic acid and 4-vinylguaiacol exhibit sustained inhibition of EGFR activation through down-regulation of Tyr 1068 autophosphorylation. Molecular docking analysis shows ferulic acid forming hydrogen bond interaction with Lys 745 and Met 793 whereas, 4-vinylguaiacol forms two hydrogen bonds with Phe 856 and exhibits stronger hydrophobic interactions with multiple amino acid residues at the EGFR kinase domain. CONCLUSIONS: Ferulic acid and 4-vinylguaiacol could serve as a potential structure for the development of new small molecule therapeutics against EGFR.

Polydimethyl siloxane based nanocomposites with antibiofilm properties for biomedical applications.

Polydimethyl siloxane (PDMS) is an excellent implant material for biomedical applications, but often fails as it is prone to microbial colonization which forms biofilms. In the present study CuO, CTAB capped CuO, and ZnO nanoparticles were tested as nanofillers to enhance the antibiofilm property of PDMS against Staphylococcus aureus and Escherichia coli. In general S. aurues (Gram positive and more hydrophobic) favor PDMS surface than glass while E. coli (Gram negative and more hydrophilic) behaves in a reverse way. Incorporation of nanofillers renders the PDMS surface antibacterial and reduces the attachment of both bacteria. These surfaces are also not cytotoxic nor show any cell damage. Contact angle of the material and the cell surface hydrophobicity influenced the extent of bacterial attachment. Cell viability in biofilms was dependent on the antimicrobial property of the nanoparticles incorporated in the PDMS matrix. Simple regression relationships were able to predict the bacterial attachment and number of dead cells on these nanocomposites. Among the nanocomposites tested, PDMS incorporated with CTAB (cetyl trimethylammonium bromide)-capped CuO appears to be the best antibacterial material with good cyto-compatibility. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1075-1082, 2017.

AKT-p53 axis protect cancer cells from autophagic cell death during nutrition deprivation.

An altered metabolism supports growth of tumor. AKT, a major signal integrator plays a key role in cell metabolism. We have shown that nutritional deprivation activates AKT as observed by increased phosphorylation of both Thr308 and Ser473. Pharmacological inhibition or silencing of AKT by siRNA affects cell viability during starvation. The tumor suppressor, p53 is also observed to be elevated during nutritional deprivation due to AKT. Silencing of AKT and p53 enhanced autophagy as evidenced by increased acidic vesicular organelles and LC3B II levels, suggesting AKT-p53 to play a significant role in cell survival through regulating autophagy during nutritional deprivation.

Estrogen suppresses breast cancer proliferation through GPER / p38 MAPK axis during hypoxia.

Breast cancer cells frequently experience hypoxia which is associated with resistance to hormonal therapy and poor clinical prognosis, making it important to understand the function of estrogen under hypoxic condition. Here, we demonstrate that estrogen suppresses breast cancer cell growth under hypoxia, through inhibition at G1/S phase of cell cycle, by elevation of p21 expression. The involvement of GPER in estrogen mediated growth arrest was elucidated using specific ligands and siRNA. Although, estrogen was observed to activate both p44/42 and p38 MAPK signaling, pharmacological inhibition and silencing of p38 MAPK abrogated the induction of p21 expression and growth arrest, during hypoxia. The involvement of estrogen induced ROS in the p38 MAPK mediated p21 expression and cell growth arrest was established by observing that scavenging of ROS by NAC abrogated p38 MAPK activation and p21 expression during hypoxia. In conclusion, Estrogen suppresses breast cancer growth by inhibiting G1/S phase transition through GPER/ROS/p38 MAPK/p21 mediated signaling during hypoxic condition.

Residential Proximity to Major Roadways Is Associated With Increased Levels of AC133+ Circulating Angiogenic Cells.

OBJECTIVES: Previous studies have shown that residential proximity to a roadway is associated with increased cardiovascular disease risk. Yet, the nature of this association remains unclear, and its effect on individual cardiovascular disease risk factors has not been assessed. The objective of this study was to determine whether residential proximity to roadways influences systemic inflammation and the levels of circulating angiogenic cells. APPROACH AND RESULTS: In a cross-sectional study, cardiovascular disease risk factors, blood levels of C-reactive protein, and 15 antigenically defined circulating angiogenic cell populations were measured in participants (n=316) with moderate-to-high cardiovascular disease risk. Attributes of roadways surrounding residential locations were assessed using geographic information systems. Associations between road proximity and cardiovascular indices were analyzed using generalized linear models. Close proximity (<50 m) to a major roadway was associated with lower income and higher rates of smoking but not C-reactive protein levels. After adjustment for potential confounders, the levels of circulating angiogenic cells in peripheral blood were significantly elevated in people living in close proximity to a major roadway (CD31(+)/AC133(+), AC133(+), CD34(+)/AC133(+), and CD34(+)/45(dim)/AC133(+) cells) and positively associated with road segment distance (CD31(+)/AC133(+), AC133(+), and CD34(+)/AC133(+) cells), traffic intensity (CD31(+)/AC133(+) and AC133(+) cells), and distance-weighted traffic intensity (CD31(+)/34(+)/45(+)/AC133(+) cells). CONCLUSIONS: Living close to a major roadway is associated with elevated levels of circulating cells positive for the early stem marker AC133(+). This may reflect an increased need for vascular repair. Levels of these cells in peripheral blood may be a sensitive index of cardiovascular injury because of residential proximity to roadways.

Crystal structure of 4-methyl-N-[2-(piperidin-1-yl)eth-yl]benzamide monohydrate.

In the title compound, C15H22N2O·H2O, the dihedral angle between the planes of the piperidine and benzene rings is 31.63 (1)°. The piperidine ring adopts a chair conformation. The water solvent mol-ecule is involved in inter-species O-H⋯O, O-H⋯N, N-H⋯O and weak C-H⋯O hydrogen-bonding inter-actions, giving rise to chains extending along [010].

Crystal structure of 5-(4-benzyl-oxyphen-yl)-3-(4-meth-oxy-phen-yl)-6-methyl-cyclo-hex-2-en-1-one.

The title compound, C27H26O3, crystallized with two independent mol-ecules (A and B) in the asymmetric unit. In mol-ecule A, the plane of the central benzene ring forms dihedral angles of 75.78 (14) and 52.75 (16)° with that of the terminal benzene rings, and the dihedral angle between the planes of the terminal benzene rings is 51.49 (17)°. The corresponding values for mol-ecule B are 75.18 (14), 58.11 (16) and 47.91 (16)°, respectively. The cyclo-hexene ring adopts an envelope conformation in both mol-ecules, with the C atom to which is attached the central benzene ring as the flap. The crystal packing, is stabilized by C-H⋯π inter-actions.

Crystal structure of 4-chloro-N-[2-(piperidin-1-yl)eth-yl]benzamide monohydrate.

In the title compound, C14H19ClN2O2·H2O, the piperdine ring adopts a chair conformation. The dihedral angle between the mean plane of the piperidine ring and that of the phenyl ring is 41.64 (1)°. In the crystal, mol-ecules are linked by O-H⋯N, N-H⋯O and C-H⋯O hydrogen bonds involving the water mol-ecule, forming double-stranded chains propagating along [010].

Crystal structure of 4-chloro-N-{[1-(4-chloro-benzo-yl)piperidin-4-yl]meth-yl}benzamide monohydrate.

In the title compound, C20H20Cl2N2O2·H2O, the piperidine ring adopts a chair conformation with the two substituent benzene rings inclined to one another [dihedral angle 84.63 (9)°]. In the crystal, the components are linked by Ow-H⋯O, N-H⋯Ow (w = water) and C-H⋯O hydrogen bonds, generating a sheet structure lying parallel to (101).

Crystal structure of 3-[4-(benz-yloxy)phen-yl]-2,3-di-hydro-1H-benzo[f]chromen-1-one.

In the title compound, C26H20O3, the pyran ring has a distorted half-chair conformation and its mean plane is inclined to the naphthalene ring system, to which it is fused, by 10.79 (9)°. The dihedral angles between the napthalene unit and the benzene and phenyl rings are 54.39 (9) and 52.65 (12)°, respectively, while the benzene and phenyl rings are inclined to one another by 74.80 (14)°. There is a short C-H⋯O contact in the chromen-1-one unit. In the crystal, mol-ecules are linked by two pairs of C-H⋯O hydrogen bonds, forming inversion dimers described by graph set motifs R 2 (2)(8) and R 2 (2)(10), giving rise to chains running parallel to (101). The chains are linked via C-H⋯π inter-actions, forming sheets lying parallel to (010).

Crystal structure of 4-methyl-N-{[1-(4-methyl-benzo-yl)piperidin-4-yl]meth-yl}benzamide.

In the title compound, C22H27N2O2, the piperidine ring adopts a half-chair conformation with the benzene rings inclined in a trans orientation with respect to the piperidine ring [dihedral angle between the benzene rings = 89.1 (1)°]. In the crystal, a three-centre asymmetric N-H⋯O/C-H⋯O hydrogen-bonding inter-action leads to the formation of chains extending along the a-axis direction.

Crystal structure of (2E)-1-(4-hy-droxy-3-meth-oxy-phen-yl)-3-(4-hy-droxy-phen-yl)prop-2-en-1-one.

In the title moleclue, C16H14O4, the dihedral angle between the benzene rings is 16.1 (3)°. The meth-oxy group is essentially coplanar with the benzene ring to which it is attached, with a C-O-C C torsion angle of 5.5 (9)°. In the crystal, mol-ecules are linked by O-H⋯O and bifurcated O-H⋯(O,O) hydrogen bonds, forming a three-dimensional network. The structure was refined as a two-component inversion twin.