The role of π-linkers and electron acceptors in tuning the nonlinear optical properties of BODIPY-based zwitterionic molecules

Intramolecular charge transfer process can play a key role in developing strong nonlinear optical (NLO) response in a molecule for technological application. Herein, two series of boron dipyrromethene (BODIPY)-based push–pull systems have been designed with zwitterionic donor–acceptor groups, and their NLO properties have been evaluated using a density functional theory-based approach. Different π-conjugated linkers and electron acceptor groups were used to understand their roles in tuning the NLO properties. The molecules were analyzed through HOMO–LUMO gaps, frontier molecular orbitals, polarizabilities, hyperpolarizabilities, Δr indices, transition dipole moment densities, ionization potentials, electron affinities and reorganization energies for holes and electrons. These observations correlated well with the computed absorption spectra of the molecules. It is found that with the introduction of different π-linkers in the molecule, planarity is maintained and the HOMO–LUMO gap is systematically decreased, which leads to a large NLO response. It was noted that the electronic absorption wavelength maxima were found in the near-infrared region (934–1650 nm). The results show that compared to the pyridinium acceptor group, the imidazolium acceptor group in the BODIPY systems amplifies the NLO response to a larger extent. It is also observed that the BODIPY-based dye with an imidazolium acceptor and thienothiophene π-linker shows the highest first hyperpolarizability value of 3194 × 10⁻³⁰ esu. Furthermore, the charge transfer occurs in the z-direction, as the z-component of the first hyperpolarizability is the dominant factor in this system. Here, the designed molecules show a characteristic reorganisation energy value, which is a deciding factor in the rate of hole/electron transport for favourable intermolecular coupling. As a whole, this theoretical work highlights that π-conjugated linkers and electron acceptor groups can be used judiciously to design new molecular systems for optoelectronic applications.

BODIPY-based zwitterionic molecules with pyridinium and imidazolium electron acceptors and thienothiophene π-linkers reveal significant first hyperpolarizability.     

Evaluation of Two Optical Probes for Imaging the Integrin αvβ6− In Vitro and In Vivo in Tumor-Bearing Mice

Purpose

The purpose of this study was to develop and evaluate two α_vβ₆-targeted fluorescent imaging agents. The integrin subtype α_vβ₆ is significantly upregulated in a wide range of epithelial derived cancers, plays a key role in invasion and metastasis, and expression is often located at the invasive edge of tumors. α_vβ₆-targeted fluorescent imaging agents have the potential to guide surgical resection leading to improved patient outcomes. Both imaging agents were based on the bi-PEGylated peptide NH₂-PEG₂₈-A20FMDV2-K16R-PEG₂₈ (1), a peptide that has high affinity and selectivity for the integrin α_vβ₆: (a) 5-FAM-X-PEG₂₈-A20FMDV2-K16R-PEG₂₈ (2), and (b) IRDye800-PEG₂₈-A20FMDV2-K16R-PEG₂₈ (3).

Procedures

Peptides were synthesized using solid-phase peptide synthesis and standard Fmoc chemistry. Affinity for α_vβ₆ was evaluated by ELISA. In vitro binding, internalization, and localization of 2 was monitored using confocal microscopy in DX3puroβ₆ (α_vβ₆+) and DX3puro (α_vβ₆?) cells. The in vivo imaging and ex vivo biodistribution of 3 was evaluated in three preclinical mouse models, DX3puroβ₆/DX3puro and BxPC-3 (α_vβ₆+) tumor xenografts and a BxPC-3 orthotopic pancreatic tumor model.

Results

Peptides were obtained in >?99% purity. IC₅₀ values were 28 nM (2) and 39 nM (3). Rapid α_vβ₆-selective binding and internalization of 2 was observed. Fluorescent intensity (FLI) measurements extracted from the in vivo images and ex vivo biodistribution confirmed uptake and retention of 3 in the α_vβ₆ positive subcutaneous and orthotopic tumors, with negligible uptake in the α_vβ₆-negative tumor. Blocking studies with a known α_vβ₆-targeting peptide demonstrated α_vβ₆-specific binding of 3.

Conclusion

Two fluorescence imaging agents were developed. The α_vβ₆-specific uptake, internalization, and endosomal localization of the fluorescence agent 2 demonstrates potential for targeted therapy. The selective uptake and retention of 3 in the α_vβ₆-positive tumors enabled clear delineation of the tumors and surgical resection indicating 3 has the potential to be utilized during image-guided surgery.

     

Rapid burst of H2O2 by plant growth regulators increases intracellular Ca2+ amounts and modulates CD4+ T cell activation

The identification of small molecules that affect T cell activation is an important area of research. Three molecules that regulate plant growth and differentiation, but not their structurally similar analogs, were identified to enhance primary mouse CD4⁺ T cell activation in conjunction with soluble anti-CD3 stimulation: Indoleacetic acid (natural plant auxin), 1-Napthaleneacetic acid (synthetic plant auxin) and 2,4-Dichlorophenoxyacetic acid (synthetic plant auxin and herbicide). These effects are distinct in comparison to Curcumin, the well known phenolic immunomodulator, which lowers T cell activation. An investigation into the mechanisms of action of the three plant growth regulators revealed a rapid induction of reactive oxygen species (ROS), mainly comprising H₂O₂. In addition, these three molecules synergize with soluble anti-CD3 signaling to enhance intracellular Ca²⁺ concentrations [Ca²⁺]_i, leading to greater T cell activation, e.g. induction of CD25 and IL-2. Enhanced production of TNFα and IFNγ by CD4⁺ T cells is also observed upon plant growth regulator treatment with soluble anti-CD3. Interestingly, maximal IL-2 production and CD4⁺ T cell cycle progression are observed upon activation with soluble anti-CD3 and phorbol 12-myristate 13-acetate (PMA), a phorbol ester. Additionally, stimulation with PMA and Ionomcyin (a Ca²⁺ ionophore), which activates T cells by circumventing the TCR, and plant growth regulators also demonstrated the role of the strength of signal (SOS): T cell cycle progression is enhanced with gentle activation conditions but decreased with strong activation conditions. This study demonstrates the direct effects of three plant growth regulators on CD4⁺ T cell activation and cycling.     

Sensitivity of paediatric AIDS score vs. WHO case classification in Indian children--a retrospective study

This study was conducted at the Department of Paediatrics, Dr Ram Manohar Lohia Hospital, to test the statistical significance of existing World Health Organization (WHO) clinical case definition (CCD) for diagnosis of AIDS in areas where diagnostic resources are limited. A total of 360 cases between 18 months and 12 years of age satisfying WHO case definitions of AIDS were included in study group. Our study detected 16.66% (60) of HIV incidence in children visiting the paediatrics outpatient clinic. Twenty percent of cases manifested three major and two minor signs, which had sensitivity of 73.33%; specificity, 90.66% and positive predictive value (PPV), 61.11%. Stepwise logistic analysis identified weight loss, chronic fever >1 month and total lymphocyte count <1500 cells mm(-3) as important predictors. Eighty-six cases (23.89%) showed two major and two minor signs with sensitivity and specificity of 86.66 and 88.66%, respectively. Thus a CCD based on 13 clinical signs/symptoms was proposed for paediatric AIDS with better sensitivity and PPV than the WHO case definition but with almost similar specificity.     

Potential Biological Fate of Emulsion-Based Delivery Systems: Lipid Particles Nanolaminated with Lactoferrin and β-lactoglobulin Coatings

Purpose

To develop lipid particles coated by nanolaminated protein coatings as potential oral delivery systems to encapsulate, protect, and deliver lipophilic bioactives.

Methods

Nanolaminated protein coatings were formed by sequential electrostatic deposition of cationic lactoferrin (LF) and anionic β-lactoglobulin (BLG) at pH?6.5: LF, LF-BLG, LF-BLG-LF, and LF-BLG-LF-BLG. Changes in physicochemical properties were characterized after exposure to environmental stresses (pH?2 to 9; 0 to 200 mM NaCl) and simulated gastrointestinal tract (GIT) conditions (mouth, stomach, small intestine). Triglyceride digestion and β-carotene bioaccessibility were also measured.

Results

The pH and salt dependence of the electrical charge and aggregation stability of the emulsions were strongly influence by the structure of the interfacial coatings. All emulsions behaved similarly under simulated GIT conditions: extensive droplet aggregation occurred in the stomach and small intestine; triglycerides were rapidly and fully digested after exposure to intestinal fluids; the bioaccessibility of β-carotene was low (< 4%).

Conclusions

Nanolaminated protein coatings may be useful for stabilizing encapsulated lipids in functional food and pharmaceutical products during storage, but releasing them after ingestion. Protein coatings had little impact on triglyceride digestion, but they greatly reduced β-carotene bioaccessibility, possibly due to binding to lactoferrin.

     

Sclerostin and bone strength in women in their 10th decade of life

Sclerostin is a potent inhibitor of bone formation but has been shown to correlate positively with areal bone mineral density (aBMD). Little is known about its relationship to parameters of bone strength and volumetric BMD (vBMD) as measured by peripheral quantitative computed tomography (pQCT). We measured both serum sclerostin and parameters of tibial bone size and strength by pQCT to characterize this relationship. Our study population consisted of 223 white and 35 African American women (mean age 87 years) from the Study of Osteoporotic Fractures (SOF) cohort, who had usable pQCT scans of the tibia at sites 4% (T4%), 33% (T33%), and 66% (T66%) from the ankle. Analysis of covariance was used to test for differences in age‐adjusted means of aBMD, pQCT variables, and serum biomarkers across sclerostin quartiles. African American women had significantly lower median sclerostin (34.3 pmol/L) than white women (48.5 pmol/L) (p = 0.05). Women in the highest sclerostin quartile had 7% to 14.5% higher hip aBMD and pQCT parameters of vBMD and bone size than those in the lowest quartile in multivariate models adjusting for age, race, weight, height, and diabetes status. The association of sclerostin with parameters of bone strength differed dramatically between T33% and T66% sites. At T66%, women in the highest sclerostin quartile had pQCT strength parameters 9.4% to 15.3% greater than the lowest quartile, whereas no trend was found for the T33% site. Our results suggest paradoxical associations between circulating sclerostin and bone size, density, and strength.     

Development of Tomato Sambar Paste Stabilized by Hurdle Technology and Evaluation of Storage Stability

The study was undertaken to develop ready-to-use sambar paste stabilized by various hurdles vis a vis water activity, pH, temperature, and preservative. Physico-chemical characteristics such as pH, titratable acidity (TA), color changes, and microbiological profiles were monitored during four months of storage at 28 ± 3°C and 37°C. A Hedonic test was used to evaluate consumer perception and acceptability of sambar paste during storage. Color analysis showed significant (p < 0.05) decrease in the lightness (L) and yellowness (b*), while redness (a*) of the paste increased during storage at both the storage temperatures. Sensory evaluation showed that there was no significant difference (p > 0.05) in most of the sensory attributes during storage except color. The sambar paste was found to be microbiologically safe for four months at 37°C.