Focus: The Aging Brain: The Significance of the Default Mode Network (DMN) in Neurological and Neuropsychiatric Disorders: A Review

The relationship of cortical structure and specific neuronal circuitry to global brain function, particularly its perturbations related to the development and progression of neuropathology, is an area of great interest in neurobehavioral science. Disruption of these neural networks can be associated with a wide range of neurological and neuropsychiatric disorders. Herein we review activity of the Default Mode Network (DMN) in neurological and neuropsychiatric disorders, including Alzheimer’s disease, Parkinson’s disease, Epilepsy (Temporal Lobe Epilepsy - TLE), attention deficit hyperactivity disorder (ADHD), and mood disorders. We discuss the implications of DMN disruptions and their relationship to the neurocognitive model of each disease entity, the utility of DMN assessment in clinical evaluation, and the changes of the DMN following treatment.     

Season,but not experimental warming,affects the activity and temperature sensitivity of extracellular enzymes

Climate change may affect the microbial production and temperature sensitivity of extracellular enzymes that release carbon (C) and nutrients from soil organic matter. We measured the response of six hydrolytic enzymes involved in C, nitrogen (N), and phosphorus (P) degradation to experimental warming in a mixed-deciduous forest persisting on highly-weathered Ultisols (Whitehall Forest, Georgia, US). We found that warming produced no consistent enzyme response. However, we observed significant seasonal variation in enzyme activities, temperature sensitivities and elemental enzyme ratios (C:N and C:P). Seasonal differences in enzyme activity and temperature sensitivity were best explained by soil moisture and temperature. Our results suggest that seasonal dynamics in soil microclimate, organic matter supply, and microbial demand exert more control on enzyme dynamics than does a uniform increase in soil temperature.     

Hyaluronic acid modified pH-sensitive liposomes for targeted intracellular delivery of doxorubicin

Context: Surface-modified pH-sensitive liposomal system may be useful for intracellular delivery of chemotherapeutics.

Objective: Achieving site-specific targeting with over-expressed hyaluronic acid (HA) receptors along with using pH sensitive liposome carrier for intracellular drug delivery was the aim of this study.

Materials and methods: Stealth HA-targeted pH-sensitive liposomes (SL-pH-HA) were developed and evaluated to achieve effective intracellular delivery of doxorubicin (DOX) vis–a-vis enhanced antitumor activity.

Results: The in vitro release studies demonstrated that the release of DOX from SL-pH-HA was pH-dependent, i.e. faster at mildly acidic pH ～5, compared to physiological pH ～7.4. SLpH-HA was evaluated for their cytotoxicity potential on CD44 receptor expressing MCF-7 cells. The half maximal inhibitory concentration (IC50) of SL-pH-HA and SL-HA were about 1.9 and 2.5?μM, respectively, after 48?h of incubation. The quantitative uptake study revealed higher localization of targeted liposomes in the receptor positive cells, which was further confirmed by fluorescent microscopy. The antitumor efficacy of the DOX-loaded HA-targeted pH-sensitive liposomes was also verified in a tumor xenograft mouse model.

Discussion: DOX was efficiently delivered to the tumor site by active targeting via HA and CD44 receptor interaction. The major side-effect of conventional DOX formulation, i.e. cardiotoxicity was also estimated by measuring serum enzyme levels of LDH and CPK and found to be minimized with developed formulation. Overall, HA targeted pH-sensitive liposomes were significantly more potent than the non-targeted liposomes in cells expressing high levels of CD44.

Conclusion: Results strongly implies the promise of such liposomal system as an intracellular drug delivery carrier developed for potential anticancer treatment.     

Acetyltransferase p300 inhibitor reverses hypertension‐induced cardiac fibrosis

Epigenetic dysregulation plays a crucial role in cardiovascular diseases. Previously, we reported that acetyltransferase p300 (ATp300) inhibitor L002 prevents hypertension‐induced cardiac hypertrophy and fibrosis in a murine model. In this short communication, we show that treatment of hypertensive mice with ATp300‐specific small molecule inhibitor L002 or C646 reverses hypertension‐induced left ventricular hypertrophy, cardiac fibrosis and diastolic dysfunction, without reducing elevated blood pressures. Biochemically, treatment with L002 and C646 also reverse hypertension‐induced histone acetylation and myofibroblast differentiation in murine ventricles. Our results confirm and extend the role of ATp300, a major epigenetic regulator, in the pathobiology of cardiac hypertrophy and fibrosis. Most importantly, we identify the efficacies of ATp300 inhibitors C646 and L002 in reversing hypertension‐induced cardiac hypertrophy and fibrosis, and discover new anti‐hypertrophic and anti‐fibrotic candidates.     

Cold chain and virus‐free oral polio booster vaccine made in lettuce chloroplasts confers protection against all three poliovirus serotypes

To prevent vaccine‐associated paralytic poliomyelitis, WHO recommended withdrawal of Oral Polio Vaccine (Serotype‐2) and a single dose of Inactivated Poliovirus Vaccine (IPV). IPV however is expensive, requires cold chain, injections and offers limited intestinal mucosal immunity, essential to prevent polio reinfection in countries with open sewer system. To date, there is no virus‐free and cold chain‐free polio vaccine capable of inducing robust mucosal immunity. We report here a novel low‐cost, cold chain/poliovirus‐free, booster vaccine using poliovirus capsid protein (VP1, conserved in all serotypes) fused with cholera non‐toxic B subunit (CTB) expressed in lettuce chloroplasts. PCR using unique primer sets confirmed site‐specific integration of CTB‐VP1 transgene cassettes. Absence of the native chloroplast genome in Southern blots confirmed homoplasmy. Codon optimization of the VP1 coding sequence enhanced its expression 9–15‐fold in chloroplasts. GM1‐ganglioside receptor‐binding ELISA confirmed pentamer assembly of CTB‐VP1 fusion protein, fulfilling a key requirement for oral antigen delivery through gut epithelium. Transmission Electron Microscope images and hydrodynamic radius analysis confirmed VP1‐VLPs of 22.3 nm size. Mice primed with IPV and boosted three times with lyophilized plant cells expressing CTB‐VP1co, formulated with plant‐derived oral adjuvants, enhanced VP1‐specific IgG1, VP1‐IgA titres and neutralization (80%–100% seropositivity of Sabin‐1, 2, 3). In contrast, IPV single dose resulted in <50% VP1‐IgG1 and negligible VP1‐IgA titres, poor neutralization and seropositivity (<20%, <40% Sabin 1,2). Mice orally boosted with CTB‐VP1co, without IPV priming, failed to produce any protective neutralizing antibody. Because global population is receiving IPV single dose, booster vaccine free of poliovirus or cold chain offers a timely low‐cost solution to eradicate polio.     

Functionalized pyrene‐based AIEgens: synthesis,photophysical characterization and density functional theory studies

Three new pyrene‐based derivatives P1 , P2 and P3 with a substituted pyrazole were designed, synthesized and characterized using standard spectroscopic techniques. Ultraviolet–visible (UV–vis) spectroscopic studies for P1–P3 uncovered a finite bathochromic shift of the molecules in solvents of varying polarity. Photoluminescence (PL) studies revealed the significant fluorescence emission of all molecules in higher polar solvents such as MeOH and dimethylformamide (DMF). Fluorescence quantum yield studies demonstrated the importance of P3 possessing cyanofunctionality for imparting higher emission with a quantum yield of 0.36%. Ratiometric studies performed in a tetrahydrofuran (THF)/H₂O mixture indicated fluorescence enhancement with increasing overall percentage of water, confirming the aggregation‐induced emission effect. Cyclic voltammetry study of molecules P1–P3 revealed an irreversible oxidation peak and the band gaps were calculated to be 2.26 eV for P1 and 2.31 eV for P2 and P3 respectively. Density functional theory (DFT) studies performed on molecules P1–P3 validate the structure correlation of the molecules. Theoretically estimated highest occupied molecular orbital ( HOMO), lowest unoccupied molecular orbital (LUMO) and bandgap correlated well with the experimental values. Furthermore, time‐dependent (TD)DFT showed that the major contribution for the electronic transitions occurring in the system was governed by HOMO‐1 and LUMO+1 orbitals.     

Architectural roles of Cren7 in folding crenarchaeal chromatin filament

Archaea have evolved various strategies in chromosomal organization. While histone homologues exist in most archaeal phyla, Cren7 is a chromatin protein conserved in the Crenarchaeota. Here, we show that Cren7 preferentially binds DNA with AT‐rich sequences over that with GC‐rich sequences with a binding size of 6~7 bp. Structural studies of Cren7 in complex with either an 18‐bp or a 20‐bp double‐stranded DNA fragment reveal that Cren7 binds to the minor groove of DNA as monomers in a head‐to‐tail manner. The neighboring Cren7 monomers are located on the opposite sides of the DNA duplex, with each introducing a single‐step sharp kink by intercalation of the hydrophobic side chain of Leu28, bending the DNA into an S‐shape conformation. A structural model for the chromatin fiber folded by Cren7 was established and verified by the analysis of cross‐linked Cren7‐DNA complexes by atomic force microscopy. Our results suggest that Cren7 differs significantly from Sul7, another chromatin protein conserved among Sulfolobus species, in both DNA binding and deformation. These data shed significant light on the strategy of chromosomal DNA organization in crenarchaea.