Tower 1978

1978 yearbook of Westbrook College in Portland, Maine.https://dune.une.edu/wchc_yearbooks/1007/thumbnail.jp

Multiscale Approach to Investigate Self-Assembly of Telodendrimer Based Nanocarriers for Anticancer Drug Delivery

Delivery of poorly soluble anticancer drugs can be achieved by employing polymeric drug delivery systems, capable of forming stable self-assembled nanocarriers with drug encapsulated within their hydrophobic cores. Computational investigations can aid the design of efficient drug-delivery platforms; however, simulations of nanocarrier self-assembly process are challenging due to high computational cost associated with the large system sizes (millions of atoms) and long time scales required for equilibration. In this work, we overcome this challenge by employing a multiscale computational approach in conjunction with experiments to analyze the role of the individual building blocks in the self-assembly of a highly tunable linear poly­(ethylene glycol)-<i>b</i>-dendritic oligo­(cholic acid) block copolymer called telodendrimer. The multiscale approach involved developing a coarse grained description of the telodendrimer, performing simulations over several microseconds to capture the self-assembly process, followed by reverse mapping of the coarse grained system to atomistic representation for structural analysis. Overcoming the computational bottleneck allowed us to run multiple self-assembly simulations and determine average size, drug-telodendrimer micellar stoichiometry, optimal drug loading capacity, and atomistic details such hydrogen-bonding and solvent accessible area of the nanocarrier. Computed results are in agreement with the experimental data, highlighting the success of the multiscale approach applied here

Simulating Gram-Negative Bacterial Outer Membrane: A Coarse Grain Model

The cell envelope of Gram-negative bacteria contains a lipopolysaccharide (LPS) rich outer membrane that acts as the first line of defense for bacterial cells in adverse physical and chemical environments. The LPS macromolecule has a negatively charged oligosaccharide domain that acts as an ionic brush, limiting the permeability of charged chemical agents through the membrane. Besides the LPS, the outer membrane has radially extending O-antigen polysaccharide chains and β-barrel membrane proteins that make the bacterial membrane physiologically unique compared to phospholipid cell membranes. Elucidating the interplay of these contributing macromolecular components and their role in the integrity of the bacterial outer membrane remains a challenge. To bridge the gap in our current understanding of the Gram-negative bacterial membrane, we have developed a coarse grained force field for outer membrane that is computationally affordable for simulating dynamical process over physiologically relevant time scales. The force field was benchmarked against available experimental and atomistic simulations data for properties such as membrane thickness, density profiles of the residues, area per lipid, gel to liquid-crystalline phase transition temperatures, and order parameters. More than 17 membrane compositions were studied with a combined simulation time of over 100 μs. A comparison of simulated structural and dynamical properties with corresponding experimental data shows that the developed force field reproduces the overall physiology of LPS rich membranes. The affordability of the developed model for long time scale simulations can be instrumental in determining the mechanistic aspects of the antimicrobial action of chemical agents as well as assist in designing antimicrobial peptides with enhanced outer membrane permeation properties

Drug-Specific Design of Telodendrimer Architecture for Effective Doxorubicin Encapsulation

Designing a versatile nanocarrier platform that can be tailored to deliver specific drug payloads is challenging. In general, effective drug encapsulation, high drug-loading capacity, uniform shape and size distribution, and enhanced stability are among the fundamental attributes of a successful nanocarrier design. These physiochemical features of the nanocarriers are intimately tied to the specific drug payload that they are tasked to deliver. The molecular architecture of the nanocarrier’s scaffold often needs to be tuned for each drug, especially if the target drugs are structurally and chemically distinct as in the case of doxorubicin (DOX) and paclitaxel (PTX). Starting from our previously reported telodendrimeric block copolymer platform optimized for PTX, we analyze three generations of telodendrimer architectures to arrive at the design that is capable of encapsulating another important chemotherapeutic drug, DOX. Multiple long-time-scale self-assembly simulations were performed both in atomistic and coarse-grained resolutions to generate equilibrated DOX-encapsulated nanocarriers. The results show how subtle changes in the molecular architecture of the telodendrimer head groups have profound effects on the nanocarrier size, morphology, and asphericity. The simulation results are in agreement with the experimental data for DOX-encapsulated nanocarriers. This work emphasizes the increasing role of molecular simulations in the rational design of nanocarriers, thereby eliminating the trial and error method that has been prevalent in experimental synthesis. The molecular-level insights gained from the simulations will be used to design the next generation of drug-specific nanocarriers

The subtypes of pituitary adenoma in 2021 patients.

<p>PRL, prolactin; GH, growth hormone; LH, luteinizing hormone; ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone; FSH, follicle-stimulating hormone. Others include multi-hormonal, LH, TSH, and unknown type.</p

Characteristics of all 2021 patients with pituitary tumors, 2005–2007.

<p>Characteristics of all 2021 patients with pituitary tumors, 2005–2007.</p

Symptoms at presentation.

<p>* Pearson's chi-squared test.</p><p>† Pearson's statistic with a continuity correction.</p><p>‡ Statistical analysis done by Fisher’s exact test.</p><p>§ These calculations include only women.</p><p>¶ These calculations include only men.</p><p>Symptoms at presentation.</p

Predictors of clinical PA in pituitary adenoma patients.

<p>Crude OR, crude odds ratios; Adjusted OR, adjusted odds ratios; CI, confidence interval.</p><p>* reference</p><p>† including PRL, FSH, GH, ACTH, TSH, and multiple staining</p><p>¶ non-functioning tumor type</p><p>Predictors of clinical PA in pituitary adenoma patients.</p

Incidence of PA in subgroups.

<p>NA, not applicable; PRL, prolactin; GH, growth hormone; LH, luteinizing hormone; ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone; FSH, follicle-stimulating hormone. PA, clinical pituitary apoplexy.</p><p>* Pearson's chi-squared test.</p><p>Incidence of PA in subgroups.</p

Data_Sheet_1_Traditional Chinese medicine prescriptions (XJZ, JSS) ameliorate spleen inflammatory response and antioxidant capacity by synergistically regulating NF-κB and Nrf2 signaling pathways in piglets.docx

Weaning transition generally impairs the immune system, inducing immune disturbance, which may be associated with post-weaning diarrhea and high mortality in piglets. The spleen is a pivotal lymphatic organ that plays a key role in the establishment of the immune system. Traditional Chinese medicine (TCM) prescriptions, XiaoJianZhong (XJZ) and Jiansananli-sepsis (JSS), are widely used prescriptions for treating spleen damage and diarrhea. Here, we hypothesized that XJZ and JSS maintain the spleen physiological function by ameliorating antioxidant capacity and inflammatory response in weaned piglets. In this study, 18 weaned piglets were assigned to the Control, XJZ and JSS groups. By hematoxylin and eosin staining, hematological analysis, flow cytometric analysis, qRT-PCR and western blot, the effects of both TCM prescriptions on the spleen antioxidant defense system and inflammatory pathway were explored. Results showed that both TCM treatment significantly ameliorated the weaning-induced morphological damage in piglets, as evidenced by clearer and more perfect spleen histology, as well as higher relative area of white pulp. Meanwhile, both XJZ and JSS exerted better blood parameters, as supported by the changes of monocyte level and lymphocyte subpopulations CD4+/CD8+ ratio. Furthermore, the levels of inflammatory markers, IL1β, IL6, IL8, and TNF-α in the spleen were markedly decreased after supplemented with both TCM prescriptions. Importantly, the inhibition of nuclear factor-kappaB (NF-κB) and its downstream effector genes (IL6, IL8, and TNF-α) in both XJZ and JSS treatment groups further confirmed alleviation of inflammatory responses in the spleen. In addition, both XJZ and JSS enhanced the antioxidant capacity of the spleen by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)-activated antioxidant defense system. Notably, the results of PCA and network correlation analysis indicated that XJZ and JSS treatment altered the expression profiles of inflammatory and antioxidant-related factors in the spleen of weaned-piglets, which may involve the synergy of NF-κB and Nrf2 signaling pathways. In summary, our study showed that TCM prescriptions, XJZ and JSS could ameliorate inflammatory response and antioxidant capacity in the spleen by synergistically regulating NF-κB and Nrf2 signaling pathways in piglets.</p