Accurately measuring antibody repertoire sequence composition in a small amount of blood is challenging yet important for understanding repertoire responses to infection and vaccination. We develop molecular identifier clustering-based immune repertoire sequencing (MIDCIRS) and use it to study age-related antibody repertoire development and diversification before and during acute malaria in infants (<12 months old) and toddlers (12-47 months old) with 4-8ml of blood. Here, we show this accurate and high-coverage repertoire-sequencing method can use as few as 1000 naive B cells. Unexpectedly, we discover high levels of somatic hypermutation in infants as young as 3 months old. Antibody clonal lineage analysis reveals that somatic hypermutation levels are increased in both infants and toddlers upon infection, and memory B cells isolated from individuals who previously experienced malaria continue to induce somatic hypermutations upon malaria rechallenge. These results highlight the potential of antibody repertoire diversification in infants and toddlers.
Amyloid-beta peptide (A beta) fibrillation is pathologically associated with Alzheimer's disease (AD), and this has resulted in the development of an A beta inhibitor which is essential for the treatment of AD. However, the design of potent agents which can target upstream secretases, inhibit A beta toxicity and aggregation, as well as cross the blood-brain barrier remains challenging. In, this research carbon dots for AD treatment were investigated in vitro using experimental and computational methods for the first time. The results presented here demonstrate a novel strategy for the discovery of novel antiamyloidogenic agents for AD treatments.
Size and pump-fluence dependent ultrafast carrier dynamics of CdSeTe QDs are investigated using femtosecond pump-probe techniques operating at two different repetition rates: 1 kHz (low-repetition rate), and 76 MHz (high-repetition rate). With a low-repetition rate laser and 3.1 eV excitation photon energy, multiple exciton generation (MEG) is observed and the optical responses of alloyed QDs clearly show three components: a fast decay ascribed to carrier recombination, an intermediate component associated with MEG decay, and a slow decay associated with radiative Auger recombination. With a high-repetition rate laser and excitation photon energy resonant with band-edge energy, obvious coherent phonon oscillations are observed in 4 nm CdSeTe QDs due to impulsive stimulated Raman scattering. Open-aperture Z-scan measurement is used to clarify the size and pump-fluence dependence of optical nonlinearity under femtosecond laser excitation. With increasing laser power, an evolution from saturable absorption to reverse saturable absorption in CdSeTe QDs is observed. The transition process is analyzed using a phenomenological model based on nonlinear absorption coefficient and saturation intensity. These results indicate that CdSeTe QDs in a glass matrix are a class of materials for potential application in all-optical switching devices.
Catalytic reduction of nitrate in ion exchange (IX) waste brine for reuse is a promising option for reducing IX costs and environmental impacts. A recycling trickle bed reactor (TBR) was designed and optimized using 0.5 percent byweight (wt%) palladium–0.05 wt% indium catalysts supported on US mesh size 12 × 14 or 12 × 30 activated carbon particles. Various liquid superficial velocities (Ur) and hydrogen gas superficial velocities (Ug-H2) were evaluated to assess performance in different flow regimes; catalyst activity increased with Ug-H2 at all Ur for both catalysts and was greatest for the 12 × 30 catalyst at thelowest Ur (8.9 m/h). The 12 × 30 catalyst demonstrated up to 100% higher catalytic activity and 280% higher mass transfer rate compared with the 12 × 14 catalyst. Optimal TBR performance was achieved with both catalysts in thetrickle flow regime. The results indicate that the TBR is a promising step forward, and continued improvements are possible to overcome remaining mass transfer limitations.
Palladium (Pd)-based catalysts hold promise as an alternative water treatment technology for nitrate (NO3–), but practical application requires a flow-through reactor that efficiently delivers hydrogen (H2) from gas to water. A trickle bed reactor (TBR) packed with a 0.1 percent by weight (wt%) Pd–0.01 wt% In/γ-Al2O3 (indium and porous aluminum oxide) catalyst was evaluated to address this challenge. Catalytic activity generally increased with H2 superficial velocity (0.65–29.6 m/h) and liquid (deionized water) superficial velocities from 14.8 to 26.6 m/h before decreasing at 38.5 m/h. This decrease corresponded to a change in flow regime and suggests that optimal TBR performance occurs at the transition from pulse to bubble flow. An optimal TBR activity of 19.5 ± 1.3 mg NO3–/min-g Pd was obtained; this is only ~18% of the batch reactor activity as a result of H2 mass transfer limitations, but three to 15 times greater than activities obtained with previous flow-through reactors. Catalyst deactivation occurred in the TBR after 41 days of operation, motivating the need for improved fouling mitigation strategies.
Immune checkpoint therapy has become the first widely adopted immunotherapy for patients with late stage malignant melanoma, with potential for a wide range of cancers. While some patients can experience long term disease remission, this is limited only to a subset of patients and tumor types. The path forward to expand this therapy to more patients and tumor types is currently thought to be combinatorial treatments, the combination of immunotherapy with other treatments. In this review, the combinatorial approach of immune checkpoint therapy combined with nanoparticle-assisted localized hyperthermia is discussed, starting with an overview of the different nanoparticle hyperthermia approaches in development, an overview of the state of immune checkpoint therapy, recent reports of immune checkpoint therapy and nanoparticle-assisted hyperthermia in a combinatorial approach, and finally a discussion of future research topics and areas to be explored in this new combinatorial approach to cancer treatment.
Laser-mediated photothermal ablation of cancer cells aided by photothermal agents is a promising strategy for localized, externally controlled cancer treatment. We report the synthesis, characterization, and in vitro evaluation of conductive polymeric nanoparticles (CPNPs) of poly(diethyl-4,4'-[2,5-bis(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-1,4-phenyle ne] bis(oxy)dibutanoate) (P1) and poly(3,4-ethylenedioxythiophene) (PEDOT) stabilized with 4-dodecylbenzenesulfonic acid and poly(4-styrenesulfonic acid-co-maleic acid) as photothermal ablation agents. The nanoparticles were prepared by oxidative-emulsion polymerization, yielding stable aqueous suspensions of spherical particles of <100 nm diameter as determined by dynamic light scattering and electron microscopy. Both types of nanoparticles show strong absorption of light in the near infrared region, with absorption peaks at 780 nm for P1 and 750 nm for PEDOT, as well as high photothermal conversion efficiencies ( 50%), that is higher than commercially available gold-based photothermal ablation agents. The nanoparticles show significant photostability as determined by their ability to achieve consistent temperatures and to maintain their morphology upon repeated cycles of laser irradiation. In vitro studies in MDA-MB-231 breast cancer cells demonstrate the cytocompatibility of the CPNPs and their ability to mediate complete cancer cell ablation upon irradiation with an 808-nm laser, thereby establishing the potential of these systems as agents for laser-induced photothermal therapy.
To explain the effects of cationic amino acids and other co-solutes on the viscosity, stability and protein-protein interactions (PPI) of highly concentrated (≥200 mg/ml) monoclonal antibody (mAb) solutions to advance subcutaneous injection.
The viscosities of ≥200 mg/ml mAb1 solutions with various co-solutes and pH were measured by capillary rheometry in some cases up to 70,000 s−1. The viscosities are analyzed in terms of dilute PPI characterized by diffusion interaction parameters (kD) from dynamic light scattering (DLS). MAb stability was measured by turbidity and size exclusion chromatography (SEC) after 4 weeks of 40°C storage.
Viscosity reductions were achieved by reducing the pH, or adding histidine, arginine, imidazole or camphorsulfonic acid, each of which contains a hydrophobic moiety. The addition of inorganic electrolytes or neutral osmolytes only weakly affected viscosity. Systems with reduced viscosities also tended to be Newtonian, while more viscous systems were shear thinning.
Viscosity reduction down to 20 cP at 220 mg/ml mAb1 was achieved with co-solutes that are both charged and contain a hydrophobic interaction domain for sufficient binding to the protein surface. These reductions are related to the DLS diffusion interaction parameter, kD, only after normalization to remove the effect of charge screening. Shear rate profiles demonstrate that select co-solutes reduce protein network formation.