A kinetic Monte-Carlo methodology is presented for simulating crystal growth in materials which contain stacking faults. By simulating a large number of potential growth and dissolution events, a ...representation of the crystal is generated at various stages throughout the crystallisation, allowing the effects of disorder on the evolution of crystal habit and nanoscale surface topography to be explored. As examples, simulations were performed on two intergrown zeolite materials - zeolite T and zeolite beta. In both zeolite T and zeolite beta, simulations demonstrate how an intergrown structure leads to a characteristic roughening of certain crystal facets. In zeolite beta, this is accompanied by the development of internal defects which shows a non-homogeneous distribution. Results of simulations are validated by direct comparison to experimental scanning electron microscopy, atomic force microscopy and X-ray diffraction data. All simulations are performed using the CrystalGrower software package with modifications to account for disorder and should be generally applicable to all classes of crystals.
A kinetic Monte Carlo approach for modelling crystal growth, allowing simulation of crystal habit and surface fine structure in materials containing high levels of stacking faults.
Noninvasive aerosol inhalation is an established method of drug delivery to the lung, and remains a desirable route for nucleic‐acid‐based therapeutics. In vitro transcribed (IVT) mRNA has broad ...therapeutic applicability as it permits temporal and dose‐dependent control of encoded protein expression. Inhaled delivery of IVT‐mRNA has not yet been demonstrated and requires development of safe and effective materials. To meet this need, hyperbranched poly(beta amino esters) (hPBAEs) are synthesized to enable nanoformulation of stable and concentrated polyplexes suitable for inhalation. This strategy achieves uniform distribution of luciferase mRNA throughout all five lobes of the lung and produces 101.2 ng g−1 of luciferase protein 24 h after inhalation of hPBAE polyplexes. Importantly, delivery is localized to the lung, and no luminescence is observed in other tissues. Furthermore, using an Ai14 reporter mouse model it is identified that 24.6% of the total lung epithelial cell population is transfected after a single dose. Repeat dosing of inhaled hPBAE‐mRNA generates consistent protein production in the lung, without local or systemic toxicity. The results indicate that nebulized delivery of IVT‐mRNA facilitated by hPBAE vectors may provide a clinically relevant delivery system to lung epithelium.
In vitro transcribed mRNA is nebulized using poly(beta amino esters) for noninvasive delivery to the lung. Hyperbranched polymers form stable mRNA‐polyplexes that distribute uniformly throughout the lungs of mice after inhalation. Reporter protein is expressed in 24.6% of the total lung epithelial cell population after a single dose and repeat dosing results in consistent protein levels without toxicity.
Touch perception on the fingers and hand is essential for fine motor control, contributes to our sense of self, allows for effective communication, and aids in our fundamental perception of the ...world. Despite increasingly sophisticated mechatronics, prosthetic devices still do not directly convey sensation back to their wearers. We show that implanted peripheral nerve interfaces in two human subjects with upper limb amputation provided stable, natural touch sensation in their hands for more than 1 year. Electrical stimulation using implanted peripheral nerve cuff electrodes that did not penetrate the nerve produced touch perceptions at many locations on the phantom hand with repeatable, stable responses in the two subjects for 16 and 24 months. Patterned stimulation intensity produced a sensation that the subjects described as natural and without "tingling," or paresthesia. Different patterns produced different types of sensory perception at the same location on the phantom hand. The two subjects reported tactile perceptions they described as natural tapping, constant pressure, light moving touch, and vibration. Changing average stimulation intensity controlled the size of the percept area; changing stimulation frequency controlled sensation strength. Artificial touch sensation improved the subjects' ability to control grasping strength of the prosthesis and enabled them to better manipulate delicate objects. Thus, electrical stimulation through peripheral nerve electrodes produced long-term sensory restoration after limb loss.
Therapeutic nucleic acids hold great promise for the treatment of disease but require vectors for safe and effective delivery. Synthetic nanoparticle vectors composed of poly(β‐amino esters) (PBAEs) ...and nucleic acids have previously demonstrated potential utility for local delivery applications. To expand this potential utility to include systemic delivery of mRNA, hybrid polymer–lipid nanoformulations for systemic delivery to the lungs were developed. Through coformulation of PBAEs with lipid–polyethylene glycol (PEG), mRNA formulations were developed with increased serum stability and increased in vitro potency. The formulations were capable of functional delivery of mRNA to the lungs after intravenous administration in mice. To our knowledge, this is the first report of the systemic administration of mRNA for delivery to the lungs using degradable polymer–lipid nanoparticles.
mRNA‐loaded nanoparticles were synthesized using degradable poly(β‐amino ester) terpolymers formulated with a PEG‐lipid. The PEG‐lipid imparted serum stability to the nanoparticles, which resulted in successful mRNA delivery to the lungs after systemic nanoparticle administration in mice.
Intracellular delivery of messenger RNA (mRNA) has the potential to induce protein production for many therapeutic applications. Although lipid nanoparticles have shown considerable promise for the ...delivery of small interfering RNAs (siRNA), their utility as agents for mRNA delivery has only recently been investigated. The most common siRNA formulations contain four components: an amine-containing lipid or lipid-like material, phospholipid, cholesterol, and lipid-anchored polyethylene glycol, the relative ratios of which can have profound effects on the formulation potency. Here, we develop a generalized strategy to optimize lipid nanoparticle formulations for mRNA delivery to the liver in vivo using Design of Experiment (DOE) methodologies including Definitive Screening and Fractional Factorial Designs. By simultaneously varying lipid ratios and structures, we developed an optimized formulation which increased the potency of erythropoietin-mRNA-loaded C12-200 lipid nanoparticles 7-fold relative to formulations previously used for siRNA delivery. Key features of this optimized formulation were the incorporation of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and increased ionizable lipid:mRNA weight ratios. Interestingly, the optimized lipid nanoparticle formulation did not improve siRNA delivery, indicating differences in optimized formulation parameter design spaces for siRNA and mRNA. We believe the general method described here can accelerate in vivo screening and optimization of nanoparticle formulations with large multidimensional design spaces.
mRNA therapeutics hold great potential for treating a variety of diseases through protein-replacement, immunomodulation, and gene editing. However, much like siRNA therapy the majority of progress in ...mRNA delivery has been confined to the liver. Previously, we demonstrated that poly(β-amino esters), a class of degradable polymers, are capable of systemic mRNA delivery to the lungs in mice when formulated into nanoparticles with poly(ethylene glycol)–lipid conjugates. Using experimental design, a statistical approach to optimization that reduces experimental burden, we demonstrate herein that these degradable polymer–lipid nanoparticles can be optimized in terms of polymer synthesis and nanoparticle formulation to achieve a multiple order-of-magnitude increase in potency. Furthermore, using genetically engineered Cre reporter mice, we demonstrate that mRNA is functionally delivered to both the lung endothelium and pulmonary immune cells, expanding the potential utility of these nanoparticles.
The 21 cm transition of neutral hydrogen is opening an observational window into the Cosmic Dawn of the universe-the epoch of first star formation. We use 28 hr of data from the Owens Valley Radio ...Observatory Long Wavelength Array to place upper limits on the spatial power spectrum of 21 cm emission at z 18.4 ( ), and within the absorption feature reported by the EDGES experiment. In the process we demonstrate the first application of the double Karhunen-Loève transform for foreground filtering, and diagnose the systematic errors that are currently limiting the measurement. We also provide an updated model for the angular power spectrum of low-frequency foreground emission measured from the northern hemisphere, which can be used to refine sensitivity forecasts for next-generation experiments.
Dozens of studies in different nations have revealed that socioeconomic status only weakly predicts an individual's subjective well-being (SWB). These results imply that although the pursuit of ...social status is a fundamental human motivation, achieving high status has little impact on one's SWB. However, we propose that sociometric status—the respect and admiration one has in face-to-face groups (e.g., among friends or coworkers)—has a stronger effect on SWB than does socioeconomic status. Using correlational, experimental, and longitudinal methodologies, four studies found consistent evidence for a local-ladder effect: Sociometric status significantly predicted satisfaction with life and the experience of positive and negative emotions. Longitudinally, as sociometric status rose or fell, SWB rose or fell accordingly. Furthermore, these effects were driven by feelings of power and social acceptance. Overall, individuals' sociometric status matters more to their SWB than does their socioeconomic status.
B lymphocytes regulate several aspects of immunity including antibody production, cytokine secretion, and T‐cell activation; moreover, B cell misregulation is implicated in autoimmune disorders and ...cancers such as multiple sclerosis and non‐Hodgkin's lymphomas. The delivery of messenger RNA (mRNA) into B cells can be used to modulate and study these biological functions by means of inducing functional protein expression in a dose‐dependent and time‐controlled manner. However, current in vivo mRNA delivery systems fail to transfect B lymphocytes and instead primarily target hepatocytes and dendritic cells. Here, the design, synthesis, and biological evaluation of a lipid nanoparticle (LNP) system that can encapsulate mRNA, navigate to the spleen, transfect B lymphocytes, and induce more than 60 pg of protein expression per million B cells within the spleen is described. Importantly, this LNP induces more than 85% of total protein production in the spleen, despite LNPs being observed transiently in the liver and other organs. These results demonstrate that LNP composition alone can be used to modulate the site of protein induction in vivo, highlighting the critical importance of designing and synthesizing new nanomaterials for nucleic acid delivery.
B‐lymphocytesregulate several aspects of immunity, but B‐cell dysfunction can also serve as the root of disease. Accordingly, it is important to develop chemical tools that can modulate pathways associated with B‐cell function. A new class of ionizable lipid materials is synthesized that, when formulated into messenger RNA lipid nanoparticles, induces protein expression within B‐lymphocytes in mice.
Watching crystals grow: In situ atomic force microscopy has been used to observe the crystal growth of the nanoporous metal–organic framework HKUST‐1. This real‐time study provides evidence that the ...growth of HKUST‐1 under the given supersaturation conditions is through a surface nucleation mechanism and presents insight into the units of attachment during the growth of the 1.5 nm high steps on the crystal surface (see picture).
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