Multivalent interactions can be applied universally for a targeted strengthening of an interaction between different interfaces or molecules. The binding partners form cooperative, multiple ...receptor–ligand interactions that are based on individually weak, noncovalent bonds and are thus generally reversible. Hence, multi‐ and polyvalent interactions play a decisive role in biological systems for recognition, adhesion, and signal processes. The scientific and practical realization of this principle will be demonstrated by the development of simple artificial and theoretical models, from natural systems to functional, application‐oriented systems. In a systematic review of scaffold architectures, the underlying effects and control options will be demonstrated, and suggestions will be given for designing effective multivalent binding systems, as well as for polyvalent therapeutics.
Unified strength: Multivalent structures function in a number of biological systems to generate a strong but reversible interaction between two objects. The chemical realization of this natural principle with organized multiple interactions enables, for example, the development of multivalent drugs for an effective inhibition of viral cell attachment.
Nanoparticles (NPs) are widely used as components of drugs or cosmetics and hold great promise for biomedicine, yet their effects on cell physiology remain poorly understood. Here we demonstrate that ...clathrin-independent dynamin 2-mediated caveolar uptake of surface-functionalized silica nanoparticles (SiNPs) impairs cell viability due to lysosomal dysfunction. We show that internalized SiNPs accumulate in lysosomes resulting in inhibition of autophagy-mediated protein turnover and impaired degradation of internalized epidermal growth factor, whereas endosomal recycling proceeds unperturbed. This phenotype is caused by perturbed delivery of cargo via autophagosomes and late endosomes to SiNP-filled cathepsin B/L-containing lysosomes rather than elevated lysosomal pH or altered mTOR activity. Given the importance of autophagy and lysosomal protein degradation for cellular proteostasis and clearance of aggregated proteins, these results raise the question of beneficial use of NPs in biomedicine and beyond.
Asymmetrically substituted tertiary phosphines and quaternary phosphonium salts are used extensively in applications throughout industry and academia. Despite their significance, classical methods to ...synthesize such compounds often demand either harsh reaction conditions, prefunctionalization of starting materials, highly sensitive organometallic reagents, or expensive transition‐metal catalysts. Mild, practical methods thus remain elusive, despite being of great current interest. Herein, we describe a visible‐light‐driven method to form these products from secondary and primary phosphines. Using an inexpensive organic photocatalyst and blue‐light irradiation, arylphosphines can be both alkylated and arylated using commercially available organohalides. In addition, the same organocatalyst can be used to transform white phosphorus (P4) directly into symmetrical aryl phosphines and phosphonium salts in a single reaction step, which has previously only been possible using precious metal catalysis.
Driven by light: A mild and facile photoredox approach towards asymmetrically substituted phosphines and phosphonium salts is reported. Blue‐light irradiation of mono‐ and diphenylphosphine with various aryl and alkyl iodides, diisopropylethylamine (DIPEA), and the organic photocatalyst 3DPAFIPN affords the desired products in good‐to‐excellent yields. In addition, the same method transforms white phosphorus (P4) directly into symmetrical aryl phosphines and phosphonium salts.
Upconversion nanoparticles (UCNPs), consisting of NaYF
doped with 18% Yb and 2% Er, were coated with microporous silica shells with thickness values of 7 ± 2 and 21 ± 3 nm. Subsequently, the ...negatively charged particles were functionalized with
-(6-aminohexyl)-3-aminopropyltrimethoxysilane (AHAPS), which provide a positive charge to the nanoparticle surface. Inductively coupled plasma optical emission spectrometry (ICP-OES) measurements revealed that, over the course of 24h, particles with thicker shells release fewer lanthanide ions than particles with thinner shells. However, even a 21 ± 3 nm thick silica layer does not entirely block the disintegration process of the UCNPs. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and cell cytometry measurements performed on macrophages (RAW 264.7 cells) indicate that cells treated with amino-functionalized particles with a thicker silica shell have a higher viability than those incubated with UCNPs with a thinner silica shell, even if more particles with a thicker shell are taken up. This effect is less significant for negatively charged particles. Cell cycle analyses with amino-functionalized particles also confirm that thicker silica shells reduce cytotoxicity. Thus, growing silica shells to a sufficient thickness is a simple approach to minimize the cytotoxicity of UCNPs.
Walking patterns can provide important indications of a person's health status and be beneficial in the early diagnosis of individuals with a potential walking disorder. For appropriate gait ...analysis, it is critical that natural functional walking characteristics are captured, rather than those experienced in artificial or observed settings. To better understand the extent to which setting influences gait patterns, and particularly whether observation plays a varying role on subjects of different ages, the current study investigates to what extent people walk differently in lab versus real-world environments and whether age dependencies exist.
The walking patterns of 20 young and 20 elderly healthy subjects were recorded with five wearable inertial measurement units (ZurichMOVE sensors) attached to both ankles, both wrists and the chest. An automated detection process based on dynamic time warping was developed to efficiently identify the relevant sequences. From the ZurichMOVE recordings, 15 spatio-temporal gait parameters were extracted, analyzed and compared between motion patterns captured in a controlled lab environment (10 m walking test) and the non-controlled ecologically valid real-world environment (72 h recording) in both groups.
Several parameters (
) showed significant differences between the two environments for both groups, including an increased outward foot rotation, step width, number of steps per 180° turn, stance to swing ratio, and cycle time deviation in the real-world. A number of parameters (
) showed only significant differences between the two environments for elderly subjects, including a decreased gait velocity (
= 0.0072), decreased cadence (
= 0.0051) and increased cycle time (
= 0.0051) in real-world settings. Importantly, the real-world environment increased the differences in several parameters between the young and elderly groups.
Elderly test subjects walked differently in controlled lab settings compared to their real-world environments, which indicates the need to better understand natural walking patterns under ecologically valid conditions before clinically relevant conclusions can be drawn on a subject's functional status. Moreover, the greater inter-group differences in real-world environments seem promising regarding the sensitive identification of subjects with indications of a walking disorder.
Nanogels are water soluble cross-linked polymer networks with nanometer size dimensions that can be designed to incorporate different types of compounds and are promising carrier systems for drugs ...and biological molecules. In this study, the interactions of thermoresponsive nanogels (tNGs) with the human skin barrier and underlying epidermis cells were investigated with the aim of using such macromolecules to improve dermal and transdermal drug delivery. The investigated tNGs were made of acrylated dendritic polyglycerol, as water soluble cross-linker, and of oligo ethylene glycol methacrylate (OEGMA) as subunit conferring thermoresponsive properties. tNGs with different polymer transition temperatures were tagged with Rhodamine B (RhdB) and analyzed for their physicochemical properties. We found that tNGs with cloud point temperatures (Tcps) of 38°C (tNG–RhdB-T38) lost softness (measured by PeakForce quantitative nanomechanics, QNM) and aggregated to bigger sized particles (measured as increase of particle average size by dynamic light scattering, DLS) when temperature changed from 15 to 37°C. On the contrary, at the same conditions, tNGs with higher Tcps (tNG–RhdB-T55) did not show any significant changes of these characteristics. Applied on excised human skin, both tNGs penetrated deep in the stratum corneum (SC). Small amounts of tNGs were detected also in cells of the viable epidermis. Interestingly, whereas tNG softness correlated with higher penetration in SC, a better cellular uptake was observed for the thermoresponsive tNG–RhdB-T38. We conclude that soft nanocarriers possess a high SC penetration ability and that thermoresponsive nanogels are attractive carrier systems for the targeting of drugs to epidermis cells.
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The influence of the surface functionalization of silica particles on their colloidal stability in physiological media is studied and correlated with their uptake in cells. The surface of 55 ± 2 nm ...diameter silica particles is functionalized by amino acids or amino- or poly(ethylene glycol) (PEG)-terminated alkoxysilanes to adjust the zeta potential from highly negative to positive values in ethanol. A transfer of the particles into water, physiological buffers, and cell culture media reduces the absolute value of the zeta potential and changes the colloidal stability. Particles stabilized by l-arginine, l-lysine, and amino silanes with short alkyl chains are only moderately stable in water and partially in PBS or TRIS buffer, but aggregate in cell culture media. Nonfunctionalized, N-(6-aminohexyl)-3-aminopropyltrimethoxy silane (AHAPS), and PEG-functionalized particles are stable in all media under study. The high colloidal stability of positively charged AHAPS-functionalized particles scales with the ionic strength of the media, indicating a mainly electrostatical stabilization. PEG-functionalized particles show, independently from the ionic strength, no or only minor aggregation due to additional steric stabilization. AHAPS stabilized particles are readily taken up by HeLa cells, likely as the positive zeta potential enhances the association with the negatively charged cell membrane. Positively charged particles stabilized by short alkyl chain aminosilanes adsorb on the cell membrane, but are weakly taken up, since aggregation inhibits their transport. Nonfunctionalized particles are barely taken up and PEG-stabilized particles are not taken up at all into HeLa cells, despite their high colloidal stability. The results indicate that a high colloidal stability of nanoparticles combined with an initial charge-driven adsorption on the cell membrane is essential for efficient cellular uptake.
Consistent inter-individual variation in cognition has been increasingly explored in recent years in terms of its patterns, causes and consequences. One of its possible causes are consistent ...inter-individual differences in behaviour, also referred to as animal personalities, which are shaped by both the physical and the social environment. The latter is particularly relevant for group-living species like common marmosets (Callithrix jacchus), apt learners that display substantial variation in both their personality and cognitive performance, yet no study to date has interlinked these with marmosets' social environment. Here we investigated (i) consistency of learning speed, and (ii) whether the PCA-derived personality traits Exploration-Avoidance and Boldness-Shyness as well as the social environment (i.e., family group membership) are linked with marmosets' speed of learning. We tested 22 individuals in series of personality and learning-focused cognitive tests, including simple motor tasks and discrimination learning tasks. We found that these marmosets showed significant inter-individual consistency in learning across the different tasks, and that females learned faster than males. Further, bolder individuals, and particularly those belonging to certain family groups, learned faster. These findings indicate that both personality and social environment affect learning speed in marmosets and could be important factors driving individual variation in cognition.
•Whole-cerebrum distortion-free 3D pCASL imaging at 7T using TFL readout.•New set of labeling parameters, OPTIM background suppression pulse, and accelerated 3D TFL readout.•Improved test-retest ...repeatability and reduced susceptibility artifacts compared to 3D GRASE pCASL.•Increased SNR compared to the same sequence at 3T and 2D simultaneous multislice (SMS) TFL pCASL at 7T.
Fulfilling potentials of ultrahigh field for pseudo-Continuous Arterial Spin Labeling (pCASL) has been hampered by B1/B0 inhomogeneities that affect pCASL labeling, background suppression (BS), and the readout sequence. This study aimed to present a whole-cerebrum distortion-free three-dimensional (3D) pCASL sequence at 7T by optimizing pCASL labeling parameters, BS pulses, and an accelerated Turbo-FLASH (TFL) readout. A new set of pCASL labeling parameters (Gave = 0.4 mT/m, Gratio = 14.67) was proposed to avoid interferences in bottom slices while achieving robust labeling efficiency (LE). An OPTIM BS pulse was designed based on the range of B1/B0 inhomogeneities at 7T. A 3D TFL readout with 2D-CAIPIRINHA undersampling (R = 2 × 2) and centric ordering was developed, and the number of segments (Nseg) and flip angle (FA) were varied in simulation to achieve the optimal trade-off between SNR and spatial blurring. In-vivo experiments were performed on 19 subjects. The results showed that the new set of labeling parameters effectively achieved whole-cerebrum coverage by eliminating interferences in bottom slices while maintaining a high LE. The OPTIM BS pulse achieved 33.3% higher perfusion signal in gray matter (GM) than the original BS pulse with a cost of 4.8-fold SAR. Incorporating a moderate FA (8°) and Nseg (2), whole-cerebrum 3D TFL-pCASL imaging was achieved with a 2 × 2 × 4 mm3 resolution without distortion and susceptibility artifacts compared to 3D GRASE-pCASL. In addition, 3D TFL-pCASL showed a good to excellent test-retest repeatability and potential of higher resolution (2 mm isotropic). The proposed technique also significantly improved SNR when compared to the same sequence at 3T and simultaneous multislice TFL-pCASL at 7T. By combining a new set of labeling parameters, OPTIM BS pulse, and accelerated 3D TFL readout, we achieved high resolution pCASL at 7T with whole-cerebrum coverage, detailed perfusion and anatomical information without distortion, and sufficient SNR.
Approaches for the controlled formation of gold nanoparticle dimers are investigated. These are based on a locally confined surface modification of gold nanoparticles followed by bridging two ...particles with an organic linker. A key factor in these approaches is the use of multivalent ligands. Citrate-stabilized gold nanoparticles are immobilized on a glass surface and mono- and multivalent thiol ligands are investigated regarding their ability to inactivate the nanoparticles sites facing away from the glass. A successful locally confined functionalization is only possible if multivalent ligands are used in this step. The application of monovalent ligands results in less stable particles without a permanent regioselective functionalization. This result can be explained by the dynamic equilibrium between bound and free ligands. Subsequently, the sites of the nanoparticles previously bound to the glass surface are functionalized with thiol ligands additionally bearing a reactive group. Approaches using dithiol linkers, diamine linkers, and coupling complementary functionalized particles are investigated. The highest yield of stable dimers is obtained from conditions where nanoparticles which are regioselectively functionalized with an N-hydroxysuccinimide ester are reacted with complementary amino-functionalized particles. The application of nanoparticles with activated carboxyl groups is essential since standard carboxyl activation agents induce an aggregation of the nanoparticles due to a reaction with remaining citrate molecules on the nanoparticle surface which reduces significantly electrostatic stabilization. This versatile approach using complementary regioselective with multivalent ligands functionalized nanoparticles may be also used for the coupling of particles with different size, shape, or composition, as well as a control of the interparticle distance.
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