A high-sensitivity flexible bionic tentacle sensor for multidimensional force sensing and autonomous obstacle avoidance applications.

Bionic tentacle sensors are important in various fields, including obstacle avoidance, human‒machine interfaces, and soft robotics. However, most traditional tentacle sensors are based on rigid substrates, resulting in difficulty in detecting multidirectional forces originating from the external environment, which limits their application in complex environments. Herein, we proposed a high-sensitivity flexible bionic tentacle sensors (FBTSs). Specifically, the FBTS featured an ultrahigh sensitivity of 37.6 N-1 and an ultralow detection limit of 2.4 mN, which benefited from the design of a whisker-like signal amplifier and crossbeam architecture. Moreover, the FBTS exhibited favorable linearity (R2 = 0.98) and remarkable durability (more than 5000 cycles). This was determined according to the improvement in the uniformity of the sensing layer through a high-shear dispersion process. In addition, the FBTS could accurately distinguish the direction of external stimuli, resulting in the FBTS achieving roughness recognition, wind speed detection and autonomous obstacle avoidance. In particular, the ability of autonomous obstacle avoidance was suitably demonstrated by leading a bionic rat through a maze with the FBTS. Notably, the proposed FBTS could be widely applied in tactile sensing, orientation perception, and obstacle avoidance.

A Smart Ski Pole for Skiing Pattern Recognition and Quantification Application.

In cross-country skiing, ski poles play a crucial role in technique, propulsion, and overall performance. The kinematic parameters of ski poles can provide valuable information about the skier's technique, which is of great significance for coaches and athletes seeking to improve their skiing performance. In this work, a new smart ski pole is proposed, which combines the uniaxial load cell and the inertial measurement unit (IMU), aiming to provide comprehensive data measurement functions more easily and to play an auxiliary role in training. The ski pole can collect data directly related to skiing technical actions, such as the skier's pole force, pole angle, inertia data, etc., and the system's design, based on wireless transmission, makes the system more convenient to provide comprehensive data acquisition functions, in order to achieve a more simple and efficient use experience. In this experiment, the characteristic data obtained from the ski poles during the Double Poling of three skiers were extracted and the sample t-test was conducted. The results showed that the three skiers had significant differences in pole force, pole angle, and pole time. Spearman correlation analysis was used to analyze the sports data of the people with good performance, and the results showed that the pole force and speed (r = 0.71) and pole support angle (r = 0.76) were significantly correlated. In addition, this study adopted the commonly used inertial sensor data for action recognition, combined with the load cell data as the input of the ski technical action recognition algorithm, and the recognition accuracy of five kinds of cross-country skiing technical actions (Diagonal Stride (DS), Double Poling (DP), Kick Double Poling (KDP), Two-stroke Glide (G2) and Five-stroke Glide (G5)) reached 99.5%, and the accuracy was significantly improved compared with similar recognition systems. Therefore, the equipment is expected to be a valuable training tool for coaches and athletes, helping them to better understand and improve their ski maneuver technique.

Effect of Micellar Morphology on the Temperature-Induced Structural Evolution of ABC Polypeptoid Triblock Terpolymers into Two-Compartment Hydrogel Network.

We investigated the temperature-dependent structural evolution of thermoreversible triblock terpolypeptoid hydrogels, namely poly(N-allyl glycine)-b-poly(N-methyl glycine)-b-poly(N-decyl glycine) (AMD), using small-angle neutron scattering (SANS) with contrast matching in conjunction with X-ray scattering and cryogenic transmission electron microscopy (cryo-TEM) techniques. At room temperature, A100M101D10 triblock terpolypeptoids self-assemble into core-corona-type spherical micelles in aqueous solution. Upon heating above the critical gelation temperature (T gel), SANS analysis revealed the formation of a two-compartment hydrogel network comprising distinct micellar cores composed of dehydrated A blocks and hydrophobic D blocks. At T ≳ T gel, the temperature-dependent dehydration of A block further leads to the gradual rearrangement of both A and D domains, forming well-ordered micellar network at higher temperatures. For AMD polymers with either longer D block or shorter A block, such as A101M111D21 and A43M92D9, elongated nonspherical micelles with a crystalline D core were observed at T < T gel. Although these enlarged crystalline micelles still undergo a sharp sol-to-gel transition upon heating, the higher aggregation number of chains results in the immediate association of the micelles into ordered aggregates at the initial stage, followed by a disruption of the spatial ordering as the temperature further increases. On the other hand, fiber-like structures were also observed for AMD with longer A block, such as A153M127D10, due to the crystallization of A domains. This also influences the assembly pathway of the two-compartment network. Our findings emphasize the critical impact of initial micellar morphology on the structural evolution of AMD hydrogels during the sol-to-gel transition, providing valuable insights for the rational design of thermoresponsive hydrogels with tunable network structures at the nanometer scale.

Flexible wide-range multidimensional force sensors inspired by bones embedded in muscle.

Flexible sensors have been widely studied for use in motion monitoring, human‒machine interactions (HMIs), personalized medicine, and soft intelligent robots. However, their practical application is limited by their low output performance, narrow measuring range, and unidirectional force detection. Here, to achieve flexibility and high performance simultaneously, we developed a flexible wide-range multidimensional force sensor (FWMFS) similar to bones embedded in muscle structures. The adjustable magnetic field endows the FWMFS with multidimensional perception for detecting forces in different directions. The multilayer stacked coils significantly improved the output from the µV to the mV level while ensuring FWMFS miniaturization. The optimized FWMFS exhibited a high voltage sensitivity of 0.227 mV/N (0.5-8.4 N) and 0.047 mV/N (8.4-60 N) in response to normal forces ranging from 0.5 N to 60 N and could detect lateral forces ranging from 0.2-1.1 N and voltage sensitivities of 1.039 mV/N (0.2-0.5 N) and 0.194 mV/N (0.5-1.1 N). In terms of normal force measurements, the FWMFS can monitor finger pressure and sliding trajectories in response to finger taps, as well as measure plantar pressure for assessing human movement. The plantar pressure signals of five human movements collected by the FWMFS were analyzed using the k-nearest neighbors classification algorithm, which achieved a recognition accuracy of 92%. Additionally, an artificial intelligence biometric authentication system is being developed that classifies and recognizes user passwords. Based on the lateral force measurement ability of the FWMFS, the direction of ball movement can be distinguished, and communication systems such as Morse Code can be expanded. This research has significant potential in intelligent sensing and personalized spatial recognition.

Nonstereotypical Distribution and Effect of Ergosterol in Lipid Membranes.

Ergosterol, found in fungi and some protist membranes, is understudied compared with cholesterol from animal membranes. Generally, ergosterol is assumed to modulate membranes in the same manner as cholesterol, based on their similar chemical structures. Here we reveal some fundamental structural and dynamical differences between them. Neutron diffraction shows that ergosterol is embedded in the lipid bilayer much shallower than cholesterol. Ergosterol does not change the membrane thickness as much as cholesterol does, indicating little condensation effect. Neutron spin echo shows that ergosterol can rigidify and soften membranes at different concentrations. The lateral lipid diffusion measured by quasielastic neutron scattering indicates that ergosterol promotes a jump diffusion of the lipid, whereas cholesterol keeps the same continuous lateral diffusion as the pure lipid membrane. Our results point to quite distinct interactions of ergosterol with membranes compared with cholesterol. These insights provide a basic understanding of membranes containing ergosterol with implications for phenomena such as lipid rafts and drug interactions.

Vortex fluidic regulated phospholipid equilibria involving liposomes down to sub-micelle size assemblies.

Conventional channel-based microfluidic platforms have gained prominence in controlling the bottom-up formation of phospholipid based nanostructures including liposomes. However, there are challenges in the production of liposomes from rapidly scalable processes. These have been overcome using a vortex fluidic device (VFD), which is a thin film microfluidic platform rather than channel-based, affording ∼110 nm diameter liposomes. The high yielding and high throughput continuous flow process has a 45° tilted rapidly rotating glass tube with an inner hydrophobic surface. Processing is also possible in the confined mode of operation which is effective for labelling pre-VFD-prepared liposomes with fluorophore tags for subsequent mechanistic studies on the fate of liposomes under shear stress in the VFD. In situ small-angle neutron scattering (SANS) established the co-existence of liposomes ∼110 nm with small rafts, micelles, distorted micelles, or sub-micelle size assemblies of phospholipid, for increasing rotation speeds. The equilibria between these smaller entities and ∼110 nm liposomes for a specific rotational speed of the tube is consistent with the spatial arrangement and dimensionality of topological fluid flow regimes in the VFD. The prevalence for the formation of ∼110 nm diameter liposomes establishes that this is typically the most stable structure from the bottom-up self-assembly of the phospholipid and is in accord with dimensions of exosomes.

Characterization of the In Vivo Deuteration of Native Phospholipids by Mass Spectrometry Yields Guidelines for Their Regiospecific Customization.

Customization of deuterated biomolecules is vital for many advanced biological experiments including neutron scattering. However, because it is challenging to control the proportion and regiospecificity of deuterium incorporation in live systems, often only two or three synthetic lipids are mixed together to form simplistic model membranes. This limits the applicability and biological accuracy of the results generated with these synthetic membranes. Despite some limited prior examination of deuterating Escherichia coli lipids in vivo, this approach has not been widely implemented. Here, an extensive mass spectrometry-based profiling of E. coli phospholipid deuteration states with several different growth media was performed, and a computational method to describe deuterium distributions with a one-number summary is introduced. The deuteration states of 36 lipid species were quantitatively profiled in 15 different growth conditions, and tandem mass spectrometry was used to reveal deuterium localization. Regressions were employed to enable the prediction of lipid deuteration for untested conditions. Small-angle neutron scattering was performed on select deuterated lipid samples, which validated the deuteration states calculated from the mass spectral data. Based on these experiments, guidelines for the design of specifically deuterated phospholipids are described. This unlocks even greater capabilities from neutron-based techniques, enabling experiments that were formerly impossible.

Insights into the volatile flavor and quality profiles of loquat (Eriobotrya japonica Lindl.) during shelf-life via HS-GC-IMS, E-nose, and E-tongue.

Loquat fruits are among the most popular Chinese fruits because of their unique taste and aroma. The quality profiles of these fruits during 18 days of shelf-life at 20 °C were elucidated by headspace gas chromatography-ion mobility spectrometry (HS-GC-IMS), E-nose, and E-tongue. During shelf-life period, the properties and variations of 43 (20 aldehydes, 7 esters, 6 ketones, 1 alcohol, and 1 furan) volatile flavored compounds were determined by GC-IMS, which showed that the contents of methyl 3-methyl butanoate, ethyl acetate, and dimethyl ketone gradually decrease with prolonged shelf-life time, while (E)-2-heptenal, heptanal, (E)-2-pentenal, 1-penten-3-one 3-pentanone and 2-pentylfuran increase. The PCA based on the signal intensity of GC-IMS and E-nose, revealed that loquat fruits are well distinguished at different shelf-life times. The taste profile alternates as the storage time increases, along with higher pH, and lower amounts of total soluble solids, vitamin C, and total phenolics. The visual plots of GC-IMS, E-nose, and E-tongue had good consistency, and they characterized the aroma characteristics of loquat fruits well during different shelf-life periods. The findings of this research provide a useful understanding of the flavors of loquat fruits during their prolonged shelf-life, and a potential research basis for advancements in the loquat industry.

Pathway complexity in fibre assembly: from liquid crystals to hyper-helical gelmorphs.

Pathway complexity results in unique materials from the same components according to the assembly conditions. Here a chiral acyl-semicarbazide gelator forms three different gels of contrasting fibre morphology (termed 'gelmorphs') as well as lyotropic liquid crystalline droplets depending on the assembly pathway. The gels have morphologies that are either hyperhelical (HH-Gel), tape-fibre (TF-Gel) or thin fibril derived from the liquid crystalline phase (LC-Gels) and exhibit very different rheological properties. The gelator exists as three slowly interconverting conformers in solution. All three gels are comprised of an unsymmetrical, intramolecular hydrogen bonded conformer. The kinetics show that formation of the remarkable HH-Gel is cooperative and is postulated to involve association of the growing fibril with a non-gelling conformer. This single molecule dynamic conformational library shows how very different materials with different morphology and hence very contrasting materials properties can arise from pathway complexity as a result of emergent interactions during the assembly process.

pH-Dependent Solution Micellar Structure of Amphoteric Polypeptoid Block Copolymers with Positionally Controlled Ionizable Sites.

While solution micellization of ionic block copolymers (BCP) with randomly distributed ionization sites along the hydrophilic segments has been extensively studied, the roles of positionally controlled ionization sites along the BCP chains in their micellization and resulting micellar structure remain comparatively less understood. Herein, three amphoteric polypeptoid block copolymers carrying two oppositely charged ionizable sites, with one fixed at the hydrophobic terminus and the other varyingly positioned along the hydrophilic segment, have been synthesized by sequential ring-opening polymerization method. The presence of the ionizable site at the hydrophobic segment terminus is expected to promote polymer association toward equilibrium micellar structures in an aqueous solution. The concurrent presence of oppositely charged ionizable sites on the polymer chains allows the polymer association to be electrostatically modulated in a broad pH range (ca. 2-12). Micellization of the amphoteric polypeptoid BCP in dilute aqueous solution and the resulting micellar structure at different solution pHs was investigated by a combination of scattering and microscopic methods. Negative-stain transmission-electron microscopy (TEM), small-angle neutron scattering (SANS), and small-angle X-ray scattering (SAXS) analyses revealed the dominant presence of core-shell-type spherical micelles and occasional rod-like micelles with liquid crystalline (LC) domains in the micellar core. The micellar structures (e.g., aggregation number, radius of gyration, chain packing in the micelle) were found to be dependent on the solution pH and the position of the ionizable site along the chain. This study has highlighted the potential of controlling the position of ionizable sites along the BCP polymer to modulate the electrostatic and LC interactions, thus tailoring the micellar structure at different solution pH values in water.

Species-Deconvolved Proteomics for In Situ Investigation of Tumor-Stroma Interactions after Treatment of Pancreatic Cancer Patient-Derived Xenografts with Combined Gemcitabine and Paclitaxel.

Tumor-stroma interactions are critical in pancreatic ductal adenocarcinoma (PDAC) progression and therapeutics. Patient-derived xenograft (PDX) models recapitulate tumor-stroma interactions, but the conventional antibody-based immunoassay is inadequate to discriminate tumor and stromal proteins. Here, we describe a species-deconvolved proteomics approach embedded in IonStar that can unambiguously quantify the tumor (human-derived) and stromal (mouse-derived) proteins in PDX samples, enabling unbiased investigation of tumor and stromal proteomes with excellent quantitative reproducibility. With this strategy, we studied tumor-stroma interactions in PDAC PDXs that responded differently to Gemcitabine combined with nab-Paclitaxel (GEM+PTX) treatment. By analyzing 48 PDX animals 24 h/192 h after treatment with/without GEM+PTX, we quantified 7262 species-specific proteins under stringent cutoff criteria, with high reproducibility. For the PDX sensitive to GEM+PTX, the drug-dysregulated proteins in tumor cells were involved in suppressed oxidative phosphorylation and the TCA cycle, and in the stroma, inhibition of glycolytic activity was predominant, suggesting a relieved reverse Warburg effect by the treatment. In GEM+PTX-resistant PDXs, protein changes suggested extracellular matrix deposition and activation of tumor cell proliferation. Key findings were validated by immunohistochemistry (IHC). Overall, this approach provides a species-deconvolved proteomic platform that could advance cancer therapeutic studies by enabling unbiased exploration of tumor-stroma interactions in the large number of PDX samples required for such investigations.

An ensemble of cadherin-catenin-vinculin complex employs vinculin as the major F-actin binding mode.

The cell-cell adhesion cadherin-catenin complexes recruit vinculin to the adherens junction (AJ) to modulate the mechanical couplings between neighboring cells. However, it is unclear how vinculin influences the AJ structure and function. Here, we identified two patches of salt bridges that lock vinculin in the head-tail autoinhibited conformation and reconstituted the full-length vinculin activation mimetics bound to the cadherin-catenin complex. The cadherin-catenin-vinculin complex contains multiple disordered linkers and is highly dynamic, which poses a challenge for structural studies. We determined the ensemble conformation of this complex using small-angle x-ray and selective deuteration/contrast variation small-angle neutron scattering. In the complex, both α-catenin and vinculin adopt an ensemble of flexible conformations, but vinculin has fully open conformations with the vinculin head and actin-binding tail domains well separated from each other. F-actin binding experiments show that the cadherin-catenin-vinculin complex binds and bundles F-actin. However, when the vinculin actin-binding domain is removed from the complex, only a minor fraction of the complex binds to F-actin. The results show that the dynamic cadherin-catenin-vinculin complex employs vinculin as the primary F-actin binding mode to strengthen AJ-cytoskeleton interactions.

Quantitative Proteomics of Human Retinal Pigment Epithelium Reveals Key Regulators for the Pathogenesis of Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people, with limited treatment options available for most patients. AMD involves the death of retinal pigment epithelium (RPE) and photoreceptor cells, with mitochondria dysfunction being a critical early event. In the current study, we utilized our unique resource of human donor RPE graded for AMD presence and severity to investigate proteome-wide dysregulation involved in early AMD. Organelle-enriched fractions of RPE were isolated from donors with early AMD (n = 45) and healthy age-matched controls (n = 32) and were analyzed by UHR-IonStar, an integrated proteomics platform enabling reliable and in-depth proteomic quantification in large cohorts. A total of 5941 proteins were quantified with excellent analytical reproducibility, and with further informatics analysis, many biological functions and pathways were found to be significantly dysregulated in donor RPE samples with early AMD. Several of these directly pinpointed changes in mitochondrial functions, e.g., translation, ATP metabolic process, lipid homeostasis, and oxidative stress. These novel findings highlighted the value of our proteomics investigation by allowing a better understanding of the molecular mechanisms underlying early AMD onset and facilitating both treatment development and biomarker discovery.

Spatially confined protein assembly in hierarchical mesoporous metal-organic framework.

Immobilization of biomolecules into porous materials could lead to significantly enhanced performance in terms of stability towards harsh reaction conditions and easier separation for their reuse. Metal-Organic Frameworks (MOFs), offering unique structural features, have emerged as a promising platform for immobilizing large biomolecules. Although many indirect methods have been used to investigate the immobilized biomolecules for diverse applications, understanding their spatial arrangement in the pores of MOFs is still preliminary due to the difficulties in directly monitoring their conformations. To gain insights into the spatial arrangement of biomolecules within the nanopores. We used in situ small-angle neutron scattering (SANS) to probe deuterated green fluorescent protein (d-GFP) entrapped in a mesoporous MOF. Our work revealed that GFP molecules are spatially arranged in adjacent nanosized cavities of MOF-919 to form "assembly" through adsorbate-adsorbate interactions across pore apertures. Our findings, therefore, lay a crucial foundation for the identification of proteins structural basics under confinement environment of MOFs.

High-quality and robust protein quantification in large clinical/pharmaceutical cohorts with IonStar proteomics investigation.

Robust, reliable quantification of large sample cohorts is often essential for meaningful clinical or pharmaceutical proteomics investigations, but it is technically challenging. When analyzing very large numbers of samples, isotope labeling approaches may suffer from substantial batch effects, and even with label-free methods, it becomes evident that low-abundance proteins are not reliably measured owing to unsufficient reproducibility for quantification. The MS1-based quantitative proteomics pipeline IonStar was designed to address these challenges. IonStar is a label-free approach that takes advantage of the high sensitivity/selectivity attainable by ultrahigh-resolution (UHR)-MS1 acquisition (e.g., 120-240k full width at half maximum at m/z = 200) which is now widely available on ultrahigh-field Orbitrap instruments. By selectively and accurately procuring quantitative features of peptides within precisely defined, very narrow m/z windows corresponding to the UHR-MS1 resolution, the method minimizes co-eluted interferences and substantially enhances signal-to-noise ratio of low-abundance species by decreasing noise level. This feature results in high sensitivity, selectivity, accuracy and precision for quantification of low-abundance proteins, as well as fewer missing data and fewer false positives. This protocol also emphasizes the importance of well-controlled, robust experimental procedures to achieve high-quality quantification across a large cohort. It includes a surfactant cocktail-aided sample preparation procedure that achieves high/reproducible protein/peptide recoveries among many samples, and a trapping nano-liquid chromatography-mass spectrometry strategy for sensitive and reproducible acquisition of UHR-MS1 peptide signal robustly across a large cohort. Data processing and quality evaluation are illustrated using an example dataset ( http://proteomecentral.proteomexchange.org ), and example results from pharmaceutical project and one clinical project (patients with acute respiratory distress syndrome) are shown. The complete IonStar pipeline takes ~1-2 weeks for a sample cohort containing ~50-100 samples.

In-depth mapping of protein localizations in whole tissue by micro-scaffold assisted spatial proteomics (MASP).

Accurate, in-depth mapping of proteins on whole-tissue levels provides comprehensive insights into the spatially-organized regulatory processes/networks in tissues, but is challenging. Here we describe a micro-scaffold assisted spatial proteomics (MASP) strategy, based on spatially-resolved micro-compartmentalization of tissue using a 3D-printed micro-scaffold, capable of mapping thousands of proteins across a whole-tissue slice with excellent quantitative accuracy/precision. The pipeline includes robust tissue micro-compartmentalization with precisely-preserved spatial information, reproducible procurement and preparation of the micro-specimens, followed by sensitive LC-MS analysis and map generation by a MAsP app. The mapping accuracy was validated by comparing the MASP-generated maps of spiked-in peptides and brain-region-specific markers with known patterns, and by correlating the maps of the two protein components of the same heterodimer. The MASP was applied in mapping >5000 cerebral proteins in the mouse brain, encompassing numerous important brain markers, regulators, and transporters, where many of these proteins had not previously been mapped on the whole-tissue level.

CENTAUR-The small- and wide-angle neutron scattering diffractometer/spectrometer for the Second Target Station of the Spallation Neutron Source.

CENTAUR has been selected as one of the eight initial instruments to be built at the Second Target Station (STS) of the Spallation Neutron Source at Oak Ridge National Laboratory. It is a small-angle neutron scattering (SANS) and wide-angle neutron scattering (WANS) instrument with diffraction and spectroscopic capabilities. This instrument will maximally leverage the high brightness of the STS source, the state-of-the-art neutron optics, and a suite of detectors to deliver unprecedented capabilities that enable measurements over a wide range of length scales with excellent resolution, measurements on smaller samples, and time-resolved investigations of evolving structures. Notably, the simultaneous WANS and diffraction capability will be unique among neutron scattering instruments in the United States. This instrument will provide much needed capabilities for soft matter and polymer sciences, geology, biology, quantum condensed matter, and other materials sciences that need in situ and operando experiments for kinetic and/or out-of-equilibrium studies. Beam polarization and a high-resolution chopper will enable detailed structural and dynamical investigations of magnetic and quantum materials. CENTAUR's excellent resolution makes it ideal for low-angle diffraction studies of highly ordered large-scale structures, such as skyrmions, shear-induced ordering in colloids, and biomembranes. Additionally, the spectroscopic mode of this instrument extends to lower momentum transfers than are currently possible with existing spectrometers, thereby providing a unique capability for inelastic SANS studies.

Small angle neutron scattering and lipidomic analysis of a native, trimeric PSI-SMALP from a thermophilic cyanobacteria.

The use of styrene-maleic acid copolymers (SMAs) to produce membrane protein-containing nanodiscs without the initial detergent isolation has gained significant interest over the last decade. We have previously shown that a Photosystem I SMALP from the thermophilic cyanobacterium, Thermosynechococcus elongatus (PSI-SMALP), has much more rapid energy transfer and charge separation in vitro than detergent isolated PSI complexes. In this study, we have utilized small-angle neutron scattering (SANS) to better understand the geometry of these SMALPs. These techniques allow us to investigate the size and shape of these particles in their fully solvated state. Further, the particle's proteolipid core and detergent shell or copolymer belt can be interrogated separately using contrast variation, a capability unique to SANS. Here we report the dimensions of the Thermosynechococcus elongatus PSI-SMALP containing a PSI trimer. At ~1.5 MDa, PSI-SMALP is the largest SMALP to be isolated; our lipidomic analysis indicates it contains ~1300 lipids/per trimeric particle, >40-fold more than the PSI-DDM particle and > 100 fold more than identified in the 1JB0 crystal structure. Interestingly, the lipid composition to the PSI trimer in the PSI-SMALP differs significantly from bulk thylakoid composition, being enriched ~50 % in the anionic sulfolipid, SQDG. Finally, utilizing the contrast match point for the SMA 1440 copolymer, we also can observe the ~1 nm SMA copolymer belt surrounding this SMALP for the first time, consistent with most models of SMA organization.

Bilirubin Encephalopathy.

PURPOSE OF REVIEW: Hyperbilirubinemia is commonly seen in neonates. Though hyperbilirubinemia is typically asymptomatic, severe elevation of bilirubin levels can lead to acute bilirubin encephalopathy and progress to kernicterus spectrum disorder, a chronic condition characterized by hearing loss, extrapyramidal dysfunction, ophthalmoplegia, and enamel hypoplasia. Epidemiological data show that the implementation of universal pre-discharge bilirubin screening programs has reduced the rates of hyperbilirubinemia-associated complications. However, acute bilirubin encephalopathy and kernicterus spectrum disorder are still particularly common in low- and middle-income countries. RECENT FINDINGS: The understanding of the genetic and biochemical processes that increase the susceptibility of defined anatomical areas of the central nervous system to the deleterious effects of bilirubin may facilitate the development of effective treatments for acute bilirubin encephalopathy and kernicterus spectrum disorder. Scoring systems are available for the diagnosis and severity grading of these conditions. The treatment of hyperbilirubinemia in newborns relies on the use of phototherapy and exchange transfusion. However, novel therapeutic options including deep brain stimulation, brain-computer interface, and stem cell transplantation may alleviate the heavy disease burden associated with kernicterus spectrum disorder. Despite improved screening and treatment options, the prevalence of acute bilirubin encephalopathy and kernicterus spectrum disorder remains elevated in low- and middle-income countries. The continued presence and associated long-term disability of these conditions warrant further research to improve their prevention and management.

Poly(N-vinylpyrrolidone)-block-Poly(dimethylsiloxane)-block-Poly(N-vinylpyrrolidone) Triblock Copolymer Polymersomes for Delivery of PARP1 siRNA to Breast Cancers.

Nearly 20% of HER2-positive breast cancers develop resistance to HER2-targeted therapies requiring the use of advanced therapies. Silencing RNA therapy may be a powerful modality for treating resistant HER2 cancers due to its high specificity and low toxicity. However, the systemic administration of siRNAs requires a safe and efficient delivery platform because of siRNA's low stability in physiological fluids, inefficient cellular uptake, immunoreactivity, and rapid clearance. We have developed theranostic polymeric vesicles to overcome these hurdles for encapsulation and delivery of small functional molecules and PARP1 siRNA for in vivo delivery to breast cancer tumors. The 100 nm polymer vesicles were assembled from biodegradable and non-ionic poly(N-vinylpyrrolidone)14-block-poly(dimethylsiloxane)47-block-poly(N-vinylpyrrolidone)14 triblock copolymer PVPON14-PDMS47-PVPON14 using nanoprecipitation and thin-film hydration. We demonstrated that the vesicles assembled from the copolymer covalently tagged with the Cy5.5 fluorescent dye for in vivo imaging could also encapsulate the model drug with high loading efficiency (40%). The dye-loaded vesicles were accumulated in tumors after 18 h circulation in 4TR breast tumor-bearing mice via passive targeting. We found that PARP1 siRNA encapsulated into the vesicles was released intact (13%) into solution by the therapeutic ultrasound treatment as quantified by gel electrophoresis. The PARP1 siRNA-loaded polymersomes inhibited the proliferation of MDA-MB-361TR cells by 34% after 6 days of treatment by suppressing the NF-kB signaling pathway, unlike their scrambled siRNA-loaded counterparts. Finally, the treatment by PARP1 siRNA-loaded vesicles prolonged the survival of the mice bearing 4T1 breast cancer xenografts, with the 4-fold survival increase, unlike the untreated mice after 3 weeks following the treatment. These biodegradable, non-ionic PVPON14-PDMS47-PVPON14 polymeric nanovesicles capable of the efficient encapsulation and delivery of PARP1 siRNA to successfully knock down PARP1 in vivo can provide an advanced platform for the development of precision-targeted therapeutic carriers, which could help develop highly effective drug delivery nanovehicles for breast cancer gene therapy.