A Jurassic gliding euharamiyidan mammal with an ear of five auditory bones.

Gliding is a distinctive locomotion type that has been identified in only three mammal species from the Mesozoic era. Here we describe another Jurassic glider that belongs to the euharamiyidan mammals and shows hair details on its gliding membrane that are highly similar to those of extant gliding mammals. This species possesses a five-boned auditory apparatus consisting of the stapes, incus, malleus, ectotympanic and surangular, representing, to our knowledge, the earliest known definitive mammalian middle ear. The surangular has not been previously identified in any mammalian middle ear, and the morphology of each auditory bone differs from those of known mammals and their kin. We conclude that gliding locomotion was probably common in euharamiyidans, which lends support to idea that there was a major adaptive radiation of mammals in the mid-Jurassic period. The acquisition of the auditory bones in euharamiyidans was related to the formation of the dentary-squamosal jaw joint, which allows a posterior chewing movement, and must have evolved independently from the middle ear structures of monotremes and therian mammals.

A Diode-Like Dye-Cu Anisotropic Junction in a Coordination Polymer as a Logic State Ratchet for Intratumor Redox Photomodulation.

Redox logic materials offer new avenues to modulate intracellular pathologic redox environment area-specifically, but the unambiguity of redox logic states and their unidirectional and repetitive switchability are challenging to realize. By merging a bistable diisophthalic phenazine dye ligand with CuII salt, a multistable coordination polymer (CP) was constructed, of which the dye-Cu anisotropic junction achieved the diode-like unidirectional electron transfer and logic state ratchet for the first time. Radical cationic CP maintained OFF status with low toxicity in healthy tissues, but was reduced to the neutral SERVO state by the overexpressed glutathione (GSH) in hypoxic tumors. After photoirradiation, the stabilized charge-separated ON status promoted photo-Fenton reaction for reactive oxygen species (ROS) signal transduction, and simultaneously recovered the initial state for catalytic signal amplification of ROS, furnishing intratumor redox photomodulation for therapy.

Self-Assembled Metal-Organic Framework Stabilized Organic Cocrystals for Biological Phototherapy.

Organic self-assembled co-crystals have garnered considerable attention due to their facile synthesis and intriguing properties, but supramolecular interactions restrict their stability in aqueous solution, which is especially important for biological applications. Herein, we report on the first biological application of aqueous dispersible self-assembled organic co-crystals via the construction of metal-organic framework (MOF) -stabilized co-crystals. In particular, we built an electron-deficient MOF with naphthalene diimide (NDI) as the ligand and biocompatible Ca2+ as the metal nodes. An electron donor molecule, pyrene, was encapsulated to form the host-guest MOF self-assembled co-crystal. We observed that such MOF structure leads to uniquely high-density ordered arrangement and the close intermolecular distance (3.47 Å) of the charge transfer pairs. Hence, the concomitant superior charge transfer interaction between pyrene/NDI can be attained and the resultant photothermal conversion efficiency of Py@Ca-NDI in aqueous solution can thus reach up to 41.8 %, which, to the best of our knowledge, is the highest value among the reported organic co-crystal materials; it is also much higher than that of the FDA approved photothermal agent ICG as well as most of the reported MOFs. Based on this realization, as a proof of concept, we demonstrated that such a self-assembled organic co-crystal platform can be used in biological applications that are exemplified via highly effective long wavelength light photothermal therapy.

A comparative study on auditory and hyoid bones of Jurassic euharamiyidans and contrasting evidence for mammalian middle ear evolution.

The holotypes of euharamiyidan Arboroharamiya allinhopsoni and Arboroharamiya jenkinsi preserve the auditory and hyoid bones, respectively. With additional structures revealed by micro-computerized tomography (CT) and X-ray micro-computed laminography (CL), we provide a detailed description of these minuscule bones. The stapes in the two species of Arboroharamiya are similar in having a strong process for insertion of the stapedius muscle. The incus is similar in having an almond-shaped body and a slim short process, in addition to a robust stapedial process with a short lenticular process preserved in A. allinhopsoni. The plate-like ectotympanic in the two species of Arboroharamiya is similar and comparable to that of Qishou jizantang. The surangular in the two species has a fan-shaped body and a needle-shaped anterior process. The malleus, ectotympanic, and surangular are fully detached from the dentary and should have functioned exclusively for hearing. All the auditory bones of Arboroharamiya display unique features unknown in other mammaliaforms. Moreover, hyoid elements are found in the two species of Arboroharamiya and co-exist with the five auditory bones in the holotype of A. allinhopsoni. The element interpreted as the stylohyal is similar to the bone identified as the ectotympanic in Vilevolodon. We reconstruct the auditory apparatus of Arboroharamiya and compare it with that of Vilevolodon as well as those in extant mammals and basal mammaliaforms. The comparison shows diverse morphological patterns of the auditory region in mammaliaforms. In particular, those of Vilevolodon and Arboroharamiya differ significantly: the former has a mandibular middle ear, whereas the latter possesses a definitive mammalian middle ear. It is puzzling that the two sympatric and dentally similar taxa have such different auditory apparatuses. In light of the available evidence, we argue that the mandibular middle ear reconstructed in Vilevolodon encounters many problems, and the so-called ectotympanic in Vilevolodon may be interpreted as a stylohyal; thus, the dilemma can be resolved.

Zero-Dimensional Carbon Dots Enhance Bone Regeneration, Osteosarcoma Ablation, and Clinical Bacterial Eradication.

Zero-dimensional carbon dots (CD) and their effects on osteogenesis have been rarely studied in bone repair scaffolds. Here, we fabricate a novel CD doped chitosan/nanohydroxyapatite (CS/nHA/CD) scaffold with full potential to promote bone regeneration by a facile freeze-drying method. The CS/nHA/CD scaffolds enhanced cell adhesion and osteoinductivity in rat bone mesenchymal stem cells by up-regulating genes involved in focal adhesion and osteogenesis in vitro, which significantly improved the formation of vascularized new bone tissue at 4 weeks compared to pure CS/nHA scaffolds in vivo. Inspired by the excellent photothermal effect of CD, the scaffolds were applied in tumor photothermal therapy (PTT) under near-infrared (NIR) irradiation (808 nm, 1 W/cm2). The scaffolds significantly inhibited osteosarcoma cell proliferation in vitro and effectively suppressed tumor growth in vivo. Moreover, the CS/nHA/CD scaffolds possessed distinct antibacterial properties toward clinically collected S. aureus and E. coli, and their antibacterial activity was further enhanced under NIR irradiation. This work demonstrates that zero-dimensional CD can enhance the osteogenesis-inducing property of bone repair scaffolds and that CD doped scaffolds have potential for use in PTT for tumors and infections.

Advanced Anti-Fouling Membranes for Osmotic Power Generation from Wastewater via Pressure Retarded Osmosis (PRO).

A facile and versatile approach was demonstrated for the fabrication of low-fouling pressure retarded osmosis (PRO) membranes for osmotic power generation from highly polluted wastewater. A water-soluble zwitterionic random copolymer with superior hydrophilicity and unique chemistry was molecularly designed and synthesized via a single-step free-radical polymerization between 2-methacryloyloxyethyl phosphorylcholine (MPC) and 2-aminoethyl methacrylate hydrochloride (AEMA). The P[MPC- co-AEMA] copolymer was then chemically grafted onto the surface of PES/Torlon hollow fibers via amino groups coupling of poly(AEMA) with the polyimide structures of Torlon, leaving the zwitterions of poly(MPC) in the feed solution. Because of the outstanding hydrophilicity, unique cationic and anionic groups, and electrical neutrality of the zwitterionic brush, the newly developed membrane showed great resistances to both inorganic scaling and organic fouling in PRO operations. When using a real wastewater brine comprising multifoulants as the feed, the P[MPC- co-AEMA] modified membrane exhibits a much lower flux decline of 37% at Δ P = 0 bar after 24-h tests and a smaller power density decrease of 28% at Δ P = 15 bar within 12-h tests, compared to 61% and 42% respectively for the unmodified one. In addition to the low fouling tendency, the modified membrane shows outstanding performance stability and fouling reversibility, where the flux is almost fully recovered by physical backwash of water at 15 bar for 0.5 h. This study provides valuable insights and strategies for the design and fabrication of effective antifouling materials and membranes for PRO osmotic power generation.

Low-Pressure Nanofiltration Hollow Fiber Membranes for Effective Fractionation of Dyes and Inorganic Salts in Textile Wastewater.

In this work, novel loose nanofiltration (NF) hollow fiber membranes with ultrahigh water permeability and well-defined nanopore and surface charge characteristics were developed for effective fractionation of dyes and inorganic salts in textile wastewater treatment. The as-spun NF hollow fiber possesses a high pure water permeability (PWP) of 80 L·m-2·h-1·bar-1 with a small pore size of 1.0 nm in diameter and a MWCO of 1000 Da. The surface modification by means of hyperbranched polyethylenimine (PEI) further lowers the pore diameter to 0.85 nm and MWCO to 680 Da. The membrane surface also becomes more hydrophilic and positively charged after the PEI modification. Because of the synergistic effects from size exclusion and charge repulsion, the newly developed NF hollow fibers show high permeation fluxes of 7.0-71.2 L·m-2·h-1 and great rejections of 95.5-99.9% to various dyes at a low operating pressure of 1 bar. At the same time, they have ultralow rejections of less than 10% to inorganic salts (i.e., Na2SO4), suggesting that more than 90% of the salts would permeate through the fibers. In addition, the two hollow fibers exhibit outstanding performance stability, low fouling tendency, and great fouling reversibility. Their fluxes can be brought back to be more than 80% of the original values by a simple physical backwash. The newly developed loose NF hollow fiber membranes may have great potential for effective fractionation and treatment of textile wastewater.

Phase Inversion Directly Induced Tight Ultrafiltration (UF) Hollow Fiber Membranes for Effective Removal of Textile Dyes.

This study has demonstrated the application of tight ultrafiltration (UF) membranes for effective removal of textile dyes from water at a low pressure. Novel UF hollow fiber membranes with well-defined nanopores and surface charges were developed via a single-step spinning process without any post-treatment. The newly developed tight UF hollow fibers not only possess a small mean pore diameter of 1.0-1.3 nm with a molecular weight cutoff (MWCO) of 1000-2000 Da but also have a high pure water permeability (PWP) of 82.5-117.6 L m-2 h-1 bar-1. Through the synergistic effects of size exclusion and charge repulsion, the novel UF hollow fibers can effectively remove various dyes with impressive rejections of 93.2-99.9% at 1 bar. At the same time, more than 92% of inorganic salts (i.e., NaCl and Na2SO4) would permeate through the fibers, reducing the detrimental effects of concentration polarization and providing an attracted avenue for salts reuse. The tight UF hollow fibers also exhibit robust performance in a continuous operation of 170 h or at a high feed recovery of 90%. The fouled fibers can be easily regenerated by backwash of water with a flux recovery of larger than 92%. The newly developed tight UF hollow fiber membranes display huge potential for treating textile wastewater and other impaired effluents because of their great separation performance and simple fabrication process.

Expanding Anti-Stokes Shifting in Triplet-Triplet Annihilation Upconversion for In†Vivo Anticancer Prodrug Activation.

A strategy to expand anti-Stokes shifting from the far-red to deep-blue region in metal-free triplet-triplet annihilation upconversion (TTA-UC) is presented. The method is demonstrated by in vivo titration of the photorelease of an anticancer prodrug. This new TTA system has robust brightness and the longest anti-Stokes shift of any reported TTA system. TTA core-shell-structured prodrug delivery capsules that benefit from these properties were developed; they can operate with low-power density far-red light-emitting diode light. These capsules contain mesoporous silica nanoparticles preloaded with TTA molecules as the core, and amphiphilic polymers encapsulating anticancer prodrug molecules as the shell. When stimulated by far-red light, the intense TTA upconversion blue emission in the system activates the anticancer prodrug molecules and shows effective tumor growth inhibition in vivo. This work paves the way to new organic TTA upconversion techniques that are applicable to in vivo photocontrollable drug release and other biophotonic applications.

Effective As(III) Removal by A Multi-Charged Hydroacid Complex Draw Solute Facilitated Forward Osmosis-Membrane Distillation (FO-MD) Processes.

Effective removal of As(III) from water by an oxalic acid complex with the formula of Na3[Cr(C2O4)3] (Na-Cr-OA) is demonstrated via an forward osmosis-membrane distillation (FO-MD) hybrid system in this study. Na-Cr-OA first proved its superiority as a draw solute with high water fluxes and negligible reverse fluxes in FO, then a systematic investigation of the Na-Cr-OA promoted FO process was conducted to ascertain the factors in As(III) removal. Relatively high water fluxes of 28 LMH under the FO mode and 74 LMH under the pressure retarded osmosis (PRO) mode were achieved when using a 1000 ppm As(III) solution as the feed and 1.0 M Na-Cr-OA as the draw solution at 60 °C. As(III) removal with a water recovery up to 21.6% (FO mode) and 48.3% (PRO mode) were also achieved in 2 h. An outstanding As(III) rejection with 30-3000 µg/L As(III) in the permeate was accomplished when As(III) feed solutions varied from 5 × 10(4) to 1 × 10(6) µg/L, superior to the best FO performance reported for As(III) removal. Incorporating MD into FO not only makes As(III) removal sustainable by reconcentrating the Na-Cr-OA solution simultaneously, but also reduces the As(III) concentration below 10 µg/L in the product water, meeting the WHO standard.

Gold nanoparticles stabilized with MPEG-grafted poly(l-lysine): in vitro and in vivo evaluation of a potential theranostic agent.

As the number of diagnostic and therapeutic applications utilizing gold nanoparticles (AuNPs) increases, so does the need for AuNPs that are stable in vivo, biocompatible, and suitable for bioconjugation. We investigated a strategy for AuNP stabilization that uses methoxypolyethylene glycol-graft-poly(l-lysine) copolymer (MPEG-gPLL) bearing free amino groups as a stabilizing molecule. MPEG-gPLL injected into water solutions of HAuCl4 with or without trisodium citrate resulted in spherical (Zav = 36 nm), monodisperse (PDI = 0.27), weakly positively charged nanoparticles (AuNP3) with electron-dense cores (diameter: 10.4 ± 2.5 nm) and surface amino groups that were amenable to covalent modification. The AuNP3 were stable against aggregation in the presence of phosphate and serum proteins and remained dispersed after their uptake into endosomes. MPEG-gPLL-stabilized AuNP3 exhibited high uptake and very low toxicity in human endothelial cells, but showed a high dose-dependent toxicity in epithelioid cancer cells. Highly stable radioactive labeling of AuNP3 with (99m)Tc allowed imaging of AuNP3 biodistribution and revealed dose-dependent long circulation in the blood. The minor fraction of AuGNP3 was found in major organs and at sites of experimentally induced inflammation. Gold analysis showed evidence of a partial degradation of the MPEG-gPLL layer in AuNP3 particles accumulated in major organs. Radiofrequency-mediated heating of AuNP3 solutions showed that AuNP3 exhibited heating behavior consistent with 10 nm core nanoparticles. We conclude that PEG-pPLL coating of AuNPs confers "stealth" properties that enable these particles to exist in vivo in a nonaggregating, biocompatible state making them suitable for potential use in biomedical applications such as noninvasive radiofrequency cancer therapy.

Novel nanofiltration membranes consisting of a sulfonated pentablock copolymer rejection layer for heavy metal removal.

Facing stringent regulations on wastewater discharge containing heavy metal ions, various industries are demanding more efficient and effective treatment methods. Among the methods available, nanofiltration (NF) is a feasible and promising option. However, the development of new membrane materials is constantly required for the advancement of this technology. This is a report of the first attempt to develop a composite NF membrane comprising a molecularly designed pentablock copolymer selective layer for the removal of heavy metal ions. The resultant NF membrane has a mean effective pore diameter of 0.50 nm, a molecular weight cutoff of 255 Da, and a reasonably high pure water permeability (A) of 2.4 LMH/bar. The newly developed NF membrane can effectively remove heavy metal cations such as Pb(2+), Cd(2+), Zn(2+), and Ni(2+) with a rejection of >98.0%. On the other hand, the membrane also shows reasonably high rejections toward anions such as HAsO4(2-) (99.9%) and HCrO4(-) (92.3%). This performance can be attributed to (1) the pentablock copolymer's unique ability to form a continuous water transport passageway with a defined pore size and (2) the incorporation of polyethylenimine as a gutter layer between the selective layer and the substrate. To the best of our knowledge, this is the first reported NF membrane comprising this pentablock copolymer as the selective material. The promising preliminary results achieved in this study provide a useful platform for the development of new NF membranes for heavy metal removal.

Chitosan Phytate Nanoparticles: A Synergistic Strategy for Effective Dental Caries Prevention.

Dental caries is a widespread oral disease that poses a significant medical challenge. Traditional caries prevention methods, primarily the application of fluoride, often fall short in effectively destroying biofilms and preventing enamel demineralization, thereby providing limited efficacy in halting the progression of caries over time. To address this issue, we have developed a green and cost-effective synergistic strategy for the prevention of dental caries. By combining natural sodium phytate and chitosan, we have created chitosan-sodium phytate nanoparticles that offer both the antimicrobial properties of chitosan and the enamel demineralization-inhibiting capabilities of sodium phytate. In an ex vivo biofilm model of human teeth, we found that these nanoparticles effectively prevent biofilm buildup and acid damage to the mineralized tissue. Additionally, topical treatment of dental caries in rodent models has shown that these nanoparticles effectively suppress disease progression without negatively impacting oral microbiota diversity or causing harm to the gingival-mucosal tissues, unlike traditional prevention methods.

Highly robust thin-film composite pressure retarded osmosis (PRO) hollow fiber membranes with high power densities for renewable salinity-gradient energy generation.

The practical application of pressure retarded osmosis (PRO) technology for renewable blue energy (i.e., osmotic power generation) from salinity gradient is being hindered by the absence of effective membranes. Compared to flat-sheet membranes, membranes with a hollow fiber configuration are of great interest due to their high packing density and spacer-free module fabrication. However, the development of PRO hollow fiber membranes is still in its infancy. This study aims to open up new perspectives and design strategies to molecularly construct highly robust thin film composite (TFC) PRO hollow fiber membranes with high power densities. The newly developed TFC PRO membranes consist of a selective polyamide skin formed on the lumen side of well-constructed Matrimid hollow fiber supports via interfacial polymerization. For the first time, laboratory PRO power generation tests demonstrate that the newly developed PRO hollow fiber membranes can withstand trans-membrane pressures up to 16 bar and exhibit a peak power density as high as 14 W/m(2) using seawater brine (1.0 M NaCl) as the draw solution and deionized water as the feed. We believe that the developed TFC PRO hollow fiber membranes have great potential for osmotic power harvesting.

Non-blinking and photostable upconverted luminescence from single lanthanide-doped nanocrystals.

The development of probes for single-molecule imaging has dramatically facilitated the study of individual molecules in cells and other complex environments. Single-molecule probes ideally exhibit good brightness, uninterrupted emission, resistance to photobleaching, and minimal spectral overlap with cellular autofluorescence. However, most single-molecule probes are imperfect in several of these aspects, and none have been shown to possess all of these characteristics. Here we show that individual lanthanide-doped upconverting nanoparticles (UCNPs)--specifically, hexagonal phase NaYF(4) (beta-NaYF(4)) nanocrystals with multiple Yb(3+) and Er(3+) dopants--emit bright anti-Stokes visible upconverted luminescence with exceptional photostability when excited by a 980-nm continuous wave laser. Individual UCNPs exhibit no on/off emission behavior, or "blinking," down to the millisecond timescale, and no loss of intensity following an hour of continuous excitation. Amphiphilic polymer coatings permit the transfer of hydrophobic UCNPs into water, resulting in individual water-soluble nanoparticles with undiminished photophysical characteristics. These UCNPs are endocytosed by cells and show strong upconverted luminescence, with no measurable anti-Stokes background autofluorescence, suggesting that UCNPs are ideally suited for single-molecule imaging experiments.

Application of molecularly imprinted polymers as artificial receptors for imaging.

Medical diagnostics aims at specific localization of molecular targets as well as detection of abnormalities associated with numerous diseases. Molecularly imprinted polymers (MIPs) represent an approach of creating a synthetic material exhibiting selective recognition properties toward the desired template. The fabricated target-specific MIPs are usually well reproducible, economically efficient, and stable under critical conditions as compared to routinely used biorecognition elements such as fluorescent proteins, antibodies, enzymes, or aptamers and can even be created to those targets for which no antibodies are available. In this review, we summarize the methods of polymer fabrication. Further, we provide key for selection of the core material with imaging function depending on the imaging modality used. Finally, MIP-based imaging applications are highlighted and presented in a comprehensive form from different aspects. STATEMENT OF SIGNIFICANCE: In this review, we summarize the methods of polymer fabrication. Key applications of Molecularly imprinted polymers (MIPs) in imaging are highlighted and discussed with regard to the selection of the core material for imaging as well as commonly used imaging targets. MIPs represent an approach of creating a synthetic material exhibiting selective recognition properties toward the desired template. The fabricated target-specific MIPs are usually well reproducible, economically efficient, and stable under critical conditions as compared to routinely used biorecognition elements, e.g., antibodies, fluorescent proteins, enzymes, or aptamers, and can even be created to those targets for which no antibodies are available.

Modulation of enzyme-substrate selectivity using tetraethylene glycol functionalized gold nanoparticles.

Tetraethylene glycol (TEG) functionalized gold nanoparticles with 2 nm core diameters (AuTEG) enhance alpha-chymotrypsin (ChT) enzyme activity in a substrate-selective fashion. We explored the hydrolysis of four different substrates and observed a marked increase in activity with the most hydrophobic substrate N-succinyl-alanine-alanine-proline-phenylalanine- p-nitroanilide (TP), while the other substrates remain virtually unaffected by the AuTEG 'crowding effect' in solution. The enhancement in catalysis is indicated by an increase in K(cat)/K(m) as obtained from Lineweaver-Burk analysis and we hypothesize it to arise from a macromolecular crowding effect analogous to that observed with high molecular weight poly(ethylene glycol) (PEG) polymers.

[Preparation and drug releasing property of curcumin nanoparticles].

OBJECTIVE: To prepare curcumin nanoparticles and evaluate the in vitro release of curcumin. METHODS: The chitosan-graft-vinyl acetate copolymers were synthesized by free radical polymerization. Curcumin nanoparticles were synthesized by ultrasonic irradiation. The encapsulation efficiency of the nanoparticles and the in vitro release of curcumin were studied. RESULTS: The nanoparticles were discrete and uniform spheres, covered with positive charges. The encapsulation efficiency of nanoparticles was up to 91.6%. The in vitro release profile showed the slower release rate of curcumin. CONCLUSION: The methods is simple. The nanoparticles possess good physical performance and sustained release character in vitro.

Designing next generation of photon upconversion: Recent advances in organic triplet-triplet annihilation upconversion nanoparticles.

Organic triplet-triplet annihilation upconversion (TTA-UC) nanoparticles have emerged as exciting therapeutic agents and imaging probes in recent years due to their unique chemical and optical properties such as outstanding biocompatibility and low power excitation density. In this review, we focus on the latest breakthroughs in such new version of upconversion nanoparticle, including their design, preparation, and applications. First, we will discuss the key principles and design concept of these organic-based photon upconversion in regard to the methods of selection of the related triplet TTA dye pairs (photosensitizer and emitter). Then, we will discuss the recent approaches s to construct TTA-UCNPs including silica TTA-UCNPs, lipid-coated TTA-UCNPs, polymer encapsulated TTA-UCNPs, nano-droplet TTA-UCNPs and metal-organic frameworks (MOFs) constructed TTA-UCNPs. In addition, the applications of TTA-UCNPs will be discussed. Finally, we will discuss the challenges posed by current TTA-UCNP development.

A photo-inducible protein-inorganic nanoparticle assembly for active targeted tumour theranostics.

The assembly of protein-inorganic nanoparticles is an important yet challenging approach that is utilized to develop functional materials in numerous areas, such as bio-catalysis, drug delivery, and biosensing. In this study, we report on a facile, photo-inducible self-assembly method to generate protein-inorganic hybrid nanoplatforms. More specifically, photo-treated disulfide bond rich proteins of lysozyme (LYS) were able to be used as host materials in order to encapsulate nanoparticles (i.e., as-synthesized hydrophobic NIR quantum dots (QDs)) and anti-cancer small molecule drugs (i.e., paclitaxel (PTX)), constructing functional theranostic protein-inorganic hybrid nanoparticles. The modification of the functional polymer of cRGD-PEG contributes to the active tumour targeting characteristic of this protein-inorganic nanocarrier. This novel PTX loaded protein-inorganic hybrid nanoplatform showed high tumour homing accumulation as well as effective tumour inhibition. We believe that this general approach represents a new direction for the development of a photo-induced assembly of protein-inorganic nanoparticles towards versatile applications in both materials science and biomedical fields.