Apremilast is a potentially useful treatment for severe palmoplantar pustulosis with extra-palmoplantar symptoms.

Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disorder affecting the palms and soles. In rare cases, severe patients develop acute extra-palmoplantar lesions often accompanied by arthralgia. Such cases with extensive symptoms often necessitate systemic treatments with variable efficacy and potential side effects. Apremilast, known for its broad immune response modulation, presents promise as a therapeutic option for severe PPP with joint and extra-palmoplantar lesions. This case highlights apremilast as a potential systemic treatment for such cases with minimal side effects.

Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis.

Porokeratosis is a clonal keratinization disorder characterized by solitary, linearly arranged, or generally distributed multiple skin lesions. Previous studies showed that genetic alterations in MVK, PMVK, MVD, or FDPS-genes in the mevalonate pathway-cause hereditary porokeratosis, with skin lesions harboring germline and lesion-specific somatic variants on opposite alleles. Here, we identified non-hereditary porokeratosis associated with epigenetic silencing of FDFT1, another gene in the mevalonate pathway. Skin lesions of the generalized form had germline and lesion-specific somatic variants on opposite alleles in FDFT1, representing FDFT1-associated hereditary porokeratosis identified in this study. Conversely, lesions of the solitary or linearly arranged localized form had somatic bi-allelic promoter hypermethylation or mono-allelic promoter hypermethylation with somatic genetic alterations on opposite alleles in FDFT1, indicating non-hereditary porokeratosis. FDFT1 localization was uniformly diminished within the lesions, and lesion-derived keratinocytes showed cholesterol dependence for cell growth and altered expression of genes related to cell-cycle and epidermal development, confirming that lesions form by clonal expansion of FDFT1-deficient keratinocytes. In some individuals with the localized form, gene-specific promoter hypermethylation of FDFT1 was detected in morphologically normal epidermis adjacent to methylation-related lesions but not distal to these lesions, suggesting that asymptomatic somatic epigenetic mosaicism of FDFT1 predisposes certain skin areas to the disease. Finally, consistent with its genetic etiology, topical statin treatment ameliorated lesions in FDFT1-deficient porokeratosis. In conclusion, we identified bi-allelic genetic and/or epigenetic alterations of FDFT1 as a cause of porokeratosis and shed light on the pathogenesis of skin mosaicism involving clonal expansion of epigenetically altered cells.

All-solution-processed ultraflexible wearable sensor enabled with universal trilayer structure for organic optoelectronic devices.

All-solution-processed organic optoelectronic devices can enable the large-scale manufacture of ultrathin wearable electronics with integrated diverse functions. However, the complex multilayer-stacking device structure of organic optoelectronics poses challenges for scalable production. Here, we establish all-solution processes to fabricate a wearable, self-powered photoplethysmogram (PPG) sensor. We achieve comparable performance and improved stability compared to complex reference devices with evaporated electrodes by using a trilayer device structure applicable to organic photovoltaics, photodetectors, and light-emitting diodes. The PPG sensor array based on all-solution-processed organic light-emitting diodes and photodetectors can be fabricated on a large-area ultrathin substrate to achieve long storage stability. We integrate it with a large-area, all-solution-processed organic solar module to realize a self-powered health monitoring system. We fabricate high-throughput wearable electronic devices with complex functions on large-area ultrathin substrates based on organic optoelectronics. Our findings can advance the high-throughput manufacture of ultrathin electronic devices integrating complex functions.

Factors Related to Favorable Outcomes in Older Adults Undergoing Home-Visit Rehabilitation Therapy.

BACKGROUND: Increasing elderly population is a major health concern worldwide, requiring various at-home care services. The aim of home-visit rehabilitation therapy is to support at-home living of the elderly and to promote their participation in social activities. There is a paucity of data about the clinical conditions of this population that can contribute to the achievement of goals in-home visit rehabilitation therapy. AIM: This study aimed to clarify clinical variables that could be related to the achievement of goals in-home visit rehabilitation therapy. METHODS: We collected retrospective clinical data of the older adults who underwent home-visit rehabilitation therapy between July 2006 and June 2021. We searched the clinical variables of home-visit rehabilitation therapy users and their frequency of utilization of home-visit rehabilitation therapy services from the clinical record. The initial and final clinical variables evaluated in this study included the abilities of daily living, degree of being bedridden, dementia rating, and levels of support or long-term care. Those variables were evaluated by rehabilitation therapists and doctors. The users were divided into three groups according to the reason for terminating rehabilitation therapy: goal achievement (achieved group), aggravation of underlying disease (aggravated group), and treatment suspension because of their own/others' wish (suspended group). The clinical parameters concerning the rehabilitation program, care level, and activities of daily living were evaluated among the groups. The clinical parameters concerning the rehabilitation program, care level, and activities of daily living were statistically evaluated among those three groups, using the chi-square test and Kruskal-Wallis test. RESULTS: In the achieved, aggravated, and suspended groups, 45, 190, and 38 users were respectively enrolled. The aggravated group showed significantly higher final care level (p = 0.002), degree of being bedridden (p=0.001), and dementia rating (p = 0.017) and significantly lower Barthel index scores (p < 0.001) and Frenchay Activities Index scores (p = 0.001) than the achieved group. Persons requesting the therapy were significantly older adults themselves in the achieved group (p = 0.018). The therapy was significantly performed more than once per week in the achieved group (p = 0.018). CONCLUSIONS: Older adults undergoing self-motivated home-visit rehabilitation therapy more than once per week may contribute to the achievement of the goal.

Mussel inspired sequential protein delivery based on self-healing injectable nanocomposite hydrogel.

Polysaccharide based self-healing and injectable hydrogels with reversible characteristics have widespread potential in protein drug delivery. However, it is a challenge to design the dynamic hydrogel for sequential release of protein drugs. Herein, we developed a novel mussel inspired sequential protein delivery dynamic polysaccharide hydrogel. The nanocomposite hydrogel can be fabricated through doping polydopamine nanoparticles (PDA NPs) into reversible covalent bond (imine bonds) crosslinked polymer networks of oxidized hyaluronic acid (OHA) and carboxymethyl chitosan (CEC), named PDA NPs@OHA-l-CEC. Besides multiple capabilities (i.e., injection, self-healing, and biodegradability), the nanocomposite hydrogel can achieve sustained and sequential protein delivery of vascular endothelial growth factor (VEGF) and bovine serum albumin (BSA). PDA NPs doped in hydrogel matrix serve dual roles, acting as secondary protein release structures and form dynamic non-covalent interactions (i.e., hydrogen bonds) with polysaccharides. Moreover, by adjusting the oxidation degree of OHA, the hydrogels with different crosslinking density could control overall protein release rate. Analysis of different release kinetic models revealed that Fickian diffusion drove rapid VEGF release, while the slower BSA release followed a Super Case II transport mechanism. The novel biocompatible system achieved sequential release of protein drugs has potentials in multi-stage synergistic drug deliver based on dynamic hydrogel.

An osteoinductive surface by adhesive bone morphogenetic protein-2 prepared using the bioorthogonal approach for tight binding of titanium with bone.

Inorganic biomaterials are used in various orthopedic and dental implants. Nevertheless, they cause clinical issues such as loosening of implants and patient morbidity. Therefore, inspired by mussel adhesive proteins, we aimed to design an adhesive and dimer-forming highly active bone morphogenetic protein-2 (BMP-2) using bioorthogonal chemistry, in which recombinant DNA technology was combined with enzymatic modifications, to achieve long-term osseointegration with titanium. The prepared BMP-2 exhibited substantially higher binding activity than wild-type BMP-2, while the adhered BMP-2 was more active than soluble BMP-2. Therefore, the adhesive BMP-2 was immobilized onto titanium wires and screws and implanted into rat bones, and long-term osteogenesis was evaluated. Adhesive BMP-2 promoted the mechanical binding of titanium to bones, enabling efficient bone regeneration and effective stabilization of implants. Thus, such adhesive biosignaling proteins can be used in regenerative medicine.

Tough, self-healing and injectable dynamic nanocomposite hydrogel based on gelatin and sodium alginate.

Biomacromolecules based injectable and self-healing hydrogels possessing high mechanical properties have widespread potential in biomedical field. However, dynamic features are usually inversely proportional to toughness. It is challenging to simultaneously endow these properties to the dynamic hydrogels. Here, we fabricated an injectable nanocomposite hydrogel (CS-NPs@OSA-l-Gtn) stimultaneously possessing excellent autonomous self-healing performance and high mechanical strength by doping chitosan nanoparticles (CS-NPs) into dynamic polymer networks of oxidized sodium alginate (OSA) and gelatin (Gtn) in the presence of borax. The synergistic effect of the multiple reversible interactions combining dynamic covalent bonds (i.e., imine bond and borate ester bond) and noncovalent interactions (i.e., electrostatic interaction and hydrogen bond) provide effective energy dissipation to endure high fatigue resistance and cyclic loading. The dynamic hydrogel exhibited excellent mechanical properties like maximum 2.43 MPa compressive strength, 493.91 % fracture strain, and 89.54 kJ/m3 toughness. Moreover, the integrated hydrogel after injection and self-healing could withstand 150 successive compressive cycles. Besides, the bovine serum albumin embedded in CS-NPs could be sustainably released from the nanocomposite hydrogel for 12 days. This study proposes a novel strategy to synthesize an injectable and self-healing hydrogel combined with excellent mechanical properties for designing high-strength natural carriers with sustained protein delivery.

Peptide-lipid hybrid vesicles with stimuli-responsive phase separation for controlled membrane functions.

A disulfide-tethered peptide-lipid conjugate self-assembled into a homogeneously distributed peptide-lipid hybrid vesicle. Upon dithiothreitol treatment, the homogeneous peptide-lipid membrane spontaneously divided into lipid-rich and peptide-rich domains, while the vesicle retained its size and shape. Membrane phase separation enhanced temperature-dependent cargo release.

Polysarcosine-Coated liposomes attenuating immune response induction and prolonging blood circulation.

HYPOTHESIS: Liposomes coated with long polysarcosine (PSar) chains at a high density might enable long blood circulation and attenuate accelerated blood clearance (ABC) phenomenon. EXPERIMENTS: In this study, we controlled the length (23, 45, 68 mers) and density (5, 10, 15 mol%) of PSar on liposomal coatings and, furthermore, investigated the effects of PSar length and density on the blood circulation time, biodistribution, immune response, and ABC phenomenon induction. Length-controlled PSar-bound lipids (PSar-PEs) were synthesized using a click reaction and inserted into bare liposomes at different combinations of chain lengths and proportions. FINDINGS: Although all PSar-coated liposomes (PSar-lipos) had similar morphological, physical, and chemical properties, they had different blood circulation times and biodistribution, and exerted varied effects on the immune system. All PSar-lipos with different PSar length and density showed a similar anti-PSar IgM response. Liposomes modified with the longest PSar chain (68 mers) at a high density (15 mol%) showed the longest blood circulation time and, additionally, attenuated ABC phenomenon compared with PEG-lipo. The ex vivo analysis of the biodistribution of liposomes revealed that a thick PSar layer enhanced the blood circulation time of liposomes due to the reduction of the accumulation of liposomes in the liver and spleen. These findings provide new insights into the relationship between IgM expression and ABC phenomenon inhibition.

Reversible transformation of peptide assembly between densified-polysarcosine-driven kinetically and helix-orientation-driven thermodynamically stable morphologies.

Stimuli-responsive transformable biomaterials development can be manipulated practically by fine-tuning the built-in molecular design of their structural segments. Here, we demonstrate a peptide assembly by the bola-type amphiphilic polypeptide, glycolic acid-polysarcosine (PSar)13-b-(L-Leu-Aib)6-b-PSar13-glycolic acid (S13L12S13), which shows morphological transformations between hydrophilic chain-driven and hydrophobic unit-driven morphologies. The hydrophobic α-helical unit (L-Leu-Aib)6 precisely controls packing in the hydrophobic layer of the assembly and induces tubule formation. The densified, hydrophilic PSar chain on the assembly surface becomes slightly more hydrophobic as the temperature increases above 70 °C, starting to disturb the helix-helix interaction-driven formation of tubules. As a result, the S13L12S13 peptide assembly undergoes a reversible vesicle-nanotube transformation following a time course at room temperature and a heat treatment above 80 °C. Using membrane fluidity analysis with DPH and TMA-DPH and evaluating the environment surrounding the PSar side chain with NMR, we clarify that the vesicle was in a kinetically stable state driven by the dehydrated PSar chain, while the nanotube was in a thermodynamically stable state.

Cyclic stretch modulates the cell morphology transition under geometrical confinement by covalently immobilized gelatin.

Fibroblasts geometrically confined by photo-immobilized gelatin micropatterns were subjected to cyclic stretch on the silicone elastomer. By using covalently micropatterned surfaces, the cell morphologies such as cell area and length were quantitatively investigated under a cyclic stretch for 20 hours. The mechanical forces did not affect the cell growth but significantly altered the cellular morphology on both non-patterned and micropatterned surfaces. It was found that cells on non-patterns showed increasing cell length and decreasing cell area under the stretch. The width of the strip micropatterns provided a different extent of contact guidance for fibroblasts. The highly extended cells on the 10 µm pattern under static conditions would perform a contraction behavior once treated by cyclic stretch. In contrast, cells with a low extension on the 2 µm pattern kept elongating according to the micropattern under the cyclic stretch. The vertical stretch induced an increase in cell area and length more than the parallel stretch in both the 10 µm and 2 µm patterns. These results provided new insights into cell behaviors under geometrical confinement in a dynamic biomechanical environment and may guide biomaterial design for tissue engineering in the future.

Chemical Storage of Ammonia through Dynamic Structural Transformation of a Hybrid Perovskite Compound.

Toward renewable energy for global leveling, compounds that can store ammonia (NH3), a carbon-free energy carrier of hydrogen, will be of great value. Here, we report an organic-inorganic halide perovskite compound that can chemically store NH3 through dynamic structural transformation. Upon NH3 uptake, a chemical structure change occurs from a one-dimensional columnar structure to a two-dimensional layered structure by addition reaction. NH3 uptake is estimated to be 10.2 mmol g-1 at 1 bar and 25 °C. In addition, NH3 extraction can be performed by a condensation reaction at 50 °C under vacuum. X-ray diffraction analysis reveals that reversible NH3 uptake/extraction originates from a cation/anion exchange reaction. This structural transformation shows the potential to integrate efficient uptake and extraction in a hybrid perovskite compound through chemical reaction. These findings will pave the way for further exploration of dynamic, reversible, and functionally useful compounds for chemical storage of NH3.

Survey of oligoethylene glycol-based self-assembled monolayers on electrochemical aptamer-based sensor in biological fluids.

The ability to monitor levels of endogenous markers and clearance profiles of drugs and their metabolites can improve the quality of biomedical research and precision with which therapies are individualized. Towards this end, electrochemical aptamer-based (EAB) sensors have been developed that support the real-time monitoring of specific analytes in vivo with clinically relevant specificity and sensitivity. A challenge associated with the in vivo deployment of EAB sensors, however, is how to manage the signal drift which, although correctable, ultimately leads to unacceptably low signal-to-noise ratios, limiting the measurement duration. Motivated by the correction of signal drift, in this paper, we have explored the use of oligoethylene glycol (OEG), a widely employed antifouling coating, to reduce the signal drift in EAB sensors. Counter to expectations, however, when challenged in 37 °C whole blood in vitro, EAB sensors employing OEG-modified self-assembled monolayers exhibit both greater drift and reduced signal gain, compared with those employ a simple, hydroxyl-terminated monolayer. On the other hand, when EAB sensor was prepared with a mix monolayer using MCH and lipoamido OEG 2 alcohol, reduced signal noise was observed compared to the same sensor prepared with MCH presumably due to improved SAM construction. These results suggest broader exploration of antifouling materials will be required to improve the signal drift of EAB sensors.

Biogenic Solution Map Based on the Definition of the Metabolic Correlation Distance between 4-Dimensional Fingerprints.

Accurate discrimination and classification of unknown species are the basis to predict its characteristics or applications to make correct decisions. However, for biogenic solutions that are ubiquitous in nature and our daily lives, direct determination of their similarities and disparities by their molecular compositions remains a scientific challenge. Here, we explore a standard and visualizable ontology, termed "biogenic solution map", that organizes multifarious classes of biogenic solutions into a map of hierarchical structures. To build the map, a novel 4-dimensional (4D) fingerprinting method based on data-independent acquisition data sets of untargeted metabolomics is developed, enabling accurate characterization of complex biogenic solutions. A generic parameter of metabolic correlation distance, calculated based on averaged similarities between 4D fingerprints of sample groups, is able to define "species", "genus", and "family" of each solution in the map. With the help of the "biogenic solution map", species of unknown biogenic solutions can be explicitly defined. Simultaneously, intrinsic correlations and subtle variations among biogenic solutions in the map are accurately illustrated. Moreover, it is worth mentioning that samples of the same analyte but prepared by alternative protocols may have significantly different metabolic compositions and could be classified into different "genera".

Natural polyphenol tannin-immobilized composites: rational design and versatile applications.

Tannins, which are natural plant polyphenols, are widely used in different fields, especially in biomedical applications due to their unique properties, including high abundance, low cost, structural diversity, protein precipitation, biocompatibility, and biodegradability. However, they fail to satisfy the requirements in some specific applications (e.g., environmental remediation) on account of their water solubility, making their separation and regeneration difficult. Inspired by the design of composite materials, tannin-immobilized composites have emerged as promising and novel materials and combine or even surpass the advantages of each of their components. This strategy can endow tannin-immobilized composites with efficient manufacturing properties, high strength, good stability, easy chelating/coordinating ability, excellent antibacterial property, biological compatibility, bioactivity, chemical/corrosion resistance, and strong adhesive performance, which significantly expand their application in various fields. In this review, initially we summarize the design strategy of tannin-immobilized composites, mainly concentrating on the choice of immobilized substrate (e.g., natural polymers, synthetic polymers, and inorganic materials) as well as the binding interaction (e.g., Mannich reaction, Schiff base reaction, graft copolymerization, oxidation coupling, electrostatic interaction, and hydrogen bonding) between them. Further, the application of tannin-immobilized composites in the biomedical (tissue engineering, wound healing, cancer therapy, and biosensors) and other (leather materials, environmental remediation, and functional food packaging) fields is highlighted. Finally, we conclude with some thoughts on the open challenges and future perspectives of tannin composites. It can be anticipated that tannin-immobilized composites will continuously draw attention from more and more researchers, and further promising applications of tannin composites will be explored.

Dynamic and self-biodegradable polysaccharide hydrogel stores embryonic stem cell construct under ambient condition.

The proper microenvironment is critical for the storage and transportation of embryonic stem cells (ESCs). To mimic a dynamic 3D microenvironment as it exists in vivo and consider "off-the-shelf" availability reaching the destination, we proposed an alternative approach that allows for facile storage and transportation of stem cells in the form of ESCs-dynamic hydrogel construct (CDHC) under ambient conditions. To form CDHC, mouse embryonic stem cells (mESCs) were in-situ encapsulated within a polysaccharide-based dynamic and self-biodegradable hydrogel. After storing CDHC in a sterile and hermetic environment for 3 days and then transferring to a sealed vessel with fresh medium for another 3 days, the large and compact colonies retained a 90% survival rate and pluripotency. Furthermore, after transporting and arriving at the destination, the encapsulated stem cell could be automatically released from the self-biodegradable hydrogel. After continuous cultivation of 15 generations of retrieved cells, automatically released from the CDHC, the mESCs underwent 3D encapsulation, storage, transportation, release, and continuous long-term subculture; resumed colony forming capacity and pluripotency were revealed by stem cell markers both in protein and mRNA levels. We believe that the dynamic and self-biodegradable hydrogel provides a simple, cost-effective, and valuable tool for storing and transporting "ready-to-use" CDHC under ambient conditions, facilitating "off-the-shelf" availability and widespread applications.

Dissecting skin microbiota and microenvironment for the development of therapeutic strategies.

The skin is a pivotal barrier between the human body and the environment, and is a habitat for numerous microorganisms. While host-microbiota interactions in the skin are essential for homeostasis, disturbances in microbial composition and the abnormal growth of certain bacteria are associated with various diseases. Here, we identify strains and communities of skin commensals that contribute to or impair skin barrier function. Furthermore, we discuss the skin microenvironments suitable for specific microbiota that exert therapeutic effects and suggest focus areas for the prospective development of therapeutic strategies using bacterial agents. Finally, we highlight recent efforts to treat skin diseases associated with live bacteria.

Efficient Microfluidic Screening Method Using a Fluorescent Immunosensor for Recombinant Protein Secretions.

Microbial secretory protein expression is widely used for biopharmaceutical protein production. However, establishing genetically modified industrial strains that secrete large amounts of a protein of interest is time-consuming. In this study, a simple and versatile high-throughput screening method for protein-secreting bacterial strains is developed. Different genotype variants induced by mutagens are encapsulated in microemulsions and cultured to secrete proteins inside the emulsions. The secreted protein of interest is detected as a fluorescence signal by the fluorescent immunosensor quenchbody (Q-body), and a cell sorter is used to select emulsions containing improved protein-secreting strains based on the fluorescence intensity. The concept of the screening method is demonstrated by culturing Corynebacterium glutamicum in emulsions and detecting the secreted proteins. Finally, productive strains of fibroblast growth factor 9 (FGF9) are screened, and the FGF9 secretion increased threefold compared to that of parent strain. This screening method can be applied to a wide range of proteins by fusing a small detection tag. This is a highly simple process that requires only the addition of a Q-body to the medium and does not require the addition of any substrates or chemical treatments. Furthermore, this method shortens the development period of industrial strains for biopharmaceutical protein production.

Analysis method of cellular stress caused by intermediate dose-rate irradiation using a cell lysate array technique.

Ionizing radiation damages DNA and may lead to the development of cancer. Irradiation also generates reactive oxygen species (ROS) which cause damage to various biological molecules. Relatively low dose-rate irradiation causes less damage. However, the damage and its effects on cell fate are difficult to evaluate. To develop a method to analyze the damage and accompanying changes in physiology in cells irradiated by γ-rays at a relatively low dose-rate, we used the protein array technique to quantify marker proteins involved in the stress response and the regulation of cell growth and death. This method enabled efficient analyses of many replicates of experimental data on cell lysate samples. We detected relatively small changes in the levels of these proteins in the irradiated cells. Changes in protein levels suggested ROS production and DNA damage as well as cell cycle retardation and the progression of cellular senescence. Thus, our approach shows promise for analyzing the biological effects of relatively low dose-rate irradiation.

Photo-reactive polymers for the immobilisation of epidermal growth factors.

Photo-reactive polymers are important for biomaterials, including devices with a 3D-structure. Here, different types of photo-reactive polymers were prepared and utilised for immobilisation of growth factors. They were synthesised by conjugation of gelatin with the azidophenyl group or by copolymerisation of the azidophenyl group-coupled methacrylate with poly(ethylene glycol) methacrylate. The azidophenyl content and the zeta potential of the prepared polymers were measured. After spin coating of polymers, the thickness and the water contact angle of coated layers were measured. The amount of the immobilised epidermal growth factor (EGF) was determined using fluorescence labelling. Cell adhesion responded to the nature of photo-reactive polymers but did not depend on the immobilised EGF. However, cell growth was dependent on the amount of immobilised EGF and was significantly affected by the nature of photo-reactive polymers. The study shows that the properties of the photo-immobilisation matrix significantly influence the biological activity.