Area-Specific, Hierarchical Nanowrinkling of Two-Dimensional Materials.

This paper describes an approach to generate hierarchical wrinkles in two-dimensional (2D) electronic materials with spatial control over adjacent wavelengths. A rigid fluoropolymer mold was used to pattern a sacrificial polymer skin layer on monolayer graphene, molybdenum disulfide, and hexagonal boron nitride on prestrained thermoplastic sheets. Strain relief and removal of the polymer layer resulted in 2D-material wrinkles whose wavelengths scaled linearly with the local skin thickness. A second generation of wrinkles could be created on top of the first generation by applying a subsequent cycle of polymer skin coating, strain relief, and polymer removal. This area-specific hierarchical wrinkling is general and will facilitate the engineering of the local properties of various 2D materials and their heterostructures.

Prenatal exposure to phthalate and decreased body mass index of children: a systematic review and meta-analysis.

Phthalates are well-known endocrine-disrupting chemicals. Many detrimental health effects of phthalates were investigated, but studies on the association of phthalates with obesity in children showed inconsistent results. Thus, this systematic review and meta-analysis were performed to clarify whether prenatal and postnatal exposures to phthalates are associated with physical growth disturbances in children. We performed the systematic review and meta-analysis following the PRISMA 2020 statement guidelines, and found 39 studies that met our inclusion criteria, including 22 longitudinal and 17 cross-sectional studies. We observed a significant negative association between the prenatal exposure to DEHP and the body mass index (BMI) z-score of the offspring (ß = - 0.05; 95% CI: - 0.10, - 0.001) in the meta-analysis, while no significant association between the prenatal exposure to DEHP and the body fat percentage of the offspring was observed (ß = 0.01; 95% CI: - 0.41, 0.44). In the systematic review, studies on the association between phthalates exposure in childhood and obesity were inconsistent. Prenatal exposure to phthalates was found to be associated with decreased BMI z-score in children, but not associated with body fat percentage. Our findings suggest that phthalates disturb the normal muscle growth of children, rather than induce obesity, as previous studies have hypothesized.

Programmable Self-Regulation with Wrinkled Hydrogels and Plasmonic Nanoparticle Lattices.

This paper describes a self-regulating system that combines wrinkle-patterned hydrogels with plasmonic nanoparticle (NP) lattices. In the feedback loop, the wrinkle patterns flatten in response to moisture, which then allows light to reach the NP lattice on the bottom layer. Upon light absorption, the NP lattice produces a photothermal effect that dries the hydrogel, and the system then returns to the initial wrinkled configuration. The timescale of this regulatory cycle can be programmed by tuning the degree of photothermal heating by NP size and substrate material. Time-dependent finite element analysis reveals the thermal and mechanical mechanisms of wrinkle formation. This self-regulating system couples morphological, optical, and thermo-mechanical properties of different materials components and offers promising design principles for future smart systems.

Children's Greenness Exposure and IQ-Associated DNA Methylation: A Prospective Cohort Study.

Epigenetics is known to be involved in regulatory pathways through which greenness exposure influences child development and health. We aimed to investigate the associations between residential surrounding greenness and DNA methylation changes in children, and further assessed the association between DNA methylation and children's intelligence quotient (IQ) in a prospective cohort study. We identified cytosine-guanine dinucleotide sites (CpGs) associated with cognitive abilities from epigenome- and genome-wide association studies through a systematic literature review for candidate gene analysis. We estimated the residential surrounding greenness at age 2 using a geographic information system. DNA methylation was analyzed from whole blood using the HumanMethylationEPIC array in 59 children at age 2. We analyzed the association between greenness exposure and DNA methylation at age 2 at the selected CpGs using multivariable linear regression. We further investigated the relationship between DNA methylation and children's IQ. We identified 8743 CpGs associated with cognitive ability based on the literature review. Among these CpGs, we found that 25 CpGs were significantly associated with greenness exposure at age 2, including cg26269038 (Bonferroni-corrected p ≤ 0.05) located in the body of SLC6A3, which encodes a dopamine transporter. DNA methylation at cg26269038 at age 2 was significantly associated with children's performance IQ at age 6. Exposure to surrounding greenness was associated with cognitive ability-related DNA methylation changes, which was also associated with children's IQ. Further studies are warranted to clarify the epigenetic pathways linking greenness exposure and neurocognitive function.

The study on the first women doctors in Korea, AHN Soo-kyung, KIM Young-heung, and KIM Hae-ji.

This study examined three women, AHN Soo-kyung, KIM Youngheung and KIM Hae-ji, who were officially licensed as doctors for the first time in Joseon. I wanted to find a new "starting point" of women's medicine history by scrutinizing their home environment, medical classes, graduation and medical license, and life after becoming doctors. The parents of KIM Young-heung and KIM Hae-ji might have been enlightened and Christians. AHN Soo-kyung did not have a Christian family. Her father, AHN Wang-geo, who was both an educator and a poet, was aware of the need for women's education or modern education. Female medical missionaries such as Rosetta S. Hall and Mary Cutler also worked hard to get them admitted to the medical class. They went to school with a female guardian and a brother and adapted to school life safely. After graduating from Kyongsung Medical College they obtained doctors' licenses and continued their medical activities at the hospital. KIM Young-heung actively engaged in social activities as a female intellectual by giving public lectures. She worked as a doctor in Kyongsung, Pyongyang, and Incheon. KIM Hae-ji did medical work and got married in Pyongyang. However, she had a hard time due to her husband's death and a medical accident. In the end, she seems to have left the medical field by returning her medical license. AHN Soo-kyung had been working at Dongdaemun (East Gate) Women's Hospital for more than 20 years and was willing to participate in what she could do as a woman, doctor and intellectual. Therefore, she established a free maternity clinic in the hospital. She defended Joseon's students and hospitals in protest of the controversy of nursing school and the move to abolish Dongdaemun Women's Hospital. She quietly participated in the Dong-Ah Women's Association and 6.10 the Independence Movement by doing anything she could do to help. She had a shy personality, but she faithfully fulfilled her duty as a doctor with a strong professional sense that saving people was her calling.

To Believe or Not to Believe: Framing Analysis of Content and Audience Response of Top 10 Deepfake Videos on YouTube.

This study explores popular deepfake media content and audience response in an effort to gain better understanding of the potential social and psychological impacts of deepfakes. A content analysis of the top 10 YouTube deepfake videos and their audience comments (n = 2,689) was conducted to investigate the degree to which media meta-frame influenced audience response. The results suggested that media meta-frame, the type of video (deepfake videos with commentaries or original deepfake videos), and the number of dislikes on the video had considerable influence on audience response (attitudes and perceived realism), while the majority of the audience expressed neutral or irrelevant attitudes. Our exploratory observation revealed a dynamic interplay of how deepfake was presented and how others react to it might influence the public. Thus, it is necessary to appropriately caution the public about their vulnerability to the ever-advancing deepfake technologies.

Clinical and Genetic Characteristics of 23 Korean Patients with Haploinsufficiency of the Short-stature Homeobox-containing Gene.

BACKGROUND: The short-stature homeobox-containing gene (SHOX) is one of the major growth genes in humans. The clinical spectrum of SHOX haploinsufficiency ranges from Léri-Weill dyschondrosteosis to idiopathic short stature. Herein, we describe the clinical and genetic characteristics of 23 Korean patients with SHOX deficiency disorders. METHODS: Medical records of 23 patients (19 females and 4 males) from 15 unrelated families who were genetically confirmed to have SHOX deficiency were retrospectively reviewed. SHOX gene deletions or mutations were determined by sequence analyses using multiplex ligation-dependent probe amplification, chromosomal microarray, and/or Sanger sequencing methods. RESULTS: In the 15 families, 9 probands were de novo cases. All 23 patients showed mesomelia. Madelung deformity and tibia vara were observed in 13 (56.5%) and 3 (13.1%) patients, respectively. Genetically, 11 (73.3%) of the 15 families showed SHOX deletions of various sizes, and the other 4 families harboured SHOX sequence variants. Four patients had undergone orthopaedic surgeries (3 for tibia vara and 1 for Madelung deformity). Among 7 patients who had received growth hormone treatment for ≥1 year, 5 showed good responses, with a median first-year change-in-height standard deviation score of +0.6. There were no significant differences in the clinical characteristics of the deletion and point mutation groups. CONCLUSIONS: A high index of suspicion and the genetic confirmation of SHOX deficiency are helpful for the timely management of the condition and are needed to provide genetic counselling to the family members of the patients.

Heparin-Coated Albumin Nanoparticles for Drug Combination in Targeting Inflamed Intestine.

Targeting areas of inflammation offers potential therapeutic and diagnostic benefits by maximizing drug and imaging marker on-target effects while minimizing systemic exposure that can be associated with adverse side effects. This strategy is particularly beneficial in the management of inflammatory bowel disease (IBD). Here an inflammation-targeting (IT) approach based on heparin-coated human serum albumin nanoparticles (HEP-HSA NPs) that utilize the increased intestinal permeability and changes in electrostatic interaction at the site of intestinal inflammation is described. Using small-molecule and biologic drugs as a model for drug combination, the HEP-HSA NPs demonstrate the capacity to load both drugs simultaneously; the dual-drug loaded HEP-HSA NPs exhibit a higher anti-inflammatory effect than both of the single-drug loaded NPs in vitro and selectively bind to inflamed intestine after enema administration in vivo in a murine model of colitis. Importantly, analyses of the physicochemical characteristics and targeting capacities of these NPs indicate that HEP coating modulates NP binding to the inflamed intestine, providing a foundation for future IT-NP formulation development.

Robotically handled whole-tissue culture system for the screening of oral drug formulations.

Monolayers of cancer-derived cell lines are widely used in the modelling of the gastrointestinal (GI) absorption of drugs and in oral drug development. However, they do not generally predict drug absorption in vivo. Here, we report a robotically handled system that uses large porcine GI tissue explants that are functionally maintained for an extended period in culture for the high-throughput interrogation (several thousand samples per day) of whole segments of the GI tract. The automated culture system provided higher predictability of drug absorption in the human GI tract than a Caco-2 Transwell system (Spearman's correlation coefficients of 0.906 and 0.302, respectively). By using the culture system to analyse the intestinal absorption of 2,930 formulations of the peptide drug oxytocin, we discovered an absorption enhancer that resulted in a 11.3-fold increase in the oral bioavailability of oxytocin in pigs in the absence of cellular disruption of the intestinal tissue. The robotically handled whole-tissue culture system should help advance the development of oral drug formulations and might also be useful for drug screening applications.

Strain-Dependent Nanowrinkle Confinement of Block Copolymers.

This paper describes an all-soft, templated assembly of block copolymers (BCPs) with programmable alignment. Using polymeric nanowrinkles as a confining scaffold, poly(styrene)-block-poly(dimethylsiloxane) (PS-b-PDMS) BCPs were assembled to be parallel or perpendicular to the wrinkle orientation by manipulating the substrate strain. Self-consistent field theory modeling revealed that wrinkle curvature and surface affinity govern the BCP structural formation. Furthermore, control of BCP alignment was demonstrated for complex wrinkle geometries, various copolymer molecular weights, and functional wrinkle skin layers. This integration of BCP patterning with flexible 3D architectures offers a promising nanolithography approach for next-generation soft electronics.

Prenatal exposure to di-(2-ethylhexyl) phthalate and decreased skeletal muscle mass in 6-year-old children: A prospective birth cohort study.

BACKGROUND/AIM: Phthalate is a well-known endocrine-disrupting chemical that has anti-androgenic effects. Although there are several studies on the relationship between body composition and phthalate, studies that investigated the effects of phthalate on skeletal muscle during childhood are lacking. METHODS: We analyzed data from 481 mother-and-child pairs enrolled in the Environment and Development of Children cohort in South Korea. We examined the association between phthalate metabolites (mono [2-ethyl-5-hydroxyhexyl] phthalate [MEHHP], mono [2-ethyl-5-oxohexyl] phthalate [MEOHP], molar sum of MEHHP and MEOHP [Σ DEHP], and mono-n-butyl phthalate [MnBP]) in prenatal maternal urine and children's urine at the age of 6, and body composition indices (body mass index [BMI] z-score, percentage of fat mass, fat mass index, percentage of skeletal muscle, and the skeletal muscle index [SMI]) measured when the child was 6 years using a bioelectrical impedance analyzer. RESULTS: A 2-fold increase in Σ DEHP and MnBP in the prenatal maternal urine was significantly associated with a -0.07 unit (95% CI: -0.11, -0.03) and -0.09 unit (95% CI: -0.14, -0.03) change in SMI, respectively, in 6-year old girls alone. BMI z-score was also negatively associated with a 2-fold increase in MEHHP and MnBP in prenatal maternal urine as -0.11 unit (95% CI: -0.22, -0.01) and -0.15 unit (95% CI: -0.28, -0.02) change, respectively, only among girls. Among boys, phthalate metabolites in the prenatal and children's urine were not significantly associated with any body composition indices. CONCLUSIONS: Our longitudinal study shows that high levels of prenatal exposure to phthalates are significantly associated with decreased SMI among girls. We can postulate that anti-androgenic effects of phthalates during pregnancy may affect girl offspring's muscle growth.

Scalable Gastric Resident Systems for Veterinary Application.

Gastric resident dosage forms have been used successfully in farm animals for the delivery of a variety of drugs helping address the challenge of extended dosing. Despite these advances, there remains a significant challenge across the range of species with large variation in body size. To address this, we investigate a scalable gastric resident platform capable of prolonged retention. We investigate prototypes in dimensions consistent with administration and retention in the stomachs of two species (rabbit and pig). We investigate sustained gastric retention of our scalable dosage form platform, and in pigs show the capacity to modulate drug release kinetics of a model drug in veterinary practice, meloxicam, with our dosage form. The ability to achieve gastric residence and thereby enable sustained drug levels across different species may have a significant impact in the welfare of animals in both research, agricultural, zoological, and clinical practice settings.

Monolithic Polymer Nanoridges with Programmable Wetting Transitions.

This paper describes polymeric nanostructures with dynamically tunable wetting properties. Centimeter-scale areas of monolithic nanoridges can be generated by strain relief of thermoplastic polyolefin films with fluoropolymer skin layers. Changing the amount of strain results in polyolefin ridges with aspect ratios greater than four with controlled feature densities. Surface chemistry and topography are demonstrated to be able to be tailored by SF6 -plasma etching to access multiple wetting states: Wenzel, Cassie-Baxter, and Cassie-impregnating states. Reversible transitions among the wetting states can be realized in a programmable manner by cyclic stretching and reshrinking the patterned substrates without delamination and cracking.

Caffeine-catalyzed gels.

Covalently cross-linked gels are utilized in a broad range of biomedical applications though their synthesis often compromises easy implementation. Cross-linking reactions commonly utilize catalysts or conditions that can damage biologics and sensitive compounds, producing materials that require extensive post processing to achieve acceptable biocompatibility. As an alternative, we report a batch synthesis platform to produce covalently cross-linked materials appropriate for direct biomedical application enabled by green chemistry and commonly available food grade ingredients. Using caffeine, a mild base, to catalyze anhydrous carboxylate ring-opening of diglycidyl-ether functionalized monomers with citric acid as a tri-functional crosslinking agent we introduce a novel poly(ester-ether) gel synthesis platform. We demonstrate that biocompatible Caffeine Catalyzed Gels (CCGs) exhibit dynamic physical, chemical, and mechanical properties, which can be tailored in shape, surface texture, solvent response, cargo release, shear and tensile strength, among other potential attributes. The demonstrated versatility, low cost and facile synthesis of these CCGs renders them appropriate for a broad range of customized engineering applications including drug delivery constructs, tissue engineering scaffolds, and medical devices.

Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy.

The efficacy of antiretroviral therapy is significantly compromised by medication non-adherence. Long-acting enteral systems that can ease the burden of daily adherence have not yet been developed. Here we describe an oral dosage form composed of distinct drug-polymer matrices which achieved week-long systemic drug levels of the antiretrovirals dolutegravir, rilpivirine and cabotegravir in a pig. Simulations of viral dynamics and patient adherence patterns indicate that such systems would significantly reduce therapeutic failures and epidemiological modelling suggests that using such an intervention prophylactically could avert hundreds of thousands of new HIV cases. In sum, weekly administration of long-acting antiretrovirals via a novel oral dosage form is a promising intervention to help control the HIV epidemic worldwide.

Defining optimal permeant characteristics for ultrasound-mediated gastrointestinal delivery.

Ultrasound-mediated drug delivery in the gastrointestinal (GI) tract is a bourgeoning area of study. Localized, low-frequency ultrasound has recently been shown to enable significant enhancement in delivery of a broad set of active pharmaceutical ingredients including small molecules, proteins, and nucleic acids without any formulation or encapsulation of the therapeutic. Traditional chemical formulations are typically required to protect, stabilize, and enable the successful delivery of a given therapeutic. The use of ultrasound, however, may make delivery insensitive to the chemical formulation. This might open the door to chemical formulations being developed to address other properties besides the deliverability of a therapeutic. Instead, chemical formulations could potentially be developed to achieve novel pharmacokinetics, without consideration of that particular formulation's ability to penetrate the mucus barrier passively. Here we investigated the effect of permeant size, charge, and the presence of chemical penetration enhancers on delivery to GI tissue using ultrasound. Short ultrasound treatments enabled delivery of large permeants, including microparticles, deep into colonic tissue ex vivo. Delivery was relatively independent of size and charge but did depend on conformation, with regular, spherical particles being delivered to a greater extent than long-chain polymers. The subsequent residence time of model permeants in tissue after ultrasound-mediated delivery was found to depend on size, with large microparticles demonstrating negligible clearance from the local tissue 24h after delivery ex vivo. The dependence of clearance time on permeant size was further confirmed in vivo in mice using fluorescently labeled 3kDa and 70kDa dextran. The use of low-frequency ultrasound in the GI tract represents a novel tool for the delivery of a wide-range of therapeutics independent of formulation, potentially allowing for the tailoring of formulations to impart novel pharmacokinetic profiles once delivered into tissue.

Triggerable tough hydrogels for gastric resident dosage forms.

Systems capable of residing for prolonged periods of time in the gastric cavity have transformed our ability to diagnose and treat patients. Gastric resident systems for drug delivery, ideally need to be: ingestible, be able to change shape or swell to ensure prolonged gastric residence, have the mechanical integrity to withstand the forces associated with gastrointestinal motility, be triggerable to address any side effects, and be drug loadable and release drug over a prolonged period of time. Materials that have been primarily utilized for these applications have been largely restricted to thermoplastics and thermosets. Here we describe a novel set of materials, triggerable tough hydrogels, meeting all these requirement, supported by evaluation in a large animal model and ultimately demonstrate the potential of triggerable tough hydrogels to serve as prolonged gastric resident drug depots. Triggerable tough hydrogels may be applied in myriad of applications, including bariatric interventions, drug delivery, and tissue engineering.The use of drug delivery systems for the gastrointestinal tract has been faced with a number of drawbacks related to their prolonged use. Here, the authors develop a drug-loaded hydrogel with high strength to withstand long-term gastrointestinal motility and can be triggered to dissolve on demand.

Oral, ultra-long-lasting drug delivery: Application toward malaria elimination goals.

Efforts at elimination of scourges, such as malaria, are limited by the logistic challenges of reaching large rural populations and ensuring patient adherence to adequate pharmacologic treatment. We have developed an oral, ultra-long-acting capsule that dissolves in the stomach and deploys a star-shaped dosage form that releases drug while assuming a geometry that prevents passage through the pylorus yet allows passage of food, enabling prolonged gastric residence. This gastric-resident, drug delivery dosage form releases small-molecule drugs for days to weeks and potentially longer. Upon dissolution of the macrostructure, the components can safely pass through the gastrointestinal tract. Clinical, radiographic, and endoscopic evaluation of a swine large-animal model that received these dosage forms showed no evidence of gastrointestinal obstruction or mucosal injury. We generated long-acting formulations for controlled release of ivermectin, a drug that targets malaria-transmitting mosquitoes, in the gastric environment and incorporated these into our dosage form, which then delivered a sustained therapeutic dose of ivermectin for up to 14 days in our swine model. Further, by using mathematical models of malaria transmission that incorporate the lethal effect of ivermectin against malaria-transmitting mosquitoes, we demonstrated that this system will boost the efficacy of mass drug administration toward malaria elimination goals. Encapsulated, gastric-resident dosage forms for ultra-long-acting drug delivery have the potential to revolutionize treatment options for malaria and other diseases that affect large populations around the globe for which treatment adherence is essential for efficacy.

A Janus Mucoadhesive and Omniphobic Device for Gastrointestinal Retention.

A novel Janus device with omniphobic and mucoadhesive sides that exhibit the unique capacity for antifouling and extended gastrointestinal retention is fabricated. This system enables repulsion of the food and fluid stream by the luminal-facing omniphobic side and allows attachment to the gastrointestinal mucosa by the mucoadhesive side.

Protective effect of pterostilbene on testicular ischemia/reperfusion injury in rats.

PURPOSE: To evaluate protective effect of pterostilbene against testicular ischemia/reperfusion (I/R) injury, which results in increased formation of oxidative stress, leading to testicular apoptosis and impaired spermatogenesis. METHODS: Thirty two pubertal male Sprague-Dawley rats weighing 180-220g were selected and randomly divided into the following four groups: group A (normal control group), group B (sham-operated group), group C (induced I/R injury group), group D (induced I/R injury group receiving pterostilbene treatment). Johnsen's scores and mean seminiferous tubule diameters were evaluated for histopathologic assessment; germinal cell apoptosis was evaluated by the transferase dUTP nick end labeling (TUNEL) assay and immunohistochemistry for caspases. Malondialdehyde (MDA) levels were assessed as an indicator of oxidative stress and total antioxidant capacity (TAC) was measured. RESULTS: Germ cell apoptosis and MDA level significantly increased whereas TAC significantly decreased in group C; moreover, abnormal morphology and impaired spermatogenesis were observed in group C. In contrast, treatment with pterostilbene inhibited lipid peroxidation and apoptosis induced by ROS and restored the antioxidant capacity in group D. CONCLUSIONS: These results show that treatment with pterostilbene may be a promising therapy for testicular I/R injury.