Interfacial Science for Electrosynthesis.

Interfacial science and electroorganic syntheses are inextricably linked because all electrochemical reactions occur at the interface between the electrode and the solution. Thus, the surface chemistry of the electrode material impacts the organic reaction selectivity. In this short review, we highlight emergent examples of electrode surface chemistries that enable selective electroorganic synthesis in three reaction classes: (1) hydrogenation, (2) oxidation, and (3) reductive C‒C bond formation between two electrophiles. We showcase the breadth of techniques, including materials and in-situ characterization, requisite to establish mechanistic schemes consistent with the observed reactivity patterns. Leveraging an electrode's unique surface chemistry will provide complementary approaches to tune the selectivity of electroorganic syntheses and unlock an electrode's catalytic properties.

Gray-Scale Extraction of Bone Features from Chest Radiographs Based on Deep Learning Technique for Personal Identification and Classification in Forensic Medicine.

Post-mortem (PM) imaging has potential for identifying individuals by comparing ante-mortem (AM) and PM images. Radiographic images of bones contain significant information for personal identification. However, PM images are affected by soft tissue decomposition; therefore, it is desirable to extract only images of bones that change little over time. This study evaluated the effectiveness of U-Net for bone image extraction from two-dimensional (2D) X-ray images. Two types of pseudo 2D X-ray images were created from the PM computed tomography (CT) volumetric data using ray-summation processing for training U-Net. One was a projection of all body tissues, and the other was a projection of only bones. The performance of the U-Net for bone extraction was evaluated using Intersection over Union, Dice coefficient, and the area under the receiver operating characteristic curve. Additionally, AM chest radiographs were used to evaluate its performance with real 2D images. Our results indicated that bones could be extracted visually and accurately from both AM and PM images using U-Net. The extracted bone images could provide useful information for personal identification in forensic pathology.

Dopamine-modified hyaluronic acid (DA-HA) as a novel dopamine-mimetics with minimal autoxidation and cytotoxicity.

Dopamine-modified hyaluronic acid (DA-HA) has been initially developed as an efficient coating and adhesion material for industrial uses. However, the biological activity and safety of DA-HA in the brain have not been explored yet. Here, we report a series of evidence that DA-HA exhibits similar functionality as dopamine (DA), but with much lower toxicity arising from autoxidation. DA-HA shows very little autoxidation even after 48-h incubation. This is profoundly different from DA and its derivatives including l-DOPA, which all induce severe neuronal death after pre-autoxidation, indicating that autoxidation is the cause of neuronal death. Furthermore, in vivo injection of DA-HA induces significantly lower toxicity compared to 6-OHDA, a well-known oxidized and toxic form of DA, and alleviates the apomorphine-induced rotational behavior in the 6-OHDA animal model of Parkinson's disease. Our study proposes that DA-HA with DA-like functionalities and minimal toxicity has a great potential to treat DA-related disease.

A Pressure-Sensitive, Repositionable Bioadhesive for Instant, Atraumatic Surgical Application on Internal Organs.

Pressure-sensitive adhesives are widely utilized due to their instant and reversible adhesion to various dry substrates. Though offering intuitive and robust attachment of medical devices on skin, currently available clinical pressure-sensitive adhesives do not attach to internal organs, mainly due to the presence of interfacial water on the tissue surface that acts as a barrier to adhesion. In this work, a pressure-sensitive, repositionable bioadhesive (PSB) that adheres to internal organs by synergistically combining the characteristic viscoelastic properties of pressure-sensitive adhesives and the interfacial behavior of hydrogel bioadhesives, is introduced. Composed of a viscoelastic copolymer, the PSB absorbs interfacial water to enable instant adhesion on wet internal organs, such as the heart and lungs, and removal after use without causing any tissue damage. The PSB's capabilities in diverse on-demand surgical and analytical scenarios including tissue stabilization of soft organs and the integration of bioelectronic devices in rat and porcine models, are demonstrated.

Exosomes from Human iPSC-Derived Retinal Organoids Enhance Corneal Epithelial Wound Healing.

This study investigated the therapeutic effects of exosomes derived from human-induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs) on corneal epithelial wound healing. Exosomes were isolated from the culture medium of the hiPSC-derived ROs (Exo-ROs) using ultracentrifugation, and then they were characterized by a nanoparticle tracking analysis and transmission electron microscopy. In a murine model of corneal epithelial wounds, these exosomes were topically applied to evaluate their healing efficacy. The results demonstrated that the exosome-treated eyes showed significantly enhanced wound closures compared with the controls at 24 h post-injury. The 5-ethyl-2'-deoxyuridine assay and quantitative reverse transcription polymerase chain reaction revealed a substantial increase in cell proliferation and a decrease in inflammatory marker contents in the exosome-treated group. The RNA sequencing and exosomal microRNA analysis revealed that the Exo-RO treatment targeted various pathways related to inflammation and cell proliferation, including the PI3K-Akt, TNF, MAPK, and IL-17 signaling pathways. Moreover, the upregulation of genes related to retinoic acid and eicosanoid metabolism may have enhanced corneal epithelial healing in the eyes treated with the Exo-ROs. These findings suggest that hiPSC-derived RO exosomes could be novel therapeutic agents for promoting corneal epithelial wound healing.

NLRP3 Negative Regulation Mechanisms in the Resting State and Its Implications for Therapeutic Development.

The NACHT-, leucine-rich-repeat-, and pyrin domain-containing protein 3 (NLRP3) is a critical intracellular sensor of the innate immune system that detects various pathogen- and danger-associated molecular patterns, leading to the assembly of the NLRP3 inflammasome and release of interleukin (IL) 1ß and IL-18. However, the abnormal activation of the NLRP3 inflammasome has been implicated in the pathogenesis of autoinflammatory diseases such as cryopyrin-associated autoinflammatory syndromes (CAPS) and common diseases such as Alzheimer's disease and asthma. Recent studies have revealed that pyrin functions as an indirect sensor, similar to the plant guard system, and is regulated by binding to inhibitory 14-3-3 proteins. Upon activation, pyrin transitions to its active form. NLRP3 is predicted to follow a similar regulatory mechanism and maintain its inactive form in the cage model, as it also acts as an indirect sensor. Additionally, newly developed NLRP3 inhibitors have been found to inhibit NLRP3 activity by stabilizing its inactive form. Most studies and reviews on NLRP3 have focused on the activation of the NLRP3 inflammasome. This review highlights the molecular mechanisms that regulate NLRP3 in its resting state, and discusses how targeting this inhibitory mechanism can lead to novel therapeutic strategies for NLRP3-related diseases.

Inulin-gel-based oral immunotherapy remodels the small intestinal microbiome and suppresses food allergy.

Despite the potential of oral immunotherapy against food allergy, adverse reactions and loss of desensitization hinder its clinical uptake. Dysbiosis of the gut microbiota is implicated in the increasing prevalence of food allergy, which will need to be regulated to enable for an effective oral immunotherapy against food allergy. Here we report an inulin gel formulated with an allergen that normalizes the dysregulated ileal microbiota and metabolites in allergic mice, establishes allergen-specific oral tolerance and achieves robust oral immunotherapy efficacy with sustained unresponsiveness in food allergy models. These positive outcomes are associated with enhanced allergen uptake by antigen-sampling dendritic cells in the small intestine, suppressed pathogenic type 2 immune responses, increased interferon-γ+ and interleukin-10+ regulatory T cell populations, and restored ileal abundances of Eggerthellaceae and Enterorhabdus in allergic mice. Overall, our findings underscore the therapeutic potential of the engineered allergen gel as a suitable microbiome-modulating platform for food allergy and other allergic diseases.

Transcriptional regulation of Tfh dynamics and the formation of immunological synapses.

Inside germinal centers (GCs), antigen-specific B cells rely on precise interactions with immune cells and strategic localization between the dark and light zones to clonally expand, undergo affinity maturation, and differentiate into long-lived plasma cells or memory B cells. Follicular helper T (Tfh) cells, the key gatekeepers of GC-dependent humoral immunity, exhibit remarkable dynamic positioning within secondary lymphoid tissues and rely on intercellular interactions with antigen-presenting cells (APCs) during their differentiation and execution of B-cell-facilitating functions within GCs. In this review, we briefly cover the transcriptional regulation of Tfh cell differentiation and function and explore the molecular mechanisms governing Tfh cell motility, their interactions with B cells within GCs, and the impact of their dynamic behavior on humoral responses.

Does prior rotator cuff surgery influence the outcomes and complications after reverse total shoulder arthroplasty in patients with cuff tear arthropathy or massive rotator cuff tear? A propensity score-matched study.

BACKGROUND: The aim of this study was to compare outcomes and complications in patients with and without a history of prior rotator cuff surgery who underwent reverse total shoulder arthroplasty (RTSA). METHODS: Two-hundred and nine consecutive patients who had undergone RTSA for rotator cuff insufficiency with a minimum 12-months follow-up period were reviewed. A total of 35 patients with a history of prior rotator cuff surgery were made the study group (PS group). Using propensity score matching for age and sex, these patients were matched 1:3 with a control group of 105 patients with no history of prior surgery (NPS group). The mean follow-up period was 41.4 months. RESULTS: Both groups showed a significant improvement of clinical scores and range of motion after RTSA. The PS group showed a significantly higher final visual analog scale (VAS) pain score compared with the NPS group (P = 0.020). The PS group showed a significantly higher incidence of acromial stress fracture compared with the NPS group (17.1% vs 4.8%, P = 0.018), but no significant difference in the overall complication rate was observed (25.7% vs 13.3%, P > 0.05). The PS group showed a significantly higher reoperation rate compared with the NPS group (14.3% vs 1.9%, P = 0.004). CONCLUSIONS: Our study demonstrated that a history of prior rotator cuff surgery was associated with a high incidence of acromial stress fracture and reoperation after RTSA as well as a high final VAS pain score, although satisfactory clinical outcomes after RTSA were achieved in both groups.

Cumulative effect of metabolic syndrome on the risk of retinal vein occlusion in young patients: A nationwide population-based study.

This study aimed to investigate the impact of the cumulative burden of metabolic syndrome (MetS) on the incidence of retinal vein occlusion (RVO) in young adults. We included 1,408,093 subjects aged ≥20 and <40 years without a history of RVO who underwent four consecutive annual health examinations during 2009-2012 from the database of the Korean National Health Insurance Service. The metabolic burden was evaluated based on the cumulative number of MetS diagnoses at each health examination (0-4 times) and the cumulative number of each MetS component diagnosed at each health examination (0-4 times per MetS component). Cox proportional hazards models were used to estimate the risk of RVO according to metabolic burden. The risk of RVO was positively correlated with the cumulative number of MetS diagnoses over the four health examinations. All five MetS components were independently associated with an increased risk of RVO. Subgroup analysis for the impact of MetS on RVO occurrence revealed that MetS had a greater impact on female subjects (P <0.001). Prompt detection of metabolic derangements and their treatment might be important to decrease the risk of RVO in young adults, especially women.

Multifunctional and Flexible Neural Probe with Thermally Drawn Fibers for Bidirectional Synaptic Probing in the Brain.

Synapses in the brain utilize two distinct communication mechanisms: chemical and electrical. For a comprehensive investigation of neural circuitry, neural interfaces should be capable of both monitoring and stimulating these types of physiological interactions. However, previously developed interfaces for neurotransmitter monitoring have been limited in interaction modality due to constraints in device size, fabrication techniques, and the usage of flexible materials. To address this obstacle, we propose a multifunctional and flexible fiber probe fabricated through the microwire codrawing thermal drawing process, which enables the high-density integration of functional components with various materials such as polymers, metals, and carbon fibers. The fiber enables real-time monitoring of transient dopamine release in vivo, real-time stimulation of cell-specific neuronal populations via optogenetic stimulation, single-unit electrophysiology of individual neurons localized to the tip of the neural probe, and chemical stimulation via drug delivery. This fiber will improve the accessibility and functionality of bidirectional interrogation of neurochemical mechanisms in implantable neural probes.

Synthetic ShK-like Peptide from the Jellyfish Nemopilema nomurai Has Human Voltage-Gated Potassium-Channel-Blocking Activity.

We identified a new human voltage-gated potassium channel blocker, NnK-1, in the jellyfish Nemopilema nomurai based on its genomic information. The gene sequence encoding NnK-1 contains 5408 base pairs, with five introns and six exons. The coding sequence of the NnK-1 precursor is 894 nucleotides long and encodes 297 amino acids containing five presumptive ShK-like peptides. An electrophysiological assay demonstrated that the fifth peptide, NnK-1, which was chemically synthesized, is an effective blocker of hKv1.3, hKv1.4, and hKv1.5. Multiple-sequence alignment with cnidarian Shk-like peptides, which have Kv1.3-blocking activity, revealed that three residues (3Asp, 25Lys, and 34Thr) of NnK-1, together with six cysteine residues, were conserved. Therefore, we hypothesized that these three residues are crucial for the binding of the toxin to voltage-gated potassium channels. This notion was confirmed by an electrophysiological assay with a synthetic peptide (NnK-1 mu) where these three peptides were substituted with 3Glu, 25Arg, and 34Met. In conclusion, we successfully identified and characterized a new voltage-gated potassium channel blocker in jellyfish that interacts with three different voltage-gated potassium channels. A peptide that interacts with multiple voltage-gated potassium channels has many therapeutic applications in various physiological and pathophysiological contexts.

Downregulation of otulin induces inflammasome activation in neutrophilic asthma.

BACKGROUND: Neutrophilic asthma (NA) is a severe asthma phenotype associated with steroid resistance and IL-1ß overproduction; however, the exact mechanism remains unclear. Moreover, the dysfunction of TNF-α signaling pathway, a regulator of IL-1ß production, was associated with the deficiency of ovarian tumor protease deubiquitinase with linear linkage specificity (otulin) in autoimmune patients. OBJECTIVE: We hypothesized that otulin downregulation in macrophages (Mφ) could trigger Mφ activation via the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome signaling pathway. METHODS: We assessed the expressions of otulin in blood monocyte subsets from NA patients and in alveolar Mφ from NA mice. Additionally, we evaluated the functional consequences of otulin deficiency in bone marrow-derived Mφ. The effects of inhibiting receptor-interacting protein kinase (RIPK)-1 and RIPK-3 on neutrophils and group 3 innate lymphoid cells (ILC3s) were assessed in vitro and in vivo. RESULTS: When comparing nonclassical monocytes, a significant downregulation of otulin in the intracellular components was observed in NA patients compared to healthy controls (P = .005). Moreover, isolated alveolar Mφ from the NA mice exhibited lower otulin expression compared to those from control mice. After otulin knockdown in bone marrow-derived Mφ, we observed spontaneous IL-1ß production depending on NLRP3 inflammasome. Moreover, the infiltrated neutrophils and ILC3s were significantly decreased by combined treatment of RIPK-1 and RIPK-3 inhibitors through blocking IL-1ß release in NA. CONCLUSIONS: IL-1ß overproduction caused by a deficiency of otulin, an upstream triggering factor, could be a promising diagnostic and therapeutic target for NA.

Anti-inflammatory effect of Trichospira verticillata via suppression of the NLRP3 inflammasome in neutrophilic asthma.

Trichospira verticillata is an annual herb that belongs to the family Asteraceae. Trichospira verticillata extract (TVE) elicits anti-plasmodial activity; however, there has been no detailed report about its anti-inflammatory effects and molecular mechanisms. In addition, herbal plants exhibit anti-inflammatory effects by suppressing the NLRP3 inflammasome. Therefore, the primary goal of this study was to examine the effects of TVE on NLRP3 inflammasome activation by measuring interleukin-1ß (IL-1ß) secretion. We treated lipopolysaccharides (LPS)-primed J774A.1 and THP-1 cells with TVE, which attenuated NLRP3 inflammasome activation. Notably, TVE did not affect nuclear factor-kappa B (NF-κB) signalling or intracellular reactive oxygen species (ROS) production and potassium efflux, suggesting that it inactivates the NLRP3 inflammasome via other mechanisms. Moreover, TVE suppressed the formation of apoptosis-associated speck-like protein (ASC) speck and oligomerization. Immunoprecipitation data revealed that TVE reduced the binding of NLRP3 to NIMA-related kinase 7 (NEK7), resulting in reduced ASC oligomerization and speck formation. Moreover, TVE alleviated neutrophilic asthma (NA) symptoms in mice. This study demonstrates that TVE modulates the binding of NLPR3 to NEK7, thereby reporting novel insights into the mechanism by which TVE inhibits NLRP3 inflammasome. These findings suggest TVE as a potential therapeutic of NLRP3 inflammasome-mediated diseases, particularly NA.

Oral pathobiont Klebsiella chaperon usher pili provide site-specific adaptation for the inflamed gut mucosa.

The ectopic gut colonization by orally derived pathobionts has been implicated in the pathogenesis of various gastrointestinal diseases, including inflammatory bowel disease (IBD). For example, gut colonization by orally derived Klebsiella spp. has been linked to IBD in mice and humans. However, the mechanisms whereby oral pathobionts colonize extra-oral niches, such as the gut mucosa, remain largely unknown. Here, we performed a high-density transposon (Tn) screening to identify genes required for the adaptation of an oral Klebsiella strain to different mucosal sites - the oral and gut mucosae - at the steady state and during inflammation. We find that K. aerogenes, an oral pathobiont associated with both oral and gut inflammation in mice, harbors a newly identified genomic locus named "locus of colonization in the inflamed gut (LIG)" that encodes genes related to iron acquisition (Sit and Chu) and host adhesion (chaperon usher pili [CUP] system). The LIG locus is highly conserved among K. aerogenes strains, and these genes are also present in several other Klebsiella species. The Tn screening revealed that the LIG locus is required for the adaptation of K. aerogenes in its ectopic niche. In particular, we determined K. aerogenes employs a CUP system (CUP1) present in the LIG locus for colonization in the inflamed gut, but not in the oral mucosa. Thus, oral pathobionts likely exploit distinct adaptation mechanisms in their ectopically colonized intestinal niche compared to their native niche.

Structurally Aligned Multifunctional Neural Probe (SAMP) Using Forest-Drawn CNT Sheet onto Thermally Drawn Polymer Fiber for Long-Term In Vivo Operation.

Neural probe engineering is a dynamic field, driving innovation in neuroscience and addressing scientific and medical demands. Recent advancements involve integrating nanomaterials to improve performance, aiming for sustained in vivo functionality. However, challenges persist due to size, stiffness, complexity, and manufacturing intricacies. To address these issues, a neural interface utilizing freestanding CNT-sheets drawn from CNT-forests integrated onto thermally drawn functional polymer fibers is proposed. This approach yields a device with structural alignment, resulting in exceptional electrical, mechanical, and electrochemical properties while retaining biocompatibility for prolonged periods of implantation. This Structurally Aligned Multifunctional neural Probe (SAMP) employing forest-drawn CNT sheets demonstrates in vivo capabilities in neural recording, neurotransmitter detection, and brain/spinal cord circuit manipulation via optogenetics, maintaining functionality for over a year post-implantation. The straightforward fabrication method's versatility, coupled with the device's functional reliability, underscores the significance of this technique in the next-generation carbon-based implants. Moreover, the device's longevity and multifunctionality position it as a promising platform for long-term neuroscience research.

Prevalence and Risk Factors of Age-Related Macular Degeneration in South Korea: Korea National Health and Nutrition Examination Survey.

PURPOSE: To evaluate the prevalence and risk factors of age-related macular degeneration (AMD) in the Korean population. METHODS: In this cross-sectional study based on the Korea National Health and Nutrition Examination Survey (2017-2020) data 13,737 participants aged ≥ 40 years with assessable fundus images were included. The prevalence and risk factors of AMD were evaluated. The prevalence of early AMD, geographic atrophy (GA), and neovascular AMD were also assessed. Logistic regression analyses were used to identify risk factors. RESULTS: The prevalence (95% confidence interval [CI]) of AMD was 13.94% (13.15-14.72). The prevalence (95% CI) of early AMD, GA, and neovascular AMD was 13.07% (12.29-13.85), 0.26% (0.17-0.35), and 0.61% (0.47-0.75), respectively. The prevalence increased with age; it was 3.61%, 11.33%, 20.31%, 31.37%, and 33.98% in participants in their 40s, 50s, 60s, 70s, and ≥ 80 years, respectively. In multivariate analysis, AMD was positively associated with older age (p < 0.001; odds ratio [OR], 1.08; 95% CI, 1.07-1.09), male sex (p = 0.014; OR, 1.27; 95% CI, 1.05-1.53), and lower degree of education (p < 0.001; OR, 1.36 (for junior high school graduates); 95% CI, 1.12-1.65). CONCLUSIONS: AMD was detected in approximately one-third of individuals aged ≥ 70 years, thus indicating that AMD is a common disease among older Koreans. Regular fundus examinations in populations with risk factors for AMD as well as education on methods to prevent or delay AMD progression, such as the Mediterranean diet, are necessary.

Aiouea padiformis extract exhibits anti-inflammatory effects by inhibiting the ATPase activity of NLRP3.

Inflammation is implicated as a cause in many diseases. Most of the anti-inflammatory agents in use are synthetic and there is an unmet need for natural substance-derived anti-inflammatory agents with minimal side effects. Aiouea padiformis belongs to the Lauraceae family and is primarily found in tropical regions. While some members of the Aiouea genus are known to possess anti-inflammatory properties, the anti-inflammatory properties of Aiouea padiformis extract (AP) have not been investigated. In this study, we aimed to examine the anti-inflammatory function of AP through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and elucidate the underlying mechanisms. Treatment with AP inhibited the secretion of interleukin-1 beta (IL-1ß) mediated by NLRP3 inflammasome in J774A.1 and THP-1 cells without affecting the viability. In addition, AP treatment did not influence NF-κB signaling, potassium efflux, or intracellular reactive oxygen species (ROS) production-all of which are associated with NLRP3 inflammasome activation. However, intriguingly, AP treatment significantly reduced the ATPase activity of NLRP3, leading to the inhibition of ASC oligomerization and speck formation. Consistent with cellular experiments, the anti-inflammatory property of AP in vivo was also evaluated using an LPS-induced inflammation model in zebrafish, demonstrating that AP hinders NLRP3 inflammasome activation.

CRIF1 deficiency induces FOXP3LOW inflammatory non-suppressive regulatory T cells, thereby promoting antitumor immunity.

Recently identified human FOXP3lowCD45RA- inflammatory non-suppressive (INS) cells produce proinflammatory cytokines, exhibit reduced suppressiveness, and promote antitumor immunity unlike conventional regulatory T cells (Tregs). In spite of their implication in tumors, the mechanism for generation of FOXP3lowCD45RA- INS cells in vivo is unclear. We showed that the FOXP3lowCD45RA- cells in human tumors demonstrate attenuated expression of CRIF1, a vital mitochondrial regulator. Mice with CRIF1 deficiency in Tregs bore Foxp3lowINS-Tregs with mitochondrial dysfunction and metabolic reprograming. The enhanced glutaminolysis activated α-ketoglutarate-mTORC1 axis, which promoted proinflammatory cytokine expression by inducing EOMES and SATB1 expression. Moreover, chromatin openness of the regulatory regions of the Ifng and Il4 genes was increased, which facilitated EOMES/SATB1 binding. The increased α-ketoglutarate-derived 2-hydroxyglutarate down-regulated Foxp3 expression by methylating the Foxp3 gene regulatory regions. Furthermore, CRIF1 deficiency-induced Foxp3lowINS-Tregs suppressed tumor growth in an IFN-γ-dependent manner. Thus, CRIF1 deficiency-mediated mitochondrial dysfunction results in the induction of Foxp3lowINS-Tregs including FOXP3lowCD45RA- cells that promote antitumor immunity.