Gut Bacterial Metabolites from Tryptophan and Phenylalanine Induce Melatonin Synthesis and Extend Sleep Duration in Mice.

The human gut microbiota significantly influences various physiological systems, including immune, nervous, and metabolic systems. Recent studies suggest that gut microbiota may affect sleep quality with certain bacteria and metabolites being linked to sleep patterns. However, the underlying chemical signaling pathway remains unclear. In this study, we investigated the effect of four gut bacteria-derived metabolites, tryptamine (1), indolokine A5 (2), 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE, 3), and phenethylamine (PEA, 4), on sleep characteristics in mice and melatonin biosynthesis pathways in zebrafish. Their sleep-promoting effects were evaluated in a pentobarbital-induced sleep mouse model, revealing significant increases in sleep duration and blood melatonin levels, particularly with ITE (3) and PEA (4). Further tests in zebrafish embryos showed that ITE (3) and PEA (4) increased the expression of genes for melatonin biosynthesis (Aanat1, Aanat2, Tph1a, and Hiomt) in a concentration-dependent manner, indicating their potential as therapeutic agents for sleep disorders.

Advanced Technique of Unilateral Biportal Endoscopy on Revision Surgery for Recurred Herniated Interverbral Disc: A Technical Note.

Introduction: Revision surgery in the spine poses considerable challenges due to the presence of scar tissue and structural differences, necessitating careful surgical planning and precise techniques. In this technical note, we focus on lumbar unilateral biportal endoscopy (UBE) for single-level reoperations, outlining principles and methods for handling soft tissue in such cases. Materials and Methods: We reviewed our surgical approach for lumbar reoperations with UBE, emphasizing the importance of meticulous preoperative planning and bone-centered manipulation. Our technique involves utilizing biportal endoscopy for enhanced visualization and employing specific strategies for managing scar tissue, including the "pull-and-cut technique." We present two illustrative cases to demonstrate the application of our method. Results: The described approach yielded successful outcomes in both cases presented. Case 1 involved a posterior interlaminar approach for a recurrent disc at the L4-5 level, while Case 2 utilized a far lateral approach for recurrent disc herniation at the L4-5 level. Both surgeries were completed with relatively short operation time, minimal blood loss, and immediate improvement in symptoms postoperatively. Conclusion: Lumbar UBE offers a promising option for safe and effective reoperation in spinal surgery. Our technique, emphasizing bone-centered manipulation and specific strategies for scar tissue management, provides excellent visibility and enables precise tissue handling. Overall, UBE facilitates relatively simple and safe reoperations, contributing to improved patient outcomes in the challenging field of spinal surgery.

The Skin Histopathology of Pro- and Parabiotics in a Mouse Model of Atopic Dermatitis.

As it has been revealed that the activation of human immune cells through the activity of intestinal microorganisms such as pro- and prebiotics plays a vital role, controlling the proliferation of beneficial bacteria and suppressing harmful bacteria in the intestine has become essential. The importance of probiotics, especially for skin health and the immune system, has led to the emergence of products in various forms, including probiotics, prebiotics, and parabiotics. In particular, atopic dermatitis (AD) produces hypersensitive immunosuppressive substances by promoting the differentiation and activity of immune regulatory T cells. As a result, it has been in the Th1 and Th2 immune balance through a mechanism that suppresses skin inflammation or allergic immune responses caused by bacteria. Furthermore, an immune mechanism has recently emerged that simultaneously controls the expression of IL-17 produced by Th17. Therefore, the anti-atopic effect was investigated by administering doses of anti-atopic candidate substances (Lactobacilus sakei CVL-001, Lactobacilus casei MCL, and Lactobacilus sakei CVL-001 Lactobacilus casei MCL mixed at a ratio of 4:3) in an atopy model using 2,4-dinitrochlorobenzene and observing symptom changes for 2 weeks to confirm the effect of pro-, para-, and mixed biotics on AD. First, the body weight and feed intake of the experimental animals were investigated, and total IgG and IgM were confirmed through blood biochemical tests. Afterward, histopathological staining was performed using H&E staining, Toluidine blue staining, Filaggrin staining, and CD8 antibody staining. In the treatment group, the hyperproliferation of the epidermal layer, the inflammatory cell infiltration of the dermal layer, the expression of CD8, the expression of filaggrin, and the secretion of mast cells were confirmed to be significantly reduced. Lastly, small intestine villi were observed through a scanning microscope, and scoring evaluation was performed through skin damage. Through these results, it was confirmed that AD was reduced when treated with pro-, para-, and mixed biotics containing probiotics and parabiotics.

Strain-graded quantum dots with spectrally pure, stable and polarized emission.

Structural deformation modifies the bandgap, exciton fine structure and phonon energy of semiconductors, providing an additional knob to control their optical properties. The impact can be exploited in colloidal semiconductor quantum dots (QDs), wherein structural stresses can be imposed in three dimensions while defect formation is suppressed by controlling surface growth kinetics. Yet, the control over the structural deformation of QDs free from optically active defects has not been reached. Here, we demonstrate strain-graded CdSe-ZnSe core-shell QDs with compositionally abrupt interface by the coherent pseudomorphic heteroepitaxy. Resulting QDs tolerate mutual elastic deformation of varying magnitudes at the interface with high structural fidelity, allowing for spectrally stable and pure emission of photons at accelerated rates with near unity luminescence efficiency. We capitalize on the asymmetric strain effect together with the quantum confinement effect to expand emission envelope of QDs spanning the entire visible region and exemplify their use in photonic applications.

Impact of Alternating-Current Operation on All-Inorganic Quantum Dot Light-Emitting Diodes.

In colloidal quantum dot light-emitting diodes (QD-LEDs), replacing organic hole transport layers (HTLs) with their inorganic counterparts is expected to yield distinct advantages due to their inherent material robustness. However, despite the promising characteristics of all-inorganic QD-LEDs, some challenges persist in achieving stable operation; for example, the electron overflow toward the inorganic HTL and charge accumulation within working devices return a temporal inconsistency in device characteristics. To address these challenges, we propose an operational approach that employs an alternating-current (AC) in all-inorganic QD-LEDs. We carry out comprehensive studies on the optoelectrical characteristics of all-inorganic QD-LEDs under direct-current (DC) or AC operation and demonstrate that AC operation can facilitate efficient charge carrier recombination within the QD emissive layer, leading to improved device efficiency and temporally invariant optoelectronic characteristics. Leveraging the intrinsic material robustness of inorganic charge transport layers (CTLs), our current study suggests a promising pathway toward enhancing the performance and stability of QD-LEDs, particularly for futuristic display applications.

DRG2 is required for surface localization of PD-L1 and the efficacy of anti-PD-1 therapy.

More than half of tumor patients with high PD-L1 expression do not respond to anti-PD-1/PD-L1 therapy, and the underlying mechanisms are yet to be clarified. Here we show that developmentally regulated GTP-binding protein 2 (DRG2) is required for response of PD-L1-expressing tumors to anti-PD-1 therapy. DRG2 depletion enhanced IFN-γ signaling and increased the PD-L1 level in melanoma cells. However, it inhibited recycling of endosomal PD-L1 and reduced surface PD-L1 levels, which led to defects in interaction with PD-1. Anti-PD-1 did not expand effector-like T cells within DRG2-depleted tumors and failed to improve the survival of DRG2-depleted tumor-bearing mice. Cohort analysis revealed that patients bearing melanoma with low DRG2 protein levels were resistant to anti-PD-1 therapy. These findings identify DRG2 as a key regulator of recycling of endosomal PD-L1 and response to anti-PD-1 therapy and provide insights into how to increase the correlation between PD-L1 expression and response to anti-PD-1 therapy.

A Review of Novel Medical Treatments for Thyroid Eye Disease.

Thyroid eye disease (TED) is the most common extrathyroidal manifestation of Graves disease. There has been no effective medication to prevent proptosis in thyroid eye disease until 2020 when the anti-insulin-like growth factor 1 receptor (anti-IGF-1R) antibody, Teprotumumab, was approved by the US Food and Drug Administration, sparking increased interest in immune-based drug development. This study aims to review the newly developed drug therapy as well as conventional treatment for TED. Treatment of TED has traditionally been high-dose steroids and orbital radiotherapy, but recently there has been a paradigm shift in the treatment of TED in the United States with the introduction of the therapeutic agent teprotumumab, which dramatically reduces proptosis. However, concerns remain about the development of hearing impairment as a potentially fatal complication and long-term safety. Recently, several clinical trials are underway to assess the efficacy and safety of novel drugs targeting mammalian target of rapamycin complex 1, interleukin-6, fragment crystallizable receptor, and IGF-1R in treating TED. With the explosive increase in interest from academia and pharmaceutical companies in TED, there is anticipation for the development of drugs that are equivalent or superior to teprotumumab while being safer.

Inhibition of DAPK3 Suppresses Radiation-Induced Cellular Senescence by Activation of a PGC1α-Dependent Metabolism Pathway in Brain Endothelial Cells.

In the brain, environmental changes, such as neuroinflammation, can induce senescence, characterized by the decreased proliferation of neurons and dendrites and synaptic and vascular damage, resulting in cognitive decline. Senescence promotes neuroinflammatory disorders by senescence-associated secretory phenotypes and reactive oxygen species. In human brain microvascular endothelial cells (HBMVECs), we demonstrate that chronological aging and irradiation increase death-associated protein kinase 3 (DAPK3) expression. To confirm the role of DAPK3 in HBMVEC senescence, we disrupted DAPK3 activity using small interfering RNA (siRNA) or a dominant-negative mutant (DAPK3-P216S), which reduced cellular senescence phenotypes, as assessed by changes in tube formation, senescence-associated beta-galactosidase activity, and cell proliferation. In endothelial cells, DAPK3 promotes cellular senescence by regulating the phosphorylation and inactivation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) via the protein kinase B pathway, resulting in the decreased expression of mitochondrial metabolism-associated genes, such as ATP5G1, BDNF, and COX5A. Our studies show that DAPK3 is involved in cellular senescence and PGC1α regulation, suggesting that DAPK3 regulation may be important for treating aging-related brain diseases or the response to radiation therapy.

Growth Control of InP/ZnSe Heterostructured Nanocrystals.

The morphology of heterostructured semiconductor nanocrystals (h-NCs) dictates the spatial distribution of charge carriers and their recombination dynamics and/or transport, which are the main performance indicators of photonic applications utilizing h-NCs. The inability to control the morphology of heterovalent III-V/II-VI h-NCs composed of heavy-metal-free elements hinders their practical use. As a case study of III-V/II-VI h-NCs, the growth control of ZnSe epilayers on InP NCs is demonstrated here. The anisotropic morphology in InP/ZnSe h-NCs is attributed to the facet-dependent energy costs for the growth of ZnSe epilayers on different facets of InP NCs, and effective chemical means for controlling the growth rates of ZnSe on different surface planes are demonstrated. Ultimately, this article capitalizes on the controlled morphology of InP/ZnSe h-NCs to expand their photophysical characteristics from stable and pure emission to environment-sensitive one, which will facilitate their use in a variety of photonic applications.

Effect of polystyrene nanoplastics exposure on gene expression and pathogenesis of zoonotic pathogen, Edwardsiella piscicida.

A surge in the number of anthropogenic pollutants has been caused by increasing industrial activities. Nanoplastics are spotlighted as a new aquatic pollutant that are a threat to microbes and larger organisms. Our previous study showed that the subinhibitory concentrations of aquatic pollutants such as phenol and formalin act as signaling molecules and modulate global gene expression and metabolism. In this study, we aimed to investigate the impact of a new type of anthropogenic contaminant, polystyrene (PS) nanoplastics, on the expression of key virulence factors in zoonotic pathogen Edwardsiella piscicida and the assessment of potential changes in the susceptibility of zebrafish as a model host. The TEM data indicated a noticeable change in the cell membrane indicating that PS particles were possibly entering the bacterial cells. Transcriptome analyses performed to identify the differentially expressed genes upon PS exposure revealed that the genes involved in major virulence factor type VI secretion system (T6SS) were down-regulated. However, the expression of T6SS-related genes was recovered from the PS adapted E. piscicida when nanoplastics are free. This demonstrated the hypervirulence of pathogen in infection assays with both cell lines and in vivo zebrafish model. Therefore, this study provides experimental evidence elucidating the direct regulatory impact of nanoplastics influx into aquatic ecosystems on fish pathogenic bacteria, notably influencing the expression of virulence factors.

Effects of Antibiotic Residues on Fish Gut Microbiome Dysbiosis and Mucosal Barrier-Related Pathogen Susceptibility in Zebrafish Experimental Model.

The symbiotic community of microorganisms in the gut plays an important role in the health of the host. While many previous studies have been performed on the interactions between the gut microbiome and the host in mammals, studies in fish are still lacking. In this study, we investigated changes in the intestinal microbiome and pathogen susceptibility of zebrafish (Danio rerio) following chronic antibiotics exposure. The chronic antibiotics exposure assay was performed on zebrafish for 30 days using oxytetracycline (Otc), sulfamethoxazole/trimethoprim (Smx/Tmp), or erythromycin (Ery), which are antibiotics widely used in the aquaculture industry. The microbiome analysis indicated that Fusobacteria, Proteobacteria, Firmicutes, and Bacteroidetes were the dominant phyla in the gut microbiome of the zebrafish used in this study. However, in Smx/Tmp-treated zebrafish, the compositions of Fusobacteria and Proteobacteria were changed significantly, and in Ery-treated zebrafish, the compositions of Proteobacteria and Firmicutes were altered significantly. Although alpha diversity analysis showed that there was no significant difference in the richness, beta diversity analysis revealed a community imbalance in the gut microbiome of all chronically antibiotics-exposed zebrafish. Intriguingly, in zebrafish with dysbiosis in the gut microbiome, the pathogen susceptibility to Edwardsiella piscicida, a representative Gram-negative fish pathogen, was reduced. Gut microbiome imbalance resulted in a higher count of goblet cells in intestinal tissue and an upregulation of genes related to the intestinal mucosal barrier. In addition, as innate immunity was enhanced by the increased mucosal barrier, immune and stress-related gene expression in the intestinal tissue was downregulated. In this study, we provide new insight into the effect of gut microbiome dysbiosis on pathogen susceptibility.

Hedgehog signalling is involved in acquired resistance to KRASG12C inhibitors in lung cancer cells.

Although KRASG12C inhibitors have shown promising activity in lung adenocarcinomas harbouring KRASG12C, acquired resistance to these therapies eventually occurs in most patients. Re-expression of KRAS is thought to be one of the main causes of acquired resistance. However, the mechanism through which cancer cells re-express KRAS is not fully understood. Here, we report that the Hedgehog signal is induced by KRASG12C inhibitors and mediates KRAS re-expression in cancer cells treated with a KRASG12C inhibitor. Further, KRASG12C inhibitors induced the formation of primary cilia and activated the Hedgehog-GLI-1 pathway. GLI-1 binds to the KRAS promoter region, enhancing KRAS promoter activity and KRAS expression. Inhibition of GLI using siRNA or the smoothened (Smo) inhibitor suppressed re-expression of KRAS in cells treated with a KRASG12C inhibitor. In addition, we demonstrate that KRASG12C inhibitors decreased Aurora kinase A (AURKA) levels in cancer cells, and inhibition of AURKA using siRNA or inhibitors led to increased expression levels of GLI-1 and KRAS even in the absence of KRAS inhibitor. Ectopic expression of AURKA attenuated the effect of KRASG12C inhibitors on the expression of GLI-1 and re-expression of KRAS. Together, these findings demonstrate the important role of AURKA, primary cilia, and Hedgehog signals in the re-expression of KRAS and therefore the induction of acquired resistance to KRASG12C inhibitors, and provide a rationale for targeting Hedgehog signalling to overcome acquired resistance to KRASG12C inhibitors.

Serotype-Dependent Inhibition of Streptococcus pneumoniae Growth by Short-Chain Fatty Acids.

Streptococcus pneumoniae (pneumococcus) is an opportunistic pathogen that can cause severe infectious diseases such as pneumonia, meningitis, and otitis media. Despite the availability of antibiotics and pneumococcal vaccines against some invasive serotypes, pneumococcal infection remains a tremendous clinical challenge due to the increasing frequency of infection by antimicrobial resistant, nonencapsulated, and/or non-vaccine serotype strains. Short-chain fatty acids (SCFAs), which are produced at various mucosal sites in the body, have potent antimicrobial activity, including inhibition of pathogen growth and/or bacterial biofilm formation. In this study, we investigated the antimicrobial activity of SCFAs (acetate, propionate, and butyrate) against various serotypes pneumococci. Propionate generally inhibited the growth of S. pneumoniae serotypes included in the pneumococcal conjugate vaccine (PCV) 13, except for serotypes 3 and 7F, though butyrate and acetate showed no or low inhibition, depending on the serotypes. Of note, butyrate showed strong inhibition against serotype 3, the most prevalent invasive strain since the introduction of the PCV. No SCFAs showed inhibitory effects against serotype 7F. Remarkably, the nonencapsulated pneumococcal strain had more sensitivity to SCFAs than encapsulated parental strains. Taken together, these results suggest that propionate showing the most potent inhibition of pneumococcal growth may be used as an alternative treatment for pneumococcal infection, and that butyrate could be used against serotype 3, which is becoming a serious threat.

DRG2 in macrophages is crucial for initial inflammatory response and protection against Listeria monocytogenes infection.

Innate immune response is critical for the control of Listeria monocytogenes infection. Here, we identified developmentally regulated GTP-binding protein 2 (DRG2) in macrophages as a major regulator of the innate immune response against L. monocytogenes infection. Both whole-body DRG2 knockout (KO) mice and macrophage-specific DRG2 KO mice had low levels of IL-6 during early infection and increased susceptibility to L. monocytogenes infection. Following an initial impaired inflammatory response of macrophages upon i.p. L. monocytogenes infection, DRG2-/- mice showed delayed recruitment of neutrophils and monocytes into the peritoneal cavity, which led to elevated bacterial burden, inflammatory cytokine production at a late infection time point, and liver micro-abscesses. DRG2 deficiency decreased the transcriptional activity of NF-κB and impaired the inflammatory response of both bone marrow-derived and peritoneal macrophages upon L. monocytogenes stimulation. Our findings reveal that DRG2 in macrophages is critical for the initial inflammatory response and protection against L. monocytogenes infection.

Sirtuin1-Mediated Deacetylation of Hypothalamic TTF-1 Contributes to the Energy Deficiency Response.

TTF-1 stimulates appetite by regulating the expression of agouti-related peptide (AgRP) and proopiomelanocortin (POMC) genes in the hypothalamus of starving animals. However, the mechanism underlying TTF-1's response to decreased energy levels remains elusive. Here, we provide evidence that the NAD+-dependent deacetylase, sirtuin1 (Sirt1), activates TTF-1 in response to energy deficiency. Energy deficiency leads to a twofold increase in the expression of both Sirt1 and TTF-1, leading to the deacetylation of TTF-1 through the interaction between the two proteins. The activation of Sirt1, induced by energy deficiency or resveratrol treatment, leads to a significant increase in the deacetylation of TTF-1 and promotes its nuclear translocation. Conversely, the inhibition of Sirt1 prevents these Sirt1 effects. Notably, a point mutation in a lysine residue of TTF-1 significantly disrupts its deacetylation and thus nearly completely hinders its ability to regulate AgRP and POMC gene expression. These findings highlight the importance of energy-deficiency-induced deacetylation of TTF-1 in the control of AgRP and POMC gene expression.

Bridging Energy Need and Feeding Behavior: The Impact of eIF2α Phosphorylation in AgRP Neurons.

Eukaryotic translation initiation factor 2α (eIF2α) is a key mediator of the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR). In mammals, eIF2α is phosphorylated by overnutrition-induced ER stress and is related to the development of obesity. Here, we studied the function of phosphorylated eIF2α (p-eIF2α) in agouti-related peptide (AgRP) neurons using a mouse model (AgRPeIF2αA/A) with an AgRP neuron-specific substitution from Ser 51 to Ala in eIF2α, which impairs eIF2α phosphorylation in AgRP neurons. These AgRPeIF2αA/A mice had decreases in starvation-induced AgRP neuronal activity and food intake and an increased responsiveness to leptin. Intriguingly, impairment of eIF2α phosphorylation produced decreases in the starvation-induced expression of UPR and autophagy genes in AgRP neurons. Collectively, these findings suggest that eIF2α phosphorylation regulates AgRP neuronal activity by affecting intracellular responses such as the UPR and autophagy during starvation, thereby participating in the homeostatic control of whole-body energy metabolism. ARTICLE HIGHLIGHTS: This study examines the impact of eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, triggered by an energy deficit, on hypothalamic AgRP neurons and its subsequent influence on whole-body energy homeostasis. Impaired eIF2α phosphorylation diminishes the unfolded protein response and autophagy, both of which are crucial for energy deficit-induced activation of AgRP neurons. This study highlights the significance of eIF2α phosphorylation as a cellular marker indicating the availability of energy in AgRP neurons and as a molecular switch that regulates homeostatic feeding behavior.

Coherent heteroepitaxial growth of I-III-VI2 Ag(In,Ga)S2 colloidal nanocrystals with near-unity quantum yield for use in luminescent solar concentrators.

Colloidal Ag(In,Ga)S2 nanocrystals (AIGS NCs) with the band gap tunability by their size and composition within visible range have garnered surging interest. High absorption cross-section and narrow emission linewidth of AIGS NCs make them ideally suited to address the challenges of Cd-free NCs in wide-ranging photonic applications. However, AIGS NCs have shown relatively underwhelming photoluminescence quantum yield (PL QY) to date, primarily because coherent heteroepitaxy has not been realized. Here, we report the heteroepitaxy for AIGS-AgGaS2 (AIGS-AGS) core-shell NCs bearing near-unity PL QYs in almost full visible range (460 to 620 nm) and enhanced photochemical stability. Key to the successful growth of AIGS-AGS NCs is the use of the Ag-S-Ga(OA)2 complex, which complements the reactivities among cations for both homogeneous AIGS cores in various compositions and uniform AGS shell growth. The heteroepitaxy between AIGS and AGS results in the Type I heterojunction that effectively confines charge carriers within the emissive core without optically active interfacial defects. AIGS-AGS NCs show higher extinction coefficient and narrower spectral linewidth compared to state-of-the-art heavy metal-free NCs, prompting their immediate use in practicable applications including displays and luminescent solar concentrators (LSCs).

CO-Induced TTP Activation Alleviates Cellular Senescence and Age-Dependent Hepatic Steatosis via Downregulation of PAI-1.

Aging can increase the risk of various hepatic diseases, especially non-alcoholic fatty liver disease (NAFLD). Although the mechanisms underlying the pathogenesis of age-related disorders such as NAFLD remain incompletely understood, recent studies have implicated the accumulation of senescent cells as a contributing factor. Here, we show that tristetraprolin (TTP) deficiency accelerates NAFLD during aging by enhancing the senescence-associated secretory phenotype (SASP) as well as several hallmarks of senescence. The sequestration of plasminogen activator inhibitor (PAI)-1, a mediator of cellular senescence, in stress granules, (SGs) inhibits cellular senescence. In our previous report, we have shown that carbon monoxide (CO), a small gaseous mediator, can induce the assembly of SGs via an integrated stress response. Here, we show that CO treatment promotes the assembly of SGs which can sequester PAI-1, resulting in the inhibition of etoposide (ETO)-induced cellular senescence. Notably, CO-induced TTP activation enhances PAI-1 degradation, leading to protection against ETO-induced cellular senescence. CO-dependent Sirt1 activation promotes the inclusion of TTP into SGs, leading to decreased PAI-1 levels. Therefore, our findings highlight the importance of TTP as a therapeutic target in age-related NAFLD and offer a potential new strategy to reduce the detrimental effects of senescent cells in hepatic disorders.

Activation of ROS-PERK-TFEB by filbertone ameliorates neurodegenerative diseases via enhancing the autophagy-lysosomal pathway.

The molecular mechanisms underlying the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease (PD), and Huntington's disease remain enigmatic, resulting in an unmet need for therapeutics development. Here, we suggest that filbertone, a key flavor compound found in the fruits of hazel trees of the genus Corylus, can ameliorate PD via lowering the abundance of aggregated α-synuclein. We previously reported that inhibition of hypothalamic inflammation by filbertone is mediated by suppression of nuclear factor kappa-B. Here, we report that filbertone activates PERK through mitochondrial reactive oxygen species production, resulting in the increased nuclear translocation of transcription factor-EB in SH-SY5Y human neuroblastoma cells. TFEB activation by filbertone promotes the autophagy-lysosomal pathway, which in turn alleviates the accumulation of α-synuclein. We also demonstrate that filbertone prevented the loss of dopaminergic neurons in the substantia nigra and striatum of mice on high-fat diet. Filbertone treatment also reduced high-fat diet-induced α-synuclein accumulation through upregulation of the autophagy-lysosomal pathway. In addition, filbertone improved behavioral abnormalities (i.e., latency time to fall and decrease of running distance) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD murine model. In conclusion, filbertone may show promise as a potential therapeutic for neurodegenerative disease.

Simple surgical punctal occlusion with high frequency radiowave electrosurgery.

BACKGROUND: To introduce and evaluate the efficacy of a simple punctal occlusion technique for dry eye patients. METHODS: Medical records of 79 eyes from 40 patients refractory to common dry eye conservative treatment who underwent multiple high-frequency radio-wave electro-punctal occlusion were retrospectively reviewed. Pre- and post-procedural ocular surface indices (Schirmer test, tear break-up time (TBUT), and corneal staining grade (Oxford scheme)) and subjective symptom scores (including frequency of artificial tear use, interval between procedures, and total repeat time) were analyzed. RESULTS: Average Schirmer test result was significantly (P < 0.05) improved from 4.10 ± 1.39 mm to 8.14 ± 3.13 mm at 6 weeks after the procedure (n = 79). A total of 32 eyes from 16 patients underwent repeated procedure with a mean interval of 8.00 ± 4.86 months, while 24 patients had a single procedure. Twenty-five of 30 patients showed improvement for subjective symptom scores. No complications related to the procedure were observed. CONCLUSIONS: A simple, less-invasive punctal occlusion technique using a fine-needle tip with high-frequency radio-wave could significantly relieve subjective symptoms and improve ocular surface indices of patients with aqueous deficient dry eye without causing a major complication. This procedure may play a considerable role in treating dry eye refractory to common practices.