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Glycine transporters (GlyT1 and GlyT2) that regulate levels of brain glycine, an inhibitory neurotransmitter with co‐agonist activity for NMDA receptors (NMDARs), have been considered to be important targets for the treatment of brain disorders with suppressed NMDAR function such as schizophrenia. However, it remains unclear whether other amino acid transporters expressed in the brain can also regulate brain glycine levels and NMDAR function. Here, we report that SLC6A20A, an amino acid transporter known to transport proline based on in vitro data but is understudied in the brain, regulates proline and glycine levels and NMDAR function in the mouse brain. SLC6A20A transcript and protein levels were abnormally increased in mice carrying a mutant PTEN protein lacking the C terminus through enhanced β‐catenin binding to the Slc6a20a gene. These mice displayed reduced extracellular levels of brain proline and glycine and decreased NMDAR currents. Elevating glycine levels back to normal ranges by antisense oligonucleotide‐induced SLC6A20 knockdown, or the competitive GlyT1 antagonist sarcosine, normalized NMDAR currents and repetitive climbing behavior observed in these mice. Conversely, mice lacking SLC6A20A displayed increased extracellular glycine levels and NMDAR currents. Lastly, both mouse and human SLC6A20 proteins mediated proline and glycine transports, and SLC6A20 proteins could be detected in human neurons. These results suggest that SLC6A20 regulates proline and glycine homeostasis in the brain and that SLC6A20 inhibition has therapeutic potential for brain disorders involving NMDAR hypofunction. Synopsis This study reveals that SLC6A20A, an amino acid transporter previously known to transport proline, also transports glycine, a co‐agonist of NMDA receptors. SLC6A20A inhibition holds therapeutic potential for brain disorders with suppressed NMDAR function such as schizophrenia. SLC6A20A transports both glycine and proline in mammalian cells. PTEN C‐terminal deletion enhances SLC6A20A expression, brain glycine levels, and NMDA receptor function in mice. SLC6A20A haploinsufficient mice display increased brain glycine levels and enhanced NMDA receptor function. Graphical Abstract This study reveals that SLC6A20A, an amino acid transporter previously known to transport proline, also transports glycine, a co‐agonist of NMDA receptors. SLC6A20A inhibition holds therapeutic potential for brain disorders with suppressed NMDAR function such as schizophrenia.

Turmeric oleoresin (TO), a natural pigment derived from Curcuma longa rhizomes, is valued for its health benefits, which are primarily attributed to its rich curcuminoid content (curcumin, demethoxycurcumin, and bisdemethoxycurcumin). Despite these benefits, curcuminoids are known to be light-sensitive and possess photosensitizing properties. This study investigated the impact of common light sources, fluorescent light and white LED (both at 10 W/m2), on the chemical stability, antioxidant activity, cytotoxicity, and photosensitizing properties of TO. Exposure to both light sources significantly reduced TO’s color and fluorescence intensity, with white LED causing greater instability. HPLC analysis confirmed a decrease in individual curcuminoid levels, with curcumin degrading most rapidly under both conditions. The DPPH radical scavenging activity of irradiated TO decreased compared to fresh or dark-stored turmeric, whereas its ABTS radical scavenging activity increased upon light exposure. Photosensitizing potency, measured by formazan decolorization and lipid peroxide formation, declined as TO decomposed under light. Conversely, the cytotoxicity of TO against B16F10 melanoma cells was significantly enhanced under light exposure, though this effect was diminished significantly after 24 h of pre-irradiation. These findings underscore the instability of turmeric pigment under common lighting conditions, which should be a crucial consideration when processing, storing, and distributing turmeric-containing products.

Background Subcutaneous emphysema and pneumomediastinum are rare complications associated with orbital blowout pathological fracture. Case presentation A 7-year old, castrated male Abbysinian cat presented with anorexia, lethargy, nausea, eyelid swelling, nasal discharge, and sneezing. Based on the clinical and diagnostic work-up, the cat was diagnosed with T cell high-grade nasal lymphoma associated with orbital pathological fracture due to the tumour invasion. After chemotherapy, the cat showed massive subcutaneous emphysema from frontal region to abdomen and pneumomediastinum due to orbital blowout pathological fracture. As the nasal mass decreased in volume; the air had moved from the maxillary sinus to the subcutaneous region and the mediastinum through fascial planes in the head and neck region. Conclusions This is a first case report of a massive subcutaneous emphysema and pneumomediastinum due to an orbital blowout pathological fracture following chemotherapy in feline nasal lymphoma in veterinary medicine.

Retinal organoids derived from human-induced pluripotent stem cells (hiPSC) are powerful tools for studying retinal development as they model spatial and temporal differentiation of retinal cell types. Vertebrate retinal development involves a delicate and coordinated process of retinal progenitor cell (RPC) differentiation, and the mammalian target of rapamycin complex 1 (mTORC1) has been reported to play a significant role in this complex process. Herein, using hiPSC-derived retinal organoids, we identify the time-dependent role of mTORC1 in retinal development, specifically in retinal ganglion cell (RGC) differentiation and the retinal lamination process, during the early stages of retinal organoid (RO) development. mTORC1 activity in ROs was the highest at 40 days of differentiation. MHY1485-induced hyperactivation of mTORC1 during this period resulted in a significant increase in the overall size of ROs compared to the untreated controls and rapamycin-treated Ros; there was also a marked increase in proliferative activity within the inner and outer layers of ROs. Moreover, the MHY1485-treated ROs showed a significant increase in the number of ectopic RGCs in the outer layers (indicating disruption of retinal laminar structure), with robust expression of HuC/D-binding proteins in the inner layers. These results demonstrate that mTORC1 plays a critical role in the development of hiPSC-derived ROs, especially during the early stages of differentiation.

Pathological protein inclusion formation and propagation are the main causes of neuronal dysfunction in diverse neurodegenerative diseases; therefore, current disease-modifying therapeutic strategies have targeted this disease protein aggregation process. Recently, we reported that peucedanocoumarin III (PCiii) is a promising therapeutic compound with the ability to disaggregate α-synuclein inclusion and protect dopaminergic neurons in Parkinson’s disease (PD). Here, we found that trans-4′-acetyl-3′-tigloylkhellactone (racemic peucedanocoumarin IV [PCiv]), a structural isomer of PCiii with a higher synthetic yield presented a strong anti-aggregate activity to a degree comparable to that of PCiii. PCiv retained effective inhibitory function against β-sheet aggregate-mimic β23 cytotoxicities and potently prevented α-synucleinopathy in α-synuclein preformed fibril (PFF)-treated mice cortical neurons. In detailed pharmacokinetic profiling of PCiv, oral administration of PCiv in rats exhibited an approximately 97-min half-life and 10% bioavailability. Moreover, tissue distribution analysis revealed favorable profiles of brain penetration with a 6.4 brain-to-plasma concentration ratio. The therapeutic efficacy of PCiv was further evaluated in a sporadic PD mouse model with a combinatorial co-injection of α-synuclein preformed fibril and recombinant adeno-associated virus expressing α-synuclein. Motor dysfunctions induced in this combinatorial α-synucleinopathy PD mouse model was almost completely rescued by PCiv diet administration, and this therapeutic effect is consistent with the marked prevention of dopaminergic neuron loss and suppression of α-synuclein aggregation. Taken together, our translational study suggests that PCiv is advantageous as a therapeutic agent for neurodegenerative diseases, especially with its good synthetic yield, high brain distribution, and anti-aggregate activity. PCiv may be useful in the management of α-synuclein inclusion formation and propagation at different stages of PD.

The impact of heat type, sample type, temperature and time on the heat-induced conversion of gingerols to shogaols in ginger were studied by an UHPLC–ESI–MS/MS. Heat treatments greatly induced the conversion of gingerols to shogaols in ginger. As the temperature increased, the faster conversion of gingerols into shogaols were observed. However, the efficiency of the heat-induced conversion differed greatly with the heat types. Moist heat treatment induced significantly higher quantity of shogaols than dry heat treatment. The moist heat treatment at 120 °C for 360 min induced the highest conversion, reaching to 2991 mg 6-shogaol per kg ginger. In addition, dry-heat induced conversion was affected by the sample type. The dry-heat treatment on dried powder induced significantly higher quantity of shogaols than that on sliced fresh ginger. This represents the first systematic comparative study on the heat and sample types on the heat-induced conversion of gingerols into shogaols in ginger.

Syndecan-2 expression is elevated during chronic inflammation and cancer development, and its shedding is observed in cancer patients. However, it remained unknown whether inflammation triggers syndecan-2 shedding. The colitis model was produced in C57BL/6 mice by oral administration of 2-3% dextran sulfate sodium (DSS) in the drinking water. Syndecan-2 and MMP-7 expression levels in tissues and cells were detected by real-time PCR, Western blotting, and immunohistochemistry. Shed syndecan-2 levels were detected by slot blotting. For tissue culture, colon tissues were divided into proximal, transverse, and distal parts, and incubated in culture media. In C57BL/6 mice with DSS-induced colitis, syndecan-2 shedding began to increase after week 12 of chronic inflammation and continued to increase at week 15. The level of shed syndecan-2 correlated with the colocalization of syndecan-2 and MMP-7 in distal colon tissues. The mRNA expression of IL-6 was increased specifically in trans-distal colon tissues from weeks 9 to 15. IL-6 induced syndecan-2 expression and shedding and MMP-7 expression in ex vivo-cultured distal colon tissues and adenoma cell lines derived from the distal colon. IL-6 treatment induced STAT3 phosphorylation and MMP-7 expression in DLD-1 cells. The application of MMP-7 to ex vivo-cultured colon tissues increased the shedding of syndecan-2 to the culture medium. Our findings suggest that chronic inflammation induces syndecan-2 shedding via the site-specific colocalization of syndecan-2 with MMP-7 in the distal colon.

Although many schizencephaly patients suffer from epilepsy, the relationship between schizencephalic lesions and epileptic foci remains unclear. Previous studies have shown that schizencephalic lesions may be associated with, rather than contain, epileptogenic zones. Thus, the purpose of this study was to investigate the current source distribution (CSD) of epileptiform discharges in schizencephalic patients and to correlate this activity with existing structural lesions. A consecutive series of 30 schizencephalic patients who were diagnosed using brain magnetic resonance imaging (MRI) were selected retrospectively and prospectively. Of the original 30 subjects selected, 13 had epilepsy, and 6 of these patients exhibited schizencephaly, epilepsy, and interictal spikes on electroencephalograms (EEG) and were enrolled in the present study investigating the current source analysis of interictal spikes. The CSDs of the initial rising phases and the peak points of the interictal spikes were obtained using standardized low-resolution brain electromagnetic tomography (LORETA). Five patients exhibited a single focus of interictal spikes, while 1 patient showed 2 foci. Relative to the structural brain lesions, 5 patients displayed extrinsically localized CSDs, while 1 patient showed a partially intrinsically localized CSD. The present findings demonstrate that the CSDs of interictal spikes in schizencephalic patients are in general anatomically distinct from the cerebral schizencephalic lesions and that these lesions may display an extrinsic epileptogenicity.

The non-local dependency between a noun and its associate quantifier has been widely discussed. The details may differ, but the formal analyses on floating quantifiers can be divided into three schools of research. One is an adnominal approach, which argues that the noun and the quantifier are externally-merged together (at some point of the derivation), and that the noun has undergone leftward movement in a later derivation (e.g. Kuroda 1983, Sportiche 1988, Ueda 1990, Bošković 2004). Another is an adverbial approach, which claims that the quantifier modifies the event structure of the verb phrase, and that the noun and the quantifier are not related to each other by movement (e.g. Kayne 1975, Fukushima 1991, Bobaljik 1995, 2003, Brisson 1998, Nakanish 2003, Kim and Yang 2006). The other is a hybrid approach (e.g. Ishii 1998, Kang 2002, Ko 2005, 2007, Fitzpatrick 2006) which argues that some floating quantifiers are adnominals while some are adverbials. This paper evaluates the predictions and validity of the three approaches with new experimental data, and provides evidence for the hybrid approach from on-line processing and off-line judgment data.