Differences in glycemic trends due to reconstruction methods after proximal gastrectomy from the perspective of continuous glucose-monitoring.

PURPOSE: In recent years, clinicians have focused on the importance of preventing hypoglycemia. We evaluated the impact of different reconstruction procedures after proximal gastrectomy on glycemic variability in non-diabetic patients with gastric cancer. METHODS: This prospective observational study was conducted between April 2020 and March 2023. Flash continuous glucose-monitoring, a novel method for assessing glycemic control, was used to evaluate the glycemic profiles after gastrectomy. A flash continuous glucose-monitoring sensor was placed subcutaneously at the time of discharge, and glucose trends were evaluated for 2 weeks. RESULTS: The anastomotic methods for proximal gastrectomy were esophagogastrostomy in 10 patients and double-tract reconstruction in 10 patients. The time below this range (glucose levels < 70 mg/dL) was significantly higher in the double-tract reconstruction group than in the esophagogastrostomy group (p = 0.049). A higher nocturnal time below this range was significantly correlated with an older age and double-tract reconstruction (p = 0.025 and p = 0.025, respectively). CONCLUSION: These findings provide new insights into reconstruction methods after proximal gastrectomy by assessing postoperative hypoglycemia in non-diabetic patients with gastric cancer.

Investigating Cytoglobin Expression in Colon Cancer: Clinicopathological Insights from Immunohistochemical Analysis.

BACKGROUND/AIM: Cytoglobin (Cygb), a protein involved in cellular oxygen metabolism and protection, has garnered attention owing to its potential role in the initiation and progression of cancer, particularly colon cancer (CC). This study investigated the expression and significance of Cygb in CC. PATIENTS AND METHODS: This study included 145 patients who underwent R0 surgery for CC (clinical stage II/III) at our institution between January 2007 and December 2014. Immunohistochemical analysis was performed to evaluate the Cygb expression patterns in CC tissues. Additionally, the correlation between Cygb expression levels and the clinicopathological characteristics of patients with CC was investigated. RESULTS: Colon cancer tissues were categorized into high-expression (95 cases) and low-expression (50 cases) groups. Cygb was highly expressed in well-differentiated cases, whereas its expression decreased in poorly differentiated cases. No significant differences in other clinicopathological factors were observed between the two groups. Cygb expression had no significant effect on recurrence-free survival or overall survival. CONCLUSION: This study contributes to the growing understanding of Cygb expression and its significance in CC. The expression of Cygb in CC was found to be unrelated to the recurrence rate and prognosis, but showed a correlation with differentiation status.

Effect of Step Count Measurement on Glycemic Control: Secondary Analysis of a Randomized Controlled Trial.

Although walking has proven efficacy for glycemic control, patients struggle to meet daily step goals. This secondary analysis investigated the effect of step count measurement rate on glycemic control. Patients with type 2 diabetes from eight hospitals in Japan participated in a 12-month randomized controlled trial. The intervention group received DialBetesPlus, a self-management support system that allowed patients to monitor step count using a pedometer. We divided the intervention group into two groups based on whether daily step count measurement rate (the percentage of days with pedometer use) increased or decreased during the last three months of the intervention (month 10-12), relative to the first three months of the intervention (month 1-3). Patients with a reduced measurement rate experienced a worsening in glycemic control, with between-group difference of 0.516% in the amount of change in HbA1c (p=0.012). We conclude that step count measurement may lead to a better glycemic profile.

Prognostic Impact of Stromal Profiles Educated by Gastric Cancer.

BACKGROUND: Cancer-associated fibroblasts exhibit diversity and have several subtypes. The underlying relationship between the diversity of cancer-associated fibroblasts and their effect on gastric cancer progression remains unclear. In this study, mesenchymal stem cells were differentiated into cancer-associated fibroblasts with gastric cancer cell lines; clinical specimens were used to further investigate the impact of cancer-associated fibroblast diversity on cancer progression. METHODS: Nine gastric cancer cell lines (NUGC3, NUGC4, MKN7, MKN45, MKN74, FU97, OCUM1, NCI-N87, and KATOIII) were used to induce mesenchymal stem cell differentiation into cancer-associated fibroblasts. The cancer-associated fibroblasts were classified based on ACTA2 and PDPN expression. Cell function analysis was used to examine the impact of cancer-associated fibroblast subtypes on cancer cell phenotype. Tissue samples from 97gastric patients who underwent gastrectomy were used to examine the clinical significance of each subtype classified according to cancer-associated fibroblast expression. RESULTS: Co-culture of mesenchymal stem cells with nine gastric cancer cell lines revealed different subtypes of ACTA2 and PDPN expression in differentiated cancer-associated fibroblasts. Cancer-associated fibroblast subtypes with high ACTA2 plus PDPN expression levels significantly increased gastric cancer cell migration, invasion, and proliferation. The cancer-associated fibroblast subtype with ACTA2 plus PDPN expression was an independent prognostic factor along with lymph node metastasis for patients who had gastric cancer and were undergoing surgery. CONCLUSIONS: Cancer-associated fibroblasts are educated by gastric cancer cells during the development of cancer-associated fibroblast diversity. Differentiated cancer-associated fibroblasts with distinct expression patterns could affect gastric cancer progression and enable prognostic stratification for gastric cancer.

Two-pore channel-2 and inositol trisphosphate receptors coordinate Ca2+ signals between lysosomes and the endoplasmic reticulum.

Lysosomes and the endoplasmic reticulum (ER) are Ca2+ stores mobilized by the second messengers NAADP and IP3, respectively. Here, we establish Ca2+ signals between the two sources as fundamental building blocks that couple local release to global changes in Ca2+. Cell-wide Ca2+ signals evoked by activation of endogenous NAADP-sensitive channels on lysosomes comprise both local and global components and exhibit a major dependence on ER Ca2+ despite their lysosomal origin. Knockout of ER IP3 receptor channels delays these signals, whereas expression of lysosomal TPC2 channels accelerates them. High-resolution Ca2+ imaging reveals elementary events upon TPC2 opening and signals coupled to IP3 receptors. Biasing TPC2 activation to a Ca2+-permeable state sensitizes local Ca2+ signals to IP3. This increases the potency of a physiological agonist to evoke global Ca2+ signals and activate a downstream target. Our data provide a conceptual framework to understand how Ca2+ release from physically separated stores is coordinated.

Causative alleles for chondrodysplastic dwarfism, factor XI deficiency, and factor XIII deficiency in the Kumamoto sub-breed of Japanese Brown cattle.

Japanese Brown cattle are the second most popular Wagyu breed, and the Kumamoto sub-breed shows better daily gain and carcass weight. One of the breeding objectives for this sub-breed is to reduce genetic defects. Chondrodysplastic dwarfism and factor VIII deficiency have been identified as genetic diseases in the Kumamoto sub-breed. Previously, we detected individuals in the Kumamoto sub-breed with causative alleles of genetic diseases identified in Japanese Black cattle. In the current study, 11 mutations responsible for genetic diseases in the Wagyu breeds were analyzed to evaluate the risk of genetic diseases in the Kumamoto sub-breed. Genotyping revealed the causative mutations of chondrodysplastic dwarfism, factor XI deficiency, and factor XIII deficiency and suggested the appearance of affected animals in this sub-breed. DNA testing for these diseases is needed to prevent economic loses in beef production using the Kumamoto sub-breed.

Oncostatin M suppresses IL31RA expression in dorsal root ganglia and interleukin-31-induced itching.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intermittent itchy rash. Type 2 inflammatory cytokines such as interleukin (IL)-4, IL-13, and IL-31 are strongly implicated in AD pathogenesis. Stimulation of IL-31 cognate receptors on C-fiber nerve endings is believed to activate neurons in the dorsal root ganglion (DRG), causing itch. The IL-31 receptor is a heterodimer of OSMRß and IL31RA subunits, and OSMRß can also bind oncostatin M (OSM), a pro-inflammatory cytokine released by monocytes/macrophages, dendritic cells, and T lymphocytes. Further, OSM expression is enhanced in the skin lesions of AD and psoriasis vulgaris patients. Objective: The current study aimed to examine the contributions of OSM to AD pathogenesis and symptom expression. Methods: The expression levels of the OSM gene (OSM) and various cytokine receptor genes were measured in human patient skin samples, isolated human monocytes, mouse skin samples, and mouse DRG by RT-qPCR. Itching responses to various pruritogens were measured in mice by counting scratching episodes. Results: We confirmed overexpression of OSM in skin lesions of patients with AD and psoriasis vulgaris. Monocytes isolated from the blood of healthy subjects overexpressed OSM upon stimulation with IL-4 or GM-CSF. Systemic administration of OSM suppressed IL31RA expression in the mouse DRG and IL-31-stimulated scratching behavior. In contrast, systemic administration of OSM increased the expression of IL-4- and IL-13-related receptors in the DRG. Conclusion: These results suggest that OSM is an important cytokine in the regulation of skin monocytes, promoting the actions of IL-4 and IL-13 in the DRG and suppressing the action of IL-31. It is speculated that OSM released from monocytes in skin modulates the sensitivity of DRG neurons to type 2 inflammatory cytokines and thereby the severity of AD-associated skin itch.

Inhibition of cancer cell­platelet adhesion as a promising therapeutic target for preventing peritoneal dissemination of gastric cancer.

Platelets form complexes with gastric cancer (GC) cells via direct contact, enhancing their malignant behavior. In the present study, the molecules responsible for GC cell-platelet interactions were examined and their therapeutic application in inhibiting the peritoneal dissemination of GC was investigated. First, the inhibitory effects of various candidate surface molecules were investigated on platelets and GC cells, such as C-type lectin-like receptor 2 (CLEC-2), glycoprotein VI (GPVI) and integrin αIIbß3, in the platelet-induced enhancement of GC cell malignant potential. Second, the therapeutic effects of molecules responsible for the development and progression of GC were investigated in a mouse model of peritoneal dissemination. Platelet-induced enhancement of the migratory ability of GC cells was markedly inhibited by an anti-GPVI antibody and inhibitor of galectin-3, a GPVI ligand. However, neither the CLEC-2 inhibitor nor the integrin-blocking peptide significantly suppressed this enhanced migratory ability. In experiments using mouse GC cells and platelets, the migratory and invasive abilities enhanced by platelets were significantly suppressed by the anti-GPVI antibody and galectin-3 inhibitor. Furthermore, in vivo analyses demonstrated that the platelet-induced enhancement of peritoneal dissemination was significantly suppressed by the coadministration of anti-GPVI antibody and galectin-3 inhibitor, and was nearly eliminated by the combined treatment. The inhibition of adhesion resulting from GPVI-galectin-3 interaction may be a promising therapeutic strategy for preventing peritoneal dissemination in patients with GC.

Postoperative Remission of Diabetes Mellitus After Gastrectomy in Patients With Diabetes Mellitus and Gastric Cancer.

BACKGROUND/AIM: We investigated the postoperative treatment status for diabetes mellitus and perioperative HbA1c levels in patients with diabetes mellitus and examined the effects of clinical factors on the remission of diabetes mellitus. PATIENTS AND METHODS: In this study, 126 patients with gastric cancer were considered to have diabetes mellitus preoperatively, of whom 79 were treated with oral antidiabetic drugs and/or insulin treatment. We compared diabetic treatment status and HbA1c values between the preoperative and postoperative periods in patients who underwent gastrectomy and examined the effects of clinical factors on improving diabetes mellitus. RESULTS: Of the 79 patients treated preoperatively for diabetes mellitus, 34 (43%) discontinued all medications for diabetes mellitus and for 37 (47%) the therapeutic dose was reduced or switched from insulin to oral antidiabetic drugs. Total gastrectomy was an independent factor for remission of antidiabetic treatments after gastrectomy. Concerning HbA1c levels, only the absence of preoperative insulin use was an independent factor for improvement. However, reconstruction was not a significantly correlated factor for the improvement of postoperative HbA1c levels and reduction of antidiabetic medications after distal gastrectomy. CONCLUSION: Almost all patients discontinued or had their dose of antidiabetic medications reduced after gastrectomy in clinical practice, and special attention should be paid in the management methods for diabetes mellitus in patients who underwent total gastrectomy for gastric cancer.

The expression of platelet-derived growth factor and its receptor in canine and feline meningiomas.

Feline meningiomas usually have benign biological behavior, while canine and human meningiomas are often classified as grade 2 or 3. Activation of the platelet-derived growth factor (PDGF) and its receptor signal pathway through PDGFß/Rß autocrine and paracrine is considered to play an important role in the tumor proliferation and malignant transformation of human meningiomas. However, there have been few studies about the expression of these molecules in canine meningiomas and no studies about their expression in feline meningiomas. We analyzed the PDGFα/Rα and PDGFß/Rß expression in canine and feline meningiomas by immunohistochemistry and western blotting. Immunohistochemically, most canine meningiomas showed the expression of PDGFα (42/44; 95.5%), PDGFRα (44/44; 100%) and PDGFRß (35/44; 79.5%), and a few showed the expression of PDGFß (8/44; 18.2%). In contrast, feline meningiomas were immunopositive for PDGFRα and PDGFRß in all cases (14/14; 100%), while no or a few cases expressed PDGFα (0/14; 0%) and PDGFß (2/14; 14.3%). Western blotting revealed specific bands for PDGFα, PDGFRα and PDGFRß, but not for PDGFß in a canine meningioma. In a feline meningioma, specific bands for PDGFRα and PDGFRß were detected, but not for PDGFα and PDGFß. These results suggested that canine meningiomas commonly express PDGFα/Rα, and thus autocrine or paracrine PDGFα/Rα signaling may be involved in their initiation and progression. Moreover, PDGF negativity may be related to benign biological behavior and a low histopathological grade in feline meningioma.

Convergent activation of Ca2+ permeability in two-pore channel 2 through distinct molecular routes.

TPC2 is a pathophysiologically relevant lysosomal ion channel that is activated directly by the phosphoinositide PI(3,5)P2 and indirectly by the calcium ion (Ca2+)-mobilizing molecule NAADP through accessory proteins that associate with the channel. TPC2 toggles between PI(3,5)P2-induced, sodium ion (Na+)-selective and NAADP-induced, Ca2+-permeable states in response to these cues. To address the molecular basis of polymodal gating and ion-selectivity switching, we investigated the mechanism by which NAADP and its synthetic functional agonist, TPC2-A1-N, induced Ca2+ release through TPC2 in human cells. Whereas NAADP required the NAADP-binding proteins JPT2 and LSM12 to evoke endogenous calcium ion signals, TPC2-A1-N did not. Residues in TPC2 that bind to PI(3,5)P2 were required for channel activation by NAADP but not for activation by TPC2-A1-N. The cryptic voltage-sensing region of TPC2 was required for the actions of TPC2-A1-N and PI(3,5)P2 but not for those of NAADP. These data mechanistically distinguish natural and synthetic agonist action at TPC2 despite convergent effects on Ca2+ permeability and delineate a route for pharmacologically correcting impaired NAADP-evoked Ca2+ signals.

Analysis of surgical outcomes and risk factors for anastomotic leakage following trans-hiatal resection of esophagogastric junction cancer.

BACKGROUND: The trans-hiatal lower esophagectomy is considered less invasive than the trans-thoracic esophagectomy for resection of esophagogastric junction (EGJ) cancer. However, the optimal procedure remains controversial and should be determined while considering both oncological and safety aspects. METHODS: This retrospective study comprised 124 patients that underwent curative resection for EGJ cancer. The study analysis included 93 patients with tumor centers located within 2 cm of the EGJ. Clinicopathological findings and surgical outcomes were compared between patients treated using trans-hiatal and trans-thoracic approaches. RESULTS: Sixty-three patients underwent lower esophagectomy using the trans-hiatal approach (TH-G). The remaining 30 patients underwent esophagectomy using the trans-thoracic approach (TT-E). The TH-G group were older, had a lower prevalence of lymphatic spread, shorter length of esophageal invasion, and shorter operative duration compared to the TT-E group. Although no significant differences in the frequency of postoperative complications, a higher proportion of patients in the TH-G group developed anastomotic leakage (16% vs. 7%, p = 0.33). Univariate and multivariate analyses demonstrated that cardiac comorbidity was an independent risk factor for anastomotic leakage (odds ratio, 5.24; 95% CI, 1.06-25.9; P < 0.05) in TH-G group. Further examination revealed that preoperative cardiothoracic ratio (CTR) with 50% or greater could be surrogate marker as risk factor for anastomotic leakage in TH-G group (35% vs. 7.5%, p < 0.05). CONCLUSIONS: The trans-hiatal approach can be used for resection of EGJ cancer. However, special attention should be paid to the prevention of anastomotic leakage in patients with cardiac comorbidities or a large preoperative CTR.

Defects in early synaptic formation and neuronal function in Prader-Willi syndrome.

Prader-Willi syndrome (PWS), which is a complex epigenetic disorder caused by the deficiency of paternally expressed genes in chromosome 15q11-q13, is associated with several psychiatric dimensions, including autism spectrum disorder. We have previously reported that iPS cells derived from PWS patients exhibited aberrant differentiation and transcriptomic dysregulation in differentiated neural stem cells (NSCs) and neurons. Here, we identified SLITRK1 as a downregulated gene in NSCs differentiated from PWS patient iPS cells by RNA sequencing analysis. Because SLITRK1 is involved in synaptogenesis, we focused on the synaptic formation and function of neurons differentiated from PWS patient iPS cells and NDN or MAGEL2 single gene defect mutant iPS cells. Although ßIII tubulin expression levels in all the neurons were comparable to the level of differentiation in the control, pre- and postsynaptic markers were significantly lower in PWS and mutant neurons than in control neurons. PSD-95 puncta along ßIII tubulin neurites were also decreased. Membrane potential responses were measured while exposed to high K+ stimulation. The neuronal excitabilities in PWS and mutant neurons showed significantly lower intensity than that of control neurons. These functional defects in PWS neurons may reflect phenotypes of neurodevelopmental disorders in PWS.

Fluorescent indicator displacement assay for the discovery of UGGAA repeat-targeted small molecules.

We report that a selective fluorescent indicator NBD-NCD for UGGAA repeats resulted in fluorescence quenching upon binding to RNA and recovered the fluorescence by displacing NBD-NCD with UGGAA repeat-targeted small molecules. The fluorescent indicator displacement assay using NBD-NCD can detect the interaction of small molecules with UGGAA repeats.

Edge-preserving smoothing filter using fast M-estimation method with an automatic determination algorithm for basic width.

Digital filtering is essential for digital imaging, image recognition, and super-resolution technology. For example, the presence of noise in images captured by digital cameras causes deterioration of the image quality and image recognition rate. In order to improve the image recognition rate, noise reduction and edge preservation must be performed during preprocessing. Noise is generally reduced using low-pass filters, such as the Gaussian filter. Although they reduce noise, such filters also have the properties of blurring edge. A strong edge blur reduces the accuracy of the feature detection in image recognition. Therefore, in our previous study, a fast M-estimation Gaussian filter for images (FMGFI) was proposed as an image filter that simultaneously achieves denoising and edge preservation. In the FMGFI, the setting of the optimal basic width of the 2nd order B-spline basis functions is important for achieving simultaneous denoising and edge preservation. In this method, the optimal basic width of the FMGFI was determined not only by manually setting the basic width but also by human judgment of the filtered images. Consequently, the inability to automatically determine the optimal basic width hindered efficient denoising during image processing Therefore, in this research, we develop and propose a method that can automatically determine the optimal basic width of the FMGFI. The previously proposed method calculates using the same basic width for all the pixels over the entire image; in contrast, the proposed method calculates using the basic width automatically determined for each pixel. The experiments confirmed that the method proposed in this study achieves higher denoising and edge preservation performance than the ones used in previous research. The results also showed that it has the highest denoising performance against salt-and-pepper noise as compared to other filters: non-local mean filter, Gaussian filter, median filter, bilateral filter, adaptive bilateral filter, and FMGFI. The experimental results for the Gaussian noise sowed that the proposed method has the same denoising and edge preservation performance as the other filters in visual evaluation. From the above, the proposed method is expected to contribute to efficient denoising and improvement of image quality by using it as a preprocessing.

The Prognostic Implications of Perioperative Serum Cholesterol Levels in Patients With Gastric Cancer.

BACKGROUND/AIM: Although cholesterol is an important indicator of nutritional status, it is also involved in cancer progression. In this study, we investigated the clinical significance of the dynamics of perioperative total cholesterol (T-Cho) levels in patients with gastric cancer (GC). PATIENTS AND METHODS: A total of 212 patients with pathological stage II/III disease who underwent gastrectomy between 2004 and 2020 were enrolled in this retrospective study. The preoperative and postoperative serum T-Cho levels were measured in these patients. RESULTS: Increased serum T-Cho levels were significantly correlated with low preoperative serum albumin levels (p<0.001). Patients with increased serum T-Cho levels after surgery had significantly lower overall and recurrence-free survival rates (p=0.030 and p=0.013, respectively; log-rank test). Cox proportional hazards model revealed that increased serum T-Cho levels (p=0.040), advanced pathological stage (p<0.001), and the provision of adjuvant chemotherapy (p=0.006) were independent prognostic factors for recurrence-free survival in patients with GC. CONCLUSION: Increased serum T-Cho levels after gastrectomy may be an independent prognostic factor in patients with GC.

New Diagnostic Modality Combining Mass Spectrometry and Machine Learning for the Discrimination of Malignant Intraductal Papillary Mucinous Neoplasms.

BACKGROUND: An intraductal papillary mucinous neoplasm (IPMN) is a pancreatic tumor with malignant potential. Although we anticipate a sensitive method to diagnose the malignant conversion of IPMN, an effective strategy has not yet been established. The combination of probe electrospray ionization-mass spectrometry (PESI-MS) and machine learning provides a promising solution for this purpose. METHODS: We prospectively analyzed 42 serum samples obtained from IPMN patients who underwent pancreatic resection between 2020 and 2021. Based on the postoperative pathological diagnosis, patients were classified into two groups: IPMN-low grade dysplasia (n = 17) and advanced-IPMN (n = 25). Serum samples were analyzed by PESI-MS, and the obtained mass spectral data were converted into continuous variables. These variables were used to discriminate advanced-IPMN from IPMN-low grade dysplasia by partial least square regression or support vector machine analysis. The areas under receiver operating characteristics curves were obtained to visualize the difference between the two groups. RESULTS: Partial least square regression successfully discriminated the two disease classes. From another standpoint, we selected 130 parameters from the entire dataset by PESI-MS, which were fed into the support vector machine. The diagnostic accuracy was 88.1%, and the area under the receiver operating characteristics curve was 0.924 by this method. Approximately 10 min were required to perform each method. CONCLUSION: PESI-MS combined with machine learning is an easy-to-use tool with the advantage of rapid on-site analysis. Here, we show the great potential of our system to diagnose the malignant conversion of IPMN, which would be a promising diagnostic tool in clinical settings.

Sel1l May Contributes to the Determinants of Neuronal Lineage and Neuronal Maturation Regardless of Hrd1 via Atf6-Sel1l Signaling.

The endoplasmic reticulum (ER) is the primary site of intracellular quality control involved in the recognition and degradation of unfolded proteins. A variety of stresses, including hypoxia and glucose starvation, can lead to accumulation of unfolded proteins triggering the ER-associated degradation (ERAD) pathway. Suppressor Enhancer Lin12/Notch1 Like (Sel1l) acts as a "gate keeper" in the quality control of de novo synthesized proteins and complexes with the ubiquitin ligase Hrd1 in the ER membrane. We previously demonstrated that ER stress-induced aberrant neural stem cell (NSC) differentiation and inhibited neurite outgrowth. Inhibition of neurite outgrowth was associated with increased Hrd1 expression; however, the contribution of Sel1l remained unclear. To investigate whether ER stress is induced during normal neuronal differentiation, we semi-quantitatively evaluated mRNA expression levels of unfolded protein response (UPR)-related genes in P19 embryonic carcinoma cells undergoing neuronal differentiation in vitro. Stimulation with all-trans retinoic acid (ATRA) for 4 days induced the upregulation of Nestin and several UPR-related genes (Atf6, Xbp1, Chop, Hrd1, and Sel1l), whereas Atf4 and Grp78/Bip were unchanged. Small-interfering RNA (siRNA)-mediated knockdown of Sel1l uncovered that mRNA levels of the neural progenitor marker Math1 (also known as Atoh1) and the neuronal marker Math3 (also known as Atoh3 and NeuroD4) were significantly suppressed at 4 days after ATRA stimulation. Consistent with this result, Sel1l silencing significantly reduced protein levels of immature neuronal marker ßIII-tubulin (also known as Tuj-1) at 8 days after induction of neuronal differentiation, whereas synaptogenic factors, such as cell adhesion molecule 1 (CADM1) and SH3 and multiple ankyrin repeat domain protein 3 (Shank3) were accumulated in Sel1l silenced cells. These results indicate that neuronal differentiation triggers ER stress and suggest that Sel1l may facilitate neuronal lineage through the regulation of Math1 and Math3 expression.