Human stem-cell-derived models provide the promise of accelerating our understanding of brain disorders, but not knowing whether they possess the ability to mature beyond mid- to late-fetal stages ...potentially limits their utility. We leveraged a directed differentiation protocol to comprehensively assess maturation in vitro. Based on genome-wide analysis of the epigenetic clock and transcriptomics, as well as RNA editing, we observe that three-dimensional human cortical organoids reach postnatal stages between 250 and 300 days, a timeline paralleling in vivo development. We demonstrate the presence of several known developmental milestones, including switches in the histone deacetylase complex and NMDA receptor subunits, which we confirm at the protein and physiological levels. These results suggest that important components of an intrinsic in vivo developmental program persist in vitro. We further map neurodevelopmental and neurodegenerative disease risk genes onto in vitro gene expression trajectories to provide a resource and webtool (Gene Expression in Cortical Organoids, GECO) to guide disease modeling.
Gastric cancer is a considerable burden for worldwide patients. And diffuse gastric cancer is the most insidious subgroup with poor survival. The phenotypic characterization of the diffuse gastric ...cancer cell line can be useful for gastric cancer researchers. In this article, we aimed to characterize the diffuse gastric cancer cells with MRI and transcriptomic data. We hypothesized that gene expression pattern is associated with the phenotype of the cells and that the heterogeneous enhancement pattern and the high tumorigenicity of SNU484 can be modulated by the perturbation of the highly expressed gene.
We evaluated the 9.4 T magnetic resonance imaging and transcriptomic data of the orthotopic mice models from diffuse gastric cancer cells such as SNU484, Hs746T, SNU668, and KATO III. We included MKN74 as an intestinal cancer control cell. After comprehensive analysis integrating MRI and transcriptomic data, we selected CD34 and validated the effect by shRNA in the BALB/c nude mice models.
SNU484, SNU668, Hs746T, and MKN74 formed orthotopic tumors by the 5 weeks after cell injection. The diffuse phenotype was found in the SNU484 and Hs746T. SNU484 was the only tumor showing the heterogeneous enhancement pattern on T2 images with a high level of CD34 expression. Knockdown of CD34 decreased the round-void shape in the H&E staining (P = 0.028), the heterogeneous T2 enhancement, and orthotopic tumorigenicity (100% vs 66.7%). The RNAseq showed that the suppressed CD34 is associated with the downregulated gene-sets of the extracellular matrix remodeling.
Suppression of CD34 in the human-originated gastric cancer cell suggests that it is important for the round-void histologic shape, heterogeneous enhancement pattern on MRI, and the growth of gastric cancer cell line.
In eukaryotic cells, mitochondria are closely tethered to the endoplasmic reticulum (ER) at sites called mitochondria‐associated ER membranes (MAMs). Ca2+ ion and phospholipid transfer occurs at MAMs ...to support diverse cellular functions. Unlike those in yeast, the protein complexes involved in phospholipid transfer at MAMs in humans have not been identified. Here, we determine the crystal structure of the tetratricopeptide repeat domain of PTPIP51 (PTPIP51_TPR), a mitochondrial protein that interacts with the ER‐anchored VAPB protein at MAMs. The structure of PTPIP51_TPR shows an archetypal TPR fold, and an electron density map corresponding to an unidentified lipid‐like molecule probably derived from the protein expression host is found in the structure. We reveal functions of PTPIP51 in phospholipid binding/transfer, particularly of phosphatidic acid, in vitro. Depletion of PTPIP51 in cells reduces the mitochondrial cardiolipin level. Additionally, we confirm that the PTPIP51–VAPB interaction is mediated by the FFAT‐like motif of PTPIP51 and the MSP domain of VAPB. Our findings suggest that PTPIP51 is a phospholipid transfer protein with a MAM‐tethering function.
SYNOPSIS
The crystal structure and biochemical analyses of PTPIP51, a mitochondrial protein localized at the mitochondria‐associated ER membrane (MAM), revealed its phospholipid binding and transfer activity.
The crystal structure of the TPR domain of PTPIP51 at 1.45 Å resolution revealed the presence of a lipid‐like serpentine electron density.
PTPIP51 has phospholipid (especially phosphatidic acid) binding and transfer functions in vitro.
Mitochondrial cardiolipin levels are affected by PTPIP51.
The crystal structure and biochemical analyses of PTPIP51, a mitochondrial protein localized at the mitochondria‐associated ER membrane (MAM), revealed its phospholipid binding and transfer activity.
Objective
Helicobacter pylori
(HP) is known to play an important role in the development of gastric cancer (GC). The aim of this study was to analyze the effect of HP eradication on the survival rate ...and cancer recurrence in patients who underwent subtotal gastrectomy for GC.
Design
Totally 1,031 patients diagnosed with gastric adenocarcinoma who received surgical treatment at the Seoul National University Bundang Hospital from 2003 to 2017 and positive for HP infection were analyzed. The overall and GC-related survival according to HP eradication were compared; risk factors for GC-specific death and cancer recurrence were analyzed, and propensity score matching (PSM) was performed.
Results
Statistically significant benefits of overall and GC-specific survival were observed in the eradicated group compared to the non-eradicated group (
P
< 0.001), and these benefits were maintained after PSM (
P
< 0.001) in both of early and advance stage. In Cox proportional hazards multivariate analyses, cancer stage (stage II, adjusted hazard ratio aHR = 9.33,
P
< 0.001; stage III or IV, aHR = 26.17,
P
< 0.001), and HP positivity (aHR = 3.41,
P
= 0.001) were independent risk factors for GC-specific death; cancer stage (cancer stage II, aHR = 7.08,
P
< 0.001; cancer stage III or IV, aHR = 19.64,
P
< 0.001) and HP positivity (aHR = 2.70;
P
= 0.005) were independent risk factors for cancer recurrence.
Conclusion
Our results suggest that HP needed to be conducted more intensively in patients who are surgically treated for GC, regardless of cancer stage.
In this review article, we focus on the various types of materials used in biomedical implantable devices, including the polymeric materials used as substrates and for the packaging of such devices. ...Polymeric materials are used because of the ease of fabrication, flexibility, and their biocompatible nature as well as their wide range of mechanical, electrical, chemical, and thermal behaviors when combined with different materials as composites. Biocompatible and biostable polymers are extensively used to package implanted devices, with the main criteria that include gas permeability and water permeability of the packaging polymer to protect the electronic circuit of the device from moisture and ions inside the human body. Polymeric materials must also have considerable tensile strength and should be able to contain the device over the envisioned lifetime of the implant. For substrates, structural properties and, at times, electrical properties would be of greater concern. Section gives an introduction of some medical devices and implants along with the material requirements and properties needed. Different synthetic polymeric materials such as polyvinylidene fluoride, polyethylene, polypropylene, polydimethylsiloxane, parylene, polyamide, polytetrafluoroethylene, poly(methyl methacrylate), polyimide, and polyurethane have been examined, and liquid crystalline polymers and nanocomposites have been evaluated as biomaterials that are suitable for biomedical packaging (section ). A summary and glimpse of the future trend in this area has also been given (section ). Materials and information used in this manuscript are adapted from papers published between 2010 and 2015 representing the most updated information available on each material.
Once a key factor behind Vietnam's successful Doi Moi (restoration) economic reforms, the rice-centered agriculture of the VMD is now confronted by the new pressure of climate change impacts, ...including the intensifying salinity intrusion (SI). The SI menace has partly triggered the delta-wide emergence of new adaptive livelihood models across the VMD, including the prawn rice rotational crop (PRRC) that is arguably the most prominent. Research on the SI-driving factors is rapidly increasing in numbers, yet little synthesis has been done. Likewise, several studies have investigated the economic benefits of PRRC; less emphasis has placed on environmental and societal aspects, hence the questionable sustainability. This study, therefore, contributes a composite literature review, targeting two SI-related aspects: (i) key factors driving the intensification of SI in recent years across the Mekong Delta, and (ii) current understanding of the sustainability of PRRC. Results from the first review assignment highlight the four key SI-driving factors: riverbed incision, land subsidence, upstream dams, and sea-level rise. Also remarked are the critical absence of studies addressing multiple drivers and the need for a decoupling model to quantify the relative importance of each factor to strategize the adaptive measures. For PRRC, we reveal that while economic benefits have been widely reported, potential negative impacts of this model related to environmental and social aspects are lacking. Therefore, while the lucrative prawn trade might financially benefit the farmers', the economic benefit is marred by the underlying negative environmental impacts and social inequalities, limiting overall sustainability. This study also provides a case study to notify the spatial-temporal trends of PRRC in the last three decades and evaluate the associated geographical and social factors. Kien Giang province was selected as the study site since it is the largest PRRCacross the VMD. The lessons from Kien Giang can also be applied to other transformative agricultural models in both Mekong Delta and other deltas worldwide.
Display omitted
•113 studies of Vietnamese Mekong Delta salinity intrusion are reviewed.•Sea level rise, hydropower dams and land subsidence are the commonly cited drivers.•42 studies related to the prawn rice rotational crops are reviewed.•Little evidence of social and environment sustainability while economic benefits are common.•Provides an example of the spatial-temporal development of the rotational crop from the 1990s.
Although different gender associations between self-rated health (SRH) and mortality have been reported, the results of the respective studies have been inconsistent and little is known about the ...cause-specific relation of mortality with SRH by gender. Therefore, to evaluate the gender differences in all-cause or specific causes of mortality by SRH, this retrospective cohort study was conducted using the data of 19,770 Korean adults aged 50 years and over who underwent health screening at Seoul National University Hospital between March 1995 and December 2008. SRH was surveyed using a simple questionnaire, and the all-cause mortality and cause-specific mortality were followed up from baseline screening until December 31, 2016. Results showed that the relationship between SRH and all-cause mortality differed by gender, and the differences also varied depending on the cause of death. In men, the adjusted hazard ratio (aHR) of all-cause mortality was higher in the poor SRH group than the very good SRH groups even after adjustment for socio-demographic, clinical, and behavioral risk factors (aHR:1.97, 95% CI 1.51-2.56), and these results were similar to those for cancer, cardiovascular, and respiratory disease mortalities (aHR:1.52, 95% CI 0.93-2.50; aHR: 2.11, 95% CI 1.19-3.74; aHR:10.30, 95% CI 2.39-44.44, respectively). However, in women, the association between SRH and all-cause mortality was insignificant, and inverse relationships were found for cardiovascular and respiratory disease mortalities in the poor and very good SRH groups. Cancer mortality had a positive relation with SRH (aHR: 1.14, 95% CI 0.75-1.72; aHR: 2.58, 95% CI 1.03-6.48; aHR: 0.49, 95% CI 0.24-0.98; aHR: 0.15, 95% CI 0.04-0.57: all-cause, cancer, cardiovascular, and respiratory disease mortalities, respectively). Clinicians need to take these gender differences by SRH into account when evaluating the health status of over-middle aged adults.
Strand selection is a critical step in microRNA (miRNA) biogenesis. Although the dominant strand may change depending on cellular contexts, the molecular mechanism and physiological significance of ...such alternative strand selection (or “arm switching”) remain elusive. Here we find miR-324 to be one of the strongly regulated miRNAs by arm switching and identify the terminal uridylyl transferases TUT4 and TUT7 to be the key regulators. Uridylation of pre-miR-324 by TUT4/7 re-positions DICER on the pre-miRNA and shifts the cleavage site. This alternative processing produces a duplex with a different terminus from which the 3′ strand (3p) is selected instead of the 5′ strand (5p). In glioblastoma, the TUT4/7 and 3p levels are upregulated, whereas the 5p level is reduced. Manipulation of the strand ratio is sufficient to impair glioblastoma cell proliferation. This study uncovers a role of uridylation as a molecular switch in alternative strand selection and implicates its therapeutic potential.
Display omitted
•Arm switching of miR-324 is regulated by terminal uridylyl transferases•TUT4 and TUT7 uridylate pre-miR-324, resulting in alternative processing by DICER•The altered cleavage leads to selection of the 3p strand instead of the 5p strand•Perturbation of the miR-324 arm usage disrupts glioblastoma cell proliferation
Alternative strand selection (or “arm switching”) of miRNAs takes place depending on cellular context, but its molecular mechanism is unknown. Kim et al. identify miR-324 as one of the prominently regulated miRNAs by arm switching and reveal the mechanism involving uridylation.
Background
Ambient air pollutants are considered significant factors that influence allergic diseases. This study aimed to evaluate the effect of ambient air pollution on the medical costs of ...allergic rhinitis (AR) through a time‐series analysis.
Methods
We used data from the Korean National Health Insurance Database from January 2016 to December 2019. The total cost for medical management and outpatient prescriptions for AR, estimated by the National Health Insurance Service for 25 districts, was summed as the total medical costs. The monthly concentrations of PM10, PM2.5, NO2, CO, O3, and SO2 were calculated, and time‐series analysis was performed to evaluate the effect of ambient air pollutants on the medical cost of AR using the seasonal autoregressive integrated moving average (SARIMA) model.
Results
Time‐series analysis revealed that the concentrations of PM10, NO2, and CO were significantly associated with an increased medical cost of AR when adjusting for monthly differences and seasonality (p = 0.048, p = 0.001, and p = 0.001 respectively). The increase in medical costs of AR was 6.22% (95% confidence interval CI: 0.0%–12.37%), 11.27% (95% CI: 6.03%–16.50%), and 11.05% (95% CI: 7.09%–15.01%) per one standard deviation increase in PM10, NO2, and CO respectively.
Conclusions
The monthly concentrations of PM10, NO2, and CO were significantly associated with the increased medical costs of AR when adjusting for monthly differences and seasonality. This analysis provides a better understanding of the health and economic effects of ambient air pollutants on AR.
Level of Evidence
N/A Laryngoscope, 133:1828–1833, 2023
To consider the seasonality and monthly differences of both allergic rhinitis and air pollutants, we performed a time‐series analysis using the seasonal autoregressive integrated moving average (SARIMA) model to adjust for monthly differences and seasonality. Covariate‐adjusted SARIMA analysis showed that 6.22%, 11.27%, and 11.05% increases in the medical costs of AR corresponded to an increase in 1 SD of PM10, NO2, and CO. This analysis provides a better understanding of the health and economic effects of ambient air pollutants on allergic rhinitis.
Although renal hyperfiltration (RHF) or an abnormal increase in GFR has been associated with many lifestyles and clinical conditions, including diabetes, its clinical consequence is not clear. RHF is ...frequently considered to be the result of overestimating true GFR in subjects with muscle wasting. To evaluate the association between RHF and mortality, 43,503 adult Koreans who underwent voluntary health screening at Seoul National University Hospital between March of 1995 and May of 2006 with baseline GFR≥60 ml/min per 1.73 m(2) were followed up for mortality until December 31, 2012. GFR was estimated with the Chronic Kidney Disease Epidemiology Collaboration creatinine equation, and RHF was defined as GFR>95th percentile after adjustment for age, sex, muscle mass, and history of diabetes and/or hypertension medication. Muscle mass was measured with bioimpedance analysis at baseline. During the median follow-up of 12.4 years, 1743 deaths occurred. The odds ratio of RHF in participants with the highest quartile of muscle mass was 1.31 (95% confidence interval 95% CI, 1.11 to 1.54) compared with the lowest quartile after adjusting for confounding factors, including body mass index. The hazard ratio of all-cause mortality for RHF was 1.37 (95% CI, 1.11 to 1.70) by Cox proportional hazards model with adjustment for known risk factors, including smoking. These data suggest RHF may be associated with increased all-cause mortality in an apparently healthy population. The possibility of RHF as a novel marker of all-cause mortality should be confirmed.
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