Human mesenchymal stem cells (MSCs) are known to have anti-inflammatory and immunomodulatory functions; thus, several MSC products have been applied as cell therapy in clinical trials worldwide. ...Recent studies have demonstrated that MSC spheroids have superior anti-inflammatory and immunomodulatory functions to a single cell suspension. Current methods to prepare MSC spheroids include hanging drop, concave microwell aggregation, spinner flask, and gravity circulation. However, all these methods have limitations such as low scalability, easy cell clumping, low viability, and irregular size distribution. Here, we present a nano-patterned culture plasticware named PAMcell™ 3D plate to overcome these limitations. Nano-sized silica particles (700 nm) coated with RGD peptide were arrayed into fusiform onto the PLGA film. This uniform array enabled the seeded MSCs to grow only on the silica particles, forming uniform-sized semi-spheroids within 48 h. These MSC spheroids have been shown to have enhanced stemness, anti-inflammatory, and immunomodulatory functions, as revealed by the increased expression of stem cell markers (Oct4, Sox2, and Nanog), anti-inflammatory (IL-10, TSG6, and IDO), and immunomodulatory molecules (HGF, VEGF, CXCR4) both at mRNA and protein expression levels. Furthermore, these MSC spheroids demonstrated an increased palliative effect on glycemic control in a multiple low-dose streptozotocin-induced diabetes model compared with the same number of MSC single cell suspensions. Taken together, this study presents a new method to produce uniform-sized MSC spheroids with enhanced anti-inflammatory and immunomodulatory functions in vitro and in vivo.
•Mesenchymal stem cells have anti-inflammatory and immunomodulatory functions.•3D MSC spheroids have superior anti-inflammatory and immunomodulatory functions to 2D monolayer cells.•MSC spheroids formed on a new culture device named PAMcell™ have enhanced functions in vitro and in vivo.
Multi-attribute recognition is one of the main topics attaining much attention in the pattern recognition field these days. The conventional approaches to multi-attribute recognition has mainly ...focused on developing an individual classifier for each attribute. However, due to rapid growth of deep learning techniques, multi-attribute recognition using multi-task learning enables the simultaneous recognition of more than two relevant recognition tasks through a single network. A number of studies on multi-task learning have shown that it is effective in improving recognition performance for all tasks when related tasks are learned together. However, since there are no specific criteria for determining the relationship among attributes, it is difficult and confusing to choose a good combination of tasks that have a positive impact on recognition performance. As one way to solve this problem, we propose a multi-attribute recognition method based on the novel output representations of a deep learning network which automatically learns the exclusive and joint relationship among attribute recognition tasks. We apply our proposed method to multi-attribute recognition of facial images, and confirm the effectiveness through experiments on a benchmark database.
Background
The Korean regulatory authority has enacted legislation to expedite the new drug approval (NDA) process. However, the effectiveness of such efforts in reducing review time and drug ...approval delays between Korea and the USA/EU remains to be evaluated.
Methods
We investigated NDA trends in Korea from 2011 to 2020 using approval information from pharmaceutical companies. We compared the changes in the actual review duration according to active ingredient (chemical vs. biological), orphan status, therapeutic class, and NDA review process. We estimated the submission and approval gaps of new drugs between Korea and the US and EU across the study period.
Results
For 235 new drugs, the median NDA review time was 315 days, with a significant increase in the delay (average 15.4 days) over time. Biological drugs had a 43.2-day delay for approval than the time taken for approving chemical drugs. The median NDA review time for orphan drugs was 130.4 days faster than that for others, although the difference diminished after 2016. Good manufacturing practice reviews played a crucial role in delaying review time. The median submission and approval gaps in Korea were 493 and 551 days, respectively, compared to those of the US and EU.
Conclusions
Despite recent legislative initiatives, the delay in the NDA review timeline has steadily increased over 10 years in Korea. Delays in orphan drugs reviews increased after the enactment of the ‘Rare Disease Management Act’ in 2016. Careful enforcement of relevant laws and supplementary actions is required to increase new drug accessibility.
Background: Diet modification, especially a decrease in salt intake, might be an important non-pharmacological strategy to improve chronic kidney disease (CKD) prognosis. Objectives: We conducted a ...prospective cohort study to investigate whether an intensive low-salt diet education program effectively attenuated the rate of renal function decline in hypertensive patients with CKD. Methods: This cohort study recruited 171 participants from a previous open-labelled, case-controlled, randomized clinical trial that originally consisted of 245 hypertensive CKD patients who were assigned to two groups, intensive low-salt diet or conventional education. We evaluated the renal outcomes, which included the rate of change in estimated glomerular filtration rate (eGFR) per year, the increase in serum creatinine ≥50%, the decrease in eGFR ≥30%, and the percent change in albuminuria throughout the entire study period. Results: The baseline characteristics of the cohort participants between the two groups were similar at the time of trial phase randomization. During the whole study period, the rate of renal function decline was significantly faster in the conventional group (0.11 ± 4.63 vs. –1.53 ± 3.04 mL/min/1.73 m 2 /year, p = 0.01). The percent of incremental change in serum creatinine ≥50% was 1.1% in the intensive group and 8.2% in the conventional group (p = 0.025), and the percent of decremental change in eGFR ≥30% was 3.3% in the intensive group and 11.1% in the conventional group (p= 0.048). With logistic regression analysis adjusted for related factors, we found that the conventional group showed a higher risk for deterioration in serum creatinine and eGFR during the entire study period. Especially, we found that the intensive education program preserved eGFR in participants with one, several, or all of the following characteristics at the time of randomization: older age, female, obese, had higher protein intake, higher amounts of albuminuria, higher salt intake. Conclusion: This cohort study demonstrated that an intensive low-salt diet education program attenuated the rate of renal function decline in hypertensive CKD patients independent of its effect on lowering salt intake or albuminuria during the 36 months of follow-up.
Abstract Objectives This study was aimed to investigate gastrointestinal (GI) dysfunction in patients with Parkinson's disease (PD) compared with those in patients with other parkinsonian disorders, ...and to characterize parkinsonian motor and non-motor correlates for GI dysfunction. Methods Consecutive patients with PD, atypical parkinsonism (P-plus) and vascular parkinsonism (VP) were enrolled in this multicenter systematic survey. Data for weight loss, appetite loss, sialorrhea, dysphagia, gastroesophageal reflux disease (GERD) and constipation were simultaneously collected using symptom-specific, structured questionnaires. For the PD group, information for onset age, PD duration, anti-parkinsonian drug dosages, unified PD rating scale, and Hoehn & Yahr stage were collected at the time of the interview. Results Enrolled in the study were 329 PD, 82 P-plus, and 62 VP patients. GI symptom frequencies were similar in PD and other parkinsonian groups. Among the PD patients, constipation was the most common symptom, followed by appetite loss, weight loss, dysphagia, sialorrhea, and GERD (64.9%, 45.4%, 35.7%, 19.4%, 15.0%, and 9.6%, respectively). Dysphagia, sialorrhea, and constipation became more frequent with more advanced PD stages. Cognition, sleep and mood disturbances were significantly associated with weight loss, appetite loss, and dysphagia, whereas bradykinesia, axial and postural instability with gait disturbance were associated with dysphagia. Conclusions GI disturbance is common in patients with non-PD parkinsonism as well as in those with PD. GI symptoms correlated with distinct parkinsonian motor and nonmotor features in PD. Further studies are warranted to reveal the pathophysiological mechanisms and prognostic features of GI disturbances in parkinsonian disorders.
SCA17 is an autosomal dominant cerebellar ataxia with expansion of the CAG/CAA trinucleotide repeats in the TATA-binding protein (TBP) gene. SCA17 can have various clinical presentations including ...parkinsonism, ataxia, chorea and dystonia. SCA17 is diagnosed by detecting the expanded CAG repeats in the TBP gene; however, in the literature, pathologic repeat numbers as low as 41 overlap with normal repeat numbers.
The subjects in this study included patients with involuntary movement disorders such as cerebellar ataxia, parkinsonism, chorea and dystonia who visited Seoul National University Hospital between Jan. 2006 and Apr. 2014 and were screened for SCA17. Those who were diagnosed with other genetic diseases or nondegenerative diseases were excluded. DNA from healthy subjects who did not have a family history of parkinsonism, ataxia, psychiatric symptoms, chorea or dystonia served as the control. In total, 5242 chromosomes from 2099 patients and 522 normal controls were analyzed.
The total number of patients included in the analysis was 2099 (parkinsonism, 1706; ataxia, 345; chorea, 37; and dystonia, 11). In the normal control, up to 44 repeats were found. In the 44 repeat group, there were 7 (0.3%) patients and 1 (0.2%) normal control. In 43 repeat group, there were 8 (0.4%) patients and 2 (0.4%) normal controls. In the 42 repeat group, there were 16 (0.8%) patients and 3 (0.6%) normal controls. In 41 repeat group, there were 48 (2.3%) patients and 8 (1.5%) normal controls. Considering the overlaps and non-significant differences in allelic frequencies between the patients and the normal controls with low-expansions, we could not determine a definitive cutoff value for the pathologic CAG repeat number of SCA17.
Because the statistical analysis between the normal controls and patients with low range expansions failed to show any differences so far, we must consider that clinical cases with low range expansions could be idiopathic movement disorders showing coincidental CAG/CAA expansions. Thus, we need to reconsider the pathologic role of low range expansions (41-42). Long term follow up and comprehensive investigations using autopsy and imaging studies in patients and controls with low range expansions are necessary to determine the cutoff value for the pathologic CAG repeat number of SCA17.
Ischemic stroke mainly caused by middle cerebral artery occlusion (MCAo) represents the major type of stroke; however, there are still very limited therapeutic options for the stroke-damaged ...patients. In this study, we evaluated the neurogenic and therapeutic potentials of human neural stem cells (NSCs) overexpressing brain-derived neurotrophic factor (HB1.F3.BDNF) following transplantation into a rodent model of MCAo. F3.BDNF human NSCs (F3.BDNF) were transplanted into the contralateral side of striatum at 7 days after MCAo, and the transplanted animals were monitored up to 8 weeks using animal MRI and various behavioral tests before they were sacrificed for immunohistochemical analysis. Interestingly, animal MRI results indicate that the majority of contralaterally transplanted neural stem cells were migrated to the peri-infarct area, showing a pathotropism. Transplanted animals exhibited significant behavioral improvements in stepping, rotarod, and modified neurological severity score (mNSS) tests. We also found that the transplanted human cells were colocalized with nestin, DCX, MAP2, DARPP-32, TH, GAD65/67-positive cells, of which results can be correlated with neural regeneration and behavioral recovery in the transplanted animals. More importantly, we were able to detect high levels of human BDNF protein expression, presumably derived from the transplanted F3.BDNF. Taken together, these results provide strong evidence that human neural stem cells (F3.BDNF) are effective in treating stroke animal models.
•Patients with major depression had 14 proteins dysregulated compared to controls.•Six proteins were altered in patients with bipolar disorder compared to controls.•F13A1, PPBP, PF4, GAPDH, and ...TMSB4X were dysregulated in both disorders.
Emerging high-throughput proteomic technologies have recently been considered as a powerful means of identifying substrates involved in mood disorders. We performed proteomic profiling using liquid chromatography–tandem mass spectrometry to identify dysregulated proteins in plasma samples of 42 and 45 patients with major depressive disorder (MDD) and bipolar disorder (BD), respectively, in comparison to 51 healthy controls (HCs). Fourteen and six proteins in MDD and BD patients, respectively, were differentially expressed compared to HCs, among which coagulation factor XIII A chain (F13A1), platelet basic protein (PPBP), platelet facor 4 (PF4), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and thymosin beta-4 (TMSB4X) were altered in both disorders. For proteins dysregulated in both, except F13A1, higher fold changes were observed in MDD than in BD patients. These findings may help identify candidate biomarkers of mood disorders and elucidate their underlying pathophysiology and biochemical abnormalities.
Although suicide among older adults is increasing in severity in the aging among South Koreans, older adult depression and anxiety, which are two crucial factors affecting suicide in this population, ...are not adequately addressed by the status quo. Existing products and services emphasize physical needs; however, they still lack a user-oriented approach. Moreover, offers for mental health care are costly and exclude potential users from the development process, thus inhibiting older adults from having better access to such services. To address this problem, we designed and developed a mental health care chatbot, Yeonheebot, to decrease anxiety and depression among older adults. Yeonheebot initiates conversations regarding daily care for the well-being of older adults and provides features related to their interests as initiatives for using the mental health care chatbot. To examine whether a short-term, yet repeating conversation with the agent could help reduce anxiety and depression among older adults, we conducted a 2-week field study with 25 users. The results indicate that the constant use of Yeonheebot decreased the levels of anxiety and depression by 36% and 18%, respectively. Our research implies that simple and repeated interactions could help Korean older adults cope with anxiety and depression.
This study was to optimize the composition and content of precursors and reaction conditions (reaction temperature and time, and water content) for a desirable beef broth-like reaction flavor with ...Tenebrio molitor (mealworm) based on consumer acceptability. Four precursors, such as cysteine, methionine, garlic powder, and mushroom powder, were selected by omission test. A total of 10 precursor combinations with 15 points, the highest value of consumer acceptability, were optimized in the response surface methodology (RSM) model using the composition and content of the selected four precursors as independent variables and consumer acceptability as the dependent variable. The reaction temperature (122.027°C), reaction time (60 min), and water content (5.053 mL) was also selected as the optimal reaction condition in this study. This study is significant in that it is the development of beef broth-like reaction flavor with edible insect and then is possible to develop domestic flavor and/or seasoning materials with quality competitiveness.
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