Structural atlas of human primary microRNAs generated by SHAPE-MaP.

MicroRNA (miRNA) maturation is critically dependent on structural features of primary transcripts (pri-miRNAs). However, the scarcity of determined pri-miRNA structures has limited our understanding of miRNA maturation. Here, we employed selective 2'-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP), a high-throughput RNA structure probing method, to unravel the secondary structures of 476 high-confidence human pri-miRNAs. Our SHAPE-based structures diverge substantially from those inferred solely from computation, particularly in the apical loop and basal segments, underlining the need for experimental data in RNA structure prediction. By comparing the structures with high-throughput processing data, we determined the optimal structural features of pri-miRNAs. The sequence determinants are influenced substantially by their structural contexts. Moreover, we identified an element termed the bulged GWG motif (bGWG) with a 3' bulge in the lower stem, which promotes processing. Our structure-function mapping better annotates the determinants of pri-miRNA processing and offers practical implications for designing small hairpin RNAs and predicting the impacts of miRNA mutations.

A quantitative map of human primary microRNA processing sites.

Maturation of canonical microRNA (miRNA) is initiated by DROSHA that cleaves the primary transcript (pri-miRNA). More than 1,800 miRNA loci are annotated in humans, but it remains largely unknown whether and at which sites pri-miRNAs are cleaved by DROSHA. Here, we performed in vitro processing on a full set of human pri-miRNAs (miRBase version 21) followed by sequencing. This comprehensive profiling enabled us to classify miRNAs on the basis of DROSHA dependence and map their cleavage sites with respective processing efficiency measures. Only 758 pri-miRNAs are confidently processed by DROSHA, while the majority may be non-canonical or false entries. Analyses of the DROSHA-dependent pri-miRNAs show key cis-elements for processing. We observe widespread alternative processing and unproductive cleavage events such as "nick" or "inverse" processing. SRSF3 is a broad-acting auxiliary factor modulating alternative processing and suppressing unproductive processing. The profiling data and methods developed in this study will allow systematic analyses of miRNA regulation.

Genomic Clustering Facilitates Nuclear Processing of Suboptimal Pri-miRNA Loci.

Nuclear processing of most miRNAs is mediated by Microprocessor, comprised of RNase III enzyme Drosha and its cofactor DGCR8. Here, we uncover a hidden layer of Microprocessor regulation via studies of Dicer-independent mir-451, which is clustered with canonical mir-144. Although mir-451 is fully dependent on Drosha/DGCR8, its short stem and small terminal loop render it an intrinsically weak Microprocessor substrate. Thus, it must reside within a cluster for normal biogenesis, although the identity and orientation of its neighbor are flexible. We use DGCR8 tethering assays and operon structure-function assays to demonstrate that local recruitment and transfer of Microprocessor enhances suboptimal substrate processing. This principle applies more broadly since genomic analysis indicates suboptimal canonical miRNAs are enriched in operons, and we validate several of these experimentally. Proximity-based enhancement of suboptimal hairpin processing provides a rationale for genomic retention of certain miRNA operons and may explain preferential evolutionary emergence of miRNA operons.

Molecular Basis for the Single-Nucleotide Precision of Primary microRNA Processing.

Microprocessor, composed of DROSHA and its cofactor DGCR8, initiates microRNA (miRNA) biogenesis by processing the primary transcripts of miRNA (pri-miRNAs). Here we investigate the mechanism by which Microprocessor selects the cleavage site with single-nucleotide precision, which is crucial for the specificity and functionality of miRNAs. By testing ∼40,000 pri-miRNA variants, we find that for some pri-miRNAs the cleavage site is dictated mainly by the mGHG motif embedded in the lower stem region of pri-miRNA. Structural modeling and deep-sequencing-based complementation experiments show that the double-stranded RNA-binding domain (dsRBD) of DROSHA recognizes mGHG to place the catalytic center in the appropriate position. The mGHG motif as well as the mGHG-recognizing residues in DROSHA dsRBD are conserved across eumetazoans, suggesting that this mechanism emerged in an early ancestor of the animal lineage. Our findings provide a basis for the understanding of miRNA biogenesis and rational design of accurate small-RNA-based gene silencing.

Accuracy of artificial intelligence-assisted growth prediction in skeletal Class I preadolescent patients using serial lateral cephalograms for a 2-year growth interval.

OBJECTIVE: To investigate the accuracy of artificial intelligence-assisted growth prediction using a convolutional neural network (CNN) algorithm and longitudinal lateral cephalograms (Lat-cephs). MATERIALS AND METHODS: A total of 198 Japanese preadolescent children, who had skeletal Class I malocclusion and whose Lat-cephs were available at age 8 years (T0) and 10 years (T1), were allocated into the training, validation, and test phases (n = 161, n = 17, n = 20). Orthodontists and the CNN model identified 28 hard-tissue landmarks (HTL) and 19 soft-tissue landmarks (STL). The mean prediction error values were defined as 'excellent,' 'very good,' 'good,' 'acceptable,' and 'unsatisfactory' (criteria: 0.5 mm, 1.0 mm, 1.5 mm, and 2.0 mm, respectively). The degree of accurate prediction percentage (APP) was defined as 'very high,' 'high,' 'medium,' and 'low' (criteria: 90%, 70%, and 50%, respectively) according to the percentage of subjects that showed the error range within 1.5 mm. RESULTS: All HTLs showed acceptable-to-excellent mean PE values, while the STLs Pog', Gn', and Me' showed unsatisfactory values, and the rest showed good-to-acceptable values. Regarding the degree of APP, HTLs Ba, ramus posterior, Pm, Pog, B-point, Me, and mandibular first molar root apex exhibited low APPs. The STLs labrale superius, lower embrasure, lower lip, point of lower profile, B', Pog,' Gn' and Me' also exhibited low APPs. The remainder of HTLs and STLs showed medium-to-very high APPs. CONCLUSION: Despite the possibility of using the CNN model to predict growth, further studies are needed to improve the prediction accuracy in HTLs and STLs of the chin area.

Association between social jetlag and leisure-time physical activity and muscle strengthening exercise in young adults: findings from a nationally representative sample in South Korea.

OBJECTIVES: Social jetlag (SJL), which is characterised by a misalignment between biological and social time, is associated with cardiometabolic risk factors. This study investigated the relationship between SJL, leisure-time physical activity (LTPA) and muscle strengthening exercise (MSE) in young adults. STUDY DESIGN: This was a cross-sectional study. METHODS: This cross-sectional study included a nationally representative sample of young adults aged 19-29 years (n = 2113). SJL was calculated as the difference in the midpoint of sleep onset and offset time between weekdays and weekends. The dependent variables were engagement in ≥150 min/week of moderate-to-vigorous LTPA and engagement in MSE ≥2 days/week based on guidelines provided by the World Health Organisation. Logistic regression analysis was performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Non-linear relationships were estimated using restricted cubic spline regression. RESULTS: The study population comprised 975 men and 1138 women. Among participants, 4.6% had <0 min, 41.9% had 0-59 min, 25.7% had 60-119 min and 27.7% had ≥120 min SJL. Those with ≥120 min SJL had a reduced likelihood of achieving the recommended level of LTPA (OR: 0.71, 95% CI: 0.52-0.95) and MSE (OR: 0.73, 95% CI: 0.55-0.97). In the non-linear model, an inverse U-shaped association was observed, wherein the highest probability of meeting the recommended level of LTPA and MSE was observed in those with 45 min SJL, decreasing after this threshold. CONCLUSIONS: Individuals with ≥120 min SJL were less likely to engage in the recommended level of both aerobic and anaerobic exercise. Although future studies using a longitudinal design are required to elucidate the causal relationship between SJL and physical activity, the current findings suggest that physical inactivity during leisure time may play an important role in the increased risk of cardiometabolic abnormalities in young adults with SJL.

Association between long working hours and metabolic dysfunction-associated steatotic liver disease: a nationwide population-based study in Korea.

OBJECTIVES: Long working hour is a known risk factor for metabolic diseases. We explored the association between working hours and metabolic dysfunction-associated steatotic liver disease (MASLD). STUDY DESIGN: Data on working hours among 22,818 workers (11,999 females) from the Korea National Health and Nutrition Examination Survey (2013-2021) were used for this study. METHODS: MASLD was defined as a combination of hepatic steatosis combined with one or more of cardiometabolic risk factors (overweight/obesity, prediabetes/diabetes, raised blood pressure, hypertriglyceridemia, low high-density lipoprotein cholesterol). Hepatic steatosis was assessed using the hepatic steatosis index. Logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The overall prevalence of MASLD was 30.4% in men and 18.1% in women. Among male workers, 20.2% worked ≥55 h/week, whereas among female workers, 10.1% worked ≥55 h/week. Compared with working 35-40 h/week, working ≥55 h/week was positively associated with overweight/obesity (OR: 1.21; 95% CI: 1.05-1.40), pre-diabetes mellitus (pre-DM)/DM (OR: 1.20; 95% CI: 1.04-1.38), raised blood pressure (OR: 1.17; 95% CI: 1.02-1.35), and presence of any cardiometabolic risk factors (OR: 1.56; 95% CI: 1.21-2.02). The adjusted OR (95% CI) of the association between working hours and MASLD was 1.27 (1.09-1.47) for ≥55 h/week compared with working 35-40 h/week in male workers. In female workers, long working hours were not clearly associated with cardiometabolic risk factors and MASLD. CONCLUSION: Long working hours are positively associated with MASLD among Korean male workers. Policy interventions are needed to mitigate the adverse metabolic effects of prolonged working hours.

Deep Electric Field Predictions by Drift-Reduced Braginskii Theory with Plasma-Neutral Interactions Based on Experimental Images of Boundary Turbulence.

We present two-dimensional turbulent electric field calculations via physics-informed deep learning consistent with (i) drift-reduced Braginskii theory under the framework of an axisymmetric fusion plasma with purely toroidal field and (ii) experimental estimates of the fluctuating electron density and temperature on open field lines obtained from analysis of gas puff imaging of a discharge on the Alcator C-Mod tokamak. The inclusion of effects from the locally puffed atomic helium on particle and energy sources within the reduced plasma turbulence model is found to strengthen correlations between the electric field and electron pressure. The neutrals are also directly associated with broadening the distribution of turbulent field amplitudes and increasing E×B shearing rates. This demonstrates a novel approach in plasma experiments by solving for nonlinear dynamics consistent with partial differential equations and data without encoding explicit boundary nor initial conditions.

ERH facilitates microRNA maturation through the interaction with the N-terminus of DGCR8.

The microprocessor complex cleaves the primary transcript of microRNA (pri-miRNA) to initiate miRNA maturation. Microprocessor is known to consist of RNase III DROSHA and dsRNA-binding DGCR8. Here, we identify Enhancer of Rudimentary Homolog (ERH) as a new component of Microprocessor. Through a crystal structure and biochemical experiments, we reveal that ERH uses its hydrophobic groove to bind to a conserved region in the N-terminus of DGCR8, in a 2:2 stoichiometry. Knock-down of ERH or deletion of the DGCR8 N-terminus results in a reduced processing of suboptimal pri-miRNAs in polycistronic miRNA clusters. ERH increases the processing of suboptimal pri-miR-451 in a manner dependent on its neighboring pri-miR-144. Thus, the ERH dimer may mediate 'cluster assistance' in which Microprocessor is loaded onto a poor substrate with help from a high-affinity substrate in the same cluster. Our study reveals a role of ERH in the miRNA biogenesis pathway.

Effects of 24-week basketball programme on body composition and functional fitness on adults with Down syndrome.

BACKGROUND: The body index [body mass, body mass index (BMI), waist circumference and waist-height ratio] and functional fitness (aerobic capacity, muscular strength, balance, flexibility and functional ability) of people with Down syndrome (DS) are substantially lower than those in the general population, as DS has an overall negative impact on health. AIMS: This study explored the effect of a 24-week basketball training programme on the body composition and functional fitness of adults with DS. METHODS AND PROCEDURE OUTCOMES: Twenty-two adults with DS (24 ± 6 years; 25 ± 4 kg/m2 ) were randomly allocated to the experimental (n = 11, 67.04 kg) and control groups (n = 11, 69.36 kg). The experimental group performed 24 weeks of basketball programme training (3 times per week, 60 min per session), while the control group maintained their daily activities without any special physical training. Body composition and functional fitness parameters were measured before and after the intervention. To evaluate the differences between groups, an analysis of covariance (ANCOVA) was used while controlling for differences at baseline. RESULTS: Hip circumference and waist-height ratio were statistically different at baseline between the intervention and control groups. After the 24-week basketball training programme, the results showed significant differences between the exercise and control groups for hip circumference, body mass, BMI, waist circumference, hip circumference, waist-height ratio, flexibility, aerobic capacity, static and dynamic balance, balance and basketball functional ability (P < 0.05). The exercise group showed significant improvements in all variables of body composition and functional fitness (P < 0.05) except for the waist-hip ratio. There was no statistical significance between all physical composition and functional health variables in the control group except for the standing long jump (P > 0.05), with effect sizes ranging from small to large. CONCLUSIONS AND IMPLICATIONS: The basketball training programme improved body composition and functional fitness of adults with DS.

Da Vinci SP robotic approach to colorectal surgery: two specific indications and short-term results.

BACKGROUND: Da Vinci® Single Port (dvSP) was recently developed. Its application in colorectal surgery is under investigation. The aim of this study was to explore the safety and feasibility of dvSP for intersphincteric (dvSP-ISR), right colectomy (dvSP-RC), and transverse colectomy (dvSP-TC). Surgical indication and short-term results were analyzed. METHODS: All consecutive patients from a prospective database of patients who underwent dvSP-ISR, dvSP-RC, and dvSP-TC at Korea University Anam Hospital from November 2020 to December 2021, were analyzed. Perioperative, pathological, and oncological short-term outcomes were analyzed. RESULTS: A total of 7 dvSP-ISR, 5 dvSP-RC, and 1 dvSP-TC were performed. Median age was 56.0 (55.0-61.0) years for the dvSP-ISR and 54.0 (44.7-63.5) years for the dvSP-RC/TC. Median body mass index was 22.8 (17.1-24.8) kg/m2 for the dvSP-ISR and 23.6 (20.8-26.9) kg/m2 for the dvSP-RC/TC. All dvSP-ISR patients received neoadjuvant long-course chemoradiotherapy, including one patient with squamocellular carcinoma who was treated with 5-fluorouracil (5-FU)/mitomycin. All other patients, excluding one dvSP-RC patient with Crohn's disease, had an adenocarcinoma. Median operation time was 280 (240-370) minutes for the dvSP-ISR and 220 (201-270) minutes for the dvSP-RC/TC. Estimated blood loss was insignificant. No intraoperative complications or conversions to multiport/open surgery was reported. Median post-operative stay was 7.0 (6.0-10.0) days for the dvSP-ISR and 5.0 (4.0-6.7) days for the dvSP-RC/TC. Quality of mesorectum was complete for six patients, and nearly complete for one. Median number of retrieved lymph nodes were 21 (17-25) for the dvSP-ISR and 28 (24-49) for the dvSP-RC/TC. Proximal and distal resection margins were tumor free. Four patients experienced post-operative complications not related to the platform which were: ileus, voiding dysfunction, infected pelvic hematoma, and wound infection. Median follow-up was 9 (6-11) months and 11 (7-17) months for the dvSP-ISR and dvSP-RC/TC, respectively. Two patients had systemic recurrence; all others were tumor free. CONCLUSIONS: The dvSP platform is safe and feasible for intersphincteric resection with right lower quadrant access, and right/transverse colectomy with suprapubic access. Further studies are needed to evaluate benefit differences compared to multiport robotic platform.

Assessment of thirty-day readmission rate, timing, causes and predictors after hospitalization with COVID-19.

BACKGROUND: There are limited data on the characteristics of 30-day readmission after hospitalization with coronavirus disease 2019 (COVID-19). OBJECTIVES: To examine the rate, timing, causes, predictors and outcomes of 30-day readmission after COVID-19 hospitalization. METHODS: From 13 March to 9 April 2020, all patients hospitalized with COVID-19 and discharged alive were included in this retrospective observational study. Multivariable logistic regression was used to identify the predictors of 30-day readmission, and a restricted cubic spline function was utilized to assess the linearity of the association between continuous predictors and 30-day readmission. RESULTS: A total of 1062 patients were included in the analysis, with a median follow-up time of 62 days. The mean age of patients was 56.5 years, and 40.5% were women. At the end of the study, a total of 48 (4.5%) patients were readmitted within 30 days of discharge, and a median time to readmission was 5 days. The most common primary diagnosis of 30-day readmission was a hypoxic respiratory failure (68.8%) followed by thromboembolism (12.5%) and sepsis (6.3%). The patients with a peak serum creatinine level of ≥1.29 mg/dL during the index hospitalization, compared to those with a creatinine of <1.29 mg/dL, had 2.4 times increased risk of 30-day readmission (adjusted odds ratio: 2.41; 95% CI: 1.23-4.74). The mortality rate during the readmission was 22.9%. CONCLUSION: With 4.5% of the thirty-day readmission rate, COVID-19 survivors were readmitted early after hospital discharge, mainly due to morbidities of COVID-19. One in five readmitted COVID-19 survivors died during their readmission.

Prenylflavonoids isolated from Macaranga tanarius stimulate odontoblast differentiation of human dental pulp stem cells and tooth root formation via the mitogen-activated protein kinase and protein kinase B pathways.

AIM: To identify odontogenesis-promoting compounds and examine the molecular mechanism underlying enhanced odontoblast differentiation and tooth formation. METHODOLOGY: Five different nymphaeols, nymphaeol B (NB), isonymphaeol B (INB), nymphaeol A (NA), 3'-geranyl-naringenin (GN) and nymphaeol C (NC) were isolated from the fruit of Macaranga tanarius. The cytotoxic effect of nymphaeols on human DPSCs was observed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effect of nymphaeols on odontoblast differentiation was analysed with Alizarin Red S staining and odontoblast marker expression was assessed using real-time polymerase chain reaction and Western blot analysis. The molecular mechanism was investigated with Western blot analysis. In order to examine the effect of INB on dentine formation in the developing tooth germ, INB-soaked beads were placed under the tooth bud explants in the collagen gel; thereafter, the tooth bud explant-bead complexes were implanted into the sub-renal capsules for 3 weeks. Tooth root formation was analysed using micro-computed tomography and histological analysis. Data are presented as mean ± standard error (SEM) values of three independent experiments, and results are compared using a two-tailed Student's t-test. The data were considered to have statistical significance when the P-value was less than 0.05. RESULTS: Three of the compounds, NB, INB, and GN, did not exert a cytotoxic effect on human DPSCs. However, INB was most effective in promoting the deposition of calcium minerals in vitro (P < 0.001) and induced the expression of odontogenic marker genes (P < 0.05). Moreover, this compound strongly induced the phosphorylation of mitogen-activated protein (MAP) kinases and protein kinase B (AKT) (P < 0.05). The inhibition of p38 MAP, c-Jun N-terminal kinase (JNK), and AKT substantially suppressed the INB-induced odontoblast differentiation (P < 0.001). In addition, isonymphaeol B significantly induced the formation of dentine and elongation of the tooth root in vivo (P < 0.05). CONCLUSIONS: Prenylflavonoids, including INB, exerted stimulatory effects on odontoblast differentiation and tooth root and dentine formation via the MAP kinase and AKT signalling pathways. These results suggest that nymphaeols could stimulate the repair processes for dentine defects or injuries.

The organ-specific differential roles of rice DXS and DXR, the first two enzymes of the MEP pathway, in carotenoid metabolism in Oryza sativa leaves and seeds.

BACKGROUND: Deoxyxylulose 5-phosphate synthase (DXS) and deoxyxylulose 5-phosphate reductoisomerase (DXR) are the enzymes that catalyze the first two enzyme steps of the methylerythritol 4-phosphate (MEP) pathway to supply the isoprene building-blocks of carotenoids. Plant DXR and DXS enzymes have been reported to function differently depending on the plant species. In this study, the differential roles of rice DXS and DXR genes in carotenoid metabolism were investigated. RESULTS: The accumulation of carotenoids in rice seeds co-expressing OsDXS2 and stPAC was largely enhanced by 3.4-fold relative to the stPAC seeds and 315.3-fold relative to non-transgenic (NT) seeds, while the overexpression of each OsDXS2 or OsDXR caused no positive effect on the accumulation of either carotenoids or chlorophylls in leaves and seeds, suggesting that OsDXS2 functions as a rate-limiting enzyme supplying IPP/DMAPPs to seed carotenoid metabolism, but OsDXR doesn't in either leaves or seeds. The expressions of OsDXS1, OsPSY1, OsPSY2, and OsBCH2 genes were upregulated regardless of the reductions of chlorophylls and carotenoids in leaves; however, there was no significant change in the expression of most carotenogenic genes, even though there was a 315.3-fold increase in the amount of carotenoid in rice seeds. These non-proportional expression patterns in leaves and seeds suggest that those metabolic changes of carotenoids were associated with overexpression of the OsDXS2, OsDXR and stPAC transgenes, and the capacities of the intermediate biosynthetic enzymes might be much more important for those metabolic alterations than the transcript levels of intermediate biosynthetic genes are. Taken together, we propose a 'Three Faucets and Cisterns Model' about the relationship among the rate-limiting enzymes OsDXSs, OsPSYs, and OsBCHs as a "Faucet", the biosynthetic capacity of intermediate metabolites as a "Cistern", and the carotenoid accumulations as the content of "Cistern". CONCLUSION: Our study suggests that OsDXS2 plays an important role as a rate-limiting enzyme supplying IPP/DMAPPs to the seed-carotenoid accumulation, and rice seed carotenoid metabolism could be largely enhanced without any significant transcriptional alteration of carotenogenic genes. Finally, the "Three Faucets and Cisterns model" presents the extenuating circumstance to elucidate rice seed carotenoid metabolism.

A multicentre comparative study between laparoscopic and open surgery for intussusception in adults.

AIM: Intussusception in adults is rare and requires surgery in most cases. While abdominal laparoscopic surgery (LS) is becoming more popular, there are few reports on the outcomes of adult intussusception treated with LS. This study compared the feasibility of LS vs open surgery (OS) for adult intussusception. METHOD: We reviewed retrospectively the medical records of adult patients with intussusception from three tertiary hospitals between 2000 and 2016. The patients were divided into LS and OS groups, and their surgical outcomes were compared. RESULTS: Surgery was indicated in 71 patients with intussusception (41 LS and 30 OS). The median age of the patients was 49.0 and 51.5 years in the LS and OS groups, respectively (P = 0.930). Overall, nine (12.7%) patients had a negative laparotomy or laparoscopy with spontaneous reduction of the intussusception. Conversion to OS from LS was necessary in one patient (2.4%). The operative time and intra-operative and postoperative complication rates were not significantly different. However, there were more serious complications such as bowel perforation and major vessel injury in the LS group. The patients in the LS group had a shorter time to first food intake and hospital stay vs patients in the OS group (4.0 vs 6.0 days, P < 0.001, and 7.0 vs 10.5 days, P < 0.001, respectively). CONCLUSION: LS may be feasible for adult intussusception; there may be more severe intra-operative complications than in OS.

Dissolving microneedle with high molecular weight hyaluronic acid to improve skin wrinkles, dermal density and elasticity.

OBJECTIVES: Dissolving microneedle patches have been extensively studied in the field of cosmetics comparison with topical cosmetics focusing on the delivery of active ingredients. Nevertheless, the skin improvement effect of hyaluronic acid, which is mainly used as a backbone material for dissolving microneedle, was not analyzed. In this study, adenosine encapsulated high and low molecular weight hyaluronic acid dissolving microneedle patch (Ad-HMN and Ad-LMN) were evaluated with respect to skin wrinkling, dermal density, elasticity, and safety in a clinical test on the crow's feet area. METHODS: Clinical efficacy and safety tests were performed for 12 weeks on twenty three female subjects with wrinkles around their eyes. The Ad-HMN and Ad-LMN patch were applied once every 3 days, in the evening, for 8 weeks to the designated crow's feet area. Skin wrinkling, dermal density, and elasticity were measured by using PRIMOS® premium, Dermascan® C, Cutometer® MPA580, and Corneometer® CM 825, respectively. RESULTS: Both Ad-HMN and Ad-LMN groups showed statistically significant efficacy for almost all parameters. The Ad-HMN patch had better effect on the mean depth of biggest wrinkles, maximum depth of biggest wrinkles, dermal density, and skin elasticity than the Ad-LMN patch. No adverse effects were observed in either group during the test period. CONCLUSION: In the clinical efficacy test of four skin-improvement parameters, the Ad-HMN patch showed the better effect than the Ad-LMN patch with the similar adenosine dose.

OBJECTIFS: Les patches à micro-aiguilles dissolvantes ont fait l'objet d'études approfondies dans le domaine de la cosmétique en comparaison avec la cosmétique topique axée sur la diffusion de principes actifs. Cependant, l'effet améliorant de l'acide hyaluronique sur la peau, principalement utilisée comme matière de base pour la dissolution des micro-aiguilles, n'a pas été analysé. Dans la présente étude, les patchs à micro-éguilles dissolvant l'acide hyaluronique à poids moléculaire élevé et faible, encapsulé dans l'adénosine (Ad-HMN et Ad-LMN) ont été analysés par rapport à la formation des rides, la densité cutanée, l'élasticité et la sécurité d'emploi lors d'un test clinique sur la zone de pattes d'oie. MÉTHODES: Des tests d'efficacité et de sécurité cliniques ont été réalisés pendant 12 semaines sur 23 sujets féminins ayant des rides autour des yeux. Les patchs Ad-HMN et Ad-LMN ont été appliqués une fois tous les trois jours, le soir, pendant huit semaines, dans la zone à pattes d'oie désignée. La formation de rides, la densité cutanée et l'élasticité ont été mesurées à l'aide de PRIMOS® premium, Dermascan® C, Cutometer® MPA580 et Corneometer® CM825, respectivement. RÉSULTATS: Les deux groupes Ad-HMN et Ad-LMN ont présenté une efficacité statistiquement significative pour la quasi-totalité des paramètres. Le patch Ad-HMN a eu un meilleur effet sur la profondeur moyenne des rides les plus importantes, la profondeur maximale des rides les plus importantes, la densité cutanée et l'élasticité de la peau par rapport au patch Ad-LMN. Aucun effet indésirable n'a été observé dans aucun des groupes pendant la période d'essai. CONCLUSION: Lors du test d'efficacité clinique des quatre paramètres d'amélioration de la peau, le patch Ad-HMN a eu un meilleur effet que le patch Ad-LMN avec la dose d'adénosine similaire.

Observation of Efficient Lower Hybrid Current Drive at High Density in Diverted Plasmas on the Alcator C-Mod Tokamak.

Efficient lower hybrid current drive (LHCD) is demonstrated at densities up to n[over ¯]_{e}≈1.5×10^{20} m^{-3} in diverted plasmas on the Alcator C-Mod tokamak by operating at increased plasma current-and therefore reduced Greenwald density fraction. This density exceeds the nominal "LH density limit" at n[over ¯]_{e}≈1.0×10^{20} m^{-3} reported previously, above which an anomalous loss of current drive efficiency was observed. The recovery of current drive efficiency to a level consistent with engineering scalings is correlated with a reduction in density shoulders and turbulence levels in the far scrape-off layer. Concurrently, rf wave interaction with the edge and/or scrape-off-layer plasma is reduced, as indicated by a minimal broadening of the wave frequency spectrum measured at the plasma edge. These results have important implications for sustaining steady-state tokamak operation and indicate a pathway forward for implementing efficient LHCD in a reactor.

Generation of embryonic stem-like cells from in vivo-derived porcine blastocysts at a low concentration of basic fibroblast growth factor.

Although basic fibroblast growth factor (bFGF) is an essential factor supporting the maintenance of porcine embryonic stem (ES) cell self-renewal and pluripotency, its high cost has limited previous studies, and the development of a low-cost culture system is required. For these systems, in vivo blastocysts were progressively cultured under various conditions consisting of different culture mediums and/or different feeder cell numbers at a low concentration of bFGF. As the results, the sequential culture of in vivo-derived porcine blastocysts on 5.0 × 105 mouse embryonic fibroblast (MEF) feeder cells in alpha minimum essential medium-based medium for primary culture, on 2.5 × 105 MEF feeder cells in Mixture medium for the 1st subpassage, and on 2.5 × 105 MEF feeder cells in DMEM/Ham's F10-based medium for the post-2nd subpassage could support the establishment and maintenance of porcine ES-like cells at the low concentration of bFGF. The established porcine ES-like cells showed ES cell-specific characteristics such as self-renewal and pluripotency. We confirmed that porcine ES-like cells could be generated from in vivo-derived porcine blastocysts at a low concentration of bFGF.

A Dual Phosphodiesterase Inhibitor, Zardaverine (Type 3/4), Enhances Motility of Frozen-thawed Boar Sperm.

BACKGROUND: Cryopreserved semen is useful for animal breeding via artificial insemination (AI); however, the use of frozen-thawed boar sperm is limited due to cryodamage. OBJECTIVE: The goal of this study was to improve post-thaw motility of boar semen by supplementing the thawing medium with a phosphodiesterase inhibitor, Zardaverine. MATERIALS AND METHODS: Thawed boar semen samples were treated with different concentrations of Zardaverine (0, 20, 50, 75, 100 µM) and the motility was evaluated using a computer-assisted sperm analyser. Toxic effects (sperm viability, DNA integrity, mitochondrial activity) were examined by eosin-nigrosin staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and MitoTracker. RESULTS: Sperm motility values included curvilinear velocity, rectilinear speed, average value, linearity index, straightness index, and progressive motility. The kinetic values were significantly higher with the 50 uM Zardaverine supplementation compared to non-treated control. Furthermore, there were no toxic effects of the Zardaverine treatment. CONCLUSION: The dual phosphodiesterase inhibitor (type 3/4) Zardaverine significantly enhanced the motility of thawed spermatozoa without adverse effects.

Evidence for a Field-Induced Quantum Spin Liquid in α-RuCl_{3}.

We report a ^{35}Cl nuclear magnetic resonance study in the honeycomb lattice α-RuCl_{3}, a material that has been suggested to potentially realize a Kitaev quantum spin liquid (QSL) ground state. Our results provide direct evidence that α-RuCl_{3} exhibits a magnetic-field-induced QSL. For fields larger than ∼10 T, a spin gap opens up while resonance lines remain sharp, evidencing that spins are quantum disordered and locally fluctuating. The spin gap increases linearly with an increasing magnetic field, reaching ∼50 K at 15 T, and is nearly isotropic with respect to the field direction. The unusual rapid increase of the spin gap with increasing field and its isotropic nature are incompatible with conventional magnetic ordering and, in particular, exclude that the ground state is a fully polarized ferromagnet. The presence of such a field-induced gapped QSL phase has indeed been predicted in the Kitaev model.