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Background: Longer follow-up after radiofrequency ablation (RFA) of benign thyroid nodules is needed to understand regrowth and other causes of delayed surgery and long-term complications. Methods: This retrospective study included consecutive patients treated with RFA for symptomatic benign nonfunctioning thyroid nodules between March 2007 and December 2010. RFA was performed according to the standard protocol. We followed up patients at 1, 6, and 12 months, then yearly, until August 2022, and calculated the volume reduction ratio (VRR) at each follow-up. We assessed the incidence of regrowth according to three published criteria, delayed surgery, and complications. The Kaplan–Meier method was used to evaluate the cumulative incidence of regrowth, and univariable and multivariable Cox regression analyses were performed to identify risk factors for regrowth. Results: This study included 421 patients (mean age, 47 ± 13 years; 372 women) with 456 nodules (mean volume, 21 ± 23 mL). The median follow-up period was 90 months (interquartile range, 24–143 months). The mean VRR was 81% at 2 years, 90% at 5 years, and 94% at ≥10 years. Overall regrowth was noted in 12% (53/456) of nodules and was treated with repeat RFA (n = 33) or surgery (n = 4) or left under observation (n = 16). Thyroid nodules with ≥20 mL initial volume had significantly higher risk of regrowth compared with nodules with <10 mL initial volume (hazard ratio, 2.315 [95% confidence interval, 1.183–4.530]; p = 0.014 on multivariable Cox regression analysis). Delayed surgery was performed in 6% (26/421) of patients because of regrowth and/or persistent symptoms (n = 4) or newly detected thyroid tumors (n = 22), one benign and 21 malignant. The overall complication rate was 2.4% (10/421), with no procedure-related deaths or long-term complications. Conclusion: RFA is safe and effective for treating benign thyroid nodules, with a high VRR at long-term follow-up. Regular follow-up after initial success is warranted because of the possibility of regrowth of ablated nodules and the need for delayed surgery in some patients. [ABSTRACT FROM AUTHOR]

This study predicted habitat distribution changes according to the current distribu seedtion 14 and future climate using the MaxEnt model for endangered Abies nephrolepis Maxim., which is vulnerable to 15 climate change and is a least-concerned species. This study aimed to predict the current distribution and future habitat distribution changes of the endangered A. nephrolepis under climate change using the MaxEnt model. The purpose was to predict the future habitat of the declining A. nephrolepis, to identify the necessity of in situ conservation, and to devise appropriate ex situ seed storage methods. The study utilized climate data from 513 GPS coordinates of A. nephrolepis habitats in South Korea to predict the changes in habitat distribution using the MaxEnt model. The seeds used in the seed experiment were collected from Pyeongchang-gun, Gangwon-do, Republic of Korea in 2019. After confirming an initial seed filling, germination tests were performed under constant temperatures of 15, 20, and 25 °C and alternating day/night temperatures of 25/5, 25/10, 25/10, 20/15, 25/15, 30/15, and 35/15 °C. The seed germination conditions were investigated under 10 different temperature settings. For the determination of storage behavior, seeds were dried at a consistent temperature of 15 °C and relative humidity (eRH) levels of 15, 20, 30, 40, and 50%. Subsequently, the seeds were stored for three months at temperatures of −20 °C and 5 °C, and the vitality tests of the seeds were conducted. Based on these experiments, the storage characteristics of seeds were identified. The results indicated that in all SSP scenarios, it is predicted that A. nephrolepis will become extinct in its habitat by the 2090s. Therefore, it has been shown that on-site and ex situ conservation is necessary. As a result of the seed germination characteristics, the highest germination rate (52.5 ± 16.01%) was achieved at a constant temperature of 20 °C, followed by 25 °C (50.0 ± 10.81%) and 25/10 °C (47.5 ± 4.79%). The highest viability was obtained under 20% eRH (64.0 ± 0%) but was not statistically different from that determined immediately after seed collection. The moisture content was approximately 4.33% fresh weight under 15% eRH at 15 °C. A. nephrolepis seeds are classified as orthodox-type seeds, which do not lose viability at 3%–7% moisture content and after drying under 15% eRH conditions at 15 °C. In conclusion, it can be observed that the seeds can be stored long-term at −20 °C. This research was conducted as a basic study to predict the habitat distribution of the endangered species A. nephrolepis and to establish seed conservation methods. According to the results, it is deemed necessary to conduct both domestic and international analyses of the habitat of A. nephrolepis. In addition, the germination and storage characteristics of A. nephrolepis seeds were confirmed, and based on this, effective seed conservation methods were suggested. [ABSTRACT FROM AUTHOR]

Berberis amurensis var. latifolia Nakai is a plant native to the Ulleung Island in Korea. In this study, we aimed to identify seed dormancy-breaking and germination requirements of this species using water imbibition experiments, gibberellic acid (GA3) treatment (0, 10, 100, or 1000 mg/L), cold stratification (0, 2, 4, 8, or 12 weeks at 5 °C), move-along experiments, and phenological studies. In the water imbibition experiment, the seed weight increased by more than 120% after 24 h. Analysis of the internal morphological characteristics of the seeds revealed that the embryo in freshly matured seeds was fully grown and did not grow thereafter. The final germination percentages after 12 weeks of cold stratification at 5 °C were 49 ± 6.4% and 63 ± 3.4% under light and dark conditions, respectively. In move-along and phenological studies, a longer cold stratification treatment period resulted in a higher germination percentage; however, the warm stratification treatment did not affect germination significantly. The GA3 treatment had little effect on seed germination. Therefore, we concluded that B. amurensis var. latifolia seeds have intermediate physiological dormancy, and pre-treatment with cold stratification for 12 weeks and incubation in the dark are required for effective seed propagation. [ABSTRACT FROM AUTHOR]

Rhodotypos scandens (Thunb.) Makino is known to have a seed dispersal that is thick and stony (endocarp + seeds) and has potential as a landscaping tree seed. In several Rosaceae species, seeds are covered with a hard endocarp, making the internal seeds water-impermeable and germination difficult. Here, we analyzed the morphoanatomical traits and germination properties of R. scandens seeds. To identify ideal seed propagation conditions, we immersed R. scandens seeds in sulfuric acid for varying durations and subjected them to phytohormone (gibberellic acid A3 and fluridone) and a cold stratification (CS) (5 °C) treatment after endocarp removal (ER). The R. scandens stony seeds did not increase in mass by ≥25.0%. Following ER, the seed mass increased by ≥50.0% with water absorption when compared to the initial dry mass. Seed surfaces showed damage and cracks through scarification after 1 h of immersion in sulfuric acid, failing to germinate. A combination of ER, phytohormone treatment, and CS improved seed germination compared to ER alone (26.0 ± 5.3%). Overall, R. scandens seeds showed a dispersal with a hard endocarp from the parent plant, and a pre-treatment with ER, phytohormones, and CS was required for effective seed propagation. [ABSTRACT FROM AUTHOR]

Titanium dioxide was coated by hydrothermal reaction on the surface of CaAl2O4:Eu2+,Nd3+ long-lasting phosphor beads on which a silver noble metal was impregnated to enhance photocatalytic reactivity. The phosphor composite as a TiO2 supporter was fabricated in the form of beads for convenient applications. Silver was impregnated on the CaAl2O4:Eu2+,Nd3+ long-lasting phosphor using a silver nitrate aqueous solution prior to TiO2 coating process. The morphological and compositional characteristics of the TiO2 coated phosphor composite materials were measured using scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and X-ray photoelectron spectrometer (XPS). The photocatalytic properties of the TiO2 coated phosphor composite materials were analyzed through decompositions of both methylene blue dye solution and toluene gas under ultraviolet and visible light irradiation. Through measuring the variation of photocatalytic reaction with different Ag concentrations, 0.035 M Ag-impregnated TiO2/CaAl2O4:Eu2+,Nd3+ phosphor composite showed the best photocatalysis efficiency under UV and visible light illumination. [ABSTRACT FROM AUTHOR]

Context It is not clear how to integrate artificial intelligence (AI)-based models into diagnostic workflows. Objective To develop and validate a deep-learning–based AI model (AI-Thyroid) for thyroid cancer diagnosis, and to explore how this improves diagnostic performance. Methods The system was trained using 19 711 images of 6163 patients in a tertiary hospital (Ajou University Medical Center; AUMC). It was validated using 11 185 images of 4820 patients in 24 hospitals (test set 1) and 4490 images of 2367 patients in AUMC (test set 2). The clinical implications were determined by comparing the findings of six physicians with different levels of experience (group 1: 4 trainees, and group 2: 2 faculty radiologists) before and after AI-Thyroid assistance. Results The area under the receiver operating characteristic (AUROC) curve of AI-Thyroid was 0.939. The AUROC, sensitivity, and specificity were 0.922, 87.0%, and 81.5% for test set 1 and 0.938, 89.9%, and 81.6% for test set 2. The AUROCs of AI-Thyroid did not differ significantly according to the prevalence of malignancies (>15.0% vs ≤15.0%, P =.226). In the simulated scenario, AI-Thyroid assistance changed the AUROC, sensitivity, and specificity from 0.854 to 0.945, from 84.2% to 92.7%, and from 72.9% to 86.6% (all P <.001) in group 1, and from 0.914 to 0.939 (P =.022), from 78.6% to 85.5% (P =.053) and from 91.9% to 92.5% (P =.683) in group 2. The interobserver agreement improved from moderate to substantial in both groups. Conclusion AI-Thyroid can improve diagnostic performance and interobserver agreement in thyroid cancer diagnosis, especially in less-experienced physicians. [ABSTRACT FROM AUTHOR]

Korean bellflower (Campanula takesimana Nakai) is a rare and perennial herb with medicinal and ornamental values, is endemic to the Ulleung Island of Korea. In this study, we investigated the dormancy-release and germination characteristics of C. takesimana (Campanulaceae) seeds by subjecting them to varying temperatures (5, 10, 15, 20, and 25°C and diurnal/nocturnal temperatures of 15/6, 20/10, and 25/15°C), cold stratification periods (0, 4, 8, or 12 weeks at 5°C), and gibberellic acid (GA3) concentrations (0, 10, 100, or 1,000 mg·L-1 at 15/6°C and 25/15°C) to identify the ideal seed propagation conditions. The seeds were stimulated to germinate (at 25°C, 12-h photoperiod with fluorescent lamps at 40 ± 10 μmol∙m-2∙s-1) after cold stratification. To examine the germination characteristics, the seeds were tested for water imbibition and found to readily absorb water. The seeds exhibited underdeveloped embryos during dispersal, showed final germination of 37.00% ± 4.43 at 25°C and were not influenced by temperature. The seeds subjected to 0, 4, 8, or 12 weeks of cold stratification germinated at a success rate of 22.00% ± 4.76, 87.00% ± 6.80, 79.00% ± 2.52, and 77.00% ± 1.91, respectively. Additionally, the germination characteristics, which were based on final germination, mean germination time, and germination velocity (Timson index), were significantly greater in the seeds pretreated with 1,000 mg·L-1 GA3 at 25/15°C than in seeds pretreated with 0 mg·L-1 GA3. Overall, the seeds broke dormancy with GA3 and short-term cold stratification. Therefore, we concluded that C. takesimana seeds have non-deep, simple, morphophysiological dormancy, and pretreatment with cold stratification and GA3 is required for effective seed propagation. [ABSTRACT FROM AUTHOR]

The genus Allium comprises some of the most commonly consumed food crops worldwide. The chloroplast genomes of A. sacculiferum, A. thunbergii, and A. taquetii are 152,444, 153,459, and 154,056 bp circular molecular genomes, respectively. The annotation results revealed the presence of 132 (89 protein-coding, 35 tRNA, and eight rRNA), 132 (86 protein-coding, 38 tRNA, and eight rRNA), and 132 (86 protein-coding, 38 tRNA, and eight rRNA) genes with 36.78%, 36.83%, and 36.88% total GC content in each genome, respectively. The chloroplast genome of each Allium species contains an 81,254, 82,473, and 83,068 bp LSC region, an 18,176, 18,006, and 17,958 bp SSC region, and a pair of 26,507, 26,490, and 26,515 bp IR regions, respectively. Phylogenetic analysis based on the 21 complete chloroplast genomes indicates that A. sacculiferum is closely related to A. koreanum; A. thunbergii and A taquetii are closely related to A. hookeri. This study shows that the three Allium species are Korean crop wild relatives that may be used to develop new Allium varieties in the future. [ABSTRACT FROM AUTHOR]

Although defects in intracellular calcium homeostasis are known to play a role in the pathogenesis of Parkinson's disease (PD), the underlying molecular mechanisms remain unclear. Here, we show that loss of PTEN-induced kinase 1 (PINK1) and Parkin leads to dysregulation of inositol 1,4,5-trisphosphate receptor (IP3R) activity, robustly increasing ER calcium release. In addition, we identify that CDGSH iron sulfur domain 1 (CISD1, also known as mitoNEET) functions downstream of Parkin to directly control IP3R. Both genetic and pharmacologic suppression of CISD1 and its Drosophila homolog CISD (also known as Dosmit) restore the increased ER calcium release in PINK1 and Parkin null mammalian cells and flies, respectively, demonstrating the evolutionarily conserved regulatory mechanism of intracellular calcium homeostasis by the PINK1-Parkin pathway. More importantly, suppression of CISD in PINK1 and Parkin null flies rescues PD-related phenotypes including defective locomotor activity and dopaminergic neuronal degeneration. Based on these data, we propose that the regulation of ER calcium release by PINK1 and Parkin through CISD1 and IP3R is a feasible target for treating PD pathogenesis. Loss of two PD genes, PINK1 and Parkin, leads to a robust increase in ER calcium release. Here, the authors show that suppression of IP3R activity via inhibiting CISD1 is sufficient to rescue the PD-related phenotypes in PINK1 or Parkin null animal models. [ABSTRACT FROM AUTHOR]

This study was conducted to elucidate the germination characteristics and dormancy types in Maianthemum dilatatum (A. W. Wood) A. Nelson and J. F. Macbr. M. dilatatum seeds were collected from the Nari Basin on Ulleungdo Island, South Korea and used in a water imbibition test; the seed weight increased by approximately 20% within 48 h. The embryo-to-seed ratio at the time of seed dispersal was 0.57 ± 0.03. When the seeds were incubated under light and dark conditions, they germinated under dark conditions, and the germination rate was higher at 25 °C than at 20 °C. However, the final germination rates under dark conditions were 27.4 ± 3.6 and 47.1 ± 7.6%, respectively. Under 4, 8, 12, and 16 weeks of cold stratification treatment, the highest germination rate of 83.6 ± 3.6% was observed at 25 °C at 12 weeks of cold stratification treatment, the germination start date was decreased by more than 10 d, and the mean germination time (MGT) was shortened from 50 d to 39 d. However, the germination rate, germination start date, and MGT did not differ significantly among the gibberellic acid hormone treatments. Therefore, it was evident that M. dilatatum demonstrated physiological dormancy (PD) that can broken by cold stratification treatment and dark conditions. [ABSTRACT FROM AUTHOR]

Vaccinium oldhamii Miq. is an edible berry; however, little is known about its seed dormancy-break and germination. Therefore, the aim of this study was to elucidate the seed-dormancy break and germination characteristics of V. oldhamii. The results showed that the length and width of the seeds of V. oldhamii were 2.4588 ± 0.0273 mm and 1.7028 ± 0.0248 mm, respectively, the filled percentage was 49.0 ± 3.0%, and the 1000-seed weight was 0.9453 g. Additionally, water imbibition test showed that the seed weight of V. oldhamii increased by more than 70% after 24 h, indicating the absence of physical dormancy. Embryo length measured at dispersal and just before germination did not differ significantly. There was no significant difference in E:S (Embryo:Seed) ratio in length at the time of seed dispersal (0.6780 ± 0.0258) and before germination (0.7370 ± 0.0469), indicating the absence of morphological dominance. Temperature treatments showed that the germination of the seed was 0, 6.0, 6.0, 20.0, and 0% under 15, 20, 25, 25/15, and 15/6 °C, respectively. However, treatment with 250 ppm of GA3 increased the germination of the seeds to 22.0, 36.0, 32.0, 40.0, and 1.0%, respectively. Additionally, treatment with 500 ppm of GA3 increased the germination to 34.6, 40.0, 40.0, 46.0 %, respectively. These results indicated that the seeds of V. oldhamii exhibited Nondeep physiological dormancy (Nondeep PD). Overall, the findings of this study showed that treatment with 500 ppm of GA3 at 25/15 °C can effectively break the dormancy of V. oldhamii seeds, which could facilitate further research on the species. [ABSTRACT FROM AUTHOR]

Background Ursodeoxycholic acid (UDCA), statins, and ezetimibe (EZE) have demonstrated beneficial effects against non-alcoholic fatty liver disease (NAFLD). We investigated the efficacy of the combination of UDCA and the mix of rosuvastatin (RSV)/EZE in the treatment of NAFLD. Methods NAFLD mouse models were developed by injecting thioacetamide, fasting, and high-carbohydrate refeeding, high-fat diet, and choline-deficient L-amino acid-defined high-fat diet (CDAHFD). Low-dose UDCA (L-UDCA; 15 mg/kg) or high-dose UDCA (H-UDCA; 30 mg/kg) was administered with RSV/EZE. We also employed an in vitro model of NAFLD developed using palmitic acid-treated Hepa1c1c7 cells. Results Co-administration of RSV/EZE with UDCA significantly decreased the collagen accumulation, serum alanine aminotransferase (ALT) levels, and mRNA levels of fibrosis-related markers than those observed in the vehicle group in thioacetamide-treated mice (all P  < 0.01). In addition, in the group fasted and refed with a high-carbohydrate diet, UDCA/RSV/EZE treatment decreased the number of apoptotic cells and serum ALT levels compared with those observed in the vehicle group (all P  < 0.05). Subsequently, H-UDCA/RSV/EZE treatment decreased the number of ballooned hepatocytes and stearoyl-CoA desaturase 1 (SCD-1) mRNA levels (P  = 0.027) in the liver of high-fat diet-fed mice compared with those observed in the vehicle group. In the CDAHFD-fed mouse model, UDCA/RSV/EZE significantly attenuated collagen accumulation and fibrosis-related markers compared to those observed in the vehicle group (all P  < 0.05). In addition, UDCA/RSV/EZE treatment significantly restored cell survival and decreased the protein levels of apoptosis-related markers compared to RSV/EZE treatment in palmitic acid-treated Hepa1c1c7 cells (all P  < 0.05). Conclusion Combination therapy involving UDCA and RSV/EZE may be a novel strategy for potent inhibition of NAFLD progression. [ABSTRACT FROM AUTHOR]

Previous studies have shown that the CB1 receptor antagonist reverses steatohepatitis and its related features of metabolic syndrome, such as obesity and type 2 diabetes. However, the beneficial effects of CB1 receptor blockade on hepatic steatosis and inflammation have not been investigated independently of its effects on body weight and glycemic control. At 32 weeks of age, OLETF rats were administered with rimonabant (10 mg·kg−1·day−1) by oral gavage for 6 weeks. No significant changes in body weight, OGTT, and serum glucose were observed in spite of rimonabant-decreased food intake. Moreover, there was a significant difference between initial and final body weight, regardless of rimonabant administration, indicating that OLETF rats were severely diabetic rats. Rimonabant administration significantly decreased serum liver enzyme levels such as ALT and AST, hepatic fat accumulation, lipid peroxidation, and cell death as demonstrated by the number of TUNEL-positive cells in severely uncontrolled diabetic OLETF rats. Significant decreases in hepatic gene expression of proinflammatory cytokines (CD11b, F4/80, MCP1, and TNFα), negative inflammatory mediators (SOCS1 and SOCS3), and fibrosis-related proteins (TGFβ, collagen 1, and TIMP1) were found in rimonabant-treated OLETF rats. Six-week administration of rimonabant significantly upregulated mRNA levels of CPT1α and PPARα related to β-oxidation. Moreover, significant increases in Nrf2 gene expression and its downstream genes, NQO1, GSAT, HO-1, and TXNRD1 along with increased AMPK phosphorylation were noted in uncontrolled diabetic rats treated with rimonabant. The observed potent inhibitory effects of CB1 receptor blockade on hepatic fat infiltration and cellular death in severely uncontrolled diabetic rats indicate that CB1 receptor is a possible therapeutic target. Increased Nrf2 and AMPK phosphorylation may play a role in the mechanism of rimonabant action. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress is triggered by various cellular stresses that disturb protein folding or calcium homeostasis in the ER. To cope with these stresses, ER stress activates the unfolded protein response (UPR) pathway, but unresolved ER stress induces reactive oxygen species (ROS) accumulation leading to apoptotic cell death. However, the mechanisms that underlie protection from ER stress-induced cell death are not clearly defined. The nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway plays a crucial role in the protection of cells against ROS-mediated oxidative damage. Keap1 acts as a negative regulator of Nrf2 activation. In this study, we investigated the role of the Nrf2-Keap1 pathway in protection from ER stress-induced cell death using tunicamycin (TM) as an ER stress inducer. We found that Nrf2 is an essential protein for the prevention from TM-induced apoptotic cell death and its activation is driven by autophagic Keap1 degradation. Furthermore, ablation of p62, an adapter protein in the autophagy process, attenuates the Keap1 degradation and Nrf2 activation that was induced by TM treatment, and thereby increases susceptibility to apoptotic cell death. Conversely, reinforcement of p62 alleviated TM-induced cell death in p62-deficient cells. Taken together, these results demonstrate that p62 plays an important role in protecting cells from TM-induced cell death through Nrf2 activation. [ABSTRACT FROM PUBLISHER]

Oxidative stress is important for the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a chronic disease that ranges from hepatic steatosis to nonalcoholic steatohepatitis (NASH). The nuclear factor erythroid 2-related factor 2–Kelch-like ECH associated protein 1 (Nrf2-Keap1) pathway is essential for cytoprotection against oxidative stress. In this study, we found that oxidative stress or inflammatory biomarkers and TUNEL positive cells were markedly increased in NASH patients compared to normal or simple steatosis. In addition, we identified that the hepatic mRNA levels of Nrf2 target genes such as Nqo-1 and GSTA-1 were significantly increased in NASH patients. Ezetimibe, a drug approved by the Food and Drug Administration for the treatment of hypercholesterolemia, improves NAFLD and alleviates oxidative stress. However, the precise mechanism of its antioxidant function remains largely unknown. We now demonstrate that ezetimibe activates Nrf2-Keap1 pathway which was dependent of autophagy adaptor protein p62, without causing cytotoxicity. Ezetimibe activates AMP-activated protein kinase (AMPK), which in turn phosphorylates p62 (p-S351) via their direct interaction. Correspondingly, Ezetimibe protected liver cells from saturated fatty acid-induced apoptotic cell death through p62-dependent Nrf2 activation. Furthermore, its role as an Nrf2 activator was supported by methione- and choline- deficient (MCD) diet-induced NASH mouse model, showing that ezetimibe decreased the susceptibility of the liver to oxidative injury. These data demonstrate that the molecular mechanisms underlying ezetimibe's antioxidant role in the pathogenesis of NASH. [ABSTRACT FROM AUTHOR]

This study investigated the kind of seed dormancy and seed germination of Gentiana triflora var. japonica (Kusn.) H. Hara for developing a seed propagation method. The seeds were collected in October 2020 from plants at Mt. Sobaeksan, Korea. In a water imbibition experiment, seed weights increased by >101.9% of their initial masses over 12 h. Effects of incubation temperature (5, 15, 20, 25, 15/6, or 25/15 °C), cold stratification period (5 °C; 0, 4, 8, or 12 weeks), and gibberellic acid (GA3; 0, 10, 100, or 1000 mg∙L−1) and potassium nitrate treatment (KNO3; 0, 1000, 2000, or 4000 mg∙L−1) on seed germination were investigated to characterize seed dormancy. These seeds exhibited underdeveloped embryos during seed dispersal. The seeds failed to reach the final germination of 15.0% after treatment at 5, 15, 20, 25, 15/6, or 25/15 °C. After cold stratification for 8 weeks, the germination increased dramatically by >90.0% compared to that at 0 weeks. After the GA3 treatment, the germination reached >80.0% within 5 days. The final germination was 90.0% in the 100 mg∙L−1 GA3 treatment group. However, the KNO3 treatment had no effect on seed germination. Therefore, the G. triflora var. japonica seeds exhibited non-deep simple morphophysiological dormancy. [ABSTRACT FROM AUTHOR]

The timing of behavior under natural light-dark conditions is a function of circadian clocks and photic input pathways, but a mechanistic understanding of how these pathways collaborate in animals is lacking. Here we demonstrate in Drosophila that the Phosphatase of Regenerating Liver-1 (PRL-1) sets period length and behavioral phase gated by photic signals. PRL-1 knockdown in PDF clock neurons dramatically lengthens circadian period. PRL-1 mutants exhibit allele-specific interactions with the light- and clock-regulated gene timeless (tim). Moreover, we show that PRL-1 promotes TIM accumulation and dephosphorylation. Interestingly, the PRL-1 mutant period lengthening is suppressed in constant light, and PRL-1 mutants display a delayed phase under short, but not long, photoperiod conditions. Thus, our studies reveal that PRL-1-dependent dephosphorylation of TIM is a core mechanism of the clock that sets period length and phase in darkness, enabling the behavioral adjustment to change day-night cycles. • Loss of PRL-1 in PDF clock neurons dramatically lengthens circadian period • PRL-1 dephosphorylates TIM, promoting its nuclear accumulation • PRL-1 mutant period lengthening is suppressed in constant light • PRL-1 mutants display delayed phase under short, but not long, photoperiods Daily behavioral patterns are determined by the integration of internal clocks and the external environment. Kula et al. find that Phosphatase of Regenerating Liver-1 acts on the clock component TIMELESS to set period length in constant darkness as well as behavioral phase under winter-like, but not summer-like, photoperiods. [ABSTRACT FROM AUTHOR]

Artificial liver models have been extensively developed for pathological modeling and toxicological studies. However, the prediction of existing in vitro liver models rarely corresponds to what is consequently observed in vivo owing to the structural and functional complexity of the liver. Here, a new liver model designed to enable the implantation and maintenance of liver buds in perfusable 3D hydrogels where a microvascular network develops within a 200 µm diffusion limit is developed. This system replicates inflammation, lipid accumulation, and fibrosis during the progressive processes of nonalcoholic fatty liver disease, in which this model predicted the results from a mouse model. This model reveals that a hepatic steatosis‐reducing drug restored mitochondrial activities with significant reduction of inflammation, oxidative stress, and lipid accumulation. This liver model is not only highly predictive but also scalable and easy to apply to high‐throughput drug screening and implantation studies, suggesting a promising alternative to animal models. [ABSTRACT FROM AUTHOR]