Technical performance scores associate with early prognosis of tetralogy of Fallot repair.

Objective: This study aimed to investigate the relationship between technical performance scores (TPS) and the early prognosis of tetralogy of Fallot repair (TOF). Methods: A retrospective study was conducted on TOF repair patients at our center from Oct 2017 to Oct 2022. Patients were classified into Class 1 (no residua), Class 2 (minor residua), or Class 3 (major residua) based on TPS derived from predischarge echocardiograms and need for reintervention. Statistical methods were used to assess the association between TPS and early prognosis. Results: A total of 75 TOF repair patients (40% female, 60% male) were analyzed and categorized into TPS1 (24%), TPS2 (53.3%), and TPS3 (22.6%) based on pre-discharge echocardiographic findings. The median follow-up time was 7.0 months. The multivariable Cox regression analysis indicated that TPS3 scores are associated with a 12.68-fold increase in risk compared to TPS1 and TPS2 scores [95% CI = 12.68 (0.9∼179.28), P = 0.06]. The Spearman rank correlation analysis revealed a weak positive correlation between TPS classification and low cardiac output syndrome (r = 0.26, P = 0.03). However, there were no significant differences in ICU stay or duration of mechanical ventilation among the groups. Conclusion: TPS3 after intracardiac TOF repair is associated with higher risk of early re-intervention, highlighting the importance of close follow-up and monitoring in this patient population. Patients who develop low cardiac output syndrome in the early postoperative period may have residual defects that require prompt identification.

Case report: Use of three-dimensional technology in criss-cross heart with double outlet right ventricle.

Background: In this case report, we utilized a three-dimensional printing model to replicate the complex anatomy of a criss-cross heart with double outlet right ventricle-an extremely rare congenital cardiac abnormality. This approach facilitated our understanding of the patient's unique condition and enabled us to plan the surgical procedure with greater precision. Case presentation: Our department received a 13-year-old female patient who presented with a pronounced heart murmur and a decrease in exercise capacity. Subsequent two-dimensional imaging revealed the presence of a criss-cross heart with double outlet right ventricle-an intricate and uncommon cardiac malformation that poses challenges for accurate visualization through conventional two-dimensional modalities. To address this challenge, we constructed and printed a three-dimensional model using computed tomography data, which enabled us to visualize and understand the complex intracardiac structures and plan surgical interventions with greater precision. Using this approach, we successfully performed a right ventricular double outlet repair, and the patient made a full recovery following the procedure. Conclusion: The criss-cross heart with double outlet right ventricle constitutes a complex and uncommon cardiac anomaly that poses considerable challenges in terms of diagnosis and surgical intervention. Employing three-dimensional modeling and printing represents a promising approach, given its potential to enhance the precision and comprehensiveness of the anatomical evaluation of the heart. As a result, this method holds significant promise in facilitating accurate diagnosis, meticulous surgical planning, and ultimately improving clinical outcomes for patients affected by this condition.

A giant teratoma in the anterior mediastinum found prenatally: A case report.

Prenatal anterior mediastinal teratomas are rare. Anterior mediastinal teratomas can cause edema during the perinatal period. Color Doppler ultrasonography and chest computed tomography (CT) are of great value in diagnosing neonatal anterior mediastinal teratomas. Here, we report a case of prenatally diagnosed neonatal anterior mediastinal teratoma. After birth, transthoracic echocardiography and chest enhanced CT showed a large solid mass in the pericardial cavity. Owing to compression of the heart, the tumor was completely removed 1 day after birth, and cardiopulmonary bypass was performed. Pathology results indicated an immature teratoma (Grade I). At 9-month follow-up, the patient remained in good overall condition without observed recurrences.

Biventricular repair of double-outlet left ventricle by handmade trileaflet-valved conduit: A case report.

RATIONALE: Double-outlet left ventricle (DOLV) is a rare congenital cardiac malformation in which both great arteries arise entirely or predominantly from the left ventricle. An extracardiac conduit is the first surgical option for repairing DOLV, specifically because its placement of the extracardiac conduit can be customized to accommodate all possible anatomical variations. The bovine jugular veins and homograft valves are often used as conduits. There have been no reports on the use of handmade trileaflet-valved conduits for correcting DORV. PATIENT CONCERNS: A 1-year old male was admitted for significant heart murmur and cyanosis, according to the results of transthoracic echocardiography, computed tomography angiography, and cardioangiography, and was diagnosed with DOLV and pulmonary stenosis. DIAGNOSIS AND INTERVENTIONS: The patient underwent biventricular repair with a handmade trileaflet-valved extracardiac conduit. The postoperative course was uneventful. OUTCOME: Three months after the surgery, TTF indicated mild right ventricular outflow obstruction and pulmonary valve regurgitation. LESSONS: Correction of the left ventricular double outlet with a handmade trileaflet-valved conduit has been shown to have excellent performance, and long-term outcomes should be followed over time.

Middle to long-term outcomes of surgical repair for atrioventricular septal defect: a single-center study.

Background: The exact incidence and predictors of mortality and left atrioventricular valve (LAVV) re-operation in congenital atrioventricular septal defect (AVSD) repair are still unclear. This study analyzed the middle to long-term outcomes of surgical repair for AVSD. Methods: A total of 150 patients (69 males and 81 females) who underwent AVSD repair at Children's Hospital of Fudan University from January 2013 to December 2021 were divided into complete defect group (C-group, 67 cases), transitional defect group (T-group, 26 cases), and partial defect group (P-group, 57 cases). Outcomes during the peri-operative and 10-year follow-up periods were evaluated. Results: The total mortality was 5.33% (8/150), including seven early deaths (10.4%) and no late deaths in the C-group, no early deaths (0%) and one late death (1.8%) in the P-group, and no early or late deaths in the T-group. Up to the last follow-up, severe LAVV regurgitation had occurred in 27 patients, including 16 in the C-group, four in the T-group, and seven in the P-group. In total, 12 (12/150, 8.0%) patients received LAVV re-operation, including seven in the C-group, three in the T-group, and two in the P-group. Cox regression analysis showed that pre-operative severe pulmonary hypertension (P=0.006) and severe LAVV regurgitation within 24 hours after the first surgery (P=0.023) were independent risk factors for mortality. ≥ Moderate LAVV regurgitation within the first 24 hours after surgery (P=0.014) was an independent risk factor for LAVV re-operation. Conclusions: Complete AVSD repair increased the risk of early death, severe LAVV regurgitation and re-operation. Pre-operative severe pulmonary hypertension and residual severe LAVV regurgitation indicated high risk for mortality. ≥ Moderate LAVV regurgitation within 24 hours after the first surgery predicted a high probability of LAVV re-operation.

Electrohydrodynamic Jet-Printed Ultrathin Polycaprolactone Scaffolds Mimicking Bruch's Membrane for Retinal Pigment Epithelial Tissue Engineering.

Age-related macular degeneration (AMD) is the leading cause of visual loss and affects millions of people worldwide. Dysfunction of the retinal pigment epithelium (RPE) is associated with the pathogenesis of AMD. The purpose of this work is to build and evaluate the performance of ultrathin scaffolds with an electrohydrodynamic jet (EHDJ) printing method for RPE cell culture. We printed two types of ultrathin (around 7 µm) polycaprolactone scaffolds with 20 µm and 50 µm pores, which possess mechanical properties resembling that of native human Bruch's membrane and are biodegradable. Light microscopy and cell proliferation assay showed that adult human retinal pigment epithelial (ARPE-19) cells adhered and proliferated to form a monolayer on the scaffolds. The progress of culture matured on the scaffolds was demonstrated by immunofluorescence (actin, ZO-1, and Na+/K+-ATPase) and Western blot analysis of the respective proteins. The RPE cells cultured on EHDJ-printed scaffolds with 20 µm pores presented higher permeability, higher transepithelial potential difference, and higher expression level of Na+/K+-ATPase than those cultured on Transwell inserts. These findings suggest that the EHDJ printing can fabricate scaffolds that mimic Bruch's membrane by promoting maturation of RPE cells to form a polarized and functional monolayered epithelium with potential as an in vitro model for studying retinal diseases and treatment methods.

Climate-smart planting for potato to balance economic return and environmental impact across China.

Potato production plays an important role in safeguarding food security in China since the central government implemented the 'Potato-as-Staple-Food' policy in 2015. However, a key challenge facing China's potato production is to realize a tradeoff between economic return and environmental impact. Effective strategies for reducing carbon emission without compromising potato yield remain to be developed. This study conducted a comprehensive assessment by integrating climate, soil, crop, and agricultural input data, crop model and life cycle impact assessment model to quantify potato yields, GHG emission amounts and intensities (GHGI), and economic benefits under the conventional planting pattern (CPP), the lowest GHG emission pattern (LEP), and the highest yield pattern (HYP) across China's potato planting regions including four sub-regions, i.e., North Single planting region (NS), Central Double planting region (CD), South Winter planting region (SW), and Southwest Mixed planting region (SWM). Averaged fresh potato yield, GHG emission amount, and GHGI under the CPP were 21.7 t ha-1, 2815.1 kg CO2eq ha-1, and 137.3 kg CO2eq t-1, respectively, in China's potato planting region. Compared with the CPP, averaged GHG emission amount and GHGI under the LEP could be decreased by 48.2 % and 51.5 % respectively while the fresh potato yield and economic benefit could be enhanced by 8.1 % and 18.5 %, respectively. For the HYP, averaged GHG emission amount and GHGI could be decreased by 24.2 % and 39.8 % respectively while the fresh potato yield and economic benefit could be enhanced by 18.7 % and 39.6 %, respectively, compared with the CPP. Across the four potato planting regions, SW had the largest potential in reducing GHG emissions owing to a high reduction amount of nitrogen application rate. Our study demonstrates that optimizing agronomic management could reduce environmental impact without compromising economic benefit and provides a scientific method for assessing crop potential to realize the climate-smart planting.

Pan-cancer assessment of mutational landscape in intrinsically disordered hotspots reveals potential driver genes.

Large-scale cancer genome sequencing has enabled the catalogs of somatic mutations; however, the mutational impact on intrinsically disordered protein regions (IDRs) has not been systematically investigated to date. Here, we comprehensively characterized the mutational landscapes of IDRs and found that IDRs have higher mutation frequencies across diverse cancers. We thus developed a computational method, ROI-Driver, to identify putative driver genes enriching IDR and domain hotspots in cancer. Numerous well-known cancer-related oncogenes or tumor suppressors that play important roles in cancer signaling regulation, development and immune response were identified at a higher resolution. In particular, the incorporation of IDR structures helps in the identification of novel potential driver genes that play central roles in human protein-protein interaction networks. Interestingly, we found that the putative driver genes with IDR hotspots were significantly enriched with predicted phase separation propensities, suggesting that IDR mutations disrupt phase separation in key cellular pathways. We also identified an appreciable number of clinically relevant genes enriching IDR mutational hotspots that exhibited differential expression patterns and are associated with cancer patient survival. In summary, combinations of mutational effects on IDRs significantly increase the sensitivity of driver detection and are likely to open new therapeutic avenues for various cancers.

Investigating the potential use of an ionic liquid (1-Butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide) as an anti-fungal treatment against the amphibian chytrid fungus, Batrachochytrium dendrobatidis.

The disease chytridiomycosis, caused by the pathogenic chytrid fungus, Batrachochytrium dendrobatidis (Bd), has contributed to global amphibian declines. Bd infects the keratinized epidermal tissue in amphibians and causes hyperkeratosis and excessive skin shedding. In individuals of susceptible species, the regulatory function of the amphibian's skin is disrupted resulting in an electrolyte depletion, osmotic imbalance, and eventually death. Safe and effective treatments for chytridiomycosis are urgently needed to control chytrid fungal infections and stabilize populations of endangered amphibian species in captivity and in the wild. Currently, the most widely used anti-Bd treatment is itraconazole. Preparations of itraconazole formulated for amphibian use has proved effective, but treatment involves short baths over seven to ten days, a process which is logistically challenging, stressful, and causes long-term health effects. Here, we explore a novel anti-fungal therapeutic using a single application of the ionic liquid, 1-Butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide (BMP-NTf2), for the treatment of chytridiomycosis. BMP-NTf2 was found be effective at killing Bd in vitro at low concentrations (1:1000 dilution). We tested BMP-NTf2 in vivo on two amphibian species, one that is relatively tolerant of chytridiomycosis (Pseudacris regilla) and one that is highly susceptible (Dendrobates tinctorius). A toxicity trial revealed a surprising interaction between Bd infection status and the impact of BMP-NTf2 on D. tinctorius survival. Uninfected D. tinctorius tolerated BMP-NTf2 (mean ± SE; 96.01 ± 9.00 µl/g), such that only 1 out of 30 frogs died following treatment (at a dose of 156.95 µL/g), whereas, a lower dose (mean ± SE; 97.45 ± 3.52 µL/g) was not tolerated by Bd-infected D. tinctorius, where 15 of 23 frogs died shortly upon BMP-NTf2 application. Those that tolerated the BMP-NTf2 application did not exhibit Bd clearance. Thus, BMP-NTf2 application, under the conditions tested here, is not a suitable option for clearing Bd infection in D. tinctorius. However, different results were obtained for P. regilla. Two topical applications of BMP-NTf2 on Bd-infected P. regilla (using a lower BMP-NTf2 dose than on D. tinctorius, mean ± SE; 9.42 ± 1.43 µL/g) reduced Bd growth, although the effect was lower than that obtained by daily doses of itracanozole (50% frogs exhibited complete clearance on day 16 vs. 100% for itracanozole). Our findings suggest that BMP-NTf2 has the potential to treat Bd infection, however the effect depends on several parameters. Further optimization of dose and schedule are needed before BMP-NTf2 can be considered as a safe and effective alternative to more conventional antifungal agents, such as itraconazole.

Residual Shunts Following Isolated Surgical Ventricular Septal Defect Closure: Risk Factors and Spontaneous Closure.

Although isolated congenital ventricular septal defects (VSD) can be repaired with a high degree of success, residual shunts (RS) are commonplace postoperatively. Small RS are relatively innocuous and tend to spontaneously close with time, despite the emotional burden it poses for the patient and family. A large RS, however, needs ongoing surveillance and may necessitate reintervention. Factors influencing the incidence of RS as well as the likelihood and expected timing of its spontaneous closure are discussed in this study. The patient records and relevant data of 362 consecutive patients undergoing cardiac operation with isolated congenital VSD closure as primary procedure between January 2017 and December 2017 were included in the study. Postoperative transthoracic echocardiograms were performed at hospital discharge, and during follow-up, at 1 month, 3 months, 6 months and 1 year postoperatively. Residual defects were measured under echocardiogram at every follow-up. Factors expected to be associated with RS occurrence and spontaneous closure were included for logistic and Cox regression statistical analysis. There were 113 cases where RS occurred according to the first postoperative echocardiograms that were performed at discharge, of which 80 were confirmed closed during subsequent follow-up, with a median follow-up of 96 days. A cutoff of 1.25 mm for the initial RS was found to be the best predictor of spontaneous closure at 6-month follow-up. Small shunts had higher closure rate than larger ones by a follow-up duration of 300 days, at which the two groups tended to reach a similar spontaneous closure rate. Longer surgical bypass time distinguished small from larger residual shunts measured upon discharge. Following repair of isolated congenital VSDs, the incidence of a residual shunt is high. The majority spontaneously close within 300 days following surgery. Longer bypass time predicted a larger residual shunt upon discharge. Larger than 1.25 mm shunts had lower short-term closure rate but seemed not to differ from smaller shunts beyond 300 days postoperatively.

Intestinal iontophoresis from mucoadhesive patches: a strategy for oral delivery.

Biologics have limited permeability across the intestine and are prone to degradation in the acidic-proteolytic milieu of the gastrointestinal tract, leading to poor oral bioavailability. Iontophoresis is a promising technology that can substantially improve transport of drugs across biological barriers and has been particularly explored for skin. In this study, we investigated whether iontophoresis across the intestine can be utilized to improve oral insulin transport. Application of electric current to intestinal cells resulted in opening of the tight junctions in vitro and a consequent about 3-fold improvement in paracellular transport of insulin. When evaluated in vivo using insulin-loaded mucoadhesive patches, iontophoresis produced profound hypoglycemia (63% blood glucose drop in 3 h) without damaging the intestinal tissue and the efficacy depended on insulin dose and current density. This study presents a proof of principle for intestinal iontophoresis as a novel method for oral protein delivery.

Displacement of occluder as a rare complication of transcatheter closure of ventricular septal defect: A case report.

RATIONALE: Ventricular septal defects are the most common congenital heart defect in children. As this method avoids sternotomy, the post-procedural morbidity is lower. However, transcatheter closure of perimembranous ventricular septal defects are still associated with complications such as arrhythmia (particularly, Atrioventricular Block), device embolization, atrioventricularvalve and/or aortic valves regurgitation, residual shunts. Some complications can be life threatening and require urgent surgical intervention. PATIENT CONCERNS: An 32-months-old boy was admitted for a significant precordial systolic murmur. The patient underwent transcatheter perimembranous ventricular septal defects closure. 12 months later, Transthoracic echocardiography revealed the device displaced, 4 mm shunt acrocss the ventricular septum and moderate tricuspid regurgitation detected. DIAGNOSIS: According to the echocardiography result, the patient was diagnosed with displacement of the ventricular septal defect occluder and tricuspid regurgitation. INTERVENTIONS: After the diagnosis, the patient underwent removal of the ventricular septal defect occluder and closure of the perimembranous ventricular septal defect. OUTCOMES: The post-operative recovery was uneventful. One year post-procedural follow-up transthoracic echocardiography showed there was no residual shunt and no tricuspid regurgitation. LESSONS: Transcatheter closure of Ventricular septal defects is an attractive alternative to surgery in simple perimembranous ventricular septal defects. Proper follow-up should be emphasized to the patient.

Ionic liquids for oral insulin delivery.

With the rise in diabetes mellitus cases worldwide and lack of patient adherence to glycemia management using injectable insulin, there is an urgent need for the development of efficient oral insulin formulations. However, the gastrointestinal tract presents a formidable barrier to oral delivery of biologics. Here we report the development of a highly effective oral insulin formulation using choline and geranate (CAGE) ionic liquid. CAGE significantly enhanced paracellular transport of insulin, while protecting it from enzymatic degradation and by interacting with the mucus layer resulting in its thinning. In vivo, insulin-CAGE demonstrated exceptional pharmacokinetic and pharmacodynamic outcome after jejunal administration in rats. Low insulin doses (3-10 U/kg) brought about a significant decrease in blood glucose levels, which were sustained for longer periods (up to 12 hours), unlike s.c. injected insulin. When 10 U/kg insulin-CAGE was orally delivered in enterically coated capsules using an oral gavage, a sustained decrease in blood glucose of up to 45% was observed. The formulation exhibited high biocompatibility and was stable for 2 months at room temperature and for at least 4 months under refrigeration. Taken together, the results indicate that CAGE is a promising oral delivery vehicle and should be further explored for oral delivery of insulin and other biologics that are currently marketed as injectables.

Calcified inferior vena cava and right atrial myxoma in an 18-month-old male: A case report.

INTRODUCTION: Cardiac myxomas are the most frequent primary cardiac tumor in adults. The incidence in pediatric patients is extremely low. Heavy calcification of an atrial myxoma is uncommon in children. CASE PRESENTATION: An 18-month-old boy was admitted for a significant precordial systolic murmur. Transthoracic echocardiography revealed a cardiac mass extending from the inferior vena cava across the right atrium and tricuspid valve into the right ventricle with severe tricuspid regurgitation. According to the echocardiography result, the patient was diagnosed with an inferior vena cava and right atrial tumor with tricuspid regurgitation. After the diagnosis, the patient underwent removal of the tumor via median sternotomy. The mass was removed under cardiopulmonary bypass with deep hypothermia circulatory arrest. The tricuspid valve was repaired by valvuloplasty and annuloplasty. The postoperative recovery was unremarkable. Follow-up echocardiogram at 1 month revealed moderate tricuspid regurgitation without myxoma recurrence. CONCLUSION: Heavy calcification of an atrial myxoma is uncommon especially in children. Definitive therapy for myxomas requires prompt surgical excision and long-term follow-up is recommended in children although recurrence after excision is rare.

Schedule dependent synergy of gemcitabine and doxorubicin: Improvement of in vitro efficacy and lack of in vitro-in vivo correlation.

Combination chemotherapy is commonly used to treat late stage cancer; however, treatment is often limited by systemic toxicity. Optimizing drug ratio and schedule can improve drug combination activity and reduce dose to lower toxicity. Here, we identify gemcitabine (GEM) and doxorubicin (DOX) as a synergistic drug pair in vitro for the triple negative breast cancer cell line MDA-MB-231. Drug synergy and caspase activity were increased the most by exposing cells to GEM prior to DOX in vitro. While the combination was more effective than the single drugs at inhibiting MDA-MB-231 growth in vivo, the clear schedule dependence observed in vitro was not observed in vivo. Differences in drug exposure and cellular behavior in vivo compared to in vitro are likely responsible. This study emphasizes the importance in understanding how schedule impacts drug synergy and the need to develop more advanced strategies to translate synergy to the clinic.

Downregulation of Bit1 expression promotes growth, anoikis resistance, and transformation of immortalized human bronchial epithelial cells via Erk activation-dependent suppression of E-cadherin.

The mitochondrial Bit1 protein exerts tumor-suppressive function in NSCLC through induction of anoikis and inhibition of EMT. Having this dual tumor suppressive effect, its downregulation in the established human lung adenocarcinoma A549 cell line resulted in potentiation of tumorigenicity and metastasis in vivo. However, the exact role of Bit1 in regulating malignant growth and transformation of human lung epithelial cells, which are origin of most forms of human lung cancers, has not been examined. To this end, we have downregulated the endogenous Bit1 expression in the immortalized non-tumorigenic human bronchial epithelial BEAS-2B cells. Knockdown of Bit1 enhanced the growth and anoikis insensitivity of BEAS-2B cells. In line with their acquired anoikis resistance, the Bit1 knockdown BEAS-2B cells exhibited enhanced anchorage-independent growth in vitro but failed to form tumors in vivo. The loss of Bit1-induced transformed phenotypes was in part attributable to the repression of E-cadherin expression since forced exogenous E-cadherin expression attenuated the malignant phenotypes of the Bit1 knockdown cells. Importantly, we show that the loss of Bit1 expression in BEAS-2B cells resulted in increased Erk activation, which functions upstream to promote TLE1-mediated transcriptional repression of E-cadherin. These collective findings indicate that loss of Bit1 expression contributes to the acquisition of malignant phenotype of human lung epithelial cells via Erk activation-induced suppression of E-cadherin expression.

TLE1 inhibits anoikis and promotes tumorigenicity in human lung cancer cells through ZEB1-mediated E-cadherin repression.

The Transducin-like enhancer of split 1 (TLE1) corepressor protein is overexpressed in human lung tumors and is a putative lung-specific oncogene. However, the molecular mechanism underlying its oncogenic function remains to be delineated. Here, we report an important role of TLE1 in promoting lung tumorigenesis by a mechanism involving induction of anoikis resistance. Using the human lung adenocarcinoma A549 and immortalized bronchial epithelial BEAS-2B cell lines, we observed that TLE1 inhibits anoikis through transcriptional repression of E-cadherin gene. In support of E-cadherin as a downstream target of TLE1 to block anoikis, forced expression of E-cadherin attenuated TLE1-induced anoikis resistance while E-cadherin downregulation decreased the anoikis sensitivity of TLE1 knockdown cells. Furthermore, we determined that E-cadherin expression is transcriptionally induced upon loss of cell attachment and functions as an effector of anoikis. Loss of E-cadherin via the siRNA strategy or exogenous TLE1 expression was sufficient to attenuate anoikis in A549 and BEAS-2B cells. Importantly, we demonstrated that the ZEB1 transcriptional factor is required for TLE1-mediated E-cadherin repression and anoikis resistance. ZEB1 interacted with and recruited the TLE1 to the E-cadherin promoter to impose histone deacetylation and gene silencing. In vivo, TLE1 strongly promoted tumorigenicity of A549 cells in a ZEB1-dependent manner. Underscoring its role in anoikis insensitivity of lung cancer cells, the TLE1-mediated E-cadherin repression was negatively regulated by the tumor suppressor Bcl-2 inhibitor of transcription 1 (Bit1) to effect anoikis. These findings identify the ZEB1/TLE1/E-cadherin transcriptional mechanism as a novel pathway that promotes anoikis resistance and oncogenicity of lung cancer cells.

Spatiotemporal variation of endogenous cell-generated stresses within 3D multicellular spheroids.

Multicellular spheroids serve as an excellent platform to study tissue behavior and tumor growth in a controlled, three-dimensional (3D) environment. While molecular and cellular studies have long used this platform to study cell behavior in 3D, only recently have studies using multicellular spheroids shown an important role for the mechanics of the microenvironment in a wide range of cellular processes, including during tumor progression. Despite the well-established relevance of mechanical cues to cell behavior and the numerous studies on mechanics using 2D cell culture systems, the spatial and temporal variations in endogenous cellular forces within growing multicellular aggregates remain unknown. Using cell-sized oil droplets with controlled physicochemical properties as force transducers in mesenchymal cell aggregates, we show that the magnitude of cell-generated stresses varies only weakly with spatial location within the spherical aggregate, but it increases considerably over time during aggregate compaction and growth. Moreover, our results indicate that the temporal increase in cellular stresses is due to increasing cell pulling forces transmitted via integrin-mediated cell adhesion, consistent with the need for larger intercellular pulling forces to compact cell aggregates.

Effects of flavonoids from Allium mongolicum Regel on growth performance and growth-related hormones in meat sheep.

This study was conducted to investigate the effects of different doses of flavonoids from Allium mongolicum Regel on the production performance and neuroendocrine hormones in meat sheep and to determine the optimum dosage of Allium mongolicum Regel flavonoids to add to the basal diet of dry lot-feeding meat sheep. Sixty meat sheep (initial body weight = 39.9 ± 3.2 kg; 6-month-old) were randomly assigned to 4 groups (15 sheep per group). The sheep in the control group were fed a basal diet, and the 3 experimental groups were fed the basal diet supplemented with flavonoids at 11, 22 and 33 mg/kg. Blood samples were collected via the jugular vein at d 0, 15, 30, 45, and 60 to determine the neuroendocrine hormone levels. The fasting weight of the sheep was measured during the experimental period, and feed offered and refusals were recorded daily. The basal diet supplemented with flavonoids from 11 to 33 mg/kg significantly increased the daily weight gain and average daily feed intake (P < 0.05) and significantly decreased the feed conversion ratio (P < 0.05), but there were no differences among the supplementation groups (P > 0.05). Starting on d 30, the growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels in the sera of the sheep in the supplementation groups increased significantly (P < 0.05), and the increases occurred in a time-dependent manner. Compared with control group, after d 30, the serum corticosterone (CORT) levels were reduced in the sheep that consumed the basal diet supplemented with 22 mg/kg flavonoids (P < 0.05), but among the other experimental groups, there was a non-significant effect (P > 0.05). The serum adrenocorticotropic hormone (ACTH) levels were increased by the supplementation of flavonoids, but compared with the control group, the effect was not significant. The basal diet supplemented with flavonoids at levels from 11 to 33 mg/kg had a significant effect on the production performance and neuroendocrine hormone levels of meat sheep, and the effect occurred in a time-dependent manner. The effect was especially obvious after 30 d of feeding.