Does growth hormone supplementation of in vitro fertilization/intracytoplasmic sperm injection improve cumulative live birth rates in women with poor embryonic development in the previous cycle?

BACKGROUND: Growth hormone (GH) has been proposed as an adjunct in in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles, especially in women with poor ovarian response. However, it is unclear whether GH supplementation is effective in women with poor embryonic development in the previous IVF cycle. The aim of this study was to evaluate the effectiveness of GH supplementation in IVF/ICSI cycles in women with poor embryonic development in the previous cycle. METHODS: This is a retrospective cohort study from a public fertility center in China, in which we performed propensity score-matching (PSM) for female age and AFC in a ratio of 1:1. We compared the cumulative live birth rate per started cycle, as well as a series of secondary outcomes. We included 3,043 women with poor embryonic development in the previous IVF/ICSI cycle, of which 1,326 had GH as adjuvant therapy and 1,717 had not. After PSM, there were 694 women in each group. RESULTS: After PSM, multivariate analyses showed the cumulative live birth rate to be significantly higher in the GH group than the control group [N = 694, 34.7% vs. N = 694, 27.5%, risk ratio (RR): 1.4 (95%CI: 1.1-1.8)]. Endometrial thickness, number of oocytes retrieved, number of embryos available, and number of good-quality embryos were significantly higher in the GH group compared to controls. Pregnancy outcomes in terms of birth weight, gestational age, fetal sex, preterm birth rate, and type of delivery were comparable. When we evaluated the impact of GH on different categories of female age, the observed benefit in the GH group did not appear to be significant. When we assessed the effect of GH in different AFC categories, the effect of GH was strongest in women with an AFC5-6 (32.2% versus 19.5%; RR 2.0; 95% CI 1.2-3.3). CONCLUSIONS: Women with poor embryonic quality in the previous IVF/ICSI cycles have higher rates of cumulative live birth with GH supplementation.

Assessing the hydromechanical control of plant growth.

Multicellular organisms grow and acquire their shapes through the differential expansion and deformation of their cells. Recent research has addressed the role of cell and tissue mechanical properties in these processes. In plants, it is believed that growth rate is a function of the mechanical stress exerted on the cell wall, the thin polymeric layer surrounding cells, involving an effective viscosity. Nevertheless, recent studies have questioned this view, suggesting that cell wall elasticity sets the growth rate or that uptake of water is limiting for plant growth. To assess these issues, we developed a microfluidic device to quantify the growth rates, elastic properties and hydraulic conductivity of individual Marchantia polymorpha plants in a controlled environment with a high throughput. We characterized the effect of osmotic treatment and abscisic acid on growth and hydromechanical properties. Overall, the instantaneous growth rate of individuals is correlated with both bulk elastic modulus and hydraulic conductivity. Our results are consistent with a framework in which the growth rate is determined primarily by the elasticity of the wall and its remodelling, and secondarily by hydraulic conductivity. Accordingly, the coupling between the chemistry of the cell wall and the hydromechanics of the cell appears as key to set growth patterns during morphogenesis.

Green economic growth in BRIC and CIVETS countries: The effects of trade openness and sustainable development goals.

This study aims to analyze the impact of trade openness and Sustainable Development Goals, Financial Development, and Technology on the economic growth of Brazil, Russia, India, China and Colombia, Indonesia, Vietnam, Egypt, Turkey, South Africa countries. The present analysis employs a balanced panel data set from 1996 to 2022. This study also uses various tests, such as the Johansen-Fisher cointegration and Granger causality test. The study's findings suggest that economic growth, trade openness, Sustainable Development Goals, financial development, inflation, technology, labor forces, and financial openness have a long-term relationship among them. In the long run, a positive relationship exists between economic growth, trade openness, and the sustainable development goals index in (BRIC) and (CIVETS) countries. Based on the heterogeneous panel non-causality tests, the findings demonstrate that trade openness and Sustainable Development Goals are a unidirectional causality between trade openness, Sustainable Development Goals, and economic growth.

Plasma IGFBP-3 and IGFBP-5 levels are decreased during acute manic episodes in bipolar disorder patients.

Introduction: Bipolar disorder (BD) is a recurrent and disabling psychiatric disorder related to low-grade peripheral inflammation and altered levels of the members of the insulin-like growth factor (IGF) family. The aim of this study was to evaluate the plasma levels of IGF-2, insulin-like growth factor-binding protein 1 (IGFBP-1), IGFBP-3, IGFBP-5, IGFBP-7, and inflammatory markers such as tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1ß (MIP-1ß). Methods: We used the Young Mania Rating Scale (YMRS) to determine the severity of the symptomatology, while proteins were measured by enzyme-linked immunosorbent assay (ELISA). We included 20 patients with BD who suffered a manic episode and 20 controls. Some BD patients (n = 10) were evaluated after a period (17 ± 8 days) of pharmacological treatment. Results: No statistical difference was found in IGF-2, IGFBP-1, IGFBP-7, TNF-α, and MIP-1ß levels. However, IGFBP-3 and IGFBP-5 levels were found to be statistically decreased in BD patients. Conversely, the MCP-1 level was significantly increased in BD patients, but their levels were normalized after treatment. Intriguingly, only IGFBP-1 levels were significantly decreased after treatment. No significant correlation was found between the YMRS and any of the proteins studied either before or after treatment or between IGF proteins and inflammatory markers. Discussion: To some extent, IGFBP-3 and IGFBP-5 might be further explored as potential indicators of treatment responsiveness or diagnosis biomarkers in BD.

Perinatal substance use disorder: Examining the impact on adverse pregnancy outcomes.

Objective: Substance use disorder is a growing concern in the USA, especially among pregnant women. This study was undertaken to assess the impact of substance use disorder on adverse pregnancy outcomes using a nationwide sample of inpatient pregnancy hospitalizations in the USA, and to elucidate the influence on each type of adverse pregnancy outcome. Study design: A cross-sectional analysis of inpatient pregnancy hospitalizations in the USA from the Healthcare Cost and Utilization Project National Inpatient Sample from 2016 to 2020 was conducted. International Classification of Diseases - 10th revision and diagnosis-related group codes were used to identify inpatient pregnancy-related delivery hospitalizations with a substance use disorder and/or adverse pregnancy outcomes. Propensity score matching and multiple logistic regression analyses were undertaken to predict the likelihood of adverse pregnancy outcomes among pregnancy hospitalizations with and without substance use disorder. Subgroup analyses were performed to estimate the impact of substance use disorder on each adverse pregnancy outcome. Results: From 3,238,558 hospitalizations, the prevalence of adverse pregnancy outcomes was substantially higher among pregnancy hospitalizations with substance use disorder (35.6 %) compared with pregnancy hospitalizations without substance use disorder (25.1 %, p < 0.001). After matching and model adjustment for sociodemographic covariates, substance use disorder was identified as an independent predictor of adverse pregnancy outcomes [adjusted odds ratio (aOR) 1.47, 95 % confidence interval (CI) 1.45-1.49]. In subgroup analyses based on type of adverse pregnancy outcome, the greatest exposure risks were fetal growth restriction (aOR 1.96, 95 % CI 1.91-2.01), antepartum hemorrhage (aOR 1.79, 95 % CI 1.73-1.85) and preterm birth (aOR 1.65, 95 % CI 1.62-1.68). Conclusion: Patients with substance use disorder are at higher risk of adverse pregnancy outcomes, particularly fetal growth restriction, antepartum hemorrhage and preterm birth.

Electrocautery-Assisted Management of Unilateral Pyogenic Granuloma: A Case Report.

Pyogenic granuloma (PG) refers to an acquired benign proliferation most commonly seen within the oral cavity involving lips, palate, and gingiva. The term is misleading since it is a type of lobular capillary haemangioma but not an infection. It frequently recurs but lacks the capacity for malignant alteration. Depending on where the PG is located, one may experience discomfort or irritation. PGs often lead to differential diagnoses by clinicians, which include capillary hemangioma, neurofibroma, melanoma, and hyperplasia. Therefore, one must confirm a PG by diagnosing and analysing it by clinical and histopathological examinations, and treatment options should be formulated according to the evaluation. Sometimes, a biopsy of the lesion can be taken for final diagnosis. Various treatment approaches are available, including conventional scalpel excision, laser, electrocautery, and cryotherapy. Surgical excision is preferable due to the likelihood of malignancy, as it provides the best cosmetic appearance and produces a specimen for pathologic assessment. After confirming all the clinical evaluatory parameters and routine haematological examinations, which proved satisfactory and within normal ranges, this case of a 45-year-old female with soft tissue growth of the gingival origin was managed by electrocautery, and the PG was confirmed by a clinical-histopathological examination.

Evaluating the Injection of Platelet-Rich Plasma on Second Lower Molars Protraction: A Randomized Controlled Clinical Trial.

Background The use of platelet-rich plasma (PRP) in dentistry was entered several decades ago, yet its clinical use in orthodontics still requires further investigation. The aim of this study was to evaluate the possible effects of local injection of PRP on the rate and type of mandibular second molar protraction movement compared with the comparator (no PRP) group. Material and methods Eighteen patients aged between 17 and 25 years were randomly allocated in a split-mouth study design to receive PRP injections on one side immediately before the start of molar protraction (PRP group), while the other side received only saline solution (comparator group). Eligibility criteria included bilaterally extracted mandibular first molars cases and indicated mandibular second molars protraction. The primary outcome of the study consisted of measuring the rate of molar protraction from the beginning of protraction (T0) to the end of the seventh month (TF), using a digital gauge. The secondary outcome included measuring the type of second molar protraction movement between T0 and TF by lateral cephalometric images. Randomization of the intervention side was performed by picking out opaque sealed envelopes. The blinding of the principal investigator was impossible but blinding of the patient was achieved by injection of saline. Analyses were done using paired samples T-test to compare the changes in all variables between T0 and TF. The level of significance was taken at a P-value < 0.05. Results No significant difference was detected between the PRP and comparator groups in the rate of second lower molar protraction during seven months (0.56±0.07 mm per month in the comparator group, whereas, was 0.6±0.11 mm per month in the PRP group). Molar protraction parameters in both groups showed second lower molars moving by controlled tipping closer to bodily movement (Root Movement:Crown Movement≈0.8). Conclusions Platelet-rich plasma (PRP) is ineffective in accelerating the rate of orthodontic tooth movement (OTM) during molar protraction, and it has no effect on the type of tooth movement. In addition, the mechanics that we used (6 mm power arm in combination with miniscrews) are effective in mandibular second molar protraction by controlled tipping closer to bodily movement.

Effect of TGF-ß3 on wound healing of bone cell monolayer in static and hydrodynamic shear stress conditions.

Introduction: Wound healing is characterized as a complicated and sophisticated biological process through which tissue heals and repairs itself after injury. However, the normal wound healing process relies on different growth factors as well as the presence of an accurate cytokine level to ensure appropriate cellular responses. In the case of wound healing, the effects of various growth factors have been studied, but the effects of transforming growth factor beta (TGF-ß) on wound healing have been found to be more significant because of its broad spectrum of impacts on healing the wounded tissues or skins. Methods: In the current study, the impact of TGF-ß3 in bone cells' wound healing was examined in vitro. Furthermore, the activities and characteristics of TGF-ß3, as well as those of related growth factors throughout this wound healing process, were studied under hydrodynamic shear stress conditions as well as static conditions of cultured bone cells. Results: We demonstrated that a positive outcome of TGF-ß3 treatment was found after 24 h under a static condition, while TGF-ß3 treatment was found to be effective under a dynamic condition for wound closure. In the case of the dynamic condition, a full wound closure was obtained after 18 h in both the control and TGF-ß3 treatment, while in the case of static conditions, wounds were found to remain open, even after 24 h, for both the control and TGF-ß3 treatment. Additionally, in the static condition, the wound closure rate with TGF-ß3 treatment was found to be quicker than that of the control flask, which implies that wound healing can be postponed in the static condition. In the dynamic condition, the wound healing process became more rapid in a cultured cell environment. Conclusion: The synergistic effect of TGF-ß3 and hydrodynamic shear stress conditions had a positive impact on increasing wound healing and improving the rate of wound closure.

Three-year outcome of photodynamic therapy combined with VEGF inhibitor for pachychoroid neovasculopathy.

BACKGROUND: Long-term results of photodynamic therapy (PDT) combined with vascular endothelial growth factor (VEGF) inhibitors for pachychoroid neovasculopathy (PNV) are not yet clear. METHODS: This study is a retrospective, observational case series. We retrospectively examined untreated PNV cases (22 cases, 22 eyes, mean age of 71.0 years) who underwent PDT therapy in combination with VEGF inhibitors followed by additional treatments with pro re nata protocol. Visual acuity, number of treatments, and time to recurrence were examined. In addition, foveal choroidal thickness and choroidal vascularity index (CVI) were evaluated in 13 of 22 patients who were followed up with SpectralisOCTR from baseline. RESULTS: Fifteen (68%) cases had polyps at baseline. LogMAR visual acuity averaged 0.24 ± 0.20 (range, - 0.079 to 0.82) at baseline and significantly improved after 1, 2, and 3 years (p = 0. 004, 0.0003, 0.002, respectively). Fourteen patients (64%) recurred, with an average time to recurrence of 1.8 ± 0.9 years. Foveal choroidal thickness decreased significantly after 1 year (average from 326 µm to 263 µm) and remained unchanged up to 3 years (255 µm). CVI also decreased after 1 year (average from 0.62 to 0.61) and remained unchanged until 3 years later (0.60). CONCLUSIONS: We examined the 3-year course of PDT in combination with the VEGF inhibitor for untreated PNV. Visual acuity was improved, foveal choroidal thickness and CVI were decreased after 3 years.

Developing a simple and efficient modeling solution for predicting key phenological stages of table grapes in a non-traditional viticulture zone in south Asia.

Phenological shifts are one of the most visible signs of climatic variability and change in the biosphere. However, modeling plant phenological responses has always been a key challenge due to climatic variability and plant adaptation. Grapevine is a phenologically sensitive crop and, thus, its developmental stages are affected by the increase in temperature. The goal of this study was to develop a temperature-based grapevine phenology model (GPM) for predicting key developmental stages for different table grape cultivars for a non-traditional viticulture zone in south Asia. Experiments were conducted in two vineyards at two locations (Chakwal and Islamabad) in the Pothawar region of Pakistan during the 2019 and 2020 growing seasons for four cultivars including Perlette, King's Ruby, Sugraone and NARC Black. Detailed phenological observations were obtained starting in January until harvest of the grapes. The Mitscherlich monomolecular equation was used to develop the phenology model for table grapes. There was a strong non-linear correlation between the Eichhorn and Lorenz phenological (ELP) scale and growing degree days (GDD) for all cultivars with coefficient of determinations (R2) ranging from 0.90 to 0.94. The results for model development indicated that GPM was able to predict phenological stages with high skill scores, i.e., a root mean square (RMSE) of 2.14 to 2.78 and mean absolute error (MAE) of 1.86 to 2.26 days. The prediction variability of the model for the onset timings of phenological stages was up to 3 days. The results also reveal that the phenology model based on GDD approach provides an efficient planning tool for viticulture industry in different grape growing regions. The proposed methodology, being a simpler one, can be easily applied to other regions and cultivars as a predictor for grapevine phenology.

Status of visfatin in female reproductive function under normal and pathological conditions: a mini review.

Adipokines are now well-known to regulate reproduction. Visfatin is an adipokine expressed in the hypothalamus, pituitary, ovary, uterus, and placenta of different species, and since it has been found to modulate the endocrine secretion of the hypothalamus, pituitary gland and ovary, it may be considered a novel regulator of female reproduction. Although the majority of the literature explored its role in ovarian regulation, visfatin has also been shown to regulate uterine remodeling, endometrial receptivity and embryo development, and its expression in the uterus is steroid dependent. Like other adipokines, visfatin expression and levels are deregulated in pathological conditions including polycystic ovary syndrome. Thus, the present mini-review focuses on the role of visfatin in female reproduction under both physiological and pathological conditions.

Impact of dichromatic lighted incubation on hatching result and post-hatch performance of broiler chickens.

This study was planned to evaluate the impact of dichromatic lights during incubation on the hatching and post-hatch performance of broiler chickens. A total of 500 eggs of broiler breeder (Ross 308; Age 44 weeks) were evenly divided according to a completely randomized design into 4 treatments having 5 replicates and 25 eggs each. Treatments consisted of dichromatic lights Blue + Red (BR), Green + Red (GR) and Green + Blue (GB) provided at an intensity of 250 lx for 12 h a day along with a Dark (D) environment. After hatching 200 chicks (50 from each respective light group) were divided into 4 treatments with 5 replicates each having 10 chicks. Results indicated a higher embryo index (13.12%) in the GR group on the 12th day of incubation; while an ideal hatch window was observed in GR and GB (98.18% and 96.00% hatched chicks) lighting groups. In hatching traits, higher hatchability (86.15) and hatch of fertile (93.85) percentages were observed in GR lighting followed by GB, BR and Dark treatment groups; while dead-in shell embryos were lowest in the GR group. In growth performance, higher feed intake (513.20 g) and body weight (479.20 g) were observed in the GB group followed by GR, BR and dark group; and feed conversion ratio (FCR) was better in the GR group (1.06). In welfare parameters, improved physical asymmetry (0.90 mm) and tonic immobility (54.40 s) were measured in the GR group followed by GB, BR and the dark group. It was concluded that under experimental conditions when broiler breeder eggs are provided with GR lighting during incubation, it can help to improve hatchability, growth performance and welfare traits in chicks.

Dimension-Confined Growth of a Crack-Free PbS Microplate Array for Infrared Image Sensing.

Epitaxy of semiconductors is a necessary step toward the development of electronic devices such as lasers, detectors, transistors, and solar cells. However, the lattice ordering of semiconductor functional films is inevitably disrupted by excessive concentrated stress due to the mismatch of the thermal expansion coefficient. Herein, combined with the first-principles calculation, we find that a rigid film/substrate bilayer heterostructure with a large thermal expansion mismatch upon cooling to room temperature from growth is free of surface cracks when the rigid film exhibits a dimension smaller than the critical condition for the breaking energy. The principle has been verified in a PbS/SrTiO3 bilayer system that is crack free on PbS single-crystalline microplate arrays through the designing of a dimension-confined growth (DCG) method. Interestingly, this crack-free, large-scale PbS microplate array exhibits exceptional uniformity in morphology, dimensions, thickness, and photodetection properties, enabling a broad-band infrared image sensing. This work provides a new perspective to design materials and arrays that demand smooth and continuous surfaces, which are not limited only to semiconductor electronics but also include mechanical structures, optical materials, biomedical materials, and others.

Assessing future intra-basin water availability in madagascar: Accounting for climate change, population growth, and land use change.

The Major River Basins in Madagascar (MRBM) play a crucial role in providing water to the Malagasy population as well as the ecosystem. Little is known about the impact of climate change on these basins, and it is not clear what factors have the most significant impact on them. There are two central objectives of this study: 1. To assess the future potential water available for daily life and agriculture use across the MRBM. 2. To compare the projected change within the MRBM with the historical trends analysis and identify the water-stressed basins. In this paper, a new method for assessing the future available Intra-basin water resources combined with the impacts of climate change, land use, and population is proposed. Three imbalance indicators are introduced to quantify the spatial availability (indicator N°1), distribution (indicator N°2), and variability (indicator N°3) of the Potential Water Resources (PWR) available and have been applied to the MRBM. Under the SSP2-4.5 scenario, results showed a decreasing trend of the PWR in most of the basins by 2050 with a rise in evapotranspiration and a decline in precipitation. The increasing trend and uneven distribution of the population and agricultural land upstream/downstream are found to cause the reduction of the PWR available per capita (by 37 %) and agriculture area (by 69 %) across the MRBM. This study predicts water scarcity for most of the basins by 2050, especially in the Mangoro and Onilahy Basins. Upstream populations are expected to grow in Mahajamba, Mahavavy, Betsiboka, Manambolo, Tsiribihina, Mangoro, Onilahy, Mananara, and Mandrare basins, along with an expansion of the downstream agricultural land in Sofia, Betsiboka, Manambolo, Mangoky, and Mandrare basins. These findings enhance the cause-effect relationship between climate change, land use change, population growth, and water scarcity in the MRBM. Urgent action is therefore needed for an efficient and sustainable management of these water-stressed basins.

Foetal programming in sheep: Reproductive and productive implications.

The aim of this study was to evaluate the effects of pregnant ewe nutrition on the performance of offspring in terms of meat, wool production, and reproduction. Foetal programming in sheep has focused on several aspects related to foetal growth, postnatal production, behaviour, and immunological performance. Currently, significant efforts are being made to understand the endocrine, metabolic, and epigenetic mechanisms involved in offspring development. Current studies have not only evaluated the foetal period, despite the pre-conception parental nutrition has demonstrated an effect on the foetal, embryonic, and pre-implantation periods and can generate permanent effects in the foetal and postnatal phases. The performance of offspring is the result of interactions between the genome, epigenome, and environmental interventions during conception. Several factors influence the expression of phenotypic characteristics in progenies; however, this study focused on presenting data on the effect of pregnant ewe nutrition alone on foetal growth and the productive aspects of their offspring.

Erlotinib suppresses tumorigenesis in a mouse model of colitis-associated cancer.

Colitis-associated cancer (CAC) in inflammatory bowel diseases exhibits more aggressive behavior than sporadic colorectal cancer; however, the molecular mechanisms remain unclear. No definitive preventative agent against CAC is currently established in the clinical setting. We investigated the molecular mechanisms of CAC in the azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model and assessed the antitumor efficacy of erlotinib, a small molecule inhibitor of the epidermal growth factor receptor (EGFR). Erlotinib premixed with AIN-93 G diet at 70 or 140 parts per million (ppm) inhibited tumor multiplicity significantly by 96%, with ∼60% of the treated mice exhibiting zero polyps at 12 weeks. Bulk RNA-sequencing revealed more than a thousand significant gene alterations in the colons of AOM/DSS-treated mice, with KEGG enrichment analysis highlighting 46 signaling pathways in CAC development. Erlotinib altered several signaling pathways and rescued 40 key genes dysregulated in CAC, including those involved in the Hippo and Wnt signaling. These findings suggest that the clinically-used antitumor agent erlotinib might be repurposed for suppression of CAC, and that further studies are warranted on the crosstalk between dysregulated Wnt and EGFR signaling in the corresponding patient population.

The intersection of Growth Mindset and Accreditation in Pharmacy Education.

OBJECTIVE: To describe existing growth mindset literature within pharmacy and healthcare education, describe how a growth mindset can be beneficial in the accreditation process, and propose potential ways to promote a growth mindset in faculty, preceptors, students, and staff within pharmacy education. FINDINGS: To help pharmacy learners develop a growth mindset, existing literature emphasizes the need for a shift toward and aligning assessment with growth mindset, helping to create self-directed adaptive learners, leading to healthcare providers who can adjust their practice to tackle expected and unexpected challenges throughout their careers. Strategies to create a culture of growth mindset identified include training faculty and learners on growth mindset and developing new assessments that track a learner's growth. Recommendations for pharmacy educators include encouraging educators to assess their own growth mindset and use a variety of teaching methods and provide feedback on learner effort that encourages the process of learning rather than focusing on individual attributes, traits, and results. SUMMARY: Growth mindset intersects with accreditation standards for both professional degree programs and providers of continuing pharmacy education. Continuing professional development process (CPD) is one way to encourage faculty, staff, and students to develop a growth mindset. While a growth mindset can have many positive impacts on pharmacy accreditation, it is essential to recognize that achieving and maintaining accreditation is a multifaceted process involving numerous factors. A growth mindset can positively influence pharmacy education accreditation by fostering a culture of continuous improvement, innovation, resilience, student-centeredness, data-driven decision-making, collaboration, and effective leadership.

Novel IL-4/HB-EGF-dependent crosstalk between eosinophils and macrophages controls liver regeneration after ischaemia and reperfusion injury.

OBJECTIVE: Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair. DESIGN: Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding epidermal growth factor-like growth factor (hb-egf). RESULT: We observed that eosinophils persisted over a week following hepatic IR injury. Their peak accumulation coincided with that of hepatocyte proliferation. Functional studies showed that eosinophil deficiency was associated with a dramatic delay in liver repair, which was normalised by the adoptive transfer of bmEos. Mechanistic studies demonstrated that eosinophil-derived IL-4, but not IL-13, was critically involved in the reparative function of these cells. The data further revealed a selective role of macrophage-dependent IL-4 signalling in liver regeneration. Eosinophil-derived IL-4 stimulated macrophages to produce HB-EGF. Moreover, macrophage-specific hb-egf deletion impaired hepatocyte regeneration after IR injury. CONCLUSION: Together, these studies uncovered an indispensable role of eosinophils in liver repair after acute injury and identified a novel crosstalk between eosinophils and macrophages through the IL-4/HB-EGF axis.

Non-pituitary growth hormone enables colon cell senescence evasion.

DNA damage-induced senescence is initially sustained by p53. Senescent cells produce a senescence-associated secretory phenotype (SASP) that impacts the aging microenvironment, often promoting cell transformation. Employing normal non-tumorous human colon cells (hNCC) derived from surgical biopsies and three-dimensional human intestinal organoids, we show that local non-pituitary growth hormone (npGH) induced in senescent cells is a SASP component acting to suppress p53. npGH autocrine/paracrine suppression of p53 results in senescence evasion and cell-cycle reentry, as evidenced by increased Ki67 and BrdU incorporation. Post-senescent cells exhibit activated epithelial-to-mesenchymal transition (EMT), and increased cell motility. Nu/J mice harboring GH-secreting HCT116 xenografts with resultant high GH levels and injected intrasplenic with post-senescent hNCC developed fourfold more metastases than did mice harboring control xenografts, suggesting that paracrine npGH enables post-senescent cell transformation. By contrast, senescent cells with suppressed npGH exhibit downregulated Ki67 and decreased soft agar colony formation. Mechanisms underlying these observations include npGH induction by the SASP chemokine CXCL1, which attracts immune effectors to eliminate senescent cells; GH, in turn, suppresses CXCL1, likely by inhibiting phospho-NFκB, resulting in SASP cytokine downregulation. Consistent with these findings, GH-receptor knockout mice exhibited increased colon phospho-NFκB and CXCL1, while GH excess decreased colon CXCL1. The results elucidate mechanisms for local hormonal regulation of microenvironmental changes in DNA-damaged non-tumorous epithelial cells and portray a heretofore unappreciated GH action favoring age-associated epithelial cell transformation.

Mitochondrial respiration is lower in the intrauterine growth-restricted fetal sheep heart.

Fetuses affected by intrauterine growth restriction have an increased risk of developing heart disease and failure in adulthood. Compared with controls, late gestation intrauterine growth-restricted (IUGR) fetal sheep have fewer binucleated cardiomyocytes, reflecting a more immature heart, which may reduce mitochondrial capacity to oxidize substrates. We hypothesized that the late gestation IUGR fetal heart has a lower capacity for mitochondrial oxidative phosphorylation. Left (LV) and right (RV) ventricles from IUGR and control (CON) fetal sheep at 90% gestation were harvested. Mitochondrial respiration (states 1-3, LeakOmy, and maximal respiration) in response to carbohydrates and lipids, citrate synthase (CS) activity, protein expression levels of mitochondrial oxidative phosphorylation complexes (CI-CV), and mRNA expression levels of mitochondrial biosynthesis regulators were measured. The carbohydrate and lipid state 3 respiration rates were lower in IUGR than CON, and CS activity was lower in IUGR LV than CON LV. However, relative CII and CV protein levels were higher in IUGR than CON; CV expression level was higher in IUGR than CON. Genes involved in lipid metabolism had lower expression in IUGR than CON. In addition, the LV and RV demonstrated distinct differences in oxygen flux and gene expression levels, which were independent from CON and IUGR status. Low mitochondrial respiration and CS activity in the IUGR heart compared with CON are consistent with delayed cardiomyocyte maturation, and CII and CV protein expression levels may be upregulated to support ATP production. These insights will provide a better understanding of fetal heart development in an adverse in utero environment. KEY POINTS: Growth-restricted fetuses have a higher risk of developing and dying from cardiovascular diseases in adulthood. Mitochondria are the main supplier of energy for the heart. As the heart matures, the substrate preference of the mitochondria switches from carbohydrates to lipids. We used a sheep model of intrauterine growth restriction to study the capacity of the mitochondria in the heart to produce energy using either carbohydrate or lipid substrates by measuring how much oxygen was consumed. Our data show that the mitochondria respiration levels in the growth-restricted fetal heart were lower than in the normally growing fetuses, and the expression levels of genes involved in lipid metabolism were also lower. Differences between the right and left ventricles that are independent of the fetal growth restriction condition were identified. These results indicate an impaired metabolic maturation of the growth-restricted fetal heart associated with a decreased capacity to oxidize lipids postnatally.